OVERCOMING REGIOSELECTIVITY CHALLENGES IN IRIDIUM CATALYZED C–H BORYLATION VIA NONCOVALENT INTERACTIONS AND ADVANCES ON CROSS COUPLING REACTIONS OF ARYL IMIDAZOLYLSULFONATES By Jose Raul Montero Bastidas A DISSERTATION Submitted to Michigan State University in partial fulfillment of the requirements for the degree of Chemistry—Doctor of Philosophy 2021 ABSTRACT OVERCOMING REGIOSELECTIVITY CHALLENGES IN IRIDIUM CATALYZED C–H BORYLATION VIA NONCOVALENT INTERACTIONS AND ADVANCES ON CROSS COUPLING REACTIONS OF ARYL IMIDAZOLYLSULFONATES By Jose Raul Montero Bastidas Direct functionalization of C‒H bonds reduces the number of synthetic steps for a target molecule enhancing efficiency and avoiding undesired waste material. Iridium catalyzed C–H activation-borylation (CHB) is an established method to access aryl boronic esters. Regioselectivity challenges can arise when multiple hydrogens are present in the molecule. This thesis describes the design of novel strategies to selective direct the CHB to one specific position. Ortho selective CHB has the challenge to go against the traditional CHB selectivity dictated by steric effects. Previously, our group reported a strategy for highly ortho-selective CHB of anilines by using a small B2eg2 (eg = ethanediol) as the borylating reagent. However, the products were unstable and transesterification with pinacol was needed. Chapter 2 builds upon this issue and presents a solution based on the modulation of the size of the boron partner. Small diboron partners retain the high ortho regioselectivity for CHB of aniline but larger borylating reagents generate more stable products. In our estimation, B2bg2 (bg = 1,2-butanediol) represents the best balance of reactivity, regioselectivity and stability. Remote functionalization including para selective reactions are difficult because a potential directing group would be far from the desired reactive site. Chapter 3 details how para CHB of tetraalkylammonium sulfates and sulfamates have been achieved using bipyridine-ligated Ir boryl catalysts. Selectivities can be modulated by both the length of the alkyl groups in the tetraalkylammonium cations and the substituents on the bipyridine ligands. Ion pairing, where the alkyl groups of the cation shield the meta C−H bonds in the counteranions, is proposed to account for para selectivity. The 4,4’-dimethoxy-2,2’-bipyridine ligand gave superior selectivities. The next chapter describes how intramolecular hydrogen bonding (IMHB) can lead to steric shielding effects that can direct CHB regiochemistry. Bpin/arene IMHB can promote remote borylations of N-borylated anilines, 2-amino-N-alkylpyridine, tetrahydroquinolines, indoles and 1-borylated naphthalenes. Our studies support molecular geometries with the Bpin orientation controlled by a C–H•••O IMHB. Calculated rotation barriers to displace the Bpin group are above 4 kcal/mol, suggesting that the planar ground conformation of the borylated arenes is retained during CHB. This study informs researchers to evaluate not only inter- but also intramolecular noncovalent interactions as potential drivers of remote CHB regioselectivity. The borylated products from CHB can be further manipulated in Suzuki-Miyaura cross- coupling (SMC) with aryl halides as the typical electrophilic partner. Aryl imidazolylsulfonates are nongenotoxic electrophiles that can be used in palladium catalyzed SMC to avoid halogenated materials. Chapter 5 shows the efforts towards a nickel-catalyzed SMC of aryl imidazolyl- sulfonates. Results show considerable amounts of the corresponding diarylsulfate formed during the reaction. Interestingly, the diaryl sulfa byproducts were found to be competent electrophilic partners for both palladium and nickel-catalyzed SMC. In summary, this thesis presents novel methodologies to access challenging transformations as the para borylations of phenols, anilines and benzyl alcohols. This was possible by the analysis of the different components of the catalytic system: design of ligands, diboron partners and substrate directing groups and how they interact during the reaction. Finally, the potential of aryl imidazolylsulfonates as nongenotoxic pseudohalides in nickel-catalyzed SMC was evaluated. To my family. Thanks for your patience and continued support. iv ACKNOWLEDGMENTS I decided to write this section at the end, because I knew it will be the most difficult part to write. How do you summarize and describe in some words the impact that family, friends, and mentors have in your life? I believe the PhD journey is not only about gaining knowledge, but also about personal and professional growth. I will try my best in the next paragraphs to say thank you and express my gratitude. I need to recognize that I began the PhD with more questions than certainties. I knew that my passion was in Organic Chemistry, but I was not sure where did I want to go or who I want to be. I can’t find another word other than luck to describe the fortune to meet and work with you Professor Robert Edward Maleczka, Jr. I learned what it means to be a mentor when I met you. With your guidance and your example, I found again my motivation and realized how fun research can be. The freedom you gave me to pursuit the projects I wanted and your support that allowed me to be involved in programs outside chemistry helped find the pathway I want to follow in my future. The impact you had in my life is impossible to describe in words; the least I can say is that I will be forever thankful with you. What I was not expecting is how much fortunate I will be to work in collaboration with Professor Milton Rudolph Smith, III (Mitch). Your insight and advice on my projects were not only key for the research but taught me how to overpass my limits and think deeply about the chemistry. Your passion to go beyond the frontiers of chemistry inspired me, I learned from you to be brave and pursuit exciting projects even if they seem less likely to work. I would also like to express my gratitude to Professor James E. Jackson (Ned), Professor Melanie M. Cooper, Professor Babak Borhan, Professor William Wulff for their advice during our meetings, the v courses you taught me and towards these years. Your comments truly helped me become a better chemist. During a Chemistry PhD, the lab becomes your second home and your labmates your second family. In this family, my older brother would be the now Professor Jonathan E. Dannatt, your guidance and our everyday discussions about chemistry truly taught me how to conduct research. Thank you for your friendship and mentorship towards me which are unvaluable. To my friends and exlabmates Dr. Ruwi Jayasundara and Dr. Suzi Miller, thank you for making everyday more enjoyable and for being such wonderful partners in the projects we collaborate later on. To my labmates, collaborators and friends: Thomas Oleskey, Arzoo Chhabra, Feng Yilong (Deuca) and Lauren Kotsull, I really enjoyed working with you guys and I learned a lot from everyone, sorry if I was a little bossy sometimes. I am sure you will become great chemists and I am excited to listen about your new discoveries in the future. Also, I would like to thank Thomas for the late “coffee” drinks he prepared when we needed to spend long days at the lab. To Emmanuel Maloba, you become a close friend to me, and I hope you know I will be there for you if you need me as you were there for me during these years. To Dr. Badru-Deen Barry, Dr. Fangyi Shen, Austin King, our adopted labmembers: Anshu Yadav and Aditya Patil, and the boron group: Alex O’Connell, Chris Peruzzi, Pauline Mansour and Cash Jowers, it has been an honor to work with you guys and I wish you all the best in your future endeavors. Life has ups and downs and friends that help you navigate in the difficult moments and celebrate the good ones are unreplaceable. Each of you guys: Dr. Katarina Lynn Keel, Dr. Peng Chao, Dr. Shafaat Shishir, Dr. Dhwani Kansal and future doctors Seokjoo Lee and Kiyoto Aramis Tanemura, have been wonderful friends during grad school and the time I shared with you will be always in my heart. A special thanks to Kat for her support during the most difficult PhD moments. vi To my siblings from another parents: Ana Belen Gutierrez, Antonio Prada, Ruben Villareal and Andrea Broncano, even if we are far away in different countries, our friendship has perdure and I owe you part of this PhD to you guys. A special thanks to my brother Dr. Emiliano Deustua, there are not enough words to express my gratitude to you, you become family to me during these years and I hope someday I can give you back at least 1% of what you have done for me, thank you. I have been blessed to find a great group of close friends here in Michigan and this journey would not be the same without you guys: Carolina Vargas, Carol Morales, Kimberly Morales, Cristina Castillo, Jorge Anaya, Dr. Marco Lopez, Marcela Tabares, Dr. Fernando Aguate, Maria Pia Garcia, Paulo Izquierdo, Viviana Ortiz, Andres Galindo, Dr. James Cabrera and my homie Emilie Cole. The main reason I was able to finish this journey is because of the support of my family which deserved my biggest thanks. I would like to write this paragraph in Spanish to thank them. Mama, Maria Rosario Bastidas Quispe, nosotros sabemos lo difícil que han sido estos años desde Olaya, no tengo palabras para agradecerle todo el amor y el apoyo que me ha dado. Este doctorado se lo dedico a usted, espero que este título me ayude a regresarle una parte de lo que usted ha hecho por mí. Papa y hermanita: Claudio Montero Mullo y Liz Paola Montero Bastidas (Oshin) gracias también a ustedes por el amor, el apoyo y la paciencia pues sé que este camino del doctorado ha tomado tiempo, pero finalmente llegamos a esta meta. vii TABLE OF CONTENTS LIST OF TABLES .................................................................................................................. xi LIST OF FIGURES ............................................................................................................... xii LIST OF SCHEMES ..............................................................................................................xiv CHAPTER 1. INTRODUCTION .............................................................................................1 1.1. Iridium-Catalyzed C–H Borylations .................................................................................1 1.2. Diversification of Aryl Boronic Esters ..............................................................................1 1.3. Traditional Synthesis of Aryl Boronic Esters ....................................................................2 1.4. CHB: Regioselectivity, Mechanism and Applications .......................................................3 1.5. Ortho regioselective CHB ................................................................................................6 1.6. Meta and Para Regioselective CHB .................................................................................9 1.7. Conclusions .................................................................................................................... 11 REFERENCES ..................................................................................................................... 12 CHAPTER 2. BALANCING ACTIVITY AND REGIOSELECTIVITY IN ORTHO C–H BORYLATIONS OF ANILINES BY MODULATING THE DIBORON PARTNER ......... 18 2.1. Introduction .................................................................................................................... 18 2.2. Results and Discussion ................................................................................................... 22 2.2.1. Regioselectivity of a novel diboron partner: B2pg2 ................................................... 22 2.2.2. Optimization of reaction conditions: catalyst loading ............................................... 24 2.2.3. Optimization of reaction conditions: boron partner equivalents and temperature ...... 25 2.2.4. Effect of the base for ortho-CHB of aniline .............................................................. 26 2.2.5. Modulating the diboron partner ................................................................................ 28 2.2.6. Factors controlling stability of the borylated product ................................................ 30 2.2.7. Substrate Scope........................................................................................................ 31 2.3. Conclusions .................................................................................................................... 31 2.4. Experimental .................................................................................................................. 32 2.4.1. General Information ................................................................................................. 32 2.4.2. Synthesis of diboron partners ................................................................................... 33 2.4.3. Synthesis of ortho, meta and Para Bpg-borylated aniline by transesterification........ 36 2.4.4. Synthesis of ortho borylated acetamide with a Bpg group by transesterification ....... 38 2.4.5. CHB of anilines with B2bg2 as diboron partner......................................................... 39 APPENDIX........................................................................................................................... 43 REFERENCES ..................................................................................................................... 82 CHAPTER 3. PARA-SELECTIVE, IRIDIUM-CATALYZED C−H BORYLATIONS OF SULFATED PHENOLS, BENZYL ALCOHOLS, AND ANILINES DIRECTED BY ION- PAIR ELECTROSTATIC INTERACTIONS ....................................................................... 85 3.1. Introduction .................................................................................................................... 85 3.2. Results and Discussion ................................................................................................... 87 3.2.1. Unexpected Discovery ............................................................................................. 87 viii 3.2.2. Optimization of Conditions ...................................................................................... 88 3.2.3. Para CHB of sulfated phenols ................................................................................. 91 3.2.4. Para CHB of sulfated anilines ................................................................................. 93 3.2.5. Para CHB of sulfated benzyl alcohols ..................................................................... 94 3.3. Conclusions .................................................................................................................... 96 3.4. Experimental Procedures ................................................................................................ 97 3.4.1. General Information ................................................................................................. 97 3.4.2. Determining Product Ratios by NMR Integration ..................................................... 98 3.4.3. Preparation of Sulfated Phenols ............................................................................. 100 3.4.4. CHB of Sulfated Phenols ....................................................................................... 116 3.4.5. Preparation of Sulfated Anilines............................................................................. 133 3.4.6. CHB of Sulfated Anilines ...................................................................................... 139 3.4.7. Preparation of Sulfated Benzyl Alcohols ................................................................ 147 3.4.8. CHB of Sulfated Benzyl Alcohols.......................................................................... 157 3.5. Notes ............................................................................................................................ 166 APPENDIX......................................................................................................................... 167 REFERENCES ................................................................................................................... 396 CHAPTER 4. STERIC SHIELDING EFFECTS INDUCED BY INTRAMOLECULAR C– H•••O HYDROGEN BONDING: REMOTE BORYLATION DIRECTED BY BPIN GROUPS ............................................................................................................................... 401 4.1. Introduction .................................................................................................................. 401 4.2. RESULTS AND DISCUSSION ................................................................................... 403 4.2.1. Para C–H borylation of anilines, N-alkylated anilines and indoles. ........................ 403 4.2.1.1. Optimization of Conditions ............................................................................. 403 4.2.1.2. Para CHB of anilines ...................................................................................... 405 4.2.1.3. Para CHB of N-alkylated anilines ................................................................... 407 4.2.1.4.. C5 CHB of Indoles......................................................................................... 409 4.2.2. C6 borylation of 1-borylated naphthalenes. ............................................................ 410 4.2.2.1. Borylations ..................................................................................................... 410 4.2.2.2. Silylations ....................................................................................................... 411 4.2.3. Mechanistic Studies. .............................................................................................. 413 4.2.4. Application of IMHB to remote borylation............................................................. 423 4.2.4.1. 7-member ring IMHB ..................................................................................... 423 4.2.4.2. Pyrimidines as directing groups....................................................................... 424 4.3. Conclusions .................................................................................................................. 425 4.4. Experimental Procedures .............................................................................................. 426 4.4.1. General Information ............................................................................................... 426 4.4.2. Para CHB of anilines............................................................................................. 428 4.4.3. Para CHB of N-alkylated anilines ......................................................................... 446 4.4.4. C5 CHB of Indoles ................................................................................................ 462 4.4.5. Synthesis 1-borylated naphthalenes ........................................................................ 469 4.4.6. C6 CHB of 1-borylated naphthalenes ..................................................................... 476 4.4.7. Silylation of 1-borylated naphthalenes ................................................................... 487 4.4.8. CHB of substrates without selectivity..................................................................... 489 4.4.9. Synthesis N-borylated scaffolds ............................................................................. 491 ix 4.4.10. Applications of IMHB to remote borylation ......................................................... 499 4.5. Notes ............................................................................................................................ 502 APPENDIX......................................................................................................................... 503 REFERENCES ................................................................................................................... 804 CHAPTER 5. STUDY OF REACTIVITY OF ARYL IMIDAZOLYLSULFONATES IN SUZUKI-MIYAURA CROSS-COUPLING REACTIONS ................................................. 812 5.1. Introduction .................................................................................................................. 812 5.2. Results and Discussion ................................................................................................. 818 5.2.1. Aryl imidazolyl sulfonates vs aryl halides .............................................................. 818 5.2.2. Unexpected results in the nickel-catalyzed SMC of aryl imidazolylsulfonates ........ 820 5.2.3. Nickel-catalyzed SMC of diaryl sulfates: ............................................................... 821 5.2.4. Conditions for the formation of diaryl sulfate from aryl imidazolylsulfonate .......... 824 5.2.5. Nickel catalyzed SMC of aryl imidazolylsulfonates ............................................... 825 5.3. Conclusions .................................................................................................................. 826 5.4. Experimental Procedures .............................................................................................. 827 5.4.1. General Materials and Methods.............................................................................. 827 5.4.2. Synthesis of reagents: electrophiles and catalyst ..................................................... 828 5.4.3. Cross coupling reactions ........................................................................................ 831 APPENDIX......................................................................................................................... 836 REFERENCES ................................................................................................................... 857 x LIST OF TABLES Table 2.1: Optimization of reaction conditions: catalyst loading ............................................... 24 Table 2.2: Optimization of reaction conditions: boron partner equivalents ................................. 25 Table 3.1: Temperature effect on para CHB of 3.1’ .................................................................. 89 Table 3.2: Integration of known ratios of para-2a to meta-2a .................................................... 99 Table 5.1: Optimization of reaction conditions for SMC of diaryl sulfates .............................. 822 Table 5.2: Optimization of reaction conditions for SMC of diaryl sulfates with crown ethers...823 Table 5.3: Test of reaction conditions for the formation of diaryl sulfates ................................ 824 Table 5.4: Effect of reaction conditions in the formation of diaryl sulfates............................... 825 Table 5.5: Nickel catalyzed SMC of aryl imidazolylsulfonates at different reaction conditions 826 xi LIST OF FIGURES Figure 1.1: Ligands used for ortho-CHB via chelate directed mechanism ....................................7 Figure 2.1: Examples of dyes, agrochemicals, pharmaceuticals, biomolecules, and polymers with an aniline ring ........................................................................................................................... 18 Figure 2.2: 1H NMR of a racemic mixture of B2pg2 with NMR shift reagents ............................ 23 Figure 2.3: Optimization of reaction conditions: effect of the temperature. ............................... 26 Figure 2.4: Screening of trialkylamine bases and effect of equivalents on ortho CHB of aniline 28 Figure 2.5: Effect of diboron partner on the ortho CHB of aniline ............................................. 29 Figure 3.1: Para C−H borylations ............................................................................................. 86 Figure 3.2: Para C−H borylation sterically driven by ion-pair electrostatic interactions............. 87 Figure 3.3: Lowest energy conformation geometry of 1a’ (front and lateral view) ..................... 90 Figure 4.1: a) Unexpected para CHB of anilines (only reported compounds), b) Previously reported para CHB of anilines driven by ion-pair electrostatic interactions ............................. 402 Figure 4.2: This approach: remote CHB driven by intramolecular hydrogen bonding .............. 403 Figure 4.3: Temperature and solvent effect on para CHB of 2-chloroaniline. Blue and orange bars represent conversion to the para and meta isomer, respectively. CyH: cyclohexane, THF: tetrahydrofuran........................................................................................................................ 404 Figure 4.4: 1H NMR comparison of N-borylated and unborylated 2-chloro and 2-methylaniline, and  displacement due to C–H•••N and C–H•••O IMHB in 4.11a-c and 4.1a’, 4.1i’ respectively ............................................................................................................................................... 414 Figure 4.5: a) Diboron partner effect on CHB of 2-chloroaniline, b) Boron glycolate shield effect on the CHB of 2-chloroaniline, 2-methylaniline and 2-methylindole. ...................................... 416 Figure 4.6: a) QTAIM analysis of N-borylated 2-chloro and 2-methylaniline (left and right respectively), b) 1H NMR chemical shift deviation of N-borylated 2-chloro and 2-methylaniline respect to the unborylated anilines. .......................................................................................... 417 Figure 4.7: C–N rotation barrier for N-borylated 2-chloroaniline (left) and 2-methylaniline (right). ............................................................................................................................................... 419 Figure 4.8: Correlation between presence of IMHB and remote CHB selectivity. The 1H NMR chemical shift displacements are shown by the numbers in blue respect to the corresponding non- xii borylated compound as reference. The lowest energy conformations are shown which were calculated by B3LYP functional and 6-311++G(d,p) basis set. QTAIM was performed in each optimized structure and the critical points are shown by the dots in orange (BCP) and yellow (RCP). The energy of the C–H•••O IMHB was calculate from V(r) at the corresponding BCP by using Afonin’s equation and by the displacement of the 1H NMR chemical shift of the proton involved in the IMHB. ............................................................................................................ 421 Figure 4.9: Correlation between absence of IMHB and CHB selectivity. The 1H NMR chemical shift displacements are shown by the numbers in blue respect to the corresponding non-borylated compound as reference. The lowest energy conformations are shown which were calculated by B3LYP functional and 6-311++G(d,p) basis set. QTAIM was performed in each optimized structure and the critical points are shown by the dots in orange (BCP) and yellow (RCP). ..... 422 Figure 4.10: 7-member ring IMHB: C6 borylation of 3-aminoindazol. .................................... 423 Figure 4.11: Expanding IMHB to other scaffolds: C6 borylation of an Osimertinib analogue with a pyrimidine directing group directed by a C–H•••N IMHB..................................................... 425 Figure 5.1: SMC reactivity comparison between 4-fluorophenyl imidazolylsulfonates vs halides. ............................................................................................................................................... 819 xiii LIST OF SCHEMES Scheme 1.1: Iridium catalyzed CHB............................................................................................1 Scheme 1.2: Types of reactions of aryl boronic acids and esters ..................................................2 Scheme 1.3: Traditional methods for the synthesis of aryl boronic acids and esters .....................3 Scheme 1.4: Sterically driven CHB regisoelectivity ....................................................................4 Scheme 1.5: Mechanism of CHB.................................................................................................4 Scheme 1.6: Examples of the application of CHB in academia and industry. ...............................5 Scheme 1.7: Ortho-CHB via relay directed mechanism ...............................................................8 Scheme 1.8: Ortho-CHB via outer-sphere mechanism .................................................................9 Scheme 1.9: Meta- and para-CHB directed by noncovalent interactions.................................... 10 Scheme 2.1: Selected examples of ortho functionalization of anilines ....................................... 19 Scheme 2.2: Ortho-CHB of anilines with pre-installation of a directing group........................... 20 Scheme 2.3: Traceless ortho-CHB of anilines ........................................................................... 21 Scheme 2.4: CHB regioselectivity of aniline with B2eg2, racemic B2pg2 and (S)-B2pg2.............. 23 Scheme 2.5: Role of triethylamine in the CHB of phenols and anilines. ..................................... 26 Scheme 2.6: Base effect on the ortho CHB of aniline ................................................................ 27 Scheme 2.7: Balance between regioselectivity and stability for the ortho CHB of aniline .......... 30 Scheme 2.8: Synthesis of a stable ortho borylated aniline via intramolecular interaction ........... 31 Scheme 2.9: Synthesis of a stable ortho borylated aniline via CHB ........................................... 31 Scheme 3.1: Ligand effect on para CHB of 3.1a’ ...................................................................... 88 Scheme 3.2: Effect of alkyl chain length and ligand on para CHB of 2-chlorophenyl sulfates ... 91 Scheme 3.3: Borylation of phenol derived sulfates .................................................................... 92 Scheme 3.4: Borylation of aniline derived sulfamates................................................................ 94 xiv Scheme 3.5: Effect of alkyl chain length and ligand on para CHB of 2-chlorobenzyl sulfate ..... 95 Scheme 3.6: Borylation of benzyl alcohol derived sulfates ........................................................ 96 Scheme 4.1: Ligand effect on the selectivity of the para CHB of 2-chloroaniline ................... 404 Scheme 4.2: Para CHB of anilines driven by a N–Bpin steric shield ...................................... 406 Scheme 4.3: Para CHB of alkylated anilines driven by a N–Bpin steric shield ....................... 408 Scheme 4.4: C5-CHB of 3-substitued indoles driven by a N–Bpin steric shield ...................... 410 Scheme 4.5: Ligand effect on the selectivity of the C6 CHB of 1-borylated naphthalenes....... 411 Scheme 4.6: C6 borylation of 1-borylated naphthalenes ......................................................... 412 Scheme 4.7: C–H silylation of 1-borylated naphthalenes ......................................................... 412 Scheme 5.1: Types of cross-coupling reactions with different nucleophiles ............................. 812 Scheme 5.2: Possible mechanisms for SMC ............................................................................ 813 Scheme 5.3: Traditional methods for the synthesis of aryl halides ........................................... 814 Scheme 5.4: Reported SMC of aryl imidazolylsulfonates with boronic nucleophiles ............... 815 Scheme 5.5: One pot C-H borylation/oxidation route to aryl imidazolylsulfonate and their incorporation into C-H borylation/SMC .................................................................................. 816 Scheme 5.6: Metal-catalyzed cross-coupling reactions of aryl imidazolylsulfonates ................ 817 Scheme 5.7: Nickel and palladium-catalyzed SMC of 4-fluorophenyl imidazolylsulfonate ...... 820 Scheme 5.8: Nickel-catalyzed SMC of bis(4-fluorophenyl) sulfate .......................................... 821 Scheme 5.9: Previously report nickel-catalyzed Kumada coupling of diaryl sulfates................ 821 Scheme 5.10: Palladium-catalyzed SMC of diaryl sulfate ........................................................ 823 xv KEY TO ABREVIATIONS °C Celsius degrees  chemical shift  wavelength Aq aqueous B2pin2 Bis(pinacolato)diboron BCP Bond Critical Point Boc tert-butyloxycarbonyl bs broad single peak in NMR spectrum CHB C–H activation/borylation CHS C–H activation/silylation cod 1,5-cyclooctadiene d double peak in NMR spectrum DABCO 1,4-diazabicyclo[2.2.2]octane DBU 1,8-Diazabicyclo[5.4.0]undec-7-ene DFT Density Functional Theory DG directing group DMAP 4-Dimethylaminopyridine DMF dimethylformamide DoM directed ortho metalation dtbpy 4,4’diterbutyl-2,2’-bipyridine EAS electrophilic aromatic substitution EI Electron ionization xvi eg ethylene glycol equiv equivalents ESI Electrospray ionization GC-MS Gas Chromatography-Mass Spectrometry h hours HBpin 4,4,5,5-Tetramethyl-1,3,2-dioxaborolane HRMS High resolution Mass Spectrometry IMHB Intramolecular Hydrogen Bonding J coupling constant kcal kilocalories M molar MHz Megahertz min minutes mL milliliters mol moles mol % mole percentage mp melting point n-Pr n-propyl n-Bu n-butyl NBS N-bromosuccinimide nm nanometers NMR Nuclear Magnetic Resonance NOE Nuclear Overhauser Effect xvii ppm parts per million q quartet peak in NMR spectrum Q-TOF quadrupole time-of-flight QTAIM Quantum Theory of Atoms in Molecules rt room temperature s seconds s single peak in NMR spectrum SMC Suzuki-Miyaura cross-coupling t triplet peak in NMR spectrum TBAF Tetra-n-butylammonium fluoride TBHP tert-Butyl hydroperoxide TFA trifluoroacetic acid THF tetrahydrofuran TIPS Triisopropyl silane tmphen tetramethylphenanthroline L microliters W watts wt. by weight xviii CHAPTER 1. INTRODUCTION 1.1. Iridium-Catalyzed C–H Borylations As organic chemists, we look to create tools that can mold one molecule into another that is completely new. Nowadays, the chemistry world seeks economical syntheses and tools that convert widely available compounds to others not as abundant. The key piece of this puzzle would be an easily installed group with the versatility to be replaced by a diverse array of other functionalities. C–H activation/borylation reactions (CHB) are a robust method to break ubiquitous C–H bonds and place a boronic ester in place of the hydrogen (Scheme 1.1). Due to the p empty orbital of boron and the possibility of the C–B bond to be involved in transmetalation steps, aryl boronic esters are precursors to C–C and different C–Heteroatom bonds. Scheme 1.1: Iridium catalyzed CHB 1.2. Diversification of Aryl Boronic Esters Catalytic cross-coupling, nucleophilic attack to an electrophile, oxidative cross-coupling, and 1,2-migration of boron ate complexes are among the more common processes aryl boronic esters undergo (Scheme 1.2).1,2 Akira Suzuki shared the 2010 Novel Prize for the development of a cross-coupling reaction of aryl boronic esters with aryl halides;3 which based on a 2011 survey is the most common method used in pharma to create C–C bonds.4 Other common reactions of 1 aryl boronic esters include Liebeskind-Srogl coupling with thioesters,5 Petasis reaction with imines,6–8 and Chan-Lam coupling with alcohols and amines.9 Functionalization of aryl boronic acids and esters can be approached through more than one mechanism in some cases. For example, bromination can occur via nucleophilic attack to N-bromosuccinimide (NBS) or via copper catalyzed oxidative coupling with bromide salts like KBr. 2,10 Scheme 1.2: Types of reactions of aryl boronic acids and esters 1.3. Traditional Synthesis of Aryl Boronic Esters Owing to the attractive characteristics of aryl boronic esters, their synthesis has been a subject of research well before appearance of CHB. Traditional methods to access boronic esters includes transmetallation of the corresponding halide (Scheme 1.3) followed by addition of a trialkyl borate to afford the final product.1 Miyaura developed a more directed route that involves 2 Pd-catalyzed coupling of an aryl halide with a base activated diboron or borane reagent. Although this method improves the step economy, the need for aryl halides can be limiting owing to substrate availability and/or other issues associated with aryl halides. Scheme 1.3: Traditional methods for the synthesis of aryl boronic acids and esters CHB is a way to generate aryl boronic esters without the need for a preinstalled halogen. Indeed, since the first thermal iridium catalyzed C-H borylation (CHB) of arenes was reported by the Smith group,11 CHB has increasingly become the method of choice for the generation of aryl boronic esters. Its high functional group tolerance and the ability to tune the catalyst system for specific regioselectivities are among the attractive features of CHB. Nowadays, the standard procedure for CHB (Scheme 1.1) involves B2pin2 (pin = pinacolate) or HBpin as the boron partner, [Ir(cod)OMe]2 (cod = 1,5-cyclooctadiene) as the precatalyst and 4,4′-di-tert-butyl-2,2′-dipyridyl (dtbpy) as the ligand. 1.4. CHB: Regioselectivity, Mechanism and Applications CHB-regiochemistry is controlled by steric factors.12,13 Substituents around the aromatic ring can block the access of the iridium catalyst to C–H bonds (Scheme 1.4). 1,3-Disubstiuted arenes will lead to the 5-selective borylated product selectively regardless of the electronics of the substituents as shown by the formation of 1.1-1.4 (Scheme 1.4).14 The chlorine atoms in 1,2- dichlorobenzene block the 3 and 6 positions leaving the product 1.5 as the only isomer generated. The steric presence of a neighboring substituent can be overcome if no other C–H bond is available as shown by the successful (but sluggish) formation of 1.6. Scheme 1.4 highlights the functional 3 group tolerance of CHB; most strikingly, the tolerance of halogens contrasts with traditional cross coupling reactions catalyzed by metals like palladium. Scheme 1.4: Sterically driven CHB regisoelectivity As stated above, [Ir(cod)OMe]2 or other viable Ir(I) reagents are precatalysts. Mechanistic studies support trisboryl Ir(III) I as the active form of the catalyst (Scheme 1.5).15,16 Scheme 1.5: Mechanism of CHB 4 After formation of trisboryl I, a rate determining C-H activation occurs at the iridium center to yield an Ir(V) complex II. The arene approaches the metal so as to minimize steric interactions, i.e. from the 5-position for a 1,3-disubstitued arene. After reductive elimination, the borylated product and intermediate III is formed. To recover I, B2pin2 or HBpin adds to the metal center to form IV followed by reductive elimination of HBPin or H2 respectively to complete the catalytic cycle. CHB has found utility in both academia and industry (Scheme 1.6). Baran’s research group employed CHB as part of the total synthesis of teleocidins B-1−B-4.17 An N-TPS protected indole intermediate with substituents at C3 and C4 yield the 6-borylated product selectively. Merck’s research laboratories made use of CHB to access the meta phenol from 1-chloro-3-iodobenzene via a one pot CHB/oxidation strategy.18 Scheme 1.6: Examples of the application of CHB in academia and industry. 5 This method, initially developed during the Maleczka’s group collaboration with the Smith group,19,20 uses oxone as the oxidant to be added to the crude borylation mixture and yield the corresponding phenol. Researchers at Merck scaled up this reaction to 75 kilograms, which shows how robust CHB reactions are. 1.5. Ortho regioselective CHB CHB-regioselectivity can be switched to the sterically less available ortho position by manipulating the ligand and/or using different directing groups (DG). Three strategies for ortho- regioselective CHB are: chelate direction, relay direction and direction via an outer-sphere mechanism.21 In the chelate directed mechanism, a DG interacts with the iridium center of the trisboryl complex I; different types of ligands can leave an open site in I for this interaction. Monodentate ligands like triaryl phosphines and arsines can be used to direct ortho-CHB of ketones and esters respectively.22–26 The substrate scope can be expanded if the phosphine ligand is supported by a silica surface (Silica-SMAP-Ir) (Figure 1.1a).27,28 Unfortunately, monodentate ligands do not stabilize the trisboryl I resulting in a loss of activity for CHB. Hemilabile ligands can allow for ortho-directed CHB without losing reactivity. Pyridine hydrazones, 2-picolylamine and 8-amino quinoline are used for ortho-borylations of phenyl hydrazones, benzylamines and benzaldehydes respectively (Figure 1.1b).29–35 Highly active ortho-CHB of phenol derivatives, benzoic acid derivatives and aryl imines among others can be performed with bidentate ligands (Figure 1.1c).36 One site of the ligand coordinates to the metal via a dative bond while another atom forms a sigma bond with the iridium center replacing one boron of the trisboryl I. Some substrates with specially strong directing groups can also serve as ligands with this last approach e.g. benzyl phosphines and dithioacetal arenes. 37,38 6 Figure 1.1: Ligands used for ortho-CHB via chelate directed mechanism 7 Ortho-CHB can also be directed via the formation of a sigma bond between the metal center and the directing group; this is called a relay directed mechanism (Scheme 1.7). Hartwig and cowrokers developed this strategy with pendant silane as directing group.39 Si-H inserts on the trisboryl I and elimination of HBpin leaves an open space for the C-H activation, enabling ortho- CHB of benzylic silanes and phenols. Phenols form first a hydrosilyl ether that is removed after the CHB in a one pot process.39,40 Scheme 1.7: Ortho-CHB via relay directed mechanism Chelate and relay directed mechanisms direct ortho-CHB via strong interactions between the metal and a DG. These strong interactions can reduce significantly the reactivity of the substrates. Weak interactions between the catalyst and the substrate (∆∆G‡ = 2.7 kcal.mol-1) can be enough to get high regioselectivity (99:1 at 25 °C). Based on this principle, ortho-CHB can be directed by non-covalent interactions between the DG and the ligand via an outer-sphere mechanism. Electrostatic interactions can direct the ortho-CHB of phenols (Scheme 1.8a).41 Borylation of the hydroxyl group yields an electron rich (δ-) O-glycolate that is attracted to the electron deficient (δ+) dtbpy ligand of the catalyst. B2pin2 does not give high regioselectivity due to steric repulsions. A less crowded B2eg2 (eg = ethylene glycol) works better. Transesterification of the product yields the more stable aryl boronic acid pinacol ester for isolation. Another example of an outer-sphere mechanism is the ortho-CHB of thioanisoles, directed by a Lewis acid-base interaction (Scheme 1.8b).42 The empty orbital of the boron ligand interacts with the lone pair on the sulfur of the substrate. 8 Scheme 1.8: Ortho-CHB via outer-sphere mechanism 1.6. Meta and Para Regioselective CHB Although asymmetrical 1,3-disubsitued arenes can yield exclusively the meta borylated product in most of the cases; any other arrangement of substituents will lead to a mixture of products. Remote functionalization like meta and para CHB is difficult to achieve because any potential directing group is distal from the reactive position. Fortunately, strategies based on noncovalent interactions have been found to direct CHB to remote positions (Scheme 1.9). Kanai and Kuninobus’s group made the first report in this area. Urea-type ligands as hydrogen bond donors and benzamide reagents as acceptors led to meta borylated products.43,44 Later, the Phipps group showed that bipyridine ligands with sulfated pendant groups can also direct meta CHB of benzylamine, phenethylamine and phenylpropylamine derived amides by intermolecular hydrogen bonding.45 These directing groups vary by the length between the phenyl group and the amide; interestingly the selectivity remains even as the degrees of freedom increase with every methylene 9 group added. Additionally, the sulfated bipyridine ligand can direct meta CHB of phenyl, benzyl, phenylethyl and phenylpropyl ammonium compounds by ion-pair electrostatic interactions.46–49 Para CHB have also succumbed to noncovalent interactions as directors for selectivity; although there are fewer reported examples than for meta CHB. One example comes from the Chattopadhyay group which invokes a potassium ion as a linker between the phenyl ester substrate and an anionic ligand by virtue of ion-pair electrostatic and Lewis acid-base interactions.50 Lewis acid-base interactions have also been applied to meta and para CHB of benzamides by Nakao’s group. Meta CHB of benzamides is directed by a bipyridine ligand with an aluminum Lewis acid pendant group.51 Meanwhile, a bulky aluminum Lewis acid additive is used to direct the para CHB of benzamides.52 The Lewis acid coordinates to the amide creating a steric shield that blocks the meta position leaving the para C–H as the only viable reactive site Scheme 1.9: Meta- and para-CHB directed by noncovalent interactions. 10 1.7. Conclusions CHB is an established method to access aryl boronic esters with unique selectivities. Noncovalent interactions are sufficient to direct CHB to any position desired by careful design of the ligand with the right choice of directing group and with key additives in some cases. One component less explored when optimizing CHB reactions is the diboron partners. Our group has shown that modifications of the diboron reagent, a component less commonly screened during CHB optimization, can lead to significant improvement of selectivities. In the next chapter we will discuss how modulation of the diboron partner affects CHB selectivity and the stability of the borylated products. Para CHB remains scarce and novel methods are required. In the following chapters, we described how steric shielding effects directed by both inter- and intramolecular noncovalent interactions can be used to direct para CHB in an array of directing groups. 11 REFERENCES 12 REFERENCES (1) Boronic Acids, 2nd ed.; Hall, D. G., Ed.; Wiley-VCH Verlag: Weinheim, Germany, 2012. (2) Zhu, C.; Falck, J. R. Transition-Metal-Free Ipso-Functionalization of Arylboronic Acids and Derivatives. Adv. Synth. Catal. 2014, 356, 2395–2410. (3) Miyaura, N.; Yamada, K.; Suzuki, A. A New Stereospecific Cross-Coupling by the Palladium-Catalyzed Reaction of 1-Alkenylboranes with 1-Alkenyl or 1-Alkynyl Halides. Tetrahedron Lett. 1979, 20, 3437–3440. (4) Colacot, T. J. The 2010 Nobel Prize in Chemistry: Palladium-Catalysed Cross-Coupling. Platin. Met. Rev. 2011, 55, 84–90. (5) Cheng, H.-G.; Chen, H.; Liu, Y.; Zhou, Q. The Liebeskind-Srogl Cross-Coupling Reaction and Its Synthetic Applications. Asian J. Org. Chem. 2018, 7, 490–508. (6) Petasis, N. A.; Akritopoulou, I. The Boronic Acid Mannich Reaction: A New Method for the Synthesis of Geometrically Pure Allylamines. Tetrahedron Lett. 1993, 34, 583–586. (7) Petasis, N. A.; Zavialov, I. A. A New and Practical Synthesis of α-Amino Acids from Alkenyl Boronic Acids. J. Am. Chem. Soc. 1997, 119, 445–446. (8) Petasis, N. A.; Zavialov, I. A. Highly Stereocontrolled One-Step Synthesis Ofanti-β-Amino Alcohols from Organoboronic Acids, Amines, and α-Hydroxy Aldehydes. J. Am. Chem. Soc. 1998, 120, 11798–11799. (9) Qiao, J. X.; Lam, P. Y. S. Recent Advances in Chan-Lam Coupling Reaction: Copper- Promoted C-Heteroatom Bond Cross-Coupling Reactions with Boronic Acids and Derivatives. In Boronic Acids; Wiley-VCH Verlag GmbH & Co. KGaA: Weinheim, Germany, 2011; pp 315–361. (10) Murphy, J. M.; Liao, X.; Hartwig, J. F. Meta Halogenation of 1,3-Disubstituted Arenes via Iridium-Catalyzed Arene Borylation. J. Am. Chem. Soc. 2007, 129, 15434–15435. (11) Cho, J.-Y.; Tse, M. K.; Holmes, D.; Maleczka, R. E., Jr; Smith, M. R., III. Remarkably Selective Iridium Catalysts for the Elaboration of Aromatic C-H Bonds. Science 2002, 295, 305–308. (12) Mkhalid, I. A. I.; Barnard, J. H.; Marder, T. B.; Murphy, J. M.; Hartwig, J. F. C-H Activation for the Construction of C-B Bonds. Chem. Rev. 2010, 110, 890–931. (13) Xu, L.; Wang, G.; Zhang, S.; Wang, H.; Wang, L.; Liu, L.; Jiao, J.; Li, P. Recent Advances in Catalytic C−H Borylation Reactions. Tetrahedron 2017, 73, 7123–7157. (14) Ishiyama, T.; Takagi, J.; Hartwig, J. F.; Miyaura, N. A Stoichiometric Aromatic C-H 13 Borylation Catalyzed by Iridium(I)/2,2’-Bipyridine Complexes at Room Temperature. Angew. Chem. Int. Ed. 2002, 41, 3056–3058. (15) Tamura, H.; Yamazaki, H.; Sato, H.; Sakaki, S. Iridium-Catalyzed Borylation of Benzene with Diboron. Theoretical Elucidation of Catalytic Cycle Including Unusual Iridium(v) Intermediate. J. Am. Chem. Soc. 2003, 125, 16114–16126. (16) Boller, T. M.; Murphy, J. M.; Hapke, M.; Ishiyama, T.; Miyaura, N.; Hartwig, J. F. Mechanism of the Mild Functionalization of Arenes by Diboron Reagents Catalyzed by Iridium Complexes. Intermediacy and Chemistry of Bipyridine-Ligated Iridium Trisboryl Complexes. J. Am. Chem. Soc. 2005, 127, 14263–14278. (17) Nakamura, H.; Yasui, K.; Kanda, Y.; Baran, P. S. 11-Step Total Synthesis of Teleocidins B- 1-B-4. J. Am. Chem. Soc. 2019, 141, 1494–1497. (18) Campeau, L.-C.; Chen, Q.; Gauvreau, D.; Girardin, M.; Belyk, K.; Maligres, P.; Zhou, G.; Gu, C.; Zhang, W.; Tan, L.; O’Shea, P. D. A Robust Kilo-Scale Synthesis of Doravirine. Org. Process Res. Dev. 2016, 20, 1476–1481. (19) Maleczka, R. E., Jr; Shi, F.; Holmes, D.; Smith, M. R., III. C-H Activation/Borylation/Oxidation: A One-Pot Unified Route to Meta-Substituted Phenols Bearing Ortho-/Para-Directing Groups. J. Am. Chem. Soc. 2003, 125, 7792–7793. (20) Norberg, A. M.; Smith, M. R., III; Maleczka, R. E., Jr. Practical One-Pot C-H Activation/Borylation/Oxidation: Preparation of 3-Bromo-5-Methylphenol on a Multigram Scale. Synthesis 2011, 2011, 857–859. (21) Ros, A.; Fernández, R.; Lassaletta, J. M. Functional Group Directed C–H Borylation. Chem. Soc. Rev. 2014, 43, 3229–3243. (22) Ishiyama, T.; Isou, H.; Kikuchi, T.; Miyaura, N. Ortho-C–H Borylation of Benzoate Esters with Bis(Pinacolato)Diboron Catalyzed by Iridium–Phosphine Complexes. Chem. Commun. 2010, 46, 159–161. (23) Itoh, H.; Kikuchi, T.; Ishiyama, T.; Miyaura, N. Iridium-Catalyzed Ortho-C–H Borylation of Aryl Ketones with Bis(Pinacolato)Diboron. Chem. Lett. 2011, 40, 1007–1008. (24) Jover, J.; Maseras, F. Mechanistic Investigation of Iridium-Catalyzed C–H Borylation of Methyl Benzoate: Ligand Effects in Regioselectivity and Activity. Organometallics 2016, 35, 3221–3226. (25) Sasaki, I.; Amou, T.; Ito, H.; Ishiyama, T. Iridium-Catalyzed Ortho-C–H Borylation of Aromatic Aldimines Derived from Pentafluoroaniline with Bis(Pinacolate)Diboron. Org. Biomol. Chem. 2014, 12, 2041–2044. (26) Xu, F.; Duke, O. M.; Rojas, D.; Eichelberger, H. M.; Kim, R. S.; Clark, T. B.; Watson, D. A. Arylphosphonate-Directed Ortho C-H Borylation: Rapid Entry into Highly-Substituted Phosphoarenes. J. Am. Chem. Soc. 2020, 142, 11988–11992. 14 (27) Kawamorita, S.; Ohmiya, H.; Hara, K.; Fukuoka, A.; Sawamura, M. Directed Ortho Borylation of Functionalized Arenes Catalyzed by a Silica-Supported Compact Phosphine- Iridium System. J. Am. Chem. Soc. 2009, 131, 5058–5059. (28) Yamazaki, K.; Kawamorita, S.; Ohmiya, H.; Sawamura, M. Directed Ortho Borylation of Phenol Derivatives Catalyzed by a Silica-Supported Iridium Complex. Org. Lett. 2010, 12, 3978–3981. (29) Ros, A.; Estepa, B.; López-Rodríguez, R.; Álvarez, E.; Fernández, R.; Lassaletta, J. M. Use of Hemilabile N,N Ligands in Nitrogen-Directed Iridium-Catalyzed Borylations of Arenes. Angew. Chem. Int. Ed. 2011, 50, 11724–11728. (30) Ros, A.; López-Rodríguez, R.; Estepa, B.; Álvarez, E.; Fernández, R.; Lassaletta, J. M. Hydrazone as the Directing Group for Ir-Catalyzed Arene Diborylations and Sequential Functionalizations. J. Am. Chem. Soc. 2012, 134, 4573–4576. (31) López-Rodríguez, R.; Ros, A.; Fernández, R.; Lassaletta, J. M. Pinacolborane as the Boron Source in Nitrogen-Directed Borylations of Aromatic N,N-Dimethylhydrazones. J. Org. Chem. 2012, 77, 9915–9920. (32) Roering, A. J.; Hale, L. V. A.; Squier, P. A.; Ringgold, M. A.; Wiederspan, E. R.; Clark, T. B. Iridium-Catalyzed, Substrate-Directed C-H Borylation Reactions of Benzylic Amines. Org. Lett. 2012, 14, 3558–3561. (33) Hale, L. V. A.; Emmerson, D. G.; Ling, E. F.; Roering, A. J.; Ringgold, M. A.; Clark, T. B. An Ortho-Directed C–H Borylation/Suzuki Coupling Sequence in the Formation of Biphenylbenzylic Amines. Org. Chem. Front. 2015, 2, 661–664. (34) Hale, L. V. A.; McGarry, K. A.; Ringgold, M. A.; Clark, T. B. Role of Hemilabile Diamine Ligands in the Amine-Directed C–H Borylation of Arenes. Organometallics 2015, 34, 51– 55. (35) Bisht, R.; Chattopadhyay, B. Formal Ir-Catalyzed Ligand-Enabled Ortho and Meta Borylation of Aromatic Aldehydes via in Situ-Generated Imines. J. Am. Chem. Soc. 2016, 138, 84–87. (36) Ghaffari, B.; Preshlock, S. M.; Plattner, D. L.; Staples, R. J.; Maligres, P. E.; Krska, S. W.; Maleczka, R. E., Jr; Smith, M. R., III. Silyl Phosphorus and Nitrogen Donor Chelates for Homogeneous Ortho Borylation Catalysis. J. Am. Chem. Soc. 2014, 136, 14345–14348. (37) Crawford, K. M.; Ramseyer, T. R.; Daley, C. J. A.; Clark, T. B. Phosphine-Directed C-H Borylation Reactions: Facile and Selective Access to Ambiphilic Phosphine Boronate Esters. Angew. Chem. Int. Ed. 2014, 53, 7589–7593. (38) Liu, L.; Wang, G.; Jiao, J.; Li, P. Sulfur-Directed Ligand-Free C-H Borylation by Iridium Catalysis. Org. Lett. 2017, 19, 6132–6135. (39) Boebel, T. A.; Hartwig, J. F. Silyl-Directed, Iridium-Catalyzed Ortho-Borylation of Arenes. 15 A One-Pot Ortho-Borylation of Phenols, Arylamines, and Alkylarenes. J. Am. Chem. Soc. 2008, 130, 7534–7535. (40) Su, B.; Zhou, T.-G.; Xu, P.-L.; Shi, Z.-J.; Hartwig, J. F. Enantioselective Borylation of Aromatic C-H Bonds with Chiral Dinitrogen Ligands. Angew. Chem. Int. Ed. 2017, 56, 7205–7208. (41) Chattopadhyay, B.; Dannatt, J. E.; Andujar-De Sanctis, I. L.; Gore, K. A.; Maleczka, R. E., Jr; Singleton, D. A.; Smith, M. R., III. Ir-Catalyzed Ortho-Borylation of Phenols Directed by Substrate-Ligand Electrostatic Interactions: A Combined Experimental/in Silico Strategy for Optimizing Weak Interactions. J. Am. Chem. Soc. 2017, 139, 7864–7871. (42) Li, H. L.; Kuninobu, Y.; Kanai, M. Lewis Acid-Base Interaction-Controlled Ortho-Selective C-H Borylation of Aryl Sulfides. Angew. Chem. Int. Ed. 2017, 56, 1495–1499. (43) Kuninobu, Y.; Ida, H.; Nishi, M.; Kanai, M. A Meta-Selective C-H Borylation Directed by a Secondary Interaction between Ligand and Substrate. Nat. Chem. 2015, 7, 712–717. (44) Lu, X.; Yoshigoe, Y.; Ida, H.; Nishi, M.; Kanai, M.; Kuninobu, Y. Hydrogen Bond- Accelerated Meta-Selective C–H Borylation of Aromatic Compounds and Expression of Functional Group and Substrate Specificities. ACS Catalysis 2019, 9, 1705–1709. (45) Davis, H. J.; Genov, G. R.; Phipps, R. J. Meta-Selective C-H Borylation of Benzylamine-, Phenethylamine-, and Phenylpropylamine-Derived Amides Enabled by a Single Anionic Ligand. Angew. Chem. Int. Ed. 2017, 56, 13351–13355. (46) Davis, H. J.; Mihai, M. T.; Phipps, R. J. Ion Pair-Directed Regiocontrol in Transition-Metal Catalysis: A Meta-Selective C–H Borylation of Aromatic Quaternary Ammonium Salts. J. Am. Chem. Soc. 2016, 138, 12759–12762. (47) Mihai, M. T.; Davis, H. J.; Genov, G. R.; Phipps, R. J. Ion Pair-Directed C–H Activation on Flexible Ammonium Salts:Meta-Selective Borylation of Quaternized Phenethylamines and Phenylpropylamines. ACS Catalysis 2018, 8, 3764–3769. (48) Mihai, M. T.; Phipps, R. J. Ion-Pair-Directed Meta-Selective C–H Borylation of Aromatic Quaternary Ammonium Salts. Synlett 2017, 28, 1011–1017. (49) Lee, B.; Mihai, M. T.; Stojalnikova, V.; Phipps, R. J. Ion-Pair-Directed Borylation of Aromatic Phosphonium Salts. J. Org. Chem. 2019, 84, 13124–13134. (50) Hoque, M. E.; Bisht, R.; Haldar, C.; Chattopadhyay, B. Noncovalent Interactions in Ir- Catalyzed C-H Activation: L-Shaped Ligand for Para-Selective Borylation of Aromatic Esters. J. Am. Chem. Soc. 2017, 139, 7745–7748. (51) Yang, L.; Uemura, N.; Nakao, Y. Meta-Selective C-H Borylation of Benzamides and Pyridines by an Iridium-Lewis Acid Bifunctional Catalyst. J. Am. Chem. Soc. 2019, 141, 7972–7979. 16 (52) Yang, L.; Semba, K.; Nakao, Y. Para-Selective C-H Borylation of (Hetero)Arenes by Cooperative Iridium/Aluminum Catalysis. Angew. Chem. Int. Ed. 2017, 56, 4853–4857. 17 CHAPTER 2. BALANCING ACTIVITY AND REGIOSELECTIVITY IN ORTHO C–H BORYLATIONS OF ANILINES BY MODULATING THE DIBORON PARTNER 2.1. Introduction Anilines can be found in dyes, agrochemicals, pharmaceuticals, and polymers (Figure 2.1).1 Historically, anilines were important compounds for the synthesis of diazo dyes; aniline yellow is the first example in this class. Aniline can also be found in other types of colorants; one famous example being indigo which gives the blue color to jeans. 1 The use of anilines as agrochemicals is also known, with one of the most prominent examples being alachlor, which is the second most used herbicide in US. The aniline skeleton also appears in therapeutically important molecules like diazepam and the vitamins riboflavin (vitamin B2) and folic acid. Furthermore, anilines also have a presence in polymer chemistry, where common examples include the polymer Kevlar and 2-mercaptobenzothiazole (MBT), an additive in polymerization. Figure 2.1: Examples of dyes, agrochemicals, pharmaceuticals, biomolecules, and polymers with an aniline ring Traditional functionalization of anilines is done by electrophilic aromatic substitution (EAS), which affords mainly the para isomer. Regioselectivity can be switched under special 18 conditions; one example is the ortho-iodination of anilines with N-iodosuccinimide (NIS) under acidic conditions using non-polar solvents (Scheme 2.1a).2 The hydrogen bond between the protonated aniline and the carbonyl group of the NIS directs iodine to the ortho position. Aside from this case, ortho-functionalization of anilines is commonly accomplished through directed ortho-metalation (DoM). For instance, acylation of amides can afford the ortho-acylated product via palladium C-H activation (Scheme 2.1b).3,4 The mechanism of this reaction involves chelation of the carbonyl to the metal center directing the regioselectivity of the C-H oxidative addition. This methodology, while seemingly useful, requires the introduction of a directing group in the aniline which limits functional group tolerance and reduces the step economy efficiency. Scheme 2.1: Selected examples of ortho functionalization of anilines To overcome the limitations of DoM, a traceless method to selectively functionalize anilines is needed. Furthermore, it would be synthetically attractive if the methodology could give access to a wide variety of functional groups. Ortho-borylation of anilines can be a good strategy because aryl boronic acids and esters are versatile precursors.5 Biaryls, benzyl amines, benzyl alcohols, aryl halides, aryl cyanides, trifluoro toluenes, benzoic acids, anilines, phenols, etc. can be synthesized via boron exchange reactions.5,6 The first reports of this methodology installed a directing group in the aniline prior to CHB. Hartwig used a relay directing mechanism for the 19 ortho-CHB of 2-chloro-N-methyl aniline. However, this method was only used on one substrate and was low yielding (37%, Scheme 2.2a).7 Scheme 2.2: Ortho-CHB of anilines with pre-installation of a directing group Introduction of a (methylthio)methyl group in acetanilides can also direct ortho-CHB. It is believed that this goes through a chelate directed mechanism with an hemilabile ligand or an outer- sphere mechanism with an Lewis acid-base interaction (Scheme 2.2b).8 Singleton, Maleczka and Smith showed that ortho-CHB of N-(Boc)-anilines are also possible due to a hydrogen bond N– 20 H•••O between the hydrogen of the aniline and the oxygen in one of the Bpins on the iridium (Scheme 2.2c).9 Aside from Ir-catalyzed CHB, Pd-catalyzed DoM is another option for the ortho- CHB of acetanilides (Scheme 2.2d).10 Traceless ortho-CHB of anilines can improve step and atom economy efficiency (Scheme 2.3). In 2013, Krska, Maleczka and Smith reported the first traceless ortho-borylation of anilines using HBpin as the boron partner.11 It is proposed that ArNH–Bpin is formed first followed by ortho-CHB that is directed by a similar hydrogen bond interaction N–H•••O as that proposed for N-(Boc)-anilines (Scheme 2.2c). This protocol works well only when there is a C4 substituent on the substrate. Scheme 2.3: Traceless ortho-CHB of anilines In 2018, it was reported that using B2eg2 as the boronic partner yields high ortho regioselectivity without the necessity of a C4 substituent (Scheme 2.3).12 This improvement in selectivity is due to the decreased steric demand of the Beg group that stabilizes the transition state. 21 However, high catalyst loadings were used and the borylated (2-Beg)ArNH2 product needed to be treated with pinacol to convert it to the more stable (2-Bpin)ArNH2, allowing practical purification. If one could remove the last esterification step and retain the regioselectivity of CHB, the result would be a very valuable asset. Boronic partners bulkier than B2eg2 may yield more stable borylated products, allowing for the possibility of direct isolation, but at the risk of reducing the ortho CHB regioselectivity. Herein, we sought to find a balance between regioselectivity and stability of the borylated product for the ortho CHB of anilines by optimization of the diboron partner. 2.2. Results and Discussion 2.2.1. Regioselectivity of a novel diboron partner: B2pg2 A variety of diboron partners can be envisioned with sizes lying between B2pin2 and B2eg2. Our journey began with the simplest version, B2pg2 (pg = propylene glycol), which present a pendant methyl group in each glycolate chain of B2eg2. Preliminary studies by Behnaz Ghaffari showed that B2pg2 yields a highly ortho regioselective CHB of aniline like B2eg2 (unpublished results). The B2pg2 was made starting with a racemic mixture of propylene glycol that should lead to a racemic mixture of B2pg2. Addition of NMR shift reagents helped to measure the ratio of the stereoisomers in the B2pg2 mixture (Figure 2.2). As expected, the two B2pg2 diastereomers are present in a 50:50 mixture corresponding to the meso isomer (S,R)-B2pg2 and an equimolar mixture of the enantiomers (S,S)-B2pg2 and (R,R)-B2pg2. 22 NMR chiral shift reagent: (Eu(hfc)3) added Figure 2.2: 1H NMR of a racemic mixture of B2pg2 with NMR shift reagents We wondered if the individual stereoisomers of B2pg2 would induce as high selectivity as the mixture of stereoisomers. We made the pure (S,S)-B2pg2 enantiomer from (S)-propylene glycol and tested it under CHB conditions (Scheme 2.4). Comparable reactivity and regioselectivity were found with (S,S)-B2pg2 and the mixture of stereoisomers. This result suggests that all the diasteromers in the B2pg2 mixture are equally efficient for the ortho CHB of anilines. We continued our studies with the mixture of B2pg2 stereoisomers as its synthesis is less expensive than making the pure enantiomers. Scheme 2.4: CHB regioselectivity of aniline with B2eg2, racemic B2pg2 and (S)-B2pg2 23 2.2.2. Optimization of reaction conditions: catalyst loading The previously reported ortho CHB of anilines with B2eg2 did not need extended screening of conditions since high regioselectivity and very good yields were obtained early during the optimization.12 We wondered if milder conditions, e.g. lower catalyst loading, boron partner equivalents and temperature, could achieve comparable conversions with B2pg2 as the boron partner. Catalyst loading is another important parameter to explore for the CHB of anilines. By increasing the catalyst loading one can improve conversions of CHB, but it is not synthetically desirable to invest in more catalyst than necessary. Catalyst loadings from 1.0 to 2.5 mol % of [Ir(cod)OMe]2 were screened for the ortho-CHB of aniline (Table 2.1). A slight improvement in conversion was seen with 1.5 mol % of [Ir(cod)OMe]2 respect to the use of 1.0 mol % catalyst loading, but conversion remained unchanged even with 2.0-2.5 mol % of catalyst. Table 2.1: Optimization of reaction conditions: catalyst loading a % [Ir(cod)OMe]2 % conversion % ortho % diborylated 1.0 62 60 2 1.5 80 74 6 2.0 81 73 8 2.5 81 74 7 a Reaction conditions: aniline (1 mmol), B2pg2 (2.5 mmol), [Ir(cod)OMe]2 (0.01 mmol), dtbpy (0.02 mmol), Et3N (2 mmol), THF (3 mL), 80 °C, 12 h This project was a group effort with Seokjoo Lee, who also performed screening of conditions to evaluate the effect of base loading, boron partner and temperature on CHB. These studies were done at the same time as the experiments shown above, and thus initial loading 24 conditions of 1 mol % of [Ir(cod)OMe]2 were used instead of the optimized 1.5 mol %. Seokjoo’s results are presented in the following paragraphs of Section 2.2.3. 2.2.3. Optimization of reaction conditions: boron partner equivalents and temperature The amount of B2pg2 were varied to find how many equivalents of boron partner is necessary for successful CHB (Table 2.2). There is a clear improvement in conversion as the equivalents of B2pg2 increase and using 2.5 equivalents of B2pg2 was found to be the best choice. More than one equivalent is necessary for good conversions because the first step is the formation of PhN(H)Bpg, which uses one equivalent of boron partner per equivalent of aniline. Table 2.2: Optimization of reaction conditions: boron partner equivalents a B2pg2 (equiv) % conversion 1 (%) 2 (%) 1 4 4 0 1.5 44 43 0 2 68 65 2 2.5 83 76 7 a Reaction conditions: aniline (1 mmol), B2pg2 (x mmol), [Ir(cod)OMe]2 (0.01 mmol), dtbpy (0.02 mmol), Et3N (2 mmol), THF (3 mL), 80 °C, 12 h CHB of aniline at different temperatures was also evaluated. Reactions were followed by 1 H NMR over a period of time (Figure 2.3). When the reaction was performed at 40 °C, it appeared slightly slower than at 60 °C and at 80 °C. However, all the reactions achieve the same conversions to both monoborylated and diborylated product in the end. This study was performed before the catalyst loading screen. Therefore, it will be important to perform the same temperature experiment with 1.5 mol % of [Ir(cod)OMe]2. If a same pattern is displayed, a lower temperature than 80 °C is a viable reaction condition. 25 80 70 60 % conversion 50 40 30 20 10 0 0 2 4 6 8 10 12 14 16 18 Time (h) 40 °C, 1 mol % cat., ortho 40 °C, 1 mol % cat., diborylated 60 °C, 1 mol % cat., ortho 60 °C, 1 mol % cat., diborylated 60 °C, 0.5 mol% cat., ortho 60 °C, 0.5 mol % cat., diborylated 80 °C, 1 mol % cat., ortho 80 °C, 1 mol % cat., diborylated Figure 2.3: Optimization of reaction conditions: effect of the temperature. 2.2.4. Effect of the base for ortho-CHB of aniline Ortho-CHB of phenols and anilines with B2eg2 is improved by addition of triethyl amine. It was proposed that the purpose of the base is to stabilize the H–Beg side product in order to avoid undesirable reactions. Trimethylamine has been reported to stabilize this type of compounds by complexation: HBeg•NMe3.13,14 The idea is that triethylamine might have the same effect on ortho- CHB of anilines with B2eg2 (Scheme 2.5).12,15 When the base is absent, the borane might react with the aniline to generate a trianiline borane, which will be unactive towards CHB with B2eg2. Scheme 2.5: Role of triethylamine in the CHB of phenols and anilines. Other amines like diisopropylethyl amine (DIPEA, Hünig base), DBU and DABCO were also tested for ortho-CHB of aniline to observe if they have a similar or greater effect than 26 triethylamine (Scheme 2.6). However, triethyl amine was the best, affording the highest conversion as well as the selective formation of the ortho-monoborylated product. Scheme 2.6: Base effect on the ortho CHB of aniline a a Reaction conditions: aniline (1 mmol), B2pg2 (2.5 mmol), [Ir(cod)OMe]2 (0.01 mmol), dtbpy (0.02 mmol), base (2 mmol), THF (3 mL), 80 °C, 12 h Effect of the equivalents of triethylamine on the ortho-borylation of anilines was evaluated; results are shown in Figure 2.4. Conversions to the ortho monoborylated aniline are represented by the bars in blue and the diborylated product by the bars in orange. Surprisingly, there is formation of the ortho-borylated product even without base. Increasing the amount of base to 0.5 equivalents improves the conversion considerably. Excess of base harms the reaction. Perhaps excess base can break the N–B bond of the intermediate PhN(H)Bpg thereby losing reactivity. Lower reactivity with Hunig base, DBU and DABCO might be due to the large sizes of these bases in comparison to triethylamine. The HBeg•Base complex may be destabilized by sterics when a larger base is attached to the borane. Therefore, we tested diethylmethyl amine and ethyldimethyl amine which should be smaller than triethylamine. Conversions comparable to those with triethylamine were found. 27 Figure 2.4: Screening of trialkylamine bases and effect of equivalents on ortho CHB of aniline 2.2.5. Modulating the diboron partner With the optimized conditions in hand, we continue to evaluate different diboron partners and find which leads to the best balance of ortho regioselectivity and stability of the borylated product for the CHB of anilines. Diboranes were synthesized from the corresponding glycol and B2(OH)4 via a procedure developed in the Smith lab by Ryan Fornwald (unpublished results). Diboron partners with an ethyl pendant group (B2bg2) and with two pendant methyl groups in the glycolate chain (B2mpg2 and B2((2R,3R)bg)2) were prepared (Figure 2.5). CHB of unsubstituted aniline was evaluated with the diboron partners at different equivalents of triethylamine. In terms of reactivity, 0.25 equiv of base was optimal for all the cases. Diboron partners with one pendant alkyl group in the glycolate backbone (B2pg2 and B2bg2) retain the high regioselectivity for ortho 28 CHB of aniline. Introduction of additional alkyl chains in the boron partner (B2mpg2 and B2((2R,3R)bg)2)) has a detrimental effect on the selectivity yielding the meta and para products (gray and yellow bars respectively). Figure 2.5: Effect of diboron partner on the ortho CHB of aniline Attempts at product purification by silica chromatography showed us that ArBeg and ArBpg decompose, but ArBbg and ArBmpg survive. As stated above, B2bg2 was more selective towards the ortho borylated product than B2mpg2. Therefore, B2bg2 represents the best balance of reactivity, regioselectivity and stability (Scheme 2.7). 29 Scheme 2.7: Balance between regioselectivity and stability for the ortho CHB of aniline 2.2.6. Factors controlling stability of the borylated product Ortho borylated anilines with small boron groups tend to be unstable. A smaller glycolate chain around the boron group can leave the boron atom more exposed to attack by nucleophiles. We speculate that hydrolysis or reactions with silica during chromatography are responsible for the troubles during isolation of ArBpg. A previous report has shown that an ortho borylated acetamide with a Beg group hydrolyzes slower than the corresponding meta or para borylated acetamides.16 To further evaluate our hypothesis, we synthesized 2.3, which has an acetamide group in the aniline that can coordinate to the boron blocking any potential side reaction (Scheme 2.8). Amide 2.3 is a crystalline solid that is bench stable even after 1 year as shown by 1H NMR. 11 The B NMR chemical shift of 10.3 ppm for a C–Bgly group is shielded with respect to the common range 25-30 ppm for this type of boron. This is indicative of the boron atom coordinating with a Lewis base like the acetamide group. 30 Scheme 2.8: Synthesis of a stable ortho borylated aniline via intramolecular interaction 2.2.7. Substrate Scope We wondered if the stability conferred by the Bbg group in ortho borylated anilines as well as the high selectivity induced by B2bg2 could be extrapolated to other substituted anilines. In fact, this was the case for 2.5-2.7 which were isolated under the same optimized conditions of 2.4 (Scheme 2.9). Although moderate yields were obtained, this protocol obviates the previously needed transesterification step with pinacol. Scheme 2.9: Synthesis of a stable ortho borylated aniline via CHB 2.3. Conclusions In summary, ortho CHB of anilines can achieve high selectivities with B2bg2 as the diboron partner and yield products that can be isolated directly without the need of a transesterification step. Diboron partners with one pendant alkyl group in the glycolate backbone (B2pg2 and B2bg2) 31 retain the high regioselectivity for ortho CHB of aniline but additional alkyl chains in the boron partner (B2mpg2 and B2(2R,3R)bg2) has a detrimental effect on the selectivity. The best conversions for each diboron partner were obtained using 0.25 equivalents of triethyl amine; excess or lower amounts of base were detrimental for the formation of the ortho-borylated aniline Attempts at product purification by silica chromatography showed that ArBeg and ArBpg decompose, but ArBbg and ArBmpg survive. Unwanted reactions during purification might occur from nucleophilic attack to the boron. In fact, ortho borylated acetamide with Bpg is stabilized by an intramolecular Lewis acid-base interaction. This report shows some of the benefits and unique selectivities that can be achieved by modulating the diboron partner; a reagent not commonly screened during development of CHB reactions. 2.4. Experimental 2.4.1. General Information All commercially available chemicals were used as received unless otherwise indicated. Bis(4-1,5-cyclooctadiene)-di--methoxy-diiridium(I) [Ir(OMe)COD]2 was prepared from a well reported procedure in the literature.17 Tetrahydrofuran (THF) were refluxed over sodium/benzophenone ketyl, distilled and degassed twice before borylation. Column chromatography was performed on flash silica gel (ACME). Thin layer chromatography was performed on 0.25 mm thick aluminum-backed silica gel plates purchased from Merck and visualized with ultraviolet light ( = 254 nm). 1 H, 13C, and 11B NMR spectra were recorded on Agilent DirectDrive2 (500 MHz for 1H, 126 MHz for 13C and 160 MHz for 11B). All coupling constants are apparent J values measured at the indicated field strengths in Hertz (s = singlet, d = doublet, t = triplet, q = quartet, dd = doublet of doublets, bs = broad singlet, dt = doublet of triplet, td = triplet of doublet, ttt = triplet of triplet 32 of triplet). Spectra taken in CDCl3 were referenced to 7.26 ppm in 1H NMR and 77.2 ppm in 13C NMR. 11B NMR spectra were referenced to neat BF3•Et2O as the external standard. 13 C NMR resonances for the boron-bearing carbon atom were not observed due to quadrupolar relaxation. High-resolution mass spectra were acquired at the MSU Mass Spectrometry facility using a Waters QTOF Ultima mass spectrometer (ESI). 2.4.2. Synthesis of diboron partners Synthesis of racemic B2pg2 B2(OH)4 (3.59 g, 40 mmol, 1 equiv) and CH(OMe)3 (16.98 g, 160 mmol, 4 equiv) were stirred in a Schlenk flask and the suspension was degassed with N2 for 15 minutes. One drop of acetyl chloride, AcCl, was added and the mixture became a homogenous solution. Propylene glycol (pg, 6.09 g, 80 mmol, 2 equiv) was added and the reaction was stirred at room temperature overnight. The mixture was concentrated and then distilled under reduce pressure to yield 4.20 g of B2pg2 as a colorless oil (62% yield). 1 H NMR (500 MHz, CDCl3) δ 4.62 – 4.51 (m, 1H), 4.28 (dd, J = 9.0, 7.9 Hz, 1H), 3.71 (ddd, J = 9.0, 7.4, 1.0 Hz, 1H), 1.33 (dd, J = 6.2, 0.5 Hz, 3H). 13 C NMR (126 MHz, CDCl3) δ 73.4, 73.3, 11 71.9, 21.6. B NMR (160 MHz, CDCl3) δ 30.7. GC-MS (EI) m/z calcd for C6H12B2O4 [M] 170.1, found: 170.1 33 Synthesis of (S)-B2pg2 B2(OH)4 (896 mg, 10 mmol, 1 equiv) and CH(OMe)3 (4.24 g, 40 mmol, 4 equiv) were stirred in a Schlenk flask and the suspension was degassed with N2 for 15 minutes. One drop of acetyl chloride, AcCl, was added and the mixture became a homogenous solution. (S)-Propylene glycol ((S)-pg, 1.52 g, 20 mmol, 2 equiv) was added and the reaction was stirred at room temperature overnight. The mixture was concentrated and then distilled under reduce pressure. A solid crashed out on the distilled arm and receiving flask that after recollection yielded 840 mg of (S)-B2pg2 as a white solid (49% yield). 1 H NMR (500 MHz, CDCl3) δ 4.63 – 4.46 (m, 1H), 4.25 (dd, J = 9.0, 7.9 Hz, 1H), 3.69 (dd, J = 9.0, 7.4 Hz, 1H), 1.30 (d, J = 6.3 Hz, 3H). 13C NMR (126 MHz, CDCl3) δ 73.5, 72.1, 21.8. 11 B NMR (160 MHz, CDCl3) δ 30.7. GC-MS (EI) m/z calcd for C6H12B2O4 [M] 170.1, found: 170.1 Synthesis of B2bg2 B2(OH)4 (3.59 g, 40 mmol, 1 equiv) and CH(OMe)3 (16.98 g, 160 mmol, 4 equiv) were stirred in a Schlenk flask and the suspension was degassed with N2 for 15 minutes. One drop of acetyl chloride, AcCl, was added and the mixture becomes a homogenous solution. Butylene glycol (bg, 7.21 g, 80 mmol, 2 equiv) was added and the reaction was stirred at room temperature 34 overnight. The mixture was concentrated and then distilled under reduce pressure to yield 6.78 g of B2bg2 as a colorless oil (86% yield). 1 H NMR (500 MHz, CDCl3) δ 4.40 – 4.30 (m, 1H), 4.23 (dd, J = 9.0, 8.1 Hz, 1H), 3.77 (ddd, J = 9.0, 7.3, 1.7 Hz, 1H), 1.73 – 1.50 (m, 2H), 0.94 (t, J = 7.4 Hz, 3H). 13C NMR (126 MHz, CDCl3) 11 δ 78.44, 70.19, 28.79, 28.78, 9.13. B NMR (160 MHz, CDCl3) δ 30.62. GC-MS (EI) m/z calcd for C8H16B2O4 [M] 198.1, found: 198.1 Synthesis of B2mpg2 B2(OH)4 (896 mg, 10 mmol, 1 equiv) and CH(OMe)3 (4.24 g, 40 mmol, 4 equiv) were stirred in a Schlenk flask and the suspension was degassed with N2 for 15 minutes. One drop of acetyl chloride, AcCl, was added and the mixture becomes a homogenous solution. 2-methyl-1,2- propandiol (mpg, 1.80 g, 20 mmol, 2 equiv) was added and the reaction was stirred at room temperature overnight. The mixture was concentrated and then distilled under reduce pressure to yield 730 mg of B2mpg2 as a colorless oil (37% yield). 1 H NMR (500 MHz, CDCl3) δ 3.90 (s, 1H), 1.37 (s, 3H). 13C NMR (126 MHz, CDCl3) δ 80.27, 11 77.10, 28.40. B NMR (160 MHz, CDCl3) δ 30.81. GC-MS (EI) m/z calcd for C8H16B2O4 [M] 198.1, found: 198.1 Synthesis of B2((2R,3R)bg)2 35 B2(OH)4 (896 mg, 10 mmol, 1 equiv) and CH(OMe)3 (4.24 g, 40 mmol, 4 equiv) were stirred in a Schlenk flask and the suspension was degassed with N2 for 15 minutes. One drop of acetyl chloride, AcCl, was added and the mixture becomes a homogenous solution. (2R,3R)- butanediol ((2R,3R)bg, 1.80 g, 20 mmol, 2 equiv) was added and the reaction was stirred at room temperature overnight. The mixture was concentrated and then distilled under reduce pressure to yield 820 mg of B2(2R,3R)bg2 as a colorless oil (41% yield). 1 H NMR (500 MHz, CDCl3) δ 4.00 (qd, J = 4.0, 2.1 Hz, 4H), 1.33 – 1.22 (m, 12H). 13C NMR (126 MHz, CDCl3) δ 80.3, 20.9. 11 B NMR (160 MHz, CDCl3) δ 30.5. GC-MS (EI) m/z calcd for C8H16B2O4 [M] 198.1, found: 198.1 2.4.3. Synthesis of ortho, meta and Para Bpg-borylated aniline by transesterification Synthesis of ortho borylated aniline with a Bpg group by transesterification (2.1) 2-Aminophenyl boronic acid (274 mg, 2 mmol, 1 equiv), 1,2-propandiol (517 mg, 6.8 mmol, 3.4 equiv), Mg2SO4 anhydrous (100 mg) and THF (1.6 mL) were placed in a round bottom flask and stirred overnight at room temperature. After 12 h, the mixture was concentrated and purified by column chromatography with silica gel (hexane: ethyl acetate = 4: 1 as eluent) to remove the excess of diol. The fractions containing product were collected and concentrated to give 56 mg of 2.1 as a colorless oil (16% yield). 1 H NMR (500 MHz, CDCl3) δ 7.62 (dd, J = 7.5, 1.7 Hz, 1H), 7.23 (ddd, J = 8.2, 7.2, 1.7 Hz, 1H), 6.69 (td, J = 7.3, 1.0 Hz, 1H), 6.61 (dd, J = 8.2 Hz, 0.9 Hz, 1H), 4.84-4.53 (m, 3H), 4.44 (dd, J = 36 11 8.8, 7.6 Hz, 1H), 3.88 (dd, J = 8.8, 7.2 Hz, 1H), 1.41 (d, J = 6.2 Hz, 3H). B NMR (160 MHz, CDCl3) δ 31.4. HRMS (ESI) m/z calcd for C9H13BNO2 [M+H]+ 178.1039, found: 178.1043. Synthesis of meta borylated aniline with a Bpg group by transesterification 3-Aminophenyl boronic acid (274 mg, 2 mmol, 1 equiv), 1,2-propandiol (517 mg, 6.8 mmol, 3.4 equiv) and THF (1.6 mL) were placed in a round bottom flask and stirred overnight at room temperature. After 12 h, the mixture was concentrated and purified by column chromatography with silica gel (hexane: ethyl acetate = 3: 2 as eluent) to remove the excess of diol. The fractions containing product were collected and concentrated to give 300 mg of the product as a colorless oil (85% yield). 1 H NMR (500 MHz, CDCl3): δ 7.25 – 7.17 (m, 2H), 7.15 (dd, J = 2.6, 0.9 Hz, 1H), 6.81 (ddd, J = 7.6, 2.6, 1.5 Hz, 1H), 4.71 (ddt, J = 13.7, 7.5, 6.2 Hz, 1H), 4.44 (dd, J = 8.8, 7.7 Hz, 1H), 3.88 (dd, J = 8.8, 7.2 Hz, 1H), 3.66 (s, 2H), 1.41 (d, J = 6.2 Hz, 3H). 13C NMR (126 MHz, CDCl3) δ 145.82, 11 128.84, 124.99, 121.16, 118.18, 73.71, 72.50, 21.80. B NMR (160 MHz, CDCl3) δ 31.44. Synthesis of para borylated aniline with a Bpg group by transesterification 4-Aminophenyl boronic acid hydrochloride (347 mg, 2 mmol, 1 equiv) was fractionated between ethyl acetate and NaOH 0.01 M. The organic phase was evaporated and 1,2-propandiol (517 mg, 6.8 mmol, 3.4 equiv), THF (1.6 mL) were added. The reaction mixture was stirred 37 overnight at room temperature. After 12 h, the mixture was concentrated and purified by column chromatography with silica gel (hexane: ethyl acetate = 3: 2 as eluent) to remove the excess of diol. The fractions containing product were collected and concentrated to give 160 mg of the product as a light brown solid (45% yield). 1 H NMR (500 MHz, CDCl3) δ 7.66 – 7.59 (m, 2H), 6.73 – 6.64 (m, 2H), 4.68 (ddt, J = 13.7, 7.4, 6.3 Hz, 1H), 4.41 (dd, J = 8.8, 7.6 Hz, 1H), 3.85 (dd, J = 8.8, 7.2 Hz, 3H), 1.40 (d, J = 6.2 Hz, 3H). 11 13 C NMR (126 MHz, CDCl3) δ 149.38, 136.43, 114.15, 73.45, 72.35, 21.77. B NMR (160 MHz, CDCl3) δ 31.38. HRMS (ESI) m/z calcd for C9H13BNO2 [M+H]+ 178.1039, found: 178.1039. 2.4.4. Synthesis of ortho borylated acetamide with a Bpg group by transesterification (2.3) In a 20 mL vial, 2.1 (177 mg, 1 mmol, 1 equiv) was stirred with acetic anhydride (0.15 mL, 1.6 mmol, 1.6 equiv) in DCM (2.7 mL) at room temperature. After 2 h, the mixture was concentrated under reduce pressure and diethyl ether was added to crashed out a solid. The white solid was filtrate to yield 197 mg of 2.3 (90% yield, mp 192.5-194.5 °C) 1 H NMR (500 MHz, CDCl3) δ 12.39 (bs, 1H), 7.59 (dd, J = 6.9, 2.0 Hz, 1H), 7.17 (m, 2H), 6.96 (d, J = 7.5 Hz, 1H), 4.52 (dq, J = 12.2, 6.1 Hz, 1H), 4.27 (dd, J = 8.3, 6.1 Hz, 1H), 3.70 (t, J = 7.9 Hz, 1H), 1.64 (s, 3H), 1.34 (d, J = 6.1 Hz, 3H). 13C NMR (126 MHz, CDCl3) δ 169.6, 137.9, 133.2, 128.6, 126.6, 116.1, 71.7, 71.5, 21.1, 20.6. 11B NMR (160 MHz, CDCl3) δ 10.4. 38 2.4.5. CHB of anilines with B2bg2 as diboron partner Borylation of aniline with B2bg2 (2.4) In a nitrogen filled glove box, a 5.0 mL conical vial was charged with [Ir(cod)(OMe)]2 (10 mg, 1.5 mol %), dtbpy (8 mg, 3.0 mol %), B2bg2 (495 mg, 2.5 mmol, 2.5 equiv), aniline (93 mg, 1.0 mmol, 1 equiv) and Et3N (0.04 mL, 0.25 mmol, 0.25 equiv) in dry THF (3.0 mL). The vial was capped with a teflon pressure cap, taken out of the glove box and stirred into a pre-heated aluminum block at 80 ºC. After 24 h, the mixture was concentrated under reduced pressure and purified by gradient column chromatography with silica gel (hexane/ethyl acetate 10:90 → hexane/ ethyl acetate 30:70). The fractions containing product were collected to yield 103 mg of 2.4 as a thick oil (54% yield). 1 H NMR (500 MHz, CDCl3) δ 7.62 (dd, J = 7.5, 1.7 Hz, 1H), 7.23 (ddd, J = 8.2, 7.2, 1.7 Hz, 1H), 6.69 (ddd, J = 7.2, 7.5, 1.0 Hz, 1H), 6.61 (dd, J = 8.2, 1.0 Hz, 1H), 4.71 (bs, 2H), 4.52 (dtd, J = 7.8, 6.9, 5.8 Hz, 1H), 4.40 (dd, J = 8.8, 7.8 Hz, 1H), 3.95 (dd, J = 8.8, 6.9 Hz, 1H), 1.80 – 1.61 (m, 2H), 1.01 (t, J = 7.4 Hz, 3H). 13C NMR (126 MHz, CDCl3) δ 153.7, 137.0, 133.0, 117.1, 115.0, 78.5, 70.5, 29.1, 9.3. 11B NMR (160 MHz, CDCl3) δ 31.5. Borylation of 4-chloroaniline with B2bg2 (2.5) 39 In a nitrogen filled glove box, a 5.0 mL conical vial was charged with [Ir(cod)(OMe)]2 (10 mg, 1.5 mol %), dtbpy (8 mg, 3.0 mol %), B2bg2 (495 mg, 2.5 mmol, 2.5 equiv), 4-chloroaniline (127 mg, 1.0 mmol, 1 equiv) and Et3N (0.04 mL, 0.25 mmol, 0.25 equiv) in dry THF (3.0 mL). The vial was capped with a teflon pressure cap, taken out of the glove box and stirred into a pre- heated aluminum block at 80 ºC. After 17 h, the mixture was concentrated under reduced pressure and purified by gradient column chromatography with silica gel (hexane/ethyl acetate 10:90 → hexane/ ethyl acetate 20:80). The fractions containing product were collected to yield 131 mg of 2.5 as a thick oil (58% yield). 1 H NMR (500 MHz, CDCl3) δ 7.55 (d, J = 2.6 Hz, 1H), 7.15 (dd, J = 8.6, 2.6 Hz, 1H), 6.54 (d, J = 8.6 Hz, 1H), 4.71 (bs, 2H), 4.52 (dtd, J = 7.8, 7.0, 5.7 Hz, 1H), 4.41 (dd, J = 8.9, 7.8 Hz, 1H), 3.95 (dd, J = 8.9, 7.0 Hz, 1H), 1.78 – 1.61 (m, 2H), 1.01 (t, J = 7.4 Hz, 3H). 13C NMR (126 MHz, CDCl3) δ 152.1, 136.0, 132.8, 121.8, 116.4, 78.7, 70.7, 29.0, 9.3. 11B NMR (160 MHz, CDCl3) δ 31.1. Borylation of 4-bromoaniline with B2bg2 (2.6) In a nitrogen filled glove box, a 5.0 mL conical vial was charged with [Ir(cod)(OMe)]2 (10 mg, 1.5 mol %), dtbpy (8 mg, 3.0 mol %), B2bg2 (495 mg, 2.5 mmol, 2.5 equiv), 4-bromoaniline (172 mg, 1.0 mmol, 1 equiv) and Et3N (0.04 mL, 0.25 mmol, 0.25 equiv) in dry THF (3.0 mL). The vial was capped with a teflon pressure cap, taken out of the glove box and stirred into a pre- heated aluminum block at 80 ºC. After 13 h, the mixture was concentrated under reduced pressure 40 and purified by gradient column chromatography with silica gel (hexane/ethyl acetate 10:90 → hexane/ ethyl acetate 20:80). The fractions containing product were collected to yield 183 mg of 2.6 as a thick oil (68% yield). 1 H NMR (500 MHz, CDCl3) δ 7.69 (d, J = 2.5 Hz, 1H), 7.28 (dd, J = 8.6, 2.5 Hz, 1H), 6.49 (d, J = 8.6 Hz, 1H), 4.72 (bs, 2H), 4.52 (dtd, J = 7.8, 7.0, 5.7 Hz, 1H), 4.41 (dd, J = 8.9, 7.8 Hz, 1H), 3.95 (dd, J = 8.9, 7.0 Hz, 1H), 1.80 – 1.61 (m, 2H), 1.01 (t, J = 7.4 Hz, 3H). 13C NMR (126 MHz, CDCl3) δ 152.5, 139.0, 135.6, 116.9, 108.9, 78.7, 70.7, 29.0, 9.3. 11B NMR (160 MHz, CDCl3) δ 31.0. Borylation of 4-iodoaniline with B2bg2 (2.7) In a nitrogen filled glove box, a 5.0 mL conical vial was charged with [Ir(cod)(OMe)]2 (10 mg, 1.5 mol %), dtbpy (8 mg, 3.0 mol %), B2bg2 (495 mg, 2.5 mmol, 2.5 equiv), 4-iodoaniline (219 mg, 1.0 mmol, 1 equiv) and Et3N (0.04 mL, 0.25 mmol, 0.25 equiv) in dry THF (3.0 mL). The vial was capped with a teflon pressure cap, taken out of the glove box and stirred into a pre- heated aluminum block at 80 ºC. After 24 h, the mixture was concentrated under reduced pressure and purified by gradient column chromatography with silica gel (hexane/ethyl acetate 10:90 → hexane/ ethyl acetate 30:70). The fractions containing product were collected to yield 158 mg of 2.7 as a thick oil (50% yield). 1 H NMR (500 MHz, CDCl3) δ 7.86 (d, J = 2.3 Hz, 1H), 7.44 (dd, J = 8.5, 2.3 Hz, 1H), 6.41 (d, J = 8.5 Hz, 1H), 4.51 (ddd, J = 7.8, 7.0, 5.7 Hz, 1H), 4.40 (dd, J = 8.9, 7.8 Hz, 1H), 4.18 (bs, 1H), 3.94 (dd, J = 8.9, 7.0 Hz, 1H), 1.80 – 1.60 (m, 2H), 1.01 (t, J = 7.4 Hz, 3H). 13C NMR (126 MHz, 41 CDCl3) δ 153.0, 145.1, 141.2, 138.0, 117.4, 78.7, 70.7, 29.0, 9.3. 11B NMR (160 MHz, CDCl3) δ 30.7. 42 APPENDIX 43 1 H NMR of racemic B2pg2 (CDCl3, 500 MHz) 44 13 C NMR of racemic B2pg2 (CDCl3, 126 MHz) 45 11 B NMR of racemic B2pg2 (CDCl3, 160 MHz) 46 1 H NMR of (S)-B2pg2 (CDCl3, 500 MHz) 47 13 C NMR of (S)-B2pg2 (CDCl3, 126 MHz) 48 11 B NMR of (S)-B2pg2 (CDCl3, 160 MHz) 49 1 H NMR of B2bg2 (CDCl3, 500 MHz) 50 13 C NMR of B2bg2 (CDCl3, 126 MHz) 51 11 B NMR of B2bg2 (CDCl3, 160 MHz) 52 1 H NMR of B2mpg2 (CDCl3, 500 MHz) 53 13 C NMR of B2mpg2 (CDCl3, 126 MHz) 54 11 B NMR of B2mpg2 (CDCl3, 160 MHz) 55 1 H NMR of B2((2R,3R)bg)2 (CDCl3, 500 MHz) 56 13 C NMR of B2((2R,3R)bg)2 (CDCl3, 126 MHz) 57 11 B NMR of B2((2R,3R)bg)2 (CDCl3, 160 MHz) 58 1 H NMR of ortho Bpg-borylated aniline (2.1) (CDCl3, 500 MHz) 59 11 B NMR of ortho Bpg-borylated aniline (2.1) (CDCl3, 160 MHz) 60 1 H NMR of meta Bpg-borylated aniline (CDCl3, 500 MHz) 61 13 C NMR of meta Bpg-borylated aniline (CDCl3, 126 MHz) 62 11 B NMR of meta Bpg-borylated aniline (CDCl3, 160 MHz) 63 1 H NMR of Para Bpg-borylated aniline (CDCl3, 500 MHz) 64 13 C NMR of Para Bpg-borylated aniline (CDCl3, 126 MHz) 65 11 B NMR of Para Bpg-borylated aniline (CDCl3, 160 MHz) 66 1 H NMR of ortho Bpg-borylated phenylacetamide (2.3) (CDCl3, 500 MHz) 67 13 C NMR of ortho Bpg-borylated phenylacetamide (2.3) (CDCl3, 160 MHz) 68 11 B NMR of ortho Bpg-borylated phenylacetamide (2.3) (CDCl3, 126 MHz) 69 1 H NMR of ortho Bbg-borylated aniline (2.4) (CDCl3, 500 MHz) 70 13 C NMR of ortho Bbg-borylated aniline (2.4) (CDCl3, 160 MHz) 71 11 B NMR of ortho Bbg-borylated aniline (2.4) (CDCl3, 126 MHz) 72 1 H NMR of ortho Bbg-borylated 4-chloroaniline (2.5) (CDCl3, 500 MHz) 73 13 C NMR of ortho Bbg-borylated 4-chloroaniline (2.5) (CDCl3, 160 MHz) 74 11 B NMR of ortho Bbg-borylated 4-chloroaniline (2.5) (CDCl3, 126 MHz) 75 1 H NMR of ortho Bbg-borylated 4-bromoaniline (2.6) (CDCl3, 500 MHz) 76 13 C NMR of ortho Bbg-borylated 4-bromoaniline (2.6) (CDCl3, 160 MHz) 77 11 B NMR of ortho Bbg-borylated 4-bromoaniline (2.6) (CDCl3, 126 MHz) 78 1 H NMR of ortho Bbg-borylated 4-iodoaniline (2.7) (CDCl3, 500 MHz) 79 13 C NMR of ortho Bbg-borylated 4-iodoaniline (2.7) (CDCl3, 160 MHz) 80 11 B NMR of ortho Bbg-borylated 4-iodoaniline (2.7) (CDCl3, 126 MHz) 81 REFERENCES 82 REFERENCES (1) The Chemistry of Anilines, 1st ed.; Rappoport, Z., Ed.; PATAI’S Chemistry of Functional Groups; Wiley-Blackwell: Hoboken, NJ, 2007. (2) Vollhardt, K.; Shen, H. Remarkable Switch in the Regiochemistry of the Iodination of Anilines by N-Iodosuccinimide: Synthesis of 1,2-Dichloro-3,4-Diiodobenzene. Synlett 2012, 2012, 208–214. (3) Chen, Z.; Wang, B.; Zhang, J.; Yu, W.; Liu, Z.; Zhang, Y. Transition Metal-Catalyzed C–H Bond Functionalizations by the Use of Diverse Directing Groups. Org. Chem. Front. 2015, 2, 1107–1295. (4) Tischler, M. O.; Tóth, M. B.; Novák, Z. Mild Palladium Catalyzed Ortho C-H Bond Functionalizations of Aniline Derivatives. Chem. Rec. 2017, 17, 184–199. (5) Boronic Acids, 2nd ed.; Hall, D. G., Ed.; Wiley-VCH Verlag: Weinheim, Germany, 2012. (6) Zhu, C.; Falck, J. R. Transition-Metal-Free Ipso-Functionalization of Arylboronic Acids and Derivatives. Adv. Synth. Catal. 2014, 356, 2395–2410. (7) Boebel, T. A.; Hartwig, J. F. Silyl-Directed, Iridium-Catalyzed Ortho-Borylation of Arenes. A One-Pot Ortho-Borylation of Phenols, Arylamines, and Alkylarenes. J. Am. Chem. Soc. 2008, 130, 7534–7535. (8) Li, H.-L.; Kanai, M.; Kuninobu, Y. Iridium/Bipyridine-Catalyzed Ortho-Selective C-H Borylation of Phenol and Aniline Derivatives. Org. Lett. 2017, 19, 5944–5947. (9) Roosen, P. C.; Kallepalli, V. A.; Chattopadhyay, B.; Singleton, D. A.; Maleczka, R. E., Jr; Smith, M. R., III. Outer-Sphere Direction in Iridium C-H Borylation. J. Am. Chem. Soc. 2012, 134, 11350–11353. (10) Xiao, B.; Li, Y.-M.; Liu, Z.-J.; Yang, H.-Y.; Fu, Y. Palladium-Catalyzed Monoselective C-H Borylation of Acetanilides under Acidic Conditions. Chem. Commun. 2012, 48, 4854–4856. (11) Preshlock, S. M.; Plattner, D. L.; Maligres, P. E.; Krska, S. W.; Maleczka, R. E., Jr.; Smith, M. R., III. A Traceless Directing Group for C-H Borylation. Angew. Chem. Int. Ed. 2013, 52, 12915–12919. (12) Smith, M. R., III; Bisht, R.; Haldar, C.; Pandey, G.; Dannatt, J. E.; Ghaffari, B.; Maleczka, R. E., Jr; Chattopadhyay, B. Achieving High Ortho Selectivity in Aniline C-H Borylations by Modifying Boron Substituents. ACS Catal. 2018, 8, 6216–6223. (13) Rose, S. H.; Shore, S. G. Boron Heterocycles. I. Preparation and Properties of 1,3,2- Dioxaborolane. Inorg. Chem. 1962, 1, 744–748. (14) McAchran, G. E.; Shore, S. G. Boron Heterocycles. IV. Relative Stabilities toward Disproportionation and Base-Acceptor Character of 1,3,2-Dioxaborolane and 1,3,2- Dioxaborinane. Inorg. Chem. 1966, 5, 2044–2046. 83 (15) Chattopadhyay, B.; Dannatt, J. E.; Andujar-De Sanctis, I. L.; Gore, K. A.; Maleczka, R. E., Jr; Singleton, D. A.; Smith, M. R., III Ir-Catalyzed Ortho-Borylation of Phenols Directed by Substrate-Ligand Electrostatic Interactions: A Combined Experimental/in Silico Strategy for Optimizing Weak Interactions. J. Am. Chem. Soc. 2017, 139, 7864–7871. (16) Cai, S. X.; Keana, J. F. W. O-Acetamidophenylboronate Esters Stabilized toward Hydrolysis by an Intramolecular Oxygen-Boron Interaction: Potential Linkers for Selective Bioconjugation via Vicinal Diol Moieties of Carbohydrates. Bioconjug. Chem. 1991, 2, 317– 322. (17) Uson, R.; Oro, L. A.; Cabeza, J. A.; Bryndza, H. E.; Stepro, M. P. Dinuclear Methoxy, Cyclooctadiene, and Barrelene Complexes of Rhodium(I) and Iridium(I). In Inorganic Syntheses; John Wiley & Sons, Inc.: Hoboken, NJ, USA, 2007; pp 126–130. 84 CHAPTER 3. PARA-SELECTIVE, IRIDIUM-CATALYZED C−H BORYLATIONS OF SULFATED PHENOLS, BENZYL ALCOHOLS, AND ANILINES DIRECTED BY ION-PAIR ELECTROSTATIC INTERACTIONS 3.1. Introduction For two competing pathways, a difference in barrier heights of 2.5 kcal·mol −1 is sufficient for 99% of the reactants to follow the favored pathway in a chemical reaction. This is lower than the barrier for converting the anticonformer of butane to the gauche form.1 In transition-metal mediated reactions, a classic mode for selectively functionalizing bonds in a substrate relies on the coordination of an atom in a reactant functional group to the metal center of a compound or catalytic intermediate. The magnitudes of the ligand−metal interactions are at least an order of magnitude greater than the difference in barrier heights necessary for 99:1 selectivity. Consequently, design of catalysts where selectivity is conferred by weakly coordinating groups, 2 as well as catalysts that leverage even weaker interactions (e.g., hydrogen-bonding, ion-pairing, dipole−dipole, etc.) for selective transformations, 3,4 is attracting significant attention. C−H functionalizations offer both atom and step economical means of converting ubiquitous C−H bonds to a range of functional groups. 5,6 CHB convert C−H bonds to C−B bonds and are mediated by both metal and metal-free catalysts.7–9 CHB reactions are valuable due to (i) facile substitution of the boron moiety by numerous functional groups and (ii) functional group tolerance of CHB catalysts, particularly those containing Ir. The first Ir CHB catalysts enabled C(sp2)−H functionalizations with high selectivity for the most sterically accessible C−H bonds.10–12 In substrates where multiple C−H bonds are sterically accessible, early generation catalysts often give isomer mixtures, as well as multiply borylated 85 products. To overcome these limitations, more selective Ir catalysts have been designed. The first examples were ortho-selective,13 relying on strongly coordinating functional groups in the substrate,14,15 while later reports exploited weaker interactions for ortho selectivity.16,17 By comparison, meta and para CHBs pose different challenges because their C−H bonds are farther from the functional group. One meta-selective CHB has been ascribed to a classical chelate-directed mechanism,18 while others rely on Ir ligands bearing groups that engage in noncovalent interactions with substrate functional groups to effect meta CHB.19–24 Figure 3.1 depicts approaches for para-selective CHB. The first CHBs with high para selectivity involved electrophilic additions of borenium cations to arenes bearing ortho, para- directors.25 Sterically directed CHBs rely on hindered phosphine ligands and substrates with large substituents.26,27 More recently, para borylations of esters and amides have been achieved through noncovalent interactions with K ions or coordination of the amide oxygen to hindered Lewis acids.28,29 Figure 3.1: Para C−H borylations 86 3.2. Results and Discussion 3.2.1. Unexpected Discovery Our inspiration was based on the Phipps’ group ion-pair directed CHBs with one key difference.20,22 Instead of using oppositely charged groups on the ligand and substrate, combinations where groups on the ligand and substrate had the same charge were surveyed with the expectation that para borylation would be favored because electrostatic repulsions between the ligand and substrate would be minimized. However, a control experiment where tetrabutylammonium 2-chlorophenyl sulfate (3.1a’) was subjected to standard borylation conditions with a neutral bipyridine ligand (sealed tube with B2pin2 as the boron source, 1.5 mol % [Ir(cod)OMe]2 as the precatalyst and 3 mol % dtbpy as the ligand, in THF at 80 °C) showed promising results with 6:1 para to meta regioselectivity (Figure 3.2). We hypothesized that substrate ion-pairing interactions, where the n-butyl groups of the cation shield the meta C−H bonds of the counter-anions, accounted for the para selectivity. Figure 3.2: Para C−H borylation sterically driven by ion-pair electrostatic interactions 87 3.2.2. Optimization of Conditions In Nakao’s study, ligand geometry played a key role in enhancement of the para selectivity.29 Similarly, we have observed that ligand choice can impact CHB regiochemistry where there is little steric differentiation between different arene C−H bonds. 30 Therefore, we tested commercially available substituted bipyridine and phenanthroline ligands (Scheme 3.1) in CHB reactions run at 80 °C. The reactivity of the ligands is in accordance with previously noted electronic effects,31 with electron-rich ligands affording a more active system relative to electron- poor ligands. The borylation in THF with 4,4’-dimethoxy-2,2’-bipyridine (L8) as the ligand went to >95% conversion and afforded the best para selectivity (13:1). This observation is notable in that L8 is a nontraditional CHB ligand. Switching the solvent to dioxane slightly increased the para selectivity, whereas other apolar solvents worsened regioselectivity. Scheme 3.1: Ligand effect on para CHB of 3.1a’ 88 Running the reactions at lower temperature (60 °C and 40 °C) further improved the para selectivity while still allowing for full conversion (Table 3.1). The reaction at room temperature afforded 21:1 para selectivity, but starting material remained even after 50 h. Table 3.1: Temperature effect on para CHB of 3.1’ T (°C) % conv p:m rt 83 21:1 40 100 17:1 60 100 16:1 80 100 14:1 With the experiments in Scheme 3.1 and Table 3.1 establishing 4,4’-dimethoxy-2,2’- bipyridine L8 and dioxane as our ligand and solvent of choice, we next investigated the effect of the tetraalkylammonium salt on para selectivity. DFT geometry optimization of 1a’, using the B3LYP functional and 6-31G* basis set for all the atoms in a vacuum media, places one alkyl chain of the cation parallel to the aromatic ring in support of the presence of a steric shield (Figure 3.3). Looking more in detail, we observed relative short distances between the alpha hydrogens in the alkylammonium cation with the oxygens in the sulfate (Figure 3.3a) which suggests to us an intermolecular hydrogen bond interaction. Tetraalkylammonium cations have been described as hydrogen bond donors by previous studies.32 The intermolecular hydrogen bond can help maintain the tetralkyl ammonium in the conformation needed for a steric shield during the CHB reaction. We also observed an intriguing difference between the distances of the meta Cm and para Cp carbons in the arene to carbons C3 and C4 in the cation (Figure 3.3b). C3 is closest to Cm than Cp as expect, but surprisingly C4 is closest to Cp than Cm. This led us to propose that a slightly shorter alkyl chain would still block the meta position but leave the para position more exposed, thus potentially leading to improved para selectivity. 89 Figure 3.3: Lowest energy conformation geometry of 1a’ (front and lateral view) As shown in Scheme 3.2, the CHB of tetrapropylammonium 2-chlorophenyl sulfate (3.1a) validated this hypothesis, as running the reaction with ligand L8 in dioxane at 40 °C pushed the para selectivity to 22:1. We also examined tetraethylammonium 2-chlorophenyl sulfate (3.1a’’) as a substrate. In terms of chain shortening, clearly diminishing returns had set in as the para selectivity decreased to 6:1. Based on our results, we chose to test a series of phenol derived sulfates with n-Pr4N+ as the counterion to determine substrate scope (Scheme 3.3). During the course of this project, we become aware that the Phipps group has developed a similar approach to para-selective borylation. Fortunately, our works complement each other, and we are grateful to them for agreeing to publish their results in a back-to-back fashion with our own.33,34 We focused more on a deep optimization of reaction conditions as shown above, from which we discovered the key role of the ligand and the importance of the careful design of the cation. On the other hand, Phipps group expanded the steric shielding effect driven by ion-pair electrostatic interactions to a diverse array of scaffolds although with lower selectivity than our protocol in the substrates we shared. For comparison, the selectivities obtained by the Phipps group are shown in brackets in Scheme 3.3. This lower selectivity comes mainly from the use of the standard ligand dtbpy (L2) and higher temperatures. 90 Scheme 3.2: Effect of alkyl chain length and ligand on para CHB of 2-chlorophenyl sulfates 3.2.3. Para CHB of sulfated phenols As illustrated in Scheme 3.3, borylations of a series of 2-substituted phenol derived sulfates produced the para regioisomer as the major isomer, often with >20:1 selectivity. Most isolated yields were in the 70−80% range. Notably upon isolation the para to meta isomer was enhanced, in some cases to >50:1. Ortho substituents with lone pairs favor the para selectivity (3.2a-e) which bears some relationship to previous reports of these groups favoring meta CHB;35 in our case that position is para respect to the sulfated group. The selectivity drops by half without lone pairs in the ortho substituent as exhibit by 3.2f and 3.2g. A larger ortho substituent like isopropyl in 3.1h seems to improve the selectivity by twice if its compare with 3.1g which have a smaller methyl group. 91 Scheme 3.3: Borylation of phenol derived sulfates a Para/meta ratios were measured by 1H NMR on crude reaction mixtures of the borylated sulfates. Yields refer to isolated material with the para/meta ratio of the isolated material given in parentheses (3.2o and 3.2p were not isolated). Conditions P refers to the reaction conditions employed by the Phipps group. Given that CHB ortho to small substituents is common,36 borylation at the C-3 and C-5 meta CH bonds of 2-cyano-(3.2i) and 2-fluorophenol sulfate (3.2j) are possible. Indeed, analysis of the crude reaction mixture indicated that 3.2i gave a mixture of the para to 5-Bpin to 3,5-diBpin products in a ratio of approximately 7.5:1:0.4. For substrates 3.1j and 3.1k, the observed minor 92 isomer was that with the Bpin ortho to the fluoro group and no diborylation was observed. Given this preference, it was perhaps somewhat surprising that 3-fluorophenol sulfate (3.1l) produced a relatively large amount of the meta regioisomer. In comparison, 2,3-difluorophenol sulfate (3.1m) yielded the para borylated product in relatively high selectivity (23:1). The ten-fold improvement from 3.2l to 3.2m is in accordance with the previously observed improvement of selectivity conferred by ortho substituents with lone pairs. Not surprising was that the CHB of 3-substituted phenol sulfates (3.1n−p) gave the meta isomer as the major product, showing that such ion-pair interactions are limited in their ability to overcome steric crowding of the para CH position. Last, we borylated the sulfate of phenol (3.1q) and observed the para, meta, and 3,5-dimeta Borylated products in a ratio of 4.4:1:1.8, or a para/meta ratio of 1.6:1. This result is consistent with the assumption that the ion pairing can only block one meta site and thus the reactions need a 2-substituent to sterically block the second meta CH bond. 3.2.4. Para CHB of sulfated anilines Turning to anilines (Scheme 3.4), we subjected tetrapropylammonium 2- chlorophenylsulfamate (3.3a) to our now standard conditions. The para selectivity (40:1) was even better than that observed for 3.1a. Questioning if the chain length of the tetraalkylammonium salt would also impact the para selectivity for aniline derivatives, we prepared and reacted the tetrabutylammonium salt (3.3a’). In contrast to the phenol sulfates, employing this counterion met with 43:1 para selectivity and a higher isolated yield. Owing to this result and that the tetrabutylammonium salts are somewhat easier to prepare and isolate, we chose n-Bu4N+ as the counterion for CHBs of a series of aniline sulfamates. The para selectivities for 3.3b’ and 3.3d’ were excellent, while again selectivity for a 3-fluoro substrate (3.3c’) suffered, giving only a 2.4:1 93 para/meta ratio. Isolation of the hydrolyzed aniline following borylation of 3.3c’ proved difficult. Therefore, the reaction was quenched with acetyl chloride, facilitating the isolation of 3.4c’. The Phipps group applied their protocol to 3.3a’ and 3.3b’ as well and got very good selectivity as ours even with their nonoptimal conditions. This highlights the intrinsic tendency to yield the para borylated product of phenyl sulfamates respect to phenyl sulfates. Scheme 3.4: Borylation of aniline derived sulfamates a Para/meta ratios were measured by 1H NMR (or 19F NMR for 3.4c’) on crude reaction mixtures of the borylated sulfamates. Yields refer to isolated material with the para/meta ratio of the isolated material given in parentheses. b Run with the n-Pr4N+ counterion. c Product isolated as the acetamide. 3.2.5. Para CHB of sulfated benzyl alcohols Finally, we surveyed benzyl alcohol derived sulfates and fortunately the para borylated product was observed in significant selectivities. We began by optimizing the counterion and ligand of 2-chlorobenzyl sulfate (Scheme 3.5) which again were key factors on the para CHB regioselectivity. Although having an additional methylene group in benzyl sulfates respect to phenyl sulfates, tetrapropyl ammonium cations were found to be optimal for this case as well. L3 was again the best ligand choice to reach a 18:1 selectivity. 94 Scheme 3.5: Effect of alkyl chain length and ligand on para CHB of 2-chlorobenzyl sulfate Generally, benzyl alcohol derived sulfates reacted with somewhat diminished para selectivity relative to their phenol and aniline counterparts (Scheme 3.6). Products 3.6b and 3.6d were generated in lower yields owing in part to lower conversions and, for 3.6d, loss of the meta isomer upon isolation. Again, borylation of a substrate with fluorine in the 2-position (3.5g) afforded a significant amount of product with the Bpin ortho to the fluorine. By applying the CHB conditions to the n-Bu4N+ counterion, 3.5a−3.5c revealed that the counterion has a similar influence on the regioselectivity as observed for the phenols. For comparison, the selectivities obtained by the Phipps group are shown in brackets, the lower values are due to the nonoptimized conditions used in that protocol. 95 Scheme 3.6: Borylation of benzyl alcohol derived sulfates a Para/meta ratios were measured by 1H NMR on crude reaction mixtures of the borylated sulfates. Yields refer to isolated material with the para/meta ratio of the isolated material given in parentheses. b Run with the n-Bu4N+ counterion. 3.3. Conclusions In summary, ion-pair electrostatic interactions can be used to direct Ir-catalyzed borylation to the para position of sulfates and sulfamates derived from phenols, anilines, and benzyl alcohols. We hypothesize that the source of the para selectivity is a steric block created by the carbon chain of the tetrabutylammonium counterion. For sulfates derived from phenols and benzyl alcohols, n- Pr4N+ salts gave better selectivity than their n-Bu4N+ counterparts. The chain length of 96 tetralkylammonium salt was not as influential on the borylation of the sulfamates derived from anilines. Notably, optimal results were observed with the nontraditional CHB ligand 4,4’- dimethoxy-2,2’-bipyridine. This serves to remind the community to look beyond dtbpy or tmphen when optimizing CHB reactions. 3.4. Experimental Procedures 3.4.1. General Information All commercially available chemicals were used as received unless otherwise indicated. Bis(pinacolato)diboron (B2pin2) was generously supplied by BoroPharm, Inc. Bis(η4-1,5- cyclooctadiene)-di-μ-methoxy-diiridium(I) [Ir(cod)(OMe)]2 was made by a literature procedure 37 or purchased from Sigma-Aldrich. Dioxane was refluxed over sodium/benzophenone ketyl, distilled and degassed. Column chromatography was performed on 240 - 400 mesh Silica P-Flash silica gel. Thin layer chromatography was performed on 0.25 mm thick aluminum–backed silica gel plates and visualized with ultraviolet light (λ = 254 nm) and alizarin stain to visualize boronic esters according to a literature procedure.38 1 H, 13C, 11B and 19F NMR spectra were recorded on a Varian 500 MHz DD2 Spectrometer equipped with a 1H-19F/15N-31P 5 mm Pulsed Field Gradient (PFG) Probe, or an Innova 300 MHz spectrometer equipped with a QUAD (1H/19F and 11B) PFG probe. Spectra taken in CDCl3 referenced to 7.26 ppm in 1H NMR and 77.0 ppm in 13C NMR. Spectra taken in C6D6 referenced to 7.16 ppm in 1H NMR and 128.06 ppm in 13C NMR. 11B NMR spectra were referenced to neat BF3·Et2O as the external standard. 19F NMR spectra taken in CDCl3 were referenced with C6F6 as internal standard to -161.64 ppm. 97 Resonances for the boron-bearing carbon atom were not observed due to quadrupolar relaxation. All coupling constants are apparent J values measured at the indicated field strengths in Hertz (s = singlet, d = doublet, t = triplet, q = quartet, dd = doublet of doublets, ddd = doublet of doublet of doublets, bs = broad singlet). NMR spectra were processed for display using the MNova software program with only phasing and baseline corrections applied. High-resolution mass spectra (HRMS) were obtained at the Michigan State University Mass Spectrometry Service Center using electrospray ionization (ESI+ or ESI-) on quadrupole time-of-flight (Q-TOF) instruments. Melting points were measured in a capillary melting point apparatus and are uncorrected. 3.4.2. Determining Product Ratios by NMR Integration Product ratios were determined by integration of 1H or 19 F NMR spectra. To verify the accuracy of the 1H NMR integration, stock solutions of commercial samples of 3-chloro-4- hydroxyphenylBpin (meta borylated 3.2a) and 4-chloro-3-hydroxyphenylBpin (para borylated 3.2a) were accurately mixed in known amounts with Hamilton gas-tight micro syringes. The ratio determined by integration was compared to the known ratio. All 1H NMR spectra were taken at 500 MHz with 32 scans and a delay of 10 seconds. All spectra were processed in MNova software with application of an auto-phase correction and a Bernstein polynomial fit baseline correction, followed by manual peak integration. Two 0.196 M stock solutions of 3-chloro-4-hydroxyphenylBpin (meta borylated 3.2a) and 4-chloro-3-hydroxyphenylBpin (para borylated 3.2a) were prepared as follows: A mass of 50.0 mg of commercial 3-chloro-4-hydroxyphenylBpin (meta-3.2a) was dissolved in CDCl3 in a 1.0 mL volumetric flask and CDCl3 was added up to the mark. A mass of 100.0 mg of commercial 4- 98 chloro-3-hydroxyphenylBpin (para-3.2a) was dissolved in CDCl3 in a 2.0 mL volumetric flask and CDCl3 was added up to the mark. A volume of 6 µL of meta-3.2a stock solution was diluted with CDCl3 to 1.0 mL in a 1.0 mL volumetric flask, resulting in a 1.18 x 10-3 M solution. A volume of 600 µL of this solution was transferred into an NMR tube, making 7.0 x 10-7 mols of the meta-3.2a compound present in the sample. A 1H NMR spectrum was taken. Meta-3.2a was clearly observed and all peaks integrated properly, with the data as follows: 1H NMR (500 MHz, CDCl3) δ 7.43 (d, J = 1.2 Hz, 1H), 7.34 – 7.27 (m, 2H), 5.47 (s, 1H), 1.33 (s, 12H). The 1H data for the commercial sample of para-3.2a was as follows: 1H NMR (500 MHz, CDCl3) δ 7.77 (d, J = 1.5 Hz, 1H), 7.62 (dd, J = 8.1, 1.5 Hz, 1H), 7.01 (d, J = 8.1 Hz, 1H), 5.75 (s, 1H), 1.33 (s, 12H). A sequence of additions of 50 microliters of para-3.2a stock solution was added directly into the NMR tube and NMR spectra were taken after each addition. For each 50 microliters of stock solution added, 9.8 x 10-6 mols of para compound was introduced into the NMR tube. This was repeated 4 times for a total of 3.92 x 10-5 mols para-3.2a compound to 7.0 x 10-7 mols of meta- 3.2a compound, a 56-fold excess of para-3.2a compound. The integration of the peak at 7.43 ppm of the meta-3.2a compound was compared to the integration of the peak at 7.77 ppm of the para- 3.2a compound for all determinations of para:meta ratio. The results are shown in Table 3.2. All NMR spectra are shown in the Appendix section. Table 3.2: Integration of known ratios of para-2a to meta-2a calculated integrated entry mols para-2a mols meta-2a para:meta ratio para:meta ratio 1 0 7.0 x 10-7 -- -- 2 9.8 x 10-6 7.0 x 10-7 14:1 14.10:1.00 3 1.96 x 10-5 7.0 x 10-7 28:1 27.26:1.00 4 2.94 x 10-5 7.0 x 10-7 42:1 44.19:1.00 5 3.92 x 10-5 7.0 x 10-7 56:1 54.68:1.00 99 3.4.3. Preparation of Sulfated Phenols Synthesis of tetrabutylammonium 2-chlorophenyl sulfate (3.1a′) 2-Chlorophenol (3.21 g, 25 mmol) and SO3•pyridine complex (4.39 g, 27.5 mmol) were placed in a 100 mL round bottom flask. Pyridine (33 mL) and dry dichloromethane (20 mL) were added and the mixture was stirred at rt for 18 h. After this time, the reaction was heated to 40 ºC for 1 h. Water (300 mL) was added and the mixture was washed once with dichloromethane (1 x 300 mL). The aqueous phase was treated with tetrabutylammonium hydrogensulfate (8.45 g, 25 mmol) and stirred for 1 h. The solution was extracted with dichloromethane (3 x 300 mL). The organic layer was dried over MgSO4, filtered, and concentrated, resulting in a clear oil. To the concentrated oil, hexanes were added and the suspension was again concentrated by rotary evaporation. This process was repeated until the product was obtained as a white solid. After overnight drying under high vacuum 3.1a′ (6.56 g, 58% yield) was isolated as a white solid. 1 H NMR (500 MHz, CDCl3) δ 7.78 (dd, J = 7.9, 1.5 Hz, 1H), 7.29 (dd, J = 7.9, 1.6 Hz, 1H), 7.15 (td, J = 7.9, 1.6 Hz, 1H), 6.95 (td, J = 7.9, 1.5 Hz, 1H), 3.23–3.01 (m, 8H), 1.64–1.45 (m, 8H), 1.35 (m, 8H), 0.93 (t, J = 7.3 Hz, 12H). 13 C NMR (126 MHz, CDCl3) δ 149.8, 129.7, 127.3, 125.3, 123.8, 122.1, 58.4, 23.8, 19.6, 13.7. HRMS (ESI) m/z calc for C6H4ClO4S [M–Nn-Bu4]– 206.9519, found 206.9722. 100 Synthesis of tetrapropylammonium 2-chlorophenyl sulfate (3.1a) 2-Chlorophenol (0.964 g, 7.5 mmol) and SO3•pyridine complex (1.31 g, 8.2 mmol) were placed in a 100 mL round bottom flask. Pyridine (10 mL) and dry dichloromethane (6 mL) were added and the mixture was stirred at rt for 18 h. After this time, the reaction was heated to 40 ºC for 1 h. Water (90 mL) was added and the mixture was washed once with dichloromethane (1 x 90 mL). The aqueous phase was treated with tetrapropyl ammonium hydrogensulfate (2.12 g, 7.5 mmol) and stirred for 1 h. The solution was extracted with dichloromethane (3 x 90 mL). The organic layer was dried over MgSO4, filtered, and concentrated, resulting in a clear oil. To the concentrated oil, hexanes were added and the suspension was again concentrated by rotary evaporation. This process was repeated until the product was obtained as a white solid. After overnight drying under high vacuum (3.1a) was obtained as a white solid (1.53 g, 52% yield). 1 H NMR (500 MHz, CDCl3) δ 7.74 (dd, J = 8.0, 1.5 Hz, 1H), 7.29 (dd, J = 7.8, 1.7 Hz, 1H), 7.15 (td, J = 8.0, 1.7 Hz, 1H), 6.95 (td, J = 7.8, 1.5 Hz, 1H), 3.15–3.01 (m, 8H), 1.59 (m, J = 17.0, 7.3 Hz, 8H), 0.91 (t, J = 7.3 Hz, 12H). 13 C NMR (126 MHz, CDCl3) δ 149.8, 129.8, 127.4, 125.5, 124.0, 122.3, 60.3, 15.6, 10.8. HRMS (ESI) m/z calc for C6H4ClO4S [M–Nn-Bu4]– 206.9519, found 206.9505. Synthesis of tetraethylammonium 2-chlorophenyl sulfate (3.1a′′) 101 2-Chlorophenol (1.54 g, 12 mmol) and SO3•pyridine complex (2.1 g, 12.2 mmol) were placed in a 100 mL round bottom flask. Pyridine (16 mL) and dry dichloromethane (10 mL) were added and the mixture was stirred at rt for 18 h. After this time, the reaction was heated to 40 ºC for 1 h. Water (140 mL) was added and the mixture was washed once with dichloromethane (1 x 140 mL). The aqueous phase was treated with tetraethyl ammonium hydrogensulfate (2.73 g, 12 mmol) and stirred for 1 h. The solution was extracted with dichloromethane (3 x 70 mL). The organic layer was dried over MgSO4, filtered, and concentrated. The concentrated oil was dissolved in dichloromethane (50 mL) and washed once with 0.1 M NaOH aq. (1 x 50 mL). The organic layer was dried over MgSO4, filtered, and concentrated, resulting in a clear oil. To the concentrated oil, hexanes and ether were added and the suspension was concentrated by rotary evaporation. This hexane/ether process was repeated until the product was obtained as a white solid. After overnight drying under high vacuum (3.1a”) was obtained as a white solid (216 mg, 5% yield). 1 H NMR (500 MHz, CDCl3) δ 7.72 (dd, J = 8.0, 1.5 Hz, 1H), 7.32 (dd, J = 8.0, 1.6 Hz, 1H), 7.18 (td, J = 8.0, 1.6 Hz, 1H), 7.00 (td, J = 8.0, 1.5 Hz, 1H), 3.21 (q, J = 7.3 Hz, 8H), 1.21 (t, J = 7.3, 12H). 13C NMR (126 MHz, CDCl3) δ 149.6, 129.9, 127.5, 125.7, 124.4, 122.4, 52.4, 7.5. HRMS (ESI) m/z calcd for C6H4ClO4S [M–NEt4]– 206.9519, found 206.8556. Synthesis of tetrapropylammonium 2-bromophenyl sulfate (3.1b) 2-Bromophenol (1.038 g, 6 mmol) and SO3•pyridine complex (1.05 g, 6.6 mmol) were placed in a 100 mL round bottom flask. Pyridine (8 mL) and dry dichloromethane (5 mL) were 102 added and the mixture was stirred at rt for 18 h. After this time, the reaction was heated to 40 ºC for 1 h. Water (70 mL) was added and the mixture was washed once with dichloromethane (1 x 70 mL). The aqueous phase was treated with tetrapropyl ammonium bromide (1.60 g, 6 mmol) and stirred for 1 h. The solution was extracted with dichloromethane (3 x 70 mL). The organic layer was dried over MgSO4, filtered, and concentrated, resulting in a clear oil. To the concentrated oil, hexanes were added and the suspension was concentrated by rotary evaporation. This process was repeated the product was obtained as a white solid. After overnight drying under high vacuum (3.1b) was obtained as a white solid (1.31 g, 50% yield). 1 H NMR (500 MHz, CDCl3) δ 7.68 (dd, J = 8.3, 1.5 Hz, 1H), 7.41 (dd, J = 8.0, 1.6 Hz, 1H), 7.14 (ddd, J = 8.3, 8.0, 1.6 Hz, 1H), 6.84 (td, J = 8.0, 1.5 Hz, 1H), 3.11–2.82 (m, 8H), 1.52 (m, 8H), 0.84 (t, J = 7.4 Hz, 12H). 13C NMR (126 MHz, CDCl3) δ 150.6, 132.7, 128.0, 124.3, 121.8, 114.6, 60.0, 15.4, 10.6. HRMS (ESI) m/z calcd for C6H4BrO4S [M–Nn-Pr4]– 250.9014, found 250.9032. Synthesis of tetrapropylammonium 2-iodophenyl sulfate (3.1c) 2-Iodophenol (1.32 g, 6 mmol) and SO3•pyridine complex (1.05 g, 6.6 mmol) were placed in a 100 mL round bottom flask. Pyridine (8 mL) and dry dichloromethane (5 mL) were added and the mixture was stirred at rt for 18 h. After this time, the reaction was heated to 40 ºC for 1 h. Water (70 mL) was added and the mixture was washed once with dichloromethane (1 x 70 mL). The aqueous phase was treated with tetrapropyl ammonium bromide (1.60 g, 6 mmol) and stirred for 1 h. The solution was extracted with dichloromethane (3 x 70 mL). The organic layer was dried over MgSO4, filtered, and concentrated, resulting in a clear oil. To the concentrated oil, hexanes 103 and ether were added and the suspension was again concentrated by rotary evaporation. This process was repeated until the product was obtained as a white solid. After overnight drying under high vacuum (3.1c) was obtained as a white solid (1.51 g, 52% yield). 1 H NMR (500 MHz, CDCl3) 7.63 (m, 2H), 7.15 (ddd, J = 8.6, 7.3, 1.6 Hz, 1H), 6.68 (td, J = 7.6, 13 1.5 Hz, 1H), 3.10–2.90 (m, 8H), 1.60–1.40 (m, 8H), 0.83 (t, J = 7.3 Hz, 12H). C NMR (126 MHz, CDCl3) δ 153.4, 138.9, 129.1, 124.8, 120.8, 89.5, 60.2, 15.5, 10.8. HRMS (ESI) m/z calcd. for C6H4IO4S [M–Nn-Pr4]– 298.8875, found 298.8890. Synthesis of tetrapropylammonium 2-(trifluoromethoxy)phenyl sulfate (3.1d) 2-(Trifluoromethoxy)phenol (1.07 g, 6 mmol) and SO3•pyridine complex (1.05 g, 6.6 mmol) were placed in a 100 mL round bottom flask. Pyridine (8 mL) and dry dichloromethane (5 mL) were added and the mixture was stirred at rt for 18 h. After this time, the reaction was heated to 40 ºC for 1 h. Water (70 mL) was added and the mixture was washed once with dichloromethane (1 x 70 mL). The aqueous phase was treated with tetrapropyl ammonium bromide (1.60 g, 6 mmol) and stirred for 1 h. The solution was extracted with dichloromethane (3 x 70 mL). The organic layer was dried over MgSO4, filtered, and concentrated, resulting in a clear oil. To the concentrated oil, hexanes and ether were added and the suspension was again concentrated by rotary evaporation. This process was repeated until the product was obtained as a white solid. After overnight drying under high vacuum (3.1d) was obtained as a white solid (1.09 g, 41% yield). 1 H NMR (500 MHz, CDCl3) δ 7.81 (dd, J = 8.2, 1.6 Hz, 1H), 7.23 – 7.10 (m, 2H), 7.00 (t, J = 7.1 Hz, 1H), 3.27 – 2.89 (m, 8H), 1.85 – 1.40 (m, 8H), 0.90 (t, J = 7.3 Hz, 12H). 13C NMR (126 MHz, 104 CDCl3) δ 146.0, 139.7, 127.4, 123.4, 122.5, 122.0, 120.7 (q, J = 257 Hz), 60.3, 15.5, 10.6. 19 F NMR (470 MHz, CDCl3) δ -57.3. HRMS (ESI) m/z calcd. for C7H4F3O5S [M–Nn-Pr4]– 256.9732, found 256.9768. Synthesis of tetrapropylammonium 2-methoxyphenyl sulfate (3.1e) 2-Methoxyphenol (0.74 g, 6 mmol) and SO3•pyridine complex (1.05 g, 6.6 mmol) were placed in a 100 mL round bottom flask. Pyridine (8 mL) and dry dichloromethane (5 mL) were added and the mixture was stirred at rt for 18 h. After this time, the reaction was heated to 40 ºC for 1 h. Water (70 mL) was added and the mixture was washed once with dichloromethane (1 x 70 mL). The aqueous phase was treated with tetrapropyl ammonium bromide (1.60 g, 6 mmol) and stirred for 1 h. The solution was extracted with dichloromethane (3 x 70 mL). The organic layer was dried over MgSO4, filtered, and concentrated, resulting in a clear oil. To the concentrated oil, hexanes and ether were added and the suspension was again concentrated by rotary evaporation. This process was repeated until the product was obtained as a white solid. After overnight drying under high vacuum (3.1e) was obtained as a white solid (1.08 g, 46% yield). 1 H NMR (500 MHz, CDCl3) δ 7.64 (dd, J = 8.0, 1.6 Hz, 1H), 6.97 (ddd, J = 8.0, 7.3, 1.6 Hz, 1H), 6.87 – 6.80 (m, 2H), 3.79 (s, 3H), 3.26 – 3.04 (m, 8H), 1.68 – 1.46 (m, 8H), 0.92 (t, J = 7.3 Hz, 12H). 13C NMR (126 MHz, CDCl3) δ 151.3, 143.1, 123.9, 122.0, 120.7, 113.1, 60.3, 56.4, 15.6, 10.8. HRMS (ESI) m/z calcd. for C7H7O5S [M–Nn-Pr4]– 203.0014, found 203.0053. 105 Synthesis of tetrapropylammonium 2-(trifluoromethyl)phenyl sulfate (3.1f) 2-(Trifluoromethyl)phenol (0.973 g, 6 mmol) and SO3•pyridine complex (1.05 g, 6.6 mmol) were placed in a 100 mL round bottom flask. Pyridine (8 mL) and dry dichloromethane (5 mL) were added and the mixture was stirred at rt for 18 h. After this time, the reaction was heated to 40 ºC for 1 h. Water (70 mL) was added and the mixture was washed once with dichloromethane (1 x 70 mL). The aqueous phase was treated with tetrapropyl ammonium bromide (1.60 g, 6 mmol) and stirred for 1 h. The solution was extracted with dichloromethane (3 x 70 mL). The organic layer was dried over MgSO4, filtered, and concentrated, resulting in a clear oil. To the concentrated oil, hexanes and ether were added and the suspension was again concentrated by rotary evaporation. This process was repeated until the product was obtained as a white solid. After overnight drying under high vacuum (3.1f) was obtained as a white solid (0.991 g, 39% yield). 1 H NMR (500 MHz, CDCl3) δ 7.90 (d, J = 8 Hz, 1H), 7.46 (dd, J = 7.6, 1.6 Hz, 1H), 7.39 (td, J = 8.0, 1.6 Hz, 1H), 7.02 (t, J = 7.6 Hz, 1H), 3.13–2.93 (m, 8H), 1.67–1.45 (m, 8H), 0.85 (t, J = 7.4 Hz, 12H). 13C NMR (126 MHz, CDCl3) δ 151.9 (q, J = 1.8 Hz), 132.8 (s), 126.2 (q, J = 5.0 Hz), 123.5 (q, J = 272.4 Hz), 122.2 (s), 120.7 (s), 120.4 (q, J = 30.6 Hz), 60.1, 15.4, 10.5. 19F NMR (470 MHz, CDCl3) δ –60.9. HRMS (ESI) m/z calcd. for C7H4F3O4S [M–Nn-Pr4]– 240.9782, found 240.9784. 106 Synthesis of tetrapropylammonium 2-methylphenyl sulfate (3.1g) 2-Methylphenol (0.645 g, 6 mmol) and SO3•pyridine complex (1.05 g, 6.6 mmol) were placed in a 100 mL round bottom flask. Pyridine (8 mL) and dry dichloromethane (5 mL) were added and the mixture was stirred at rt for 18 h. After this time, the reaction was heated to 40 ºC for 1 h. Water (70 mL) was added and the mixture was washed once with dichloromethane (1 x 70 mL). The aqueous phase was treated with tetrapropyl ammonium bromide (1.60 g, 6 mmol) and stirred for 1 h. The solution was extracted with dichloromethane (3 x 70 mL). The organic layer was dried over MgSO4, filtered, and concentrated, resulting in a clear oil. To the concentrated oil, hexanes were added and the suspension was concentrated by rotary evaporation. This process was repeated until the product was obtained as a white solid. After overnight drying under high vacuum (3.1g) was obtained as a yellowish white solid (1.24 g, 55% yield). 1 H NMR (500 MHz, CDCl3) δ 7.47 (dd, J = 7.7, 1.2 Hz, 1H), 7.09 (dd, J = 7.7, 1.7 Hz, 1H), 7.05 (td, J = 7.7, 1.7 Hz, 1H), 6.94 (td, J = 7.7, 1.2 Hz, 1H), 3.17 – 2.88 (m, 8H), 2.31 (s, 3H), 1.69 – 1.43 (m, 8H), 0.91 (t, J = 7.3 Hz, 12H). 13C NMR (126 MHz, CDCl3) δ 151.8, 131.2 130.5, 126.2, 123.8, 122.0, 60.2, 16.9, 15.5, 10.8. HRMS (ESI) m/z calcd for C7H7O4S [M–Nn-Pr4]– 187.0065, found 187.0069. Synthesis of tetrapropylammonium 2-isopropylphenyl sulfate (3.1h) 107 2-Isopropylphenol (0.645 g, 6 mmol) and SO3•pyridine complex (1.05 g, 6.6 mmol) were placed in a 100 mL round bottom flask. Pyridine (8 mL) and dry dichloromethane (5 mL) were added and the mixture was stirred at rt for 18 h. After this time, the reaction was heated to 40 ºC for 1 h. Water (70 mL) was added and the mixture was washed once with dichloromethane (1 x 70 mL). The aqueous phase was treated with tetrapropyl ammonium bromide (1.60 g, 6 mmol) and stirred for 1 h. The solution was extracted with dichloromethane (3 x 70 mL). The organic layer was dried over MgSO4, filtered, and concentrated, resulting in a clear oil. To the concentrated oil, hexanes and ether were added and the suspension was again concentrated by rotary evaporation. This process was repeated until the product was obtained as a white solid. After overnight drying under high vacuum (3.1h) was obtained as a white solid (1.39 g, 58% yield). 1 H NMR (500 MHz, CDCl3) δ 7.50 (dd, J = 7.3, 1.6 Hz, 1H), 7.16 (dd, J = 7.3, 2.2 Hz, 1H), 7.01 (td, J = 7.3, 2.1 Hz, 1H), 6.98 (td, J = 7.3, 1.6 Hz, 1H), 3.53 (p, J = 6.9 Hz, 1H), 3.13 – 2.94 (m, 8H), 1.59 – 1.44 (m, 8H), 1.14 (d, J = 7.0 Hz, 6H), 0.88 (t, J = 7.3 Hz, 12H). 13 C NMR (126 MHz, CDCl3) δ 150.6, 140.9, 125.9, 125.7, 123.9, 121.5, 60.2, 26.4, 23.3, 15.5, 10.7. HRMS (ESI) m/z calcd. for C9H11O4S [M–Nn-Pr4]– 215.0378, found 215.0397. Synthesis of tetrapropylammonium 2-cyanophenyl sulfate (1i) 2-Cyanophenol (0.714 g, 6 mmol) and SO3•pyridine complex (1.05 g, 6.6 mmol) were placed in a 100 mL round bottom flask. Pyridine (8 mL) and dry dichloromethane (5 mL) were added and the mixture was stirred at rt for 18 h. After this time, the reaction was heated to 40 ºC for 1 h. Water (70 mL) was added and the mixture was washed once with dichloromethane (1 x 70 108 mL). The aqueous phase was treated with tetrapropyl ammonium bromide (1.60 g, 6 mmol) and stirred for 1 h. The solution was extracted with dichloromethane (3 x 70 mL). The organic layer was dried over MgSO4, filtered, and concentrated, resulting in a clear oil. To the concentrated oil, hexanes and ether were added and the suspension was again concentrated by rotary evaporation. This process was repeated until the product was obtained as a white solid. After overnight drying under high vacuum (3.1i) was obtained as a white solid (1.03 g, 45% yield). 1 H NMR (500 MHz, CDCl3) δ 7.78 (dd, J = 7.6, 1.1 Hz, 1H), 7.45 (dd, J = 7.6, 1.8 Hz, 1H), 7.44 (td, J = 7.6, 1.8 Hz, 1H), 7.04 (td, J = 7.6, 1.1 Hz, 1H), 3.26 – 2.73 (m, 8H), 1.62 (m, 8H), 0.89 (t, J = 7.3 Hz, 12H). 13C NMR (126 MHz, CDCl3) δ 155.6, 133.9, 132.8, 123.1, 120.9, 116.8, 104.5, 60.2, 15.4, 10.6. HRMS (ESI) m/z calcd. for C7H4NO4S [M–Nn-Pr4]– 197.9861, found 197.8931. Synthesis of tetrapropylammonium 2-fluorophenyl sulfate (3.1j) 2-Fluorophenol (0.673 g, 6 mmol) and SO3•pyridine complex (1.05 g, 6.6 mmol) were placed in a 100 mL round bottom flask. Pyridine (8 mL) and dry dichloromethane (5 mL) were added and the mixture was stirred at rt for 18 h. After this time, the reaction was heated to 40 ºC for 1 h. Water (70 mL) was added and the mixture was washed once with dichloromethane (1 x 70 mL). The aqueous phase was treated with tetrapropyl ammonium bromide (1.60 g, 6 mmol) and stirred for 1 h. The solution was extracted with dichloromethane (3 x 70 mL). The organic layer was dried over MgSO4, filtered, and concentrated, resulting in a clear oil. To the concentrated oil, hexanes and ether were added and the suspension was again concentrated by rotary evaporation. 109 This process was repeated until the product was obtained as a white solid. After overnight drying under high vacuum (3.1j) was obtained as a white solid (1.00 g, 44% yield). 1 H NMR (500 MHz, CDCl3) δ 7.71–7.60 (m, 1H), 7.07–6.94 (m, 3H), 3.23–3.03 (m, 8H), 1.76 – 1.46 (m, 8H), 0.93 (t, J = 7.3 Hz, 12H). 13C NMR (126 MHz, CDCl3) δ 154.3 (d, J = 247.1 Hz), 141.2 (d, J = 11.3 Hz), 124.2 (d, J = 7.1 Hz), 124.0 (d, J = 3.8 Hz), 123.8, 116.1 (d, J = 18.8 Hz), 60.3, 15.6, 10.8. 19F NMR (470 MHz, CDCl3) δ –130.6. HRMS (ESI) m/z calcd. for C6H4FO4S [M–Nn-Pr4]– 190.9814, found 190.9830. Synthesis of tetrapropylammonium 2-bromo-6-fluorophenyl sulfate (3.1k) 2-Bromo-6-fluorophenol (1.15 g, 6 mmol) and SO3•pyridine complex (1.05 g, 6.6 mmol) were placed in a 100 mL round bottom flask. Pyridine (8 mL) and dry dichloromethane (5 mL) were added and the mixture was stirred at rt for 18 h. After this time, the reaction was heated to 40 ºC for 1 h. Water (70 mL) was added and the mixture was washed once with dichloromethane (1 x 70 mL). The aqueous phase was treated with tetrapropyl ammonium bromide (1.60 g, 6 mmol) and stirred for 1 h. The solution was extracted with dichloromethane (3 x 70 mL). The organic layer was dried over MgSO4, filtered, and concentrated, resulting in a clear oil. To the concentrated oil, hexanes and ether were added and the suspension was again concentrated by rotary evaporation. This process was repeated until the product was obtained as a white solid. After overnight drying under high vacuum (3.1k) was obtained as a white solid (0.78 g, 28% yield). 1 H NMR (500 MHz, CDCl3) δ 7.24 (d, J = 8.2 Hz, 1H), 6.97 (t, J = 8.2 Hz, 1H), 6.89 (td, J = 8.2, 5.1 Hz, 1H), 3.16 – 2.96 (m, 8H), 1.63 – 1.42 (m, 8H), 0.89 (t, J = 7.3 Hz, 12H). 13C NMR (126 110 MHz, CDCl3) δ 156.7 (d, J = 253.7 Hz), 139.7 (d, J = 14.6 Hz), 128.3 (d, J = 3.5 Hz), 125.5 (d, J 19 = 8.1 Hz), 119.8 (d, J = 1.9 Hz), 115.7 (d, J = 19.9 Hz), 60.2, 15.5, 10.7. F NMR (470 MHz, CDCl3) δ –121.2 (dd, J = 8.2, 5.1 Hz). HRMS (ESI) m/z calcd. for C6H3BrFO4S [M–Nn-Pr4]– 268.8919, found 268.8919. Synthesis of tetrapropylammonium 3-fluorophenyl sulfate (3.1l) 3-Fluorophenol (0.673 g, 6 mmol) and SO3•pyridine complex (1.05 g, 6.6 mmol) were placed in a 100 mL round bottom flask. Pyridine (8 mL) and dry dichloromethane (5 mL) were added and the mixture was stirred at rt for 18 h. After this time, the reaction was heated to 40 ºC for 1 h. Water (70 mL) was added and the mixture was washed once with dichloromethane (1 x 70 mL). The aqueous phase was treated with tetrapropyl ammonium bromide (1.60 g, 6 mmol) and stirred for 1 h. The solution was extracted with dichloromethane (3 x 70 mL). The organic layer was dried over MgSO4, filtered, and concentrated, resulting in a clear oil. To the concentrated oil, hexanes were added and the suspension was concentrated by rotary evaporation. This process was repeated until the product was obtained as a white solid. After overnight drying under high vacuum (3.1l) was obtained as a white solid (1.46 g, 64% yield). 1 H NMR (500 MHz, CDCl3) δ 7.18 (td, J = 8.2, 6.8 Hz, 1H), 7.13 (dt, J = 10.6, 2.4 Hz, 1H), 7.06 (ddd, J = 8.2, 2.4, 0.9 Hz, 1H), 6.73 (tdd, J = 8.2, 2.4, 0.9 Hz, 1H), 3.15–2.90 (m, 8H), 1.68–1.51 (m, 8H), 0.92 (t, J = 7.3 Hz, 12H). 13C NMR (126 MHz, CDCl3) δ 162.8 (d, J = 244.6 Hz), 154.8 (d, J = 11.2 Hz), 129.6 (d, J = 9.6 Hz), 116.5 (d, J = 2.9 Hz), 110.1 (d, J = 21.1 Hz), 108.4 (d, J = 111 24.3 Hz), 60.3, 15.5, 10.7. 19F NMR (470 MHz, CDCl3) δ –112.5 (m) HRMS (ESI) m/z calcd. for C6H4FO4S [M–Nn-Pr4]– 190.9814, found 190.9821. Synthesis of tetrapropylammonium 2,3-difluorophenyl sulfate (3.1m) 2,3-Difluorophenol (0.78 g, 6 mmol) and SO3•pyridine complex (1.05 g, 6.6 mmol) were placed in a 100 mL round bottom flask. Pyridine (8 mL) and dry dichloromethane (5 mL) were added and the mixture was stirred at rt for 18 h. After this time, the reaction was heated to 40 ºC for 1 h. Water (70 mL) was added and the mixture was washed once with dichloromethane (1 x 70 mL). The aqueous phase was treated with tetrapropyl ammonium bromide (1.60 g, 6 mmol) and stirred for 1 h. The solution was extracted with dichloromethane (3 x 70 mL). The organic layer was dried over MgSO4, filtered, and concentrated, resulting in a clear oil. To the concentrated oil, hexanes and ether were added and the suspension was again concentrated by rotary evaporation. This process was repeated until the product was obtained as a white solid. After overnight drying under high vacuum (3.1m) was obtained as a white solid (1.33 g, 56% yield). 1 H NMR (500 MHz, CDCl3) δ 7.40 (ddt, J = 8.4, 6.9, 1.6 Hz, 1H), 6.91 (tdd, J = 8.4, 6.2, 2.2 Hz, 1H), 6.82 (dddd, J = 9.7, 8.4, 6.8, 1.6 Hz, 1H), 3.23 – 2.95 (m, 8H), 1.60 (m, 8H), 0.91 (t, J = 7.3 Hz, 12H). 13C NMR (126 MHz, CDCl3) δ 151.0 (dd, J = 246.4, 11.0 Hz), 143.2 (dd, J = 248.2, 14.0 Hz), 142.8 (dd, J = 8.7, 2.6 Hz), 122.7 (dd, J = 8.3, 5.1 Hz), 118.7 (d, J = 3.3 Hz), 111.7 (d, J = 17.1 Hz), 60.3, 15.4, 10.6. 19F NMR (470 MHz, CDCl3) δ –137.9 (ddd, J = 20.3, 9.7, 6.2 Hz), –155.0 (dt, J = 20.3, 6.8 Hz). HRMS (ESI) m/z calcd. for C6H3F2O4S [M–Nn-Pr4]– 208.9720, found 208.8767. 112 Synthesis of tetrapropylammonium 3-cyanophenyl sulfate (3.1n) 3-Cyanophenol (0.72 g, 6 mmol) and SO3•pyridine complex (1.05 g, 6.6 mmol) were placed in a 100 mL round bottom flask. Pyridine (8 mL) and dry dichloromethane (5 mL) were added and the mixture was stirred at rt for 18 h. After this time, the reaction was heated to 40 ºC for 1 h. Water (70 mL) was added and the mixture was washed once with dichloromethane (1 x 70 mL). The aqueous phase was treated with tetrapropyl ammonium bromide (1.60 g, 6 mmol) and stirred for 1 h. The solution was extracted with dichloromethane (3 x 70 mL). The organic layer was dried over MgSO4, filtered, and concentrated, resulting in a clear oil. To the concentrated oil, hexanes and ether were added and the suspension was again concentrated by rotary evaporation. This process was repeated until the product was obtained as a white solid. After overnight drying under high vacuum (3.1n) was obtained as a white solid (1.19 g, 52% yield). 1 H NMR (500 MHz, CDCl3) δ 7.69 (dd, J = 2.4, 1.4 Hz, 1H), 7.53 (ddd, J = 8.2, 2.4, 1.3 Hz, 1H), 7.35 (t, J = 7.9 Hz, 1H), 7.31 (dt, J = 7.6, 1.4 Hz, 1H), 3.24 – 2.94 (m, 8H), 1.60–1.72 (m, 8H), 0.95 (t, J = 7.3 Hz, 12H). 13C NMR (126 MHz, CDCl3) δ 154.0, 130.1, 127.0, 125.8, 124.1, 118.8, 112.5, 60.5, 15.6, 10.8. HRMS (ESI) m/z calcd. for C7H4NO4S [M–Nn-Pr4]– 197.9861, found 197.9884. 113 Synthesis of tetrapropylammonium 3-methoxyphenyl sulfate (3.1o) 3-Methoxyphenol (0.74 g, 6 mmol) and SO3•pyridine complex (1.05 g, 6.6 mmol) were placed in a 100 mL round bottom flask. Pyridine (8 mL) and dry dichloromethane (5 mL) were added and the mixture was stirred at rt for 18 h. After this time, the reaction was heated to 40 ºC for 1 h. Water (70 mL) was added and the mixture was washed once with dichloromethane (1 x 70 mL). The aqueous phase was treated with tetrapropyl ammonium bromide (1.60 g, 6 mmol) and stirred for 1 h. The solution was extracted with dichloromethane (3 x 70 mL). The organic layer was dried over MgSO4, filtered, and concentrated, resulting in a clear oil. To the concentrated oil, hexanes and ether were added and the suspension was again concentrated by rotary evaporation. This process was repeated until the product was obtained as a white solid. After overnight drying under high vacuum (3.1o) was obtained as a white solid (1.01 g, 43 yield). 1 H NMR (500 MHz, CDCl3) δ 7.10 (t, J = 8.2 Hz, 1H), 6.96-6.85 (m, 2H), 6.57 (dt, J = 8.2, 1.8 Hz, 1H), 3.71 (s, 3H), 3.11 – 3.03 (m, 8H), 1.63 – 1.46 (m, 8H), 0.90 (t, J = 7.3 Hz, 12H).13C NMR (126 MHz, CDCl3) δ 160.2, 154.7, 129.2, 113.4, 109.2, 107.1, 60.2, 55.3, 15.5, 10.8. HRMS (ESI) m/z calcd. for C7H7O5S [M–Nn-Pr4]– 203.0014, found 203.0050. Synthesis of tetrapropylammonium 3-chlorophenyl sulfate (3.1p) 114 3-Chlorophenol (0.77 g, 6 mmol) and SO3•pyridine complex (1.05 g, 6.6 mmol) were placed in a 100 mL round bottom flask. Pyridine (8 mL) and dry dichloromethane (5 mL) were added and the mixture was stirred at rt for 18 h. After this time, the reaction was heated to 40 ºC for 1 h. Water (70 mL) was added and the mixture was washed once with dichloromethane (1 x 70 mL). The aqueous phase was treated with tetrapropyl ammonium bromide (1.60 g, 6 mmol) and stirred for 1 h. The solution was extracted with dichloromethane (3 x 70 mL). The organic layer was dried over MgSO4, filtered, and concentrated, resulting in a clear oil. To the concentrated oil, hexanes and ether were added and the suspension was again concentrated by rotary evapoation. This process was repeated until the product was obtained as a white solid. After overnight drying under high vacuum (3.1p) was obtained as a white solid (0.96 g, 41% yield). 1 H NMR (500 MHz, CDCl3) δ 7.37 (t, J = 2.1 Hz, 1H), 7.18 – 7.12 (m, 2H), 6.99 (dt, J = 6.5, 2.1 Hz, 1H), 3.20 – 2.91 (m, 8H), 1.64 – 1.46 (m, 8H), 0.91 (t, J = 7.3 Hz, 12H). 13C NMR (126 MHz, CDCl3) δ 154.1, 133.5, 129.5, 123.2, 120.8, 119.0, 59.8, 15.1, 10.4. HRMS (ESI) m/z calcd. for C6H4ClO4S [M–Nn-Pr4]– 206.9519, found 206.9544. Synthesis of tetrapropylammonium 1-phenyl sulfate (3.1q) Phenol (0.56 g, 6 mmol) and SO3•pyridine complex (1.05 g, 6.6 mmol) were placed in a 100 mL round bottom flask. Pyridine (8 mL) and dry dichloromethane (5 mL) were added and the mixture was stirred at 40 ºC for 7 h. Water (70 mL) was added and the mixture was washed once with dichloromethane (1 x 70 mL). The aqueous phase was treated with tetrapropyl ammonium bromide (1.60 g, 6 mmol) and stirred for 1 h. The solution was extracted with dichloromethane (3 115 x 70 mL). The organic layer was dried over MgSO4, filtered, and concentrated, resulting in a clear oil. To the concentrated oil, hexanes and ether were added and the suspension was again concentrated by rotary evaporation. This process was repeated until the product was obtained as a white solid. After overnight drying under high vacuum (3.1q) was obtained as a white solid (1.50 g, 69% yield). 1 H NMR (500 MHz, CDCl3) δ 7.32 – 7.26 (m, 2H), 7.24 – 7.17 (m, 2H), 7.01 (td, J = 7.0, 5.4 Hz, 1H), 3.14 – 2.89 (m, 8H), 1.70 – 1.35 (m, 8H), 0.89 (t, J = 7.3 Hz, 12H). 13C NMR (126 MHz, CDCl3) δ 153.6, 128.8, 123.4, 121.0, 60.1, 15.4, 10.7. HRMS (ESI) m/z calcd. for C6H5O4S [M– Nn-Pr4]– 172.9909, found 173.0117. 3.4.4. CHB of Sulfated Phenols Para borylation of tetrapropyl ammonium 2-chlorophenyl sulfate (3.2a) 96% conversion, para : meta = 22:1 60% isolated yield, para : meta = >20 : 1 In a glove box, a 5.0 mL Wheaton microreactor was charged with tetrapropyl ammonium 2-chlorophenyl sulfate (197 mg, 0.5 mmol), [Ir(cod)(OMe)] 2 (5 mg, 1.5 mol %), 4,4′-dimethoxy- 2,2′-bipyridine (3.3 mg, 3.0 mol %), B2pin2 (159 mg, 0.625 mmol) and dioxane (1.5 mL). The microreactor was capped with a teflon pressure cap and placed into an aluminum block pre-heated to 40 oC. After 14 h, an aliquot of the reaction mixture was taken and analyzed directly by 1H NMR to find the conversion and para:meta ratio. HCl 12 M was added until pH = 1–2 and the resultant mixture was stirred for 1 h. The solution was concentrated and washed with hexanes (0.5 mL). The 116 hexane layer was decanted, and the remaining solution subjected to chromatographic separation with silica gel (CHCl3 as eluent) to give 76 mg of para borylated 2-chlorophenol with traces of the meta isomer (< 2%) as a white solid (60% yield, mp 118.6–120.1 °C). The NMR data were consistent with previously reported NMR values.33 1 H NMR (500 MHz, CDCl3) δ 7.78 (d, J = 1.4 Hz, 1H), 7.61 (dd, J = 8.1, 1.4 Hz, 1H), 6.99 (d, J = 8.1 Hz, 1H), 6.04 (bs, 1H), 1.33 (s, 12H). 13C NMR (126 MHz, CDCl3) δ 154.0, 135.8, 135.2, 120.0, 116.0, 84.1, 24.9. 11 B NMR (160 MHz, CDCl3) δ 30.2. HRMS (ESI) m/z calcd. for C12H15BClO3 [M–H]– 253.0803, found 253.1007. Performing the same borylation with tetraethylammonium 2-chlorophenyl sulfate gave a para:meta ratio of 6:1, while borylation of tetrabutylammonium 2-chloro sulfate gave a para:meta ratio of 17:1. Para borylation of tetrapropyl ammonium 2-bromophenyl sulfate (3.2b) 98% conversion, para : meta = 23:1 74% isolated yield, para : meta = >20 : 1 In a glove box, a 5.0 mL Wheaton microreactor was charged with tetrapropyl ammonium 2-bromophenyl sulfate (219 mg, 0.5 mmol), [Ir(cod)(OMe)] 2 (5 mg, 1.5 mol %), 4,4′-dimethoxy- 2,2′-bipyridine (3.3 mg, 3.0 mol %), B2pin2 (159 mg, 0.625 mmol) and dioxane (1.5 mL). The microreactor was capped with a teflon pressure cap and placed into an aluminum block pre-heated to 40 oC. After 14 h, an aliquot of the reaction mixture was taken and analyzed directly by 1H NMR to find the conversion and para:meta ratio. HCl 12 M was added until pH = 1–2 and the 117 resultant mixture was stirred for 1 h. The solution was concentrated and washed with hexanes (0.5 mL). The hexane layer was decanted, and the remaining solution subjected to chromatographic separation with silica gel (CHCl3 as eluent) to give 110 mg of para borylated 2-bromophenol with traces of the meta isomer (< 2%) as a white solid (74% yield, mp 118.4–119.6 °C). The NMR data were consistent with previously reported values.39 1 H NMR (500 MHz, CDCl3) δ 7.92 (d, J = 1.5 Hz, 1H), 7.64 (dd, J = 8.1, 1.5 Hz, 1H), 6.99 (d, J = 8.1 Hz, 1H), 5.92 (bs, 1H), 1.32 (s, 12H). 13C NMR (126 MHz, CDCl3) δ 154.9, 138.8, 136.0, 115.8, 110.4, 84.1, 24.9. 11 B NMR (160 MHz, CDCl3) δ 30.1. HRMS (ESI) m/z calcd. for C12H15BBrO3 [M–H]– 297.0298, found 297.0304. Para borylation of tetrapropyl ammonium 2-iodophenyl sulfate (3.2c) >99.9% conversion, para : meta = 22:1 76% isolated yield, para : meta = >20 : 1 In a glove box, a 5.0 mL Wheaton microreactor was charged with tetrapropyl ammonium 2-iodophenyl sulfate (243 mg, 0.5 mmol), [[Ir(cod)(OMe)] 2 (10 mg, 3 mol %), 4,4′-dimethoxy- 2,2′-bipyridine (6.6 mg, 6 mol %), B2pin2 (159 mg, 0.625 mmol) and dioxane (1.5 mL). The microreactor was capped with a teflon pressure cap and placed into an aluminum block pre-heated to 40 oC. After 20 h, an aliquot of the reaction mixture was taken and analyzed directly by 1H NMR to find the conversion and para:meta ratio. HCl 12 M was added until pH = 1–2 and the resultant mixture was stirred for 1 h. The solution was concentrated and subjected directly to chromatographic separation with silica gel (CHCl3 as eluent) to give 132 mg of para borylated 2- 118 iodophenol with traces of the meta isomer (< 2%) as a white solid (76% yield, mp 119.7–121.2 °C). 1 H NMR (500 MHz, CDCl3) δ 8.12 (s, 1H), 7.65 (d, J = 8.0 Hz, 1H), 6.95 (d, J = 8.0 Hz, 1H), 5.89 (bs, 1H), 1.32 (s, 12H). 13C NMR (126 MHz, CDCl3) δ 157.4, 145.3, 137.0, 114.8, 86.0, 84.1, 24.9. 11 B NMR (160 MHz, CDCl3) δ 29.8. HRMS (ESI) m/z calcd for C12H15BIO3 [M–H]– 345.0159, found 345.0211. Para borylation of tetrapropyl ammonium 2-trifluoromethoxyphenyl sulfate (3.2d) 96% conversion, para : meta = 23:1 77% isolated yield, para : meta = >20 : 1 In a glove box, a 5.0 mL Wheaton microreactor was charged with tetrapropyl ammonium 2-trifluoromethoxyphenyl sulfate (198 mg, 0.5 mmol), [Ir(cod)(OMe)]2 (5 mg, 1.5 mol %), 4,4′- dimethoxy-2,2′-bipyridine (3.3 mg, 3.0 mol %), B2pin2 (159 mg, 0.625 mmol) and dioxane (1.5 mL). The microreactor was capped with a teflon pressure cap and placed into an aluminum block pre-heated to 40 oC. After 16 h, an aliquot of the reaction mixture was taken and analyzed directly by 1H NMR to find the conversion and para:meta ratio. HCl 12 M was added until pH = 1–2 and the resultant mixture was stirred for 1 h. The solution was concentrated and passed through a plug of silica gel (4% EtOAc in CHCl3 as eluent). The fractions containing product were collected, concentrated and washed with hexanes (0.5 mL). The hexane layer was decanted and the residue was evaporated to give 117 mg of a mixture of para borylated 2-trifluoromethoxyphenol with traces of the meta isomer (<2%) as a white solid (77% yield, mp 129.6–131.9 °C) 119 1 H NMR (500 MHz, CDCl3) δ 7.65 (s, 1H), 7.63 (d, J = 8.08 Hz, 1H), 7.01 (d, J = 8.08 Hz, 1H), 5.97 (bs, 1H), 1.34 (s, 12H). 13C NMR (126 MHz, CDCl3) δ 150.6, 136.4 (q, J = 1.91 Hz), 135.1, 127.8, 120.8 (q, J = 259.0 Hz), 117.0, 84.2, 24.9. 11B NMR (160 MHz, CDCl3) δ 30.6. 19F NMR (470 MHz, CDCl3) δ -57.7. HRMS (ESI) m/z calcd for C13H15BF3O4 [M–H]– 303.1015, found 303.1244. Para borylation of tetrapropylammonium 2-methoxyphenyl sulfate (3.2e) >99.9% conversion, para : meta = 39:1 98% isolated yield, para : meta = 39 : 1 In a glove box, a 5.0 mL Wheaton microreactor was charged with tetrapropyl ammonium 2-methoxyphenyl sulfate (195 mg, 0.5 mmol), [Ir(cod)(OMe)]2 (10 mg, 3 mol %), 4,4′-dimethoxy- 2,2′-bipyridine (6.6 mg, 6.0 mol %), B2pin2 (159 mg, 0.625 mmol) and dioxane (1.5 mL). The microreactor was capped with a teflon pressure cap and placed into an aluminum block pre-heated to 40 oC. After 12 h, an aliquot of the reaction mixture was taken and analyzed directly by 1H NMR to find the conversion and para:meta ratio. HCl 12 M was added until pH = 1–2 and the resultant mixture was stirred for 1 h. The solution was concentrated and passed through a plug of silica gel (CHCl3 as eluent) to give 122 mg of a mixture of para borylated 2-methoxyphenol with the meta isomer (para:meta = 39:1) as a white solid (98% yield, mp 96.7–100.0 °C) 1 H NMR (500 MHz, C6D6) δ 7.76 (dd, J = 7.8, 1.3 Hz, 1H), 7.50 (d, J = 1.3 Hz, 1H), 7.06 (d, J = 7.8 Hz, 1H), 6.00 (bs, 1H), 3.16 (s, 3H), 1.15 (s, 12H). 13C NMR (126 MHz, C6D6) δ 149.6, 146.6, 120 129.9, 117.1, 114.8, 83.6, 55.1, 25.0. 11B NMR (160 MHz, C6D6) δ 31.2. HRMS (ESI) m/z calcd for C13H18BO4 [M–H]– 249.1298, found 249.0159. Para borylation of tetrapropyl ammonium 2-trifluoromethylphenyl sulfate (3.2f) >99.9% conversion, para : meta = 11:1 81% isolated yield, para : meta = 46 : 1 In a glove box, a 5.0 mL Wheaton microreactor was charged with tetrapropyl ammonium 2-trifluoromethylphenyl sulfate (214 mg, 0.5 mmol), [Ir(cod)(OMe)] 2 (5 mg, 1.5 mol %), 4,4′- dimethoxy-2,2′-bipyridine (3.3 mg, 3.0 mol %), B2pin2 (159 mg, 0.625 mmol) and dioxane (1.5 mL). The microreactor was capped with a teflon pressure cap and placed into an aluminum block pre-heated to 40 oC. After 10 h, an aliquot of the reaction mixture was taken and analyzed directly by 1H NMR to find the conversion and para:meta ratio. HCl 12 M was added until pH = 1–2 and the resultant mixture was stirred for 1 h. The solution was concentrated and washed with hexanes (0.5 mL). The hexane layer was decanted, and the remaining solution subjected to chromatographic separation with silica gel (12% EtOAc in CHCl3 as eluent) to give 116 mg of para borylated 2-trifluoromethylphenol with traces of the meta isomer (para:meta = 46:1) as a white solid (81% yield, mp 128.1–129.9 °C). The NMR data were consistent with previously reported NMR values.33 1 H NMR (500 MHz, CDCl3) δ 7.99 (d, J = 1.6 Hz, 1H), 7.80 (dd, J = 8.2, 1.6 Hz, 1H), 6.98 (bs, 1H), 6.87 (d, J = 8.2 Hz, 1H), 1.35 (s, 1H). 13C NMR (126 MHz, CDCl3) δ 156.7 (q, J = 1.9 Hz), 140.1, 134.1 (q, J = 4.7 Hz), 124.1 (q, J = 272.3 Hz), 116.9, 116.7 (q, J = 30.5 Hz), 84.5, 24.8. 121 11 B NMR (160 MHz, CDCl3) δ 31.5. 19F NMR (470 MHz, CDCl3) δ –60.6. HRMS (ESI) m/z calcd for C13H15BF3O3 [M–H]– 287.1066, found 286.9732. Para borylation of tetrapropyl ammonium 2-methylphenyl sulfate (3.2g) 73% conversion, para : meta = 11:1 57% isolated yield, para : meta = 39 : 1 2-Methylphenyl sulfate (187 mg, 0.5 mmol), [Ir(cod)(OMe)] 2 (10 mg, 3 mol %), 4,4′- dimethoxy-2,2′-bipyridine (6.6 mg, 6.0 mol %), B2pin2 (159 mg, 0.625 mmol) and dioxane (1.5 mL). The microreactor was capped with a teflon pressure cap and placed into an aluminum block pre-heated to 60 oC. After 36 h, an aliquot of the reaction mixture was taken and analyzed directly by 1H NMR to find the conversion and para:meta ratio. HCl 12 M was added until pH = 1–2 and the resultant mixture was stirred for 1 h. The solution was concentrated and washed with hexanes (0.5 mL). The hexane layer was decanted, and the remaining solution subjected to chromatographic separation with silica gel (CHCl3 as eluent) to give 67 mg of para borylated 2- methylphenol with traces of the meta isomer (para:meta = 39:1) as a white solid (57% yield, mp 100.0–102.4 °C). The NMR values were consistent with previously reported NMR values. 40 1 H NMR (500 MHz, CDCl3) δ 7.61 (d, J = 1.7 Hz, 1H), 7.54 (dd, J = 7.9, 1.6 Hz, 1H), 6.75 (d, J = 7.9 Hz, 1H), 5.81 (bs, 1H), 2.24 (s, 3H), 1.35 (s, 12H). 13 C NMR (126 MHz, CDCl3) δ 157.0, 138.0, 134.3, 123.5, 114.6, 83.8, 24.9, 15.6. 11 B NMR (160 MHz, CDCl3) δ 30.6. HRMS (ESI) m/z calcd for C13H18BO3 [M–H]– 233.1349, found 233.1367. 122 Para borylation of tetrapropyl ammonium 2-isopropylphenyl sulfate (3.2h) 62% conversion, para : meta = 25:1 62% isolated yield, para : meta = 23 : 1 In a glove box, a 5.0 mL Wheaton microreactor was charged with tetrapropyl ammonium 2-isopropylphenyl sulfate (201 mg, 0.5 mmol), [Ir(cod)(OMe)]2 (10 mg, 3 mol %), 4,4′- dimethoxy-2,2′-bipyridine (6.6 mg, 3.0 mol %), B2pin2 (159 mg, 0.625 mmol) and dioxane (1.5 mL). The microreactor was capped with a teflon pressure cap and placed into an aluminum block pre-heated to 40 oC. After 36 h, an aliquot of the reaction mixture was taken and analyzed directly by 1H NMR to find the conversion and para:meta ratio. HCl 12 M was added until pH = 1–2 and the resultant mixture was stirred for 1 h. The solution was concentrated and subjected directly to chromatographic separation with silica gel (2% EtOAc in CHCl3 as eluent) to give 81 mg of para borylated 2-isopropylphenol with traces of the meta isomer (para:meta = 23:1) as a white solid (62% yield, mp 138.3–145.9 °C). The NMR values were consistent with previously reported NMR values.41 1 H NMR (500 MHz, CDCl3) δ 7.67 (d, J = 1.6 Hz, 1H), 7.54 (dd, J = 8.0, 1.6 Hz, 1H), 6.74 (d, J = 8.0 Hz, 1H), 5.82 (s, 1H), 3.23 (hept, J = 6.9 Hz, 1H), 1.36 (s, 12H), 1.26 (d, J = 6.9 Hz, 6H). 13 C NMR (126 MHz, CDCl3) δ 156.1, 134.1, 134.0, 133.5, 114.9, 83.8, 27.2, 24.9, 22.6. 11B NMR (160 MHz, CDCl3) δ 30.7. HRMS (ESI) m/z calcd for C15H22BO3 [M–H]– 261.1662, found 261.1696. 123 Para borylation of tetrapropylammonium 2-cyanophenyl sulfate (3.2i) >99.9% conversion, para : meta : dimeta = 7.5 : 1 : 0.4 93% isolated yield, para : meta : dimeta = 7.5 : 1 :0.4 In a glove box, a 5.0 mL Wheaton microreactor was charged with tetrapropyl ammonium 2-cyanophenyl sulfate (193 mg, 0.5 mmol), [Ir(cod)(OMe)] 2 (5 mg, 1.5 mol %), 4,4′-dimethoxy- 2,2′-bipyridine (3.3 mg, 3.0 mol %), B2pin2 (159 mg, 0.625 mmol) and dioxane (1.5 mL). The microreactor was capped with a teflon pressure cap and placed into an aluminum block pre-heated to 40 oC. After 13 h, an aliquot of the reaction mixture was taken and analyzed directly by 1H NMR to find the conversion and para:meta ratio. HCl 12 M was added until pH = 1–2 and the resultant mixture was stirred for 1 h. The solution was concentrated and passed through a plug of silica gel (4% EtOAc in CHCl3 as eluent). The fractions containing product were collected and concentrated to give 117 mg of a mixture of para borylated 2-cyanophenol with the meta and dimeta isomers (para:meta:dimeta = 7.5:1:0.4) as a white solid (93% yield, mp 156.6–162.8 °C). The NMR data were consistent with previously reported NMR values.42 Para: 1 H NMR (500 MHz, CDCl3) δ 7.96 (d, J = 1.7 Hz, 1H), 8.15-7.55 (bs, 1H), 7.83 (dd, J = 8.3, 1.7 Hz, 1H), 6.97 (d, J = 8.3 Hz, 1H), 1.32 (s, 12H). 13 C NMR (126 MHz, CDCl3) δ 161.5, 141.0, 140.5, 116.6, 116.0, 99.5, 84.4, 24.9. 11B NMR (160 MHz, CDCl3) δ 30.7. HRMS (ESI) m/z calcd for C13H15BNO3 [M–H]– 244.1145, found 244.0003. 124 Meta: 1 H NMR (500 MHz, CDCl3) δ 8.15-7.55 (bs, 1H), 7.48 (d, J = 7.6 Hz, 1H), 7.39 (d, J = 0.9 Hz, 1H), 7.34 (dd, J = 7.6, 0.9 Hz, 1H), 1.32 (s, 12H). Carbon peaks were indistinguishable due to the small amount of the meta isomer in the mixture. 11B NMR (160 MHz, CDCl3) δ 30.4. HRMS (ESI) m/z calcd for C13H15BNO3 [M–H]– 244.1145, found 244.0003. Para borylation of tetrapropyl ammonium 2-fluorophenyl sulfate (3.2j) >99.9% conversion, para : meta : dimeta = 2.3 : 1 : 0.2 56% isolated yield, para : meta = 11 : 1 In a glove box, a 5.0 mL Wheaton microreactor was charged with tetrapropyl ammonium 2-fluorophenyl sulfate (189 mg, 0.5 mmol), [Ir(cod)(OMe)] 2 (5 mg, 1.5 mol %), 4,4′-dimethoxy- 2,2′-bipyridine (3.3 mg, 3.0 mol %), B2pin2 (159 mg, 0.625 mmol) and dioxane (1.5 mL). The microreactor was capped with a teflon pressure cap and placed into an aluminum block pre-heated to 40 oC. After 36 h, an aliquot of the reaction mixture was taken and analyzed directly by 1H NMR to find the conversion and para:meta ratio. HCl 12 M was added until pH = 1–2 and the resultant mixture was stirred for 1 h. The solution was concentrated and washed with hexanes (0.5 mL). The hexane layer was decanted, and the remaining solution subjected to chromatographic separation with silica gel (10% EtOAc in CHCl3 as eluent) to give 67 mg of a mixture of para and meta borylated 2-fluorophenol (para:meta = 11:1) as a white solid (56% yield, mp 85.0-91.0 °C). The NMR data were consistent with previously reported NMR values, designated as compound 22a in the cited paper.43 125 Para: 1 H NMR (500 MHz, C6D6) δ 7.81 (dd, J = 11.1, 1.4 Hz, 1H), 7.71 (dd, J = 8.1, 1.4 Hz, 1H), 6.84 (t, J = 8.1 Hz, 1H), 1.08 (s, 12H). 13C NMR (126 MHz, C6D6) δ 151.1 (d, J = 239.2 Hz), 146.9 (d, J = 13.9 Hz), 132.1 (d, J = 3.4 Hz), 121.7 (d, J = 15.8 Hz), 117.2 (d, J = 1.7 Hz), 83.6, 24.4. 11B NMR (160 MHz, CDCl3) δ 30.9. 19F NMR (470 MHz, CDCl3) δ –139.7 (dd, J = 11.1, 8.1 Hz). HRMS (ESI) m/z calcd for C12H15BFO3 [M–H]– 237.1098, found 237.1097. Meta: 1 H NMR (500 MHz, C6D6) δ 7.49 (ddd, J = 7.4, 5.0, 1.7 Hz, 1H), 6.93 (ddd, J = 8.7, 8.0, 1.7 Hz, 1H), 6.74 (ddd, J = 8.0, 7.4, 0.7 Hz, 1H).13C NMR (126 MHz, C6D6) δ 155.6 (d, J = 243.3 Hz), 143.8 (d, J = 16.1 Hz), 124.4 (d, J = 3.9 Hz), 120.6 (d, J = 2.8 Hz), 83.7, 24.4 (owing to the small amount of the isomer in the mixture some peaks were not observed). 11B NMR (160 MHz, CDCl3) δ 30.9. 19F NMR (470 MHz, CDCl3) δ –129.1 (dd, J = 8.7, 5.0 Hz). HRMS (ESI) m/z calcd for C12H15BFO3 [M–H]– 237.1098, found 237.1097. Para borylation of tetrapropylammonium 2-bromo-6-fluorophenyl sulfate (3.2k) >99.9% conversion, para : meta = 8 : 1 76% isolated yield, para : meta = 35 : 1 In a glove box, a 5.0 mL Wheaton microreactor was charged with tetrapropyl ammonium 2-bromo-6-fluorophenyl sulfate (228 mg, 0.5 mmol), [Ir(cod)(OMe)] 2 (5 mg, 1.5 mol %), 4,4′- dimethoxy-2,2′-bipyridine (3.3 mg, 3.0 mol %), B2pin2 (128 mg, 0.5 mmol) and dioxane (1.5 mL). The microreactor was capped with a teflon pressure cap and placed into an aluminum block pre- 126 heated to 40 oC. After 12 h, an aliquot of the reaction mixture was taken and analyzed directly by 1 H NMR to find the conversion and para:meta ratio. HCl 12 M was added until pH = 1–2 and the resultant mixture was stirred for 1 h. The solution was concentrated and passed through a plug of silica gel (CHCl3 as eluent). The fractions containing product were collected and concentrated to give 120 mg of a mixture of para borylated 2-bromo-6-fluorophenol with traces of the meta isomer (para:meta = 35:1) as a white solid (76% yield, mp 127.6–129.0 °C). 1 H NMR (500 MHz, CDCl3) δ 7.70 (d, J = 1.3 Hz, 1H), 7.44 (dd, J = 10.3, 1.3 Hz, 1H), 1.32 (s, 12H). 13C NMR (126 MHz, CDCl3) δ 150.8 (d, J = 246.0 Hz), 144.1 (d, J = 14.7 Hz), 134.3 (d, J = 3.0 Hz), 121.2 (d, J = 16.6 Hz), 110.8 (d, J = 1.6 Hz), 84.4, 24.9. 11B NMR (160 MHz, CDCl3) δ 30.1. 19 F NMR (470 MHz, CDCl3) δ –134.7 (d, J = 10.2 Hz). HRMS (ESI) m/z calcd for C12H14BBrFO3 [M–H]– 315.0203, found 314.8771. Para borylation of tetrapropyl ammonium 3-fluorophenyl sulfate (3.2l) >99.9% conversion, para : meta = 2.3 : 1 73% isolated yield, para : meta = 3 : 1 In a glove box, a 5.0 mL Wheaton microreactor was charged with tetrapropyl ammonium 3-fluorophenyl sulfate (189 mg, 0.5 mmol), [Ir(cod)(OMe)] 2 (5 mg, 1.5 mol %), 4,4′-dimethoxy- 2,2′-bipyridine (3.3 mg, 3.0 mol %), B2pin2 (159 mg, 0.625 mmol) and dioxane (1.5 mL). The microreactor was capped with a teflon pressure cap and placed into an aluminum block pre-heated to 40 oC. After 20 h, an aliquot of the reaction mixture was taken and analyzed directly by 1H NMR to find the conversion and para:meta ratio. HCl 12 M was added until pH = 1–2 and the resultant 127 mixture was stirred for 1 h. The solution was concentrated and washed with hexanes (0.5 mL). The hexane layer was decanted, and the remaining solution subjected to chromatographic separation with silica gel (12% EtOAc in CHCl3 as eluent) to give 87 mg of a mixture para borylated 3- fluorophenol with the meta isomer (para:meta = 3:1) as a white solid (73% yield, mp 89.4-91.2 °C) The NMR values were consistent with previously reported values.44 Para: 1 H NMR (500 MHz, CDCl3) δ 7.58 (dd, J = 8.2, 7.1 Hz, 1H), 6.76 (bs, 1H), 6.61 (dd, J = 8.2, 2.2 Hz, 1H), 6.51 (dd, J = 10.9, 2.2 Hz, 1H), 1.34 (s, 12H). 13C NMR (126 MHz, CDCl3) δ 168.6 (d, J = 250.4 Hz), 160.8 (d, J = 12.3 Hz), 138.0 (d, J = 10.2 Hz), 111.6 (d, J = 2.6 Hz), 103.1 (d, J = 27.3 Hz), 84.1, 24.8. 11B NMR (160 MHz, CDCl3) δ 31.4. 19F NMR (470 MHz, CDCl3) δ –100.6 (dd, J = 10.9, 7.1 Hz). HRMS (ESI) m/z calcd for C12H15BFO3 [M–H]– 237.1098, found 237.1320. Meta: 1 H NMR (500 MHz, CDCl3) δ 7.04 (m, 2H), 6.67 (dt, J = 9.4, 2.4 Hz, 1H), 1.33 (s, 12H). 13C NMR (126 MHz, CDCl3) δ 163.4 (d, J = 246.6 Hz), 156.8 (d, J = 10.5 Hz), 117.2 (d, J = 2.5 Hz), 113.1 (d, J = 19.8 Hz), 106.3 (d, J = 24.4 Hz), 84.5, 24.9. 11B NMR (160 MHz, CDCl3) δ 31.4. 19F NMR (470 MHz, CDCl3) δ –112.4 (t, J = 9.4 Hz). HRMS (ESI) m/z calcd for C12H15BFO3 [M–H]– 237.1098, found 237.1320. Para borylation of tetrapropyl ammonium 2,3-difluorophenyl sulfate (3.2m) >99.9% conversion, para : meta = 23 : 1 78% isolated yield, para : meta = 30 : 1 128 In a glove box, a 5.0 mL Wheaton microreactor was charged with tetrapropyl ammonium 2,3-difluorophenyl sulfate (198 mg, 0.5 mmol), [Ir(cod)(OMe)]2 (5 mg, 1.5 mol %), 4,4′- dimethoxy-2,2′-bipyridine (3.3 mg, 3.0 mol %), B2pin2 (159 mg, 0.625 mmol) and dioxane (1.5 mL). The microreactor was capped with a teflon pressure cap and placed into an aluminum block pre-heated to 40 oC. After 20 h, an aliquot of the reaction mixture was taken and analyzed directly by 1H NMR to find the conversion and para:meta ratio. HCl 12 M was added until pH = 1–2 and the resultant mixture was stirred for 1 h. The solution was concentrated and subjected directly to chromatographic separation with silica gel (10% EtOAc in CHCl3 as eluent) to give 100 mg of a mixture of para borylated 2,3-difluorophenol with the meta isomer (para:meta = 30:1) as a white solid (78% yield, mp 125.2–125.9 °C) 1 H NMR (500 MHz, CDCl3) δ 7.35 (ddd, J = 8.3, 6.0, 2.2 Hz, 1H), 6.75 (ddd, J = 8.3, 7.1, 1.6 Hz, 1H), 5.95 (bs, 1H), 1.34 (s, 12H). 13C NMR (126 MHz, CDCl3) δ 155.4 (dd, J = 251.9, 9.6 Hz), 148.4 (dd, J = 11.0, 2.9 Hz), 140.0 (dd, J = 240.9, 16.6 Hz), 130.9 (dd, J = 9.0, 4.8 Hz), 112.8 (d, J = 2.9 Hz), 84.3, 24.8. 11 B NMR (160 MHz, CDCl3) δ 29.9. 19F NMR (470 MHz, CDCl3) δ – 127.7 (dd, J = 21.3, 6.0 Hz), –164.6 (ddd, J = 21.3, 7.1, 2.2 Hz). HRMS (ESI) m/z calcd for C12H14BF2O3 [M–H]– 255.1004, found 254.9811. Para borylation of tetrapropylammonium 3-cyanophenyl sulfate (3.2n) >99.9% conversion, para : meta = 1 : 7 83% isolated yield, para : meta = 1 : 9.3 129 In a glove box, a 5.0 mL Wheaton microreactor was charged with tetrapropyl ammonium 3-cyanophenyl sulfate (192 mg, 0.5 mmol), [Ir(cod)(OMe)] 2 (5 mg, 1.5 mol %), 4,4′-dimethoxy- 2,2′-bipyridine (3.3 mg, 3.0 mol %), B2pin2 (159 mg, 0.625 mmol) and dioxane (1.5 mL). The microreactor was capped with a teflon pressure cap and placed into an aluminum block pre-heated to 40 oC. After 24 h, an aliquot of the reaction mixture was taken and analyzed directly by 1H NMR to find the conversion and para:meta ratio. HCl 12 M was added until pH = 1–2 and the resultant mixture was stirred for 1 h. The solution was concentrated and passed through a plug of silica gel (2% EtOAc in CHCl3 as eluent). The fractions containing product were collected, concentrated and washed with water (0.5 mL). The water layer was decanted and the residue was dried to give 102 mg of a mixture of para borylated 3-cyanophenol with the meta isomer (para:meta = 1:9.3) as a white solid (83% yield, mp 131.8–146.0 °C) 1 H NMR (500 MHz, CDCl3) δ 7.69 – 7.60 (m, 1H), 7.47 (dd, J = 2.7, 1.0 Hz, 1H), 7.20 (dd, J = 2.6, 1.5 Hz, 1H), 6.44 (bs, 1H), 1.33 (s, 13H). 13C NMR (126 MHz, CDCl3) δ 156.2, 130.2, 126.4, 121.1, 118.7, 112.4, 84.6, 24.8. 11B NMR (160 MHz, CDCl3) δ 30.5. HRMS (ESI) m/z calcd for C13H15BNO3 [M–H]– 244.1145, found 244.1147. Para borylation of tetrapropylammonium 3-methoxyphenyl sulfate (3.2o) 80% conversion, para : meta = 1 : 12 In a glove box, a 3.0 mL Wheaton microreactor was charged with tetrapropyl ammonium 3-methoxyphenyl sulfate (39 mg, 0.1 mmol), [Ir(cod)(OMe)] 2 (0.3 mL of 0.01 M solution, 3 mol %), 4,4′-dimethoxy-2,2′-bipyridine (0.2 mL of 0.03 M solution, 6.0 mol %) and B2pin2 (32 mg, 130 0.125 mmol). The microreactor was capped with a teflon pressure cap and placed into an aluminum block pre-heated to 40 oC. After 48 h, an aliquot of the reaction mixture was taken and analyzed directly by 1H NMR to find the conversion and para:meta ratio. Para borylation of tetrapropyl ammonium 3-chlorophenyl sulfate (3.2p) 87% conversion, para : meta < 1 : 20 In a glove box, a 3.0 mL Wheaton microreactor was charged with tetrapropyl ammonium 3-chlorophenyl sulfate (39 mg, 0.1 mmol), [Ir(cod)(OMe)] 2 (0.1 mL of 0.015 M solution, 1.5 mol %), 4,4′-dimethoxy-2,2′-bipyridine (0.1 mL of 0.03 M solution 3.0 mol %), B2pin2 (38 mg, 0.15 mmol) and dioxane (0.2 mL). The microreactor was capped with a teflon pressure cap and placed into an aluminum block pre-heated to 40 oC. After 34 h, an aliquot of the reaction mixture was taken and analyzed directly by 1H NMR to find the conversion and para:meta ratio. Para borylation of tetrapropylammonium phenyl sulfate (3.2q) >99.9% conversion, para : meta : dimeta = 4.4 : 1 : 1.8 98% isolated yield, para : meta : dimeta = 4.5 : 1 : 2.0 131 In a glove box, a 5.0 mL Wheaton microreactor was charged with tetrapropylammonium phenyl sulfate (180 mg, 0.5 mmol), [Ir(cod)(OMe)] 2 (10 mg, 3 mol %), 4,4′-dimethoxy-2,2′- bipyridine (6.6 mg, 3.0 mol %), B2pin2 (159 mg, 0.625 mmol, 1.0 equiv) and dioxane (1.5 mL). The microreactor was capped with a teflon pressure cap and placed into an aluminum block pre- heated to 40 oC. After 48 h, an aliquot of the reaction mixture was taken and analyzed directly by 1 H NMR to find the conversion and para:meta ratio. HCl 12 M was added until pH = 1–2 and the resultant mixture was stirred for 1 h. The solution was concentrated and passed through a plug of silica gel (2% EtOAc in CHCl3 as eluent). The fractions containing product were collected, concentrated and washed with water (0.5 mL). The water layer was decanted and the residue was dried to give 123 mg of a mixture of para borylated phenol with the meta and dimeta isomer (para:meta:dimeta = 1:0.22:0.44) as a colorless oil (98% yield). The NMR data of the borylated compounds in the mixture were in accordance with the literature reported data.45 Para: 1 H NMR (500 MHz, CDCl3) δ 7.70 (d, J = 8.5 Hz, 1H), 6.82 (d, J = 8.5 Hz, 1H), 5.73 (s, 1H), 1.33 (s, 12H). 13 C NMR (126 MHz, CDCl3) δ 158.6, 136.9, 115.0, 83.8, 25.0. 11 B NMR (160 MHz, CDCl3) δ 30.9. Meta: 1 H NMR (500 MHz, CDCl3) δ 7.37 (1H), 7.26 (2H), 6.95 (ddd, J = 8.1, 2.7, 1.1 Hz, 1H), 5.29 (s, 1H), 1.34 (s, 12H). The peaks at 7.26 and 6.95 are overlap with the para isomer and the solvent peak. 3C NMR (126 MHz, CDCl3) δ 155.2, 129.4, 127.2, 121.2, 118.5, 84.0, 24.9. 11B NMR (160 MHz, CDCl3) δ 30.9. 132 Dimeta: 1 H NMR (500 MHz, CDCl3) δ 7.84 (t, J = 1.0 Hz, 1H), 7.36 (d, J = 1.0 Hz, 2H), 5.16 (s, 1H), 1.33 (s, 24H). 3C NMR (126 MHz, CDCl3) δ 154.6, 133.5, 124.1, 83.9, 24.8. 11B NMR (160 MHz, CDCl3) 30.9. 3.4.5. Preparation of Sulfated Anilines Synthesis of tetrapropylammonium 2-chlorophenyl sulfamate (3.3a) 2-Chloroaniline (0.77 g, 6 mmol) and SO3•pyridine complex (1.05 g, 6.6 mmol) were placed in a 100 mL round bottom flask. Pyridine (8 mL) and dry dichloromethane (5 mL) were added and the mixture was stirred at rt for 18 h. After this time, the reaction was heated to 40 ºC for 1 h. Water (150 mL) was added and the mixture was washed once with dichloromethane (1 x 70 mL). The aqueous phase was treated with tetrapropylammonium bromide (1.60 g, 6 mmol) and stirred for 1 h. The solution was extracted with dichloromethane (3 x 70 mL). The organic layer was dried over MgSO4, filtered, and concentrated. To the concentrated oil, hexanes, and ether were added and the suspension was again evaporated. This hexane/ether process was repeated until following the evaporation of solvent the product was obtained as a white solid. After overnight drying under high vacuum (3.3a) was obtained as a light orange solid (0.72 g, 31% yield). 1 H NMR (500 MHz, CDCl3) δ 7.65 (dd, J = 8.3, 1.6 Hz, 1H), 7.08 (dd, J = 7.7, 1.5 Hz, 1H), 6.99 (ddd, J = 8.3, 7.7, 1.5 Hz, 1H), 6.61 (td, J = 7.7, 1.6 Hz, 1H), 6.50 (bs, 1H), 3.03 – 2.79 (m, 8H), 1.44 (m, 8H), 0.80 (t, J = 7.3 Hz, 12H). 13C NMR (126 MHz, CDCl3) 138.8, 128.4, 127.2, 119.9, 133 119.4, 117.2, 59.8, 15.2, 10.5. HRMS (ESI) m/z calcd for C6H5ClNO3S [M–Nn-Pr4]– 205.9679, found 205.8718 Synthesis of tetrabutylammonium 2-chlorophenyl sulfamate (3.3a´) 2-Chloroaniline (1.63 g, 12.74 mmol) and SO3•pyridine complex (2.19 g, 13.75 mmol) were placed in a 100 mL round bottom flask. Pyridine (17 mL) and dry dichloromethane (10 mL) were added and the mixture was stirred at rt for 18 h. After this time, the reaction was heated to 40 ºC for 1 h. Water (150 mL) was added and the mixture was washed once with dichloromethane (1 x 150 mL). The aqueous phase was treated with tetrabutylammonium hydrogen sulfate (4.24 g, 12.5 mmol) and stirred for 1 h. The solution was extracted with dichloromethane (3 x 150 mL). The organic layer was dried over MgSO4, filtered, and concentrated. To the concentrated oil, hexanes, and ether were added and the suspension was again evaporated. This hexane/ether process was repeated until following the evaporation of solvent the product was obtained as a white solid. After overnight drying under high vacuum (3.3a′) was obtained as a tannish white solid (3.821 g, 60% yield). 1 H NMR (500 MHz, CDCl3) δ 7.80 (d, J = 7.8 Hz, 1H), 7.19 (d, J = 7.8, 1H), 7.11 (t, J – 7.8 Hz, 1H), 6.71 (t, J = 7.8 Hz, 1H), 6.65 (bs, 1H), 3.30 – 2.98 (m, 8H), 1.60 – 1.45 (m, 8H), 1.42 – 1.13 (m, 8H), 0.94 (t, J = 7.4 Hz, 12H). 13 C NMR (126 MHz, CDCl3) δ 139.2, 128.6, 127.6, 120.1, 119.8, 117.6, 58.6, 24.0, 19.8, 13.8. HRMS (ESI) m/z calcd for C6H5ClNO3S [M–Nn-Bu4]– 205.9679, found 205.9897. 134 Synthesis of tetrabutylammonium 2-bromophenyl sulfamate (3.3b´) 2-Bromoaniline (2.14 g, 12.5 mmol) and SO3•pyridine complex (2.19 g, 13.75 mmol) were placed in a 100 mL round bottom flask. Pyridine (17 mL) and dry dichloromethane (10 mL) were added and the mixture was stirred at rt for 18 h. After this time, the reaction was heated to 40 ºC for 1 h. Water (150 mL) was added and the mixture was washed once with dichloromethane (1 x 150 mL). The aqueous phase was treated with tetrabutylammonium hydrogen sulfate (4.24 g, 12.5 mmol) and stirred for 1 h. The solution was extracted with dichloromethane (3 x 150 mL). The organic layer was dried over MgSO4, filtered, and concentrated, resulting in an oil. To the concentrated oil, hexanes, and ether were added and the suspension was again evaporated. This hexane/ether process was repeated until following the evaporation of solvent the product was obtained as a white solid. After overnight drying under high vacuum (3.3b′) was obtained as a white solid (3.84 g, 62% yield). 1 H NMR (500 MHz, CDCl3) δ 7.80 (dd, J = 8.3, 1.5 Hz, 1H), 7.36 (dd, J = 8.0, 1.5 Hz, 1H), 7.15 (ddd, J = 8.3, 7.3, 1.5 Hz, 1H), 6.67 (bs, 1H), 6.65 (ddd, J = 8.0, 7.3, 1.5 Hz, 1H), 3.22 – 3.15 (m, 8H), 1.62 – 1.52 (m, 8H), 1.37 (m, 8H), 0.95 (t, J = 7.3 Hz, 12H). 13C NMR (126 MHz, CDCl3) δ 140.3, 131.9, 128.3, 120.5, 117.7, 110.5, 58.6, 24.0, 19.8, 13.8. HRMS (ESI) m/z calcd for C6H5BrNO3S [M–Nn-Bu4]– 249.9173, found 249.8044. 135 Synthesis of tetrabutylammonium 3-fluorophenyl sulfamate (3.3c´) 3-Fluoroaniline (1.3872 g, 12.5 mmol) and SO3•pyridine complex (2.19 g, 13.75 mmol) were placed in a 100 mL round bottom flask. Pyridine (17 mL) and dry dichloromethane (10 mL) were added and the mixture was stirred at rt for 18 h. After this time, the reaction was heated to 40 ºC for 1 h. Water (150 mL) was added and the mixture was washed once with dichloromethane (1 x 150 mL). The aqueous phase was treated with tetrabutylammonium hydrogen sulfate (4.25 g, 12.5 mmol) and stirred for 1 h. The solution was extracted with dichloromethane (3 x 150 mL). The organic layer was dried over MgSO4, filtered, and concentrated, resulting in an oil. To the concentrated oil, hexanes, and ether were added and the suspension was again evaporated. This hexane/ether process was repeated until following the evaporation of solvent the product was obtained as a white solid. After overnight drying under high vacuum (3.3c′) was obtained as a light orange solid (4.12 g, 71% yield). 1 H NMR (500 MHz, CDCl3) δ 7.20 – 6.88 (m, 3H), 6.78 (dd, J = 7.6, 1.9 Hz, 1H), 6.44 (td, J = 8.5, 2.5 Hz, 1H), 3.19 – 3.08 (m, 8H), 1.51 (m, 8H), 1.33 (m, 8H), 0.91 (t, J = 7.3 Hz, 12H). 13C NMR (126 MHz, CDCl3) δ 163.2 (d, J = 241.3 Hz), 144.6 (d, J = 11.2 Hz), 129.3 (d, J = 9.8 Hz), 112.1 (d, J = 2.3 Hz), 105.5 (dd, J = 21.5, 2.0 Hz), 103.4 (d, J = 25.5 Hz), 58.0, 23.5, 19.4, 13.4. 19 F NMR (470 MHz, CDCl3) δ –113.4 (ddd, J = 11.7, 8.4, 6.7 Hz). HRMS (ESI) m/z calcd for C6H5FNO3S [M–Nn-Bu4]– 189.9974, found 189.9108. 136 Synthesis of tetrabutylammonium 2-methoxyphenyl sulfamate (3.3d´) o-Anisidine (1.34 g, 11 mmol) and SO3•pyridine complex (2.19 g, 13.75 mmol) were placed in a 100 mL round bottom flask. Pyridine (17 mL) and dry dichloromethane (10 mL) were added and the mixture was stirred at rt for 18 h. After this time, the reaction was heated to 40 ºC for 1 h. Water (150 mL) was added and the mixture was washed once with dichloromethane (1 x 150 mL). The aqueous phase was treated with tetrabutylammonium hydrogen sulfate (4.24 g, 12.5 mmol) and stirred for 1 h. The solution was extracted with dichloromethane (3 x 150 mL). The organic layer was dried over MgSO4, filtered, and concentrated, resulting in an oil. To the concentrated oil, hexanes, and ether were added and the suspension was again evaporated. This hexane/ether process was repeated until following the evaporation of solvent the product was obtained as a white solid. After overnight drying under high vacuum (3.3d′) was obtained as a pinkish white solid (4.88 g, 91% yield). 1 H NMR (500 MHz, CDCl3) δ 7.66 (dd, J = 7.8, 1.4 Hz, 1H), 6.81 (ddd, J = 7.8, 6.4, 2.4 Hz, 1H), 6.74 (ddd, J = 7.1, 6.4, 1.4 Hz, 1H), 6.72 (dd, J = 7.1, 2.4 Hz, 1H), 6.63 (bs, 1H), 3.74 (s, 3H), 3.23 – 3.04 (m, 8H), 1.52 (m, 8H), 1.35 (m, 8H), 0.93 (t, J = 7.3 Hz, 12H). 13C NMR (126 MHz, CDCl3) δ 147.0, 132.5, 121.2, 119.4, 116.6, 109.8, 58.5, 55.6, 24.0, 19.7, 13.8. HRMS (ESI) m/z calcd for C7H8NO4S [M–Nn-Bu4]– 202.0174, found 202.0198. 137 Synthesis of tetrapropylammonium 2-fluorophenyl sulfamate (3.3e) 2-Fluoroaniline (0.67 g, 6 mmol) and SO3•pyridine complex (1.05 g, 6.6 mmol) were placed in a 100 mL round bottom flask. Pyridine (8 mL) and dry dichloromethane (5 mL) were added and the mixture was stirred at rt for 18 h. After this time, the reaction was heated to 40 ºC for 1 h. Water (70 mL) was added and the mixture was washed once with dichloromethane (1 x 70 mL). The aqueous phase was treated with tetrapropyl ammonium bromide (1.60 g, 6 mmol) and stirred for 1 h. The solution was extracted with dichloromethane (3 x 70 mL). The organic layer was dried over MgSO4, filtered, and concentrated, resulting in an oil. To the concentrated oil, hexanes and ether were added and the suspension was again evaporated. This hexane/ether process was repeated until following the evaporation of solvent the product was obtained as a white solid. After overnight drying under high vacuum (3.3e) was obtained as a white solid (0.55 g, 24% yield). 1 H NMR (500 MHz, CDCl3) δ 7.68 (td, J = 8.4, 1.7 Hz, 1H), 6.91 (ddd, J = 8.4, 7.7, 1.5 Hz, 1H), 6.86 (ddd, J = 11.2, 8.1, 1.5 Hz, 1H), 6.68 (dddd, J = 8.1, 7.7, 5.0, 1.7 Hz, 1H), 6.24 (s, 1H), 3.09 – 3.01 (m, 8H), 1.61 – 1.49 (m, 8H), 0.89 (t, J = 7.3 Hz, 12H). 13 C NMR (126 MHz, CDCl3) δ 151.3 (d, J = 238.6 Hz), 130.8 (d, J = 11.7 Hz), 124.3 (d, J = 3.6 Hz), 119.8 (d, J = 7.1 Hz), 118.5 (d, J = 2.2 Hz), 114.2 (d, J = 19.2 Hz), 60.2, 15.5, 10.7. 19 F NMR (470 MHz, CDCl3) δ –134.5 (ddd, J = 10.9, 8.4, 5.0 Hz). HRMS (ESI) m/z calcd for C6H5FNO3S [M–Nn-Pr4]– 189.9974, found 190.0019. 138 3.4.6. CHB of Sulfated Anilines Para borylation of tetrapropylammonium 2-chlorophenyl sulfamate (3.4a) 86% conversion, para : meta = 40 : 1 76% isolated yield, para : meta > 50 : 1 In a glove box, a 5.0 mL Wheaton microreactor equipped with a stir bar was charged with tetrapropylammonium 2-chlorophenyl sulfamate (196 mg, 0.5 mmol, 1 equiv), [Ir(cod)(OMe)] 2 (10 mg, 3.0 mol %), 4,4′-dimethoxy-2,2′-bipyridine (6.6 mg, 3.0 mol %), B2pin2 (128 mg, 0.5 mmol, 1 equiv) and dioxane (1.5 mL). The microreactor was capped with a Supelco teflon pressure cap and placed into an aluminum block pre-heated to 60 oC. After 36 h, an aliquot of the reaction was removed and concentrated under vacuum. The residue was dissolved in CDCl3 and a 1H NMR spectrum showed 86% conversion with a ratio of 40:1 para to meta borylation. Crude para borylated 2-chlorosulfamate: 1 H NMR (500 MHz, CDCl3) δ 7.74 (d, J = 8.2 Hz, 1H), 7.63 (d, J = 1.4 Hz, 1H), 7.52 (dd, J = 8.1, 1.5 Hz, 1H), 6.82 (s, 1H), 3.10 – 3.03 (m, 8H), 1.62 – 1.52 (m, 8H), 1.28 (s, 12H), 0.93 (t, J = 7.3 Hz, 12H). 13C NMR (126 MHz, CDCl3) δ 135.1, 134.2, 116.4, 83.6, 82.9, 67.0, 60.1, 24.8, 24.5, 15.5, 10.7. Concentrated HCl was added (2 drops, pH = 1–2) and the resultant mixture was stirred for 1 h. TLC eluting in CH2Cl2 showed the appearance of a new spot at rf = 0.5, whereas the crude borylated sulfamate did not move off the baseline. The solution was concentrated and pumped down under vacuum. The crude material was dissolved in CH2Cl2 and applied to a 5 g silica plug 139 packed in 1:99 hexane/CH₂Cl₂ to yield 96 mg of para borylated 2-chloroaniline as a white solid. (76% yield, mp 100–102 °C). 1 H NMR (500 MHz, CDCl3) δ 7.69 (d, J = 1.3 Hz, 1H), 7.49 (dd, J = 7.9, 1.4 Hz, 1H), 6.73 (d, J = 7.9 Hz, 1H), 4.24 (s, 2H), 1.32 (s, 12H). 13C NMR (126 MHz, CDCl3) 145.5, 136.0, 134.3, 118.7, 114.9, 83.6, 24.8. 11B NMR (160 MHz, CDCl3) δ 30.5. HRMS (ESI) m/z calcd for C12H18BClNO2 [M+H]+ 254.1119, found 254.1151. Para borylation of tetrabutylammonium 2-chlorophenyl sulfamate (3.4a′) 98% conversion, para : meta = 43 : 1 95% isolated yield, para : meta > 50 : 1 In a glove box, a 5.0 mL Wheaton microreactor equipped with a stir bar was charged with tetrabutylammonium 2-chlorophenyl sulfamate (225 mg, 0.5 mmol, 1 equiv), [Ir(cod)(OMe)]2 (10 mg, 3.0 mol %), 4,4′-dimethoxy-2,2′-bipyridine (6.6 mg, 6.0 mol %), B2pin2 (128 mg, 0.5 mmol, 1.0 equiv) and dioxane (1.5 mL). The microreactor was capped with a Supelco teflon pressure cap and placed into an aluminum block pre-heated to 60 oC. After 36 h, an aliquot of the reaction was removed and concentrated under vacuum. The residue was dissolved in CDCl3 and a 1H NMR spectrum showed 98% conversion with a ratio of 43:1 para to meta borylation. Concentrated HCl was added (2 drops, pH = 1–2) and the resultant mixture was stirred for 1 h. TLC eluting in CH2Cl2 showed the appearance of a new spot at rf = 0.5, whereas the crude borylated sulfamate did not move off the baseline. The solution was concentrated and pumped down under vacuum. The crude material was dissolved in CH2Cl2 and applied to a 5 g silica plug packed in 1:99 hexane/CH2Cl2 140 to yield 120 mg of para borylated 2-chloroaniline as a white solid. (95% yield, mp 100–102 °C). The NMR data were consistent with previously reported values. 33 1 H NMR (500 MHz, CDCl3) δ 7.69 (d, J = 1.3 Hz, 1H), 7.49 (dd, J = 7.9, 1.4 Hz, 1H), 6.73 (d, J = 7.9 Hz, 1H), 4.24 (s, 2H), 1.32 (s, 12H). 13C NMR (126 MHz, CDCl3) 145.5, 136.0, 134.3, 118.8, 114.9, 83.6, 24.8. 11B NMR (160 MHz, CDCl3) δ 30.6. HRMS (ESI) m/z calcd for C12H18BClNO2 [M+H]+ 254.1119, found 254.1310. Para borylation of tetrabutylammonium 2-bromophenyl sulfamate (3.4b′) 89% conversion, para : meta = 66 : 1 72% isolated yield, para : meta > 50 : 1 In a glove box, a 5.0 mL Wheaton microreactor equipped with a stir bar was charged with tetrabutylammonium 2-bromophenyl sulfamate (247 mg, 0.5 mmol, 1 equiv), [Ir(cod)(OMe)]2 (10 mg, 3.0 mol%), 4,4′-dimethoxy-2,2′-bipyridine (6.6 mg, 6.0 mol %), B2pin2 (128 mg, 0.5 mmol, 1.0 equiv) and dioxane (1.5 mL). The microreactor was capped with a Supelco teflon pressure cap and placed into an aluminum block pre-heated to 60 oC. After 36 h, an aliquot of the reaction was removed and concentrated under vacuum. The residue was dissolved in CDCl3 and a 1H NMR spectrum showed 89% conversion with a ratio of 66:1 para to meta borylation. Para borylated 2- bromosulfamate determined from the crude reaction mixture: 1 H NMR (500 MHz, CDCl3) δ 7.83 – 7.79 (m, 1H), 7.75 (dd, J = 8.2, 0.8 Hz, 1H), 7.57 (dd, J = 8.1, 1.4 Hz, 1H), 6.86 (s, 1H), 3.25 – 3.09 (m, 8H), 1.56 (m, 8H), 1.37 (m, 8H), 1.29 (s, 12H), 0.97 – 0.93 (m, 12H). 141 Concentrated HCl was added (2 drops, pH = 1–2) and the resultant mixture was stirred for 1 h. TLC eluting in CH2Cl2 showed the appearance of a new spot at rf = 0.5, whereas the crude borylated sulfamate did not move off the baseline. The solution was concentrated and pumped down under vacuum. The crude material was dissolved in CH2Cl2 and applied to a 5 g silica plug packed in 1:99 hexane/CH₂Cl₂ to yield 128 mg material. 1H NMR showed B2pin2 contamination in the isolated product. The mass of B2pin2 was calculated from mol fraction based on NMR integrations and subtracted from the mass of the isolated material. The mass of para borylated 2- bromoaniline present in the material was 88 mg. (72% yield). The material was washed in cold hexane and dried under vacuum to yield 55 mg of the pure para borylated 2-bromoaniline. (37% yield, mp 101–102 °C). NMR data was consistent with previously reported NMR values.46 1 H NMR (500 MHz, CDCl3) δ 7.86 (s, 1H), 7.52 (d, J = 7.9 Hz, 1H), 6.72 (d, J = 8.0 Hz, 1H), 4.29 (s, 2H), 1.32 (s, 12H). 13C NMR (126 MHz, CDCl3) δ 146.6, 139.3, 135.0, 114.8, 108.9, 83.6, 24.8. 11B NMR (160 MHz, CDCl3) δ 30.1. HRMS (ESI) m/z calcd for C12H18BBrNO2 [M+H]+ 298.0614, found 298.0787. Para borylation of tetrabutylammonium 3-fluorophenyl sulfamate (3.4c′) 96% conversion, para : meta = 2.8 : 1 In a glove box, a 5.0 mL Wheaton microreactor equipped with a stir bar was charged with tetrabutylammonium 3-fluorophenyl sulfamate (216 mg, 0.5 mmol, 1 equiv), [Ir(cod)(OMe)] 2 (10 mg, 3.0 mol %), 4,4′-dimethoxy-2,2′-bipyridine (6.6 mg, 6 mol %), B2pin2 (159 mg, 0.625 mmol, 1.25 equiv) and dioxane (1.5 mL). The microreactor was capped with a Supelco teflon pressure 142 cap and placed into an aluminum block pre-heated to 60 oC. After 36 h, an aliquot of the reaction was removed and diluted with CDCl3 and a 19F NMR spectrum showed 96% conversion with a ratio of 2.8:1 para to meta borylation. Characterization data was determined from the crude mixture of borylated material and borate byproducts. Para borylated 3-fluorophenyl sulfamate: 1 H NMR (500 MHz, CDCl3) δ 7.44 (dd, J = 8.1, 7.1 Hz, 1H), 6.93 (dd, J = 12.1, 1.9 Hz, 1H), 6.73 (dd, J = 8.2, 1.9 Hz, 1H), 5.91 (s, 1H), 3.16 – 3.07 (m, 8H), 1.48 (m, 8H), 1.33 – 1.28 (m, 8H), 1.27 (s, 12H), 0.88 (t, J = 7.3 Hz, 12H). 13C NMR (126 MHz, CDCl3) δ 168.5 (d, J = 247.9 Hz), 147.7 (d, J = 12.1 Hz), 137.1 (d, J = 10.2 Hz), 111.9 (d, J = 2.1 Hz), 102.9 (d, J = 28.8 Hz), 83.8, 58.6, 50.7, 24.8, 24.0, 19.6, 13.6. 19F NMR (470 MHz, CDCl3) δ –105.54. Meta borylated 3-fluorophenyl sulfamate: 1 H NMR (500 MHz, CDCl3) δ 7.32 (dt, J = 11.6, 2.4 Hz, 1H), 6.96 (d, J = 2.1 Hz, 1H), 6.85 (dd, J = 8.6, 2.5 Hz, 1H), 6.75 (s, 1H), 3.17 – 3.06 (m, 8H), 1.48 (m, 8H), 1.30 (m, 8H), 1.25 (s, 12H), 0.88 (t, J = 7.3 Hz, 12H). 13C NMR (126 MHz, CDCl3) δ 163.2 (d, J = 242.9 Hz), 144.0 (d, J = 10.2 Hz), 129.6 (d, J = 9.9 Hz), 112.2 (d, J = 20.0 Hz), 107.2 (d, J = 26.0 Hz), 83.7, 58.6, 24.8, 23.9, 19.6, 13.6. 19F NMR (470 MHz, CDCl3) δ –117.5. HRMS (ESI) m/z calcd for C12H16BFNO5S [M–Nn-Bu4]– 316.0826, found 316.1525. Borylation of tetrabutylammonium 3-fluorophenyl sulfamate - Acylation work-up (3.4c′) 96% conversion, para : meta = 2.4 : 1 76% isolated yield, para : meta = 2.1 : 1 143 In a glove box, a 5.0 mL Wheaton microreactor was charged with tetrabutyl ammonium 3-fluorophenyl sulfamate (216 mg, 0.5 mmol), [Ir(cod)(OMe)]2 (10 mg, 3 mol %), 4,4′-dimethoxy- 2,2′-bipyridine (6.6 mg, 6.0 mol %), B2pin2 (159 mg, 0.625 mmol) and dioxane (1.5 mL). The microreactor was capped with a teflon pressure cap and placed into an aluminum block pre-heated to 60 oC. After 36 h, an aliquot of the reaction mixture was taken and analyzed directly by 1H NMR to find the conversion and para:meta ratio. Acetyl chloride (0.08 mL, 1 mmol) was added and the resultant mixture was stirred for 4 h. The solution was concentrated and passed through a plug of silica gel (2% EtOAc in CHCl3 as eluent). The fractions containing product were collected, concentrated and washed with water (2 mL). The water layer was decanted and the residue was dried to give 106 mg of a mixture of para borylated N-(3-fluorophenyl)acetamide with the meta isomer (para:meta = 2.1:1) as a white solid (76% yield, mp 147.1–146.7 °C) NMR data was consistent with previously reported NMR values.47 Para: 1 H NMR (500 MHz, CDCl3) δ 7.78 (bs, 1H), 7.65 (dd, J = 8.1, 6.8 Hz, 1H), 7.47 (dd, J = 11.4, 1.9 Hz, 1H), 7.14 (dd, J = 8.1, 1.9 Hz, 1H), 2.17 (s, 3H), 1.33 (s, 12H). 13C NMR (126 MHz, CDCl3) δ 168.7, 167.8 (d, J = 250.0 Hz), 142.6 (d, J = 11.7 Hz), 137.4 (d, J = 9.7 Hz), 114.3, 106.5 (d, J = 29.6 Hz), 83.9, 24.8, 24.7. 11B NMR (160 MHz, CDCl3) δ 30.0. 19F NMR (470 MHz, CDCl3) δ –100.6 (dd, J = 11.4, 6.8 Hz). Meta: 1 H NMR (500 MHz, CDCl3) δ 7.76 (dt, J = 11.1, 2.3 Hz, 1H), 7.62 (bs, 1H), 7.35 (dd, J = 2.3, 0.8 Hz, 1H), 7.20 (dd, J = 8.3, 2.3 Hz, 1H), 2.16 (s, 3H), 1.31 (s, 12H). 13C NMR (126 MHz, CDCl3) δ 168.7, 162.8 (d, J = 246.0 Hz), 139.1 (d, J = 10.2 Hz), 121.1 (d, J = 2.8 Hz), 116.6 (d, J = 19.7 Hz), 110.4 (d, J = 26.9 Hz), 84.3, 24.8, 24.7. 11B NMR (160 MHz, CDCl3) δ 30.0. 19F NMR (470 144 MHz, CDCl3) δ –112.1 (dd, J = 11.1, 8.3 Hz). HRMS (ESI) m/z calcd for C14H18BFNO3 [M–H]– 278.1364, found 278.1364. Para borylation of tetrabutylammonium 2-methoxyphenyl sulfamate (3.4d′) 75% conversion, para : meta = 20: 1 59% isolated yield, para : meta > 20 : 1 In a glove box, a 5.0 mL Wheaton microreactor equipped with a stir bar was charged with tetrabutylammonium 2-methoxyphenyl sulfamate (222 mg, 0.5 mmol, 1 equiv), [Ir(cod)(OMe)] 2 (10 mg, 3.0 mol %), 4,4′-dimethoxy-2,2′-bipyridine (6.6 mg, 6 mol %), B2pin2 (128 mg, 0.5 mmol, 1.0 equiv) and dioxane (1.5 mL). The microreactor was capped with a Supelco teflon pressure cap and placed into an aluminum block pre-heated to 60 oC. After 48 h, an aliquot of the reaction was removed and concentrated under vacuum. The residue was dissolved in CDCl3 and a 1H NMR spectrum showed 75% conversion with a ratio of 20:1 para to meta borylation. Para borylated 2-methoxyphenyl sulfamate determined from the crude material: 1 H NMR (500 MHz, CDCl3) δ 7.58 (d, J = 7.9 Hz, 1H), 7.26 (d, J = 7.9 Hz, 1H), 7.08 (s, 1H), 6.76 (s, 1H), 3.75 (s, 3H), 3.07 – 3.00 (m, 8H), 1.42 (p, J = 7.8 Hz, 8H), 1.31 – 1.23 (m, 8H), 1.26 (s, 12H), 0.87 (t, J = 7.3 Hz, 12H). 13C NMR (126 MHz, CDCl3) δ 145.9, 135.3, 128.8, 115.3, 115.2, 83.3, 24.8, 24.5, 23.8, 19.5, 13.7. 11B NMR (160 MHz, CDCl3) δ 30.9. Anhydrous methanol (1 mL) was added to the reaction with stirring. 1M HCl in ether (0.5 mmol, 0.5 mL, 1 equiv) was added dropwise by syringe, until the pH was 7. The mixture was stirred 12 hours, then concentrated to a brown oil. The crude material was dissolved in CH2Cl2 and 145 applied to a 7 g silica plug eluting in CH2Cl2. After 100 mL CH2Cl2 was eluted, the eluent was changed to 1:1:98 ethyl acetate:triethylamine:CH2Cl2. Fractions were combined and concentrated to 68 mg of a pale pink solid, 59% yield, m.p 116–117 °C. Para borylated 2-methoxyaniline: 1 H NMR (500 MHz, CDCl3) δ 7.29 (dd, J = 7.6, 1.3 Hz, 1H), 7.20 (d, J = 1.3 Hz, 1H), 6.70 (d, J = 7.6 Hz, 1H), 4.00 (s, 2H), 3.89 (s, 3H), 1.33 (s, 12H). 13 C NMR (126 MHz, CDCl3) δ 146.4, 139.5, 128.8, 115.8, 114.0, 83.3, 55.5, 24.9. 11 B NMR (160 MHz, CDCl3) δ 30.9. HRMS (ESI) m/z calcd for C13H21BNO3 [M+H]+ 250.1614, found 250.1677. Para borylation of tetrapropylammonium 2-fluorophenyl sulfamate (3.4e) 94% conversion, para : meta = 2 : 1 53% isolated yield, para : meta = 10 : 1 In a glove box, a 5.0 mL Wheaton microreactor equipped with a stir bar was charged with tetrapropylammonium 2-fluorophenyl sulfamate (188 mg, 0.5 mmol, 1 equiv), [Ir(cod)(OMe)] 2 (10 mg, 3.0 mol %), 4,4′-dimethoxy-2,2′-bipyridine (6.6 mg, 6 mol %), B2pin2 (159 mg, 0.625 mmol, 1.25 equiv) and dioxane (1.5 mL). The microreactor was capped with a Supelco teflon pressure cap and placed into an aluminum block pre-heated to 60 oC. After 36 h, an aliquot of the reaction mixture was taken and analyzed directly by 1H NMR to find the conversion and para:meta ratio. HCl 12 M was added until pH = 1–2 and the resultant mixture was stirred for 1 h. The solution was concentrated and passed through a plug of silica gel (CHCl3 as eluent) to give 62 mg 146 of a mixture of para borylated 2-fluoroaniline with the meta isomer (para:meta = 10:1) as a white solid (53% yield, mp 90.6–96.2 °C). Para: 1 H NMR (500 MHz, CDCl3) δ 7.45 – 7.32 (m, 2H), 6.77 – 6.69 (m, 1H), 3.94 (br s, 2H), 1.32 (s, 12H). 13C NMR (126 MHz, CDCl3) δ 151.1 (d, J = 239.2 Hz), 137.6 (d, J = 12.5 Hz), 131.5 (d, J = 3.2 Hz), 121.0 (d, J = 16.2 Hz), 115.9 (d, J = 3.0 Hz), 83.6, 24.8. 19F NMR (470 MHz, CDCl3) δ –137.2 (dd, J = 11.7, 8.7 Hz). 11B NMR (160 MHz, CDCl3) δ 30.3 Meta: 1 H NMR (500 MHz, CDCl3) δ 7.09 (ddd, J = 7.6, 5.1, 1.8 Hz, 1H), 6.93 (t, J = 7.6 Hz, 1H), 6.87 (ddd, J = 9.4, 7.6, 1.8 Hz, 1H), 3.78 (br s, 2H), 1.36 (s, 12H). 13C NMR (126 MHz, CDCl3) δ 155.7 (d, J = 243.6 Hz), 134.3 (d, J = 14.8 Hz), 125.2 (d, J = 7.1 Hz), 124.0 (d, J = 3.6 Hz), 120.0 (d, J = 4.3 Hz), 83.8, 24.8. 19F NMR (470 MHz, CDCl3) δ –125.5 (dt, J = 9.4, 5.1 Hz). 11 B NMR (160 MHz, CDCl3) δ 30.3. HRMS (ESI) m/z calcd for C12H18BFNO2 [M+H]+ 238.1415, found 238.1488. 3.4.7. Preparation of Sulfated Benzyl Alcohols Synthesis of tetrapropylammonium 2-chlorobenzyl sulfate (3.5a) 2-Chlorobenzyl alcohol (0.86 g, 6 mmol) and SO3•pyridine complex (1.05 g, 6.6 mmol) were placed in a 100 mL round bottom flask. Pyridine (8 mL) and dry dichloromethane (5 mL) were added and the mixture was stirred at rt for 18 h. After this time, the reaction was heated to 40 ºC for 1 h. Water (70 mL) was added and the mixture was washed once with dichloromethane (1 147 x 70 mL). The aqueous phase was treated with tetrapropyl ammonium bromide (1.60 g, 6 mmol) and stirred for 1 h. The solution was extracted with dichloromethane (3 x 70 mL). The organic layer was dried over MgSO4, filtered, and concentrated. Diethyl ether and hexanes were added to evaporate the solvent to dryness and the product was obtained as a white solid (2.02 g, 83% yield). 1 H NMR (500 MHz, CDCl3) δ 7.63 (dd, J = 7.5, 1.8Hz, 1H), 7.26 (dd, J = 7.5, 1.5 Hz, 1H), 7.19 (td, J = 7.5, 1.5 Hz, 1H), 7.15 (td, J = 7.5, 1.8 Hz, 1H), 5.14 (s, 2H), 3.26 – 2.93 (m, 8H), 1.74 – 1.46 (m, 8H), 0.96 (t, J = 7.3 Hz, 12H). 13C NMR (126 MHz, CDCl3) δ 135.4, 132.0, 128.9, 128.6, 128.3, 126.4, 65.4, 60.0, 15.3, 10.5. HRMS (ESI) m/z calcd for C7H6ClO4S [M–Nn-Pr4]– 220.9675, found 220.9680. Synthesis of tetrabutylammonium 2-chlorobenzyl sulfate (3.5a´) 2-Chlorobenzyl alcohol (0.86 g, 6 mmol) and SO3•pyridine complex (1.05 g, 6.6 mmol) were placed in a 100 mL round bottom flask. Pyridine (8 mL) and dry dichloromethane (5 mL) were added and the mixture was stirred at rt for 18 h. After this time, the reaction was heated to 40 ºC for 1 h. Water (70 mL) was added and the mixture was washed once with dichloromethane (1 x 70 mL). The aqueous phase was treated with tetrabutyl ammonium hydrogen sulfate (2.13 g, 6 mmol) and stirred for 1 h. The solution was extracted with dichloromethane (3 x 70 mL). The organic layer was dried over MgSO4, filtered, and concentrated. Diethyl ether and hexanes were added to evaporate the solvent to dryness and the product was obtained as a white solid (2.28 g, 83% yield). 148 1 H NMR (500 MHz, CDCl3) δ 7.63 (dd, J = 7.5, 1.8Hz, 1H), 7.26 (dd, J = 7.5, 1.5 Hz, 1H), 7.19 (td, J = 7.5, 1.5 Hz, 1H), 7.15 (td, J = 7.5, 1.8 Hz, 1H), 5.13 (s, 2H), 3.34 – 3.04 (m, 8H), 1.56 (dq, J = 11.9, 8.0, 7.5 Hz, 8H), 1.35 (h, J = 7.4 Hz, 8H), 0.92 (t, J = 7.3 Hz, 12H). 13C NMR (126 MHz, CDCl3) δ 135.5, 131.9, 128.8, 128.6, 128.2, 126.4, 65.4, 58.1, 23.6, 19.4, 13.4. HRMS (ESI) m/z calcd for C7H6ClO4S [M–Nn-Bu4]– 220.9675, found 220.9689. Synthesis of tetrapropylammonium 2-bromobenzyl sulfate (3.5b) 2-Bromobenzyl alcohol (1.12 g, 6 mmol) and SO3•pyridine complex (1.05 g, 6.6 mmol) were placed in a 100 mL round bottom flask. Pyridine (8 mL) and dry dichloromethane (5 mL) were added and the mixture was stirred at rt for 18 h. After this time, the reaction was heated to 40 ºC for 1 h. Water (70 mL) was added and the mixture was washed once with dichloromethane (1 x 70 mL). The aqueous phase was treated with tetrapropyl ammonium bromide (1.60 g, 6 mmol) and stirred for 1 h. The solution was extracted with dichloromethane (3 x 70 mL). The organic layer was dried over MgSO4, filtered, and concentrated, resulting in an oil. To the concentrated oil, hexanes and ether were added and the suspension was again evaporated. This hexane/ether process was repeated until following the evaporation of solvent the product was obtained as a white solid. After overnight drying under high vacuum (3.5b) was obtained as a white solid (1.93 g, 71% yield) 1 H NMR (500 MHz, CDCl3) δ 7.57 (dd, J = 7.7, 1.7 Hz, 1H), 7.42 (dd, J = 7.7, 1.2 Hz, 1H), 7.21 (td, J = 7.7, 1.2 Hz, 1H), 7.05 (td, J = 7.7, 1.7 Hz, 1H), 5.04 (s, 2H), 3.14 – 3.07 (m, 8H), 1.68 – 1.50 (m, 8H), 0.90 (t, J = 7.3 Hz, 12H). 13 C NMR (126 MHz, CDCl3) δ 137.2, 132.0, 129.2, 128.7, 149 127.2, 121.9, 67.9, 60.2, 15.5, 10.8. HRMS (ESI) m/z calcd for C7H6BrO4S [M–Nn-Pr4]– 264.91702, found 264.7968. Synthesis of tetrabutylammonium 2-bromobenzyl sulfate (3.5b′) 2-Bromobenzyl alcohol (1.12 g, 6 mmol) and SO3•pyridine complex (1.05 g, 6.6 mmol) were placed in a 100 mL round bottom flask. Pyridine (8 mL) and dry dichloromethane (5 mL) were added and the mixture was stirred at rt for 18 h. After this time, the reaction was heated to 40 ºC for 1 h. Water (70 mL) was added and the mixture was washed once with dichloromethane (1 x 70 mL). The aqueous phase was treated with tetrabutyl ammonium hydrogen sulfate (2.13 g, 6 mmol) and stirred for 1 h. The solution was extracted with dichloromethane (3 x 70 mL). The organic layer was dried over MgSO4, filtered, and concentrated. To the concentrated oil, hexanes and ether were added and the suspension was again evaporated. This hexane/ether process was repeated until following the evaporation of solvent the product was obtained as a white solid. After overnight drying under high vacuum (3.5b’) was obtained as a white solid (1.321 g, 43% yield) 1 H NMR (500 MHz, CDCl3) δ 7.50 (dd, J = 7.8, 1.8 Hz, 1H), 7.35 (dd, J = 8.0, 1.2 Hz, 1H), 7.14 (ddd, J = 7.8, 7.4, 1.2 Hz, 1H), 6.99 (ddd, J = 8.0, 7.4, 1.8 Hz, 1H), 4.97 (s, 2H), 3.24 – 2.98 (m, 8H), 1.60 – 1.37 (m, 8H), 0.83 (t, J = 7.3 Hz, 12H). 13C NMR (126 MHz, CDCl3) δ 137.0, 131.8, 128.9, 128.5, 127.0, 121.6, 67.6, 59.9, 15.2, 10.5. HRMS (ESI) m/z calcd for C7H6BrO4S [M–Nn- Bu4]– 264.9170, found 264.9280. 150 Synthesis of tetrapropylammonium 2-trifluoromethylbenzyl sulfate (3.5c) 2-Trifluoromethylbenzyl alcohol (1.06 g, 6 mmol) and SO3•pyridine complex (1.05 g, 6.6 mmol) were placed in a 100 mL round bottom flask. Pyridine (8 mL) and dry dichloromethane (5 mL) were added and the mixture was stirred at rt for 18 h. After this time, the reaction was heated to 40 ºC for 1 h. Water (70 mL) was added and the mixture was washed once with dichloromethane (1 x 70 mL). The aqueous phase was treated with tetrapropyl ammonium bromide (1.60 g, 6 mmol) and stirred for 1 h. The solution was extracted with dichloromethane (3 x 70 mL). The organic layer was dried over MgSO4, filtered, and concentrated. To the concentrated oil, hexanes and ether were added and the suspension was again evaporate. This hexane/ether process was repeated until following the evaporation of solvent the product was obtained as a white solid. After overnight drying under high vacuum (3.5c) was obtained as a white solid (1.34 g, 51% yield). 1 H NMR (500 MHz, CDCl3) δ 7.81 (d, J = 7.8 Hz, 1H), 7.52 (d, J = 7.8 Hz, 1H), 7.45 (t, J = 7.8 Hz, 1H), 7.28 (t, J = 7.8 Hz, 1H), 5.18 (s, 2H), 3.28–2.91 (m, 8H), 1.69–1.42 (m, 8H), 0.90 (t, J = 7.3 Hz, 12H). 13C NMR (126 MHz, CDCl3) δ 136.5, 131.8, 129.1, 127.1, 126.8 (q, J = 31 Hz), 125.2 (q, J = 5.67 Hz), 124.3 (q, J = 275 Hz), 64.5 (q, J = 3.3 Hz), 60.2, 15.46, 10.6. 19F NMR (470 MHz, CDCl3) δ -59.91. HRMS (ESI) m/z calcd for C8H6F3O4S [M–Nn-Pr4]– 254.9939, found 254.8768. 151 Synthesis of tetrabutylammonium 2-trifluoromethylbenzyl sulfate (3.5c’) 2-Trifluoromethylbenzyl alcohol (1.06 g, 6 mmol) and SO3•pyridine complex (1.05 g, 6.6 mmol) were placed in a 100 mL round bottom flask. Pyridine (8 mL) and dry dichloromethane (5 mL) were added and the mixture was stirred at rt for 18 h. After this time, the reaction was heated to 40 ºC for 1 h. Water (70 mL) was added and the mixture was washed once with dichloromethane (1 x 70 mL). The aqueous phase was treated with tetrabutylammonium hydrogensulfate (2.04 g, 6 mmol) and stirred for 1 h. The solution was extracted with dichloromethane (3 x 70 mL). The organic layer was dried over MgSO4, filtered, and concentrated. To the concentrated oil, hexanes and ether were added and the suspension was again evaporate. This hexane/ether process was repeated until following the evaporation of solvent the product was obtained as a white solid. After overnight drying under high vacuum (3.5c’) was obtained as a white solid (1.20 g, 40% yield). 1 H NMR (500 MHz, CDCl3) δ 7.86 (d, J = 7.7 Hz, 1H), 7.55 (dd, J = 7.7, 1.2 Hz, 1H), 7.47 (td, J = 7.7, 1.2 Hz, 1H), 7.30 (t, J = 7.7 Hz, 1H), 5.22 (s, 2H), 3.36 – 3.09 (m, 8H), 1.61–1.50 (m, 8H), 1.39–1.29 (m, 8H), 0.91 (t, J = 7.4 Hz, 12H). 13C NMR (126 MHz, CDCl3) δ 136.7 (q, J = 1.9 Hz), 131.7, 129.1, 126.9, 126.7 (q, J = 30.6 Hz), 125.1 (q, J = 5.8 Hz), 124.3 (q, J = 273.7 Hz), 64.5 (q, J = 3.1 Hz), 58.5, 23.8, 19.6, 13.6. 19F NMR (470 MHz, CDCl3) δ -59.94. HRMS (ESI) m/z calcd for C8H6F3O4S [M–Nn-Bu4]– 254.9939, found 255.0028. 152 Synthesis of tetrapropylammonium 2-methylbenzyl sulfate (3.5d) o-Tolylmethanol (0.73 g, 6 mmol) and SO3•pyridine complex (1.05 g, 6.6 mmol) were placed in a 100 mL round bottom flask. Pyridine (8 mL) and dry dichloromethane (5 mL) were added and the mixture was stirred at rt for 18 h. After this time, the reaction was heated to 40 ºC for 1 h. Water (70 mL) was added and the mixture was washed once with dichloromethane (1 x 70 mL). The aqueous phase was treated with tetrapropyl ammonium bromide (1.60 g, 6 mmol) and stirred for 1 h. The solution was extracted with dichloromethane (3 x 70 mL). The organic layer was dried over MgSO4, filtered, and concentrated. To the concentrated oil, hexanes and ether were added and the suspension was again evaporate. This hexane/ether process was repeated until following the evaporation of solvent the product was obtained as a white solid. After overnight drying under high vacuum (3.5d) was obtained as a white solid (1.41 g, 71% yield). 1 H NMR (500 MHz, CDCl3) δ 7.31 (dd, J = 7.8, 1.5 Hz, 1H), 7.13 – 7.01 (m, 3H), 4.96 (s, 2H), 3.11 – 2.84 (m, 8H), 2.29 (s, 3H), 1.60–1.44 (m, 8H), 0.88 (t, J = 7.3 Hz, 12H). 13C NMR (126 MHz, CDCl3) δ 136.9, 135.5, 129.9, 128.8, 127.7, 125.5, 67.0, 60.1, 18.8, 15.4, 10.7. HRMS (ESI) m/z calcd for C8H9O4S [M–Nn-Pr4]– 201.0222, found 201.0271. Synthesis of tetrapropylammonium 2-(trifluoromethoxy)benzyl sulfate (3.5e) 153 (2-(Trifluoromethoxy)phenyl)methanol (1.15 g, 6 mmol) and SO3•pyridine complex (1.05 g, 6.6 mmol) were placed in a 100 mL round bottom flask. Pyridine (8 mL) and dry dichloromethane (5 mL) were added and the mixture was stirred at rt for 18 h. After this time, the reaction was heated to 40 ºC for 1 h. Water (70 mL) was added and the mixture was washed once with dichloromethane (1 x 70 mL). The aqueous phase was treated with tetrapropyl ammonium bromide (1.60 g, 6 mmol) and stirred for 1 h. The solution was extracted with dichloromethane (3 x 70 mL). The organic layer was dried over MgSO4, filtered, and concentrated. To the concentrated oil, hexanes and ether were added and the suspension was again evaporate. This hexane/ether process was repeated until following the evaporation of solvent the product was obtained as a white solid. After overnight drying under high vacuum (3.5e) was obtained as a white solid (1.72 g, 63% yield). 1 H NMR (500 MHz, CDCl3) δ 7.65 (dd, J = 7.2, 2.2 Hz, 1H), 7.25 – 7.18 (m, 2H), 7.13 (dp, J = 7.5, 1.7 Hz, 1H), 5.09 (s, 2H), 3.20 – 2.95 (m, 8H), 1.70 – 1.43 (m, 8H), 0.91 (t, J = 7.3 Hz, 12H). 13 C NMR (126 MHz, CDCl3) δ 146.2 (q, J = 1.9 Hz), 130.8, 129.7, 128.4, 126.7, 120.5 (q, J = 257.3 Hz), 120.0, 62.7, 60.3, 15.5, 10.6. 19F NMR (470 MHz, CDCl3) δ -57.02. HRMS (ESI) m/z calcd for C8H6F3O5S [M–Nn-Pr4]– 270.9888, found 270.9895. Synthesis of tetrapropylammonium 1-(2-bromophenyl)ethyl sulfate (3.5f) 1-(2-Bromophenyl)ethan-1-ol (0.80 g, 4 mmol) and SO3•pyridine complex (0.70 g, 4.4 mmol) were placed in a 100 mL round bottom flask. Pyridine (5.3 mL) and dry dichloromethane (3.3 mL) were added and the mixture was stirred at rt for 18 h. After this time, the reaction was 154 heated to 40 ºC for 1 h. Water (50 mL) was added and the mixture was washed once with dichloromethane (1 x 50 mL). The aqueous phase was treated with tetrapropyl ammonium bromide (1.06 g, 4 mmol) and stirred for 1 h. The solution was extracted with dichloromethane (3 x 50 mL). The organic layer was dried over MgSO4, filtered, and concentrated. To the concentrated oil, hexanes and ether were added and the suspension was again evaporate. This hexane/ether process was repeated until following the evaporation of solvent the product was obtained as a white solid. After overnight drying under high vacuum (3.5f) was obtained as a white solid (1.30 g, 70% yield). 1 H NMR (500 MHz, CDCl3) δ 7.66 (dd, J = 7.7, 1.7 Hz, 1H), 7.41 (dd, J = 7.7, 1.2 Hz, 1H), 7.24 (td, J = 7.7, 1.2 Hz, 1H), 7.03 (td, J = 7.7, 1.7 Hz, 1H), 5.71 (q, J = 6.4 Hz, 1H), 3.17 – 2.88 (m, 8H), 1.66 – 1.54 (m, 8H), 1.51 (d, J = 6.4 Hz, 3H), 0.93 (t, J = 7.3 Hz, 13H). 13C NMR (126 MHz, CDCl3) δ 144.0, 132.1, 128.1, 127.9, 127.4, 120.8, 74.2, 60.2, 23.2, 15.5, 10.8. HRMS (ESI) m/z calcd for C8H8BrO4S [M–Nn-Pr4]– 278.9327, found 278.9380. Synthesis of tetrapropylammonium 2-fluorobenzyl sulfate (3.5g) (2-Fluorophenyl)methanol (0.76, 6 mmol) and SO3•pyridine complex (1.05 g, 6.6 mmol) were placed in a 100 mL round bottom flask. Pyridine (8 mL) and dry dichloromethane (5 mL) were added and the mixture was stirred at 40 ºC for 8 h. Water (70 mL) was added and the mixture was washed once with dichloromethane (1 x 70 mL). The aqueous phase was treated with tetrapropyl ammonium bromide (1.60 g, 6 mmol) and stirred for 1 h. The solution was extracted with dichloromethane (3 x 70 mL). The organic layer was dried over MgSO 4, filtered, and concentrated. To the concentrated oil, hexanes and ether were added and the suspension was again 155 evaporate. This hexane/ether process was repeated until following the evaporation of solvent the product was obtained as a white solid. After overnight drying under high vacuum (3.5g) was obtained as a white solid (0.94 g, 40% yield). 1 H NMR (500 MHz, CDCl3) δ 7.48 (td, J = 7.5, 1.8 Hz, 0H), 7.18 (tdd, J = 7.6, 5.2, 1.8 Hz, 0H), 7.02 (td, J = 7.5, 1.2 Hz, 0H), 6.92 (ddd, J = 9.7, 8.2, 1.2 Hz, 0H), 5.03 (d, J = 1.4 Hz, 0H), 3.58 – 2.62 (m, 1H), 1.89 – 1.24 (m, 1H), 0.89 (t, J = 7.4 Hz, 1H).13C NMR (126 MHz, CDCl3) δ 160.41 (d, J = 246.9 Hz), 130.52 (d, J = 4.0 Hz), 129.21 (d, J = 7.9 Hz), 124.83 (d, J = 14.4 Hz), 123.88 (d, J = 3.7 Hz), 114.81 (d, J = 21.4 Hz), 62.26 (d, J = 4.4 Hz), 60.18 (d, J = 2.3 Hz), 15.45, 10.67.19F NMR (470 MHz, CDCl3) δ –122.02 (d, J = 8.4 Hz), –164.90. HRMS (ESI) m/z calcd for C7H6FO4S [M–Nn-Pr4]– 204.9971, found 205.0033. Synthesis of tetrapropylammonium 3-fluorobenzyl sulfate (3.5h) (3-Fluorophenyl)methanol (0.76 g, 6 mmol) and SO3•pyridine complex (1.05 g, 6.6 mmol) were placed in a 100 mL round bottom flask. Pyridine (8 mL) and dry dichloromethane (5 mL) were added and the mixture was stirred at 40 ºC for 8 h. Water (70 mL) was added and the mixture was washed once with dichloromethane (1 x 70 mL). The aqueous phase was treated with tetrapropyl ammonium bromide (1.60 g, 6 mmol) and stirred for 1 h. The solution was extracted with dichloromethane (3 x 70 mL). The organic layer was dried over MgSO 4, filtered, and concentrated. To the concentrated oil, hexanes and ether were added and the suspension was again evaporate. This hexane/ether process was repeated until following the evaporation of solvent the 156 product was obtained as a white solid. After overnight drying under high vacuum (3.5h) was obtained as a white solid (1.75 g, 75% yield). 1 H NMR (500 MHz, CDCl3) δ 7.17 (td, J = 8.1, 6.0 Hz, 1H), 7.14 – 6.94 (m, 2H), 6.94 – 6.76 (m, 1H), 4.92 (s, 1H), 3.58 – 2.54 (m, 7H), 1.93 – 1.25 (m, 8H), 0.87 (t, J = 7.3 Hz, 11H). 13C NMR (126 MHz, CDCl3) δ 162.62 (d, J = 244.9 Hz), 140.46 (d, J = 7.5 Hz), 129.62 (d, J = 8.1 Hz), 123.18 (d, J = 2.8 Hz), 114.53 (dd, J = 21.8, 1.5 Hz), 114.15 (d, J = 21.2 Hz), 67.84 (d, J = 1.9 Hz), 60.20, 15.43, 10.66. 19F NMR (470 MHz, CDCl3) δ –116.13 – –118.06 (m), –164.90. HRMS (ESI) m/z calcd for C7H6FO4S [M–Nn-Pr4]– 204.9971, found 205.0026. 3.4.8. CHB of Sulfated Benzyl Alcohols Para borylation of tetrapropyl ammonium 2-chlorobenzyl sulfate (3.6a) >99.9% conversion, para : meta = 18 : 1 69% yield, para : meta > 20 : 1 In a glove box, a 5.0 mL Wheaton microreactor was charged with tetrapropyl ammonium 2-chlorobenzyl sulfate (204 mg, 0.5 mmol), [Ir(cod)(OMe)] 2 (5 mg, 1.5 mol %), 4,4′-dimethoxy- 2,2′-bipyridine (3.3 mg, 3.0 mol %), B2pin2 (159 mg, 0.625 mmol) and dioxane (1.5 mL). The microreactor was capped with a teflon pressure cap and placed into an aluminum block pre-heated to 40 oC. After 12 h, an aliquot of the reaction mixture was taken and analyzed directly by 1H NMR to find the conversion and para:meta ratio. HCl 12 M was added until pH = 1–2 and the resultant mixture was stirred for 1 h. The solution was concentrated and washed with hexanes (0.5 mL). The hexane layer was decanted, and the remaining solution subjected to chromatographic separation 157 with silica gel (6% EtOAc in CHCl3 as eluent) to give 93 mg of para-borylated 2-chlorobenzyl alcohol as an oil (69% yield) 1 H NMR (500 MHz, CDCl3) δ 7.76 (s, 1H), 7.68 (d, J = 7.5 Hz, 1H), 7.48 (d, J = 7.5 Hz, 1H), 4.76 (s, 2H), 2.36 (s, 1H), 1.33 (s, 12H). 13C NMR (126 MHz, CDCl3) δ 141.1, 135.3, 133.2, 132.2, 11 127.8, 84.2, 62.7, 24.8. B NMR (160 MHz, CDCl3) 30.6. HRMS (APCI+) m/z calcd for C13H17BClO2 [M–OH–] 251.1010, found 251.1057. Para borylation of tetrabutyl ammonium 2-chlorobenzyl sulfate (3.6a′) >99.9% conversion, para : meta = 15 : 1 In a glove box, a 3.0 mL Wheaton microreactor was charged with tetrabutyl ammonium 2-chlorobenzyl sulfate (46 mg, 0.1 mmol), [Ir(cod)(OMe)] 2 (0.1 mL of 0.015 M solution, 1.5 mol %), 4,4′-dimethoxy-2,2′-bipyridine (0.1 mL of 0.03 M solution 3.0 mol %), B2pin2 (38 mg, 0.15 mmol) and dioxane (0.2 mL). The microreactor was capped with a teflon pressure cap and placed into an aluminum block pre-heated to 40 oC. After 14 h, an aliquot of the reaction mixture was taken and analyzed directly by 1H NMR to find the conversion and para:meta ratio. Para borylation of tetrapropyl ammonium 2-bromobenzyl sulfate (3.6b) 82% conversion, para : meta = 30 : 1 41% yield, para : meta = 35 : 1 158 In a glove box, a 5.0 mL Wheaton microreactor was charged with tetrapropyl ammonium 2-bromo benzyl sulfate (226 mg, 0.5 mmol), [Ir(cod)(OMe)] 2 (5 mg, 1.5 mol %), 4,4′-dimethoxy- 2,2′-bipyridine (3.3 mg, 3.0 mol %), B2pin2 (159 mg, 0.625 mmol) and dioxane (1.5 mL). The microreactor was capped with a teflon pressure cap and placed into an aluminum block pre-heated to 40 oC. After 12 h, an aliquot of the reaction mixture was taken and analyzed directly by 1H NMR to find the conversion and para:meta ratio. HCl 12 M was added until pH = 1–2 and the resultant mixture was stirred for 1 h. The solution was concentrated and subjected directly to chromatographic separation with silica gel (10% EtOAc in CHCl3 as eluent) to give 64 mg of para borylated 2-bromobenzyl alcohol with traces of the meta (para:meta = 35:1) isomer as an oil (41% yield) 1 H NMR (500 MHz, CDCl3) δ 7.95 (d, J = 1.1 Hz, 1H), 7.73 (dd, J = 7.5, 1.1 Hz, 1H), 7.48 (d, J = 7.5 Hz, 1H), 4.74 (s, 2H), 1.34 (s, 12H). 13 C NMR (126 MHz, CDCl3) δ 142.6, 138.5, 133.9, 127.9, 122.2, 84.2, 65.0, 24.8. 11B NMR (160 MHz, CDCl3) 30.3. HRMS (APCI+) m/z calcd for C13H17BBrO2 [M–OH–] 295.0505, found 295.0595. Para borylation of tetrabutyl ammonium 2-bromobenzyl sulfate (3.6b′) >99.9% conversion, para : meta = 23 : 1 In a glove box, a 3.0 mL Wheaton microreactor was charged with tetrabutyl ammonium 2-bromobenzyl sulfate (51 mg, 0.1 mmol), [Ir(cod)(OMe)]2 (0.1 mL of 0.015 M solution, 1.5 mol %), 4,4′-dimethoxy-2,2′-bipyridine (0.1 mL of 0.03 M solution 3.0 mol %), B2pin2 (32 mg, 0.125 mmol) and dioxane (0.2 mL). The microreactor was capped with a teflon pressure cap and placed 159 into an aluminum block pre-heated to 40 oC. After 14 h, an aliquot of the reaction mixture was taken and analyzed directly by 1H NMR to find the conversion and para:meta ratio. Para borylation of tetrapropyl ammonium 2-trifluoromethylbenzyl sulfate (3.6c) >99.9% conversion, para : meta = 9 : 1 77% yield, para : meta = 9 : 1 In a glove box, a 5.0 mL Wheaton microreactor was charged with tetrapropyl ammonium 2-trifluoromethyl benzyl sulfate (221 mg, 0.5 mmol), [Ir(cod)(OMe)]2 (5 mg, 1.5 mol %), 4,4′- dimethoxy-2,2′-bipyridine (3.3 mg, 3.0 mol %), B2pin2 (128 mg, 0.5 mmol) and dioxane (1.5 mL). The microreactor was capped with a teflon pressure cap and placed into an aluminum block pre- heated to 40 oC. After 20 h, an aliquot of the reaction mixture was taken and analyzed directly by 1 H NMR to find the conversion and para:meta ratio. HCl 12 M was added until pH = 1–2 and the resultant mixture was stirred for 1 h. The solution was concentrated and passed through a plug of silica gel (4% EtOAc in CHCl3 as eluent) to give 117 mg of a mixture of para borylated 2- trifluorobenzyl alcohol with the meta isomer (para:meta = 9:1) as an oil (77% yield). 1 H NMR (500 MHz, CDCl3) δ 8.03 (s, 1H), 7.95 (d, J = 7.7 Hz, 1H), 7.69 (d, J = 7.7 Hz, 1H), 4.84 (s, 2H), 2.80 (bs, 1H), 1.34 (s, 12H). 13C NMR (126 MHz, CDCl3) δ 142.3 (q, J = 1.6 Hz), 138.4 (q, J = 1.4 Hz), 131.8 (q, J = 5.6 Hz), 127.5, 126.3 (q, J = 30.7 Hz), 124.5 (q, J = 275.0 Hz), 84.3, 61.1 (q, J = 5.5 Hz), 24.8. 11B NMR (160 MHz, CDCl3) 30.8. 19 F NMR (470 MHz, CDCl3) -63.2. HRMS (APCI+) m/z calcd for C14H17BF3O2 [M–OH–] 285.1274, found 285.1302. 160 Para borylation of tetrabutyl ammonium 2-trifluoromethylbenzyl sulfate (3.6c′) >99.9% conversion, para : meta = 8 : 1 In a glove box, a 3.0 mL Wheaton microreactor was charged with tetrabutylammonium 2- trifluoromethylbenzyl sulfate (50 mg, 0.1 mmol), [Ir(cod)(OMe)] 2 (0.1 mL of 0.015 M solution, 1.5 mol %), 4,4′-dimethoxy-2,2′-bipyridine (0.1 mL of 0.03 M solution 3.0 mol %), B2pin2 (25 mg, 0.10 mmol) and dioxane (0.2 mL). The microreactor was capped with a teflon pressure cap and placed into an aluminum block pre-heated to 40 oC. After 20 h, an aliquot of the reaction mixture was taken and analyzed directly by 1H NMR to find the conversion and para:meta ratio. Para borylation of tetrapropyl ammonium 2-methylbenzyl sulfate (3.6d) 78% conversion, para : meta = 5 : 1 26% yield, para : meta = 35 : 1 In a glove box, a 5.0 mL Wheaton microreactor was charged with tetrapropylammonium 2-methyl benzyl sulfate (194 mg, 0.5 mmol), [Ir(cod)(OMe)]2 (10 mg, 3 mol %), 4,4′-dimethoxy- 2,2′-bipyridine (6.6 mg, 6.0 mol %), B2pin2 (159 mg, 0.625 mmol) and dioxane (1.5 mL). The microreactor was capped with a teflon pressure cap and placed into an aluminum block pre-heated to 60 oC. After 36 h, an aliquot of the reaction mixture was taken and analyzed directly by 1H NMR to find the conversion and para:meta ratio. HCl 12 M was added until pH = 1–2 and the resultant 161 mixture was stirred for 1 h. The solution was concentrated and subjected directly to chromatographic separation with silica gel (1.5% EtOAc in CHCl3 as eluent) to give 33 mg of para borylated 2-methylbenzyl alcohol with traces of the meta (para:meta = 35:1) isomer as a colorless oil (26% yield) 1 H NMR (500 MHz, CDCl3) δ 7.67 (d, J = 7.5 Hz, 1H), 7.40 (d, J = 7.5 Hz, 1H), 4.73 (d, J = 4.6 Hz, 2H), 2.36 (s, 3H), 1.58 (bs, 1H) 1.36 (s, 13H). 13C NMR (126 MHz, CDCl3) δ 141.84, 136.57, 135.10, 132.64, 126.50, 83.77, 63.48, 24.85, 18.41. 11B NMR (160 MHz, CDCl3) δ 31.01. HRMS (APCI+) m/z calcd for C14H20BO2 [M–OH–] 231.1556, found 231.1573. Para borylation of tetrapropyl ammonium 2-trifluoromethoxybenzyl sulfate (3.6e) >99.9% conversion, para : meta = 22 : 1 79% yield, para : meta = 24 : 1 In a glove box, a 5.0 mL Wheaton microreactor was charged with tetrapropyl ammonium 2-trifluoromethoxy benzyl sulfate (229 mg, 0.5 mmol), [Ir(cod)(OMe)]2 (10 mg, 3 mol %), 4,4′- dimethoxy-2,2′-bipyridine (6.6 mg, 6.0 mol %), B2pin2 (159 mg, 0.625 mmol) and dioxane (1.5 mL). The microreactor was capped with a teflon pressure cap and placed into an aluminum block pre-heated to 40 oC. After 36 h, an aliquot of the reaction mixture was taken and analyzed directly by 1H NMR to find the conversion and para:meta ratio. HCl 12 M was added until pH = 1–2 and the resultant mixture was stirred for 1 h. The solution was concentrated and passed through a plug of silica gel (2% EtOAc in CHCl3 as eluent) to give 126 mg of a mixture of para borylated 2- trifluoromethoxyphenol with the meta isomer (para:meta = 24:1) as an oil (79% yield). 162 1 H NMR (500 MHz, CDCl3) δ 7.71 (dd, J = 7.5, 1.0 Hz, 1H), 7.61 (d, J = 1.0 Hz, 1H), 7.53 (d, J = 7.5 Hz, 1H), 4.75 (s, 2H), 2.69 (bs, 1H), 1.33 (s, 12H). 13 C NMR (126 MHz, CDCl3) δ 146.1, 136.4, 133.3, 128.0, 126.1, 120.4 (q, J = 257.5 Hz), 84.1, 59.4, 24.7. 11B NMR (160 MHz, CDCl3) δ 30.20. 19F NMR (470 MHz, CDCl3) δ -60.26. HRMS (APCI+) m/z calcd for C14H17BF3O3 [M– OH–] 301.1223, found 301.1248. Para borylation of tetrapropyl ammonium 1-(2-bromophenyl)ethyl sulfate (3.6f) >99.9% conversion, para : meta = 11 : 1 79% yield, para : meta = 13 : 1 In a glove box, a 5.0 mL Wheaton microreactor was charged with tetrapropyl ammonium 1-(2-bromophenyl)ethyl sulfate (233 mg, 0.5 mmol), [Ir(cod)(OMe)] 2 (5 mg, 1.5 mol %), 4,4′- dimethoxy-2,2′-bipyridine (3.3 mg, 3.0 mol %), B2pin2 (128 mg, 0.5 mmol) and dioxane (1.5 mL). The microreactor was capped with a teflon pressure cap and placed into an aluminum block pre- heated to 40 oC. After 24 h, an aliquot of the reaction mixture was taken and analyzed directly by 1 H NMR to find the conversion and para:meta ratio. HCl 12 M was added until pH = 1–2 and the resultant mixture was stirred for 1 h. The solution was concentrated and passed through a plug of silica gel (CHCl3 as eluent) to give 129 mg of a mixture of para borylated 1-(2- bromophenyl)ethan-1-ol with the meta isomer (para:meta = 13:1) as an oil (79% yield). 1 H NMR (500 MHz, CDCl3) δ 7.94 (d, J = 1.1 Hz, 1H), 7.75 (dd, J = 7.6, 1.1 Hz, 1H), 7.59 (d, J = 7.6 Hz, 1H), 5.23 (q, J = 6.4 Hz, 1H), 2.24 (bs, 1H), 1.47 (d, J = 6.4 Hz, 3H), 1.34 (s, 12H). 13C NMR (126 MHz, CDCl3) δ 147.6, 138.8, 134.1, 126.1, 121.6, 84.1, 69.3, 24.8, 23.5. 11 B NMR 163 (160 MHz, CDCl3) δ 30.4. HRMS (APCI+) m/z calcd for C14H19BBrO2 [M–OH–] 309.0661, found 309.0687. Para borylation of tetrapropyl ammonium 2-fluorobenzyl sulfate (3.6g) 97% conversion, para : meta : dimeta = 7 : 1 : 4 72% yield, para : meta : dimeta = 10.6 : 1 : 1.2 In a glove box, a 5.0 mL Wheaton microreactor was charged with tetrapropyl ammonium 2-fluorobenzyl sulfate (196 mg, 0.5 mmol), [Ir(cod)(OMe)] 2 (5 mg, 1.5 mol %), 4,4′-dimethoxy- 2,2′-bipyridine (3.3 mg, 3.0 mol %), B2pin2 (159 mg, 0.626 mmol) and dioxane (1.5 mL). The microreactor was capped with a teflon pressure cap and placed into an aluminum block pre-heated to 60 oC. After 36 h, an aliquot of the reaction mixture was taken and analyzed directly by 1H NMR to find the conversion and para:meta ratio. HCl 12 M was added until pH = 1–2 and the resultant mixture was stirred for 1 h. The solution was concentrated and passed through a plug of silica gel (5% EtOAc in CHCl3 as eluent) to give 91.2 mg of a mixture of para borylated (2- fluorophenyl)methanol with the meta isomer and diborylated product (para:meta:di = 10.6:1:1.2) as an oil (69% yield). 1 H NMR (500 MHz, CDCl3) δ 7.61 – 7.52 (m, 1H), 7.48 – 7.37 (m, 2H), 4.75 (d, J = 12.7 Hz, 3H), 2.17 (bs, 1H), 1.34 (s, 12H). 13C NMR (126 MHz, CDCl3) δ 160.1 (d, J = 246.6 Hz), 130.9 (d, J = 14.7 Hz), 130.6 (d, J = 3.4 Hz), 128.5 (d, J = 3.9 Hz), 120.8 (d, J = 19.5 Hz), 84.1, 59.2 (d, J = 4.6 Hz), 24.8. 11B NMR (160 MHz, CDCl3) δ 30.47.19F NMR (470 MHz, CDCl3) δ –108.48, –112.94 (d, J = 6.6 Hz), –124.36, –164.90 (t, J = 0.9 Hz). HRMS (APCI+) m/z calcd for C13H17BFO2 [M– OH–] 235.1306, found 235.1337. 164 Para borylation of tetrapropyl ammonium 3-fluorobenzyl sulfate (3.6h) >99.9% conversion, para : meta = 2 : 1 63% yield, para : meta = 1.9 : 1 In a glove box, a 5.0 mL Wheaton microreactor was charged with tetrapropyl ammonium 3-fluorobenzyl sulfate (196 mg, 0.5 mmol), [Ir(cod)(OMe)]2 (5 mg, 1.5 mol %), 4,4′-dimethoxy- 2,2′-bipyridine (3.3 mg, 3.0 mol %), B2pin2 (159 mg, 0.626 mmol) and dioxane (1.5 mL). The microreactor was capped with a teflon pressure cap and placed into an aluminum block pre-heated to 60 oC. After 36 h, an aliquot of the reaction mixture was taken and analyzed directly by 1H NMR to find the conversion and para:meta ratio. HCl 12 M was added until pH = 1–2 and the resultant mixture was stirred for 1 h. The solution was concentrated and passed through a plug of silica gel (4% EtOAc in CHCl3 as eluent) to give 79.1 mg of a mixture of para borylated (3- fluorophenyl)methanol with the meta isomer (para:meta = 1.9:1) as an oil (63% yield). 1 H NMR (500 MHz, CDCl3) δ 7.67 (dd, J = 7.6, 6.2 Hz, 1H), 7.08 (d, J = 7.6 Hz, 1H), 7.01 (dd, J = 10.1, 1.4 Hz, 1H), 4.65 (s, 2H), 2.71 (bs, 1H), 2.62 (bs, 1H), 1.35 (s, 12H). 13C NMR (126 MHz, CDCl3) δ 167.4 (d, J = 250.9 Hz), 162.7 (d, J = 246.8 Hz), 147.3 (d, J = 8.0 Hz), 143.1 (d, J = 6.3 Hz), 136.9 (d, J = 8.2 Hz), 128.4 (d, J = 2.8 Hz), 121.5 (d, J = 3.0 Hz), 119.9 (d, J = 19.5 Hz), 116.5 (d, J = 21.9 Hz), 113.2 (d, J = 24.6 Hz), 84.2, 83.9, 75.1, 64.3 (d, J = 1.7 Hz), 64.2 (d, J = 1.8 Hz), 24.8, 24.8. 11B NMR (160 MHz, CDCl3) δ 30.6. 19F NMR (470 MHz, CDCl3) δ –103.79, –107.40 (m), –117.31, –164.90. HRMS (APCI+) m/z calcd for C13H17BFO2 [M–OH–] 235.1306, found 235.1387. 165 3.5. Notes Parts of this chapter were reprinted with permission from Montero Bastidas, J. R.; Oleskey, T. J.; Miller, S. L.; Smith, M. R., III; Maleczka, R. E., Jr. Para-Selective, Iridium-Catalyzed C−H Borylations of Sulfated Phenols, Benzyl Alcohols, and Anilines Directed by Ion-Pair Electrostatic Interactions. J. Am. Chem. Soc. 2019, 141, 15483-15487. Copyright 2021 American Chemical Society The work presented in this chapter was not all conducted by Montero Bastidas, J. R. Substrate exploration was a team effort with Oleskey, T. J. (sulfated phenols and benzyl alcohols) and Miller, S. L. (sulfated anilines). 166 APPENDIX 167 1 H NMR of commercial 4-chloro-3-hydroxyphenylBpin (meta borylated 2-chlorophenol, 3.2a) (500 MHz, CDCl3) 168 1 H NMR of commercial 3-chloro-4-hydroxyphenylBpin (Para borylated 2-chlorophenol) (500 MHz, CDCl3) 169 1 H NMR control spectrum of 7.0 x10-7 mols meta-2a (500 MHz, CDCl3) 170 1 H NMR spectrum of 14:1 mixture of para-3.2a to meta-3.2a (500 MHz, CDCl3) 171 1 H NMR spectrum of 28:1 mixture of para-3.2a to meta-3.2a (500 MHz, CDCl3) 172 1 H NMR spectrum of 42:1 mixture of para-3.2a to meta-3.2a Conditions: 25 °C, 500 MHz, CDCl3 173 1 H NMR spectrum of 56:1 mixture of para-3.2a to meta-3.2a (500 MHz, CDCl3) 174 1 H NMR spectrum of tetrabutylammonium 2-chlorosulfate (3.1a′) (500 MHz, CDCl3) 175 13 C NMR spectrum of tetrabutylammonium 2-chlorosulfate (3.1a′) (126 MHz, CDCl3) 176 1 H NMR spectrum of tetrapropylammonium 2-chlorosulfate (3.1a) (500 MHz, CDCl3) 177 13 C NMR spectrum of tetrapropylammonium 2-chlorophenylsulfate (3.1a) (126 MHz, CDCl3) 178 1 H NMR spectrum of tetraethylammonium 2-chlorophenylsulfate (3.1a′′) (500 MHz, CDCl3) 179 13 C NMR spectrum of tetraethylammonium 2-chlorophenylsulfate (3.1a′′) (126 MHz, CDCl3) 180 1 H NMR spectrum of tetrapropylammonium 2-bromophenylsulfate (3.1b) (500 MHz, CDCl3) 181 13 C NMR spectrum of tetrapropylammonium 2-bromophenylsulfate (3.1b) (126 MHz, CDCl3) 182 1 H NMR spectrum of tetrapropylammonium 2-iodophenylsulfate (3.1c) (500 MHz, CDCl3) 183 13 C NMR spectrum of tetrapropylammonium 2-iodophenylsulfate (3.1c) (126 MHz, CDCl3) 184 1 H NMR spectrum of 2-(trifluoromethoxy)phenylsulfate (3.1d) (500 MHz, CDCl3) 185 13 C NMR spectrum of 2-(trifluoromethoxy)phenylsulfate (3.1d) (126 MHz, CDCl3) 186 19 F NMR spectrum of 2-(trifluoromethoxy)phenylsulfate (3.1d) (470 MHz, CDCl3) 187 1 H NMR spectrum of tetrapropylammonium 2-methoxyphenylsulfate (3.1e) (500 MHz, CDCl3) 188 13 C NMR spectrum of tetrapropylammonium 2-methoxyphenylsulfate (3.1e) (126 MHz, CDCl3) 189 1 H NMR spectrum of tetrapropylammonium 2-(trifluoromethyl)phenylsulfate (3.1f) (500 MHz, CDCl3) 190 13 C NMR spectrum of tetrapropylammonium 2-(trifluoromethyl)phenylsulfate (3.1f) (126 MHz, CDCl3) 191 19 F NMR spectrum of tetrapropylammonium 2-(trifluoromethyl)phenylsulfate (3.1f) (470 MHz, CDCl3) 192 1 H NMR spectrum of tetrapropylammonium 2-methylphenylsulfate (3.1g) (500 MHz, CDCl3) 193 13 C NMR spectrum of tetrapropylammonium 2-methylphenylsulfate (3.1g) (126 MHz, CDCl3) 194 1 H NMR spectrum of tetrapropylammonium 2-isopropylphenylsulfate (3.1h) (500 MHz, CDCl3) 195 13 C NMR spectrum of tetrapropylammonium 2-isopropylphenylsulfate (3.1h) (126 MHz, CDCl3) 196 1 H NMR spectrum of tetrapropylammonium 2-cyanophenylsulfate (3.1i) (500 MHz, CDCl3) 197 13 C NMR spectrum of tetrapropylammonium 2-cyanophenylsulfate (3.1i) (126 MHz, CDCl3) 198 1 H NMR spectrum of tetrapropylammonium 2-fluorophenylsulfate (3.1j) (500 MHz, CDCl3) 199 13 C NMR spectrum of tetrapropylammonium 2-fluorophenylsulfate (3.1j) (126 MHz, CDCl3) 200 19 F NMR spectrum of tetrapropylammonium 2-fluorophenylsulfate (3.1j) (470 MHz, CDCl3) 201 1 H NMR spectrum of tetrapropylammonium 2-bromo-6-fluorophenylsulfate (3.1k) (500 MHz, CDCl3) 202 13 C NMR spectrum of tetrapropylammonium 2-bromo-6-fluorophenylsulfate (3.1k) (126 MHz, CDCl3) 203 19 F NMR spectrum of 2-bromo-6-fluorophenylsulfate (3.1k) (470 MHz, CDCl3) 204 1 H NMR spectrum of tetrapropylammonium 3-fluorophenylsulfate (3.1l) (500 MHz, CDCl3) 205 13 C NMR spectrum of tetrapropylammonium 3-fluorophenylsulfate (3.1l) (126 MHz, CDCl3) 206 19 F NMR spectrum of tetrapropylammonium 3-fluorophenylsulfate (3.1l) (470 MHz, CDCl3) 207 1 H NMR spectrum of tetrapropylammonium 2,3-difluorophenylsulfate (3.1m) (500 MHz, CDCl3) 208 13 C NMR spectrum of tetrapropylammonium 2,3-difluorophenylsulfate (3.1m) (126 MHz, CDCl3) 209 19 F NMR spectrum of tetrapropylammonium 2,3-difluorophenylsulfate (3.1m) (470 MHz, CDCl3) 210 1 H NMR spectrum of tetrapropylammonium 3-cyanophenylsulfate (3.1n) (500 MHz, CDCl3) 211 13 C NMR spectrum of tetrapropylammonium 3-cyanophenylsulfate (3.1n) (126 MHz, CDCl3) 212 1 H NMR spectrum of tetrapropylammonium 3-methoxyphenylsulfate (3.1o) (500 MHz, CDCl3) 213 13 C NMR spectrum of tetrapropylammonium 3-methoxyphenylsulfate (3.1o) (126 MHz, CDCl3) 214 1 H NMR spectrum of tetrapropylammonium 3-chlorophenylsulfate (3.1p) (500 MHz, CDCl3) 215 13 C NMR spectrum of tetrapropylammonium 3-chlorophenylsulfate (3.1p) (126 MHz, CDCl3) 216 1 H NMR spectrum of tetrapropylammonium 2-phenylsulfate (3.1q) (500 MHz, CDCl3) 217 13 C NMR spectrum of tetrapropylammonium 2-phenylsulfate (3.1q) (126 MHz, CDCl3) 218 1 H NMR reaction mixture for the Para borylation of tetrapropylammonium 2-chlorophenylsulfate (3.2a) (500 MHz, CDCl3) 219 1 H NMR reaction mixture for the Para borylation of tetrabutylammonium 2-chlorophenylsulfate (3.2a’) (500 MHz, CDCl3) 220 1 H NMR reaction mixture for the Para borylation of tetraethylammonium 2-chlorophenylsulfate (3.2a’’) (500 MHz, CDCl3) 221 1 H NMR spectrum of Para borylated 2-chlorophenol (3.2a) (500 MHz, CDCl3) 222 13 C NMR spectrum of Para borylated 2-chlorophenol (3.2a) (126 MHz, CDCl3) 223 11 B NMR spectrum of Para borylated 2-chlorophenol (3.2a) (160 MHz, CDCl3) 224 1 H NMR reaction mixture for the Para borylation of tetrapropyl ammonium 2-bromophenylsulfate (3.2b) (500 MHz, CDCl3) 225 1 H NMR spectrum of Para borylated 2-bromophenol (3.2b) (500 MHz, CDCl3) 226 13 C NMR spectrum of Para borylated 2-bromophenol (3.2b) (126 MHz, CDCl3) 227 11 B NMR spectrum of Para borylated 2-bromophenol (3.2b) (160 MHz, CDCl3) 228 1 H NMR reaction mixture for Para borylation of tetrapropyl ammonium 2-iodophenylsulfate (crude 3.2c) (500 MHz, CDCl3) 229 1 H NMR spectrum of Para borylated 2-iodophenol (3.2c) (500 MHz, CDCl3) 230 13 C NMR spectrum of Para borylated 2-iodophenol (3.2c) (126 MHz, CDCl3) 231 11 B NMR spectrum of Para borylated 2-iodophenol (3.2c) (160 MHz, CDCl3) 232 1 H NMR reaction mixture of para-borylated tetrapropylammonium 2-(trifluoromethoxy)phenylsulfate (3.2d) (500 MHz, CDCl3) 233 1 H NMR spectrum of Para borylated 2(trifluoromethoxy)phenol (3.2d) (500 MHz, CDCl 3) 234 13 C NMR spectrum of Para borylated 2-(trifluoromethoxy)phenol (3.2d) (126 MHz, CDCl3) 235 11 B NMR spectrum of Para borylated 2-(trifluoromethoxy)phenol (3.2d) (160 MHz, CDCl3) 236 19 F NMR spectrum of Para borylated 2-(trifluoromethoxy)phenol (3.2d) (470 MHz, CDCl3) 237 1 H NMR reaction mixture of para-borylated tetrapropylammonium 2-methoxyphenylsulfate (crude 3.2e) (500 MHz, CDCl3) 238 1 H NMR spectrum of Para borylated 2-methoxyphenol (3.2e) (500 MHz, C6D6) 239 13 C NMR spectrum of Para borylated 2-methoxyphenol (3.2e) (126 MHz, C6D6) 240 11 B NMR spectrum of Para borylated 2-methoxyphenol (3.2e) (160 MHz, C6D6) 241 1 H NMR reaction mixture of para-borylated tetrapropylammonium 2-trifluoromethylphenylsulfate (3.2f) (500 MHz, C6D6) 242 1 H NMR spectrum of Para borylated 2-trifluoromethylphenol (3.2f) (500 MHz, CDCl3) 243 13 C NMR spectrum of Para borylated 2-trifluoromethylphenol (3.2f) (126 MHz, CDCl3) 244 11 B NMR of Para borylated 2-trifluoromethylphenol (3.2f) (160 MHz, CDCl3) 245 19 F NMR spectrum of 2-trifluoromethylphenol (3.2f) (470 MHz, CDCl3) 246 1 H NMR reaction mixture for the Para borylation of tetrapropyl ammonium 2-methylphenylsulfate (3.2g) (500 MHz, C6D6) 247 1 H NMR spectrum of Para borylated 2-methylphenol (3.2g) (500 MHz, CDCl3) 248 13 C NMR spectrum of Para borylated 2-methylphenol (3.2g) (126 MHz, CDCl3) 249 11 B NMR spectrum of Para borylated 2-methylphenol (3.2g) (160 MHz, CDCl3) 250 1 H NMR reaction mixture of Para borylation of tetrapropylammonium 2-isopropylphenylsulfate (3.2h) (500 MHz, CDCl3) 251 1 H NMR spectrum of Para borylated 2-isopropylphenol (3.2h) (500 MHz, CDCl3) 252 13 C NMR spectrum of Para borylated 2-isopropylphenol (3.2h) (126 MHz, CDCl3) 253 11 B NMR spectrum of Para borylated 2-isopropylphenol (3.2h) (160 MHz, CDCl3) 254 1 H NMR reaction mixture of Para borylation of tetrapropylammonium 2-cyanophenylsulfate (crude 3.2i) (500 MHz, C6D6) 255 1 H NMR spectrum of mixture of borylated 2-cyanolphenol regioisomers (3.2i) (500 MHz, CDCl3) 256 13 C NMR spectrum of mixture of borylated 2-cyanolphenol regioisomers (3.2i) (126 MHz, CDCl3) 257 11 B NMR spectrum of borylated mixture 2-cyanophenol regioisomers (3.2i) (160 MHz, CDCl3) 258 1 H NMR reaction mixture for the Para borylation of tetrapropylammonium 2-fluorophenylsulfate (3.2j) (500 MHz, C6D6) 259 1 H NMR spectrum of borylated 2-fluorophenol regioisomers (3.2j) (500 MHz, C6D6) 260 13 C NMR spectrum of borylated 2-fluorophenol regioisomers (3.2j) (126 MHz, C6D6) 261 11 B NMR spectrum of borylated 2-fluorophenol regioisomers (3.2j) (160 MHz, C6D6) 262 19 F NMR spectrum of borylated 2-fluorophenol regioisomers (3.2j) (470 MHz, C6D6) 263 1 H NMR reaction mixture of Para borylated tetrapropylammonium 2-bromo-6-fluorophenylsulfate (3.2k) (500 MHz, C6D6) 264 1 H NMR spectrum of Para borylated 2-bromo-6-fluorophenol (3.2k) (500 MHz, CDCl3) 265 13 C NMR spectrum of Para borylated 2-bromo-6-fluorophenol (3.2k) (126 MHz, CDCl3) 266 11 B NMR spectrum of Para borylated 2-bromo-6-fluorophenol (3.2k) (160 MHz, CDCl3) 267 19 F NMR spectrum of Para borylated 2-bromo-6-fluorophenol (3.2k) (470 MHz, CDCl3) 268 1 H NMR reaction mixture for the Para borylation of tetrapropylammonium 3-fluorophenylsulfate (3.2l) (500 MHz, CDCl3) 269 1 H NMR spectrum of Para borylated 3-fluorophenol (3.2l) (500 MHz, CDCl3) 270 13 C NMR spectrum of Para borylated 3-fluorophenol (3.2l) (126 MHz, CDCl3) 271 11 B NMR spectrum of Para borylated 3-fluorophenol (3.2l) (160 MHz, CDCl3) 272 19 F NMR spectrum of Para borylated 3-fluorophenol (3.2l) (470 MHz, CDCl3) 273 1 H NMR reaction mixture for the Para borylation of tetrapropylammonium 2,3-difluorophenylsulfate (3.2m) (500 MHz, CDCl3) 274 1 H NMR spectrum of Para borylated 2,3-difluorophenol (3.2m) (500 MHz, CDCl3) 275 13 C NMR spectrum of Para borylated 2,3-difluorophenol (3.2m) (126 MHz, CDCl3) 276 11 B NMR spectrum of Para borylated 2,3-difluorophenol (3.2m) (160 MHz, CDCl3) 277 19 F NMR spectrum of Para borylated 2,3-difluorophenol (3.2m) (470 MHz, CDCl3) 278 1 H NMR reaction mixture of para-borylated tetrapropylammonium 3-cyanophenylsulfate (crude 3.2n) (500 MHz, CDCl3) 279 1 H NMR spectrum of para-borylated 3-cyanophenylsulfate (3.2n) (500 MHz, CDCl3) 280 13 C NMR spectrum of para borylated 3-hydroxybenzonitrile (3.2n) (126 MHz, CDCl3) 281 11 B NMR spectrum of para borylated 3-hydroxybenzonitrile (3.2n) (160 MHz, CDCl3) 282 1 H NMR reaction mixture of para borylated tetrapropylammonium 3-methoxyphenylsulfate (crude 3.2o) (500 MHz, CDCl3) 283 1 H NMR reaction mixture of para borylated tetrapropylammonium 3-chlorophenylsulfate (crude 3.2p) (500 MHz, C6D6) 284 1 H NMR reaction mixture of borylation of tetrapropylammonium phenylsulfate (crude 3.2q) (500 MHz, CDCl3) 285 1 H NMR spectrum of para borylated phenol (3.2q) (500 MHz, CDCl3) 286 13 C NMR spectrum of para borylated phenol (3.2q) (126 MHz, CDCl3) 287 11 B NMR spectrum of para borylated phenol (3.2q) (160 MHz, CDCl3) 288 1 H NMR spectrum of tetrapropylammonium 2-chlorophenylsulfamate (3.3a) (500 MHz, CDCl3) 289 13 C NMR spectrum of tetrapropylammonium 2-chlorophenylsulfamate (3.3a) (126 MHz, CDCl3) 290 1 H NMR spectrum of tetrabutylammonium 2-chlorophenyl sulfamate (3.3a′) (500 MHz, CDCl3) 291 13 C NMR spectrum of tetrabutylammonium 2-chlorophenylsulfamate (3.3a′) (126 MHz, CDCl3) 292 1 H NMR spectrum of tetrabutylammonium 2-bromophenylsulfamate (3.3b′) (500 MHz, CDCl3) 293 13 C NMR spectrum of tetrabutylammonium 2-bromophenylsulfamate (3.3b′) (126 MHz, CDCl3) 294 1 H NMR spectrum of tetrabutylammonium 3-fluorophenylsulfamate (3.3c′) (500 MHz, CDCl3) 295 13 C NMR spectrum of tetrabutylammonium 3-fluorophenylsulfamate (3.3c′) (126 MHz, CDCl3) 296 19 F NMR spectrum of terabutylammonium 3-fluorophenylsulfamate (3.3c′) (470 MHz, CDCl3) 297 1 H NMR spectrum of tetrabutylammonium 2-(methoxy)phenylsulfamate (3.3d′) (500 MHz, CDCl3) 298 13 C NMR spectrum of tetrabutylammonium 2-(methoxy)phenylsulfamate (3.3d′) (126 MHz, CDCl3) 299 1 H NMR spectrum of tetrapropylammonium 2-fluorophenylsulfamate (3.3e) (500 MHz, CDCl3) 300 13 C NMR spectrum of tetrapropylammonium 2-fluorophenylsulfamate (3.3e) (126 MHz, CDCl3) 301 19 F NMR spectrum of tetrapropylammonium 2-fluorophenylsulfamate (3.3e) (470 MHz, CDCl3) 302 1 H NMR reaction mixture of para borylation of tetrapropylammonium 2-chlorophenylsulfamate (crude 3.4a) (500 MHz, CDCl3) 303 1 H NMR spectrum of para borylated 2-chloroaniline (3.4a) (500 MHz, CDCl3) 304 13 C NMR spectrum of para borylated 2-chloroaniline (3.4a) (126 MHz, CDCl3) 305 11 B NMR spectrum of para borylated 2-chloroaniline (3.4a) (160 MHz, CDCl3) 306 1 H NMR reaction mixture of para borylation of tetrabutylammonium 2-chlorophenylsulfamate (crude 3.4a′) 500 MHz, CDCl3 307 1 H NMR spectrum of para borylated 2-chloroaniline (3.4a′) (500 MHz, CDCl3) 308 13 C NMR spectrum of para borylated 2-chloroaniline (3.4a′) (126 MHz, CDCl3) 309 11 B NMR spectrum of para borylated 2-chloroaniline (3.4a′) (160 MHz, CDCl3) 310 1 H NMR reaction mixture of para borylation of tetrabutylammonium 2-bromophenylsulfamate (crude 3.4b′) (500 MHz, CDCl3) 311 1 H NMR spectrum of para-borylated 2-bromoaniline (3.4b′) (500 MHz, CDCl3) 312 13 C NMR spectrum of para-borylated 2-bromoaniline (3.4b′) (126 MHz, CDCl3) 313 11 B NMR spectrum of para borylated 2-bromoaniline (3.4b′) (160 MHz, CDCl3) 314 19 F NMR reaction mixture of para borylation of tetrabutylammonium 3-fluorophenylsulfamate (3.4c′) (470 MHz, CDCl3) 315 1 H NMR reaction mixture of para borylation of tetrabutylammonium 3-fluorophenylsulfamate (crude 3.4c′) (500 MHz, CDCl3) 316 13 C NMR reaction mixture of para borylation of tetrabutylammonium 3-fluorophenylsulfamate (crude 3.4c′) (500 MHz, CDCl3) 317 1 H NMR spectrum of reaction mixture of para borylation of tetrabutylammonium 3-fluorophenylsulfamate previous acetylation (crude 3.4c′) (500 MHz, CDCl3) 318 1 H NMR spectrum of para borylated N-(3-fluorophenyl)acetamide (3.4c′) (500 MHz, CDCl3) 319 13 C NMR spectrum of para borylated N-(3-fluorophenyl)acetamide (3.4c′) (126 MHz, CDCl3) 320 11 B NMR spectrum of para borylated N-(3-fluorophenyl)acetamide (3.4c′) (160 MHz, CDCl3) 321 19 F NMR spectrum of para borylated N-(3-fluorophenyl)acetamide (3.4c′) (470 MHz, CDCl3) 322 1 H NMR reaction mixture of para borylation of tetrabutylammonium 2-methoxyphenylsulfamate (3.4d′) (500 MHz, CDCl3) 323 1 H NMR spectrum para borylated 2-methoxyaniline (3.4d′) (500 MHz, CDCl3) 324 13 C NMR spectrum para borylated 2-methoxyaniline (3.4d′) (126 MHz, CDCl3) 325 11 B NMR spectrum para borylated 2-methoxyaniline (3.4d′) (160 MHz, CDCl3) 326 1 H NMR reaction mixture of para borylation of tetrapropylammonium 2-fluorophenylsulfamate (crude 3.4e) (500 MHz, CDCl3) 327 1 H NMR spectrum para borylated 2-fluoroaniline (3.4e) (500 MHz, CDCl3) 328 13 C NMR spectrum para borylated 2-fluoroaniline (3.4e) (126 MHz, CDCl3) 329 19 F NMR spectrum para borylated 2-fluoroaniline (3.4e) (470 MHz, CDCl3) 330 11 B NMR spectrum para borylated 2-fluoroaniline (3.4e) (160 MHz, CDCl3) 331 1 H NMR spectrum of tetrapropylammonium 2-chlorobenzylsulfate (3.5a) (500 MHz, CDCl3) 332 13 C NMR spectrum of tetrapropylammonium 2-chlorobenzylsulfate (3.5a) (126 MHz, CDCl3) 333 1 H NMR spectrum of tetrabutylammonium 2-chlorobenzylsulfate (3.5a′) (500 MHz, CDCl3) 334 13 C NMR spectrum of tetrabutylammonium 2-chlorobenzylsulfate (3.5a’) (126 MHz, CDCl3) 335 1 H NMR spectrum of tetrapropylammonium 2-bromobenzylsulfate (3.5b) (500 MHz, CDCl3) 336 13 C NMR spectrum of tetrapropylammonium 2-bromobenzylsulfate (3.5b) (126 MHz, CDCl3) 337 1 H NMR spectrum of tetrabutylammonium 2-bromobenzylsulfate (3.5b’) (500 MHz, CDCl3) 338 13 C NMR spectrum of tetrabutylammonium 2-bromobenzylsulfate (3.5b’) (126 MHz, CDCl3) 339 1 H NMR spectrum of tetrapropylammonium 2-trifluoromethylbenzylsulfate (3.5c) (500 MHz, CDCl3) 340 13 C NMR spectrum of tetrapropylammonium 2-trifluoromethylbenzylsulfate (3.5c) (126 MHz, CDCl3) 341 19 F NMR spectrum of tetrapropylammonium 2-trifluoromethylbenzylsulfate (3.5c) (470 MHz, CDCl3) 342 1 H NMR spectrum of tetrabutylammonium 2-trifluoromethylbenzylsulfate (3.5c′) (500 MHz, CDCl3) 343 13 C NMR spectrum of tetrabutylammonium 2-trifluoromethylbenzylsulfate (3.5c′) (126 MHz, CDCl3) 344 19 F NMR spectrum of tetrabutylammonium 2-trifluoromethylbenzylsulfate (3.5c′) (470 MHz, CDCl3) 345 1 H NMR spectrum of tetrapropylammonium 2-methylbenzylsulfate (3.5d) (500 MHz, CDCl3) 346 13 C NMR spectrum of tetrapropylammonium 2-methylbenzylsulfate (3.5d) (126 MHz, CDCl3) 347 1 H NMR spectrum of tetrapropylammonium 2-(trifluoromethoxy)benzylsulfate (3.5e) (500 MHz, CDCl3) 348 13 C NMR spectrum of tetrapropylammonium 2-(trifluoromethoxy)benzylsulfate (3.5e) (126 MHz, CDCl3) 349 19 F NMR spectrum of tetrapropylammonium 2-(trifluoromethoxy)benzylsulfate (3.5e) (470 MHz, CDCl3) 350 1 H NMR spectrum of tetrapropylammonium 1-(2-bromophenyl)ethyl sulfate (3.5f) (500 MHz, CDCl3) 351 13 C NMR spectrum of tetrapropylammonium 1-(2-bromophenyl)ethyl sulfate (3.5f) (126 MHz, CDCl3) 352 1 H NMR spectrum of tetrapropylammonium 2-fluorobenzyl sulfate (3.5g) (500 MHz, CDCl3) 353 13 C NMR spectrum of tetrapropylammonium 2-fluorobenzyl sulfate (3.5g) (126 MHz, CDCl3) 354 19 F NMR spectrum of tetrapropylammonium 2-fluorobenzyl sulfate (3.5g) (470 MHz, CDCl3) 355 1 H NMR spectrum of tetrapropylammonium 3-fluorobenzyl sulfate (3.5h) (500 MHz, CDCl3) 356 13 C NMR spectrum of tetrapropylammonium 3-fluorobenzyl sulfate (3.5h) (126 MHz, CDCl3) 357 13 C NMR spectrum of tetrapropylammonium 3-fluorobenzyl sulfate (3.5h) (470 MHz, CDCl3) 358 1 H NMR reaction mixture of para borylation of tetrapropylammonium 2-chlorobenzylsulfate (crude 3.6a) (500 MHz, CDCl3) 359 1 H NMR spectrum of para borylated 2-chlorobenzylalcohol (3.6a) (500 MHz, CDCl3) 360 13 C NMR spectrum of para borylated 2-chlorobenzylalcohol (3.6a) (126 MHz, CDCl3) 361 11 B NMR spectrum of para borylated 2-chlorobenzylalcohol (3.6a) (160 MHz, CDCl3) 362 1 H NMR reaction mixture of para borylation of tetrabutylammonium 2-chlorobenzylsulfate (crude 3.6a’) (500 MHz, CDCl3) 363 1 H NMR reaction mixture of para borylation of terapropylammonium 2-bromobenzylsulfate (crude 3.6b) 500 MHz, CDCl3 364 1 H NMR spectrum of reaction mixture of para borylation of 2-bromobenzylsulfate (3.6b) (500 MHz, CDCl3) 365 13 C NMR spectrum of para borylated 2-bromobenzylalcohol (3.6b) (126 MHz, CDCl3) 366 11 B NMR of para borylated 2-bromobenzylalcohol (3.6b) (160 MHz, CDCl3) 367 1 H NMR reaction mixture of para borylation of tetrabutylammonium 2-bromobenzylsulfate (crude 3.6b′) (500 MHz, CDCl3) 368 1 H NMR reaction mixture of para borylation of 2-(trifluoromethyl)benzylsulfate (crude 3.6c) (500 MHz, CDCl 3) 369 1 H NMR spectrum of para borylated 2-(trifluoromethyl)benzylalcohol (3.6c) (500 MHz, CDCl3) 370 13 C NMR spectrum of para borylated 2-(trifluoromethyl)benzylalcohol (3.6c) (126 MHz, CDCl3) 371 11 B NMR spectrum of para borylated 2-(trifluoromethyl)benzylalcohol (3.6c) (160 MHz, CDCl3) 372 19 F NMR spectrum of para borylated 2-(trifluoromethyl)benzylalcohol (3.6c) (470 MHz, CDCl3) 373 1 H NMR reaction mixture of para borylation of 2-(trifluoromethyl)benzylsulfate (crude 3.6c’) (500 MHz, CDCl 3) 374 1 H NMR reaction mixture of para borylation of 2-methylbenzylsulfate (crude 3.6d) (500 MHz, CDCl3) 375 1 H NMR spectrum of para borylated 2-(methyl)benzylalcohol (3.6d) (500 MHz, CDCl3) 376 13 C NMR spectrum of para borylated 2-(methyl)benzylalcohol (3.6d) (126 MHz, CDCl3) 377 11 B NMR spectrum of para borylated 2-(methyl)benzylalcohol (3.6d) (160 MHz, CDCl3) 378 1 H NMR spectrum of para borylated 2-(trifluoromethoxy)benzyl alcohol (3.6e) (500 MHz, CDCl3) 379 13 C NMR spectrum of para borylated 2-(trifluoromethoxy)benzyl alcohol (3.6e) (126 MHz, CDCl3) 380 11 B NMR spectrum of para borylated 2-(trifluoromethoxy)benzyl alcohol (3.6e) (160 MHz, CDCl3) 381 19 F NMR spectrum of para borylated 2-(trifluoromethoxy)benzyl alcohol (3.6e) (470 MHz, CDCl3) 382 1 H NMR spectrum of para borylated 1-(2-bromophenyl)ethanol (3.6f) (500 MHz, CDCl3) 383 13 C NMR spectrum of para borylated1-(2-bromophenyl)ethanol (3.6f) (126 MHz, CDCl3) 384 11 B NMR spectrum of para borylated 1-(2-bromophenyl)ethanol (3.6f) (160 MHz, CDCl3) 385 1 H NMR spectrum of para borylated (2-fluorophenyl)methanol crude reaction mixture (3.6g) (500 MHz, CDCl 3) 386 1 H NMR spectrum of para borylated (2-fluorophenyl)methanol (3.6g) (500 MHz, CDCl3) 387 13 C NMR spectrum of para borylated (2-fluorophenyl)methanol (3.6g) (126 MHz, CDCl3) 388 11 B NMR spectrum of para borylated (2-fluorophenyl)methanol (3.6g) (160 MHz, CDCl3) 389 19 F NMR spectrum of borylated (2-fluorophenyl)methanol (3.6g) (470 MHz, CDCl3) 390 1 H NMR spectrum of para borylated (3-fluorophenyl)methanol crude reaction mixture (3.6h) (500 MHz, CDCl 3) 391 1 H NMR spectrum of para borylated (3-fluorophenyl)methanol (3.6h) (500 MHz, CDCl3) 392 13 C NMR spectrum of para borylated (3-fluorophenyl)methanol (3.6h) (126 MHz, CDCl3) 393 11 B NMR spectrum of para borylated (3-fluorophenyl)methanol (3.6h) (160 MHz, CDCl3) 394 19 F NMR spectrum of borylated (3-fluorophenyl)methanol (3.6h) (470 MHz, CDCl3) 395 REFERENCES 396 REFERENCES (1) Anslyn, E. V.; Dougherty, D. A. Modern Physical Organic Chemistry; University Science Books: Sausalito, CA, 2005. (2) Engle, K. M.; Mei, T.-S.; Wasa, M.; Yu, J.-Q. Weak Coordination as a Powerful Means for Developing Broadly Useful C-H Functionalization Reactions. Acc. Chem. Res. 2012, 45, 788–802. (3) Raynal, M.; Ballester, P.; Vidal-Ferran, A.; van Leeuwen, P. W. N. M. Supramolecular Catalysis. Part 1: Non-Covalent Interactions as a Tool for Building and Modifying Homogeneous Catalysts. Chem. Soc. Rev. 2014, 43, 1660–1733. (4) Davis, H. J.; Phipps, R. J. Harnessing Non-Covalent Interactions to Exert Control over Regioselectivity and Site-Selectivity in Catalytic Reactions. Chem. Sci. 2017, 8, 864–877. (5) C-H Bond Activation and Catalytic Functionalization I; Dixneuf, P. H., Doucet, H., Eds.; Topics in Organometallic Chemistry; Springer International Publishing: Cham, Switzerland, 2018. (6) C-H Bond Activation and Catalytic Functionalization II; Dixneuf, P. H., Doucet, H., Eds.; Topics in Organometallic Chemistry; Springer Nature: Cham, Switzerland, 2018. (7) Mkhalid, I. A. I.; Barnard, J. H.; Marder, T. B.; Murphy, J. M.; Hartwig, J. F. C-H Activation for the Construction of C-B Bonds. Chem. Rev. 2010, 110, 890–931. (8) Xu, L.; Wang, G.; Zhang, S.; Wang, H.; Wang, L.; Liu, L.; Jiao, J.; Li, P. Recent Advances in Catalytic C−H Borylation Reactions. Tetrahedron 2017, 73, 7123–7157. (9) Fontaine, F.-G.; Rochette, É. Ambiphilic Molecules: From Organometallic Curiosity to Metal-Free Catalysts. Acc. Chem. Res. 2018, 51, 454–464. (10) Cho, J.-Y.; Iverson, C. N.; Smith, M. R., III. Steric and Chelate Directing Effects in Aromatic Borylation. J. Am. Chem. Soc. 2000, 122, 12868–12869. (11) Cho, J.-Y.; Tse, M. K.; Holmes, D.; Maleczka, R. E., Jr; Smith, M. R., III. Remarkably Selective Iridium Catalysts for the Elaboration of Aromatic C-H Bonds. Science 2002, 295, 305–308. (12) Ishiyama, T.; Takagi, J.; Ishida, K.; Miyaura, N.; Anastasi, N. R.; Hartwig, J. F. Mild Iridium- Catalyzed Borylation of Arenes. High Turnover Numbers, Room Temperature Reactions, and Isolation of a Potential Intermediate. J. Am. Chem. Soc. 2002, 124, 390–391. (13) Ros, A.; Fernández, R.; Lassaletta, J. M. Functional Group Directed C–H Borylation. Chem. Soc. Rev. 2014, 43, 3229–3243. 397 (14) Kawamorita, S.; Ohmiya, H.; Hara, K.; Fukuoka, A.; Sawamura, M. Directed Ortho Borylation of Functionalized Arenes Catalyzed by a Silica-Supported Compact Phosphine- Iridium System. J. Am. Chem. Soc. 2009, 131, 5058–5059. (15) Ishiyama, T.; Isou, H.; Kikuchi, T.; Miyaura, N. Ortho-C–H Borylation of Benzoate Esters with Bis(Pinacolato)Diboron Catalyzed by Iridium–Phosphine Complexes. Chem. Commun. 2010, 46, 159–161. (16) Roosen, P. C.; Kallepalli, V. A.; Chattopadhyay, B.; Singleton, D. A.; Maleczka, R. E., Jr; Smith, M. R., III. Outer-Sphere Direction in Iridium C-H Borylation. J. Am. Chem. Soc. 2012, 134, 11350–11353. (17) Chattopadhyay, B.; Dannatt, J. E.; Andujar-De Sanctis, I. L.; Gore, K. A.; Maleczka, R. E., Jr; Singleton, D. A.; Smith, M. R., III Ir-Catalyzed Ortho-Borylation of Phenols Directed by Substrate-Ligand Electrostatic Interactions: A Combined Experimental/in Silico Strategy for Optimizing Weak Interactions. J. Am. Chem. Soc. 2017, 139, 7864–7871. (18) Bisht, R.; Chattopadhyay, B. Formal Ir-Catalyzed Ligand-Enabled Ortho and Meta Borylation of Aromatic Aldehydes via in Situ-Generated Imines. J. Am. Chem. Soc. 2016, 138, 84–87. (19) Kuninobu, Y.; Ida, H.; Nishi, M.; Kanai, M. A Meta-Selective C-H Borylation Directed by a Secondary Interaction between Ligand and Substrate. Nat. Chem. 2015, 7, 712–717. (20) Davis, H. J.; Mihai, M. T.; Phipps, R. J. Ion Pair-Directed Regiocontrol in Transition-Metal Catalysis: A Meta-Selective C–H Borylation of Aromatic Quaternary Ammonium Salts. J. Am. Chem. Soc. 2016, 138, 12759–12762. (21) Yang, L.; Uemura, N.; Nakao, Y. Meta-Selective C-H Borylation of Benzamides and Pyridines by an Iridium-Lewis Acid Bifunctional Catalyst. J. Am. Chem. Soc. 2019, 141, 7972–7979. (22) Mihai, M. T.; Davis, H. J.; Genov, G. R.; Phipps, R. J. Ion Pair-Directed C–H Activation on Flexible Ammonium Salts:Meta-Selective Borylation of Quaternized Phenethylamines and Phenylpropylamines. ACS Catalysis. 2018, 8, 3764–3769. (23) Davis, H. J.; Genov, G. R.; Phipps, R. J. Meta-Selective C-H Borylation of Benzylamine-, Phenethylamine-, and Phenylpropylamine-Derived Amides Enabled by a Single Anionic Ligand. Angew. Chem. Int. Ed. 2017, 56, 13351–13355. (24) Lee, B.; Mihai, M. T.; Stojalnikova, V.; Phipps, R. J. Ion-Pair-Directed Borylation of Aromatic Phosphonium Salts. J. Org. Chem. 2019, 84, 13124–13134. (25) Del Grosso, A.; Singleton, P. J.; Muryn, C. A.; Ingleson, M. J. Pinacol Boronates by Direct Arene Borylation with Borenium Cations. Angew. Chem. Int. Ed. 2011, 50, 2102–2106. (26) Saito, Y.; Segawa, Y.; Itami, K. Para-C–H Borylation of Benzene Derivatives by a Bulky Iridium Catalyst. Journal of the American Chemical Society. 2015, 137, 5193–5198. 398 (27) Saito, Y.; Yamanoue, K.; Segawa, Y.; Itami, K. Selective Transformation of Strychnine and 1,2-Disubstituted Benzenes by C–H Borylation. Chem 2020, 6, 985-993. (28) Hoque, M. E.; Bisht, R.; Haldar, C.; Chattopadhyay, B. Noncovalent Interactions in Ir- Catalyzed C-H Activation: L-Shaped Ligand for Para-Selective Borylation of Aromatic Esters. J. Am. Chem. Soc. 2017, 139, 7745–7748. (29) Yang, L.; Semba, K.; Nakao, Y. Para-Selective C-H Borylation of (Hetero)Arenes by Cooperative Iridium/Aluminum Catalysis. Angew. Chem. Int. Ed. 2017, 56, 4853–4857. (30) Miller, S. L.; Chotana, G. A.; Fritz, J. A.; Chattopadhyay, B.; Maleczka, R. E., Jr; Smith, M. R., III. C-H Borylation Catalysts That Distinguish Between Similarly Sized Substituents Like Fluorine and Hydrogen. Org. Lett. 2019, 21, 6388–6392. (31) Ishiyama, T.; Takagi, J.; Hartwig, J. F.; Miyaura, N. A Stoichiometric Aromatic CbH Borylation Catalyzed by Iridium(I)/2,2'-Bipyridine Complexes at Room Temperature. Angew. Chem. Int. Ed. 2002, 41, 3056–3058. (32) Shirakawa, S.; Liu, S.; Kaneko, S.; Kumatabara, Y.; Fukuda, A.; Omagari, Y.; Maruoka, K. Tetraalkylammonium Salts as Hydrogen-Bonding Catalysts. Angew. Chem. Int. Ed. 2015, 54, 15767–15770. (33) Mihai, M. T.; Williams, B. D.; Phipps, R. J. Para-Selective C-H Borylation of Common Arene Building Blocks Enabled by Ion-Pairing with a Bulky Countercation. J. Am. Chem. Soc. 2019, 141, 15477–15482. (34) Montero Bastidas, J. R.; Oleskey, T. J.; Miller, S. L.; Smith, M. R., III; Maleczka, R. E., Jr. Para-Selective, Iridium-Catalyzed C-H Borylations of Sulfated Phenols, Benzyl Alcohols, and Anilines Directed by Ion-Pair Electrostatic Interactions. J. Am. Chem. Soc. 2019, 141, 15483–15487. (35) Tajuddin, H.; Harrisson, P.; Bitterlich, B.; Collings, J. C.; Sim, N.; Batsanov, A. S.; Cheung, M. S.; Kawamorita, S.; Maxwell, A. C.; Shukla, L.; Morris, J.; Lin, Z.; Marder, T. B.; Steel, P. G. Iridium-Catalyzed C–H Borylation of Quinolines and Unsymmetrical 1,2-Disubstituted Benzenes: Insights into Steric and Electronic Effects on Selectivity. Chem. Sci. 2012, 3, 3505. (36) Chotana, G. A.; Rak, M. A.; Smith, M. R., III. Sterically Directed Functionalization of Aromatic C−H Bonds: Selective Borylation Ortho to Cyano Groups in Arenes and Heterocycles. J. Am. Chem. Soc. 2005, 127, 10539–10544. (37) Uson, R.; Oro, L. A.; Cabeza, J. A.; Bryndza, H. E.; Stepro, M. P. Dinuclear Methoxy, Cyclooctadiene, and Barrelene Complexes of Rhodium(I) and Iridium(I). In Inorganic Syntheses; John Wiley & Sons, Inc.: Hoboken, NJ, USA, 2007; pp 126–130. (38) van Beek, T.; Duval, F.; Zuilhof, H. Sensitive Thin-Layer Chromatography Detection of Boronic Acids Using Alizarin. Synlett 2012, 23, 1751–1754. 399 (39) Lee, C.-Y.; Ahn, S.-J.; Cheon, C.-H. Protodeboronation of Ortho- and Para-Phenol Boronic Acids and Application to Ortho and Meta Functionalization of Phenols Using Boronic Acids as Blocking and Directing Groups. J. Org. Chem. 2013, 78, 12154–12160. (40) Williams, A. B.; Hanson, R. N. Synthesis of Substituted Asymmetrical Biphenyl Amino Esters as Alpha Helix Mimetics. Tetrahedron 2012, 68, 5406–5414. (41) Williams, A. B.; Weiser, P. T.; Hanson, R. N.; Gunther, J. R.; Katzenellenbogen, J. A. Synthesis of Biphenyl Proteomimetics as Estrogen Receptor-Alpha Coactivator Binding Inhibitors. Org. Lett. 2009, 11, 5370–5373. (42) Schulz, M. J.; Coats, S. J.; Hlasta, D. J. Microwave-Assisted Preparation of Aryltetrazoleboronate Esters. Org. Lett. 2004, 6, 3265–3268. (43) Ishikawa, S.; Manabe, K. Synthetic Method for Multifunctionalized Oligoarenes Using Pinacol Esters of Hydroxyphenylboronic Acids. Chem. Commun. 2006, 24, 2589–2591. (44) Gràcia, J.; Buil, M. A.; Castro, J.; Eichhorn, P.; Ferrer, M.; Gavaldà, A.; Hernández, B.; Segarra, V.; Lehner, M. D.; Moreno, I.; Pagès, L.; Roberts, R. S.; Serrat, J.; Sevilla, S.; Taltavull, J.; Andrés, M.; Cabedo, J.; Vilella, D.; Calama, E.; Carcasona, C.; Miralpeix, M. Biphenyl Pyridazinone Derivatives as Inhaled PDE4 Inhibitors: Structural Biology and Structure-Activity Relationships. J. Med. Chem. 2016, 59, 10479–10497. (45) Ono, K.; Aizawa, R.; Yamano, T.; Ito, S.; Yasuda, N.; Johmoto, K.; Uekusa, H.; Iwasawa, N. Procedure-Dependent Construction of Two Isomers of Trimeric Self-Assembled Boronic Esters. Chem. Commun. 2014, 50, 13683–13686. (46) Chuang, K. V.; Kieffer, M. E.; Reisman, S. E. A Mild and General Larock Indolization Protocol for the Preparation of Unnatural Tryptophans. Org. Lett. 2016, 18, 4750–4753. (47) Qiu, D.; Wang, S.; Tang, S.; Meng, H.; Jin, L.; Mo, F.; Zhang, Y.; Wang, J. Synthesis of Trimethylstannyl Arylboronate Compounds by Sandmeyer-Type Transformations and Their Applications in Chemoselective Cross-Coupling Reactions. J. Org. Chem. 2014, 79, 1979– 1988. 400 CHAPTER 4. STERIC SHIELDING EFFECTS INDUCED BY INTRAMOLECULAR C–H•••O HYDROGEN BONDING: REMOTE BORYLATION DIRECTED BY BPIN GROUPS 4.1. Introduction Nowadays, C–H bonds can be diversified via different C–H functionalization methods. Yet, targeting one C–H reactive site in the presence of like C–H bonds remains challenging.1,2 Although considered weak, noncovalent interactions can differentiate the energetics of otherwise similar reactive sites. In the area of sp2 C–H activation, pre-installed directing groups can interact with the catalyst via hydrogen bonding, Lewis acid-base or electrostatic interactions to selective functionalize the ortho, meta or para position.3–9 Nonetheless, selective reactions at distal C–H sites often require construction of long and complex directing groups/ligands. 7–11 A different strategy uses steric shields to block nearby C–H bonds thus leaving the distal position as the only viable reactive site. For instance, Nakao’s group used Lewis acidic additives that interact with aryl amides to shield the meta position and thereby afford selective para functionalization.12–15 The complementary approach where intramolecular noncovalent interactions create steric shields leading to remote functionalization is far less common. Iridium catalyzed C–H borylation (CHB) is currently a standard protocol to make aryl boronic esters.16–18 In the last decade, ortho regioselective sp2 CHB has been achieved by means of chelating and relay directing groups as well as outer sphere interactions. 4,7,19 In 2013, our group reported that meta and para substituted anilines yield the corresponding ortho borylated product courtesy of an N–H hydrogen bonding with the catalyst.20 Unexpectedly, 2-methoxyaniline gave selectively the para borylated aniline. A similar result was reported by the Phipps group during their CHB of 2-chloroaniline (Figure 4.1a).21 It was proposed that electronic effects might play a 401 role in the change of selectivity for 2-chloro and 2-methoxyaniline, but no experiments were done to corroborate this hypothesis. More recently, we and the Phipps group independently developed a protocol for para CHB of anilines directed by ion-pair electrostatic interactions of sulfamates with bulky tetraalkylammonium counterions (Figure 4.1b).21,22 Here the selectivity is presumably the result of a steric shield created when one of the alkyl chains in the cation orientates toward the aromatic ring blocking the meta position and leaving the para exposed to CHB. We wondered if a different sort of steric shielding might be playing a role as well in the para CHB of 2-methoxy and 2- chloroaniline mentioned above. Figure 4.1: a) Unexpected para CHB of anilines (only reported compounds), b) Previously reported para CHB of anilines driven by ion-pair electrostatic interactions It is well documented that N-borylation of N-unsubstituted anilines occurs rapidly under CHB conditions.20 We hypothesized that in the presence of an ortho substituent like methoxy or chloro, the N–Bpin group could orientate towards the meta C–H where it would act as a steric shield and lead to a para selective CHB (Figure 4.2). Bpin is an attractive steric shield for N- 402 unsubstituted anilines since it is installed in situ and its removal occurs upon work-up with methanol. This contrasts with our previous approach to access para borylated anilines, which required a step to install the sulfamate group and where highly acidic conditions were needed for its removal. Figure 4.2: This approach: remote CHB driven by intramolecular hydrogen bonding 4.2. RESULTS AND DISCUSSION 4.2.1. Para C–H borylation of anilines, N-alkylated anilines and indoles. 4.2.1.1. Optimization of Conditions We set out examine a para selectivity by virtue of a Bpin steric shield was a general phenomenon. To do so, we first looked to optimize the reaction on 2-chloroaniline. Starting with our previously reported conditions, we compared the regioselectivity when B2pin2 was used in place of HBpin and found that the former yielded an improved para to meta ratio. With B2pin2 as the new boron partner we compared the effects of temperature and solvent (Figure 4.3). Cyclohexane gave higher selectivity especially at lower temperatures, but conversion dropped relative to THF. The best balance between reactivity and selectivity was found with THF at 40 ºC. After 4 h, the conversion was 61% and >90% after 24 h. 403 100 1.0 1.0 1.0 90 1.0 80 70 % conversion 60 1.0 50 1.0 6.0 5.6 40 8.0 7.9 30 9.4 20 1.0 8.2 10 10.7 1.0 0 9.1 CyH THF CyH THF CyH THF CyH THF rt 40 ºC 60 ºC 80 ºC Para Meta Figure 4.3: Temperature and solvent effect on para CHB of 2-chloroaniline. Blue and orange bars represent conversion to the para and meta isomer, respectively. CyH: cyclohexane, THF: tetrahydrofuran With these conditions in hand, we evaluated the effect of the ligand and the diboron partner (Scheme 4.1). Bipyridine ligands (L1–L3) gave modest para/meta ratios (~5:1). Notably, 4,4’- dimethoxy-2,2’-bipyridine (L3), which was optimal in our previous para directed CHB of sulfamate salts, did not prove superior in this scenario. Selectivity with ligand L5 was similar, but yield suffered. Scheme 4.1: Ligand effect on the selectivity of the para CHB of 2-chloroaniline a a The para to meta ratio (p:m) and conversions were calculated by 1H NMR from the crude reaction mixture. 404 In contrast, the para/meta ratio doubled with phenanthrolines L4 and L6, while yield remained high. We choose tmphen (L4) to continue our studies due to it being slightly better than L6 in terms of regioselectivity and yield. 4.2.1.2. Para CHB of anilines With these conditions in hand, we evaluated the para borylation of different anilines (Scheme 4.2). Ortho substituents with free electron pairs (4.2a–4.2d) favored para borylated with > 7:1 selectivity. Similar electronic effects in CHB have been observed when there is a small steric difference between two reactive sites.12,21–25 In contrast, 4.2e with a trifluoromethyl ortho substituent saw selectivity drop to 4:1. Benzoate 4.2f with an electron withdrawing group by resonance gave an even lower ratio of 2 to 1 para to meta. This is result bears some relationship to previous reports of ester groups favoring para CHB; in our case that position is meta respect to the aniline nitrogen.24,26 The size of alkyl ortho substituents (4.2g–4.2i) showed little effect, as para to meta ratios only ranged from 4:1 to 6:1. It should be noted that the 6:1 observed for 2-methylaniline (2g) was achieved by forming the N-Bpin bond prior to the CHB. This suggests that N-Bpin formation is slow in this case. The Bpin steric shield even overcame the steric presence of a fused cyclopentyl and fluoro substituents as substrates 4.2j and 4.2k favored para borylation albeit slightly. This was not great surprise as borylation next to these groups have been previously observed as minor products; the major regioisomers being those from CHB of the more accessible position. 17,23,25,27– 30 As stated above, fluorine atoms are relatively small and CHB next to them is observed. CHB of 2,4-difluoroaniline (4.1l) presented a more interesting scenario. In this case, were the N– Bpin orientated away from the ortho fluorine, the resultant steric shield would block the 5-position 405 leaving the 3-borylation as the only option. This was the result as C3 borylation occurred with a 15:1 preference over C5 borylation. Scheme 4.2: Para CHB of anilines driven by a N–Bpin steric shield a,b a Conversions and regioselectivities were measured by 1H NMR on crude reaction mixtures. Yields refer to isolated material with the ratio of major to minor products in the isolated material given in parentheses. b p and m refer to para and meta product, respectively. c N–Bpin bond formed prior to CHB with HBpin (1.2 equiv), [Ir(cod)OMe]2 (0.5 mol %), THF, 80 ºC, 2h; under standard condition (A) the results are 61% conv.; p:m = 4:1 with 47% yield (>20:1) d C3 and C5 refer to 3- and 5- borylated product, respectively. e C3 and C7 refer to 3- and 7- borylated product respectively and C3C7 refers to the 3,7-diborylated product. f regioselectivity confirm by x-ray crystallography. 406 To probe other substrates with substituents at the ortho and para C–H positions, we examined the CHB of N-borylated 5-substitued 1-naphthyl amines 4.1m and 4.1n. In these substrates, C4, C6, and C8 would be blocked from CHB by substituents, leaving only C3 and C7 sterically unencumbered. However, were our hypothesis correct, the N-Bpin would sterically shield C3, thus favoring C7 in a CHB. Indeed, borylation of 4.1m and 4.1n yield their 7-borylated product selectively (C7/C3 7:1 and 10:1 respectively). In the case of 4.1n, a small amount of diborylation was observed. 4.2.1.3. Para CHB of N-alkylated anilines We next turned our attention to other in situ borylated scaffolds, namely N-alkylated anilines. Unfortunately, CHB of 2-chloro-N-methylaniline 4.3a was not para selective under the optimized conditions (Scheme 4.3). A slow rate of N–Bpin formation could explain the lack of selectivity. However, even after preformation of the N–Bpin bond no selectivity was observed. Thus, we considered other explanations. This led us to propose that a reluctance of N-borylated 4.3a to orientate in the same plane as the aromatic ring, which per our hypothesis creates the N– Bpin steric shield, is responsible for the observed regiochemical result. Such a hypothesized planar conformation is supported by modeling the lowest energy conformation of N-borylated intermediates of N-unsubstituted anilines (see Section 2.3 and Figure 4.6 for further discussion). In contrast, N-borylated 2-chloro-N-methyl aniline does not adopt a planar conformation (see Section 2.3 and Figure 4.9 for details) owing to a A(1,3) interaction between the N-methyl with the ortho chlorine. As N-borylated N-alkyl-2-aminopyridines should lack this steric clash, 4.3b and 4.3c should be para selective. This proved to be the case with 4.4b and 4.4c both being the major (4:1) CHB products. 407 Scheme 4.3: Para CHB of alkylated anilines driven by a N–Bpin steric shield a,b a Conversions and regioselectivities were measured by 1H NMR on crude reaction mixtures. Yields refer to isolated material with the ratio of major to minor products in the isolated material given in parentheses. b p and m refer to para and meta product, respectively. c C3, C4 and C5 refer to 3-, 4- and 5- borylated product, respectively. 1,2,3,4-Tetrahydroquinolines also drew our attention as in these N-alkylated anilines the covalent chain that links the aromatic ring with the nitrogen should allow the N-borylated intermediate to achieve a pseudo planar conformation (Scheme 4.3). Para products 4.4d–4.4j were obtained as the major regioisomer from their corresponding 1,2,3,4-tetrahydroquinolines. The size of the saturated ring does influence the level of selectivity, as illustrated in 4.4g where the selectivity was only 2:1. Adding a methyl group about the saturated ring did not significantly 408 change the selectivity as show by products 4.4d–4.4f. With 4.3h, borylation next to the oxygen was also observed, but the para product still predominated (8:1). The fluorinate version of 4.3h, namely 4.3i, was equally selective. Diborylation of phenoxazine 4.3j mainly yielded the bis para compound along with multiple minor products. 4.2.1.4. C5 CHB of Indoles N-Borylation of indoles is known to block the C2 CHB normally seen in the parent compounds, instead yielding the corresponding 3-borylated product.20 We asked if in an N- borylated 3-subsitued indole, the N–Bpin would shield the closer C6 position leading to the corresponding 5-borylated indoles. C5 borylation of indoles has been elusive besides some specific examples employing electrophilic borylation with borenium cations. The examples are limited to N-methyl carbazole or are trigger by the use of an amine pivaloate directing group at the 4 position.31,32 A protocol to access 3,5-diborylated indoles has been reported but suffers from low conversions (< 30%).33 Under our optimized conditions and after formation of the N–Bpin intermediate, 3- methylindole 4.5a yielded the 5-borylated with a modest 3:1 selectivity over the minor 5-borylated isomer (Scheme 4.4). Replacement of the methyl group by a methyl ester as in 4.5b resulted in the loss of selectivity. However, the presence of substituents at both C2 and C3 impacted selectivity little as shown in 4.6c and 4.6d. It should be stated that for 4.5c and 4.5d, formation of the N– Bpin intermediate is slow and additional HBpin and [Ir(cod)OMe] 2 as well as a 3-hour reaction time was needed to afford full N-borylation. 409 Scheme 4.4: C5-CHB of 3-substitued indoles driven by a N–Bpin steric shield a,b a Conversions and regioselectivities were measured by 1H NMR on crude reaction mixtures. Yields refer to isolated material with the ratio of major to minor products in the isolated material given in parentheses. b C5 and C6 refer to 5- and 6- borylated product, respectively. 4.2.2. C6 borylation of 1-borylated naphthalenes. 4.2.2.1. Borylations We speculated that Bpin groups can create a steric shield even when not part of a N–Bpin moiety. We thus focused on 1-borylated naphthalenes, which could bear geometries similar to those of N-borylated 2-substitued anilines and N-borylated tetrahydroquinolines (Scheme 4.5). If so, the Bpin derived steric shield would block the C7-position leaving the C6-position available for CHB. Borylation of 1-borylated naphthalene 4.7a supported our proposition and yielded the 1,6- diborylated product selectively. A ligand screening showed that 4,4’-dimethoxy-2,2’-bypiridine (L3) was the best choice for the C6-borylation of 1-borylated naphthalenes. This result is potentially valuable as C6 functionalization of naphthalenes remains rare.34 A notable exception, comes from Nakao’s group where a 1-naphtyl amide was made to undergo C6-alkylation by using an aluminum Lewis acid as a steric shield.13,14 410 Scheme 4.5: Ligand effect on the selectivity of the C6 CHB of 1-borylated naphthalenesa As shown in Scheme 4.6, a substituent on the C2- or C4-position is needed to avoid borylation at C3 (4.7b–4.7f). 5-Bpin acenaphthene 4.7g borylated at both the expected C8 position and at C3. Under conditions that promote diborylation, 3,5,8-triborylated product 4.8g was obtained as the major product along with the 3,5,7-triborylated product as a minor isomer. The Bpin shield in 9-borylated anthracene 4.7h enabled remote borylation of both sides of the molecule leading to a 2:1 mixture of 3,6,9-triborylated and 2,6,9-triborylated products (4.8h). 4.2.2.2. Silylations Iridium catalyzed C–H silylations (CHS) share similar features with CHB reactions, including regiochemical outcomes being traditionally driven by sterics. We tested if CHS of 1- borylated naphthalene would lead to a C6-silylated product. Subjecting 4.7a to Hartwig’s CHS conditions revealed a slight (1.6:1) preference for the C6- vs C7-silylated products 4.9 and 4.10 (Scheme 4.7).35 Ligand optimization was problematic since neocuproine is a unique ligand that is key to gaining synthetically useful CHS yields. As the field of undirected CHS evolves, new ligands may improve the C6 selectivity of 1-borylated naphthalenes. 411 Scheme 4.6: C6 borylation of 1-borylated naphthalenes a a C1C6 and C1C7 refer to 1,6- and 1,7-diborylated naphthalene products, respectively. Conversions and C1C6/C1C7 ratios were measured by 1H NMR on crude reaction mixtures. Yields refer to isolated material with the C1C6/C1C7 ratio of the isolated material given in parentheses. b For 8e there was an unknown minor isomer in the mixture besides the 7-borylated. c C3C5C8 and C3C5C7 refers to 3,5,8- and 3,5,7-triborylated acenaphthene, respectively. d C3C6C9, C2C6C9 and C2C7C9 refers to 3,6,9-, 2,6,9- and 2,7,9-triborylated anthracene, respectively. Scheme 4.7: C–H silylation of 1-borylated naphthalenes 412 4.2.3. Mechanistic Studies. We began this study by suggesting the unusual para selective CHB of 2-methoxy and 2- chloroaniline came about by virtue of a N–Bpin steric shielding in contrast to the previously evoked electronic drivers. This steric shielding hypothesis could be understandably challenged as free rotation around the C–N and N–B bonds can avoid any steric perturbation caused by the N– Bpin group. Moreover, even in the orientation that maximizes the putative steric shield, one could question if the N–Bpin group is close enough to the meta C–H so as to block its borylation. To address these questions and better understand the observed selectivities we performed the experiments describe bellow. Steel and Marder have shown that 1H NMR chemical shifts can be qualitative predictors of CHB selectivity when there is not a steric difference between two reactive sites.24 More deshielded hydrogens are expected to be more acidic and more reactive towards CHB. Based on 1D-NOE and 2D NMR experiments, we assigned the 1H NMR chemical shifts of N-borylated 2-chloro (4.1a’) and 2-tertbutylaniline (4.1i’) (Figure 4.4). We acquired the spectra in THF-d8 so as to best simulate solution structures present during the CHB. Spectra for both compounds had the meta proton appearing more downfield than the para proton. Per Steel and Marder, this would suggest the meta position should be electronically favored in a CHB. However, a preference for para borylation is the experimentally observed result. This points to factors besides electronic effects being responsible for the para preference. A closer comparison of the 1H NMR of the N-borylated intermediate versus the non-borylated version of 2-chloro and 2-tertbutyl aniline revealed a surprising deshielding effect on the chemical shift of the ortho proton after N-borylation (Figure 4.4). This displacement was also observed in other NMR solvents (C6D6, acetone-d6, CDCl3, pyridine-d5). We attribute the downfield chemical shift movement to an intramolecular C–H•••O 413 hydrogen bonding (IMHB) between the oxygen of the N–Bpin group and the ortho hydrogen in the aniline. Deshielding effects on chemical shifts caused by hydrogen bonds are well documented,36–38 and one of the closest examples to our system is the IMHB present in N1,N’- diBoc protected pyridine-2-yl guanidine 4.11a–c.39 In this scenario, a C–H ••• N IMHB is said to change the conformation, vs. analogous compound lacking a Boc group, to one where the pertinent protons are deshielded. R  H3 H (4.11a) 1.81 ppm Cl (4.11b) 1.82 ppm Me (4.11c) 1.74 ppm R  H6 Cl (4.1a’) 0.92 ppm t-Bu (4.1i’) 0.85 ppm Figure 4.4: 1H NMR comparison of N-borylated and unborylated 2-chloro and 2-methylaniline, and  displacement due to C–H•••N and C–H•••O IMHB in 4.11a-c and 4.1a’, 4.1i’ respectively 414 While the NMR studies argued against electronic effects being responsible for the para borylation of anilines, those studies did not shed light on the question of whether the N–Bpin group is actually close enough to the meta position to act as a steric shield. To begin addressing this question, we ran CHB reactions with larger diboron partners as B2hg2 and B2pp2 (Figure 4.5a). B2hg2 proved less reactive than B2pin2 in accordance with a previous report,40 but the selectivity for the para position improved. We tested a novel diboron partner for CHB, B2pp2, and interestingly the conversion to the borylated product was greater than with B2hg2. The largest para to meta ratio was also found with B2pp2, which is consistent with our steric shield hypothesis. While this improved selectivity could be due to the size of the installed N–Bpp group, a B2pp2 derived trisboryl active catalyst could also influence regiochemistry. Thus, we generated N–Bpin and N–Bpp compounds from 2-chloro and 2-methylaniline. These intermediates were then independently reacted under the same CHB conditions with B2pin2 as the diboron partner (Figure 4.5b). For 2-chloroaniline, the N–Bpp borylated derivative yielded a higher para/meta ratio as compared to the N–Bpin substrate. For 2-methylaniline, there was no observable change in selectivity; this may be a reflection of 2-methylaniline being inherently less para selective than 2- chloroaniline. To probe the significance of the IMHB acceptor ability of N-Bpin toward selectivity, we decided to generate N–BBN, a boron group without oxygen, on the aniline. With an N–BBN in place, the para selectivity dramatically drops for both 2-chloro and 2-methylaniline. This further supports IMHB playing a direct role in selectivity. With N–BBN generated from 3-methylindole the CHB regiochemical preference flips and the C6-borylated isomer is major (2:1) as opposed to the C5 selectivity (3:1) seen with N–Bpin. 415 Figure 4.5: a) Diboron partner effect on CHB of 2-chloroaniline, b) Boron glycolate shield effect on the CHB of 2-chloroaniline, 2-methylaniline and 2-methylindole. Seeking further evidence of IMHB involvement, we examined the N-borylated anilines with the Quantum Theory of Atoms in Molecules (QTAIM) developed by Bader.41 QTAIM is used to identify IMHB based on a topological analysis of the electronic distribution. Bond critical points (BCP) are defined as the position between two atoms were the electron density reaches a minimum. 416 QTAIM identifies BCP when two atoms are connected by any type of bond including interactions as IMHB. We used a B3LYP functional and 6-311++G(d,p) basis set to optimize the geometry of N-borylated 2-chloro and 2-methylaniline (Figure 4.6a). This basis set has been previously reported to work well when IMHB is present.42 The QTAIM analysis of both N-borylated anilines shows a BCP between the oxygen of the N–Bpin group and the ortho hydrogen of the aromatic ring supporting the existence of a C–H•••O IMHB. An additional BCP is found in N-borylated 2- chloroaniline between the chloride and the N–H. This additional N–H•••Cl IMHB can be one contributor to the greater para CHB selectivity of 2-chloroaniline vs. 2-methylaniline.  (ppm)  (ppm) H3 0.02 H3 -0.01 H4 0.09 H4 0.04 H5 0.08 H5 0.04 H6 0.89 H6 0.83 Figure 4.6: a) QTAIM analysis of N-borylated 2-chloro and 2-methylaniline (left and right respectively), b) 1H NMR chemical shift deviation of N-borylated 2-chloro and 2-methylaniline respect to the unborylated anilines. The energy of hydrogen bonds can be estimated with the potential energy density (V(r)) at the BCP found with QTAIM. The linear relationship initially found by Espinosa et. al. has been 417 adapted by Afonin et. al. for the case of IMHB including cases with C–H•••O interactions.42,43 Using Afonin’s corrected equation to calculate the C–H•••O IMHB energy of N-borylated 2-chloro and 2-methylaniline gave comparable energies corresponding to 1.10 kcal/mol and 1.07 kcal/mol respectively (Figure 4.6a). Experimentally, IMHB energies can be estimated by a linear relationship with the 1H chemical shift difference of the hydrogen involved in the IMHB in the target molecule versus a reference in which no IMHB occurs (Figure 4.6b).42,44 This equation was found with 1H NMR taken in CDCl3 and therefore we used CDCl3 for this experiment. We choose the non-borylated aniline as the reference and found an energy of 1.29 and 1.23 kcal/mol for the IMHB of 2-chloro and 2-methylaniline respectively, which is close to the energy given by QTAIM. One potential pitfall in attributing para selectivity to IMHB Bpin shielding is the assumption that there is only one energy minimum on the conformational energy surface. For example, the presence of a second local minimum where the plane of the N–Bpin is orthogonal to the plane containing the aryl ring could erode selectivity if (i) the second local minimum has a comparable or lower Gibbs’ energy than the IMHB local minimum, and (ii) the barrier connecting the local minima is small. Indeed, theory predicts that there are local minima similar to the aforementioned scenario for N-borylated 2-chloroaniline and 2-methylaniline at 5.4 and 3.1 kcal/mol relative to their respective IMHB local minima (Figure 4.7), and the corresponding transition states that connect these local minima are 6.6 and 4.6 kcal/mol above the IMHB local minima. Based on the energies of the higher energy local minima, theory predicts that more than 99% on the N-borylated anilines adopt the IMHB structures. These findings support the hypothesis that IMHB between the Bpin O and the C6 proton creates a steric shield that accounts for the para selectivity. 418 Figure 4.7: C–N rotation barrier for N-borylated 2-chloroaniline (left) and 2-methylaniline (right). We next asked if similar relationships could be found in other scaffolds with and without IMHB (Figure 4.8 and 4.9). Accordingly, good CHB selectivities are seen for substrates when protons proximal to Bpin substituents have the largest 1H NMR chemical shift displacement, as well as a BCP between that proton and the Bpin O from QTAIM analysis. Specific examples are described below. The H2 of N-borylated 5-bromo-1-aminonaphthalene 4.1m’ shows a 0.85 ppm difference from the reference 5-bromo-1-aminonaphthalene. By comparison, all the other protons deviate by <0.2 ppm. QTAIM shows a BCP that supports an IMHB with an energy of 1.25 kcal/mol, which is close to 1.11 kcal/mol calculated based on the spectroscopically observed 1H NMR chemical shift displacement. As expected, 5-bromo-1-aminonaphthalene undergoes a C7-selective borylation by blocking the C3 position (Scheme 4.2). In contrast, N-borylated 2- methylnaphthalene 4.1o’ show no evidence of C–H•••O IMHB with the naphthalene as the hydrogen bond donor. H8 might be available for IMHB but  is only 0.30 ppm, which is close to the  of H4 (0.28 ppm), suggesting that chemical shift displacement results from electronic 419 effects after N-borylation. No BCP is detected with the arene as the hydrogen bond donor, but a BCP corresponding to a C–H•••O IMHB between the N–Bpin and the methyl group is found. The lack of IMHB with the naphthalene ring might be due to steric effects that disrupts any 7-member ring IMHB from happening. Accordingly, no selectivity was found under CHB reaction conditions. As shown in Scheme 4.3, the CHB regioselectivity of N-alkylated aniline depends on the scaffold. CHB of N-borylated 2-chloro-N-methyl aniline 4.3a’ did not show any selectivity. The steric clash between the N–Me and Cl groups prevents IMHB formation with the Bpin O. While chemical shift for H6 is 0.57 ppm, the significant displacement of 0.45 ppm for H4 again suggests that electronic effects are the actors. CHB of N-borylated 2-amino-N-methylpyridine 4.3b’ gave the para borylated aniline selectively. This selectivity is astounding since meta selectivity would be expected by the strong electronic effects show by pyridines in CHB reactions. 45,46 Both QTAIM analysis (1.67 kcal/mol) and chemical shift displacement (1.79 kcal/mol) support Bpin shielding from C–H•••O IMHB as the directing element. Tetrahydroquinolines are also exhibit para selectivity in CHB reactions, but that could be explained by the fact that rotation about the C–N bond is impossible and N→B p-bonding lock the N–Bpin group in place. Nonetheless, QTAIM and  show evidence for IMHB in 4.3d’ with an energy comparable to N-borylated 2-amino-N-methylpyridine. Indoles have similar conformational constraints to appropriately place the N–Bpin group. However, this group of compounds gave low to moderate selectivities. A BCP is found by QTAIM of 4.5a’ but only a 0.57 ppm of difference in chemical shifts is calculated. We speculate that the lower selectivity for indoles is due to (i) the angles of the 5-member bicyclic ring increasing the distance between the Bpin O and the H at C7 and (ii) a decrease in the negative charge on the Bpin O since the N lone pairs of indoles are weak p-donors. 420  (ppm)  (ppm)  (ppm)  (ppm) H2 0.85 H6 -0.01 H3 0.04 H5 0.10 H3 0.11 H7 0.02 H4 0.19 H6 1.14 H4 0.11 H8 -0.01  (ppm)  (ppm)  (ppm)  (ppm) H2 0.19 H5 0.02 H3 1.27 H5 0.19 - - H6 0.01 H4 0.05 H6 0.18 H4 -0.11 H7 0.57 Figure 4.8: Correlation between presence of IMHB and remote CHB selectivity. The 1H NMR chemical shift displacements are shown by the numbers in blue respect to the corresponding non- borylated compound as reference. The lowest energy conformations are shown which were calculated by B3LYP functional and 6-311++G(d,p) basis set. QTAIM was performed in each optimized structure and the critical points are shown by the dots in orange (BCP) and yellow (RCP). The energy of the C–H•••O IMHB was calculate from V(r) at the corresponding BCP by using Afonin’s equation and by the displacement of the 1H NMR chemical shift of the proton involved in the IMHB. 421  (ppm)  (ppm)  (ppm)  (ppm) H3 0.10 H6 -0.07 H3 0.13 H5 0.04 H4 0.28 H7 0.00 H4 0.45 H6 0.57 H5 -0.01 H8 0.30  (ppm)  (ppm) H3 0.05 H5 0.00 H4 0.14 H6 0.15 Figure 4.9: Correlation between absence of IMHB and CHB selectivity. The 1H NMR chemical shift displacements are shown by the numbers in blue respect to the corresponding non-borylated compound as reference. The lowest energy conformations are shown which were calculated by B3LYP functional and 6-311++G(d,p) basis set. QTAIM was performed in each optimized structure and the critical points are shown by the dots in orange (BCP) and yellow (RCP). In our efforts to expand the Bpin steric effect to other directing groups without nitrogen, we found that CHB of 2-chlorophenol 4.1p did not show selectivity. Neither QTAIM nor  show any evidence of IMHB, which explains the experimental result. 422 4.2.4. Application of IMHB to remote borylation 4.2.4.1. 7-member ring IMHB Inspired by the literature precedents,37,38,42 we sought to see if a 7-member ring can be created with IMHB to N–Bpin groups. As explained in the previous section, steric effects can disrupt IMHB and therefore a 7-member ring IMHB with arenes as hydrogen bond donors are not common. However, exceptions appear when hydrogen bond donor contain a bicyclic moiety with a 5- and 6-member fused rings.46–48 We proposed that 3-aminoindazoles would form a 7-member IMHB after N-Borylation. We were pleased to find that N-methyl-3-aminoindazol 4.11 undergoes a C6-selective CHB (Figure 4.10).  (ppm) H4 0.45 H5 0.03 H6 -0.01 H7 0.01 Figure 4.10: 7-member ring IMHB: C6 borylation of 3-aminoindazol. 1 H NMR comparison of the N-borylated indazol versus the unborylated version shows a significant movement of the chemical shift of the C4 proton, as expected with an IMHB. QTAIM provides more support to this conclusion by recognizing a C–H•••O BCP between the C4 proton and the oxygen in the Bpin group. The calculate energy by QTAIM and  are a comparable 1.19 and 0.85 kcal/mol respectively. 423 4.2.4.2. Pyrimidines as directing groups. Certainly, Bpin is not the first IMHB acceptor found in molecules. Nitrogen heterocycles have appeared as part of IMHB networks including C–H•••N interactions within heteroarenes.47– 49 Pyridines, pyrimidines and triazines are key motifs of biologically active pharmaceuticals and therefore their potential use as steric shields via IMHB drew our attention.50–56. In particular, we became interested in osimertinib, an epidermal growth factor receptor tyrosine kinase inhibitor, which presents a pyrimidine group attached to an indole skeleton. 57 We subjected osimertinib analogue 4.13 to CHB conditions (Figure 4.11). The C6-borylated indole 4.14 was produced, although with moderate selectivity. We were fortunate to crystallize 4.13 and the crystal structure showed the C–H•••N that we had proposed with the pyrimidine groups as the hydrogen bond acceptor and the C4 hydrogen of the indole being the hydrogen bond donor. We used the x-ray coordinates to evaluate the QTAIM topology of 4.13 and found a BCP that supports the IMHB C– H•••N. Next, changes in 1H NMR of 4.13 taking N-methylindole as the reference were calculated. Surprisingly, we found that both C2 and C4 hydrogens showed a significant chemical shift displacement. We propose that in solution the pyrimidine ring may equilibrate between two conformations involving IMHB with H2 and H4. The IMHB energy for H4 calculate from  is 1.13 kcal/mol, which is higher than that calculated by QTAIM. This difference might be due to the different conformations found in solution in contrast to the solid state. 424  (ppm) H2 0.60 H4 0.73 H5 0.12 H6 0.01 H7 -0.09 Figure 4.11: Expanding IMHB to other scaffolds: C6 borylation of an Osimertinib analogue with a pyrimidine directing group directed by a C–H•••N IMHB. 4.3. Conclusions A diverse array of regioselective remote CHBs can be driven by intramolecular steric shields created via IMHB. The previously inexplicable para CHB found with 2-chloro and 2- methoxy aniline now is explained by a Bpin steric shield generated after in situ N-borylation. Furthermore, N–Bpin steric shields can lead to para CHB of other ortho substituted anilines, 7- borylation of 1-naphtylamines, para CHB of certain N-alkylated anilines, and to the elusive 5- borylation of indoles. Bpin steric shielding can be extended to motifs without nitrogen, such as 1- borylated naphthalenes, which undergo C6-selective CHB. The wide variety of scaffolds that can be selectively borylated at remote positions due to a Bpin group highlights the versatility of intramolecular steric shields. We traced back the remote CHB selectivity to the presence of a C–H•••O IMHB in N- borylated intermediates with the Bpin as the hydrogen bond acceptor. A BCP found by QTAIM 425 and a characteristic 1H NMR chemical shift displacement of the hydrogen bond donor, the ortho aniline hydrogen after N-borylation here, is support for an IMHB. The energetic cost to disrupt the planarity of the N-borylated anilines and the necessity of an oxygen in the boryl group to achieve a para CHB also support the observed selectivity to involve IMHB. A 7-member ring IMHB can also produce the steric as shown in the C6-selective borylation of N-methyl-3-aminoindazole. Finally, a C5-borylation of the indole ring in an osimertinib analogue where a pyrimidine forms the steric shield via a C–H•••N IMHB further expands this means of remote regiocontrol. We anticipate that our efforts presented here will be used to design other methods for remote functionalization driven by intramolecular interactions. 4.4. Experimental Procedures 4.4.1. General Information All commercially available chemicals were used as received unless otherwise indicated. Bis(pinacolato)diboron (B2pin2) was generously supplied by BoroPharm, Inc. Bis(η4-1,5- cyclooctadiene)-di-μ-methoxy-diiridium(I) [Ir(cod)(OMe)]2 was purchased from Sigma-Aldrich. THF was refluxed over sodium/benzophenone ketyl, distilled and degassed. Anhydrous dioxane was purchased from Sigma-Aldrich and used as received. Hexane and cyclohexane were refluxed over calcium hydride, distilled and degassed. 3,4,7,8-Tetramethyl-1,10-phenanthroline (tmphen) and neocuproine were purchased from Combi-blocks and recrystallized from ethanol. 2- chloroaniline, 2-methoxyaniline, 2-methylaniline, 2-ethylaniline, 2-tertbutylaniline and tetrahydroquinoline were distilled over dried molecular sieves prior to use. Column chromatography was performed on 240 - 400 mesh Silica P-Flash silica gel. Thin layer chromatography was performed on 0.25 mm thick aluminum-backed silica gel plates and 426 visualized with ultraviolet light (λ = 254 nm) and alizarin stain to visualize boronic esters according to a literature procedure.58 1 H, 13C, 11B and 19F NMR spectra were recorded on a Varian 500 MHz DD2 Spectrometer equipped with a 1H-19F/15N-31P 5 mm Pulsed Field Gradient (PFG) Probe. Spectra taken in CDCl3 were referenced to 7.26 ppm in 1H NMR and 77.2 ppm in 13C NMR. Spectra taken in C6D6 were referenced to 7.16 ppm in 1H NMR and 128.1 ppm in 13C NMR. Spectra taken in DMSO-d6 were referenced to 2.50 ppm in 1H NMR and 39.5 ppm in 13C NMR. Spectra taken in acetone-d6 were referenced to 2.05 ppm in 1H NMR and 29.8 ppm in 13C NMR. Spectra taken in THF-d8 were referenced to 3.58 ppm in 1H NMR and 67.2 ppm in 13C NMR. 11B NMR spectra were referenced to neat BF3·Et2O as the external standard. 13C NMR resonances for the boron-bearing carbon atom were not observed due to quadrupolar relaxation; nonetheless an assignment was possible by correlations shown in gHMBCAD. All coupling constants are apparent J values measured at the indicated field strengths in Hertz (s = singlet, d = doublet, t = triplet, q = quartet, dd = doublet of doublets, ddd = doublet of doublet of doublets, bs = broad singlet). NMR spectra were processed for display using the MNova software program with only phasing and baseline corrections applied. High-resolution mass spectra (HRMS) were obtained at the Molecular Metabolism and Disease Mass Spectrometry Core facility and at the Mass Spectrometry Service Center at Michigan State University using electrospray ionization (ESI+ or ESI-) on quadrupole time-of-flight (Q- TOF) instruments. 427 4.4.2. Para CHB of anilines Para borylation of 2-chloroaniline (2a) >95% conversion, para : meta = 9 : 1 86% isolated yield, para : meta = 10 : 1 In a glove box, a 5.0 mL Wheaton microreactor was charged with 2-chloroaniline (64 mg, 0.5 mmol, 1 equiv) and tmphen (3.6 mg, 3.0 mol %) in THF (0.5 mL). In a separate tube, [Ir(cod)(OMe)]2 (5.0 mg, 1.5 mol %) and B2pin2 (190 mg, 0.75 mmol, 1.5 equiv) in THF (1.0 mL) were stirred for 5 min. The [Ir(cod)(OMe)]2/B2pin2 solution was transferred to the microreactor. The microreactor was capped with a teflon pressure cap and placed into an aluminum block pre- heated to 40 ºC. After 48 h, an aliquot of the reaction mixture was taken and analyzed directly by 1 H NMR to find the conversion and para:meta borylation ratio. MeOH (2.5 mL) was added and the mixture was stirred for 1 h. The mixture was concentrated and passed through a plug of silica gel (CHCl3 as eluent). The fractions containing product were collected and concentrated to give 109 mg of para borylated 2a with a minor byproduct corresponding to the meta borylated isomer (para:meta = 10:1) as a white solid (86% yield). The NMR data were consistent with previously reported values, designated as compound 4a’ in the cited paper.22 1 H NMR (500 MHz, CDCl3) δ 7.70 (d, J = 1.2 Hz, 1H), 7.49 (dd, J = 7.9, 1.2 Hz, 1H), 6.73 (dd, J = 7.9 Hz, 1H), 4.22 (bs, 2H), 1.32 (s, 12H). 13C NMR (126 MHz, CDCl3) δ 145.6, 136.1, 134.4, 118.8, 115.0, 83.7, 24.9. 11 B NMR (160 MHz, CDCl3) δ 30.4. HRMS (ESI) m/z calcd for C12H18BClNO2 [M+H]+ 254.1119, found 254.1116 428 Para borylation of 2-chloroaniline (2a’) 76% conversion, para : meta = 16 : 1 42% isolated yield, para : meta > 20 : 1 In a glove box, a 5.0 mL Wheaton microreactor was charged with 2-chloroaniline (64 mg, 0.5 mmol, 1 equiv) and tmphen (7.1 mg, 6.0 mol %) in THF (0.5 mL). In a separate tube, [Ir(cod)(OMe)]2 (10.0 mg, 3.0 mol %) and B2pp2 (247 mg, 0.88 mmol, 1.75 equiv) in THF (1.0 mL) were stirred for 5 min. The [Ir(cod)(OMe)] 2/B2pin2 solution was transferred to the microreactor. The microreactor was capped with a teflon pressure cap and placed into an aluminum block pre-heated to 40 ºC. After 48 h, an aliquot of the reaction mixture was taken and analyzed directly by 1H NMR to find the conversion and para:meta borylation ratio. MeOH (2.5 mL) was added and the mixture was stirred for 1 h. The mixture was concentrated and passed through a plug of silica gel (CHCl3 as eluent). The fractions containing product were collected and concentrated to give 56 mg of 2a’ as a white solid (42% yield, mp 84-86 °C). 1 H NMR (500 MHz, CDCl3) δ 7.71 (d, J = 1.4 Hz, 1H), 7.53 (dd, J = 7.9, 1.4 Hz, 1H), 6.72 (d, J = 7.9 Hz, 1H), 4.15 (bs, 2H), 1.89 (s, 2H), 1.41 (s, 12H). 13 C NMR (126 MHz, CDCl3) δ 144.7, 135.1, 133.5, 118.8, 115.0, 70.8, 49.1, 31.9. 11 B NMR (160 MHz, CDCl3) δ 26.1. HRMS (ESI) m/z calcd for C13H20BClNO2 [M+H]+ 268.1276, found 268.1264 Para borylation of 2-bromoaniline (2b) 429 91% conversion, para : meta = 9 : 1 73% isolated yield, para : meta = 11 : 1 In a glove box, a 5.0 mL Wheaton microreactor was charged with 2-bromoaniline (86 mg, 0.5 mmol, 1 equiv) and tmphen (3.6 mg, 3.0 mol %) in THF (0.5 mL). In a separate tube, [Ir(cod)(OMe)]2 (5.0 mg, 1.5 mol %) and B2pin2 (190 mg, 0.75 mmol, 1.5 equiv) in THF (1.0 mL) were stirred for 5 min. The [Ir(cod)(OMe)]2/B2pin2 solution was transferred to the microreactor. The microreactor was capped with a teflon pressure cap and placed into an aluminum block pre- heated to 40 ºC. After 48 h, an aliquot of the reaction mixture was taken and analyzed directly by 1 H NMR to find the conversion and para:meta borylation ratio. MeOH (2.5 mL) was added and the mixture was stirred for 1 h. The mixture was concentrated and passed through a plug of silica gel (CHCl3 as eluent). The fractions containing product were collected, concentrated and washed with water (1 mL). The water layer was decanted and the residue was dried to give 109 mg of para borylated 2b with a minor byproduct corresponding to the meta borylated isomer (para:meta = 11:1) as a light brown solid (73% yield). The NMR data were consistent with previously reported values, designated as compound 4b’ in the cited paper.21 1 H NMR (500 MHz, CDCl3) δ 7.86 (d, J = 1.4 Hz, 1H), 7.52 (dd, J = 7.9, 1.4 Hz, 1H), 6.72 (d, J = 7.9 Hz, 1H), 4.22 (bs, 2H), 1.32 (s, 12H). 13C NMR (126 MHz, CDCl3) δ 146.8, 139.3, 135.1, 114.9, 109.0, 83.7, 24.9. 11 B NMR (160 MHz, CDCl3) δ 30.3. HRMS (EI) m/z calcd for C12H18BBrNO2 [M+H]+ 298.0614, found 298.0613 Para borylation of 2-iodoaniline (2c) 44% conversion, para : meta = 7 : 1 20% isolated yield, para : meta = >20 : 1 430 In a glove box, a 5.0 mL Wheaton microreactor was charged with 2-iodoaniline (109 mg, 0.5 mmol, 1 equiv) and tmphen (7.1 mg, 3.0 mol %) in THF (0.5 mL). In a separate tube, [Ir(cod)(OMe)]2 (10.0 mg, 1.5 mol %) and B2pin2 (190 mg, 0.75 mmol, 1.5 equiv) in THF (1.0 mL) were stirred for 5 min. The [Ir(cod)(OMe)] 2/B2pin2 solution was transferred to the microreactor. The microreactor was capped with a teflon pressure cap and placed into an aluminum block pre-heated to 80 ºC. After 48 h, an aliquot of the reaction mixture was taken and analyzed directly by 1H NMR to find the conversion and para:meta borylation ratio. MeOH (2.5 mL) was added and the mixture was stirred for 1 h. The mixture was concentrated and subjected to chromatographic separation with silica gel (CHCl3 as eluent) to give 34 mg of 2c as a white solid (20% yield, mp 113-115 °C). The 1H NMR data were consistent with previously reported values, designated as compound 3d in the cited paper. The 13C NMR data were consistent except one peak corresponding to the C–I not reported in the cited paper.22 1 H NMR (500 MHz, CDCl3) δ 8.09 (d, J = 1.4 Hz, 1H), 7.55 (dd, J = 7.9, 1.4 Hz, 1H), 6.71 (d, J = 7.9 Hz, 1H), 4.31 (s, 2H), 1.32 (s, 12H). 13 C NMR (126 MHz, CDCl3) δ 149.3, 145.9, 136.1, 113.9, 84.0, 83.7, 25.0. 11 B NMR (160 MHz, CDCl3) δ 30.2. GC-MS (EI) m/z calcd for C12H17BINO2 [M] 345.0, found 344.9 Para borylation of 2-methoxyaniline (2d) 97% conversion, para : meta = 12 : 1 91% isolated yield, para : meta = 16 : 1 In a glove box, a 5.0 mL Wheaton microreactor was charged with 2-methoxyaniline (62 mg, 0.5 mmol, 1 equiv) and tmphen (7.1 mg, 3.0 mol %) in THF (0.5 mL). In a separate tube, 431 [Ir(cod)(OMe)]2 (10.0 mg, 1.5 mol %) and B2pin2 (190 mg, 0.75 mmol, 1.5 equiv) in THF (1.0 mL) were stirred for 5 min. The [Ir(cod)(OMe)] 2/B2pin2 solution was transferred to the microreactor. The microreactor was capped with a teflon pressure cap and placed into an aluminum block pre-heated to 60 ºC. After 26 h, an aliquot of the reaction mixture was taken and analyzed directly by 1H NMR to find the conversion and para:meta borylation ratio. MeOH (2.5 mL) was added and the mixture was stirred for 1 h. The mixture was concentrated and passed through a plug of silica gel (CHCl3 as eluent). The fractions containing product were collected, concentrated and washed with water (3 mL). The water layer was decanted and the residue was dried to give 114 mg of para borylated 2d with traces of a minor byproduct corresponding to the meta borylated isomer (para:meta = 16:1) as a light red solid (91% yield). The NMR data were consistent with previously reported values, designated as compound 4d’ in the cited paper.21 1 H NMR (500 MHz, CDCl3) δ 7.30 (dd, J = 7.6, 1.3 Hz, 1H), 7.20 (d, J = 1.3 Hz, 1H), 6.70 (d, J = 7.6 Hz, 1H), 3.97 (bs, 2H), 3.89 (s, 3H), 1.33 (s, 12H). 13 C NMR (126 MHz, CDCl3) δ 146.5, 139.6, 128.9, 115.9, 114.1, 83.4, 55.6, 24.9. 11 B NMR (160 MHz, CDCl3) δ 30.8. HRMS (ESI) m/z calcd for C13H21BNO3 [M+H]+ 250.1614, found 250.1605 Para borylation of 2-trifluoromethylaniline (2e) 91% conversion, para : meta = 4 : 1 52% isolated yield, para : meta = 4 : 1 In a glove box, a 5.0 mL Wheaton microreactor was charged with 2-trifluoromethylaniline (81 mg, 0.5 mmol, 1 equiv) and tmphen (3.5 mg, 3.0 mol %) in THF (0.5 mL). In a separate tube, [Ir(cod)(OMe)]2 (5.0 mg, 1.5 mol %) and B2pin2 (190 mg, 0.75 mmol, 1.5 equiv) in THF (1.0 mL) 432 were stirred for 5 min. The [Ir(cod)(OMe)]2/B2pin2 solution was transferred to the microreactor. The microreactor was capped with a teflon pressure cap and placed into an aluminum block pre- heated to 40 ºC. After 54 h, an aliquot of the reaction mixture was taken and analyzed directly by 1 H NMR to find the conversion and para:meta borylation ratio. MeOH (2.5 mL) was added and the mixture was stirred for 1 h. The mixture was concentrated and passed through a plug of silica gel (CHCl3 as eluent). The fractions containing product were collected, concentrated and washed with water (2 mL). The water layer was decanted and the residue was dried to give 74 mg of para borylated 2e with a minor byproduct corresponding to the meta borylated isomer (para:meta = 4:1) as a brown oil (52% yield). The NMR data were consistent with previously reported values, designated as compound 3b in the cited paper.58 1 H NMR (500 MHz, CDCl3) δ 7.89 (s, 1H), 7.71 (d, J = 8.1 Hz, 1H), 6.70 (d, J = 8.1 Hz, 1H), 4.28 (bs, 2H), 1.32 (s, 12H). 13 C NMR (126 MHz, CDCl3) δ 147.1 (q, J = 1.9 Hz), 139.4 (q, J = 0.9 Hz), 133.7 (q, J = 4.9 Hz), 125.2 (q, J = 272.3 Hz), 116.2, 113.1 (q, J = 29.8 Hz), 83.8, 24.9. 11B NMR (160 MHz, CDCl3) δ 30.3. 19F NMR (470 MHz, CDCl3) δ -62.5. HRMS (ESI) m/z calcd for C13H18BF3NO2 [M+H]+ 288.1383, found 288.1372 Para borylation of methyl 2-aminobenzoate (2f) 87% conversion, para : meta = 2 : 1 66% isolated yield, para : meta = 2 : 1 In a glove box, a 5.0 mL Wheaton microreactor was charged with methyl 2-aminobenzoate (76 mg, 0.5 mmol, 1 equiv) and tmphen (3.5 mg, 3.0 mol %) in THF (0.5 mL). In a separate tube, [Ir(cod)(OMe)]2 (5.0 mg, 1.5 mol %) and B2pin2 (190 mg, 0.75 mmol, 1.5 equiv) in THF (1.0 mL) 433 were stirred for 5 min. The [Ir(cod)(OMe)]2/B2pin2 solution was transferred to the microreactor. The microreactor was capped with a teflon pressure cap and placed into an aluminum block pre- heated to 40 ºC. After 58 h, an aliquot of the reaction mixture was taken and analyzed directly by 1 H NMR to find the conversion and para:meta borylation ratio. MeOH (2.5 mL) was added and the mixture was stirred for 1 h. The mixture was concentrated and passed through a plug of silica gel (CHCl3 as eluent). The fractions containing product were collected, concentrated and washed with water (2 mL). The water layer was decanted and the residue was dried to give 92 mg of a mixture of para borylated methyl 2-aminobenzoate 2f with the meta isomer (para:meta = 2:1) as a white brownish solid (66% yield). The NMR data of the para isomer were consistent with previously reported values, designated as compound a in the cited paper.59 Para: 1 H NMR (500 MHz, CDCl3) δ 8.33 (d, J = 1.6 Hz, 1H), 7.66 (dd, J = 8.2, 1.6 Hz, 1H), 6.62 (d, J = 8.2 Hz, 1H), 5.89 (bs, 2H), 3.85 (s, 3H), 1.32 (s, 12H). 13 C NMR (126 MHz, CDCl3) δ 168.8, 152.8, 140.2, 139.0, 116.0, 110.3, 83.6, 51.5, 24.9. 11 B NMR (160 MHz, CDCl3) δ 30.9. HRMS (ESI) m/z calcd for C14H21BNO4 [M+H]+ 278.1564, found 278.1552 Meta: 1 H NMR (500 MHz, CDCl3) δ 7.83 (d, J = 8.0 Hz, 1H), 7.13 (d, J = 1.1 Hz, 1H), 7.04 (dd, J = 7.9, 1.1 Hz, 1H), 5.89 (bs, 2H), 3.86 (s, 3H), 1.33 (s, 12H). 13 C NMR (126 MHz, CDCl3) δ 168.6, 149.5, 130.3, 123.5, 122.0, 112.8, 84.2, 51.7, 24.9. 11 B NMR (160 MHz, CDCl3) δ 30.9. HRMS (ESI) m/z calcd for C14H21BNO4 [M+H]+ 278.1564, found 278.1552 434 Para borylation of 2-methylaniline (2g) 61% conversion, para : meta = 4 : 1 47% isolated yield, para : meta > 20 : 1 In a glove box, a 5.0 mL Wheaton microreactor was charged with 2-methylaniline (54 mg, 0.5 mmol, 1 equiv) and tmphen (7.1 mg, 6.0 mol %) in THF (0.5 mL). In a separate tube, [Ir(cod)(OMe)]2 (9.9 mg, 3.0 mol %) and B2pin2 (190 mg, 0.75 mmol, 1.5 equiv) in THF (1.0 mL) were stirred for 5 min. The [Ir(cod)(OMe)]2/B2pin2 solution was transferred to the microreactor. The microreactor was capped with a teflon pressure cap and placed into an aluminum block pre- heated to 60 ºC. After 68 h, an aliquot of the reaction mixture was taken and analyzed directly by 1 H NMR to find the conversion and para:meta borylation ratio. MeOH (2.5 mL) was added and the mixture was stirred for 1 h. The mixture was concentrated and passed through a plug of silica gel (CHCl3 as eluent) to remove the iridium residue. The fractions containing product were collected, concentrated and passed through silica gel column chromatography (chloroform/ethyl acetate 98:2) to give 55 mg of 2g as a light-yellow solid (47% yield). The NMR data were consistent with previously reported values.60 1 H NMR (500 MHz, CDCl3) δ 7.52-7.50 (m, 2H), 6.66 (d, J = 7.8 Hz, 1H), 3.81 (s, 2H), 2.16 (s, 3H), 1.33 (s, 12H). 13C NMR (126 MHz, CDCl3) δ 147.7, 137.3, 134.2, 121.2, 114.1, 83.4, 24.9, 17.1. 11 B NMR (160 MHz, CDCl3) δ 30.7. HRMS (ESI) m/z calcd for C13H21BNO2 [M+H]+ 234.1665, found 234.1654 435 With N-Bpin bond preformation: >95% conversion, para : meta = 6 : 1 72% isolated yield, para : meta = 10 : 1 In a glove box, a 5.0 mL Wheaton microreactor was charged with 2-methylaniline (0.1 mL of a 2.5 M solution in THF, 0.25 mmol, 1 equiv), [Ir(cod)(OMe)]2 (0.1 mL of a 12.5 mM solution in THF, 0.5 mol %), HBpin (38 mg, 0.3 mmol, 1.2 equiv) and THF (0.05 mL). The microreactor was capped with a teflon pressure cap and placed into an aluminum block pre-heated to 80 ºC. After 1 h, the microreactor was brought back to the glove box. In a separate tube, a solution of [Ir(cod)(OMe)]2 (22 mg, 16.6 mM, 0.033 mmol) and B2pin2 (423 mg, 0.83 M, 1.66 mmol) in THF (2.0 mL) was prepared. The microreactor was charged with tmphen (3.6 mg, 6.0 mol %), THF (0.05 mL) and with 0.45 mL of the solution containing [Ir(cod)(OMe)] 2 (3 mol %) and B2pin2 (0.37 mmol, 1.5 equiv). The microreactor was capped with a teflon pressure cap and placed into an aluminum block pre-heated to 60 ºC. After 48 h, an aliquot of the reaction mixture was taken and analyzed directly by 1H NMR to find the conversion and para:meta borylation ratio. MeOH (1.25 mL) was added and the mixture was stirred for 1 h. The mixture was concentrated and passed through a plug of silica gel (chloroform/ethyl acetate 98:2). The fractions containing product were collected, concentrated and washed with water (4 mL). The water layer was decanted and the residue was dried to give 42 mg of a para borylated 2-methylaniline 2g with the meta isomer as a minor byproduct (para:meta = 10:1) as a yellow solid (72% yield). 436 Para borylation of 2-ethylaniline (2h) 48% conversion, para : meta = 4 : 1 43% isolated yield, para : meta = 9 : 1 In a glove box, a 5.0 mL Wheaton microreactor was charged with 2-methylaniline (54 mg, 0.5 mmol, 1 equiv) and tmphen (7.1 mg, 6.0 mol %) in THF (0.5 mL). In a separate tube, [Ir(cod)(OMe)]2 (9.9 mg, 3.0 mol %) and B2pin2 (190 mg, 0.75 mmol, 1.5 equiv) in THF (1.0 mL) were stirred for 5 min. The [Ir(cod)(OMe)]2/B2pin2 solution was transferred to the microreactor. The microreactor was capped with a teflon pressure cap and placed into an aluminum block pre- heated to 60 ºC. After 68 h, an aliquot of the reaction mixture was taken and analyzed directly by 1 H NMR to find the conversion and para:meta borylation ratio. MeOH (2.5 mL) was added and the mixture was stirred for 1 h. The mixture was concentrated and passed through silica gel column chromatography (chloroform/ethyl acetate 98:2). The fractions containing product were collected, concentrated to give 53 mg of para borylated 2h with traces of the meta isomer (para:meta = 9:1) as a white brownish solid (43% yield). Para: 1 H NMR (500 MHz, CDCl3) δ 7.54 (d, J = 1.6 Hz, 1H), 7.52 (dd, J = 7.8, 1.6 Hz, 1H), 6.66 (d, J = 7.8 Hz, 1H), 3.84 (s, 2H), 2.53 (q, J = 7.5 Hz, 2H), 1.34 (s, 12H), 1.26 (t, J = 7.5 Hz, 3H). 13C NMR (126 MHz, CDCl3) δ 147.2, 135.5, 134.2, 127.0, 114.6, 83.3, 24.9, 24.1, 13.2. 11 B NMR (160 MHz, CDCl3) δ 30.7. HRMS (ESI) m/z calcd for C14H23BNO2 [M+H]+ 248.1822, found 248.1812 437 7 mg of a minor fraction containing mainly the meta isomer (meta:para = 2:1) was isolated as well (6% yield) Meta: 1 H NMR (500 MHz, CDCl3) δ 7.22 (dd, J = 7.4, 1.2 Hz, 1H), 7.13 (d, J = 1.2 Hz, 1H), 7.09 (d, J = 7.4 Hz, 1H), 3.77 (bs, 2H), 2.54 (q, J = 7.0 Hz, 2H), 1.33 (s, 12H), 1.25 (t, J = 7.0 Hz, 3H). HRMS (ESI) m/z calcd for C14H23BNO2 [M+H]+ 248.1822, found 248.1812 Para borylation of 2-tertbutylaniline (2i) 86% conversion, para : meta = 5 : 1 81% isolated yield, para : meta = 5 : 1 In a glove box, a 5.0 mL Wheaton microreactor was charged with methyl 2-tertbutylaniline (75 mg, 0.5 mmol, 1 equiv) and tmphen (7.1 mg, 6.0 mol %) in THF (0.5 mL). In a separate tube, [Ir(cod)(OMe)]2 (10.0 mg, 3.0 mol %) and B2pin2 (190 mg, 0.75 mmol, 1.5 equiv) in THF (1.0 mL) were stirred for 5 min. The [Ir(cod)(OMe)] 2/B2pin2 solution was transferred to the microreactor. The microreactor was capped with a teflon pressure cap and placed into an aluminum block pre-heated to 60 ºC. After 28 h, an aliquot of the reaction mixture was taken and analyzed directly by 1H NMR to find the conversion and para:meta borylation ratio. MeOH (2.5 mL) was added and the mixture was stirred for 1 h. The mixture was concentrated and passed through a plug of silica gel (CHCl3 as eluent). The fractions containing product were collected and concentrated to give 111 mg of the para borylated 2-tertbutylaniline 2i with a minor byproduct corresponding to the meta isomer (para:meta = 5:1) as a white brownish solid (81% yield). 438 Para: 1 H NMR (500 MHz, CDCl3) δ 7.70 (d, J = 1.5 Hz, 1H), 7.51 (dd, J = 7.8, 1.5 Hz, 1H), 6.63 (d, J = 7.8 Hz, 1H), 4.00 (bs, 2H), 1.45 (s, 9H), 1.33 (s, 12H). 13 C NMR (126 MHz, CDCl3) δ 147.7, 134.3, 133.5, 132.4, 117.0, 83.3, 34.3, 29.8, 25.0. 11 B NMR (160 MHz, CDCl3) δ 31.1. HRMS (ESI) m/z calcd for C16H27BNO2 [M+H]+ 276.2135, found 276.2131 Meta: 1 H NMR (500 MHz, CDCl3) δ 7.27 (d, J = 7.8 Hz, 1H), 7.21 (dd, J = 7.8, 1.3 Hz, 1H), 7.12 (d, J = 1.3 Hz, 1H), 4.00 (bs, 2H), 1.43 (s, 9H), 1.34 (s, 12H). Para borylation of 4-aminoindan (2j) 58% conversion, para : meta = 2 : 1 52% isolated yield, para : meta = 2 : 1 In a glove box, a 5.0 mL Wheaton microreactor was charged with methyl 4-aminoindan (67 mg, 0.5 mmol, 1 equiv) and tmphen (7.1 mg, 6.0 mol %) in THF (0.5 mL). In a separate tube, [Ir(cod)(OMe)]2 (10.0 mg, 3.0 mol %) and B2pin2 (190 mg, 0.75 mmol, 1.5 equiv) in THF (1.0 mL) were stirred for 5 min. The [Ir(cod)(OMe)] 2/B2pin2 solution was transferred to the microreactor. The microreactor was capped with a teflon pressure cap and placed into an aluminum block pre-heated to 60 ºC. After 48 h, an aliquot of the reaction mixture was taken and analyzed directly by 1H NMR to find the conversion and para:meta borylation ratio. MeOH (2.5 mL) was added and the mixture was stirred for 1 h. The mixture was concentrated and passed through silica gel column chromatography (chloroform/ethyl acetate 100:0 → chloroform/ethyl acetate 96:4). The fractions containing product were collected and concentrated to give 67 mg of a mixture of 439 the para borylated 4-aminoindan 2j with the meta isomer (para:meta = 2:1) as a yellowish solid (52% yield). Para: 1 H NMR (500 MHz, CDCl3) δ 7.50 (d, J = 7.8 Hz, 1H), 6.50 (d, J = 7.8 Hz, 1H), 3.71 (bs, 2H), 3.14 (t, J = 7.5 Hz, 2H), 2.69 (t, J = 7.5 Hz, 2H), 2.09 (p, J = 7.5 Hz, 3H), 1.32 (s, 12H). 13C NMR (126 MHz, cdcl3) δ 153.3, 145.4, 135.5, 127.6, 114.2 (C–B observed by HMBC), 111.7, 82.9, 34.5, 11 29.1, 25.0, 24.5. (assignments based on HSQC and HMBC correlations). B NMR (160 MHz, CDCl3) δ 31.2. HRMS (ESI) m/z calcd for C15H23BNO2 [M+H]+ 260.1822, found 260.1818 Meta: 1 H NMR (500 MHz, CDCl3) δ 7.18 (s, 1H), 6.97 (s, 1H), 3.71 (bs, 2H), 2.91 (t, J = 7.5 Hz, 2H), 2.74 (t, J = 7.4 Hz, 2H), 2.09 (p, J = 7.4 Hz, 7H), 1.34 (s, 12H). 13C NMR (126 MHz, CDCl3) δ 145.2, 142.2, 132.5, 127.6 (C–B observed by HMBC), 121.3, 118.8, 83.6, 33.0, 29.7, 24.9, 24.8. (assignments based on HSQC and HMBC correlations). 11 B NMR (160 MHz, CDCl3) δ 31.2. HRMS (ESI) m/z calcd for C15H23BNO2 [M+H]+ 260.1822, found 260.1818 Para borylation of 2-bromo-3-fluoroaniline (2k) >95% conversion, para : meta = 4 : 1 76% isolated yield, para : meta = 5 : 1 In a glove box, a 5.0 mL Wheaton microreactor was charged with methyl 2-bromo-3- fluoroaniline (95 mg, 0.5 mmol, 1 equiv) and tmphen (3.5 mg, 3.0 mol %) in THF (0.5 mL). In a separate tube, [Ir(cod)(OMe)]2 (5.0 mg, 1.5 mol %) and B2pin2 (190 mg, 0.75 mmol, 1.5 equiv) in THF (1.0 mL) were stirred for 5 min. The [Ir(cod)(OMe)] 2/B2pin2 solution was transferred to the 440 microreactor. The microreactor was capped with a teflon pressure cap and placed into an aluminum block pre-heated to 60 ºC. After 48 h, an aliquot of the reaction mixture was taken and analyzed directly by 1H NMR to find the conversion and para:meta borylation ratio. MeOH (2.5 mL) was added and the mixture was stirred for 1 h. The mixture was concentrated and passed through a plug of silica gel (CHCl3 as eluent). The fractions containing product were collected and concentrated to give 120 mg of the para borylated 2-bromo-3-fluoroaniline 2k with a minor byproduct corresponding to the meta isomer (para:meta = 5:1) as a white solid (76% yield). Para: 1 H NMR (500 MHz, CDCl3) δ 7.44 (dd, J = 8.2, 6.4 Hz, 1H), 6.50 (dd, J = 8.2, 0.9 Hz, 1H), 4.42 (bs, 2H), 1.32 (s, 12H). 19F NMR (470 MHz, CDCl3) δ -94.86 (dd, J = 6.4, 2.6 Hz). 13C NMR (126 MHz, CDCl3) δ 164.4 (d, J = 250.3 Hz), 149.0 (d, J = 3.9 Hz), 135.8 (d, J = 10.2 Hz), 110.3 (d, J = 2.4 Hz), 96.0 (d, J = 26.0 Hz), 83.7, 24.9. 11B NMR (160 MHz, CDCl3) δ 29.8. HRMS (ESI) m/z calcd for C12H17BBrFNO2 [M+H]+ 316.0520, found 316.0501 Meta: 1 H NMR (500 MHz, CDCl3) δ 6.96 (t, J = 1.1 Hz, 1H), 6.89 (dd, J = 8.5, 1.1 Hz, 1H), 4.42 (bs, 2H), 1.32 (s, 12H). 19F NMR (470 MHz, CDCl3) δ -107.45 (d, J = 8.5 Hz). 13C NMR (126 MHz, CDCl3) δ 159.6 (d, J = 245.7 Hz), 145.8 (d, J = 2.5 Hz), 116.8 (d, J = 2.4 Hz), 110.5 (d, J = 21.0 Hz), 99.7 (d, J = 23.4 Hz), 84.3, 24.9. 11B NMR (160 MHz, CDCl3) δ 29.8. HRMS (ESI) m/z calcd for C12H17BBrFNO2 [M+H]+ 316.0520, found 316.0501 Para borylation of 2,4-difluoroaniline (2l) 441 >95% conversion, C3 : C5 = 15 : 1 27% isolated yield, C3 : C5 = 13 : 1 In a glove box, a 5.0 mL Wheaton microreactor was charged with methyl 2-fluoro-4- fluoroaniline (65 mg, 0.5 mmol, 1 equiv) and tmphen (3.5 mg, 3.0 mol %) in THF (0.5 mL). In a separate tube, [Ir(cod)(OMe)]2 (5.0 mg, 1.5 mol %) and B2pin2 (190 mg, 0.75 mmol, 1.5 equiv) in THF (1.0 mL) were stirred for 5 min. The [Ir(cod)(OMe)] 2/B2pin2 solution was transferred to the microreactor. The microreactor was capped with a teflon pressure cap and placed into an aluminum block pre-heated to 40 ºC. After 48 h, an aliquot of the reaction mixture was taken and analyzed directly by 1H NMR to find the conversion and para:meta borylation ratio. MeOH (2.5 mL) was added and the mixture was stirred for 1 h. The mixture was concentrated and passed through a silica gel column chromatography (chloroform/ethyl acetate 24:1 as eluent). The fractions containing product were collected and concentrated to give 34 mg of the C3-borylated 2-fluoro-4- fluoroaniline 2l with a minor byproduct corresponding to the C5 isomer (C3:C5 = 13:1) as a pale brownish solid (27% yield). 3-borylated product, major isomer: 1 H NMR (500 MHz, C6D6) δ 6.48 (td, J = 8.5, 1.4 Hz, 1H), 6.10 (ddd, J = 9.9, 8.5, 5.6 Hz, 1H), 2.77 (bs, 2H), 1.13 (s, 12H). 19F NMR (470 MHz, C6D6) δ -114.8 (dt, J = 8.5, 4.3 Hz), -121.8 (dd, J = 9.9, 4.0 Hz). 13C NMR (126 MHz, C6D6) δ 158.8 (dd, J = 241.2, 11.6 Hz), 154.2 (dd, J = 244.1, 12.4 Hz), 130.8 (dd, J = 14.8, 3.3 Hz), 118.9 (dd, J = 9.4, 5.6 Hz), 110.6 (dd, J = 24.8, 3.9 Hz), 83.6, 24.4. 11B NMR (160 MHz, C6D6) δ 30.2. HRMS (ESI) m/z calcd for C12H17BF2NO2 [M+H]+ 256.1320, found 256.1310 442 5-borylated product, major isomer: 1 H NMR (500 MHz, C6D6) δ 7.13 (dd, J = 10.5, 5.6 Hz, 0H), 6.54 (dd, J = 11.2, 8.5 Hz, 0H), 2.77 (bs, 2H), 1.13 (s, 12H). 19F NMR (470 MHz, C6D6) δ -111.9 (dt, J = 10.2, 5.2 Hz), -126.1 (td, J = 10.8, 5.0 Hz). C7 borylation of 5-bromo-1-naphthylamine (2m) 93% conversion, C7 : C3 = 7 : 1 57% isolated yield, C7 : C3 > 20 : 1 In a glove box, a 5.0 mL Wheaton microreactor was charged with 5-bromo-1- naphthylamine (111 mg, 0.5 mmol, 1 equiv) and tmphen (3.6 mg, 3.0 mol %) in THF (0.5 mL). In a separate tube, [Ir(cod)(OMe)]2 (5.0 mg, 1.5 mol %) and B2pin2 (190 mg, 0.75 mmol, 1.5 equiv) in THF (1.0 mL) were stirred for 5 min. The [Ir(cod)(OMe)] 2/B2pin2 solution was transferred to the microreactor. The microreactor was capped with a teflon pressure cap and placed into an aluminum block pre-heated to 40 ºC. After 48 h, an aliquot of the reaction mixture was taken and analyzed directly by 1H NMR to find the conversion and 7:3 borylation ratio. MeOH (2.5 mL) was added and the mixture was stirred for 1 h. The mixture was concentrated and passed through a plug of silica gel (CHCl3 as eluent). The fractions containing product were collected and concentrated to give 99 mg of para borylated 2m with only traces of the 3-borylated isomer (C7:C3 > 20:1) as a light brown solid (57% yield, mp 190-192 °C). The solid was recrystallized over toluene to confirm the structure by x-ray crystallography. The CIF file is available for download from the CCDC and may be referenced by CCDC deposition 2062023. 443 1 H NMR (500 MHz, CDCl3) δ 8.3 (t, J = 1.0 Hz, 1H), 8.1 (d, J = 1.0 Hz, 1H), 7.7 (dt, J = 8.5, 1.0 Hz, 1H), 7.4 (dd, J = 8.5, 7.5 Hz, 1H), 6.8 (dd, J = 7.5, 1.0 Hz, 1H), 4.3 (bs, 2H), 1.4 (s, 12H). 13C NMR (126 MHz, CDCl3) δ 143.3, 134.6, 134.5, 129.2, 128.8, 124.1, 123.4, 118.0, 110.7, 84.3, 25.0. C–B not observed due to quadrupolar relaxation. 11B NMR (160 MHz, CDCl3) δ 30.4. HRMS (ESI) m/z calcd for C16H20BBrNO2 [M+H] 348.0770, found 348.0759 C7 borylation of 5-hydroxy-1-naphthylamine (2n) 68% conversion, C7 : C3 : C3C7 = 9.8 : 0.4 : 1 33% isolated yield, C7 : C3 : C3C7 = 16 : 1 : 0.2 In a glove box, a 5.0 mL Wheaton microreactor was charged with 5-hydroxy-1- naphthylamine (80 mg, 0.5 mmol, 1 equiv) and tmphen (3.6 mg, 3.0 mol %) in THF (0.5 mL). In a separate tube, [Ir(cod)(OMe)]2 (5.0 mg, 1.5 mol %) and B2pin2 (190 mg, 0.75 mmol, 1.5 equiv) in THF (1.0 mL) were stirred for 5 min. The [Ir(cod)(OMe)] 2/B2pin2 solution was transferred to the microreactor. The microreactor was capped with a teflon pressure cap and placed into an aluminum block pre-heated to 40 ºC. After 48 h, the microreactor was brought out of the glove box, open to air and MeOH (2.5 mL) was added. The mixture was stirred for 1 h. An aliquot of the reaction mixture was taken, evaporated and analyzed directly by 1H NMR to find the conversion and C7:C3:C3C7 borylation ratio. The mixture was passed through silica gel column chromatography (chloroform/ethyl acetate 9:1 → chloroform/ethyl acetate 4:1 as eluent). The 444 fractions containing product were collected to give 47 mg of C7-borylated 2n with minor byproducts corresponding to the C3-borylated and C3,C7-diborylated isomers (C7:C3:C3C7 = 16:1:0.2) as a purple solid (33% yield). C7 borylated product: 1 H NMR (500 MHz, DMSO-d6) δ 9.68 (s, 1H), 7.87 (s, 1H), 7.34 (d, J = 8.2 Hz, 1H), 7.17 (t, J = 7.9 Hz, 1H), 7.06 (s, 1H), 6.66 (dd, J = 7.5, 1.1 Hz, 1H), 5.66 (bs, 2H), 1.32 (s, 12H). 13C NMR (126 MHz, DMSO-d6) δ 152.4, 145.3, 127.4, 126.7, 123.6, 121.2, 111.7, 109.5, 108.3, 83.4, 24.8. 11 B NMR (160 MHz, DMSO-d6) δ 31.8. HRMS (ESI) m/z calcd for C16H21BNO3 [M+H]+ 286.1614, found 286.1604 C3 borylated product: 1 H NMR (500 MHz, DMSO-d6) δ 9.94 (s, 1H), 7.84 (s, 1H), 7.46 (d, J = 8.5 Hz, 1H), 7.21 (m, 1H), 6.96 (s, 1H), 6.79 (d, J = 7.2 Hz, 1H), 5.66 (bs, 2H), 1.32 (s, 12H). HRMS (ESI) m/z calcd for C16H21BNO3 [M+H]+ 286.1614, found 286.1604 A second fraction was collected corresponding to 39 mg of C7-borylated 2n with a minor byproduct corresponding to the C3,C7-diborylated product (C7:C3C7 = 4:1) (25% yield). This fraction was taken as reference to make the assignment of the C3,C7-diborylated isomer. C3-C7 diborylated product: 1 H NMR (500 MHz, DMSO-d6) δ 9.84 (s, 1H), 7.85 (s, 1H), 7.81 (s, 1H), 7.06 (s, 1H), 6.97 (s, 1H), 5.68 (bs, 2H), 1.32 (s, 12H), 1.30 (s, 12H). HRMS (ESI) m/z calcd for C22H32B2NO5 [M] 412.2467, found 412.3779. 445 4.4.3. Para CHB of N-alkylated anilines Unselective Borylation of 2-chloro-N-methylaniline (4a) >95% conversion, para : meta = 1 : 1 91% isolated yield, para : meta = 1 : 1 In a glove box, a 5.0 mL Wheaton microreactor was charged with 2-chloro-N-methyl aniline (71 mg, 0.5 mmol, 1 equiv), [Ir(cod)(OMe)]2 (1.7mg, 0.5 mol %), HBpin (77 mg, 0.6 mmol, 1.2 equiv), NEt3 (0.08 mL, 0.5 mmol), and THF (0.5 mL). The microreactor was capped with a teflon pressure cap and placed into an aluminum block pre-heated to 80 ºC. After 1 h, the microreactor was brought back to the glove box. The microreactor was charged [Ir(cod)(OMe)] 2 (10 mg, 3 mol %), B2pin2 (190 mg, 0.75 mmol), and THF (0.5 mL). The reaction was then stirred for 5 minutes over which the reaction turned a dark golden color. tmphen (3.6 mg, 6.0 mol %) and THF (0.5 mL) was then added causing the reaction to turn a dark green color. The microreactor was capped with a teflon pressure cap and placed into an aluminum block pre-heated to 40 ºC. After 24 h, an aliquot of the reaction mixture was taken and analyzed directly by 1H NMR showing complete conversion and a 1:1 para : meta borylation ratio. MeOH (2.25 mL) was added resulting in vigorous bubbling, and the mixture was stirred for 1 h at room temperature. The mixture was concentrated and passed through a plug of silica gel (2 cm x 5 cm) (hexane/ethyl acetate 4:1 as eluent). The fractions containing product were collected and concentrated to give 122 mg of a para 446 and meta borylated 2-chloro-N-methylaniline 4a as a mixture of isomers (para:meta = 1:1) as a white solid (91% yield). The reaction was repeated but this time the para and meta isomer were separate for characterization. >95% conversion, para : meta = 1 : 1 1.1% isolated yield, para : meta = > 20 : 1 13% isolated yield, para : meta = < 1 : 20 In a glove box, a 5.0 mL Wheaton microreactor was charged with 2-chloro-N-methyl aniline (71 mg, 0.5 mmol, 1 equiv), [Ir(cod)(OMe)]2 (1.7mg, 0.5 mol %), HBpin (77 mg, 0.6 mmol, 1.2 equiv), NEt3 (0.08 mL, 0.5 mmol), and THF (0.5 mL). The microreactor was capped with a teflon pressure cap and placed into an aluminum block pre-heated to 80 ºC. After 1 h, the microreactor was brought back to the glove box. The microreactor was charged [Ir(cod)(OMe)] 2 (10 mg, 3 mol %), B2pin2 (190 mg, 0.75 mmol), and THF (0.5 mL). The reaction was then stirred for 5 minutes over which the reaction turned a dark golden color. tmphen (3.6 mg, 6.0 mol %) and THF (0.5 mL) was then added causing the reaction to turn a dark green color. The microreactor was capped with a teflon pressure cap and placed into an aluminum block pre-heated to 40 ºC. After 48 h, an aliquot of the reaction mixture was taken and analyzed directly by 1H NMR showing complete conversion and a 1:1 para : meta borylation ratio. MeOH (2.25 mL) was added resulting in vigorous bubbling, and the mixture was stirred for 1 h at room temperature. The mixture was concentrated and passed through a plug of silica gel (2 cm x 5 cm) (chloroform as eluent). The 447 fractions containing product were collected and concentrated to give a first fraction containing 1.4 mg of para borylated 2-chloro-N-methylaniline 4a (1% yield). The fraction was too small to take an accurate 13C NMR but the peaks could be obtained by subtracting the meta carbon peaks from the para/meta mixture isolated previously. The NMR data of the para isomer were consistent with previously reported NMR values.61 Para: 1 H NMR (500 MHz, CDCl3) δ 7.69 (d, J = 1.4 Hz, 1H), 7.60 (dd, J = 8.1, 1.4 Hz, 1H), 6.61 (d, J = 8.1 Hz, 1H), 4.60 (bs, 1H), 2.92 (d, J = 5.2 Hz, 3H), 1.32 (s, 12H). 13C NMR (126 MHz, CDCl3) δ 147.4, 135.4, 134.9, 118.7, 109.8, 83.6, 30.3, 25.0. 11B NMR (160 MHz, CDCl3) δ 30.9. HRMS (ESI) m/z calcd for C13H20BClNO2 [M+H]+ 268.1276, found 268.1273 A second fraction was collected corresponding to 17.3 mg of meta borylated 2-chloro-N- methylaniline 4a (13% yield). Meta: 1 H NMR (500 MHz, CDCl3) δ 7.25 (d, J = 7.7 Hz, 1H), 7.08 (dd, J = 7.7, 1.4 Hz, 1H), 7.07 (d, J = 1.4 Hz, 1H), 4.32 (bs, 1H), 2.95 (s, 3H), 1.34 (s, 12H). 13 C NMR (126 MHz, CDCl3) δ 144.5, 128.6, 123.8, 122.5, 116.5, 84.0, 30.7, 25.0. 11 B NMR (160 MHz, CDCl3) δ 30.8. HRMS (ESI) m/z calcd for C13H20BClNO2 [M+H]+ 268.1276, found 268.1271 Para Borylation of N-methyl-2-aminopyridine (4b) >95% conversion, para : meta = 4 : 1 39% isolated yield, para : meta > 20 : 1 448 In a glove box, a 5.0 mL Wheaton microreactor was charged with N-methyl-2- aminopyridine (54 mg, 0.5 mmol, 1 equiv), HBpin (77 mg, 0.6 mmol, 1.2 equiv), [Ir(cod)(OMe)] 2 (1.7 mg, 0.5 mol %), triethylamine (0.08 mL, 0.5 mmol, 1.0 equiv) and THF (0.5 mL). The microreactor was capped with a teflon pressure cap and placed into an aluminum block pre-heated to 80 ºC. After 1 h, the microreactor was brought back to the glove box. In a separate tube, [Ir(cod)(OMe)]2 (10 mg, 3.0 mol %) and B2pin2 (190 mg, 1.5 mmol, 1.5 equiv) in THF (1.0 mL) were stirred for 5 min. The microreactor was charged with the [Ir(cod)(OMe)] 2/B2pin2 solution and with tmphen (7.1 mg, 6.0 mol %). The microreactor was capped with a teflon pressure cap and placed into an aluminum block pre-heated to 40 ºC. After 14 h, an aliquot of the reaction mixture was taken and analyzed directly by 1H NMR to find the conversion and para:meta borylation ratio. MeOH (2.5 mL) was added and the mixture was stirred for 1 h. The mixture was concentrated and passed through a plug of silica gel (ethyl acetate as eluent). The fractions containing product were collected and concentrated to give 46 mg of para borylated 4b with traces of the meta isomer (para:meta > 20:1) as a white solid (39% yield, mp 101-103 °C). 1 H NMR (500 MHz, CDCl3) δ 8.44 (dd, J = 1.9, 0.9 Hz, 1H), 7.78 (dd, J = 8.4, 1.9 Hz, 1H), 6.32 (dd, J = 8.4, 0.9 Hz, 1H), 5.10 (d, J = 5.1 1H), 2.90 (d, J = 5.1 Hz, 3H), 1.30 (s, 12H). 13C NMR (126 MHz, CDCl3) δ 161.2, 155.4, 143.6, 104.8, 83.4, 28.9, 24.8. 11B NMR (160 MHz, CDCl3) δ 30.8. HRMS (ESI) m/z calcd for C12H20BN2O2 [M+H]+ 235.1618, found 235.1602 Para Borylation of N-ethyl-2-aminopyridine (4c) 449 >95% conversion, para : meta = 3 : 1 50% isolated yield, para : meta > 20 : 1 In a glove box, a 5.0 mL Wheaton microreactor was charged with N-ethyl-2-aminopyridine (61 mg, 0.5 mmol, 1 equiv), HBpin (77 mg, 0.6 mmol, 1.2 equiv), [Ir(cod)(OMe)] 2 (1.7 mg, 0.5 mol %), triethylamine (0.08 mL, 0.5 mmol, 1.0 equiv) and THF (0.5 mL). The microreactor was capped with a teflon pressure cap and placed into an aluminum block pre-heated to 80 ºC. After 1 h, the microreactor was brought back to the glove box. In a separate tube, [Ir(cod)(OMe)]2 (10 mg, 3.0 mol %) and B2pin2 (190 mg, 1.5 mmol, 1.5 equiv) in THF (1.0 mL) were stirred for 5 min. The microreactor was charged with the [Ir(cod)(OMe)]2/B2pin2 solution and with tmphen (7.1 mg, 6.0 mol %). The microreactor was capped with a teflon pressure cap and placed into an aluminum block pre-heated to 40 ºC. After 14 h, an aliquot of the reaction mixture was taken and analyzed directly by 1H NMR to find the conversion and para:meta borylation ratio. MeOH (2.5 mL) was added and the mixture was stirred for 1 h. The mixture was concentrated and passed through a plug of silica gel (ethyl acetate as eluent). The fractions containing product were collected, concentrated and 3 mL of water were added. The water layer was decanted and extracted with ethyl acetate (3 mL). The organic layer was separated and concentrated to give 62 mg of para borylated 4c with traces of the meta isomer (para:meta > 20:1) as a white solid (50% yield). 1 H NMR (500 MHz, CDCl3) δ 8.38 (dd, J = 1.9, 0.9 Hz, 1H), 7.77 (dd, J = 8.4, 1.9 Hz, 1H), 6.31 (dd, J = 8.4, 0.9 Hz, 1H), 5.29 (d, J = 5.8 Hz, 1H), 3.24 (qd, J = 7.2, 5.8 Hz, 2H), 1.28 (s, 12H), 1.23 (t, J = 7.2 Hz, 3H). 13C NMR (126 MHz, CDCl3) δ 160.0, 154.7, 144.2, 105.0, 83.5, 36.9, 24.9, 14.7. 11B NMR (160 MHz, CDCl3) δ 31.1. HRMS (ESI) m/z calcd for C13H22BN2O2 [M+H]+ 249.1774, found 249.1759 450 Para Borylation of 1,2,3,4-tetrahydroquinoline (4d) >95% conversion, para : meta = 11 : 1 36% isolated yield, para : meta > 20 : 1 In a glove box, a 5.0 mL Wheaton microreactor was charged with 1,2,3,4- tetrahydroquinoline (60 mg, 0.5 mmol, 1 equiv), [Ir(cod)(OMe)]2 (1.7mg, 0.5 mol %), HBpin (77 mg, 0.6 mmol, 1.2 equiv), NEt3 (0.08 mL, 0.5 mmol), and THF (0.5 mL). The microreactor was capped with a teflon pressure cap and placed into an aluminum block pre-heated to 80 ºC. After 1 h, the microreactor was brought back to the glove box. The microreactor was charged [Ir(cod)(OMe)]2 (10 mg, 3 mol %), B2pin2 (190 mg, 0.75 mmol), and THF (0.5 mL). The reaction was then stirred for 5 minutes over which the reaction turned a dark golden color. tmphen (3.6 mg, 6.0 mol %) and THF (0.5 mL) was then added causing the reaction to turn a dark green color. The microreactor was capped with a teflon pressure cap and placed into an aluminum block pre-heated to 60 ºC. After 48 h, an aliquot of the reaction mixture was taken and analyzed directly by 1H NMR showing complete conversion and a 9:1 para : meta borylation ratio. MeOH (2.25 mL) was added resulting in vigorous bubbling, and the mixture was stirred for 1 h at room temperature. The mixture was concentrated and passed through a plug of silica gel (chloroform/hexane/ethyl acetate 7:2:1 as eluent). The fractions containing product were collected as two groups and concentrated to give 46.7 mg of a para borylated 1,2,3,4-tetrahydroquinoline 4d as a colorless oil (36% yield) with the meta isomer as a minor byproduct being collected as a white solid at 4.3 mg (3% yield). The NMR data of the para isomer were consistent with previously reported values, designated as compound 33a in the cited paper.62 451 Para: 1 H NMR (500 MHz, CDCl3) δ 7.45-7.39 (m, 2H), 6.45-6.40 (m, 1H), 4.09 (bs, 1H), 3.31 (t, J=5.5, 2H), 2.76 (t, J = 6.3, 2H), 1.95-1.87 (m, 2H), 1.32 (s, 12H). 13C NMR (126 MHz, CDCl3) δ 147.6, 136.4, 133.9, 120.3, 113.2, 83.2, 41.9, 26.9, 24.9, 22.0. 11 B NMR (160 MHz, CDCl3) δ 30.6. HRMS (ESI) m/z calcd for C15H23BNO2 [M+H]+ 260.1822, found 260.1814 Meta: 1 H NMR (500 MHz, CDCl3) δ 7.05 (d, J = 7.4 Hz, 1H), 6.96 (d, J = 7.4 Hz, 1H), 6.91 (s, 1H), 3.81 (bs, 1H), 3.34 – 3.21 (m, 2H), 2.77 (t, J = 6.3 Hz, 2H), 1.93 (p, J = 6.5 Hz, 2H), 1.32 (s, 12H). 13C NMR (126 MHz, CDCl3) δ 144.5, 129.2, 125.1, 123.5, 120.5, 83.6, 42.2, 27.3, 25.0, 22.2. 11 B NMR (160 MHz, CDCl3) δ 30.6. HRMS (ESI) m/z calcd for C15H23BNO2 [M+H]+ 260.1822, found 260.1814 Para Borylation of 4-methyl-1,2,3,4-tetrahydroquinoline (4e) 60% conversion, para : meta = 12 : 1 60% isolated yield, para : meta = 12 : 1 In a glove box, a 5.0 mL Wheaton microreactor was charged with the 4-methyl-1,2,3,4- tetrahydroquinoline (74 mgs, 0.5 mmol), [Ir(cod)(OMe)]2 (1.7 mg, 0.5 mol %), HBpin (77 mg, 0.6 mmol, 1.2 equiv), triethylamine (0.08 mL, 0.5 mmol, 1.0 equiv) and THF (0.5 mL). The microreactor was capped with a teflon pressure cap and placed into an aluminum block pre-heated to 80 ºC. After 1 h, the microreactor was brought back to the glove box. In a separate tube, [Ir(cod)(OMe)]2 (10 mg, 3.0 mol %) and B2pin2 (190 mg, 0.75 mmol, 1.5 equiv) in THF (1.0 mL) 452 were stirred for 5 min. The microreactor was charged with the [Ir(cod)(OMe)]2/B2pin2 solution and with tmphen (7.1 mg, 6.0 mol %). The microreactor was capped with a teflon pressure cap and placed into an aluminum block pre-heated to 40 ºC. After 48 h, an aliquot of the reaction mixture was taken and analyzed directly by 1H NMR to find the conversion and para:meta borylation ratio. MeOH (2.5 mL) was added and the mixture was stirred for 1 h. The mixture was concentrated and passed through a column of silica gel (chloroform as eluent). The fractions containing product were collected to give 72 mg of para borylated 4e with a minor byproduct corresponding to the meta borylated isomer (para:meta = 16:1) as a yellow sticky solid (53% yield). The para product was characterized by 1H-NOE. Major Para Borylated Product: 1 H NMR (500 MHz, CDCl3) δ 7.52 (s, 1H), 7.44 (d, J = 8.0 Hz, 1H), 6.45 (d, J = 8.0 Hz, 1H), 4.12 (bs, 1H), 3.40 – 3.26 (m, 2H), 2.98 – 2.87 (m, 1H), 2.01 – 1.90 (m, 1H), 1.74 – 1.62 (m, 1H), 1.33 (s, 12 H), 1.31 (d, J = 6.9 Hz, 3H). 13 C NMR (126 MHz, CDCl3) δ 147.0, 135.4, 134.0, 125.4, 113.2, 83.2, 38.6, 30.2, 29.4, 25.0, 24.9 (two inequivalent types of methyl groups in the Bpin group), 22.6. 11B NMR (160 MHz, CDCl3) 30.9. HRMS (ESI) m/z calcd for C16H25BNO2 [M+H]+ 274.1978, found 274.1982 A second fraction was collected corresponding to 9.6 mg of para borylated 4e with a minor byproduct corresponding to the meta borylated isomer (para:meta = 4:1) (7% yield). This fraction was taken as reference to make the assignment of the meta borylated isomer. The total yield adds up to 60% (para : meta = 12 : 1). 453 Minor Meta Borylated Product: 1 H NMR (500 MHz, CDCl3) 7.08 (s, 2H), 6.93 (s, 1H), 3.40 – 3.26 (m, 2H), 2.98 – 2.87 (m, 1H), 2.01 – 1.90 (m, 1H), 1.74 – 1.62 (m, 1H), 1.33 (s, 12 H), 1.31 (d, J = 7.0 Hz, 3H). HRMS (ESI) m/z calcd for C16H25BNO2 [M+H]+ 274.1978, found 274.1982 Para Borylation of 2-methyl-1,2,3,4-tetrahydroquinoline (4f) 45% conversion, para : meta= 10 : 1 41% isolated yield, para : meta= 13 : 1 In a glove box, a 5.0 mL Wheaton microreactor was charged with the 2-methyl-1,2,3,4- tetrahydroquinoline (74 mg, 0.5 mmol), [Ir(cod)(OMe)] 2 (1.7 mg, 0.5 mol %), HBpin (77 mg, 0.6 mmol, 1.2 equiv), triethylamine (0.08 mL, 0.5 mmol, 1.0 equiv) and THF (0.5 mL). The microreactor was capped with a teflon pressure cap and placed into an aluminum block pre-heated to 80 ºC. After 1 h, the microreactor was brought back to the glove box. In a separate tube, [Ir(cod)(OMe)]2 (10 mg, 3.0 mol %) and B2pin2 (190 mg, 0.75 mmol, 1.5 equiv) in THF (1.0 mL) were stirred for 5 min. The microreactor was charged with the [Ir(cod)(OMe)]2/B2pin2 solution and with tmphen (7.1 mg, 6.0 mol %). The microreactor was capped with a teflon pressure cap and placed into an aluminum block pre-heated to 40 ºC. After 48 h, an aliquot of the reaction mixture was taken and analyzed directly by 1H NMR to find the conversion and para:meta borylation ratio. MeOH (2.5 mL) was added and the mixture was stirred for 1 h. The mixture was concentrated and passed through a column of silica gel (chloroform as an eluent). The fractions containing product were collected and concentrated to give 48 mg of para borylated 4f with only traces of the meta 454 isomer (para:meta > 20:1) as a white solid (35% yield). The NMR data were consistent with previously reported values, designated as compound 3u in the cited paper.63 Para isomer (C6) 1 H NMR (500 MHz, C6D6) δ 7.97 (d, J = 8.0 Hz, 1H), 7.90 (s, 1H), 6.28 (d, J = 8.0, 1H), 3.36 – 3.19 (bs, 1H), 3.00 – 2.83 (m, 1H), 2.61 – 2.45 (m, 2H), 1.49 – 1.40 (m, 1H), 1.34 – 1.23 (m, 1H), 1.18 (s, 12H), 0.74 (d, J = 5.7 Hz, 3H). 1H NMR (500 MHz, CDCl3) δ 7.47 – 7.38 (m, 2H), 6.43 (d, J = 7.9 Hz, 1H), 3.93 (bs, 1H), 3.43 (ddd, J = 9.5, 6.3, 3.1 Hz, 1H), 2.91 – 2.66 (m, 2H), 1.99 – 1.87 (m, 1H), 1.57 (dddd, J = 12.8, 11.1, 9.7, 5.4 Hz, 1H), 1.32 (s, 12H), 1.21 (d, J = 6.3 Hz, 3H). 13C NMR (126 MHz, C6D6) δ 147.9, 137.2, 134.6, 119.8, 113.5, 83.1, 47.0, 30.1, 26.7, 25.1, 22.4. 11 B NMR (160 MHz, C6D6) δ 31.6. HRMS (ESI) m/z calcd for C16H25BNO2 [M+H]+ 274.1978, found 274.1982 A second fraction was collected corresponding to 8.2 mg of a mixture of the meta and para borylated isomer (para:meta = 1:1) (6% yield). This fraction was taken as reference to make the assignment of the meta borylated isomer. The total yield adds up to 41% (para : meta= 13 : 1). Meta isomer (C7) 1 H NMR (500 MHz, C6D6) 7.63 (dd, J = 7.3, 1.1 Hz, 1H), 7.26 (d, J = 1.1 Hz, 1H), 6.98 (d, J = 7.3 Hz, 1H), 3.26 – 3.12 (bs, 1H), 2.97 – 2.86 (m, 1H), 2.62 – 2.44 (m, 2H), 1.59 – 1.40 (m, 1H), 1.38 – 1.22 (m, 1H), 1.16 (s, 12H), 0.78 (d, J = 6.2 Hz, 3H). 13C NMR (126 MHz, C6D6) δ 144.8, 129.2, 124.4, 124.2, 121.4, 83.4, 47.2, 30.3, 27.1, 25.0, 22.5. 11B NMR (160 MHz, C6D6) δ 31.0. HRMS (ESI) m/z calcd for C16H25BNO2 [M+H]+ 274.1978, found 274.1982 455 Para Borylation of 2,3,4,5-tetrahydro-1H-benzo[b]azepine (4g) 92% conversion, para : meta = 3 : 1 53% isolated yield, para : meta > 20 : 1 In a glove box, a 5.0 mL Wheaton microreactor was charged with 2,3,4,9-tetrahydro-1H- carbazole (86 mg, 0.5 mmol, 1 equiv), HBpin (154 mg, 1 mmol, 2 equiv), triethylamine (0.16 mL, 1 mmol, 2.0 equiv) and THF (0.5 mL). The microreactor was capped with a teflon pressure cap and placed into an aluminum block pre-heated to 80 ºC. After 3 h, the microreactor was brought back to the glove box. In a separate tube, [Ir(cod)(OMe)]2 (10 mg, 3.0 mol %) and B2pin2 (190 mg, 1.5 mmol, 1.5 equiv) in THF (1.0 mL) were stirred for 5 min. The microreactor was charged with the [Ir(cod)(OMe)]2/B2pin2 solution and with tmphen (7.1 mg, 6.0 mol %). The microreactor was capped with a teflon pressure cap and placed into an aluminum block pre-heated to 60 ºC. After 48 h, an aliquot of the reaction mixture was taken and analyzed directly by 1H NMR to find the conversion and para:meta borylation ratio. MeOH (2.5 mL) was added and the mixture was stirred for 1 h. The mixture was concentrated and purified with a silica column (ethyl acetate:chloroform 1:25 as eluent). The fractions containing product were collected, concentrated to give 72 mg of para borylated 4g with only traces of the meta borylated isomer (para:meta > 20:1) as yellowish solid (53% yield). Para isomer is assigned equivocally by gCOSY and NOE. Major isomer, Para, (C7) 1 H NMR (500 MHz, CDCl3) δ 7.58 (s, 1H), 7.51 (d, J = 7.7 Hz, 1H), 6.71 (d, J = 7.7 Hz, 1H), 3.95 (bs, 1H), 3.12 – 3.00 (m, 2H), 2.91 – 2.75 (m, 2H), 1.84 – 1.74 (m, 2H), 1.70 – 1.61 (m, 2H), 1.33 (s, 12H). 13C NMR (126 MHz, CDCl3) δ 153.5, 137.8, 133.6, 132.0, 118.7, 83.4, 48.6, 35.8, 31.6, 456 26.8, 24.9. 11B NMR (160 MHz, CDCl3) δ 30.5. HRMS (ESI) m/z calcd for C16H25BNO2 [M+H]+ 274.1978, found 274.2035. A second fraction was collected corresponding to 29 mg of a mixture of para borylated 4g with the meta isomer (para:meta = 1:1) (21% yield). This fraction was taken as reference to make the assignment of the meta borylated isomer. Minor isomer, Meta, (C8) 1 H NMR (500 MHz, CDCl3) 7.29 (d, J = 7.4 Hz, 1H), 7.19 (s, 1H), 7.13 (d, J = 7.4 Hz, 1H), 3.89 (bs, 1H), 3.15 – 2.97 (m, 2H), 2.82 – 2.72 (m, 2H), 1.87 – 1.71 (m, 2H), 1.69 – 1.55 (m, 2H), 1.32 (s, 12H). 13C NMR (126 MHz, CDCl3) δ 149.9, 137.5, 130.4, 127.7, 125.8, 83.5, 48.6, 35.8, 31.6, 26.8, 24.9. 11B NMR (160 MHz, CDCl3) δ 31.2. HRMS (ESI) m/z calcd for C16H25BNO2 [M+H]+ 274.1978, found 274.2035 Para Borylation of 3,4-dihydro-2H-benzo[b][1,4]oxazine (4h) 83% conversion C7 : C6 : C8 = 29 : 1 : 3 77% isolated yield, C7 : C6 : C8 = 17 : 1 : 1 In a glove box, a 5.0 mL Wheaton microreactor was charged with the 3,4-dihydro-2H- benzo[1,4]oxazine (68 mgs, 0.5 mmol), [Ir(cod)(OMe)] 2 (1.7 mg, 0.5 mol %), HBpin (77 mg, 0.6 mmol, 1.2 equiv), triethylamine (0.08 mL, 0.5 mmol, 1.0 equiv) and THF (0.5 mL). The microreactor was capped with a teflon pressure cap and placed into an aluminum block pre-heated to 80 ºC. After 1 h, the microreactor was brought back to the glove box. In a separate tube, [Ir(cod)(OMe)]2 (10 mg, 3.0 mol %) and B2pin2 (190 mg, 0.75 mmol, 1.5 equiv) in THF (1.0 mL) were stirred for 5 min. The microreactor was charged with the [Ir(cod)(OMe)] 2/B2pin2 solution 457 and with tmphen (7.1 mg, 6.0 mol %). The microreactor was capped with a teflon pressure cap and placed into an aluminum block pre-heated to 40 ºC. After 48 h, an aliquot of the reaction mixture was taken and analyzed directly by 1H NMR to find the conversion and C7:C6:C8 borylation ratio. MeOH (2.5 mL) was added and the mixture was stirred for 1 h. The mixture was concentrated and passed through a plug of silica gel (chloroform/ethylacetate as eluent, 50:1). The fractions containing product were collected to give 83 mg of 7-borylated 4h with minor byproducts corresponding to the 6-borylated and 8-borylated isomers (C7:C6:C8 = 17:1:1) as pale yellow solid (77% yield). The NMR data of the 7-borylated isomer were consistent with previously reported NMR values, designated as compound 13e in the cited paper.64 7-borylated isomer, major isomer: 1 H NMR (500 MHz, CDCl3) δ 7.25 – 7.19 (m, 2H), 6.56 (d, J = 8.1 Hz, 1H), 4.24 – 4.19 (m, 2H), 3.95 (bs, 1H), 3.44 (t, J = 4.5 Hz, 3H), 1.31 (s, 11H). 1H NMR (500 MHz, C6D6) δ 7.94 (s, 1H), 7.78 (dd, J = 8.0, 0.9 Hz, 1H), 6.32 (d, J = 7.8 Hz, 1H), 3.70 – 3.65 (m, 2H), 2.80 (bs, 1H), 2.56 – 2.51 (m, 2H), 1.13 (s, 12H). 13C NMR (126 MHz, C6D6) δ 144.0, 137.5, 129.4, 124.0, 115.0, 83.5, 64.7, 41.0, 25.2. 11 B NMR (160 MHz, C6D6) δ 31.4. HRMS (ESI) m/z calcd for C14H21BNO3 [M+H]+ 262.1614, found 262.1614 6-borylated isomer, minor isomer: 1 H NMR (500 MHz, C6D6) 7.65 (dd, J = 7.5, 1.1 Hz 1H), 7.3 (d, J = 8.0 Hz, 1H), 7.0 (s, 1H), 3.73 – 3.70 (m, 2H), 2.56 – 2.51 (m, 2H), 1.17 (s, 12H). HRMS (ESI) m/z calcd for C14H21BNO3 [M+H]+ 262.1614, found 262.1614] 458 8-borylated isomer, minor isomer: 1 H NMR (500 MHz, C6D6) 7.67 (dd, J = 7.4, 1.7 Hz, 1H), 6.83 (t, J = 7.4 Hz, 1H), 6.34 (d, J =1.6 Hz, 1H), 3.88 – 3.85 (m, 2H), 2.59 – 2.56 (m, 2H), 1.15 (s, 12H). HRMS (ESI) m/z calcd for C14H21BNO3 [M+H]+ 262.1614, found 262.1614 8-borylated isomer was assigned by preparing the title compound by Miyaura Borylation. Miyaura Borylation of 8-bromo-3,4-dihydro-2H-benzo[b][1,4]oxazine In a glove box, a 5.0 mL Wheaton microreactor was charged with the 8-bromo-3,4- dihydro-2H-1,4-benzoxazine (68 mg, 0.5 mmol) and dioxane (3 mL). KOAc (98 mg, 1.0 mmol, 2.0 equiv), bis(pinacolato)diboron (190 mg, 0.75 mmol, 1.5 equiv) and [1,1’- bis(diphenylphosphino) ferrocene]dicholoropalladium(II) (37 mg, 0.05 mol, 10 mol %) were added to the microreactor. The microreactor was capped with a teflon pressure cap and placed into an aluminum block pre-heated to 80 ºC. After 2 h, the mixture was concentrated and passed through a plug of silica gel (dichloromethane as eluent). The product was collected and concentrated to give 50 mg of the borylated product as an orange solid (38% yield, mp 121-123 °C). 1 H NMR (500 MHz, C6D6) 7.66 (dd, J = 7.4, 1.6 Hz, 1H), 6.83 (t, J = 7.5 Hz, 1H), 6.43 (dd, J =7.7, 1.7, 1H), 3.88 (m, 2H), 2.60 (m, 2H), 1.16 (s, 12H). 13 C NMR (126 MHz, C6D6 δ 149.8, 133.7, 126.8, 120.6,118.8 ,83.0, 65.0, 40.5, 24.8. 11B NMR (160 MHz, C6D6) δ 31.5. GC-MS (EI) m/z calcd for C14H20BNO3 [M] 261.2, found 261.1 459 Para Borylation of 8-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazine (4i) >95% conversion, para : meta = 8 : 1 89% isolated yield, para : meta = 10 : 1 In a glove box, a 5.0 mL Wheaton microreactor was charged with 8-fluoro-3,4-dihydro- 2H-benzo[b][1,4]oxazine (77 mg, 0.5 mmol), [Ir(cod)(OMe)] 2 (1.7mg, 0.5 mol %), HBpin (77 mg, 0.6 mmol, 1.2 equiv), NEt3 (0.08 mL, 0.5 mmol), and THF (0.5 mL). The microreactor was capped with a teflon pressure cap and placed into an aluminum block pre-heated to 80 ºC. After 1 h, the microreactor was brought back to the glove box. The microreactor was charged [Ir(cod)(OMe)] 2 (10 mg, 3 mol %), B2pin2 (190 mg, 0.75 mmol), and THF (0.5 mL). The reaction was then stirred for 5 minutes over which the reaction turned a dark golden color. tmphen (3.6 mg, 6.0 mol %) and THF (0.5 mL) was then added causing the reaction to turn a dark green color. The microreactor was capped with a teflon pressure cap and placed into an aluminum block pre-heated to 60 ºC. After 24 h, an aliquot of the reaction mixture was taken and analyzed directly by 1H NMR showing complete conversion and a 8:1 para : meta borylation ratio. The mixture was concentrated and passed through a plug of silica gel (2 cm x 5 cm) (hexane/ethyl acetate 7:3 as eluent). The fractions containing product were collected, concentrated and washed with water (2 mL). The water layer was decanted and the residue was dried to yield 68 mg of a para borylated 4i with the meta isomer as a minor byproduct (para:meta = 10:1) as a tan solid that darkened over time (89% yield). Para: 1 H NMR (500 MHz, CDCl3) δ 7.07 (dd, J = 8.1, 5.9 Hz, 1H), 6.33 (dd, J = 8.1, 0.9), 4.28-4.22(m, 2H), 4.14-4.05 (m, 1H), 3.54-3.39 (m, 2H), 1.32 (s, 12H). 19F NMR (470 MHz, CDCl3) δ -127.4 460 (d, J = 6.7 Hz). 13C NMR (126 MHz, CDCl3) δ 156.5 (d, J = 248.1 Hz), 138.8 (dd, J = 5.3, 3.3 Hz), 131.4 (d, J = 15.3 Hz), 128.0 (d, J = 9.6 Hz), 110.0 (d, J = 2.4 Hz), 83.4, 64.9, 40.7, 24.9. 11B NMR (160 MHz, CDCl3) δ 30.3. HRMS (ESI) m/z calcd for C14H20BFNO3 [M+H]+ 280.1520, found 280.1508 Meta: 1 H NMR (500 MHz, CDCl3) δ 6.92 (dd, J = 10.78, 1.16 Hz, 1H), 6.82 (s, 1H), 4.33-4.30 (m, 1H), 4.14-4.05 (m, 1H), 3.54-3.39 (m, 2H), 1.31 (s, 12H). 19F NMR (470 MHz, CDCl3) δ -138.73 (d, J = 10.8 Hz). HRMS (ESI) m/z calcd for C14H20BFNO3 [M+H]+ 280.1520, found 280.1508 Para Borylation of 10H-phenoxazine (4j) >95% conversión to major diborylated product 55% isolated yield of major diborylated product In a glove box, a 5.0 mL Wheaton microreactor was charged with HBpin (67 mg, 1 mmol, 1 equiv, 10H-phenoxazine (86 mg, 0.5 mmol, 1 equiv), triethylamine (0.08 mL, 1 mmol, 1.0 equiv) and THF (0.5 mL). The microreactor was capped with a teflon pressure cap and placed into an aluminum block pre-heated to 80 ºC. After 1 h, the microreactor was brought back to the glove box. In a separate tube, [Ir(cod)(OMe)]2 (10 mg, 3.0 mol %) and B2pin2 (190 mg, 0.75 mmol, 1.5 equiv) in THF (1.0 mL) were stirred for 5 min. The microreactor was charged with the [Ir(cod)(OMe)]2/B2pin2 solution and with tmphen (7.1 mg, 6.0 mol %). The microreactor was 461 capped with a teflon pressure cap and placed into an aluminum block pre-heated to 40 ºC. After 48 h, an aliquot of the reaction mixture was taken, dissolve in DMSO-d6 and analyzed directly by 1 H NMR. Diborylated 4j appeared as the major isomer (4j:others  2:1), the NMR data were consistent with previously reported NMR values designated as compound PR1 in the cited paper.65 MeOH (2.5 mL) was added and the mixture was stirred for 1 h. The mixture was concentrated and passed through silica gel gradient column chromatography (ethyl acetate/chloroform 1:50 → ethyl acetate/chloroform 1:25 as eluent). The mixture was passed one more time through silica gel gradient column chromatography with the same solvent system (ethyl acetate/chloroform 1:50 → ethyl acetate/chloroform 1:25 as eluent). The fractions containing product were collected, concentrated to give 15 mg of mostly 4j (4j:others  4:1) as a bright yellow solid (7% yield). 1 H NMR (500 MHz, CDCl3) δ 7.17 (d, J = 7.6 Hz, 2H), 7.04 (s, 2H), 6.33 (d, J = 7.7 Hz, 2H), 5.50 (bs, 1H), 1.31 (s, 24H). 13 C NMR (126 MHz, CDCl3) δ 143.4, 133.9, 131.0, 121.6, 112.9, 83.7, 24.9. 11B NMR (160 MHz, CDCl3) δ 31.6. GC-MS (EI) m/z calcd for C24H31B2NO5 [M] 435.2, found 435.1 4.4.4. C5 CHB of Indoles C5 Borylation of 3-methyl indole (6a) >95% conversion, C5 :C6 = 3 : 1 89% isolated yield, C5 : C6 = 4 : 1 In a glove box, a 5.0 mL Wheaton microreactor was charged with 3-methyl indole (66 mg, 0.5 mmol, 1 equiv), HBpin (77 mg, 0.6 mmol, 1.2 equiv), triethylamine (0.08 mL, 0.5 mmol, 1.0 equiv) and THF (0.5 mL). The microreactor was capped with a teflon pressure cap and placed into 462 an aluminum block pre-heated to 80 ºC. After 1 h, the microreactor was brought back to the glove box. In a separate tube, [Ir(cod)(OMe)]2 (10 mg, 3.0 mol %) and B2pin2 (190 mg, 1.5 mmol, 1.5 equiv) in THF (1.0 mL) were stirred for 5 min. The microreactor was charged with the [Ir(cod)(OMe)]2/B2pin2 solution and with tmphen (7.1 mg, 6.0 mol %). The microreactor was capped with a teflon pressure cap and placed into an aluminum block pre-heated to 60 ºC. After 43 h, an aliquot of the reaction mixture was taken and analyzed directly by 1H NMR to find the conversion and 5:6 borylation ratio. MeOH (2.5 mL) was added and the mixture was stirred for 1 h. The mixture was concentrated and passed through a plug of silica gel (CHCl3 as eluent). The fractions containing product were collected and concentrated to give 114 mg of 5-borylated 6a with a minor byproduct corresponding to the 6-borylated isomer (C5:C6 = 4:1) as a white solid (89% yield). The 1H NMR data of the 5-borylated isomer were consistent with previously reported values.66 C5-borylated product: 1 H NMR (500 MHz, CDCl3) δ 8.15 (q, J = 0.9 Hz, 1H), 8.00 (bs, 1H), 7.67 (dd, J = 8.1, 1.1 Hz, 1H), 7.32 (dd, J = 8.1, 0.9 Hz, 1H), 6.93 (dq, J = 2.3, 1.1 Hz, 1H), 2.36 (d, J = 1.1 Hz, 3H), 1.40 (s, 12H). 13 C NMR (126 MHz, CDCl3) δ 138.4, 128.1, 128.1, 126.8, 121.7, 112.5, 110.5, 83.6, 25.0, 9.9. 11B NMR (160 MHz, CDCl3) δ 31.6. HRMS (ESI) m/z calcd for C15H21BNO2 [M+H]+ 258.1665, found 258.1649 C6-borylated product: 1 H NMR (500 MHz, CDCl3) δ 8.00 (bs, 1H), 7.87 (d, J = 0.9 Hz, 1H), 7.67 (dd, J = 8.1, 1.1 Hz, 3H), 7.63 – 7.55 (m, 2H), 7.01 (dq, J = 2.2, 1.1 Hz, 1H), 2.35 (d, J = 1.1 Hz, 3H), 1.39 (s, 12H). 13 C NMR (126 MHz, CDCl3) δ 136.1, 130.8, 125.0, 123.3, 118.3, 118.1, 111.8, 83.7, 25.0, 9.8. 463 11 B NMR (160 MHz, CDCl3) δ 31.6. HRMS (ESI) m/z calcd for C15H21BNO2 [M+H]+ 258.1665, found 258.1649 C5 Borylation of methyl indole-3-carboxylate (6b) >95% conversion, C5 : C6 = 1 : 1 86% isolated yield, C5 : C6 = 1 : 1 In a glove box, a 5.0 mL Wheaton microreactor was charged with methyl indole-3- carboxyltae (88 mg, 0.5 mmol, 1 equiv), HBpin (77 mg, 0.6 mmol, 1.2 equiv), triethylamine (0.08 mL, 0.5 mmol, 1.0 equiv) and THF (0.5 mL). The microreactor was capped with a teflon pressure cap and placed into an aluminum block pre-heated to 80 ºC. After 1 h, the microreactor was brought back to the glove box. In a separate tube, [Ir(cod)(OMe)]2 (10 mg, 3.0 mol %) and B2pin2 (190 mg, 1.5 mmol, 1.5 equiv) in THF (1.0 mL) were stirred for 5 min. The microreactor was charged with the [Ir(cod)(OMe)]2/B2pin2 solution and with tmphen (7.1 mg, 6.0 mol %). The microreactor was capped with a teflon pressure cap and placed into an aluminum block pre-heated to 60 ºC. After 48 h, an aliquot of the reaction mixture was taken and analyzed directly by 1H NMR to find the conversion and 5:6 borylation ratio. MeOH (2.5 mL) was added and the mixture was stirred for 1 h. The mixture was concentrated and passed through a plug of silica gel (chloroform/ethyl acetate 9:1). The fractions containing product were collected, concentrated and washed with water (3 mL). The water layer was decanted and the residue was dried to give 130 mg of 5-borylated and 464 6-borylated isomers 6b (C5:C6 = 1:1) as a beige solid (86% yield). The 1H NMR data of the 5- borylated isomer in DMSO-d6 were consistent with previously reported values.67 C5-borylated product: 1 H NMR (500 MHz, DMSO-d6) δ 12.04 (bs, 1H), 8.41 (s, 1H), 8.11 (d, J = 2.9 Hz, 1H), 7.51 (dd, J = 8.2, 1.2 Hz, 1H), 7.46 (dd, J = 8.2, 0.9 Hz, 1H), 3.81 (d, J = 2.9 Hz, 3H), 1.31 (s, 12H). 1H NMR (500 MHz, CDCl3) δ 9.01 (bs, 1H), 8.67 (d, J = 1.1 Hz, 1H), 7.91 (d, J = 3.0 Hz, 1H), 7.70 13 (dd, J = 8.2, 1.1 Hz, 1H), 7.39 (d, J = 8.2 Hz, 1H), 3.93 (s, 3H), 1.37 (s, 12H). C NMR (126 MHz, CDCl3) δ 165.9, 138.3, 131.5, 129.3, 129.1, 125.4, 111.2, 109.2, 83.8, 51.4, 25.0. 11B NMR (160 MHz, CDCl3) δ 31.6. HRMS (ESI) m/z calcd for C16H21BNO4 [M+H]+ 302.1564, found 302.1563 C6-borylated product: 1 H NMR (500 MHz, DMSO-d6) δ 12.04 (bs, 1H), 8.19 (d, J = 3.1 Hz, 1H), 7.99 (d, J = 8.0 Hz, 1H), 7.81 (d, J = 1.0 Hz, 1H), 7.47 (dd, J = 8.0, 1.0 Hz, 1H), 3.81 (d, J = 3.1 Hz, 3H), 1.31 (s, 12H). 1H NMR (500 MHz, CDCl3) δ 8.95 (bs, 1H), 8.17 (d, J = 8.0 Hz, 1H), 7.95 (d, J = 3.0 Hz, 1H), 7.91 (d, J = 0.9 Hz, 1H), 7.70 (dd, J = 8.0, 0.9 Hz, 1H), 3.93 (s, 3H), 1.37 (s, 12H). 13C NMR (126 MHz, CDCl3) δ 165.8, 136.0, 132.4, 128.3, 128.0, 120.9, 118.6, 108.9, 83.9, 51.3, 25.0. 11B NMR (160 MHz, CDCl3) δ 31.6. HRMS (ESI) m/z calcd for C16H21BNO4 [M+H]+ 302.1564, found 302.1563 C5 Borylation of 2,3-dimethyl indole (6c) 465 >95% conversion, C5 : C6 = 5 : 1 88% isolated yield, C5 : C6 = 4 : 1 In a glove box, a 5.0 mL Wheaton microreactor was charged with 2,3-dimethyl-1H-indole (73 mg, 0.5 mmol, 1 equiv), HBpin (154 mg, 1 mmol, 2 equiv), triethylamine (0.16 mL, 1 mmol, 2.0 equiv) and THF (0.5 mL). The microreactor was capped with a teflon pressure cap and placed into an aluminum block pre-heated to 80 ºC. After 1 h, the microreactor was brought back to the glove box. In a separate tube, [Ir(cod)(OMe)]2 (10 mg, 3.0 mol %) and B2pin2 (190 mg, 1.5 mmol, 1.5 equiv) in THF (1.0 mL) were stirred for 5 min. The microreactor was charged with the [Ir(cod)(OMe)]2/B2pin2 solution and with tmphen (7.1 mg, 6.0 mol %). The microreactor was capped with a teflon pressure cap and placed into an aluminum block pre-heated to 60 ºC. After 48 h, an aliquot of the reaction mixture was taken and analyzed directly by 1H NMR to find the conversion and C6:C5 borylation ratio. MeOH (2.5 mL) was added and the mixture was stirred for 1 h. The mixture was concentrated and passed through a plug of silica gel (chloroform as an eluent). The fractions containing product were collected and concentrated to yield 43 mg of the 5- borylated 6c with a minor byproduct corresponding to the 6-borylated isomer (C5:C6 = 8:1) as a yellowish solid (32% yield). The NMR data of the 5-borylated major isomer were consistent with previously reported values.68 5-borylated product, major isomer 1 H NMR (500 MHz, C6D6) 8.59 (d, J = 1.0 Hz, 1H), 8.18 (dd, J = 8.1, 1.0 Hz, 1H), 7.13 (d, J = 8.1, 1H), 6.61 (bs, 1H), 2.08 (s, 3H), 1.80 (s, 3H), 1.17 (s, 12H). 13 C NMR (126 MHz, C6D6) δ 138.2, 130.4, 130.0, 128.4,127.0, 110.2, 107.8, 83.5, 25.3, 11.3, 8.7. 11B NMR (160 MHz, C6D6) δ 32.4. HRMS (ESI) m/z calcd for C16H23BNO2 [M+H]+ 272.1822, found 272.1826 A second fraction was collected corresponding to 76 mg of the 5-borylated 6c with a minor byproduct corresponding to the 6-borylated isomer (C5:C6 = 3:1) (56% yield). This fraction was 466 taken as reference to make the assignment of the 6-borylated isomer. The total yield adds up to 88% (C5 : C6 = 4 : 1). 6-borylated isomer, minor product 1 H NMR (500 MHz, C6D6) 8.13 (dd, J = 7.9, 0.9 Hz, 1H), 8.05 (d, J = 0.9 Hz, 1H), 7.56 (d, J = 7.9 Hz, 1H) 6.61 (bs, 1H), 2.07 (s, 3H), 1.78 (s, 3H), 1.21 (s, 12H). HRMS (ESI) m/z calcd for C16H23BNO2 [M+H]+ 272.1822, found 272.1826 C5 Borylation of 2,3,4,9-tetrahydro-1H-carbazole (6d) >95% conversion, C5:C6 = 4:1 82% isolated yield, C5:C6 = 5:1 In a glove box, a 5.0 mL Wheaton microreactor was charged with 2,3,4,9-tetrahydro-1H- carbazole (86 mg, 0.5 mmol, 1 equiv), HBpin (154 mg, 1 mmol, 2 equiv), triethylamine (0.16 mL, 1 mmol, 2.0 equiv) and THF (0.5 mL). The microreactor was capped with a teflon pressure cap and placed into an aluminum block pre-heated to 80 ºC. After 3 h, the microreactor was brought back to the glove box. In a separate tube, [Ir(cod)(OMe)]2 (10 mg, 3.0 mol %) and B2pin2 (190 mg, 1.5 mmol, 1.5 equiv) in THF (1.0 mL) were stirred for 5 min. The microreactor was charged with the [Ir(cod)(OMe)]2/B2pin2 solution and with tmphen (7.1 mg, 6.0 mol %). The microreactor was capped with a teflon pressure cap and placed into an aluminum block pre-heated to 60 ºC. After 48 h, an aliquot of the reaction mixture was taken and analyzed directly by 1H NMR to find the conversion and 5:6 borylation ratio. MeOH (2.5 mL) was added and the mixture was stirred for 1 h. The mixture was concentrated and purified with a silica column (chloroform as an eluent). 467 The fractions containing product were collected and concentrated to yield 71 mg of the 5-borylated 6d with a minor byproduct corresponding to the 6-borylated isomer (C5:C6 = 5:1) as yellowish solid (82% yield). 5-borylated isomer, minor product 1 H NMR (500 MHz, C6D6) δ 8.58 (s, 1H), 8.19 (d, J = 8.1 Hz, 1H), 7.17 – 7.12 (m, 1H), 6.57 (bs, 1H), 2.61-2.54 (m, 2H), 2.23-2.17 (m, 2H), 1.61-1.55 (m, 4H), 1.21 (s, 12H). 13C NMR (126 MHz, C6D6) δ 138.5, 135.4, 133.6, 131.1, 126.5, 110.7, 110.3, 83.3, 25.2, 23.6, 23.4, 23.2, 21.1. 11 B NMR (160 MHz, C6D6) δ 31.6. HRMS (ESI) m/z calcd for C18H25BNO2 [M+H]+ 298.1978, found 298.1982 6-borylated isomer, minor product 1 H NMR (500 MHz, C6D6) 8.15 (d, J = 7.8 Hz, 1H), 8.10 (s, 1H), 7.60 (d, J = 7.9 Hz, 1H), 6.64 (bs, 1H), 2.61-2.54 (m, 2H), 2.23-2.17 (m, 2H), 1.61-1.55 (m, 4H), 1.22 (s, 12H). HRMS (ESI) m/z calcd for C18H25BNO2 [M+H]+ 298.1978, found 298.1982 The major 6-borylated isomer was confirmed by synthesizing the compound independently via Miyaura borylation. Miyaura Borylation of 6-bromo-2,3,4,9-tetrahydro-1H-carbazole In a glove box, a 5.0 mL Wheaton microreactor was charged with 6-bromo-2,3,4,9- tetrahydro-1H-carbazole (125 mg, 0.5 mmol) and dioxane (3 mL). KOAc (98 mg, 1.0 mmol, 2.0 equiv), bis(pinacolato)diboron (190 mg, 0.75 mmol, 1.5 equiv) and [1,1’-bis(diphenylphosphino) ferrocene]dicholoropalladium(II) (37 mg, 0.05 mol, 10 mol %) were added to the microreactor. 468 The microreactor was capped with a teflon pressure cap and placed into an aluminum block pre- heated to 80 ºC. After 2 h, the mixture was concentrated and passed through a plug of silica gel (dichloromethane as eluent). The product was collected and concentrated to give 72 mg of the borylated product as an orange solid (48% yield, mp 135-137 °C). 1 H NMR (500 MHz, C6D6) δ 8.62 (s, 1H), 8.24 (d, J = 8.1 Hz, 1H), 7.16 – 7.14 (m, 1H), 6.32 (bs, 1H), 2.61 (m, 2H), 2.18 (m, 2H), 1.58 (m, 4H), 1.21 (s, 12H). 13C NMR (126 MHz, C6D6) δ 138.5, 135.4, 133.8, 131.6, 126.4, 110.6, 110.3, 83.4, 25.1, 23.6, 23.4, 23.2, 21.1. 11B NMR (160 MHz, C6D6) δ 31.8. HRMS (ESI) m/z calcd for C18H25BNO2 [M+H]+ 298.1978, found 298.1958 4.4.5. Synthesis 1-borylated naphthalenes Miyaura Borylation of 1-bromo-4-methylnaphthalene (7b) In a glove box, a 100 mL Schlenk flask was charged with 1-bromo-4-methylnaphthalene (1.10 g, 5 mmol, 1 equiv), B2pin2 (1.40 g, 5.5 mmol, 1.1 equiv), Pd(dppf)Cl2 (220 mg, 6 mol %) and KOAc (1.47 g, 15 mmol, 3.0 equiv) in toluene (65 mL). The flask was covered with a septum, brought out of the glove box and connected to a condenser under nitrogen. The reaction was heated to 110 ºC for 2 days. The solution was concentrated under vacuum and redissolved in dichloromethane (150 mL). The mixture was washed with water (50 mL) and the aqueous layer was extracted with dichloromethane (2 x 150 mL). The organic layers were combined, dried over MgSO4, filtered and concentrated under reduce pressure. The residue was passed through a plug of silica gel (CHCl3 as eluent). The fractions containing product were collected and concentrated to give an oil which solidifies upon addition of MeOH. The solid was filtered and dried overnight 469 under vacuum to obtained 6a as a white solid (300 mg, 22% yield, mp 82-84 °C, lit 77-79 °C).69 The NMR data were consistent with previously reported values, designated as compound 2r in the cited paper.69,70 1 H NMR (500 MHz, CDCl3) δ 8.81 (dd, J = 8.0, 2.4 Hz, 1H), 8.02 (dd, J = 7.7, 2.2 Hz, 1H), 7.99 (d, J = 7.0 Hz, 1H), 7.59 – 7.48 (m, 2H), 7.33 (d, J = 6.9 Hz, 1H), 2.72 (s, 3H), 1.43 (s, 12H). 13C NMR (126 MHz, CDCl3) δ 138.3, 137.1, 135.8, 132.5, 129.1, 126.1, 126.1, 125.5, 124.3, 83.7, 25.1, 20.1. 11B NMR (160 MHz, CDCl3) δ 31.6. HRMS (ESI) m/z calcd for C17H22BO2 [M+H]+ 269.1713, found 269.1698 Pinacol esterification of 4-bromonaphthalene-1-boronic acid (7c) A 20 mL vial was charged with 4-bromonaphthalene-1-boronic acid (251 mg, 1 mmol, 1 equiv), pinacol (130 mg, 1.1 mmol, 1.1 equiv) in chloroform (8 mL). The flask was capped and stirred for 1 h at room temperature. The solution was concentrated under vacuum and redissolved in ethyl acetate (5 mL). The mixture was washed two times with water (2 x 5 mL). The organic layer was dried over MgSO4, filtered and concentrated under reduce pressure to give 229 mg of 5c as a white solid (69% yield, mp 97-99 °C). 1 H NMR (500 MHz, CDCl3) δ 8.86 – 8.78 (m, 1H), 8.35 – 8.26 (m, 1H), 7.93 (d, J = 7.5 Hz, 1H), 7.82 (d, J = 7.5 Hz, 1H), 7.64 – 7.57 (m, 2H), 1.43 (s, 12H). 13C NMR (126 MHz, CDCl3) δ 138.2, 135.8, 131.8, 129.4, 129.0, 127.5, 127.4, 127.3, 127.1, 84.1, 25.1. (no C-B bond observed due to quadrupolar relaxation). 11 B NMR (160 MHz, CDCl3) δ 31.3. HRMS (ESI) m/z calcd for C16H18BBrO2Na [M+Na]+ 355.0481, found 355.0730 470 Miyaura Borylation of methyl 4-bromo-1-naphthoate (7d) In a glove box, a 100 mL Schlenk flask was charged with methyl 4-bromo-1-naphthoate (795 mg, 3 mmol, 1 equiv), B2pin2 (838 mg, 3.3 mmol, 1.1 equiv), Pd(dppf)Cl2 (132 mg, 6 mol %) and KOAc (882 mg, 9 mmol, 3.0 equiv) in toluene (65 mL). The flask was covered with a septum, brought out of the glove box and connected to a condenser under nitrogen. The reaction was heated to 110 ºC for 2 days. The solution was concentrated under vacuum and redissolved in dichloromethane (150 mL). The mixture was washed with water (50 mL) and the aqueous layer was extracted with dichloromethane (2 x 150 mL). The organic layers were combined, dried over MgSO4, filtered and concentrated under reduce pressure. The mixture was passed through silica gel column chromatography (petroleum ether/ethyl acetate 40:1 as eluent). The fractions containing product were collected and concentrated to give 753 mg of 7d as a white greenish solid (80% yield, mp 69-71 °C). The NMR data were consistent with previously reported values. 71 1 H NMR (500 MHz, CDCl3) δ 8.87 – 8.74 (m, 2H), 8.10 – 8.04 (m, 2H), 7.64 – 7.55 (m, 2H), 4.01 (s, 3H), 1.44 (s, 12H). 13 C NMR (126 MHz, CDCl3) δ 168.4, 137.4, 134.0, 130.8, 130.2, 128.9, 128.5, 127.3, 126.6, 125.9, 84.3, 52.4, 25.1. 11 B NMR (160 MHz, CDCl3) δ 31.5. HRMS (ESI) m/z calcd for C18H22BO4 [M+H]+ 313.1611, found 313.1598 471 Miyaura Borylation of 1-bromo-2-methoxynaphthalene (7e) In a glove box, a 100 mL Schlenk flask was charged with 1-bromo-2-methoxynaphthalene (1.18 g, 5 mmol, 1 equiv), B2pin2 (1.40 g, 5.5 mmol, 1.1 equiv), Pd(dppf)Cl2 (220 mg, 6 mol %) and KOAc (1.47 g, 15 mmol, 3.0 equiv) in toluene (65 mL). The flask was covered with a septum, brought out of the glove box and connected to a condenser under nitrogen. The reaction was heated to 110 ºC for 2 days. The solution was concentrated under vacuum and redissolved in dichloromethane (150 mL). The mixture was washed with water (50 mL) and the aqueous layer was extracted with dichloromethane (2 x 150 mL). The organic layers were combined, dried over MgSO4, filtered and concentrated under reduce pressure. The residue was passed through a plug of silica gel (CHCl3 as eluent) to get a mixture of the product with the 2-methoxynaphthalene as the byproduct. The mixture was passed through silica gel column chromatography (CHCl 3 as eluent) to remove the byproduct. The fractions containing product were collected and concentrated to yield 644 mg of 7e as a white solid (45% yield, mp 97-99 °C, lit 93-94 °C).72 The NMR data were consistent with previously reported values, designated as compound 9 in the cited paper.72 1 H NMR (500 MHz, CDCl3) δ 7.93 (dq, J = 8.5, 0.9 Hz, 1H), 7.86 (d, J = 9.0 Hz,1H), 7.76 (dt, J = 8.2, 0.8 Hz,1H), 7.44 (ddd, J = 8.5, 6.8, 1.4 Hz, 1H), 7.31 (ddd, J = 8.0, 6.8, 1.1 Hz, 1H), 7.22 (d, J = 9.0 Hz, 1H), 3.92 (s, 3H), 1.49 (s, 12H). 13C NMR (126 MHz, CDCl3) δ 161.6, 137.2, 131.8, 129.0, 128.3, 126.9, 126.7, 123.4, 113.0, 84.1, 56.7, 25.0. 11B NMR (160 MHz, CDCl3) δ 32.2. HRMS (ESI) m/z calcd for C17H22BO3 [M+H]+ 285.1662, found 285.1654 472 Miyaura Borylation of 1-bromo-2-methylnaphthalene (7f) In a glove box, a 100 mL Schlenk flask was charged with 1-bromo-2-methylnaphthalene (1.10 g, 5 mmol, 1 equiv), B2pin2 (1.40 g, 5.5 mmol, 1.1 equiv), Pd(dppf)Cl2 (220 mg, 6 mol %) and KOAc (1.47 g, 15 mmol, 3.0 equiv) in toluene (65 mL). The flask was covered with a septum, brought out of the glove box and connected to a condenser under nitrogen. The reaction was heated to 110 ºC for 2 days. The solution was concentrated under vacuum and redissolved in dichloromethane (150 mL). The mixture was washed with water (50 mL) and the aqueous layer was extracted with dichloromethane (2 x 150 mL). The organic layers were combined, dried over MgSO4, filtered and concentrated under reduce pressure. The residue was passed through silica gel column chromatography (petroleum ether/dichloromethane 3:1 as eluent) to remove the byproduct. The fractions containing product were collected and concentrated to give 737 mg of 7f as a white solid (55% yield, mp 90-92 °C, lit 92-94 °C).73 The NMR data were consistent with previously reported values, designated as compound 3d in the cited paper.73,74 1 H NMR (500 MHz, CDCl3) δ 8.12 (d, J = 8.4 Hz, 1H), 7.81 – 7.74 (m, 2H), 7.46 (ddd, J = 8.4, 6.8, 1.5 Hz, 1H), 7.39 (ddd, J = 8.0, 6.8, 1.3 Hz, 1H), 7.29 (d, J = 8.4 Hz, 1H), 2.64 (s, 3H), 1.49 (s, 12H). 13C NMR (126 MHz, CDCl3) δ 141.5, 136.7, 131.5, 129.7, 128.6, 128.3, 127.6, 126.1, 124.7, 84.1, 25.2, 22.8. 11B NMR (160 MHz, CDCl3) δ 32.5. HRMS (ESI) m/z calcd for C17H22BO2 [M+H]+ 269.1713, found 269.1697 473 Miyaura Borylation of 5-bromoacenaphthene (7g) In a glove box, a 100 mL Schlenk flask was charged with 5-bromoacenaphthene (1.16 g, 5 mmol, 1 equiv), B2pin2 (1.40 g, 5.5 mmol, 1.1 equiv), Pd(dppf)Cl2 (220 mg, 6 mol %) and KOAc (1.47 g, 15 mmol, 3.0 equiv) in toluene (65 mL). The flask was covered with a septum, brought out of the glove box and connected to a condenser under nitrogen. The reaction was heated to 110 ºC for 2 days. The solution was concentrated under vacuum and redissolved in dichloromethane (50 mL). The mixture was washed with water (50 mL) and the aqueous layer was extracted with dichloromethane (2 x 50 mL). The organic layers were combined, dried over MgSO 4, filtered and concentrated under reduce pressure. The residue was passed through silica gel column chromatography (petroleum ether/dichloromethane 3:1 as eluent) to remove the byproduct. The fractions containing product were collected and concentrated to give 810 mg of 7g as a white solid (58% yield, mp 101-103 °C, lit 105-107 °C).75 The NMR data were consistent with previously reported values, designated as compound 43 in the cited paper.75 1 H NMR (500 MHz, CDCl3) δ 8.42 (d, J = 8.4 Hz, 1H), 8.08 (d, J = 6.9 Hz, 1H), 7.53 (dd, J = 8.4, 6.9 Hz, 1H), 7.32 (d, J = 6.9 Hz, 1H), 7.31 (d, J = 6.9 Hz, 1H), 3.41 (s, 4H), 1.44 (s, 12H). 13C NMR (126 MHz, CDCl3) δ 150.4, 146.1, 139.0, 137.7, 135.5, 128.3, 123.8, 119.2, 118.9, 83.5, 30.6, 30.3, 25.1. 11 B NMR (160 MHz, CDCl3) δ 31.5. HRMS (ESI) m/z calcd for C18H22BO2 [M+H]+ 281.1713, found 281.1696 474 Miyaura Borylation of 9-Bromoanthracene (7h) In a glove box, a 100 mL Schlenk flask was charged with 9-bromoanthracene (1.28 g, 5 mmol, 1 equiv), B2pin2 (1.40 g, 5.5 mmol, 1.1 equiv), Pd(dppf)Cl2 (220 mg, 6 mol %) and KOAc (1.47 g, 15 mmol, 3.0 equiv) in toluene (65 mL). The flask was covered with a septum, brought out of the glove box and connected to a condenser under nitrogen. The reaction was heated to 110 ºC for 2 days. The solution was concentrated under vacuum and redissolved in dichloromethane (50 mL). The mixture was washed with water (50 mL) and the aqueous layer was extracted with dichloromethane (2 x 50 mL). The organic layers were combined, dried over MgSO4, filtered and concentrated under reduce pressure. The residue was passed through silica gel column chromatography (hexane/dichloromethane 60:40 as eluent) to remove the byproduct. The fractions containing product were collected and concentrated to give 1.27 g of 7h as a white solid (83% yield, mp 137-139 °C, lit 138 °C).74 The NMR data were consistent with previously reported values, designated as compound 20a in the cited paper.74,76 1 H NMR (500 MHz, CDCl3) δ 8.50 (s, 1H), 8.48 (d, J = 8.7 Hz, 2H), 8.01 (d, J = 7.9 Hz, 2H), 7.51 13 (dd, J = 8.7, 6.5 Hz, 2H), 7.46 (dd, J = 7.9, 6.5 Hz, 2H), 1.60 (s, 12H). C NMR (126 MHz, CDCl3) δ 136.0, 131.3, 129.6, 128.9, 128.4, 125.9, 125.0, 84.5, 25.3. 11B NMR (160 MHz, CDCl3) δ 33.0. HRMS (ESI) m/z calcd for C20H22BO2 [M+H]+ 305.1713, found 305.1700 475 4.4.6. C6 CHB of 1-borylated naphthalenes C6 Borylation of 4-methoxy-1-naphthalene boronic acid, pinacol ester (8a) >95% conversion, C1C6 : C1C7 = 7 : 1 91% isolated yield, C1C6 : C1C7 = 7 : 1 In a glove box, a 5.0 mL Wheaton microreactor was charged with 7a (143 mg, 0.5 mmol, 1 equiv) and 4,4’-dimethoxy-2,2’-bypiridine (3.3 mg, 3.0 mol %) in THF (0.5 mL). In a separate tube, [Ir(cod)(OMe)]2 (5.0 mg, 1.5 mol %) and B2pin2 (190 mg, 0.75 mmol, 1.5 equiv) in THF (1.0 mL) were stirred for 5 min. The [Ir(cod)(OMe)] 2/B2pin2 solution was transferred to the microreactor. The microreactor was capped with a teflon pressure cap and placed into an aluminum block pre-heated to 40 ºC. After 48 h, an aliquot of the reaction mixture was taken and analyzed directly by 1H NMR to find the conversion and C6:C7 borylation ratio. The mixture was concentrated and passed through a plug of silica gel (CHCl3 as eluent). The fractions containing product were collected, concentrated and washed with water (6 mL). The water layer was decanted and the residue was dried to give 187 mg of 6-borylated 8a with a minor byproduct corresponding to the 7-borylated isomer (C1C6:C1C7 = 7:1) as a white solid (91% yield). C6 Borylated Product: 1 H NMR (500 MHz, CDCl3) δ 8.82 (s, 1H), 8.73 (d, J = 8.4 Hz, 1H), 8.08 (d, J = 7.8 Hz, 1H), 7.92 (dd, J = 8.4, 1.4 Hz, 1H), 6.81 (d, J = 7.8 Hz, 1H), 4.02 (s, 3H), 1.41 (s, 12H), 1.39 (s, 12H). 13C NMR (126 MHz, CDCl3) δ 158.9, 140.0, 138.2, 131.8, 130.2, 127.3, 124.8, 103.3, 83.8, 83.5, 55.5, 25.1, 25.0. 11B NMR (160 MHz, CDCl3) δ 31.2. HRMS (ESI) m/z calcd for C23H33B2O5 [M+H]+ 411.2514, found 411.2501 476 C7 Borylated Product: 1 H NMR (500 MHz, CDCl3) δ 9.25 (s, 1H), 8.26 (d, J = 8.4 Hz, 1H), 8.00 (d, J = 7.8 Hz, 1H), 7.83 (dd, J = 8.4, 1.2 Hz, 1H), 6.84 (d, J = 7.8 Hz, 1H), 4.01 (s, 3H), 1.44 (s, 12H), 1.40 (s, 12H). 13C NMR (126 MHz, CDCl3) δ 158.0, 137.4, 136.4, 136.3, 129.6, 127.1, 121.1, 104.2, 83.8, 83.6, 55.6, 25.1, 25.1. 11B NMR (160 MHz, CDCl3) δ 31.2. HRMS (ESI) m/z calcd for C23H33B2O5 [M+H]+ 411.2514, found 411.2501 C6 Borylation of 4-methylnaphthalene-1-boronic acid, pinacol ester (8b) >95% conversion, C1C6 : C1C7 = 12 : 1 85% isolated yield, C1C6 : C1C7 = 12 : 1 In a glove box, a 5.0 mL Wheaton microreactor was charged with 7b (134 mg, 0.5 mmol, 1 equiv) and 4,4’-dimethoxy-2,2’-bypiridine (3.3 mg, 3.0 mol %) in THF (0.5 mL). In a separate tube, [Ir(cod)(OMe)]2 (5.0 mg, 1.5 mol %) and B2pin2 (190 mg, 0.75 mmol, 1.5 equiv) in THF (1.0 mL) were stirred for 5 min. The [Ir(cod)(OMe)] 2/B2pin2 solution was transferred to the microreactor. The microreactor was capped with a teflon pressure cap and placed into an aluminum block pre-heated to 40 ºC. After 48 h, an aliquot of the reaction mixture was taken and analyzed directly by 1H NMR to find the conversion and C6:C7 borylation ratio. The mixture was concentrated and passed through a plug of silica gel (CHCl3 as eluent). The fractions containing product were collected and concentrated to give 167 mg of C6 borylated product 8b with a minor C7 borylated byproduct (C1C6:C1C7 = 12:1) as a white solid (85% yield). 477 C6 Borylated Product: 1 H NMR (500 MHz, CDCl3) δ 8.77 (d, J = 8.4 Hz, 1H), 8.54 (s, 1H), 8.02 (d, J = 6.9 Hz, 1H), 7.92 (dd, J = 8.4, 1.2 Hz, 1H), 7.33 (dd, J = 6.9, 1.1 Hz, 1H), 2.79 (s, 3H), 1.42 (s, 12H), 1.40 (s, 12H). 13 C NMR (126 MHz, CDCl3) δ 139.3, 138.8, 136.8, 132.4, 131.8, 130.9, 128.1, 126.1, 83.9, 83.7, 25.1, 25.0, 20.3. 11 B NMR (160 MHz, CDCl3) δ 31.9. HRMS (ESI) m/z calcd for C23H33B2O4 [M+H]+ 395.2565, found 325.2167 C7 Borylated Product: 1 H NMR (500 MHz, CDCl3) δ 9.28 (s, 1H), 7.99 (d, J = 8.4 Hz, 1H), 7.94 (d, J = 7.2 Hz, 1H), 7.87 (dd, J = 8.4, 1.2 Hz, 1H), 7.36 (dd, J = 7.2, 1.2 Hz, 1H), 2.72 (s, 3H), 1.46 (s, 12H), 1.40 (s, 12H). 11 B NMR (160 MHz, CDCl3) δ 31.9. HRMS (ESI) m/z calcd for C23H33B2O4 [M+H]+ 395.2565, found 325.2167 C6 Borylation of 4-bromonaphthalene-1-boronic acid, pinacol ester (8c) >95% conversion, C1C6 : C1C7 = 10 : 1 76% isolated yield, C1C6 : C1C7 = 12 : 1 In a glove box, a 5.0 mL Wheaton microreactor was charged with 7c (166 mg, 0.5 mmol, 1 equiv) and 4,4’-dimethoxy-2,2’-bypiridine (3.3. mg, 3.0 mol %) in THF (0.5 mL). In a separate tube, [Ir(cod)(OMe)]2 (5.0 mg, 1.5 mol %) and B2pin2 (190 mg, 0.75 mmol, 1.5 equiv) in THF (1.0 mL) were stirred for 5 min. The [Ir(cod)(OMe)] 2/B2pin2 solution was transferred to the microreactor. The microreactor was capped with a teflon pressure cap and placed into an aluminum block pre-heated to 40 ºC. After 16 h, an aliquot of the reaction mixture was taken and analyzed directly by 1H NMR to find the conversion and C6:C7 borylation ratio. The mixture was 478 concentrated and passed through a plug of silica gel (CHCl3 as eluent). The fractions containing product were collected and concentrated to give 175 mg of C6 borylated product 6b with a minor C7 borylated byproduct (C1C6 : C1C7 = 12:1) as a white solid (76% yield). C6 Borylated Product: 1 H NMR (500 MHz, CDCl3) δ 8.79 – 8.71 (m, 2H), 7.95 (dd, J = 8.4, 1.3 Hz, 1H), 7.92 (d, J = 7.5 Hz, 1H), 7.80 (d, J = 7.5 Hz, 1H), 1.42 (s, 12H), 1.40 (s, 12H). 1H NMR (500 MHz, C6D6) δ 9.41 (dd, J = 1.2, 0.7 Hz, 1H), 9.30 (dd, J = 8.5, 0.7 Hz, 1H), 8.39 (dd, J = 8.5, 1.2 Hz, 1H), 8.06 (d, J = 7.4 Hz, 1H), 7.60 (d, J = 7.4 Hz, 1H), 1.11 (s, 12H), 1.08 (s, 12H). 13C NMR (126 MHz, CDCl3) δ 139.9, 136.8, 135.3, 132.0, 131.1, 129.4, 128.2, 128.0, 84.1, 84.1, 25.1, 25.0. 11 B NMR (160 MHz, CDCl3) δ 31.8. HRMS (ESI) m/z calcd for C22H30B2BrO4 [M+H]+ 459.1514, found 459.1498 C7 Borylated Product: 1 H NMR (500 MHz, C6D6) δ 9.90 (dd, J = 1.2, 0.7 Hz, 1H), 8.49 (dd, J = 8.5, 0.7 Hz, 1H), 8.31 (dd, J = 8.5, 1.2 Hz, 1H), 8.02 (d, J = 7.5 Hz, 1H), 7.63 (d, J = 7.5 Hz, 1H), 1.15 (s, 12H), 1.14 (s, 12H). HRMS (ESI) m/z calcd for C22H30B2BrO4 [M+H]+ 459.1514, found 459.1498 C6 Borylation of 4-methylnaphthalene-1-boronic acid, pinacol ester (8d) >95% conversion, C1C6 : C1C7 = 4 : 1 93% isolated yield, C1C6 : C1C7 = 4 : 1 In a glove box, a 5.0 mL Wheaton microreactor was charged with 7d (156 mg, 0.5 mmol, 1 equiv) and 4,4’-dimethoxy-2,2’-bypiridine (6.5 mg, 6.0 mol %) in THF (0.5 mL). In a separate 479 tube, [Ir(cod)(OMe)]2 (10.0 mg, 3.0 mol %) and B2pin2 (190 mg, 0.75 mmol, 1.5 equiv) in THF (1.0 mL) were stirred for 5 min. The [Ir(cod)(OMe)] 2/B2pin2 solution was transferred to the microreactor. The microreactor was capped with a teflon pressure cap and placed into an aluminum block pre-heated to 60 ºC. After 48 h, an aliquot of the reaction mixture was taken and analyzed directly by 1H NMR to find the conversion and C6:C7 borylation ratio. The mixture was concentrated and passed through a plug of silica gel (CHCl3 as eluent). The fractions containing product were collected and concentrated to give 204 mg of C6 borylated product 8d with a minor C7 borylated byproduct (C1C6:C1C7 = 4:1) as a white solid (93% yield). C6 Borylated Product: 1 H NMR (500 MHz, CDCl3) δ 9.26 (s, 1H), 8.78 (d, J = 8.5 Hz, 1H), 8.09 (d, J = 7.2 Hz, 1H), 8.03 (d, J = 7.2 Hz, 1H), 7.95 (dd, J = 8.5, 1.3 Hz, 1H), 4.01 (s, 3H), 1.40 (s, 12H), 1.36 (s, 12H). 13C NMR (126 MHz, CDCl3) δ 168.1, 138.8, 134.9, 133.6, 131.3, 130.9, 130.0, 128.1, 127.8, 84.1, 83.9, 52.3, 25.0, 24.9. 11B NMR (160 MHz, CDCl3) δ 31.8. HRMS (ESI) m/z calcd for C24H33B2O6 [M+H]+ 439.2463, found 439.2447 C6 Borylation of 2-methoxyphthalene-1-boronic acid, pinacol ester (8e) >95% conversion, C1C6 : C1C7 : C1C4 = 4 : 1 : 0.4 71% isolated yield, C1C6 : C1C7 : C1C4 = 9 : 0.3 : 1 480 In a glove box, a 5.0 mL Wheaton microreactor was charged with 7e (142 mg, 0.5 mmol, 1 equiv) and 4,4’-dimethoxy-2,2’-bypiridine (3.3 mg, 3.0 mol %) in THF (0.5 mL). In a separate tube, [Ir(cod)(OMe)]2 (5.0 mg, 1.5 mol %) and B2pin2 (190 mg, 0.75 mmol, 1.5 equiv) in THF (1.0 mL) were stirred for 5 min. The [Ir(cod)(OMe)] 2/B2pin2 solution was transferred to the microreactor. The microreactor was capped with a teflon pressure cap and placed into an aluminum block pre-heated to 40 ºC. After 48 h, an aliquot of the reaction mixture was taken and analyzed directly by 1H NMR to find the conversion and C6:C7 borylation ratio. The mixture was concentrated and passed through a plug of silica gel (CHCl3 as eluent). The fractions containing product were collected and concentrated to give 145 mg of 6-borylated product 6b with a couple of minor isomers corresponding to the 7-borylated byproduct and an unknown isomer tentatively assigned as the 4-borylated isomer (C1C6 : C1C7 : C1C4 = 9 : 0.3 : 1) as a colorless oil (71% yield). 1,6-diborylated product, major isomer 1 H NMR (500 MHz, CDCl3) δ 8.28 (d, J = 1.2 Hz, 1H), 7.89 (d, J = 9.1 Hz, 1H), 7.87 (d, J = 8.4 Hz, 1H), 7.78 (dd, J = 8.4, 1.2 Hz, 1H), 7.20 (d, J = 9.1 Hz, 1H), 3.91 (s, 3H), 1.47 (s, 12H), 1.37 (s, 12H). 1H NMR (500 MHz, C6D6) δ 8.70 (d, J = 1.3 Hz, 1H), 8.40 (d, J = 8.4 Hz, 1H), 8.26 (dd, J = 8.4, 1.3 Hz, 1H), 7.69 (d, J = 9.0 Hz, 1H), 6.77 (d, J = 9.0 Hz, 1H), 3.41 (s, 3H), 1.23 (s, 12H), 1.16 (s, 12H). 13 C NMR (126 MHz, CDCl3) δ 162.4, 139.0, 136.7, 132.7, 131.2, 128.3, 126.0, 112.7, 84.1, 83.8, 56.5, 25.0, 25.0. 11B NMR (160 MHz, CDCl3) δ 32.2. HRMS (ESI) m/z calcd for C23H33B2O5 [M+H]+ 411.2514, found 411.2499 481 1,7-diborylated product, minor isomer 1 H NMR (500 MHz, C6D6) δ 9.08 (d, J = 1.1 Hz, 1H), 8.14 (d, J = 8.2 Hz, 1H), 8.06 (dd, J = 8.2, 1.1 Hz, 1H), 7.59 (d, J = 9.0 Hz, 1H), 6.87 (d, J = 9.0 Hz, 1H), 3.45 (s, 3H), 1.37 (s, 12H), 1.15 (s, 12H). 1,4-diborylated product, minor isomer (tentative assignment) 1 H NMR (500 MHz, C6D6) δ 9.28 (dd, J = 8.4, 1.4 Hz, 1H), 8.32 (dd, J = 8.0, 1.7 Hz, 1H), 8.13 (s, 1H), 7.44 (ddd, J = 8.4, 6.7, 1.7 Hz, 1H), 7.40 (ddd, J = 8.0, 6.7, 1.4 Hz, 1H), 3.53 (s, 3H), 1.26 (s, 12H), 1.15 (s, 12H). C6 Borylation of 2-methylphthalene-1-boronic acid, pinacol ester (8f) >95% conversion, C1C6 : C1C7 = 5 : 1 93% isolated yield, C1C6 : C1C7 = 6 : 1 In a glove box, a 5.0 mL Wheaton microreactor was charged with 7f (134 mg, 0.5 mmol, 1 equiv) and 4,4’-dimethoxy-2,2’-bypiridine (3.3 mg, 3.0 mol %) in THF (0.5 mL). In a separate tube, [Ir(cod)(OMe)]2 (5.0 mg, 1.5 mol %) and B2pin2 (190 mg, 0.75 mmol, 1.5 equiv) in THF (1.0 mL) were stirred for 5 min. The [Ir(cod)(OMe)] 2/B2pin2 solution was transferred to the microreactor. The microreactor was capped with a teflon pressure cap and placed into an aluminum block pre-heated to 40 ºC. After 44 h, an aliquot of the reaction mixture was taken and analyzed directly by 1H NMR to find the conversion and C6:C7 borylation ratio. The mixture was concentrated and passed through a plug of silica gel (CHCl3 as eluent). The fractions containing 482 product were collected and concentrated to give 184 mg of C6 borylated product 8f with a minor C7 borylated byproduct (C1C6 : C1C7 = 6:1) as a white solid (93% yield). C6 Borylated Product: 1 H NMR (500 MHz, CDCl3) δ 8.31 (s, 1H), 8.10 (d, J = 8.4 Hz, 1H), 7.83 (dd, J = 8.4, 1.3 Hz, 1H), 7.80 (d, J = 8.4 Hz, 1H), 7.29 (d, J = 8.4 Hz, 1H), 2.64 (s, 3H), 1.53 (s, 12H), 1.37 (s, 12H). 1 H NMR (500 MHz, C6D6) δ 8.75 (s, 1H), 8.69 (d, J = 8.4 Hz, 1H), 8.33 (dd, J = 8.4, 1.3 Hz, 1H), 13 7.71 (d, J = 8.4 Hz, 1H), 7.10 (d, J = 8.4 Hz, 1H), 2.63 (s, 3H), 1.16 (s, 12H), 1.15 (s, 12H). C NMR (126 MHz, C6D6) δ 143.5, 139.5, 137.6, 131.6, 131.4, 130.9, 129.1, 127.7, 83.7, 83.7, 25.1, 25.0, 23.2. 11B NMR (160 MHz, C6D6) δ 32.5. HRMS (ESI) m/z calcd for C23H33B2O4 [M+H]+ 395.2565, found 395.2555 C7 Borylated Product: 1 H NMR (500 MHz, C6D6) δ 9.31 (d, J = 1.0 Hz, 1H), 8.16 (dd, J = 8.1, 1.1 Hz, 1H), 7.69 (d, J = 8.1, 1H), 7.60 (d, J = 8.3 Hz, 1H), 7.14 (d, J = 8.3, 1H), 2.62 (s, 3H), 1.32 (s, 12H), 1.02 (s, 12H). HRMS (ESI) m/z calcd for C23H33B2O4 [M+H]+ 395.2565, found 395.2555 C3-C8 Diborylation of acenaphtene-5-boronic acid, pinacol ester (8g) 68% conversion, C3C6 : C3C5 : C3C5C8 = 1 : 1.6 : 0.8 5% isolated yield, C3C6 : C3C5 = 1 : 0.8 483 In a glove box, a 5.0 mL Wheaton microreactor was charged with 7g (140 mg, 0.5 mmol, 1 equiv) and 4,4’-dimethoxy-2,2’-bypiridine (3.3 mg, 3.0 mol %) in THF (0.5 mL). In a separate tube, [Ir(cod)(OMe)]2 (5.0 mg, 1.5 mol %) and B2pin2 (190 mg, 0.75 mmol, 1.5 equiv) in THF (1.0 mL) were stirred for 5 min. The [Ir(cod)(OMe)] 2/B2pin2 solution was transferred to the microreactor. The microreactor was capped with a teflon pressure cap and placed into an aluminum block pre-heated to 40 ºC. After 41 h, an aliquot of the reaction mixture was taken and analyzed directly by 1H NMR to find the conversion and C3C6 : C3C5 : C3C5C8 borylation ratio. The mixture was concentrated and passed through silica gel column chromatography (chloroform as eluent). The fractions containing product were collected and concentrated. One fraction containing 10 mg of monoborylated products (based on GC-MS) C3C6 and C3C5 in 1 to 0.8 ratio and without reactant was isolated (5% yield). 3,6-diborylated product: 1 H NMR (500 MHz, CDCl3) δ 8.32 (dd, J = 8.4, 1.0 Hz, 1H), 8.06 (d, J = 6.9 Hz, 1H), 7.84 (d, J = 8.4 Hz, 1H), 7.29 (dt, J = 6.9, 1.4 Hz, 1H), 3.60 – 3.53 (m, 2H), 3.40 – 3.32 (m, 2H), 1.41 (s, 12H), 1.37 (s, 12H). GC-MS (EI) m/z calcd for C24H32B2O4 [M] 406.2, found 406.1 3,5-diborylated product: 1 H NMR (500 MHz, CDCl3) δ 8.39 (s, 1H), 8.38 – 8.34 (dd, J = 8.3, 0.7, 1H), 7.52 (dd, J = 8.3, 6.8 Hz, 1H), 7.29 (dt, J = 6.9, 1.4 Hz, 1H), 3.60 – 3.53 (m, 2H), 3.40 – 3.32 (m, 2H), 1.41 (s, 12H), 1.37 (s, 12H). GC-MS (EI) m/z calcd for C24H32B2O4 [M] 406.2, found 406.1 The reaction was repeated with more equivalents of B2pin2 and higher loadings of catalyst-ligand: 484 >95% conversion, C3C5C8 : C3C5C7 = 7 : 1 68% isolated yield, C3C5C8 : C3C5C7 = 11 : 1 In a glove box, a 5.0 mL Wheaton microreactor was charged with 7g (140 mg, 0.5 mmol, 1 equiv) and 4,4’-dimethoxy-2,2’-bypiridine (6.6 mg, 6.0 mol %) in THF (0.5 mL). In a separate tube, [Ir(cod)(OMe)]2 (10.0 mg, 3.0 mol %) and B2pin2 (381 mg, 1.5 mmol, 3.0 equiv) in THF (1.5 mL) were stirred for 5 min. The [Ir(cod)(OMe)] 2/B2pin2 solution was transferred to the microreactor. The microreactor was capped with a teflon pressure cap and placed into an aluminum block pre-heated to 40 ºC. After 92 h, an aliquot of the reaction mixture was taken and analyzed directly by 1H NMR to find the conversion and C3C5C8 : C3C5C7 borylation ratio. The mixture was concentrated and passed through a plug of silica gel (chloroform as eluent). The fractions containing product were collected and concentrated to give 181 mg of the 3,5,8-triborylated acenaphthene 8g with a minor byproduct corresponding to the 3,5,7-triborylated isomer as a white solid (68% yield). 3,5,8 Triborylated Product: 1 H NMR (500 MHz, CDCl3) δ 8.44 (s, 1H), 8.35 (d, J = 8.4 Hz, 1H), 7.91 (d, J = 8.4 Hz, 1H), 3.55 (s, 4H), 1.42 (s, 12H), 1.39 (s, 12H), 1.38 (s, 12H). 13C NMR (126 MHz, CDCl3) δ 161.7, 157.6, 11 144.0, 138.8, 137.6, 134.8, 122.9, 83.5, 83.4, 83.4, 32.5, 32.1, 25.1, 25.1, 25.1. B NMR (160 MHz, CDCl3) δ 31.6. HRMS (ESI) m/z calcd for C30H44B3O6 [M+H]+ 533.3417, found 533.34 3,5,7 Triborylated Product: 1 H NMR (500 MHz, CDCl3) δ 8.88 (s, 1H), 8.39 (s, 1H), 7.70 (s, 1H), 3.55 (s, 4H), 1.45 (s, 12H), 1.40 (s, 12H), 1.38 (s, 12H). HRMS (ESI) m/z calcd for C30H44B3O6 [M+H]+ 533.3417, found 533.3412 485 C3-C9 Diborylation of anthracene-9-boronic acid, pinacol ester (8h) >95% conversion, C3C6C9 : C2C6C9 : C2C7C9 = 2 : 1 : 0.1 76% yield, C3C6C9 : C2C6C9 : C2C7C9 = 2 : 1 : 0.1 In a glove box, a 5.0 mL Wheaton microreactor was charged with 7h (152 mg, 0.5 mmol, 1 equiv) and 4,4’-dimethoxy-2,2’-bypiridine (3.3 mg, 3.0 mol %) in THF (0.5 mL). In a separate tube, [Ir(cod)(OMe)]2 (5.0 mg, 1.5 mol %) and B2pin2 (381 mg, 1.5 mmol, 3.0 equiv) in THF (1.5 mL) were stirred for 5 min. The [Ir(cod)(OMe)] 2/B2pin2 solution was transferred to the microreactor. The microreactor was capped with a teflon pressure cap and placed into an aluminum block pre-heated to 40 ºC. After 44 h, an aliquot of the reaction mixture was taken and analyzed directly by 1H NMR to find the conversion and 369 : 269 : 279 borylation ratio. The mixture was concentrated and passed through a plug of silica gel (chloroform as eluent). The fractions containing product were collected and concentrated to give 249 mg of the 3,6,9- and 2,6,9- triborylated anthracene 8h with minor byproducts corresponding to the 2,7,9-triborylated isomer and excess B2pin2 (C3C6C9 : C2C6C9 : C2C7C9 : B2pin2 = 2 : 1 : 0.1 :1.2 as a yellow solid (76% yield of the borylated products). 3,6,9 Triborylated Product: 1 H NMR (500 MHz, CDCl3) δ 8.59 (s, 1H), 8.55 (s, 2H), 8.40 (d, J = 8.7, 2H), 7.83 (dd, J = 8.7, 1.3, 2H), 1.56 (s, 12H), 1.40 (s, 24H). 13C NMR (126 MHz, CDCl3) δ 138.3, 137.9, 132.0, 130.6, 486 130.2, 127.4, 84.0, 83.6, 25.2, 25.1. 11B NMR (160 MHz, CDCl3) δ 30.5. HRMS (ESI) m/z calcd for C32H44B3O6 [M] 557.3417, found 557.3410 2,6,9 Triborylated Product: 1 H NMR (500 MHz, CDCl3) δ 9.00 (d, J = 1.1 Hz, 1H), 8.55 (d, J = 1.1 Hz, 1H), 8.49 (s, 1H), 8.33 (d, J = 8.7 Hz, 1H), 7.97 (d, J = 8.6 Hz, 1H), 7.81 (dd, J = 8.7, 1.1 Hz, 1H), 7.75 (dd, J = 8.6, 1.1 Hz, 1H), 1.60 (s, 12H), 1.40 (s, 12H), 1.38 (s, 12H). HRMS (ESI) m/z calcd for C32H44B3O6 [M] 557.3417, found 557.3410 2,7,9 Triborylated Product: 1 H NMR (500 MHz, CDCl3) δ 8.95 (d, J = 1.0 Hz, 2H), 7.94 (d, J = 8.2 Hz, 2H), 7.77 (d, J = 8.2 Hz, 2H), 1.65 (s, 12H) (some peaks were not observable due to the overlap with other signals). HRMS (ESI) m/z calcd for C32H44B3O6 [M] 557.3417, found 557.3410 4.4.7. Silylation of 1-borylated naphthalenes C6 Silylation of 2-(4-methoxynaphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane >95% conversion, 9:10 = 1.6:1 98% isolated yield, 9:10 = 1.6:1 In a glove box, a 5.0 mL Wheaton microreactor was charged with 7a (142 mg, 0.5 mmol, 1 equiv), [Ir(cod)(OMe)]2 (10.0 mg, 3.0 mol %), neocuproine (6.2 mg, 6.0 mol %) and HSiMe(OTMS)2 (334 mg, 1.5 mmol, 3.0 equiv) in dioxane (0.4 mL). The microreactor was connected to a condenser, capped with a septum and brought out of the glove box. The microreactor was connected to a continuous flux of nitrogen with a Schlenk line and heated to 90 487 ºC. After 48 h, an aliquot of the reaction mixture was taken and dried to analyze the conversion and 9:10 silylation ratio by 1H NMR. MeOH (1.0 mL) was added and the mixture was stirred for 1 h. The mixture was concentrated and passed through a plug of silica gel (CHCl 3 as eluent). The fractions containing product were collected, concentrated and washed with water (2 mL). The water layer was decanted and the residue was dried to give 248 mg of a mixture of 9 and 10 (9:10 = 1.6:1) as a tan solid (98% yield). 6-silylated product: 1 H NMR (500 MHz, CDCl3) δ 8.74 (d, J = 8.4, 0.8 Hz, 1H), 8.57 (dd, J = 1.3, 0.8 Hz, 1H), 8.07 (d, J = 7.8, 1H), 7.73 (dd, J = 8.4, 1.3 Hz, 1H), 6.83 (d, J = 7.8 Hz, 1H), 4.04 (s, 3H), 1.47 – 1.40 (s, 12H), 0.36 (s, 3H), 0.16 (s, 18H). 13C NMR (126 MHz, CDCl3) δ 158.7, 138.8, 137.6, 134.6, 130.9, 128.2, 127.1, 124.7, 118.5 (C–B, observed by gHMBCAD), 103.3, 83.5, 55.6, 25.1, 2.1, 0.3. 29Si NMR (99 MHz, CDCl3) δ 8.39, -33.62. 11B NMR (160 MHz, CDCl3) δ 31.4. HRMS (ESI) m/z calcd for C24H42BO5Si3 [M+H]+ 505.2433 , found 505.2418 5-silylated product: 1 H NMR (500 MHz, CDCl3) δ 9.02 (dd, J = 1.1, 0.8 Hz, 1H), 8.28 (dd, J = 8.3, 0.8 Hz, 1H), 8.07 (d, J = 7.8 Hz, 1H), 7.65 (dd, J = 8.3, 1.1 Hz, 1H), 6.84 (d, J = 7.8 Hz, 1H), 4.02 (s, 3H), 1.47 – 1.40 (s, 12H), 0.41 (s, 3H), 0.16 (s, 18H). 13 C NMR (126 MHz, CDCl3) δ 158.2, 137.4, 137.0, 136.8, 134.4, 128.8, 126.1, 120.9, 119.1 (C–B, observed by gHMBCAD), 103.7, 83.5, 55.6, 25.1, 2.1, 0.1. 29Si NMR (99 MHz, CDCl3) δ 8.48, -33.15. 11B NMR (160 MHz, CDCl3) δ 31.4. HRMS (ESI) m/z calcd for C24H42BO5Si3 [M+H]+ 505.2433 , found 505.2418 488 4.4.8. CHB of substrates without selectivity Para borylation of 2-chlorophenol (2p) >95% conversion, para:meta = 1 : 1 73% isolated yield, para:meta = 1.4 : 1 In a glove box, a 5.0 mL Wheaton microreactor was charged with 2-chlorophenol (64 mg, 0.5 mmol, 1 equiv) and tmphen (3.6 mg, 3.0 mol %) in THF (0.5 mL). In a separate tube, [Ir(cod)(OMe)]2 (5.0 mg, 1.5 mol %) and B2pin2 (190 mg, 0.75 mmol, 1.5 equiv) in THF (1.0 mL) were stirred for 5 min. The [Ir(cod)(OMe)]2/B2pin2 solution was transferred to the microreactor. The microreactor was capped with a teflon pressure cap and placed into an aluminum block pre- heated to 40 ºC. After 14 h, an aliquot of the reaction mixture was taken and analyzed directly by 1 H NMR to find the conversion and para:meta borylation ratio. MeOH (2.5 mL) was added and the mixture was stirred for 1 h. The mixture was concentrated and passed through a plug of silica gel (CHCl3 as eluent). The fractions containing product were collected, concentrated and washed with water (4 mL). The water layer was decanted and the residue was dried to give 93 mg of a mixture of para and meta borylated 2p (para:meta = 1.4:1) as a light orange solid (73% yield). The NMR data of the para and meta borylated isomers were consistent with previously reported values.76–78 Para borylated product: 1 H NMR (500 MHz, CDCl3) δ 7.78 (d, J = 1.5 Hz, 1H), 7.62 (dd, J = 8.0, 1.5 Hz, 1H), 7.00 (d, J = 8.0 Hz, 1H), 5.88 (bs, 1H), 1.34 (s, 12H). 13C NMR (126 MHz, CDCl3) δ 154.0, 135.8, 135.2, 120.0, 115.9, 84.1, 24.9. 11B NMR (160 MHz, CDCl3) δ 30.4. 489 Meta borylated product: 1 H NMR (500 MHz, CDCl3) δ 7.44 (d, J = 1.3 Hz, 1H), 7.32 (d, J = 7.9 Hz, 1H), 7.29 (dd, J = 7.9, 1.3 Hz, 1H), 5.88 (bs, 1H), 1.34 (s, 12H). 13 C NMR (126 MHz, CDCl3) δ 151.0, 128.8, 127.6, 123.3, 122.4, 84.2, 24.9. 11B NMR (160 MHz, CDCl3) δ 30.4. CHB borylation of 2-methyl-1-naphthylamine (2o) 89% conversion, 6:7 = 1.3:1 61% isolated yield, 6:7 = 1.6:1 In a glove box, a 5.0 mL Wheaton microreactor was charged with 2-methyl-1- naphthylamine (79 mg, 0.5 mmol, 1 equiv) and tmphen (3.6 mg, 3.0 mol %) in THF (0.5 mL). In a separate tube, [Ir(cod)(OMe)]2 (5.0 mg, 1.5 mol %) and B2pin2 (190 mg, 0.75 mmol, 1.5 equiv) in THF (1.0 mL) were stirred for 5 min. The [Ir(cod)(OMe)] 2/B2pin2 solution was transferred to the microreactor. The microreactor was capped with a teflon pressure cap and placed into an aluminum block pre-heated to 40 ºC. After 48 h, an aliquot of the reaction mixture was taken and analyzed directly by 1H NMR to find the conversion and 6:7 borylation ratio. MeOH (2.5 mL) was added and the mixture was stirred for 1 h. The mixture was concentrated and passed through a plug of silica gel (CHCl3 as eluent). The fractions containing product were collected to give 87 mg of a mixture of 6- and 7- borylated 2o (6:7 = 1.6:1) as a brown oil (61% yield) C6 borylated product 1 H NMR (500 MHz, C6D6) δ 8.8 (s, 1H), 8.2 (d, J = 8.4 Hz, 1H), 7.6 (d, J = 8.4 Hz, 2H), 7.3 (d, J = 8.2 Hz, 2H), 7.0 (d, J = 8.2 Hz, 2H), 3.6 (bs, 2H), 1.9 (s, 3H), 1.2 (s, 12H). 13C NMR (126 MHz, C6D6) δ 139.7, 137.9, 133.2, 129.7, 129.6, 125.2, 120.1, 119.0, 117.2, 83.8, 25.1, 17.7. 11B NMR 490 (160 MHz, C6D6) δ 31.7. HRMS (ESI) m/z calcd for C17H23BNO2 [M+H]+ 284.1822, found 284.1812 C7 borylated product 1 H NMR (500 MHz, C6D6) δ 8.8 (s, 1H), 8.2 (d, J = 8.2 Hz, 1H), 7.7 (d, J = 8.2 Hz, 1H), 7.2 (d, J = 8.1 Hz, 1H), 7.1 (d, J = 8.1 Hz, 1H), 3.6 (bs, 2H), 1.9 (s, 3H), 1.2 (s, 12H). 13C NMR (126 MHz, 11 C6D6) 140.7, 135.6, 131.1, 129.7, 128.2, 125.0, 123.1, 117.9, 115.7, 83.9, 25.1, 17.5. B NMR (160 MHz, C6D6) δ 31.7. HRMS (ESI) m/z calcd for C17H23BNO2 [M+H]+ 284.1822, found 284.1812 4.4.9. Synthesis N-borylated scaffolds Synthesis of N-Bpin borylated 2-chloroaniline (1a’) In a glovebox, under a N2 atmosphere, a 5.0 mL Wheaton microreactor was charged with 2-chloroaniline (383 mg, 3 mmol, 1 equiv) and HBpin (384 mg, 3 mmol, 1 equiv). The reaction was stirred at room temperature for 17 h. From the final mixture, 51 mg was measured, dissolved in 0.6 mL of CDCl3 (0.33 M solution) and transfer to J-Young NMR tube. TMS internal standard was added as reference. It is important to note that the reaction can be completed in one hour if [Ir(cod)OMe]2 (0.5 mol %) is added and the reaction heated at 80 °C. 1 H NMR (500 MHz, CDCl3) δ 7.64 (dd, J = 8.3, 1.5 Hz, 1H), 7.25 (dd, J = 8.0, 1.6 Hz, 1H), 7.13 (ddd, J = 8.4, 7.3, 1.5 Hz, 1H), 6.77 (ddd, J = 7.9, 7.3, 1.5 Hz, 1H), 5.33 (bs, 1H), 1.31 (s, 12H). 13 C NMR (126 MHz, CDCl3) δ 140.1, 128.9, 127.6, 121.5, 120.5, 118.5, 83.1, 24.6. 11B NMR (160 MHz, CDCl3) δ 24.1. 491 Synthesis of N-Bpp borylated 2-chloroaniline In a glovebox, under a N2 atmosphere, a 3.0 mL Wheaton microreactor was charged with 2-chloroaniline (32 mg, 0.25 mmol, 1 equiv), B2pp2 (42 mg, 0.15 mmol, 0.6 equiv), [Ir(cod)OMe]2 (1 mg, 0.5 mol %) and tmphen (0.6 mg, 1 mol %) in THF (0.25 mL). The microreactor was capped with a teflon pressure cap and placed into an aluminum block pre-heated to 80 ºC. After 1h, the mixture was concentrated under reduce pressure without heating inside of the glove box. The mixture was redissolved in C6D6 (0.6 mL, 0.4 M solution) and transfer to a J-Young NMR tube. 1 H NMR (500 MHz, C6D6) δ 8.11 (d, J = 8.3 Hz, 1H), 7.17 (d, J = 8.0 Hz, 1H), 7.06 (dd, J = 8.3, 13 7.3 Hz, 1H), 6.53 (dd, J = 8.0, 7.3, 1.3 Hz, 1H), 5.45 (bs, 1H), 1.37 (s, 2H), 1.14 (s, 12H). C NMR (126 MHz, C6D6) δ 141.7, 129.3, 127.8, 121.9, 120.2, 119.2, 71.5, 48.7, 31.7. 11B NMR (160 MHz, C6D6) δ 25.3. Synthesis of N-BBN borylated 2-chloroaniline In a glovebox, under a N2 atmosphere, a 3.0 mL Wheaton microreactor was charged with 2-chloroaniline (0.05 mL of a 2 M solution in THF, 0.10 mmol, 1 equiv), 9-BBN dimer (15 mg, 0.06 mmol, 0.6 equiv) and [Ir(cod)OMe]2 (0.15 mL of 3.3 mM solution in THF, 0.5 mol %) in THF. The microreactor was capped with a teflon pressure cap and placed into an aluminum block pre-heated to 80 ºC. After 1h, the mixture was concentrated under reduce pressure without heating inside of the glove box. The mixture was redissolved in C6D6 and transfer to a J-Young NMR tube. 492 1 H NMR (500 MHz, C6D6) δ 7.20 – 7.14 (dd, J = 8.1, 1.5 Hz 1H), 7.12 (dd, J = 8.0, 1.6 Hz, 1H), 6.85 (td, J = 7.7, 1.5 Hz, 1H), 6.63 (td, J = 7.7, 1.6 Hz, 1H), 6.10 (bs, 1H). The peaks in the aliphatic region were difficult to identify as they overlap with those of the 9BBN dimer residue. 11B NMR (160 MHz, C6D6) δ 52.2. Other peaks were observed in the 11B NMR spectrum corresponding to 9-BBN borates (58.7 and 56.3 ppm) and 9-BBN dimer (27.8 ppm).77–79 Synthesis of N-Bpin borylated 2-methylaniline (1g’) In a glovebox, under a N2 atmosphere, 2-methylaniline (3 mmol, 321 mg, 1 equiv) and HBpin (3 mmol, 384 mg, 1 equiv) were charged in a 5 mL vial and stirred at room temperature for 48 h. From the final mixture, 47 mg was measured, dissolved in 0.6 mL of CDCl3 (0.33 M solution) and transfer to J-Young NMR tube. It is important to note that the reaction can be completed in one hour if [Ir(cod)OMe]2 (0.5 mol %) is added and the reaction heated at 80 °C. It is important to note that the reaction can be completed in one hour if [Ir(cod)OMe]2 (0.5 mol %) is added and the reaction heated at 80 °C. 1 H NMR (500 MHz, CDCl3) δ 7.55 (d, J = 8.1 Hz, 1H), 7.14 (dd, J = 8.1, 7.2 Hz, 1H), 7.09 (d, J 13 = 7.5 Hz, 1H), 6.82 (d, J = 7.5, 7.2 Hz, 1H), 2.21 (s, 3H), 1.34 (s, 12H). C NMR (126 MHz, C6D6) δ 142.1, 130.5, 127.4, 124.4, 120.6, 118.4, 82.7, 24.7, 17.3. 11B NMR (160 MHz, CDCl3) δ 24.1. Synthesis of N-Bpp borylated 2-methylaniline 493 In a glovebox, under a N2 atmosphere, a 3.0 mL Wheaton microreactor was charged with 2-methylaniline (27 mg, 0.25 mmol, 1 equiv), B2pp2 (42 mg, 0.15 mmol, 0.6 equiv), [Ir(cod)OMe]2 (1 mg, 0.5 mol %) and tmphen (0.6 mg, 1 mol %) in THF (0.25 mL). The microreactor was capped with a teflon pressure cap and placed into an aluminum block pre-heated to 80 ºC. After 1h, the mixture was concentrated under reduce pressure without heating inside of the glove box. The mixture was redissolved in C6D6 (0.6 mL, 0.4 M solution) and transfer to a J-Young NMR tube. 1 H NMR (500 MHz, C6D6) δ 8.10 (dd, J = 8.2, 1.3 Hz, 1H), 7.26 (dd, J = 8.2, 7.3 Hz, 1H), 6.98 (d, J = 7.3 Hz, 1H), 6.82 (td, J = 7.3, 1.3 Hz, 1H), 4.47 (bs, 1H), 1.83 (s, 3H), 1.43 (s, 2H), 1.21 (s, 12H). 13C NMR (126 MHz, C6D6) δ 143.2, 130.5, 127.3, 124.4, 119.9, 118.6, 71.2, 48.9, 31.8, 17.7. 11B NMR (160 MHz, C6D6) δ 25.3. Synthesis of N-borylated 2-tertbutylaniline (1i’) In a glovebox, under a N2 atmosphere, a 3.0 mL Wheaton microreactor was charged with 2-tertbutylaniline (37 mg, 0.25 mmol, 1 equiv), HBpin (48 mg, 0.375 mmol, 1.5 equiv) and [Ir(cod)OMe]2 (0.8 mg, 0.5 mol %) in THF-d8 dried over alumina (0.75 mL). The microreactor was capped with a teflon pressure cap and stirred at room temperature. After 13 h, the mixture was transfer to a J-Young NMR tube. 1 H NMR (500 MHz, THF-d8) δ 7.41 (dd, J = 8.1, 1.4 Hz, 1H), 7.17 (dd, J = 7.9, 1.6 Hz, 1H), 6.95 (ddd, J = 8.1, 7.2, 1.6 Hz, 1H), 6.72 (ddd, J = 7.9, 7.2, 1.4 Hz, 1H), 4.89 (bs, 1H), 1.36 (s, 9H), 1.23 (s, 12H). 13 C NMR (126 MHz, THF-d8) δ 142.2, 137.0, 127.1, 126.4, 122.2, 121.2, 83.0, 34.6, 30.4, 24.8. 11B NMR (160 MHz, THF-d8) δ 24.0. 494 Synthesis of N-Bpin borylated 5-bromo-1-aminonaphthalene (1m’) In a glovebox, under a N2 atmosphere, a 3.0 mL Wheaton microreactor was charged with 5-bromo-1-aminonaphthalene (44 mg, 0.20 mmol, 1 equiv), HBpin (31 mg, 0.24 mmol, 1.2 equiv), [Ir(cod)OMe]2 (0.2 mL of 5 mM solution in THF, 0.5 mol %), NEt3 (0.04 mL, 0.20 mmol, 1 equiv) in THF (0.2 mL). The microreactor was capped with a teflon pressure cap and stirred at 80 °C. After 16 h, the mixture was concentrated under reduce pressure without heating inside of the glove box. The mixture was redissolved in CDCl3 (0.6 mL, 0.33 M solution) and transfer to a J-Young NMR tube. 1 H NMR (500 MHz, CDCl3) δ 7.85 – 7.77 (m, 2H), 7.74 (dd, J = 7.4, 0.9 Hz, 1H), 7.65 (dd, J = 7.6, 1.1 Hz, 1H), 7.48 (t, J = 8.1 Hz, 1H), 7.25 (dd, J = 8.5, 7.4 Hz, 1H), 5.26 (bs, 1H), 1.33 (s, 12H). 13C NMR (126 MHz, CDCl3) δ 138.9, 132.8, 129.9, 127.9, 126.5, 125.3, 123.9, 120.3, 120.0, 115.2, 83.2, 24.8. 11B NMR (160 MHz, CDCl3) δ 24.4. Synthesis of N-Bpin borylated N-methyl-2-aminopyridine (3b’) In a glovebox, under a N2 atmosphere, a 3.0 mL Wheaton microreactor was charged with 2-amino-N-methylpyridine (22 mg, 0.20 mmol, 1 equiv), HBpin (31 mg, 0.24 mmol, 1.2 equiv), [Ir(cod)OMe]2 (0.8 mg, 0.5 mol %), NEt3 (0.04 mL, 0.20 mmol, 1 equiv) in THF (0.2 mL). The microreactor was capped with a teflon pressure cap and stirred at 80 °C. After 17 h, the mixture 495 was concentrated under reduce pressure without heating inside of the glove box. The mixture was redissolved in CDCl3 (0.6 mL, 0.33 M solution) and transfer to a J-Young NMR tube. 1 H NMR (500 MHz, CDCl3) δ 8.26 (ddd, J = 5.0, 2.1, 0.9 Hz, 1H), 7.63 (dt, J = 8.6, 1.0 Hz, 1H), 7.46 (ddd, J = 8.6, 7.1, 2.1 Hz, 1H), 6.74 (ddd, J = 7.1, 5.0, 1.0 Hz, 1H), 3.15 (s, 3H), 1.29 (s, 12H). 13C NMR (126 MHz, CDCl3) δ 158.6, 147.3, 136.7, 115.6, 114.5, 83.2, 32.4, 24.8. 11B NMR (160 MHz, CDCl3) δ 24.9. Synthesis of N-Bpin borylated tetrahydroquinoline (3d’) In a glovebox, under a N2 atmosphere, a 3.0 mL Wheaton microreactor was charged with tetrahydroquinoline (27 mg, 0.20 mmol, 1 equiv), HBpin (31 mg, 0.24 mmol, 1.2 equiv), [Ir(cod)OMe]2 (0.8 mg, 0.5 mol %), NEt3 (0.04 mL, 0.20 mmol, 1 equiv) in THF (0.2 mL). The microreactor was capped with a teflon pressure cap and stirred at 80 °C. After 17 h, the mixture was concentrated under reduce pressure without heating inside of the glove box. The mixture was redissolved in CDCl3 (0.6 mL, 0.33 M solution) and transfer to a J-Young NMR tube. 1 H NMR (500 MHz, CDCl3) δ 7.63 (dd, J = 8.4, 1.2 Hz, 1H), 7.08 (ddd, J = 8.4, 7.3, 1.4 Hz, 1H), 7.02 (dt, J = 7.5, 1.4 Hz, 1H), 6.82 (td, J = 7.3, 1.2 Hz, 1H), 3.52 – 3.46 (m, 2H), 2.82 (t, J = 6.7 Hz, 2H), 1.94 – 1.81 (m, 2H), 1.31 (s, 12H). 13C NMR (126 MHz, CDCl3) δ 143.0, 129.6, 126.2, 125.9, 120.4, 120.2, 82.7, 44.2, 27.9, 24.8, 23.4. 11B NMR (160 MHz, CDCl3) δ 24.2. Synthesis of N-Bpin borylated 3-methylindole (5a’) 496 In a glovebox, under a N2 atmosphere, a 3.0 mL Wheaton microreactor was charged with 3-methylindole (26 mg, 0.20 mmol, 1 equiv), HBpin (31 mg, 0.24 mmol, 1.2 equiv), NEt3 (0.04 mL, 0.20 mmol, 1 equiv) in THF (0.2 mL). The microreactor was capped with a teflon pressure cap and stirred at 80 °C. After 17 h, the mixture was concentrated under reduce pressure without heating inside of the glove box. The mixture was redissolved in CDCl 3 (0.6 mL, 0.33 M solution) and transfer to a J-Young NMR tube. TMS was added as an internal standard. 1 H NMR (500 MHz, CDCl3) δ 7.91 (dt, J = 8.1, 0.9 Hz, 1H), 7.50 (ddd, J = 7.8, 1.3, 0.8 Hz, 1H), 7.23 (ddd, J = 8.1, 7.1, 1.3 Hz, 1H), 7.17 (ddd, J = 7.8, 7.1, 0.9 Hz, 1H), 7.14 (q, J = 1.3 Hz, 1H), 2.28 (d, J = 1.3 Hz, 3H), 1.37 (s, 12H). 13C NMR (126 MHz, CDCl3) δ 139.7, 132.0, 126.1, 122.7, 120.9, 118.6, 116.0, 114.7, 84.2, 24.8, 9.8. 11B NMR (160 MHz, CDCl3) δ 24.4. Synthesis of N-Bpin borylated 2-methyl-1-aminonaphthalene (1o’) In a glovebox, under a N2 atmosphere, a 3.0 mL Wheaton microreactor was charged with 2-methyl-1-aminonaphthalene (31 mg, 0.20 mmol, 1 equiv), HBpin (31 mg, 0.24 mmol, 1.2 equiv), [Ir(cod)OMe]2 (0.2 mL of 5 mM solution in THF, 0.5 mol %), NEt3 (0.04 mL, 0.20 mmol, 1 equiv) in THF (0.2 mL). The microreactor was capped with a teflon pressure cap and stirred at 80 °C. After 16 h, the mixture was concentrated under reduce pressure without heating inside of the glove box. The mixture was redissolved in CDCl3 (0.6 mL, 0.33 M solution) and transfer to a J-Young NMR tube. 1 H NMR (500 MHz, CDCl3) δ 8.06 (dt, J = 8.4, 1.0 Hz, 1H), 7.78 – 7.73 (ddd, J = 8.1, 1.4, 0.9 Hz, 1H), 7.53 (d, J = 8.3 Hz, 1H), 7.45 (ddd, J = 8.4, 6.8, 1.4 Hz, 1H), 7.38 (ddd, J = 8.1, 6.8, 1.2 Hz, 13 1H), 7.30 (d, J = 8.3 Hz, 1H), 4.32 (bs, 1H), 2.45 (s, 3H), 1.26 (s, 12H). C NMR (126 MHz, 497 CDCl3) δ 134.8, 133.0, 130.8, 129.7, 129.3, 128.0, 125.6, 124.8, 124.4, 123.0, 82.9, 24.7, 19.2. 11 B NMR (160 MHz, CDCl3) δ 24.0. Synthesis of N-Bpin borylated 2-chloro-N-methylaniline (5a’) In a glovebox, under a N2 atmosphere, a 3.0 mL Wheaton microreactor was charged with 2-chloro-N-methylaniline (28 mg, 0.20 mmol, 1 equiv), HBpin (31 mg, 0.24 mmol, 1.2 equiv), [Ir(cod)OMe]2 (0.2 mL of 5 mM solution in THF, 0.5 mol %), NEt3 (0.04 mL, 0.20 mmol, 1 equiv) in THF (0.2 mL). The microreactor was capped with a teflon pressure cap and stirred at 80 °C. After 16 h, the mixture was concentrated under reduce pressure without heating inside of the glove box. The mixture was redissolved in CDCl3 (0.6 mL, 0.33 M solution) and transfer to a J-Young NMR tube. 1 H NMR (500 MHz, CDCl3) δ 7.41 – 7.35 (m, 1H), 7.25 – 7.17 (m, 2H), 7.09 (ddd, J = 7.9, 6.8, 2.3 Hz, 1H), 2.97 (s, 3H), 1.24 (s, 12H). 13C NMR (126 MHz, CDCl3) δ 144.8, 132.6, 130.2, 129.6, 127.6, 126.5, 82.9, 37.4, 24.7. 11B NMR (160 MHz, CDCl3) δ 23.8. Synthesis of O-Bpin borylated 2-chlorophenol (1p’) In a glovebox, under a N2 atmosphere, a 3.0 mL Wheaton microreactor was charged with 2-chlorophenol (26 mg, 0.2 mmol, 1 equiv) and HBpin (28 mg, 0.22 mmol, 1.1 equiv). The microreactor was capped with a teflon pressure cap and stirred at room temperature. After 12 h, 498 the mixture was dissolved in CDCl3 (0.6 mL, 0.33 M solution) and transfer to a J-Young NMR tube. TMS was added as an internal standard. 1 H NMR (500 MHz, CDCl3) δ 7.36 (dd, J = 7.9, 1.5 Hz, 1H), 7.21 – 7.13 (m, 2H), 7.01 (ddd, J = 7.8, 6.6, 2.2 Hz, 1H), 1.31 (s, 12H). 13C NMR (126 MHz, CDCl3) δ 149.7, 130.2, 127.8, 125.3, 124.4, 121.5, 84.1, 24.7. 11B NMR (160 MHz, CDCl3) δ 21.7. 4.4.10. Applications of IMHB to remote borylation C6 Borylation of 3-amino-N-methyl indazole (12) 92% conversion, 6:5 = 6:1 82% isolated yield, 6:5 = 8:1 In a glove box, a 5.0 mL Wheaton microreactor was charged with 3-amino-N-methyl indazole (74 mg, 0.5 mmol, 1 equiv) and tmphen (12 mg, 10.0 mol %) in THF (0.5 mL). In a separate tube, [Ir(cod)(OMe)]2 (16.6 mg, 5.0 mol %) and B2pin2 (222 mg, 0.875 mmol, 1.75 equiv) in THF (1.0 mL) were stirred for 5 min. The [Ir(cod)(OMe)] 2/B2pin2 solution was transferred to the microreactor. The microreactor was capped with a teflon pressure cap and placed into an aluminum block pre-heated to 80 ºC. After 55 h, an aliquot of the reaction mixture was taken and analyzed directly by 1H NMR to find the conversion and 6:5 borylation ratio. MeOH (2.5 mL) was added and the mixture was stirred for 1 h. The mixture was concentrated and passed through a plug of silica gel (CHCl3/MeOH 24:1 as eluent). The fractions containing product were collected, concentrated and washed with water (4 mL). The water layer was decanted and the residue was dried to give 112 mg of the 6-borylated 3-amino-N-methyl indazole 12 with a minor byproduct corresponding to the 5-borylated isomer (6:5 = 8:1) as a tan solid (82% yield). 499 1 H NMR (500 MHz, CDCl3) δ 7.72 (s, 1H), 7.53 (dd, J = 8.1, 1.0 Hz, 1H), 7.42 (dd, J = 8.1, 0.7 Hz, 1H), 4.08 (bs, 2H), 3.87 (s, 3H), 1.37 (s, 12H). 13 C NMR (126 MHz, CDCl3) δ 146.9, 141.3, 123.8, 118.8, 116.2, 115.9, 84.1, 35.0, 25.0. 11 B NMR (160 MHz, CDCl3) δ 31.2. HRMS (ESI) m/z calcd for C14H21BN3O2 [M+H]+ 274.1727, found 274.1722 Synthesis Osimertinib’s Analogue (13) A 100 mL round bottom flask was charged with 3-(2-Chloropyrimidin-4-yl)-1- methylindole (487 mg, 2 mmol, 1 equiv), piperidine (204 mg, 2.4 mmol, 1.2 equiv) and triethylamine (405 mg,4 mmol, 2.0 equiv) in dioxane (10 mL). The flask was connected to a condenser and heated to 95 ºC. After 21 h, the reaction was cool down to room temperature and concentrated under reduce pressure. 10 mL of water was added and extracted with ethyl acetate (3 x 10 mL). The organic layers were collected, concentrated and recrystallized over ethyl acetate. The precipitate was filtrated and dried under vacuum to yield 180 mg of osimertinib’s analogue 13 (31% yield, mp 127-129 °C). The structure was confirmed by x-ray crystallography. 1 H NMR (500 MHz, CDCl3) δ 8.41 (ddd, J = 7.7, 1.6, 0.9 Hz, 1H), 8.25 (d, J = 5.3 Hz, 1H), 7.74 (s, 1H), 7.36 (ddd, J = 7.7, 1.5, 0.9 Hz, 1H), 7.34-7.24 (m, 2H), 6.79 (d, J = 5.3 Hz, 1H), 3.91 (dd, J = 6.2, 4.1 Hz, 4H), 3.85 (s, 3H), 1.75 – 1.64 (m, 6H). 13 C NMR (126 MHz, CDCl3) δ 162.1, 162.1, 157.1, 138.0, 130.9, 126.2, 122.5, 122.1, 121.2, 114.7, 109.8, 105.0, 45.1, 33.4, 26.0, 25.2. HMRS (ESI) m/z calcd for C18H21N4 [M+H]+ 293.1766, found 293.1740 500 C6 Borylation of Osimertinib’s Analogue (14) 81% conversion, 6:5 = 4.2:1 57% isolated yield, 6:5 = 3.5:1 In a glove box, a 5.0 mL Wheaton microreactor was charged with Osimertinib’s analogue 13 (73 mg, 0.25 mmol, 1 equiv) and tmphen (3.5 mg, 6.0 mol %) in THF (0.3 mL). In a separate tube, [Ir(cod)(OMe)]2 (5.0 mg, 3.0 mol %) and B2pin2 (95 mg, 0.375 mmol, 1.5 equiv) in THF (0.5 mL) were stirred for 5 min. The [Ir(cod)(OMe)] 2/B2pin2 solution was transferred to the microreactor. The microreactor was capped with a teflon pressure cap and placed into an aluminum block pre-heated to 60 ºC. After 48 h, an aliquot of the reaction mixture was taken and analyzed directly by 1H NMR to find the conversion and 6:5 borylation ratio. The mixture was concentrated and passed through a plug of silica gel (chloroform/ethyl acetate 4:1 as eluent). The fractions containing product were collected and concentrated to give 60 mg of 6-borylated product 14 with a minor 5-borylated byproduct (6:5 = 3.5:1) as a yellow solid (57% yield). 1 H NMR (500 MHz, CDCl3) δ 8.38 (dd, J = 8.1, 0.8 Hz, 1H), 8.25 (d, J = 5.2 Hz, 1H), 7.85 (s, 1H), 7.78 (s, 1H), 7.71 (dd, J = 8.1, 1.0 Hz, 1H), 6.79 (d, J = 5.2 Hz, 1H), 3.95 – 3.88 (m, 4H), 3.87 (s, 3H), 1.73 – 1.64 (m, 6H), 1.39 (s, 12H). 13 C NMR (126 MHz, CDCl3) δ 161.9, 157.1, 137.7, 132.2, 128.7, 127.1, 122.1, 121.2, 116.6, 114.8, 105.0, 83.8, 45.1, 33.5, 26.0, 26.0, 25.0. 11 B NMR (160 MHz, CDCl3) δ 31.5. HRMS (ESI) m/z calcd for C24H32BN4O2 [M+H]+ 419.2618, found 419.2594 501 4.5. Notes The work presented in this chapter was not all conducted by Jose R. Montero Bastidas. Substrate exploration was a team effort with Arzoo Chhabra (N-alkylated anilines and indoles), Yilong Feng (N-unsubstituted anilines and 1-borylated naphthalenes) and Thomas J. Oleskey (N-alkylated anilines). 502 APPENDIX 503 Computational Procedures and Results Calculations of structures, energies, and frequencies employed default procedures in Gaussian16 unless otherwise noted.80 Complete structures and energetics are provided in sections below. B3LYP/6-311++G** was used as basis set for all the calculations. All absolute energies are in Hartrees. All relative energies are presented in kcal/mol. 1a’-I, 2-ClPhNHBpin C 3.11064 -0.42109 0.02122 C 4.26182 0.35518 -0.01668 E(RB3LYP) = -1158.14241950 H 5.05573 2.34765 -0.13468 Zero-point correction = 0.278990 H 2.79828 3.40250 -0.22643 (Hartree/Particle) H 0.76959 2.00627 -0.16154 Thermal correction to Energy = 0.295671 H 5.22847 -0.13078 0.02369 N 0.68870 -0.66604 0.01135 Thermal correction to Enthalpy = 0.296616 H 0.89448 -1.65502 0.05877 Thermal correction to Gibbs Free Energy = C -2.66432 0.80804 0.17580 0.234713 C -2.93990 -0.71069 -0.16167 Sum of electronic and zero-point Energies = B -0.69497 -0.33629 0.01190 -1157.863429 O -1.64944 -1.32519 0.11865 Sum of electronic and thermal Energies = O -1.23223 0.92641 -0.09118 -1157.846748 C -3.40109 1.81230 -0.70360 H -4.48337 1.70799 -0.58623 Sum of electronic and thermal Enthalpies = H -3.12641 2.82749 -0.40853 -1157.845804 H -3.14980 1.68670 -1.75641 Sum of electronic and thermal Free Energies C -2.86884 1.14734 1.65613 = -1157.907706 H -2.47312 2.14697 1.84738 H -3.92750 1.13990 1.92593 E (Thermal) CV S H -2.34044 0.44460 2.30376 Kcal/mol cal/mol- cal/mol- C -3.24041 -0.95712 -1.64468 kelvin Kelvin H -3.22160 -2.03255 -1.83288 185.537 65.666 130.285 H -4.22572 -0.57657 -1.92419 H -2.49203 -0.48876 -2.28762 C -3.99493 -1.38508 0.70896 H -4.96922 -0.90493 0.58105 H -4.09334 -2.43250 0.41546 H -3.72528 -1.35505 1.76429 Cl 3.28628 -2.17736 0.13339 1a’-II, 2-ClPhNHBpin-90 E(RB3LYP) = -1158.13265068 Zero-point correction = 0.278175 (Hartree/Particle) Thermal correction to Energy = 0.295041 C 4.15958 1.73993 -0.10510 C 2.89530 2.32500 -0.15572 Thermal correction to Enthalpy = 0.295985 C 1.74639 1.54480 -0.11873 Thermal correction to Gibbs Free Energy = C 1.82273 0.14394 -0.02728 0.233547 504 Sum of electronic and zero-point Energies = H -2.18655 1.27002 2.67107 -1157.854475 H -2.42418 2.14476 1.15711 Sum of electronic and thermal Energies = C -2.41010 -1.25574 1.82380 H -1.79731 -1.14315 2.72057 -1157.837610 H -3.45069 -1.38377 2.13175 Sum of electronic and thermal Enthalpies = H -2.08739 -2.16137 1.30555 -1157.836666 C -3.13432 1.15863 -1.19344 Sum of electronic and thermal Free Energies H -3.36000 0.97057 -2.24527 = -1157.899103 H -3.99249 1.66269 -0.74236 H -2.27314 1.82843 -1.14699 E (Thermal) CV S C -4.05328 -1.09762 -0.59600 Kcal/mol cal/mol- cal/mol- H -4.88481 -0.70224 -0.00569 kelvin Kelvin H -4.38042 -1.16708 -1.63591 185.141 66.107 131.411 H -3.82383 -2.10407 -0.24667 Cl 1.55396 2.11687 -0.39421 1a’-TS, 2-ClPhNHBpin-TS E(RB3LYP) = -1158.13204019 Zero-point correction = 0.277867 (Hartree/Particle) Thermal correction to Energy = 0.293961 Thermal correction to Enthalpy = 0.294905 Thermal correction to Gibbs Free Energy = 0.234849 Sum of electronic and zero-point Energies = C 4.51567 -0.36205 0.67915 -1157.854174 C 4.05521 -1.60707 0.25466 Sum of electronic and thermal Energies = C 2.79360 -1.71951 -0.31682 -1157.838079 C 1.96491 -0.60302 -0.50087 Sum of electronic and thermal Enthalpies = C 2.46479 0.64520 -0.09715 -1157.837135 C 3.71763 0.76292 0.50123 Sum of electronic and thermal Free Energies H 5.49214 -0.26142 1.13805 = -1157.897191 H 4.66905 -2.49116 0.38238 H 2.41678 -2.69019 -0.62090 E (Thermal) CV S H 4.06591 1.74209 0.80447 Kcal/mol cal/mol- cal/mol- N 0.69966 -0.75935 -1.10657 H 0.70252 -1.32245 -1.94512 kelvin Kelvin C -2.22986 -0.01297 0.94448 184.463 64.275 126.399 C -2.83918 -0.17900 -0.50510 B -0.57815 -0.46944 -0.55718 O -1.73749 -0.79666 -1.23135 O -0.80426 0.10700 0.66822 C -2.68081 1.23432 1.69769 H -3.76139 1.21696 1.86650 505 1g’-I, 2-MePhNHBpin E(RB3LYP) = -737.845073111 Zero-point correction = 0.315939 (Hartree/Particle) Thermal correction to Energy = 0.333040 Thermal correction to Enthalpy = 0.333984 Thermal correction to Gibbs Free Energy = 0.271726 Sum of electronic and zero-point Energies = C 4.38222 -0.81032 0.60621 -737.529134 C 3.76642 -1.84213 -0.09878 Sum of electronic and thermal Energies = C 2.54421 -1.61712 -0.72435 -737.512034 C 1.91373 -0.36943 -0.67130 Sum of electronic and thermal Enthalpies = C 2.55799 0.65507 0.03812 -737.511089 C 3.77777 0.44115 0.67551 Sum of electronic and thermal Free Energies H 5.33205 -0.97352 1.10220 H 4.23123 -2.81949 -0.15602 = -737.573347 H 2.04586 -2.41260 -1.26623 E (Thermal) CV S H 4.24549 1.25404 1.21618 Kcal/mol cal/mol- cal/mol- N 0.66838 -0.16945 -1.32549 kelvin Kelvin H 0.71901 0.06448 -2.30671 208.985 67.867 131.033 C -2.24422 -0.52961 0.83366 C -2.83505 0.21078 -0.43257 B -0.60319 -0.16548 -0.70618 O -1.77207 0.03749 -1.41276 O -0.80940 -0.37706 0.63822 C -2.61559 0.08891 2.17755 H -3.69779 0.05938 2.33383 H -2.14176 -0.47770 2.98232 H -2.27834 1.12245 2.25033 C -2.53633 -2.03473 0.84545 H -1.93481 -2.50280 1.62752 H -3.58956 -2.23967 1.05242 C 4.47681 1.26201 -0.10037 H -2.27308 -2.49900 -0.10747 C 3.26594 1.94481 -0.17941 C -3.01037 1.71945 -0.22273 C 2.06055 1.25165 -0.13956 H -3.22921 2.18492 -1.18615 C 2.04598 -0.14503 -0.01684 H -3.83515 1.93816 0.45992 C 3.26863 -0.84901 0.06346 H -2.10022 2.17452 0.17344 C 4.46182 -0.12557 0.01926 C -4.11624 -0.39459 -0.99686 H 5.41815 1.79808 -0.13198 H -4.92525 -0.34708 -0.26230 H 3.25312 3.02515 -0.27456 H -4.42766 0.16917 -1.87919 H 1.12250 1.78559 -0.20406 H -3.97364 -1.43336 -1.29382 H 5.40002 -0.66815 0.08133 Cl 1.84204 2.25668 0.12270 N 0.83763 -0.86285 0.02481 H 0.94986 -1.86395 0.08117 506 C -2.40193 0.84698 0.16916 E (Thermal) CV S C -2.78354 -0.65138 -0.15524 Kcal/mol cal/mol- cal/mol- B -0.51569 -0.43288 0.01873 kelvin Kelvin O -1.54140 -1.35212 0.13440 O -0.96705 0.86270 -0.09854 208.784 68.018 130.845 C -3.06773 1.89317 -0.71834 H -4.15471 1.86607 -0.60046 H -2.72210 2.88888 -0.43156 H -2.82587 1.74201 -1.77003 C -2.58288 1.21192 1.64673 H -2.11688 2.18228 1.83003 H -3.63949 1.28158 1.91605 H -2.10523 0.47880 2.30013 C -3.09822 -0.88827 -1.63711 H -3.15548 -1.96395 -1.81656 H -4.05344 -0.44116 -1.92263 H -2.31699 -0.47924 -2.28145 C 4.65224 0.08784 0.59421 C -3.88656 -1.24111 0.71772 C 4.22079 -1.23574 0.55196 H -4.82402 -0.69431 0.58221 C 2.94842 -1.52624 0.07268 H -4.05848 -2.28171 0.43357 C 2.09444 -0.51321 -0.38182 H -3.61838 -1.22015 1.77368 C 2.53317 0.82530 -0.37488 C 3.29338 -2.35268 0.19544 C 3.81004 1.09504 0.13226 H 4.32034 -2.71703 0.24941 H 5.63835 0.33355 0.97160 H 2.81770 -2.84932 -0.65913 H 4.86363 -2.03677 0.89938 H 2.77848 -2.69465 1.10129 H 2.59466 -2.55229 0.05786 1g’-II, 2-MePhNHBpin-90 H 4.15549 2.12399 0.14192 N 0.81621 -0.87792 -0.88786 E(RB3LYP) = -737.839939421 H 0.82622 -1.71507 -1.45438 Zero-point correction = 0.315566 C -2.14995 0.40174 0.82425 (Hartree/Particle) C -2.75195 -0.35603 -0.42508 B -0.47021 -0.48581 -0.44129 Thermal correction to Energy = 0.332718 O -1.60997 -1.12490 -0.89463 Thermal correction to Enthalpy = 0.333662 O -0.74198 0.51635 0.46453 Thermal correction to Gibbs Free Energy = C -2.70402 1.80283 1.06169 0.271494 H -3.77697 1.76520 1.27049 Sum of electronic and zero-point Energies = H -2.20755 2.24986 1.92594 -737.524373 H -2.53820 2.45316 0.20311 C -2.21391 -0.41772 2.11832 Sum of electronic and thermal Energies = H -1.60539 0.07688 2.87822 -737.507221 H -3.23681 -0.49723 2.49422 Sum of electronic and thermal Enthalpies = H -1.81820 -1.42506 1.97227 -737.506277 C -3.16093 0.58514 -1.56443 Sum of electronic and thermal Free Energies H -3.37425 -0.01186 -2.45363 = -737.568446 H -4.05638 1.15843 -1.31243 H -2.35918 1.28431 -1.81166 C -3.88924 -1.32227 -0.10874 507 H -4.74578 -0.79011 0.31488 C 2.74452 0.94906 0.15652 H -4.21721 -1.81223 -1.02833 C 3.97647 0.57247 0.70216 H -3.57646 -2.09602 0.59197 H 5.46622 -0.96132 0.92922 C 1.69026 1.94567 -0.92885 H 4.21024 -2.61562 -0.44370 H 1.25331 1.66465 -1.89162 H 2.01735 -1.97183 -1.42563 H 2.29617 2.84201 -1.07556 H 4.52547 1.29004 1.30353 H 0.86161 2.19329 -0.26149 N 0.78520 0.34741 -1.21192 H 0.82873 0.74194 -2.14096 1g’-TS, 2-MePhNHBpin-TS C -2.13706 -0.60294 0.74495 C -2.75374 0.31613 -0.38401 E(RB3LYP) = -737.837858104 B -0.49125 0.14437 -0.64781 Zero-point correction = 0.314905 O -1.66178 0.40004 -1.34080 (Hartree/Particle) O -0.71523 -0.31428 0.63401 Thermal correction to Energy = 0.331451 C -2.58705 -0.27586 2.16537 Thermal correction to Enthalpy = 0.332395 H -3.66648 -0.41568 2.27366 Thermal correction to Gibbs Free Energy = H -2.08679 -0.94529 2.86878 0.271852 H -2.33761 0.74865 2.44068 Sum of electronic and zero-point Energies = C -2.31383 -2.10077 0.46802 -737.522953 H -1.69598 -2.66287 1.17143 Sum of electronic and thermal Energies = H -3.35282 -2.41479 0.59467 -737.506407 H -1.99404 -2.35883 -0.54390 Sum of electronic and thermal Enthalpies = C -3.04755 1.74377 0.09283 -737.505463 H -3.27697 2.36422 -0.77617 Sum of electronic and thermal Free Energies H -3.90255 1.77452 0.77265 = -737.566006 H -2.18469 2.17963 0.60108 E (Thermal) CV S C -3.97515 -0.26080 -1.09316 Kcal/mol cal/mol- cal/mol- H -4.80068 -0.40714 -0.39065 H -4.30924 0.43406 -1.86709 kelvin Kelvin H -3.74921 -1.21364 -1.57125 207.988 66.369 127.424 C 2.18265 2.32635 0.40464 H 1.99008 2.85805 -0.53166 H 2.87513 2.92523 0.99935 H 1.23087 2.27275 0.94067 C 4.50911 -0.69761 0.49300 C 3.80803 -1.62299 -0.27523 C 2.58025 -1.26490 -0.82652 C 2.04483 0.00778 -0.61990 508 2m’, 5-Br-1-NHBpinNaphthalene C 1.44197 2.02032 -0.10657 C 2.67111 2.62707 -0.19537 E(RB3LYP) = -3425.73395581 C 3.85112 1.85763 -0.15778 H 0.56282 2.65049 -0.15997 H 2.74252 3.70330 -0.30055 Br 5.41147 -0.49697 -0.01251 H 4.81856 2.33755 -0.22484 4b’, 2-NMeBpinPyridine E(RB3LYP) = -753.876320116 C 2.40473 -1.59944 0.14472 C 1.16628 -2.18738 0.22361 C -0.01262 -1.42172 0.22684 C 0.04002 -0.04182 0.13739 C 1.31768 0.61316 0.02727 C 2.51272 -0.19083 0.04661 H 3.30210 -2.20133 0.15566 H 1.08810 -3.26654 0.29592 H -0.97317 -1.91116 0.30491 C 4.59628 -0.98599 0.07518 C 3.75982 0.49359 -0.04383 C 3.41953 -1.72565 0.21564 N -1.12906 0.73015 0.15778 C 2.19193 -1.08787 0.18394 H -0.98490 1.72278 0.25435 C 2.16066 0.31339 0.00374 C -4.42328 -0.81030 -0.31014 N 3.28862 1.01998 -0.12687 C -4.76085 0.64206 0.21217 C 4.46399 0.38418 -0.09082 B -2.49920 0.35685 0.07304 H 5.57286 -1.45313 0.09667 O -3.48267 1.32498 0.06255 H 3.45854 -2.80101 0.35341 O -2.99824 -0.92220 -0.00475 H 1.27550 -1.64593 0.29423 C -5.15658 -1.94236 0.40071 H 5.34183 1.01550 -0.20231 H -6.23699 -1.85420 0.25600 N 0.94891 1.02919 -0.04071 H -4.83813 -2.90133 -0.01404 C 1.00487 2.50378 -0.14108 H -4.94652 -1.95007 1.46991 C -2.13105 -0.98463 -0.17275 C -4.56334 -0.95730 -1.82900 C -2.64863 0.46704 0.16404 H -4.12545 -1.91025 -2.13296 B -0.36496 0.46689 -0.01712 H -5.61131 -0.94674 -2.13766 O -1.47658 1.28100 -0.11625 H -4.03729 -0.15970 -2.35780 O -0.70157 -0.86735 0.09603 C -5.11861 0.68211 1.70232 C -2.69570 -2.09651 0.70513 H -5.14305 1.72342 2.03020 H -3.78063 -2.16870 0.58783 H -6.09908 0.23919 1.89269 H -2.26064 -3.05366 0.40879 H -4.37659 0.15505 2.30600 H -2.46805 -1.93326 1.75818 C -5.80858 1.39394 -0.60194 C -2.27621 -1.35302 -1.65357 H -6.76976 0.87296 -0.57383 H -1.72124 -2.27391 -1.84430 H -5.95235 2.39051 -0.17862 H -3.32141 -1.51972 -1.92470 H -5.50354 1.51011 -1.64156 509 H -1.86966 -0.57307 -2.30080 C -2.57686 0.90780 1.93053 C -2.98515 0.66157 1.64737 H -2.09446 1.81561 2.29854 H -3.14137 1.72579 1.83555 H -3.60914 0.89689 2.28866 H -3.89547 0.12600 1.92724 H -2.05208 0.05026 2.35702 H -2.17031 0.32077 2.28980 C -3.33441 -0.38035 -1.70664 C -3.80043 0.96144 -0.70537 H -3.40338 -1.38604 -2.12674 H -4.68397 0.32993 -0.57602 H -4.30817 0.10376 -1.81339 H -4.06693 1.97929 -0.41221 H -2.60179 0.18066 -2.29083 H -3.53101 0.97473 -1.76114 C -3.95214 -1.28169 0.55077 H 2.04233 2.81455 -0.20074 H -4.89691 -0.73398 0.61133 H 0.53503 2.95930 0.73327 H -4.14437 -2.23114 0.04587 H 0.47130 2.84234 -1.03100 H -3.60944 -1.50076 1.56175 C 3.34791 -1.80170 0.35166 4d’, N-Bpin-Tetrahydroquinoline C 2.03792 -2.57326 0.51411 H 3.98807 -1.93736 1.22908 E(RB3LYP) = -815.273863261 H 3.90562 -2.21640 -0.49805 H 1.61695 -2.41207 1.51221 H 2.20746 -3.64832 0.40117 H 1.45104 -2.22685 -1.53455 H 0.10208 -2.64217 -0.47376 6a’, N-Bpin-3-MeIndole E(RB3LYP) = -814.071515122 C 4.08084 1.92046 -0.01367 C 2.82492 2.43070 -0.33950 C 1.72862 1.58498 -0.44391 C 1.85481 0.20369 -0.21431 C 3.12434 -0.31959 0.11185 C 4.21202 0.55474 0.20495 H 4.94121 2.57473 0.06754 H 2.69575 3.49210 -0.52141 H 0.76056 1.99063 -0.69843 H 5.18402 0.14319 0.46180 H 5.14678 0.08149 0.00419 N 0.73139 -0.65910 -0.32392 C 4.19951 -0.44625 -0.02309 C 1.03506 -2.08548 -0.52749 C 1.72884 -1.84782 -0.09737 C -2.51078 0.89967 0.39876 C 2.98866 0.25850 0.00861 C -2.91428 -0.48700 -0.23570 C 4.16742 -1.83369 -0.09040 B -0.63107 -0.27878 -0.17056 C 2.94452 -2.52456 -0.12717 O -1.65509 -1.21304 -0.20297 C 1.76628 -0.45498 -0.02816 O -1.10490 1.00320 0.03319 H 5.09589 -2.39319 -0.11564 C -3.24614 2.11106 -0.16555 H 2.94634 -3.60755 -0.18094 H -4.32031 2.03713 0.02670 H 0.78683 -2.37873 -0.12854 H -2.87870 3.01904 0.31790 C 2.66574 1.66779 0.07483 H -3.08945 2.21317 -1.23916 C 1.30724 1.75048 0.07562 510 H 0.67192 2.62150 0.11694 C -3.64078 0.25834 0.26984 N 0.71974 0.47661 0.01448 H -4.58389 2.12449 0.82834 C 3.64284 2.80045 0.13049 H -2.62652 3.50428 0.27602 H 4.29474 2.81009 -0.74972 C -0.25340 2.78103 -0.75497 H 4.29118 2.72670 1.01028 C -4.75797 -0.56422 0.56751 H 3.12840 3.76297 0.17507 N -0.14901 -0.12527 -1.07099 B -0.69525 0.24141 0.01074 H -0.32261 -0.78924 -1.81308 O -1.27093 -0.99887 -0.09788 C 3.02380 0.35435 0.68900 O -1.60459 1.26525 0.11670 C 3.28938 -0.91348 -0.21770 C -2.92129 0.69816 -0.16054 B 1.16423 -0.14361 -0.54106 C -2.69920 -0.83232 0.16607 O 2.17715 -0.85895 -1.15382 C -2.91865 -1.17681 1.64291 O 1.57521 0.49436 0.60815 C -3.46799 -1.80286 -0.72364 C 3.40885 0.19390 2.15627 C -3.21741 0.96692 -1.63996 H 4.48321 0.01637 2.25908 C -3.94490 1.40601 0.72042 H 3.16399 1.10930 2.69963 H -2.36652 -0.49993 2.29827 H 2.87097 -0.62933 2.62560 H -2.55924 -2.19151 1.82563 C 3.63562 1.64048 0.12150 H -3.97695 -1.13380 1.91075 H 3.25757 2.49299 0.68969 H -3.20914 -1.67797 -1.77465 H 4.72540 1.63450 0.20008 H -4.54632 -1.66192 -0.60823 H 3.36456 1.78386 -0.92654 H -3.22929 -2.82907 -0.43593 C 3.17005 -2.23797 0.54611 H -2.48853 0.47770 -2.28959 H 3.16946 -3.05963 -0.17334 H -3.16250 2.04243 -1.82036 H 4.00689 -2.38402 1.23333 H -4.21642 0.62267 -1.91762 H 2.24022 -2.28713 1.11697 H -3.67175 1.35806 1.77416 C 4.59169 -0.88142 -1.01137 H -4.93691 0.96332 0.59412 H 5.45558 -0.85082 -0.34127 H -4.00597 2.45832 0.43442 H 4.66880 -1.78475 -1.62070 H 4.63517 -0.02089 -1.67850 2o’, 2-Me-1-NHBpinNaphthalene C -2.40502 -1.75882 -0.34905 C -3.50546 -2.52931 -0.04984 E(RB3LYP) = -891.515826157 C -4.69901 -1.92777 0.40676 H -3.45349 -3.60727 -0.15573 H -5.56048 -2.54399 0.63833 H -5.66607 -0.09305 0.92963 H -1.49173 -2.24286 -0.67163 H -0.61700 3.80028 -0.90141 H 0.22845 2.45008 -1.67825 H 0.51640 2.80187 0.02119 C -3.67719 1.66320 0.45152 C -2.58242 2.42796 0.14468 C -1.38810 1.86424 -0.37617 C -1.31580 0.48843 -0.54283 C -2.43787 -0.34449 -0.21624 511 4a’, 2-Cl-PhN-Me-N-Bpin H 1.27547 -0.95607 3.00770 H 1.49845 -2.24503 1.80502 E(RB3LYP) = -1197.44604322 H -0.12606 -1.86498 2.40592 2p’, 2-Cl-PhOBpin E(RB3LYP) = -1178.01233752 C 4.09641 1.48225 -0.40930 C 3.79028 0.19767 -0.84902 C 2.64477 -0.43727 -0.37703 C 1.78790 0.18362 0.54373 C 2.11995 1.47479 0.96741 C 3.25700 2.12478 0.49796 C 4.11914 1.57969 0.13942 H 4.98677 1.97656 -0.78038 C 2.99116 2.25020 -0.32899 H 4.42674 -0.31201 -1.56118 C 1.82407 1.54697 -0.61038 Cl 2.27127 -2.04541 -0.98335 C 1.76869 0.16568 -0.42007 H 3.48721 3.12682 0.84088 C 2.90638 -0.50089 0.05036 N 0.62532 -0.46178 1.05158 C 4.07529 0.20127 0.32847 C 0.83547 -1.43642 2.12671 H 5.03126 2.12240 0.35713 C -2.33126 0.88961 -0.59690 H 3.01707 3.32301 -0.48018 C -2.89234 -0.40558 0.11427 H 0.94169 2.05939 -0.97125 B -0.66107 -0.17368 0.54084 H 4.94080 -0.33850 0.69129 O -1.82226 -0.73053 1.04604 O 0.66317 -0.57168 -0.74087 O -0.89341 0.68850 -0.51222 C -2.42968 0.60394 0.67540 C -2.71211 1.03778 -2.06664 C -2.89325 -0.43968 -0.41995 H -3.79677 1.11999 -2.18159 B -0.62552 -0.28083 -0.39293 H -2.25907 1.94608 -2.47032 O -1.64583 -1.12128 -0.74501 H -2.35938 0.19424 -2.65937 O -1.02888 0.82262 0.31494 C -2.65071 2.18243 0.16367 C -3.15084 1.94640 0.64033 H -2.06834 2.99791 -0.27045 H -4.21794 1.81706 0.84137 H -3.71009 2.44101 0.09323 H -2.73918 2.60204 1.41078 H -2.38365 2.09966 1.21954 H -3.03536 2.44224 -0.32317 C -3.03937 -1.60004 -0.83591 C -2.43364 0.03493 2.09770 H -3.23745 -2.49701 -0.24519 H -1.91934 0.73507 2.75917 H -3.86742 -1.45926 -1.53489 H -3.45125 -0.10555 2.46944 H -2.12500 -1.76763 -1.40888 H -1.91119 -0.92276 2.14703 C -4.17921 -0.20354 0.90799 C -3.39014 0.21644 -1.71268 H -4.99536 0.11197 0.25172 H -3.49972 -0.55448 -2.47796 H -4.46941 -1.14587 1.37826 H -4.35883 0.70131 -1.57051 H -4.05461 0.54089 1.69410 H -2.68109 0.96014 -2.08306 H 1.45909 1.96132 1.67545 512 C -3.89811 -1.47974 0.06343 H 5.51462 -1.56608 -0.62865 H -4.82874 -1.00179 0.38214 H 4.54223 -3.04959 -0.56585 H -4.13226 -2.16562 -0.75352 H 5.05664 -2.26457 0.94559 H -3.50330 -2.06644 0.89234 B -1.21026 -0.77330 0.00905 Cl 2.86076 -2.23482 0.29547 H -0.02499 -2.45386 0.03828 O -1.42780 0.58676 0.03287 11’, 3-NHBpin-N-Me-Indazole O -2.38319 -1.50289 -0.04241 C -2.84527 0.80237 -0.24466 E(RB3LYP) = -885.473191201 C -3.47992 -0.57645 0.19111 C -2.96768 1.07830 -1.74728 C -3.31360 2.01344 0.55509 C -3.81522 -0.64251 1.68590 C -4.67852 -1.02670 -0.63778 H -2.63176 0.22376 -2.33837 H -2.33830 1.93358 -2.00188 H -3.99678 1.31330 -2.02932 H -3.09269 1.90507 1.61665 H -4.39017 2.16350 0.43438 H -2.80657 2.91072 0.19287 H -4.42166 -1.13341 -1.69137 H 0.43893 1.81533 0.21240 H -5.50388 -0.31477 -0.54720 C 1.49838 1.60878 0.15919 H -5.02764 -1.99627 -0.27568 C 4.29664 1.06784 0.01667 H -2.96787 -0.32897 2.29952 C 1.95463 0.28316 0.05019 H -4.05663 -1.67522 1.94610 C 2.43185 2.63061 0.19608 H -4.67508 -0.01563 1.93418 C 3.81622 2.36056 0.12620 C 3.35027 0.03059 -0.02462 H 2.09822 3.65826 0.28269 H 4.51903 3.18574 0.16191 H 5.36030 0.86751 -0.02996 C 1.36679 -1.02845 -0.00250 N 2.29901 -1.96016 -0.09726 N 3.50565 -1.31815 -0.13403 N 0.03776 -1.44339 0.03732 C 4.72650 -2.08999 -0.08482 513 Xray structure of 7-borylated 5-bromo-1-naphthylamine (2m) Formula C16H19BBrNO2 CCDC 2062023 Dcalc./ g cm-3 1.475 /mm-1 3.591 Formula Weight 348.04 Colour colourless Shape needle Size/mm3 0.23×0.09×0.04 T/K 99.9(5) Crystal System monoclinic Space Group I2/a a/Å 17.0799(2) b/Å 6.25799(8) c/Å 29.8888(4) /° 90 /° 101.0603(12)  /° 90 V/Å3 3135.35(7) Z 8 Z' 1 Wavelength/Å 1.54184 Radiation type Cu K min/° 3.013 max/° 76.503 Measured Refl's. 17475 Indep't Refl's 3172 Refl's I≥2 (I) 3032 Rint 0.0312 Parameters 202 Restraints 0 Largest Peak 0.854 Deepest Hole -0.510 GooF 1.071 wR2 (all data) 0.0685 wR2 0.0678 R1 (all data) 0.0272 R1 0.0262 514 X-ray structure of osimertinib’s analogue (13) Formula C36H40N8 CCDC 2067392 Dcalc./ g cm-3 1.288 /mm-1 0.616 Formula Weight 584.76 Colour colourless Shape plate Size/mm3 0.25×0.23×0.06 T/K 100.01(10) Crystal System monoclinic Space Group P21/n a/Å 17.7018(2) b/Å 9.27126(10) c/Å 19.4100(2)  /° 90 /° 108.7478(14)  /° 90 V/Å3 3016.52(7) Z 4 Z' 1 Wavelength/Å 1.54184 Radiation type Cu Ka min/° 2.942 max/° 77.052 Measured Refl's. 23287 Indep't Refl's 5935 Refl's I≥2 s(I) 5229 Rint 0.0330 Parameters 399 Restraints 0 Largest Peak 0.572 Deepest Hole -0.444 GooF 1.050 wR2 (all data) 0.1124 wR2 0.1083 R1 (all data) 0.0473 R1 0.0421 515 Para CHB of 2-chloroaniline (4.2a) (DMSO-d6, 500 MHz) 516 1 H NMR of para borylated 2-chloroaniline (4.2a) (CDCl3, 500 MHz) 517 13 C NMR of para borylated 2-chloroaniline (4.2a) (CDCl3, 126 MHz) 518 11 B NMR of para borylated 2-chloroaniline (4.2a) (CDCl3, 160 MHz) 519 Para CHB of 2-chloroaniline with B2pp2 (4.2a’) (DMSO-d6, 500 MHz) 520 1 H NMR of para borylated 2-chloroaniline with B2pp2 (4.2a’) (CDCl3, 500 MHz) 521 13 C NMR of para borylated 2-chloroaniline with B2pp2 (4.2a’) (CDCl3, 126 MHz) 522 11 B NMR of para borylated 2-chloroaniline with B2pp2 (4.2a’) (CDCl3, 160 MHz) 523 Para CHB of 2-bromoaniline (4.2b) (CDCl3, 500 MHz) 524 1 H NMR of para borylated 2-bromoaniline (4.2b) (CDCl3, 500 MHz) 525 13 C NMR of para borylated 2-bromoaniline (4.2b) (CDCl3, 126 MHz) 526 11 B NMR of para borylated 2-bromoaniline (4.2b) (CDCl3, 160 MHz) 527 Para CHB of 2-iodoaniline (4.2c) (CDCl3, 500 MHz) 528 1 H NMR of para borylated 2-iodoaniline (4.2c) (CDCl3, 500 MHz) 529 13 C NMR of para borylated 2-iodoaniline (4.2c) (CDCl3, 126 MHz) 530 11 B NMR of para borylated 2-iodoaniline (4.2c) (CDCl3, 160 MHz) 531 Para CHB of 2-methoxyaniline (4.2d) (CDCl3, 500 MHz) 532 1 H NMR of para borylated 2-methoxyaniline (4.2d) (CDCl3, 500 MHz) 533 13 C NMR of para borylated 2-methoxyaniline (4.2d) (CDCl3, 126 MHz) 534 11 B NMR of para borylated 2-methoxyaniline (4.2d) (CDCl3, 160 MHz) 535 Para CHB of 2-trifluoromethylaniline (4.2e) (CDCl3, 500 MHz) 536 1 H NMR of para borylated 2-trifluoromethylaniline (4.2e) (CDCl3, 500 MHz) 537 13 C NMR of para borylated 2-trifluoromethylaniline (4.2e) (CDCl3, 126 MHz) 538 11 B NMR of para borylated 2-trifluoromethylaniline (4.2e) (CDCl3, 160 MHz) 539 19 F NMR of para borylated 2-trifluoromethylaniline (4.2e) (CDCl3, 470 MHz) 540 Para CHB of methyl 2-aminobenzoate (4.2f) (CDCl3, 500 MHz) 541 1 H NMR of para borylated methyl 2-aminobenzoate (4.2f) (CDCl3, 500 MHz) 542 13 C NMR of para borylated methyl 2-aminobenzoate (4.2f) (CDCl3, 126 MHz) 543 11 B NMR of para borylated methyl 2-aminobenzoate (4.2f) (CDCl3, 160 MHz) 544 Para CHB of 2-methylaniline (4.2g) (CDCl3, 500 MHz) 545 1 H NMR of para borylated 2-methylaniline (4.2g) (CDCl3, 500 MHz) 546 13 C NMR of para borylated 2-methylaniline (4.2g) (126 MHz, CDCl3) 547 11 B NMR of para borylated 2-methylaniline (4.2g) (160 MHz, CDCl3) 548 Para CHB of 2-ethylaniline (4.2h) (CDCl3, 500 MHz) 549 1 H NMR of para borylated 2-ethylaniline (4.2h) (CDCl3, 500 MHz) 550 13 C NMR of para borylated 2-ethylaniline (4.2h) (126 MHz, CDCl3) 551 11 B NMR of para borylated 2-ethylaniline (4.2h) (CDCl3, 160 MHz) 552 1 H NMR of meta borylated 2-ethylaniline (4.2h) (CDCl3, 500 MHz) 553 Para CHB of 2-tertbutylaniline (4.2i) (CDCl3, 500 MHz) 554 1 H NMR of para borylated 2-tertbutylaniline (4.2i) (CDCl3, 500 MHz) 555 13 C NMR of para borylated 2-tertbutylaniline (4.2i) (CDCl3, 500 MHz) 556 11 B NMR of para borylated 2-tertbutylaniline (4.2i) (CDCl3, 160 MHz) 557 1D-NOE of para borylated 2-tertbutylaniline (4.2i) (CDCl3, 500 MHz) Identification of the para isomer 558 Para CHB of 4-aminoindan (4.2j) (CDCl3, 500 MHz) 559 1 H NMR of para borylated 4-aminoindan (4.2j) (CDCl3, 500 MHz) 560 13 C NMR of para borylated 4-aminoindan (4.2j) (126 MHz, CDCl3) 561 11 B NMR of para borylated 4-aminoindan (4.2j) (CDCl3, 160 MHz) 562 1D-NOE of para borylated 4-aminoindan (4.2j) (CDCl3, 500 MHz) Identification of the meta isomer 563 Para borylation of 2-bromo-3-fluoroaniline (4.2k) (CDCl3, 500 MHz) 564 1 H NMR of para borylated 2-bromo-3-fluoroaniline (4.2k) (CDCl3, 500 MHz) 565 19 F NMR of para borylated 2-bromo-3-fluoroaniline (4.2k) (CDCl3, 470 MHz) 566 13 C NMR of para borylated 2-bromo-3-fluoroaniline (4.2k) (CDCl3, 126 MHz) 567 11 B NMR of para borylated 2-bromo-3-fluoroaniline (4.2k) (CDCl3, 126 MHz) 568 19 F NMR of para borylation of 2,4-difluoroaniline (4.2l) (C6D6, 470 MHz) 569 1 H NMR of para borylated 2,4-difluoroaniline (4.2l) (C6D6, 500 MHz) 570 19 F NMR of para borylated 2,4-difluoroaniline (4.2l) (C6D6, 470 MHz) 571 13 C NMR of para borylated 2,4-difluoroaniline (4.2l) (C6D6, 126 MHz) 572 11 B NMR of para borylated 2,4-difluoroaniline (4.2l) (C6D6, 126 MHz) 573 Para CHB of 7-borylated 5-bromo-1-naphthylamine (4.2m) (CDCl3, 500 MHz) 574 1 H NMR of 7-borylated 5-bromo-1-naphtylamine (4.2m) (CDCl3, 500 MHz) 575 13 C NMR of 7-borylated 5-bromo-1-naphtylamine (4.2m) (CDCl3, 126 MHz) 576 11 B NMR of 7-borylated 5-bromo-1-naphtylamine (4.2m) (CDCl3, 160 MHz) 577 gCOSY of 7-borylated 5-bromo-1-naphtylamine (4.2m) (CDCl3, 500 MHz) 578 gHSQCAD of 7-borylated 5-bromo-1-naphtylamine (4.2m) (CDCl3, 500 MHz) 579 gHMBCAD of 7-borylated 5-bromo-1-naphtylamine (4.2m) (CDCl3, 500 MHz, Jnxh = 5 Hz) 580 C7 CHB of 5-hydroxy-1-naphthylamine (4.2n) (DMSO-d6, 500 MHz) 581 1 H NMR of 7-borylated 5-hydroxy-1-naphthylamine (4.2n) (DMSO-d6, 500 MHz) 582 13 C NMR of 7-borylated 5-hydroxy-1-naphthylamine (4.2n) (DMSO-d6, 126 MHz) 583 11 B NMR of 7-borylated 5-hydroxy-1-naphthylamine (4.2n) (DMSO-d6, 160 MHz) 584 gCOSY of 7-borylated 5-hydroxy-1-naphthylamine (4.2n) (DMSO-d6, 500 MHz) 585 HSQCAD NMR of 7-borylated 5-hydroxy-1-naphthylamine (4.2n) (DMSO-d6, 500 MHz) 586 gHMBCAD NMR of 7-borylated 5-hydroxy-1-naphthylamine (4.2n) (DMSO-d6, 500 MHz) 587 1 H NMR of 7-borylated and 3,7-diborylated 5-hydroxy-1-naphthylamine (4.2n) (DMSO-d6, 500 MHz) 588 Unselective Borylation of 2-chloro-N-methylaniline (4.4a) (CDCl3, 500 MHz) 589 1 H NMR of para and meta borylated 2-chloro-N-methylaniline (4.4a) (CDCl3, 500 MHz) 590 13 C NMR of para and meta borylated 2-chloro-N-methylaniline (4.4a) (CDCl3, 126 MHz) 591 11 B NMR of para and meta borylated 2-chloro-N-methylaniline (4.4a) (CDCl3, 126 MHz) 592 1 H NMR of para borylated 2-chloro-N-methylaniline (4.4a) (CDCl3, 500 MHz) 593 1 H NMR of meta borylated 2-chloro-N-methylaniline (4.4a) (CDCl3, 500 MHz) 594 13 C NMR of meta borylated 2-chloro-N-methylaniline (4.4a) (CDCl3, 126 MHz) 595 11 B NMR of meta borylated 2-chloro-N-methylaniline (4.4a) (CDCl3, 126 MHz) 596 1D-NOE of meta borylated 2-chloro-N-methylaniline (4.4a) (CDCl3, 500 MHz) 597 Para CHB of 2-amino-N-methylpyridine (4.4b) (CDCl3, 500 MHz) 598 1 H NMR of para borylated 2-amino-N-methylpyridine (4.4b) (CDCl3, 500 MHz) 599 13 C NMR of para borylated 2-amino-N-methylpyridine (4.4b) (CDCl3, 126 MHz) 600 11 B NMR of para borylated 2-amino-N-methylpyridine (4.4b) (CDCl3, 160 MHz) 601 1D-NOE of para borylated 2-amino-N-methylpyridine (4.4b) (CDCl3, 500 MHz) 602 Para CHB of 2-amino-N-ethylpyridine (4.4c) (CDCl3, 500 MHz) 603 1 H NMR of para borylated 2-amino-N-ethylpyridine (4.4c) (CDCl3, 500 MHz) 604 13 C NMR of para borylated 2-amino-N-ethylpyridine (4.4c) (CDCl3, 126 MHz) 605 11 B NMR of para borylated 2-amino-N-ethylpyridine (4.4c) (CDCl3, 160 MHz) 606 1D-NOE of para borylated 2-amino-N-ethylpyridine (4.4c) (CDCl3, 500 MHz) 607 Para CHB of 1,2,3,4-tetrahydroquinoline (4.4d) (DMSO-d6, 500 MHz) 608 1 H NMR of para borylated 1,2,3,4-tetrahydroquinoline (4.4d) (CDCl3, 500 MHz) 609 13 C NMR of para borylated 1,2,3,4-tetrahydroquinoline (4.4d) (CDCl3, 126 MHz) 610 11 B NMR of para borylated 1,2,3,4-tetrahydroquinoline (4.4d) (CDCl3, 126 MHz) 611 1 H NMR of meta borylated 1,2,3,4-tetrahydroquinoline (4.4d) (CDCl3, 500 MHz) 612 13 C NMR of meta borylated 1,2,3,4-tetrahydroquinoline (4.4d) (CDCl3, 126 MHz) 613 11 B NMR of meta borylated 1,2,3,4-tetrahydroquinoline (4.4d) (CDCl3, 126 MHz) 614 Para CHB of 4-methyl-1,2,3,4-tetrahydroquinoline (4.4e) (CDCl3, 500 MHz) 615 1 H NMR of para borylated 4-methyl-1,2,3,4-tetrahydroquinoline (4.4e) (CDCl3, 500 MHz) 616 13 C NMR of para borylated 4-methyl-1,2,3,4-tetrahydroquinoline (4.4e) (CDCl3, 126 MHz) 617 11 B NMR of para borylated 4-methyl-1,2,3,4-tetrahydroquinoline (4.4e) (CDCl3, 160 MHz) 618 1D-NOE of 1H NMR of para borylated 4-methyl-1,2,3,4-tetrahydroquinoline (4.4e) (CDCl3, 500 MHz) 619 1 H NMR of para borylated 4-methyl-1,2,3,4-tetrahydroquinoline, second fraction (4.4e) (CDCl3, 500 MHz) 620 11 B NMR of para borylated 4-methyl-1,2,3,4-tetrahydroquinoline, second fraction (4.4e) (CDCl3, 160 MHz) 621 Para CHB of 2-methyl-1,2,3,4-tetrahydroquinoline (4.4f) (CDCl3, 500 MHz) 622 1 H NMR of para borylated 2-methyl-1,2,3,4-tetrahydroquinoline (4.4f) (C6D6, 500 MHz) 623 1 H NMR of para borylated 2-methyl-1,2,3,4-tetrahydroquinoline (4.4f) (CDCl3, 500 MHz) 624 13 C NMR of para borylated 2-methyl-1,2,3,4-tetrahydroquinoline (4.4f) (C6D6, 126 MHz) 625 11 B NMR of para borylated 2-methyl-1,2,3,4-tetrahydroquinoline (4.4f) (C6D6, 160 MHz) 626 1D-NOE of para borylated 2-methyl-1,2,3,4-tetrahydroquinoline (4.4f) (C6D6, 500 MHz) 627 1 H NMR of para and meta borylated 2-methyl-1,2,3,4-tetrahydroquinoline, second fraction (4.4f) (C6D6, 500 MHz) 628 13 C NMR of para and meta borylated 2-methyl-1,2,3,4-tetrahydroquinoline, second fraction (4.4f) (C6D6, 126 MHz) 629 11 B NMR of para and meta borylated 2-methyl-1,2,3,4-tetrahydroquinoline, second fraction (4.4f) (C6D6, 160 MHz) 630 Para Borylation of 2,3,4,5-tetrahydro-1H-benzo[b]azepine (4.4g) (CDCl3, 500 MHz) 631 1 H NMR of para borylated 2,3,4,5-tetrahydro-1H-benzo[b]azepine (4.4g) (CDCl3, 500 MHz) 632 13 C NMR of para borylated 2,3,4,5-tetrahydro-1H-benzo[b]azepine (4.4g) (CDCl3, 126 MHz) 633 11 B NMR of para borylated 2,3,4,5-tetrahydro-1H-benzo[b]azepine (4.4g) (CDCl3, 160 MHz) 634 gCOSY of para borylated 2,3,4,5-tetrahydro-1H-benzo[b]azepine (4.4g) (CDCl3, 500 MHz) 1D-NOE of para borylated 2,3,4,5-tetrahydro-1H-benzo[b]azepine (CDCl3, 500 MHz) 635 1 H NMR of para and meta borylated 2,3,4,5-tetrahydro-1H-benzo[b]azepine, second fraction (4.4g) (CDCl3, 500 MHz) 636 13 C NMR of para and meta borylated 2,3,4,5-tetrahydro-1H-benzo[b]azepine, second fraction (4.4g) (CDCl3, 126 MHz) 637 11 B NMR of para and meta borylated 2,3,4,5-tetrahydro-1H-benzo[b]azepine, second fraction (4.4g) (CDCl3, 160 MHz) 638 Para CHB of 3,4-dihydro-2H-benzo[b][1,4]oxazine (4.4h) (CDCl3, 500 MHz) 639 1 H NMR of para borylated 3,4-dihydro-2H-benzo[b][1,4]oxazine (4.4h) (CDCl3, 500 MHz) 640 1 H NMR of para borylated 3,4-dihydro-2H-benzo[b][1,4]oxazine (4.4h) (C6D6, 500 MHz) 641 1 H NMR of para borylated 3,4-dihydro-2H-benzo[b][1,4]oxazine (4.4h) (CDCl3, 500 MHz) 642 13 C NMR of para borylated 3,4-dihydro-2H-benzo[b][1,4]oxazine (4.4h) (C6D6, 126 MHz) 643 11 B NMR of para borylated 3,4-dihydro-2H-benzo[b][1,4]oxazine (4.4h) (C6D6, 126 MHz) 644 1 H NMR of 8-borylated 2-amino-N-methylpyridine (4.4h) (C6D6, 500 MHz) 645 13 C NMR of 8-borylated 2-amino-N-methylpyridine (4.4h) (C6D6, 126 MHz) 646 11 B NMR of 8-borylated 2-amino-N-methylpyridine (4.4h) (C6D6, 126 MHz) 647 Para CHB of 8-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazine (4.4i) (CDCl3, 500 MHz) 648 1 H NMR of para borylated 8-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazine (4.4i) (CDCl3, 500 MHz) 649 13 C NMR of para borylated 8-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazine (4.4i) (CDCl3, 126 MHz) 650 11 B NMR of para borylated 8-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazine (4.4i) (CDCl3, 126 MHz) 651 19 F NMR of para borylated 8-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazine (4.4i) (CDCl3, 126 MHz) 652 Para Borylation of 1,2,3,4-tetrahydroquinoline (4.4j) (DMSO-d6, 500 MHz) 653 1 H NMR of para diborylated 10H-phenoxazine (4.4j) (CDCl3, 500 MHz) 654 13 C NMR of para diborylated 10H-phenoxazine (4.4j) (CDCl3, 126 MHz) 655 11 B NMR of para diborylated 10H-phenoxazine (4.4j) (CDCl3, 126 MHz) 656 C5 CHB of 5-borylated 3-methyl indole (4.6a) (CDCl3, 500 MHz) 657 1 H NMR of 5-borylated 3-methyl indole (4.6a) (CDCl3, 500 MHz) 658 13 C NMR of 5-borylated 3-methyl indole (4.6a) (CDCl3, 126 MHz) 659 11 B NMR of 5-borylated 3-methyl indole (4.6a) (CDCl3, 160 MHz) 660 C5 CHB of 5-borylated methyl indole-3-carboxylate (4.6b) (DMSO-d6, 500 MHz) 661 1 H NMR of 5- and 6-borylated methyl indole-3-carboxylate (4.6b) (CDCl3, 500 MHz) 662 1 H NMR of 5- and 6-borylated methyl indole-3-carboxylate (4.6b) (DMSO-d6, 500 MHz) 663 13 C NMR of 5- and 6-borylated methyl indole-3-carboxylate (4.6b) (CDCl3, 126 MHz) 664 11 B NMR of 5- and 6-borylated methyl indole-3-carboxylate (4.6b) (CDCl3, 160 MHz) 665 C5 CHB of 2,3-dimethyl indole (4.6c) (C6D6, 500 MHz) 666 1 H NMR of C5 and C6 borylated 2,3-dimethyl indole, first fraction (4.6c) (C6D6, 500 MHz) 667 1 H NMR of C5 borylated 2,3-dimethyl indole (4.6c) (C6D6, 500 MHz) 668 13 C NMR of C5 borylated 2,3-dimethyl indole (4.6c) (C6D6, 126 MHz) 669 11 B NMR of C5 borylated 2,3-dimethyl indole (4.6c) (C6D6, 126 MHz) 670 5 CHB of 2,3,4,9-tetrahydro-1H-carbazole (4.6d) (acetone-d6, 500 MHz) 671 1 H NMR of 5-borylated 2,3,4,9-tetrahydro-1H-carbazole (4.6d) (C6D6, 500 MHz) 672 13 C NMR of 5-borylated 2,3,4,9-tetrahydro-1H-carbazole (4.6d) (C6D6, 126 MHz) 673 11 B NMR of 5-borylated 2,3,4,9-tetrahydro-1H-carbazole (4.6d) (C6D6, 126 MHz) 674 1 H NMR of 5-borylated 2,3,4,9-tetrahydro-1H-carbazole by Miyaura Borylation (4.6d) (C6D6, 500 MHz) 675 13 C NMR of 5-borylated 2,3,4,9-tetrahydro-1H-carbazole by Miyaura Borylation (4.6d) (C6D6, 126 MHz) 676 11 B NMR of 5-borylated 2,3,4,9-tetrahydro-1H-carbazole by Miyaura Borylation (4.6d) (C6D6, 126 MHz) 677 1 H NMR of 4-Methylnaphthalene-1-boronic acid, pinacol ester (4.7b) (CDCl3, 500 MHz) 678 13 C NMR of 4-Methylnaphthalene-1-boronic acid, pinacol ester (4.7b) (CDCl3, 126 MHz) 679 11 B NMR of 4-Methylnaphthalene-1-boronic acid, pinacol ester (4.7b) (CDCl3, 160 MHz) 680 1 H NMR of 4-bromonaphthalene-1-boronic acid, pinacol ester (4.7c) (CDCl3, 500 MHz) 681 13 C NMR of 4-bromonaphthalene-1-boronic acid, pinacol ester (4.7c) (CDCl3, 126 MHz) 682 11 B NMR of 4-bromonaphthalene-1-boronic acid, pinacol ester (4.7c) (CDCl3, 160 MHz) 683 1 H NMR of methyl 4-(4,4’,5,5’-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-naphthoate (4.7d) (CDCl3, 500 MHz) 684 13 C NMR of methyl 4-(4,4’,5,5’-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-naphthoate (4.7d) (CDCl3, 126 MHz) 685 11 B NMR of methyl 4-(4,4’,5,5’-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-naphthoate (4.7d) (CDCl3, 160 MHz) 686 1 H NMR of 2-methoxynaphthalene-1-boronic acid, pinacol ester (4.7e) (CDCl3, 500 MHz) 687 13 C NMR of 2-methoxynaphthalene-1-boronic acid, pinacol ester (4.7e) (CDCl3, 126 MHz) 688 11 B NMR of 2-methoxynaphthalene-1-boronic acid, pinacol ester (4.7e) (CDCl3, 160 MHz) 689 1 H NMR of 2-methylnaphthalene-1-boronic acid, pinacol ester (4.7f) (CDCl3, 500 MHz) 690 13 C NMR of 2-methylnaphthalene-1-boronic acid, pinacol ester (4.7f) (CDCl3, 126 MHz) 691 11 B NMR of 2-methylnaphthalene-1-boronic acid, pinacol ester (4.7f) (CDCl3, 160 MHz) 692 1 H NMR of acenaphthene-5-boronic acid, pinacol ester (4.7g) (CDCl3, 500 MHz) 693 13 C NMR of acenaphthene-5-boronic acid, pinacol ester (4.7g) (CDCl3, 126 MHz) 694 11 B NMR of acenaphthene-5-boronic acid, pinacol ester (4.7g) (CDCl3, 160 MHz) 695 1 H NMR of anthracene-9-boronic acid, pinacol ester (4.7h) (CDCl3, 500 MHz) 696 13 C NMR of anthracene-9-boronic acid, pinacol ester (4.7h) (CDCl3, 126 MHz) 697 11 B NMR of anthracene-9-boronic acid, pinacol ester (4.7h) (CDCl3, 160 MHz) 698 C6 Borylation of 4-methoxy-1-naphthalene boronic acid, pinacol ester (4.8a) (CDCl3, 500 MHz) 699 1 H NMR of 4-methoxy-1,6-naphthalenediboronic acid bis(pinacol) ester (4.8a) (CDCl3, 500 MHz) 700 13 C NMR of 4-methoxy-1,6-naphthalenediboronic acid bis(pinacol) ester (4.8a) (CDCl3, 126 MHz) 701 11 B NMR of 4-methoxy-1,6-naphthalenediboronic acid bis(pinacol) ester (4.8a) (CDCl3, 126 MHz) 702 C6 Borylation of 4-methylnaphthalene-1-boronic acid, pinacol ester (4.8b) (CDCl3, 126 MHz) 703 1 H NMR of 4-methyl-1,6-naphthalenediboronic acid bis(pinacol) ester (4.8b) (CDCl3, 500 MHz) 704 13 C NMR of 4-methyl-1,6-naphthalenediboronic acid bis(pinacol) ester (4.8b) (CDCl3, 126 MHz) 705 11 B NMR of 4-methyl-1,6-naphthalenediboronic acid bis(pinacol) ester (4.8b) (CDCl3, 160 MHz) 706 C6 Borylation of 4-bromonaphthalene-1-boronic acid, pinacol ester (4.8c) (CDCl3, 126 MHz) 707 1 H NMR of 4-bromo-1,6-naphthalenediboronic acid bis(pinacol) ester (4.8c) (CDCl3, 500 MHz) 708 1 H NMR of 4-bromo-1,6-naphthalenediboronic acid bis(pinacol) ester (4.8c) (C6D6, 500 MHz) 709 13 C NMR of 4-bromo-1,6-naphthalenediboronic acid bis(pinacol) ester (4.8c) (CDCl3, 126 MHz) 710 11 B NMR of 4-bromo-1,6-naphthalenediboronic acid bis(pinacol) ester (4.8c) (CDCl3, 160 MHz) 711 1D-NOE of 4-bromo-1,6-naphthalenediboronic acid bis(pinacol) ester (4.8c) (C6D6, 500 MHz) Identification of the C6 isomer 712 C6 Borylation of methyl 4-naphthoate-1-boronic acid, pinacol ester (4.8d) (CDCl3, 500 MHz) 713 1 H NMR of methyl 4-naphthoate-1,6-diboronic acid bis(pinacol) ester (4.8d) (CDCl3, 500 MHz) 714 13 C NMR of methyl 4-naphthoate-1,6-diboronic acid bis(pinacol) ester (4.8d) (CDCl3, 126 MHz) 715 11 B NMR of methyl 4-naphthoate-1,6-diboronic acid bis(pinacol) ester (4.8d) (CDCl3, 160 MHz) 716 6-Borylation of 2-methoxynaphthalene-1-boronic acid, pinacol ester (4.8e) (CDCl3, 126 MHz) 717 1 H NMR of 2-methoxy-1,6-naphthalenediboronic acid bis(pinacol) ester (4.8e) (CDCl3, 500 MHz) 718 1 H NMR of 2-methoxy-1,6-naphthalenediboronic acid bis(pinacol) ester (4.8e) (C6D6, 500 MHz) 719 13 C NMR of 2-methoxy-1,6-naphthalenediboronic acid bis(pinacol) ester (4.8e) (CDCl3, 126 MHz) 720 11 B NMR of 2-methoxy-1,6-naphthalenediboronic acid bis(pinacol) ester (4.8e) (CDCl3, 160 MHz) 721 6-Borylation of 2-methylnaphthalene-1-boronic acid, pinacol ester (4.8f) (CDCl3, 126 MHz) 722 1 H NMR of 2-methyl-1,6-naphthalenediboronic acid bis(pinacol) ester (4.8f) (CDCl3, 500 MHz) 723 1 H NMR of 2-methyl-1,6-naphthalenediboronic acid bis(pinacol) ester (4.8f) (C6D6, 500 MHz) 724 13 C NMR of 2-methyl-1,6-naphthalenediboronic acid bis(pinacol) ester (4.8f) (C6D6, 126 MHz) 725 11 B NMR of 2-methyl-1,6-naphthalenediboronic acid bis(pinacol) ester (4.8f) (C6D6, 160 MHz) 726 C3 & C8 Borylation of acenaphthene-5-boronic acid, pinacol ester (4.8g) (CDCl3, 500 MHz) 727 1 H NMR of 3,5 and 3,6-acenaphthenediboronic acid bis(pinacol) ester (4.8g) (CDCl3, 500 MHz) 728 gCOSY of 3,5 and 3,6-acenaphthenediboronic acid bis(pinacol) ester (4.8g) (CDCl3, 500 MHz) 729 C3/C8 & C3/C7 Diborylation of acenaphthene-5-boronic acid, pinacol ester (4.8g) (CDCl3, 500 MHz) 730 1 H NMR of 3,5,8-acenaphthenetriboronic acid bis(pinacol) ester (4.8g) (CDCl3, 500 MHz) 731 13 C NMR of 3,5,8-acenaphthenetriboronic acid bis(pinacol) ester (4.8g) (CDCl3, 126 MHz) 732 11 B NMR of 3,5,8-acenaphthenetriboronic acid bis(pinacol) ester (4.8g) (CDCl3, 160 MHz) 733 C3/C6 Diborylation of anthracene-9-boronic acid, pinacol ester (4.8h) (CDCl3, 500 MHz) 734 1 H NMR of 3,6,9-/2,6,9-/2,7,9-anthracenetriboronic acid bis(pinacol) ester (4.8h) (CDCl3, 500 MHz) 735 13 C NMR of 3,6,9-/2,6,9-/2,7,9-anthracenetriboronic acid bis(pinacol) ester (4.8h) (CDCl3, 126 MHz) 736 11 B NMR of 3,6,9-/2,6,9-/2,7,9-anthracenetriboronic acid bis(pinacol) ester (4.8h) (CDCl3, 160 MHz) 737 C6 Silylation of 2-(4-methoxynaphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (4.9 & 4.10) (CDCl3, 500 MHz) 738 1 H NMR of 6-Silylated 2-(4-methoxynaphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (4.9 & 4.10) (CDCl3, 500 MHz) 739 13 C NMR of 6-Silylated 2-(4-methoxynaphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (4.9 & 4.10) (CDCl3, 126 MHz) 740 29 Si NMR of 6-Silylated 2-(4-methoxynaphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (4.9 & 4.10) (CDCl3, 99 MHz) 741 11 B NMR of 6-Silylated 2-(4-methoxynaphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (4.9 & 4.10) (CDCl3, 160 MHz) 742 gCOSY of 6-Silylated 2-(4-methoxynaphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (4.9 & 4.10) (CDCl3, 500 MHz) 743 gHSQCAD of 6-Silylated 2-(4-methoxynaphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (4.9 & 4.10) (CDCl3, 500 MHz) 744 gHMBCAD of 6-Silylated 2-(4-methoxynaphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (4.9 & 4.10) (CDCl3, 500 MHz) 745 NOE of 6-Silylated 2-(4-methoxynaphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (4.9 & 4.10) (CDCl3, 500 MHz) 746 CHB of 2-chlorophenol (4.2p) (CDCl3, 500 MHz) 747 1 H NMR of para and meta borylated 2-chlorophenol (4.2p) (CDCl3, 500 MHz) 748 13 C NMR of para and meta borylated 2-chlorophenol (4.2p) (CDCl3, 126 MHz) 749 11 B NMR of para and meta borylated 2-chlorophenol (4.2p) (CDCl3, 160 MHz) 750 CHB borylation of 2-methyl-1-naphthylamine (4.2o) (CDCl3, 500 MHz) 751 1 H NMR of 6- and 7-borylated 2-methyl-1-naphthylamine (4.2o) (C6D6, 500 MHz) 752 13 C NMR of 6- and 7-borylated 2-methyl-1-naphthylamine (4.2o) (C6D6, 126 MHz)\ 753 11 B NMR of 6- and 7-borylated 2-methyl-1-naphthylamine (4.2o) (C6D6, 160 MHz) 754 1 H NMR of N-Bpin borylated 2-chloroaniline (4.1a’) (CDCl3, 500 MHz) 755 13 C NMR of N-Bpin borylated 2-chloroaniline (4.1a’) (CDCl3, 126 MHz) 756 11 B NMR of N-Bpin borylated 2-chloroaniline (4.1a’) (CDCl3, 160 MHz) 757 1 H NMR of N-Bpp borylated 2-chloroaniline (C6D6, 500 MHz) 758 13 C NMR of N-Bpp borylated 2-chloroaniline (C6D6, 126 MHz) 759 11 B NMR of N-Bpp borylated 2-chloroaniline (C6D6, 160 MHz) 760 1 H NMR of N-BBN borylated 2-chloroaniline (C6D6, 500 MHz) 761 11 B NMR of N-BBN borylated 2-chloroaniline (C6D6, 160 MHz) 762 1 H NMR of N-Bpin borylated 2-methylaniline (4.1g’) (CDCl3, 500 MHz) 763 13 C NMR of N-Bpin borylated 2-methylaniline (4.1g’) (C6D6, 126 MHz) 764 11 B NMR of N-Bpin borylated 2-methylniline (4.1g’) (CDCl3, 160 MHz) 765 1 H NMR of N-Bpp borylated 2-methylaniline (C6D6, 500 MHz) 766 13 C NMR of N-Bpp borylated 2-methylaniline (C6D6, 126 MHz) 767 11 B NMR of N-Bpp borylated 2-methylaniline (C6D6, 160 MHz) 768 1 H NMR of N-Bpin borylated 2-tertbutylaniline (4.1i’) (THF-d8, 500 MHz) 769 13 C NMR of N-Bpin borylated 2-tertbutylaniline (4.1i’) (THF-d8, 126 MHz) 770 11 B NMR of N-Bpin borylated 2-tertbutylaniline (4.1i’) (THF-d8, 160 MHz) 771 1 H NMR of N-Bpin borylated 5-bromo-1-aminonaphthalene (4.1m’) (CDCl3, 500 MHz) 772 13 C NMR of N-Bpin borylated 5-bromo-1-aminonaphthalene (4.1m’) (CDCl3, 126 MHz) 773 11 B NMR of N-Bpin borylated 5-bromo-1-aminonaphthalene (4.1m’) (CDCl3, 160 MHz) 774 1 H NMR of N-Bpin borylated 2-amino-N-methylpyridine (4.3b’) (CDCl3, 500 MHz) 775 13 C NMR of N-Bpin borylated 2-amino-N-methylpyridine (4.3b’) (CDCl3, 126 MHz) 776 11 B NMR of N-Bpin borylated 2-amino-N-methylpyridine (4.3b’) (CDCl3, 160 MHz) 777 1 H NMR of N-Bpin borylated Tetrahydroquinoline (4.3d’) (CDCl3, 500 MHz) 778 13 C NMR of N-Bpin borylated Tetrahydroquinoline (4.3d’) (CDCl3, 126 MHz) 779 11 B NMR of N-Bpin borylated Tetrahydroquinoline (4.3d’) (CDCl3, 160 MHz) 780 1 H NMR of N-Bpin borylated 3-methyl indole (4.5a’) (CDCl3, 500 MHz) 781 13 C NMR of N-Bpin borylated 3-methyl indole (4.5a’) (CDCl3, 126 MHz) 782 11 B NMR of N-Bpin borylated 3-methyl indole (4.5a’) (CDCl3, 160 MHz) 783 1 H NMR of N-Bpin borylated 1-amino-2-methylnaphthalene (4.1o’) (CDCl3, 500 MHz) 784 13 C NMR of N-Bpin borylated 1-amino-2-methylnaphthalen (4.1o’) (CDCl3, 126 MHz) 785 11 B NMR of N-Bpin borylated 1-amino-2-methylnaphthalen (4.1o’) (CDCl3, 160 MHz) 786 1 H NMR of N-Bpin borylated 2-chloro-N-methylaniline (4.3a’) (CDCl3, 500 MHz) 787 13 C NMR of N-Bpin borylated 2-chloro-N-methylaniline (4.3a’) (CDCl3, 126 MHz) 788 11 B NMR of N-Bpin borylated 2-chloro-N-methylaniline (4.3a’) (CDCl3, 160 MHz) 789 1 H NMR of O-Bpin borylated 2-chlorophenol (4.1p’) (CDCl3, 500 MHz) 790 13 C NMR of O-Bpin borylated 2-chlorophenol (4.1p’) (CDCl3, 126 MHz) 791 11 B NMR of O-Bpin borylated 2-chlorophenol (4.1p’) (CDCl3, 160 MHz) 792 C6 CHB of 3-amino-N-methyl indazole (4.12) (CDCl3, 500 MHz) 793 1 H NMR of C6-borylated 3-amino-N-methyl indazole (4.12) (CDCl3, 500 MHz) 794 13 C NMR of C6-borylated 3-amino-N-methyl indazole (4.12) (CDCl3, 126 MHz) 795 11 B NMR of C6-borylated 3-amino-N-methyl indazole (4.12) (CDCl3, 160 MHz) 796 1D-NOE of C6-borylated 3-amino-N-methyl indazole (4.12) (CDCl3, 500 MHz) 797 1 H NMR of Osimertinib’s Analogue 4.13 (CDCl3, 500 MHz) 798 13 C NMR of Osimertinib’s Analogue 4.13 (CDCl3, 126 MHz) 799 C6 CHB of Osimertinib’s Analogue 4.14 (CDCl3, 500 MHz) 800 1 H NMR of 6-borylated Osimertinib’s Analogue 4.14 (CDCl3, 500 MHz) 801 13 C NMR of 6-borylated Osimertinib’s Analogue 4.14 (CDCl3, 126 MHz) 802 11 B NMR of 6-borylated Osimertinib’s Analogue 4.14 (CDCl3, 126 MHz) 803 REFERENCES 804 REFERENCES (1) Boerner, L. K. C–H Bond Breakers Seek Smarter Tools. Chemical & Engineering News. February 23, 2021. https://doi.org/10.47287/cen-09908-cover. (2) Rej, S.; Das, A.; Chatani, N. Strategic Evolution in Transition Metal-Catalyzed Directed C– H Bond Activation and Future Directions. Coord. Chem. Rev. 2021, 431, 213683. (3) Mahmudov, K. T.; Gurbanov, A. V.; da Silva, M. F. C. G.; Pombeiro, A. J. L. CHAPTER 1 Noncovalent Interactions in C–H Bond Functionalization. In Noncovalent Interactions in Catalysis; Royal Society of Chemistry, 2019; pp 1–25. (4) Haldar, C.; Hoque, E.; Bisht, R.; Chattopadhyay, B. Concept of Ir-Catalyzed CH Bond Activation/Borylation by Noncovalent Interaction. Tetrahedron Lett. 2018, 59, 1269–1277. (5) Kuninobu, Y.; Torigoe, T. Recent Progress of Transition Metal-Catalysed Regioselective C– H Transformations Based on Noncovalent Interactions. Org. Biomol. Chem. 2020, 18, 4126– 4134. (6) Trouvé, J.; Gramage-Doria, R. Beyond Hydrogen Bonding: Recent Trends of Outer Sphere Interactions in Transition Metal Catalysis. Chem. Soc. Rev. 2021, 50, 3565–3584. (7) Pandit, S.; Maiti, S.; Maiti, D. Noncovalent Interactions in Ir-Catalyzed Remote C-H Borylation: A Recent Update. Org. Chem. Front. 2021. https://doi.org/10.1039/D1QO00452B. (8) Genov, G. R.; Mihai, M. T.; Phipps, R. J. Harnessing Non‐covalent Interactions for Distal C(Sp2)–H Functionalization of Arenes. In Remote C–H Bond Functionalizations; Wiley, 2021; pp 169–189. (9) Dutta, U.; Maiti, D. Transition Metal Catalyzed Distal Para‐selective C–H Functionalization. In Remote C–H Bond Functionalizations; Wiley, 2021; pp 221–251. (10) Dutta, U.; Maiti, S.; Bhattacharya, T.; Maiti, D. Arene Diversification through Distal C(Sp2)−H Functionalization. Science 2021, 372. https://doi.org/10.1126/science.abd5992. (11) Mihai, M. T.; Phipps, R. J. Ion-Pair-Directed Meta-Selective C–H Borylation of Aromatic Quaternary Ammonium Salts. Synlett 2017, 28, 1011–1017. (12) Yang, L.; Semba, K.; Nakao, Y. Para-Selective C-H Borylation of (Hetero)Arenes by Cooperative Iridium/Aluminum Catalysis. Angew. Chem. Int. Ed. 2017, 56, 4853–4857. (13) Okumura, S.; Tang, S.; Saito, T.; Semba, K.; Sakaki, S.; Nakao, Y. Para-Selective Alkylation of Benzamides and Aromatic Ketones by Cooperative Nickel/Aluminum Catalysis. J. Am. Chem. Soc. 2016, 138, 14699–14704. (14) Nakao, Y.; Okumura, S.; Ebara, T.; Semba, K. Synthesis of N-Heterocyclic Carbene Ligands for Site-Selective C-H Alkylation by Cooperative Nickel/Aluminum Catalysis. Heterocycles 2019, 99, 1128. 805 (15) Okumura, S.; Nakao, Y. Para-Selective Alkylation of Sulfonylarenes by Cooperative Nickel/Aluminum Catalysis. Org. Lett. 2017, 19, 584–587. (16) Iverson, C. N.; Smith, M. R., III. Stoichiometric and Catalytic B−C Bond Formation from Unactivated Hydrocarbons and Boranes. J. Am. Chem. Soc. 1999, 121, 7696–7697. (17) Cho, J.-Y.; Tse, M. K.; Holmes, D.; Maleczka, R. E., Jr; Smith, M. R., III. Remarkably Selective Iridium Catalysts for the Elaboration of Aromatic C-H Bonds. Science 2002, 295, 305–308. (18) Mkhalid, I. A. I.; Barnard, J. H.; Marder, T. B.; Murphy, J. M.; Hartwig, J. F. C-H Activation for the Construction of C-B Bonds. Chem. Rev. 2010, 110, 890–931. (19) Ros, A.; Fernández, R.; Lassaletta, J. M. Functional Group Directed C–H Borylation. Chem. Soc. Rev. 2014, 43, 3229–3243. (20) Preshlock, S. M.; Plattner, D. L.; Maligres, P. E.; Krska, S. W.; Maleczka, R. E., Jr; Smith, M. R., III. A Traceless Directing Group for C-H Borylation. Angew. Chem. Int. Ed. 2013, 52, 12915–12919. (21) Mihai, M. T.; Williams, B. D.; Phipps, R. J. Para-Selective C-H Borylation of Common Arene Building Blocks Enabled by Ion-Pairing with a Bulky Countercation. J. Am. Chem. Soc. 2019, 141, 15477–15482. (22) Montero Bastidas, J. R.; Oleskey, T. J.; Miller, S. L.; Smith, M. R., III; Maleczka, R. E., Jr. Para-Selective, Iridium-Catalyzed C-H Borylations of Sulfated Phenols, Benzyl Alcohols, and Anilines Directed by Ion-Pair Electrostatic Interactions. J. Am. Chem. Soc. 2019, 141, 15483–15487. (23) Chotana, G. A.; Rak, M. A.; Smith, M. R., III. Sterically Directed Functionalization of Aromatic C−H Bonds: Selective Borylation Ortho to Cyano Groups in Arenes and Heterocycles. J. Am. Chem. Soc. 2005, 127, 10539–10544. (24) Tajuddin, H.; Harrisson, P.; Bitterlich, B.; Collings, J. C.; Sim, N.; Batsanov, A. S.; Cheung, M. S.; Kawamorita, S.; Maxwell, A. C.; Shukla, L.; Morris, J.; Lin, Z.; Marder, T. B.; Steel, P. G. Iridium-Catalyzed C–H Borylation of Quinolines and Unsymmetrical 1,2-Disubstituted Benzenes: Insights into Steric and Electronic Effects on Selectivity. Chem. Sci. 2012, 3, 3505. (25) Miller, S. L.; Chotana, G. A.; Fritz, J. A.; Chattopadhyay, B.; Maleczka, R. E., Jr; Smith, M. R., III. C-H Borylation Catalysts That Distinguish Between Similarly Sized Substituents Like Fluorine and Hydrogen. Org. Lett. 2019, 21, 6388–6392. (26) Hoque, M. E.; Bisht, R.; Haldar, C.; Chattopadhyay, B. Noncovalent Interactions in Ir- Catalyzed C-H Activation: L-Shaped Ligand for Para-Selective Borylation of Aromatic Esters. J. Am. Chem. Soc. 2017, 139, 7745–7748. (27) Weldy, N. M.; Schafer, A. G.; Owens, C. P.; Herting, C. J.; Varela-Alvarez, A.; Chen, S.; Niemeyer, Z.; Musaev, D. G.; Sigman, M. S.; Davies, H. M. L.; Blakey, S. B. Iridium(Iii)- Bis(Imidazolinyl)Phenyl Catalysts for Enantioselective C–H Functionalization with Ethyl Diazoacetate. Chem. Sci. 2016, 7, 3142–3146. 806 (28) Henley, Z. A.; Amour, A.; Barton, N.; Bantscheff, M.; Bergamini, G.; Bertrand, S. M.; Convery, M.; Down, K.; Dümpelfeld, B.; Edwards, C. D.; Grandi, P.; Gore, P. M.; Keeling, S.; Livia, S.; Mallett, D.; Maxwell, A.; Price, M.; Rau, C.; Reinhard, F. B. M.; Rowedder, J.; Rowland, P.; Taylor, J. A.; Thomas, D. A.; Hessel, E. M.; Hamblin, J. N. Optimization of Orally Bioavailable PI3Kδ Inhibitors and Identification of Vps34 as a Key Selectivity Target. J. Med. Chem. 2020, 63, 638–655. (29) Zhang, G.; Rominger, F.; Mastalerz, M. Fused π-Extended Truxenes via a Threefold Borylation as the Key Step. Chem. - Eur. J. 2016, 22, 3084–3093. (30) Davis, H. J.; Genov, G. R.; Phipps, R. J. Meta-Selective C-H Borylation of Benzylamine-, Phenethylamine-, and Phenylpropylamine-Derived Amides Enabled by a Single Anionic Ligand. Angew. Chem. Int. Ed. 2017, 56, 13351–13355. (31) Del Grosso, A.; Singleton, P. J.; Muryn, C. A.; Ingleson, M. J. Pinacol Boronates by Direct Arene Borylation with Borenium Cations. Angew. Chem. Int. Ed. 2011, 50, 2102–2106. (32) Iqbal, S. A.; Cid, J.; Procter, R. J.; Uzelac, M.; Yuan, K.; Ingleson, M. J. Acyl-Directed Ortho- Borylation of Anilines and C7 Borylation of Indoles Using Just BBr 3. Angew. Chem. Int. Ed. 2019, 58, 15381 –15385. (33) Zhang, S.; Han, Y.; He, J.; Zhang, Y. B(C6F5)3-Catalyzed C3-Selective C-H Borylation of Indoles: Synthesis, Intermediates, and Reaction Mechanism. J. Org. Chem. 2018, 83, 1377– 1386. (34) Prévost, S. Regioselective C-H Functionalization of Naphthalenes: Reactivity and Mechanistic Insights. Chempluschem 2020, 85, 476–486. (35) Karmel, C.; Chen, Z.; Hartwig, J. F. Iridium-Catalyzed Silylation of C-H Bonds in Unactivated Arenes: A Sterically Encumbered Phenanthroline Ligand Accelerates Catalysis. J. Am. Chem. Soc. 2019, 141, 7063–7072. (36) Charisiadis, P.; Kontogianni, V. G.; Tsiafoulis, C. G.; Tzakos, A. G.; Siskos, M.; Gerothanassis, I. P. 1H-NMR as a Structural and Analytical Tool of Intra- and Intermolecular Hydrogen Bonds of Phenol-Containing Natural Products and Model Compounds. Molecules 2014, 19, 13643–13682. (37) Sigalov, M. V.; Doronina, E. P.; Sidorkin, V. F. C(Ar)-H···O Hydrogen Bonds in Substituted Isobenzofuranone Derivatives: Geometric, Topological, and NMR Characterization. J. Phys. Chem. A 2012, 116, 7718–7725. (38) Sigalov, M.; Vashchenko, A.; Khodorkovsky, V. Aromatic C-H...O Interactions in a Series of Bindone Analogues. NMR and Quantum Mechanical Study. J. Org. Chem. 2005, 70, 92– 100. (39) Kelly, B.; O’Donovan, D. H.; O’Brien, J.; McCabe, T.; Blanco, F.; Rozas, I. Pyridin-2-Yl Guanidine Derivatives: Conformational Control Induced by Intramolecular Hydrogen- Bonding Interactions. J. Org. Chem. 2011, 76, 9216–9227. (40) Hartwig, J.; Liskey, C. Borylation of Arenes with Bis(Hexylene Glycolato)Diboron. Synthesis 2013, 45, 1837–1842. 807 (41) Bader, R. F. W. Atoms in Molecules; International Series of Monographs on Chemistry; Clarendon Press: Oxford, England, 1994. (42) Afonin, A. V.; Vashchenko, A. V.; Sigalov, M. V. Estimating the Energy of Intramolecular Hydrogen Bonds from 1H NMR and QTAIM Calculations. Org. Biomol. Chem. 2016, 14, 11199–11211. (43) Espinosa, E.; Molins, E.; Lecomte, C. Hydrogen Bond Strengths Revealed by Topological Analyses of Experimentally Observed Electron Densities. Chem. Phys. Lett. 1998, 285, 170– 173. (44) Schaefer, T. Relation between Hydroxyl Proton Chemical Shifts and Torsional Frequencies in Some Ortho-Substituted Phenol Derivatives. J. Phys. Chem. 1975, 79, 1888–1890. (45) Sadler, S. A.; Tajuddin, H.; Mkhalid, I. A. I.; Batsanov, A. S.; Albesa-Jove, D.; Cheung, M. S.; Maxwell, A. C.; Shukla, L.; Roberts, B.; Blakemore, D. C.; Lin, Z.; Marder, T. B.; Steel, P. G. Iridium-Catalyzed C-H Borylation of Pyridines. Org. Biomol. Chem. 2014, 12, 7318– 7327. (46) Takagi, J.; Sato, K.; Hartwig, J. F.; Ishiyama, T.; Miyaura, N. Iridium-Catalyzed C–H Coupling Reaction of Heteroaromatic Compounds with Bis(Pinacolato)Diboron: Regioselective Synthesis of Heteroarylboronates. Tetrahedron Letters 2002, 43, 5649–5651. (47) Constable, E. C.; Ward, M. D. Synthesis and Co-Ordination Behavior of 6′,6″-Bis(2-Pyridyl)- 2,2′:4,4″:2″,2″′-Quaterpyridine; ‘Back-to-Back’ 2,2′:6′,2″-Terpyridine. J. Chem. Soc., Dalton Trans. 1990, 1405–1409. (48) Avendaño, C.; Espada, M.; Ocaña, B.; García-Granda, S.; Díaz, M. del R.; Tejerina, B.; Gómez-Beltrán, F.; Martínez, A.; Elguero, J. The Problem of the Existence of C(Ar)–H⋯N Intramolecular Hydrogen Bonds in a Family of 9-Azaphenyl-9H-Carbazoles. J. Chem. Soc., Perkin Trans. 2 1993, 1547–1555. (49) Castellanos, M. L.; Olivella, S.; Roca, N.; Mendoza, J. D.; Elguero, J. N,N-Linked Biazoles. III. MNDO Calculations on the Conformation of N,N-Linked Biazoles and Their Quaternary Salts. Can. J. Chem. 1984, 62, 687–695. (50) Shinde, R. S.; Salunke, S. D. Synthesis of Novel Substituted 4,6-Dimethoxy-N-Phenyl-1,3,5- Triazin-2-Amine Derivatives and Their Antibacterial and Antifungal Activities. Asian J. Chem. 2015, 27, 4130–4134. (51) Sharma, A.; Sheyi, R.; de la Torre, B. G.; El-Faham, A.; Albericio, F. S-Triazine: A Privileged Structure for Drug Discovery and Bioconjugation. Molecules 2021, 26, 864. (52) Shah, D. R.; Modh, R. P.; Chikhalia, K. H. Privileged S-Triazines: Structure and Pharmacological Applications. Future Med. Chem. 2014, 6, 463–477. (53) Al-Zaydi, K. M.; Khalil, H. H.; El-Faham, A.; Khattab, S. N. Synthesis, Characterization and Evaluation of 1,3,5-Triazine Aminobenzoic Acid Derivatives for Their Antimicrobial Activity. Chem. Cent. J. 2017, 11. https://doi.org/10.1186/s13065-017-0267-3. (54) Palanki, M. S. S.; Erdman, P. E.; Gayo-Fung, L. M.; Shevlin, G. I.; Sullivan, R. W.; Goldman, M. E.; Ransone, L. J.; Bennett, B. L.; Manning, A. M.; Suto, M. J. Inhibitors of NF-ΚB and 808 AP-1 Gene Expression: SAR Studies on the Pyrimidine Portion of 2-Chloro-4- Trifluoromethylpyrimidine-5-[N-(3‘,5‘-Bis(Trifluoromethyl)Phenyl)Carboxamide]. J. Med. Chem. 2000, 43, 3995–4004. (55) Yang, R.; Timofte, R.; Liu, J.; Xu, Y.; Zhang, X.; Zhao, M.; Zhou, S.; Chan, K. C. K.; Zhou, S.; Xu, X.; Loy, C. C.; Li, X.; Liu, F.; Zheng, H.; Jiang, L.; Zhang, Q.; He, D.; Li, F.; Dang, Q.; Huang, Y.; Maggioni, M.; Fu, Z.; Xiao, S.; Li, C.; Tanay, T.; Song, F.; Chao, W.; Guo, Q.; Liu, Y.; Li, J.; Qu, X.; Hou, D.; Yang, J.; Jiang, L.; You, D.; Zhang, Z.; Mou, C.; Koshelev, I.; Ostyakov, P.; Somov, A.; Hao, J.; Zou, X.; Zhao, S.; Sun, X.; Liao, Y.; Zhang, Y.; Wang, Q.; Zhan, G.; Guo, M.; Li, J.; Lu, M.; Ma, Z.; Michelini, P. N.; Wang, H.; Chen, Y.; Guo, J.; Zhang, L.; Yang, W.; Kim, S.; Oh, S.; Wang, Y.; Cai, M.; Hao, W.; Shi, K.; Li, L.; Chen, J.; Gao, W.; Liu, W.; Zhang, X.; Zhou, L.; Lin, S.; Wang, R. NTIRE 2021 Challenge on Quality Enhancement of Compressed Video: Methods and Results. arXiv [eess.IV], 2021. (56) Lawrence, H. R.; Martin, M. P.; Luo, Y.; Pireddu, R.; Yang, H.; Gevariya, H.; Ozcan, S.; Zhu, J.-Y.; Kendig, R.; Rodriguez, M.; Elias, R.; Cheng, J. Q.; Sebti, S. M.; Schonbrunn, E.; Lawrence, N. J. Development of O-Chlorophenyl Substituted Pyrimidines as Exceptionally Potent Aurora Kinase Inhibitors. J. Med. Chem. 2012, 55, 7392–7416. (57) Patel, H.; Pawara, R.; Ansari, A.; Surana, S. Recent Updates on Third Generation EGFR Inhibitors and Emergence of Fourth Generation EGFR Inhibitors to Combat C797S Resistance. Eur. J. Med. Chem. 2017, 142, 32–47. (58) van Beek, T.; Duval, F.; Zuilhof, H. Sensitive Thin-Layer Chromatography Detection of Boronic Acids Using Alizarin. Synlett 2012, 23, 1751–1754. (59) Xia, G.; Shao, Q.; Liang, K.; Wang, Y.; Jiang, L.; Wang, H. A Phenyl-Removed Strategy for Accessing Efficient Dual-State Emitter at Red/NIR Region: Guided by TDDFT Calculations. J. Mater. Chem. C Mater. Opt. Electron. Devices 2020. https://doi.org/10.1039/d0tc02596h. (60) Giampietro, N. C.; Demeter, D. A.; Bachir, D. A.; Esguerra, K. V. N.; Heemstra, R. J.; Aaron, S. R.; Barton, T. J.; Horty, L. G.; Sparks, T. C.; Watson, G. B. MOLECULES HAVING CERTAIN PESTICIDAL UTILITIES, AND INTERMEDIATES, COMPOSITIONS, AND PROCESSES RELATED THERETO. 2020US42237. (61) Taylor, N. J.; Emer, E.; Preshlock, S.; Schedler, M.; Tredwell, M.; Verhoog, S.; Mercier, J.; Genicot, C.; Gouverneur, V. Derisking the Cu-Mediated 18F-Fluorination of Heterocyclic Positron Emission Tomography Radioligands. J. Am. Chem. Soc. 2017, 139, 8267–8276. (62) Zhu, W.; Hu, Q.; Hanke, N.; van Koppen, C. J.; Hartmann, R. W. Potent 11β-Hydroxylase Inhibitors with Inverse Metabolic Stability in Human Plasma and Hepatic S9 Fractions to Promote Wound Healing. J. Med. Chem. 2014, 57, 7811–7817. (63) Talwar, D.; Li, H. Y.; Durham, E.; Xiao, J. A Simple Iridicycle Catalyst for Efficient Transfer Hydrogenation of N-Heterocycles in Water. Chemistry 2015, 21, 5370–5379. (64) Trabanco, A. A.; Tresadern, G.; Macdonald, G. J.; Vega, J. A.; de Lucas, A. I.; Matesanz, E.; García, A.; Linares, M. L.; Alonso de Diego, S. A.; Alonso, J. M.; Oehlrich, D.; Ahnaou, A.; Drinkenburg, W.; Mackie, C.; Andrés, J. I.; Lavreysen, H.; Cid, J. M. Imidazo[1,2- a]Pyridines: Orally Active Positive Allosteric Modulators of the Metabotropic Glutamate 2 Receptor. J. Med. Chem. 2012, 55, 2688–2701. 809 (65) Weber, M.; Mackenzie, A. B.; Bull, S. D.; James, T. D. Fluorescence-Based Tool to Detect Endogenous Peroxynitrite in M1-Polarized Murine J774.2 Macrophages. Anal. Chem. 2018, 90, 10621–10627. (66) Ji Jianguo Li Tao Mortell Kathleen H Schrimpf Michael R Nersesian Diana L Pan Liping. Fused Bicycloheterocycle Substitued Quinuclidine Derivatives. 2006065233, June 22, 2006. (67) Finlay Maurice Raymond Verschoyle Pike Kurt Gordon. Compound-946. 2009007751, January 15, 2009. (68) Ma, D.; Zhang, Z.; Chen, M.; Lin, Z.; Sun, J. Organocatalytic Enantioselective Functionalization of Unactivated Indole C(sp3)−H Bonds. Angew. Int. Ed. 2019, 58, 15916– 15921. (69) Sun, Y.-H.; Zhu, X.-H.; Chen, Z.; Zhang, Y.; Cao, Y. Potential Solution Processible Phosphorescent Iridium Complexes toward Applications in Doped Light-Emitting Diodes: Rapid Syntheses and Optical and Morphological Characterizations. J. Org. Chem. 2006, 71, 6281–6284. (70) Bej, A.; Srimani, D.; Sarkar, A. Palladium Nanoparticle Catalysis: Borylation of Aryl and Benzyl Halides and One-Pot Biaryl Synthesis via Sequential Borylation-Suzuki–Miyaura Coupling. Green Chem. 2012, 14, 661. (71) Liu, H.; He, Y.; Jiao, J.; Bai, D.; Chen, D.-L.; Krishna, R.; Chen, B. A Porous Zirconium- Based Metal-Organic Framework with the Potential for the Separation of Butene Isomers. Chemistry 2016, 22, 14988–14997. (72) Gabriel, C. M.; Lee, N. R.; Bigorne, F.; Klumphu, P.; Parmentier, M.; Gallou, F.; Lipshutz, B. H. Effects of Co-Solvents on Reactions Run under Micellar Catalysis Conditions. Org. Lett. 2017, 19, 194–197. (73) Kancherla, S.; Jørgensen, K. B. Synthesis of Phenacene-Helicene Hybrids by Directed Remote Metalation. J. Org. Chem. 2020, 85, 11140–11153. (74) Labre, F.; Gimbert, Y.; Bannwarth, P.; Olivero, S.; Duñach, E.; Chavant, P. Y. Application of Cooperative Iron/Copper Catalysis to a Palladium-Free Borylation of Aryl Bromides with Pinacolborane. Org. Lett. 2014, 16, 2366–2369. (75) Geng, S.; Zhang, J.; Chen, S.; Liu, Z.; Zeng, X.; He, Y.; Feng, Z. Development and Mechanistic Studies of Iron-Catalyzed Construction of Csp2-B Bonds via C-O Bond Activation. Org. Lett. 2020, 22, 5582–5588. (76) Kuehn, L.; Huang, M.; Radius, U.; Marder, T. B. Copper-Catalysed Borylation of Aryl Chlorides. Org. Biomol. Chem. 2019, 17, 6601–6606. (77) Brown, H. C.; Kulkarni, S. U. Organoboranes. J. Organomet. Chem. 1979, 168, 281–293. (78) Kramer, G. W.; Brown, H. C. Organoboranes. J. Organomet. Chem. 1974, 73, 1–15. (79) Contreras, R.; Wrackmeyer, B. Anwendung Der 11B-NMR-Spektroskopie Zur Untersuchung von Hydroborierungen, II [1]Hydroborierung von 1.5-Cyclooctadien Mit Boran in Tetrahydrofuran / Application of 11B NMR Spectroscopy to the Study of Hydroboration, II 810 [1] Hydroboration of 1,5-Cyclooctadiene with Borane in Tetrahydrofurane. Z. Naturforsch. B J. Chem. Sci. 1980, 35, 1236–1240. (80) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.; Cheeseman, J. R.; Scalmani, G.; Barone, V.; Petersson, G. A.; Nakatsuji, H.; Li, X.; Caricato, M.; Marenich, A. V.; Bloino, J.; Janesko, B. G.; Gomperts, R.; Mennucci, B.; Hratchian, H. P.; Ortiz, J. V.; Izmaylov, A. F.; Sonnenberg, J. L.; Williams-Young, D.; Ding, F.; Lipparini, F.; Egidi, F.; Goings, J.; Peng, B.; Petrone, A.; Henderson, T.; Ranasinghe, D.; Zakrzewski, V. G.; Gao, J.; Rega, N.; Zheng, G.; Liang, W.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Vreven, T.; Throssell, K.; Montgomery, J. A., Jr; Peralta, J. E.; Ogliaro, F.; Bearpark, M. J.; Heyd, J. J.; Brothers, E. N.; Kudin, K. N.; Staroverov, V. N.; Keith, T. A.; Kobayashi, R.; Normand, J.; Raghavachari, K.; Rendell, A. P.; Burant, J. C.; Iyengar, S. S.; Tomasi, J.; Cossi, M.; Millam, J. M.; Klene, M.; Adamo, C.; Cammi, R.; Ochterski, J. W.; Martin, R. L.; Morokuma, K.; Farkas, O.; Foresman, J. B.; Fox, D. J. Gaussian˜16 Revision C.01. 2016. 811 CHAPTER 5. STUDY OF REACTIVITY OF ARYL IMIDAZOLYLSULFONATES IN SUZUKI- MIYAURA CROSS-COUPLING REACTIONS 5.1. Introduction The 2010 Nobel Prize in Chemistry was awarded to Richard F. Heck, Ei-ichi Negishi and Akira Suzuki for their contributions to cross-coupling reactions in organic synthesis.1 Cross- coupling is a useful method for the creation of carbon-carbon bonds from an electrophile, usually a halide, and an organometallic compound that acts as nucleophile via palladium or nickel catalysis (Scheme 5.1). Kumada reported the first cross-coupling reaction using Grignard reagents. Several efforts have been made since then to expand the reactant scope. Negishi, Sonagashira, Stille and Hiyama demonstrated that organozinc, organocuprate, organotin and organosilicon compounds, respectively, can be used in cross-coupling reactions as well.2 Scheme 5.1: Types of cross-coupling reactions with different nucleophiles In 1979, Suzuki and Miyaura reported the use of boronic acids and esters as nucleophiles in cross-coupling reactions. Nowadays, Suzuki-Miyaura cross-coupling (SMC) has become by far the most useful cross-coupling method in industry due to the availability and stability of boronic partners. This is reflected on the number of scientific publications and patents that use SMC.3 SMC requires the presence of base and two mechanisms are postulated according to the role of the base (Scheme 5.2).4–14 Both mechanisms have the same main steps: oxidative addition (1→2), 812 transmetallation (2→4), and reductive elimination (4→1); the difference is in how the base promote the transmetallation step. In mechanism A, the base reacts with 2 to make a hydroxo palladium 3, which can transmetallate with the boronic acid or ester. In mechanism B, the base reacts with the boronic acid or ester to produce the borate, which transmetallates with 2. Experimental data of Pd-catalyzed SMC of aryl boronic acids supports mechanism A due to the poor reactivity of the borate in the transmetallation step. Nonetheless, mechanism B cannot be discarded especially with boronic esters or under nickel catalysis. Scheme 5.2: Possible mechanisms for SMC There are some concerns over the use of halides as electrophilic partners in SMC. Aryl halides need to be synthesized previously via Friedel-Craft electrophilic halogenation, Sandmeyer type reactions or halogenation of organometallic arenes starting from available aromatic compounds (Scheme 5.3).15–17 Low functional group tolerance, poor regioselectivity and overhalogenation related to these methods limit the access to aryl halides. Furthermore, production of metal halogenated salts as byproduct in the synthesis of aryl halides, as well as in the cross- coupling reactions, can cause serious health and environmental problems.18,19 813 Scheme 5.3: Traditional methods for the synthesis of aryl halides These issues have spurred the search for alternative electrophiles. Among the common alternatives, electrophiles based on phenol are good candidates because they can be produced from the coal-based industry or as derivatives of lignin, giving access to them at low cost. Triflates were the first alternative tested due to their comparable reactivity with halides, but low stability led to search for other options.20 Tosylates and mesylates are more stable than triflates. However, tosylates and mesylates offer much less reactivity than triflates and these three types of sulfonates degrade to potentially genotoxic byproducts.21,22 In 2009, Albeneze-Walker reported the use of aryl imidazolylsulfonates as a new electrophile for SMC (Scheme 5.4a).23 Imidazolylsulfonates are degraded in water to produce imidazole and sulfuric acid, instead of the potentially genotoxic products produced by other aryl or alkyl sulfonates. Furthermore, the study showed that the reactivity of imidazolylsulfonates is comparable to triflates and they can be stored for months without loss of reactivity. Therefore, imidazolsulfonates are a green, reactive, and stable electrophile for SMC.23 Alonso and Najera expanded the use of aryl imidazolylsulfonates in SMC by developing a protocol under aqueous conditions using oxime-palladacycles (Scheme 5.4b).24,25 This methodology works well with both aryl and alkenyl boronic acids and trifluoroborates. Among the attractive features of this protocol are the low catalyst loading of 1 mol % Pd, the option to run the 814 reaction under microwave conditions and the in situ imidazolylsulfonate formation of the phenol followed by the SMC. Scheme 5.4: Reported SMC of aryl imidazolylsulfonates with boronic nucleophiles The Maleczka and Smith groups have also worked in this field developing a green one pot SMC of unfunctionalized arenes via the formation of aryl imidazolylsulfonates (Scheme 5.5). in situ C-H borylation of the corresponding arene followed by photocatalytic oxidation produce the phenol. This is then treated with sulfonyldiimidazole to yield the aryl imidazolylsulfonate. In a separate flask, the boronic partner is generated in situ by the C-H borylation of an heteroarene. The aryl imidazolylsulfonate is added to the flask containing the boronic ester without further purification and SMC is performed. This is a practical protocol that avoids completely the use of halides. 815 Scheme 5.5: One pot C-H borylation/oxidation route to aryl imidazolylsulfonate and their incorporation into C-H borylation/SMC Before the discovery by Albaneze-Walker, imidazolylsulfonate was used as a leaving group in substitution and elimination reactions throughout carbohydrate and nucleoside chemistry. After 2009, aryl imidazolylsulfonate emerged as a new electrophilic alternative for cross-coupling reactions (Scheme 5.6).26 Aryl imidazolylsulfonates can be coupled not only with aryl boronic acids but also with organozinc, alkynes and organosilicon reagents via Negishi, copper-free Sonagashira and Hiyama reactions.23,27 Aryl imidazolylsulfonates can be used as coupling partners in the C-H activation of heteroarenes and ketones as well. Oxazoles and benzoaxazoles are arylated at carbon C2; competition studies show that aryl imidazolylsulfonates are more reactive than bromides in this case.28 Arylation of ketones occurs regioselectively at the least steric position and diarylation of the product does not happen; this used to be a problem with other electrophiles. 29 Moreover, aryl imidazolylsulfonates can insert their aryl group into carbon monoxide via palladium catalysis; addition of methanol then release an ester as the final product.23 816 Scheme 5.6: Metal-catalyzed cross-coupling reactions of aryl imidazolylsulfonates On the other hand, coupling reactions of aryl imidazolylsulfonates can form bonds between carbon and atoms different than carbon. Albaneze-Walker reported the hydrogenolysis of naphtyl imidazolylsulfonate catalyzed by palladium on carbon; this was the only substrate tested theoretically other compounds may also work.23 Later, phosphorylation of aryl imidazolylsulfonates was developed using H-phosphonate as the coupling partner, analogous to Hirao’s report with aryl halides.30 Finally, aryl imidazolylsulfonates can be useful precursors of anilines via Bucwald-Hartwig amination.31 Since the first emergence of imidazolylsulfonates as coupling partners, the evolution of its applicability as an electrophile demonstrates its important versatility as a novel option for coupling reactions. 817 Owing to the advantages of aryl imidazolyl sulfonates, we desire to expand its applicability in SMC. Aryl imidazolyl sulfonates are as reactive as triflates for palladium catalyzed SMC, we wondered how the reactivity of this electrophile will compare to the most traditional electrophiles: aryl halides. This insight will help the spread of the use of this pseudohalide in organic synthesis. On the other hand, SMC promoted by earth abundant metals like nickel has gained considerable attention due to the increasing shortage of metals like palladium. Herein, we also report our efforts on the development of a nickel-catalyzed SMC of aryl imidazolyl sulfonates. 5.2. Results and Discussion 5.2.1. Aryl imidazolyl sulfonates vs aryl halides The reactivity comparison between aryl imidazolylsulfonates and halides was done to gain a knowledge of the general reactivity of this novel electrophile. Two sets of reaction conditions were chosen. Condition A uses Pd(dppf)Cl2 as the catalyst and follows the parameters reported for the SMC of aryl imidazolylsulfonates by Albaneze-Walker.23 Condition B uses Pd(OAc)2 and JohnPhos, a Buchwald type ligand, under optimized mild conditions for the cross coupling of aryl halides.32 Figure 5.1 shows a comparison between aryl imidazolsulfonates’s and aryl halide’s SMC rate of conversion. Aryl imidazolsulfonates coupled faster than the chloride under both Conditions A and B. Respect to the bromide and iodide, the aryl imidazolylsulfonates reacted slower. This is in accordance with the established behavior of the reactivity of aryl halides in SMC: aryl iodides react faster than bromides and these faster than chlorides. 818 Condition A Condition B 100 100 Conversion (%) Conversion (%) 80 Imidazolsulfonate 80 Imidazolsulfonate Chloride 60 60 Chloride 40 40 20 20 0 0 0 20 40 0 5 10 15 20 25 Time (h) Time (h) 100 100 Conversion (%) 80 Conversion (%) 60 50 40 Imidazolsulfonate Imidazolsulfonate 20 Bromide Bromide 0 0 0 10 20 30 40 50 0 10 20 30 Time (h) Time (h) 100 100 Conversion (%) Conversion (%) Imidazolsulfonate imidazolsulfonate Iodide Iodide 50 50 0 0 0 10 20 30 40 50 0 5 10 15 20 25 Time (h) Time (h) Figure 5.1: SMC reactivity comparison between 4-fluorophenyl imidazolylsulfonates vs halides. 819 5.2.2. Unexpected results in the nickel-catalyzed SMC of aryl imidazolylsulfonates The nickel-catalyzed SMC of aryl imidazolylsulfonates was attempted using conditions previously reported for the SMC of phenol derived electrophiles (Scheme 5.7a).33 19F NMR of the reaction mixture shows formation of cross-coupled product 5.2 with an unexpected product. Compound 5.2 was made previously from the SMC of the corresponding aryl phosphate. After work-up of the reaction mixture, it was discovered that diaryl sulfate 5.3 was the identity of the side product. After 67 hours, 51% of the aryl imidazolylsulfonate converted to compound 5.3. Diaryl sulfate 5.3 was synthesized by a known method widely report in the literature to further support this assignment.34 This result was surprising since no diaryl sulfate was reported during the palladium cross-coupling of aryl imidazolyl-sulfonates. No diaryl sulfate was seen either by GC-MS or 19F NMR after performing the palladium-catalyzed reaction (Scheme 5.7b). Scheme 5.7: Nickel and palladium-catalyzed SMC of 4-fluorophenyl imidazolylsulfonate 820 5.2.3. Nickel-catalyzed SMC of diaryl sulfates: Furthermore, it was demonstrated that diaryl sulfate 5.3 can undergo SMC under the same conditions used for aryl imidazolylsulfonates (Scheme 5.8). Based on this discovery, it was believed that diaryl sulfates would be another environmentally friendly electrophile alternative for SMC. Therefore, some studies were performed to gain knowledge on the SMC of diaryl sulfates. First, the reaction in Scheme 5.8 was followed by 19F NMR. After 12 hours no reagent was left, but the low yield of the isolated product (35 %) suggested that another product was being formed. Scheme 5.8: Nickel-catalyzed SMC of bis(4-fluorophenyl) sulfate In the literature, there are reports of Kumada cross-couplings of diaryl sulfates (Scheme 5.9).34 It has been proposed that the mechanism goes through the formation of a magnesium sulfate salt as an intermediate. The study identified the sulfate salt by ESI-MS and it was demonstrated that the sulfate salt can undergo Kumada cross-coupling successfully. Scheme 5.9: Previously report nickel-catalyzed Kumada coupling of diaryl sulfates It was thought that the SMC of the diaryl sulfate (Scheme 5.8) might also go through the 19 sulfate salt, which precipitate out of solution and therefore cannot be seen by F NMR. After 821 repeating the reaction and adding a certain amount of internal standard C6F6 at the end, the real conversion (50 %) to the product 5.2 was measured. Some attempts were made to improve the conversion of the SMC of diaryl sulfate. If the sulfate salt is an intermediate, changing solvent, temperature or the nature of the base can change the solubility of the salt and perhaps improve the cross-coupling. Using K3PO4 as base, the best solvent was dioxane and increasing temperature until reflux also improved the conversion (Table 5.1, entries 1-4). Other bases like Cs2CO3 and Mg3PO4 were not effective (entries 5-9). Mg3PO4 is not soluble in organic solvents and therefore all conversion to product is lost (entries 7-9). Table 5.1: Optimization of reaction conditions for SMC of diaryl sulfatesa Entry Base Solvent Temperature Conversion (%) 1 K3PO4 Dioxane rt 33 2 K3PO4 Dioxane 110 °C 50 3 K3PO4 Et2O rt 36 4 K3PO4 THF rt 36 5 Cs2CO3 THF rt 0 6 Cs2CO3 THF 40 °C 5 7 Mg3PO4 Dioxane 110 °C 0 8 Mg3PO4 Et2O rt 0 9 Mg3PO4 THF 40 °C 0 a Reaction conditions: 5.3 (0.2 mmol), 4-MeOPhB(OH)2 (0.6 mmol), NiCl2(PCy3)2 (0.01 mmol), PCy3 (0.02 mmol), base (0.9 mmol), solvent (2 mL), 24 h Palladium catalysis was also attempted for SMC of diaryl sulfates (Scheme 5.10). Similar conversion as with nickel catalysis was obtained. 822 Scheme 5.10: Palladium-catalyzed SMC of diaryl sulfate The next reaction condition attempted was using crown ethers to dissolve the sulfate salt intermediate (Table 5.2). 18-crown-6 and dibenzo-18-crown-6 were used because they are known 19 to trap potassium cations. In fact, upon addition of the ether, a new peak was seen by F NMR. While it was suspected that the ether helped dissolve the sulfate salts, the crown ethers also trap the base K3PO4 which may explain the decrease in conversion respective to the reactions without addition of crown ether. Table 5.2: Optimization of reaction conditions for SMC of diaryl sulfates with crown ethers b Entry Crown ether Solvent Temperature Conversion (%) 1 18-crown-6 dioxane 110 °C 12 2 18-crown-6 THF 110 °C 0 3 dibenzo-18-crown-6 dioxane 110 °C 27 b Reaction conditions: 5.3 (0.2 mmol), 4-MeOPhB(OH)2 (0.6 mmol), NiCl2(PCy3)2 (0.01 mmol), PCy3 (0.02 mmol), K3PO4 (0.9 mmol), crown ether (2.7 mmol), solvent (4 mL), 24 h Based on these results, the best conversion for the SMC of diaryl sulfate was afforded with Ni(PCy3)Cl2, PCy3, and K3PO4 in dioxane (Scheme 5.8) or with Pd(dppf)Cl2 and K2CO3 in DMF 823 (Scheme 5.10). Although high yields were not obtained, due to the formation of the sulfate salt, it is noteworthy that the SMC of diaryl sulfates can be done in both nickel and palladium conditions. 5.2.4. Conditions for the formation of diaryl sulfate from aryl imidazolylsulfonate We returned to our main goal: development of a nickel-catalyzed SMC of aryl imidazolyl sulfonates. Previously, formation of diaryl sulfate during the SMC prevent us to find optimal conditions. Uncovering the conditions which promote the formation of diaryl sulfates during the SMC is key to overcome this issue. Control reactions were performed in the presence of each component of the SMC: base, Ni catalyst, boronic acid (Table 5.3, entries 1-4). No diaryl sulfate product was formed with any of these components alone but combining the boronic acid with the base produced diaryl sulfate in 60% conversion (Table 5.3, entry 5). Table 5.3: Test of reaction conditions for the formation of diaryl sulfates c Entry Conditions Conversion (%) 1 None 0 2 K3PO4 0 3 NiCl2(PCy3)2 0 4 4-MeOPhB(OH)2 0 5 4-MeOPhB(OH)2, K3PO4 60 c Reaction conditions: 4-FPhOSO2Im (0.25 mmol), 4-MeOPhB(OH)2 (0.375 mmol), NiCl2(PCy3)2 (0.025 mmol), K3PO4 (1.125 mmol), dioxane (2 mL), 22 h It can be concluded that the combination of the base, boronic acid and solvent is crucial for the formation of the diaryl sulfate. In the study of reactivity between aryl imidazolylsulfonates and other electrophiles different conditions will be used to avoid such diaryl sulfate formation. Therefore, it is important to have a good understanding on how certain conditions lead to the formation of the diaryl sulfate (Table 5.4). Solvents like dioxane, toluene and THF with K3PO4 as 824 base were chosen because these are common conditions used for the cross-coupling of phenol derivatives (entries 1-8). It can be deduced that an increase in temperature promotes the formation of diaryl sulfate. Additionally, changing the solvent also affects the conversion; in general, dioxane enhances formation of 5.3 more than THF or toluene. Interestingly, the reaction was performed with K2CO3 and DMF at 60 °C and only a small amount of diaryl sulfate was formed. This supports the observed effectiveness of palladium catalyzed SMC of aryl imidazolylsulfonate (Scheme 5.7b) under these conditions. Table 5.4: Effect of reaction conditions in the formation of diaryl sulfates a Entry Base Solvent Temperature Conversion (%) 1 K3PO4 Dioxane 60 °C 22 2 K3PO4 Dioxane 80 °C 37 3 K3PO4 Dioxane 100 °C 60 4 K3PO4 Toluene 60 °C 0 5 K3PO4 Toluene 80 °C 3 6 K3PO4 Toluene 100 °C 5 7 K3PO4 THF 25 °C 0 8 K3PO4 THF 40 °C 1 9 K2CO3 DMF 60 °C 3.8 10 K2CO3 DMF 100 °C 42 a Reaction conditions: 5.1 (0.25 mmol), 4-MeOPhB(OH)2 (0.375 mmol), base (1.125 mmol), solvent (2 mL), 24 h 5.2.5. Nickel catalyzed SMC of aryl imidazolylsulfonates Based on the results of Table 5.4, the SMC of aryl imidazolylsulfonate was performed under the conditions that gave the lowest yields of the diaryl sulfate (Table 5.5). K3PO4 with toluene or THF formed small amounts of diaryl sulfate but also little conversion to cross-coupling product 5 (entries 1-2). With DMF as the solvent, the main product was the diaryl sulfate (entry 825 3). Using DMF and K2CO3 at 60 °C does not make diaryl sulfate 6 as expected but the cross- coupling product 5 was not obtained either (entry 4). Changing the base to KF (entry 5) does not affect these results. In summary, conditions that do not promote formation of diaryl sulfate give lower conversions to the cross-coupling product. Table 5.5: Nickel catalyzed SMC of aryl imidazolylsulfonates at different reaction conditions Entry Base Solvent Temperature Time Conversion 5 (%) Conversion 6 (%) 22 h 5 16 1 K3PO4 Toluenee 100 °C 44 h 4 19 66 h 7 35 22 h 6 10 2 K3PO4 THFe 40 °C 44 h 7 13 66 h 5 19 22 h 15 77 3 K3PO4 DMFf 60 °C 44 h 12 81 4 K2CO3 DMFf 60 °C 22 h 0 0 5 KF DMFf 60 °C 22 h 2 0 e Reaction conditions: 5.1 (0.25 mmol), 4-MeOPhB(OH)2 (0.375 mmol), NiCl2(PCy3)2 (0.025 mmol), base (1.125 mmol), solvent (2 mL). f Reaction conditions: 5.1 (0.42 mmol), 4- MeOPhB(OH)2 (0.64 mmol), NiCl2(PCy3)2 (0.042 mmol), base (0.85 mmol), solvent (2.5 mL) 5.3. Conclusions Aryl imidazolyl sulfonates have emerged as novel pseudohalides for cross-coupling reactions. Its reactivity is comparable to triflates as previously reported, and to bromides as described here. Attempts to expand its utility to nickel-catalyzed SMC have not been promising due to the formation of a diarylsulfate side product. Presence of boronic acid and base are sufficient to promote the decomposition of aryl imidazolylsulfonates to diarylsulfates. 826 Unfortunately, conditions that diminished the formation of the diarylsulfate also harm the production of the cross-coupled product. Nonetheless, the diaryl sulfates have shown to be alternative electrophiles for nickel-catalyzed SMC although with conversion lower than 50%. It is hypothesized that precipitation of an aryl sulfate salt after coupling of one aryl group stop the reaction to go further. 5.4. Experimental Procedures 5.4.1. General Materials and Methods All commercially available chemicals were used as received unless otherwise indicated. All solvents were reagent grade. All the electrophiles and the catalyst Ni(PCy3)2Cl2 were prepared based on reported methods. Tetrahydrofuran (THF) was distilled from sodium/benzophenone under nitrogen atmosphere before use. Toluene was distilled from CaH2 under nitrogen atmosphere before use. Dioxane was distilled from sodium/benzophenone under nitrogen atmosphere before use. K3PO4, K2CO3 and KF were dehydrated at 150 °C under vacuum overnight and use immediately. Column chromatography was performed on flash silica gel (ACME). Thin layer chromatography was performed on 0.25 mm thick aluminum-backed silica gel plates purchased from Merck and visualized with ultraviolet light ( = 254 nm). 1 H, 13C, and 19F NMR spectra were recorded on Agilent DirectDrive2 (500 MHz for 1H, 126 MHz for 13C and 470 MHz for 19F). All coupling constants are apparent J values measured at the indicated field strengths in Hertz (s = singlet, d = doublet, t = triplet, q = quartet, dd = doublet of doublets, bs = broad singlet, dt = doublet of triplet, td = triplet of doublet, ttt = triplet of triplet of triplet). High-resolution mass spectra were acquired at the MSU Mass Spectrometry facility using a Waters QTOF Ultima mass spectrometer (ESI). 827 5.4.2. Synthesis of reagents: electrophiles and catalyst 1,1’-sulfonylbis(1H-imidazole) 26 Sulfonyl chloride (3.48 mL, 43 mmol) and dichloromethane (20 mL) were placed on a round bottom flask submerged on a dry ice bath. Other flask was charged with imidazole (14 g, 206 mmol) and dissolve with dichloromethane (147 mL). After all the imidazole was dissolved, the mixture was cooled in a dry ice bath and the sulfonyl chloride solution was added dropwise. The reaction mixture was allowed to warm up to room temperature and stirred for 16 h. After vacuum filtration, the filtrate was evaporated under reduce pressure until dryness. The solid obtained was recrystallized with isopropanol (70 mL). The mixture was cooled in an ice bath and then filtrated. 1,1’-Sulfonylbis(1H-imidazole) was obtained as a white solid in 69% yield (5.91 g). 1 H NMR data match with those reported by Sigma Aldrich. 1 H NMR (500 MHz, CDCl3): δ 8.06 (t, J = 1.0 Hz, 1H), 7.32 (t, J = 1.5 Hz, 1H), 7.19 – 7.15 (m, 1H) 4-fluorophenyl 1H-imidazole-1-sulfonate (5.1) 24,44 A round bottom flask was charged with 4-fluorophenol (750 mg, 6.7 mmol), 1,1’- sulfonylbis(1H-imidazole) (2.65 g, 13.4 mmol), Cs2CO3 (1.09 g, 3.35 mmol) and THF (22.5 mL). The solution was stirred at room temperature for 24 hours. Solvent was evaporated under reduced pressure. The mixture was partitioned between ethyl acetate (15 mL) and water (15 mL). The 828 organic phase was washed with a saturated solution of NH4Cl (15 mL) and with brine (15 mL). The organic layer was dried over Na2SO4, filtered, and evaporated under reduced pressure. Purification by flash column chromatography (hexane: ethyl acetate = 1: 1) afforded 4- fluorophenyl 1H-imidazole-1-sulfonate in 77 % yield (1.25 g) as a white solid. NMR data matches those reported in the literature.44 1 H NMR (500 MHz, CDCl3): δ 7.73 (t, J = 1.0 Hz, 1H), 7.29 (t, J = 1.5 Hz, 1H), 7.17 (dd, J = 1.7, 0.8 Hz, 1H), 7.08 – 7.02 (m, 2H), 6.94 – 6.87 (m, 2H). 13C NMR (126 MHz, CDCl3): δ 161.8 (d, J = 249 Hz), 144.63 (d, J = 3.8 Hz), 137.46 (s), 131.50 (s), 123.12 (d, J = 8.8 Hz), 118.28 (s), 117.18 (d, J = 23.9 Hz). 19F NMR (470 MHz, CDCl3): δ -111.6 (m). HRMS (ESI) m/z calcd for C9H8FN2O3S [M+H]+ 243.0240, found: 243.0240. Bis(4-fluorophenyl) sulfate (5.3) 4-fluorophenol (1.68 g, 15 mmol), 1,1’-sulfonylbis(1H-imidazole) (991 mg, 5 mmol), CsCO3 (1.63 g, 5 mmol) and THF (5 mL) were placed in a round bottom flask. The mixture was stirred and heated until reflux overnight. The reaction mixture was filtrated under vacuum and the filtrate was evaporated until dryness. Purification by flash column chromatography (hexane: ethyl acetate = 4:1) afforded compound 5.3 in 89% yield (1.27g). 1 H NMR (500 MHz, CDCl3): δ 7.30 (m, 4H), 7.12 (m, 4H). 13C NMR (500 MHz, CDCl3): δ 161.3 (d, J = 990 Hz), 146.0 (d, 15 Hz), 122.8 (d, 35 Hz), 116.9 (d, 95 Hz). 19F NMR (500 MHz, CDCl3): δ -113.3 (m). 829 Diethyl (4-fluorophenyl) phosphate 45 A Schlenk flask was charged with 4-fluorophenol (897 mg, 8 mmol) and toluene (9.2 mL). The Schlenk flask was degassed with nitrogen for 15 minutes. Schlenk flask was placed under an ice bath and diethyl chlorophosphate (1.2 mL, 8 mmol) was added dropwise. The reaction mixture was degassed with nitrogen for 15 minutes. NaOH aqueous (1.8 mL of NaOH 4.4 M) was added to the Schenk flask. The reaction mixture was degassed for 15 minutes and left at room temperature for 24 hours. The organic phase was separated from the aqueous phase and then it was washed with NaOH aqueous (8 mL of NaOH 10 % w/w). The organic layer was washed with water (8 mL) and the solvent was evaporated under reduced pressure. Diethyl (4-fluorophenyl) phosphate was obtained in 50% yield (1.02 g). 1 H NMR (500 MHz, CDCl3): δ 7.17 (dqd, J = 9.5, 3.9, 1.2 Hz, 1H), 7.05 – 6.97 (m, 1H), 4.20 (dqd, J = 8.2, 7.1, 3.7 Hz, 2H), 1.34 (td, J = 7.1, 1.1 Hz, 3H). 13C NMR (126 MHz, CDCl3): δ 159.63 (d, J = 244 Hz), 146.60 (dd, J = 6.9, 2.5 Hz), 121.4 (dd, J = 7.6, 5.0 Hz), 116.20 (d, J = 23.9 Hz), 64.65 (d, J = 6.3 Hz), 16.08 (d, J = 7.6 Hz). 19 F NMR (470 MHz, CDCl3): δ -118.0 (m). HRMS (ESI) m/z calcd for C10H15FO4P [M+H]+ 249.0692, found: 249.0692. Bis(tricyclohexyl)nickel (II) dichloride 38 Ethanol (50 mL) was degassed with nitrogen for 15 minutes. One Schlenk flask was charged with NiCl2 (1.25 g, 9.7 mmol) and purged with nitrogen and vacuum three times with 5 830 minutes per cycle. Degassed ethanol (25 mL) was transferred via positive pressure with a cannula to the Schlenk flask charged with NiCl2. The mixture was heated until a yellow dark homogenous solution was obtained (approx. 70 °C). Another Schenk flask was charged with PCy3 (7.10 g, 25.4 mmol) and purged with nitrogen and vacuum three times with 5 minutes per cycle. The degassed ethanol (25 mL) and NiCl2 solution were transferred via positive pressure with a cannula to the Schlenk flask charged with PCy3. A condenser was connected to the flask and the reaction mixture was heated until reflux for 1 hour. The reaction mixture was left to cool down at room temperature. The reaction mixture was filtered, the solid was washed with cold ethanol (25 mL) and diethyl ether (25 mL). The solid was dried overnight under vacuum to afford a reddish-purple product in 84% yield (5.66 g). UV-Vis matched those reported in the literature.47 UV-Vis: 276 nm, 393 nm, 514-532 nm (500) 5.4.3. Cross coupling reactions General Procedure for the SMC Method A: A Schlenk flask was charged with the boronic acid, the catalyst, and the base. The Schlenk flask was purged with nitrogen and vacuum three times with 5 minutes per cycle. Another flask was charged with the electrophile(s), the ligand, and the solvent. The solution was stirred and degassed with nitrogen for 15 minutes, then it was transferred via a positive pressure through a cannula to the Schlenk flask. The reaction mixture was degassed for 15 minutes and then stirred at room temperature or heated in an oil bath with a fitted condenser. Reactions in Scheme 5.7a, 5.8, 5.10 and Table 5.1, 5.2 were run with this method. 831 Method B: In a nitrogen filled glove box, a 5.0 mL conical vial was charged with the electrophile(s), boronic acid, catalyst, ligand, base, and solvent. The vial was capped with a teflon pressure cap. If the reaction was run at room temperature, the vial was left inside of the glove box. If the reaction need to be heated, the vial was taken out of the glove box and placed into a pre-heated aluminum block at the indicated temperature. Reactions in Figure 5.1, Scheme 5.8, Table 5.3, 5.4 and 5.5 were run with this method. Reactions were followed by 19F NMR using C6F6 as standard. In the case of coupling of aryl sulfates a measured amount of C6F6 (1/6 equivalents respect to the diaryl sulfate) was added at the end of the reaction to have a quantitative measurement of the conversion. 4-fluoro-4’-methoxy-1,1’-biphenyl (5.2) Method A was followed with this quantity of reagents: 4-Fluorophenyl diethyl phosphate (372 mg, 1.5 mmol), 4-methoxyphenyl boronic acid (342 mg, 2.25 mmol), NiCl2(PCy3)2 (104 mg, 0.15 mmol, K3PO4 (1.43 g, 6.75 mmol), and dioxane (6 mL), no extra ligand was added. After 24 h the reaction was stopped, and the mixture was evaporated under reduced pressure. Purification by flash column chromatography (hexane: ethyl acetate = 9:1) afford compound 5.2 in 77% yield. 1 H NMR (500 MHz, CDCl3): δ 7.53 – 7.44 (m, 4H), 7.14 – 7.06 (m, 2H), 7.01 – 6.94 (m, 2H), 3.85 (s, 3H). 13C NMR (126 MHz, CDCl3): δ 162.06 (d, J = 246 Hz), 159.07 (s), 136.94 (d, J = 2.5 Hz), 132.81 (s), 128.19 (d, J = 8.8 Hz), 128.01 (s), 115.51 (d, J = 21.4 Hz), 114.22 (s), 55.35 (s). 832 SMC Reactivity Comparison Imidazolylsulfonates Vs Halides (Figure 5.1): condition A In a nitrogen filled glove box, a 5.0 mL Wheaton microreactor was charged with 4- fluorophenyl imidazolyl sulfonate (0.5 mL of a 0.42 M solution in DMF, 0.21 mmol, 0.5 equiv) and the corresponding aryl halide: 1-chloro-4-fluorobenzene (28 mg, 0.21 mmol, 0.5 equiv) or 1- bromo-4-fluorobenzene (37 mg, 0.21 mmol, 0.5 equiv) or 1-fluoro-4-iodobenzene (47 mg, 0.21 mmol, 0.5 equiv). The conical vial was charged with 4-methoxyphenyl boronic acid (1 mL of a 0.64 M solution in DMF, 0.64 mmol, 1.5 equiv), Pd(dppf)Cl2.CH2Cl2 (0.5 mL of a 0.042 M solution in DMF, 5 mol %), K2CO3 (117 mg, 0.85 mmol, 2 equiv) in DMF (0.5 mL). The microreactor was capped with a teflon pressure cap and placed into an aluminum block pre-heated to 60 ºC. The reaction mixture was monitored over time by taking aliquots and analyzing them by 19 F NMR. SMC Reactivity Comparison Imidazolylsulfonates Vs Halides (Figure 5.1): condition B In a nitrogen filled glove box, a 5.0 mL Wheaton microreactor was charged with 4- fluorophenyl imidazolyl sulfonate (121 mg, 0.50 mmol, 0.5 equiv) and the corresponding aryl halide: 1-chloro-4-fluorobenzene (65 mg, 0.50 mmol, 0.5 equiv) or 1-bromo-4-fluorobenzene (87 833 mg, 0.50 mmol, 0.5 equiv) or 1-fluoro-4-iodobenzene (111 mg, 0.50 mmol, 0.5 equiv). The conical vial was charged with 4-methoxyphenyl boronic acid (228 mg, 1.5 mmol, 1.5 equiv), Pd(OAc)2 (2.2 mg, 1 mol %), JohnPhos (6.0 mg, 2 mol %), KF (174 mg, 3.0 mmol, 3 equiv) in THF (3.0 mL). The microreactor was capped with a teflon pressure cap and stirred at room temperature. The reaction mixture was monitored over time by taking aliquots and analyzing them by 19F NMR. Nickel-catalyzed SMC of bis(4-fluorophenyl)sulfate A 10 mL Schlenk flask was charged with 4-methoxyphenyl boronic acid (91 mg, 0.6 mmol, 3 equiv), NiCl2(PCy3)2 (6.9 mg, 5 mol %), PCy3 (5.6 mg, 10 mol %) and K3PO4 (191 mg, 0.9 mmol, 4.5 equiv). The Schlenk flask was purged with nitrogen and vacuum three times with 5 minutes per cycle. Bis(4-fluorophenyl)sulfate (57 mg, 0.20 mmol, 1 equiv) was dissolved in dioxane (2 mL) in a 10 mL round bottom flaks and sparged with nitrogen for 15 minutes. The bis(4-fluorophenyl)sulfate solution was transferred to the Schlenk flask via cannula under a positive pressure of nitrogen. Extra dioxane (1.5 mL) was added to the Schlenk flask. A condenser was connected to the Schlenk flask and the mixture was heated to 100 °C. After 3 h, the mixture was concentrated under reduce pressure and passed through silica column chromatography (hexane/ethyl acetate 98:2 as eluent). The fractions containing product were collected and concentrated to give 28 mg of 5.2 as a white solid (35% yield). To measure the conversion, the reaction was repeated under the same conditions and set up described above. The reaction was cool down and C6F6 (12 mg, 0.07 mmol) was added as an internal standard. An aliquot of the mixture was analyzed by 19F NMR to measure the conversion (50% conversion). 834 Palladium-catalyzed SMC of bis(4-fluorophenyl)sulfate A 10 mL Schlenk flask was charged with 4-methoxyphenyl boronic acid (97 mg, 0.63 mmol, 3 equiv), Pd(dppf)Cl2 (15 mg, 10 mol %) and K2CO3 (117 mg, 0.85 mmol, 4 equiv). The Schlenk flask was purged with nitrogen and vacuum three times with 5 minutes per cycle. Bis(4- fluorophenyl)sulfate (61 mg, 0.21 mmol, 1 equiv) was dissolved in DMF (2.5 mL) in a 10 mL round bottom flaks and sparged with nitrogen for 15 minutes. The bis(4-fluorophenyl)sulfate solution was transferred to the Schlenk flask via cannula under a positive pressure of nitrogen. A condenser was connected to the Schlenk flask and the mixture was heated to 60 °C. After 27 h, the mixture was cool down and C6F6 (12 mg, 0.07 mmol) was added as an internal standard. An aliquot of the mixture was analyzed by 19F NMR to measure the conversion (45% conversion). 835 APPENDIX 836 1 H NMR of 4-fluorophenyl imidazolylsulfonate (500 MHz, CDCl3) (5.1) 837 13 C NMR of 4-fluorophenyl imidazolylsulfonates (126 MHz, CDCl3) (5.1) 838 19 F NMR of 4-fluorophenyl imidazolylsulfonate (470 MHz, CDCl3) (5.1) 839 1 H NMR of bis(4-fluorophenyl) sulfate (500 MHz, CDCl3) (5.3) 840 13 C NMR of bis(4-fluorophenyl) sulfate (126 MHz, CDCl3) (5.3) 841 19 F NMR of bis(4-fluorophenyl) sulfate (470 MHz, CDCl3) (5.3) 842 1 H NMR of diethyl (4-fluorophenyl) phosphate (500 MHz, CDCl3) 843 13 C NMR of diethyl (4-fluorophenyl) phosphate (126 MHz, CDCl3) 844 19 F NMR of diethyl (4-fluorophenyl) phosphate (470 MHz, CDCl3) 845 UV-Vis of bis(tricyclohexyl)nickel (II) dichloride 2 1.8 1.6 1.4 1.2 Absorbance 1 0.8 0.6 0.4 0.2 0 200 300 400 500 600 700 800 900 Wavelength (nm) 846 1 H NMR of 4-fluoro-4’-methoxy-1,1’-biphenyl (500 MHz, CDCl3) (5.2) 847 13 C NMR of 4-fluoro-4’-methoxy-1,1’-biphenyl (126 MHz, CDCl3) (5.2) 848 Reactivity Comparison of 4-fluorophenyl chloride vs 4-fluorophenyl imidazolyl sulfonate (condition A): 19F NMR of SMC over time (470 MHz, CDCl3) 849 Reactivity Comparison of 4-fluorophenyl chloride vs 4-fluorophenyl imidazolyl sulfonate (condition B): 19F NMR of SMC over time (470 MHz, CDCl3) 850 Reactivity Comparison of 4-fluorophenyl bromide vs 4-fluorophenyl imidazolyl sulfonate (condition A): 19F NMR of SMC over time (470 MHz, CDCl3) 851 Reactivity Comparison of 4-fluorophenyl bromide vs 4-fluorophenyl imidazolyl sulfonate (condition B): 19F NMR of SMC over time (470 MHz, CDCl3) 852 Reactivity Comparison of 4-fluorophenyl iodide vs 4-fluorophenyl imidazolyl sulfonate (condition A): 19F NMR of SMC over time (470 MHz, CDCl3) 853 Reactivity Comparison of 4-fluorophenyl iodide vs 4-fluorophenyl imidazolyl sulfonate (condition B): 19F NMR of SMC over time (470 MHz, CDCl3) 854 19 F NMR of nickel-catalyzed SMC of bis(4-fluorophenyl)sulfate (470 MHz, CDCl3) 855 19 F NMR of palladium-catalyzed SMC of bis(4-fluorophenyl)sulfate (470 MHz, CDCl3) 856 REFERENCES 857 REFERENCES (1) Astruc, D. The 2010 Chemistry Nobel Prize to R.F. Heck, E. Negishi, and A. Suzuki for Palladium-Catalyzed Cross-Coupling Reactions. Anal. Bioanal. Chem. 2011, 399, 1811– 1814. (2) Astruc, D. Organometallic Chemistry and Catalysis; Springer: Berlin, Germany, 2016. (3) Colacot, T. J. The 2010 Nobel Prize in Chemistry: Palladium-Catalysed Cross-Coupling. Platin. Met. Rev. 2011, 55, 84–90. (4) Matos, K.; Soderquist, J. A. Alkylboranes in the Suzuki-Miyaura Coupling: Stereochemical and Mechanistic Studies. J. Org. Chem. 1998, 63, 461–470. (5) Nunes, C. M.; Monteiro, A. L. Pd-Catalyzed Suzuki Cross-Coupling Reaction of Bromostilbene: Insights on the Nature of the Boron Species. J. Braz. Chem. Soc. 2007, 18, 1443–1447. (6) Braga, A. A. C.; Ujaque, G.; Maseras, F. A DFT Study of the Full Catalytic Cycle of the Suzuki−Miyaura Cross-Coupling on a Model System. Organometallics 2006, 25, 3647–3658. (7) Cammidge, A. N.; Goddard, V. H. M.; Gopee, H.; Harrison, N. L.; Hughes, D. L.; Schubert, C. J.; Sutton, B. M.; Watts, G. L.; Whitehead, A. J. Aryl Trihydroxyborates: Easily Isolated Discrete Species Convenient for Direct Application in Coupling Reactions. Org. Lett. 2006, 8, 4071–4074. (8) Braga, A. A. C.; Morgon, N. H.; Ujaque, G.; Lledós, A.; Maseras, F. Computational Study of the Transmetalation Process in the Suzuki–Miyaura Cross-Coupling of Aryls. J. Organomet. Chem. 2006, 691, 4459–4466. (9) Amatore, C.; Le Duc, G.; Jutand, A. Mechanism of Palladium-Catalyzed Suzuki-Miyaura Reactions: Multiple and Antagonistic Roles of Anionic “Bases” and Their Countercations. Chemistry 2013, 19, 10082–10093. (10) Braga, A. A. C.; Morgon, N. H.; Ujaque, G.; Maseras, F. Computational Characterization of the Role of the Base in the Suzuki-Miyaura Cross-Coupling Reaction. J. Am. Chem. Soc. 2005, 127, 9298–9307. (11) Amatore, C.; Jutand, A.; Le Duc, G. Kinetic Data for the Transmetalation/Reductive Elimination in Palladium-Catalyzed Suzuki-Miyaura Reactions: Unexpected Triple Role of Hydroxide Ions Used as Base. Chemistry 2011, 17, 2492–2503. (12) Amatore, C.; Jutand, A.; Le Duc, G. Mechanistic Origin of Antagonist Effects of Usual Anionic Bases (OH-, CO32-) as Modulated by Their Countercations (Na+, Cs+, K+) in Palladium-Catalyzed Suzuki-Miyaura Reactions. Chemistry 2012, 18, 6616–6625. 858 (13) Carrow, B. P.; Hartwig, J. F. Distinguishing between Pathways for Transmetalation in Suzuki-Miyaura Reactions. J. Am. Chem. Soc. 2011, 133, 2116–2119. (14) Kurokhtina, A. A.; Larina, E. V.; Yarosh, E. V.; Schmidt, A. F. Role of the Base and Endogenous Anions in “Ligand-Free” Catalytic Systems for the Suzuki–Miyaura Reaction. Kinet. Catal. 2016, 57, 373–379. (15) Snieckus, V. Directed Ortho Metalation. Tertiary Amide and O-Carbamate Directors in Synthetic Strategies for Polysubstituted Aromatics. Chem. Rev. 1990, 90, 879–933. (16) Petrone, D. A.; Ye, J.; Lautens, M. Modern Transition-Metal-Catalyzed Carbon-Halogen Bond Formation. Chem. Rev. 2016, 116, 8003–8104. (17) Amal Joseph, P. J.; Priyadarshini, S. Copper-Mediated C–X Functionalization of Aryl Halides. Org. Process Res. Dev. 2017, 21, 1889–1924. (18) Henschler, D. Toxicity of Chlorinated Organic Compounds: Effects of the Introduction of Chlorine in Organic Molecules. Angew. Chem. Int. Ed. 1994, 33, 1920–1935. (19) Wiley-VCH. Ullmann’s Encyclopedia of Industrial Chemistry; Wiley-VCH Verlag: Weinheim, Germany, 2011. (20) Littke, A. F.; Dai, C.; Fu, G. C. Versatile Catalysts for the Suzuki Cross-Coupling of Arylboronic Acids with Aryl and Vinyl Halides and Triflates under Mild Conditions. J. Am. Chem. Soc. 2000, 122, 4020–4028. (21) Nguyen, H. N.; Huang, X.; Buchwald, S. L. The First General Palladium Catalyst for the Suzuki-Miyaura and Carbonyl Enolate Coupling of Aryl Arenesulfonates. J. Am. Chem. Soc. 2003, 125, 11818–11819. (22) Percec, V.; Bae, J.-Y.; Hill, D. H. Aryl Mesylates in Metal Catalyzed Homocoupling and Cross-Coupling Reactions. 2. Suzuki-Type Nickel-Catalyzed Cross-Coupling of Aryl Arenesulfonates and Aryl Mesylates with Arylboronic Acids. J. Org. Chem. 1995, 60, 1060– 1065. (23) Albaneze-Walker, J.; Raju, R.; Vance, J. A.; Goodman, A. J.; Reeder, M. R.; Liao, J.; Maust, M. T.; Irish, P. A.; Espino, P.; Andrews, D. R. Imidazolylsulfonates: Electrophilic Partners in Cross-Coupling Reactions. Org. Lett. 2009, 11, 1463–1466. (24) Cívicos, J. F.; Gholinejad, M.; Alonso, D. A.; Nájera, C. Phosphane-Free Suzuki–Miyaura Coupling of Aryl Imidazolesulfonates with Arylboronic Acids and Potassium Aryltrifluoroborates under Aqueous Conditions. Chem. Lett. 2011, 40, 907–909. (25) Cívicos, J. F.; Alonso, D. A.; Nájera, C. Microwave-Promoted Suzuki-Miyaura Cross- Coupling of Aryl Imidazolylsulfonates in Water. Adv. Synth. Catal. 2012, 354, 2771–2776. 859 (26) Saeidian, H.; Abdoli, M. The First General Protocol ForN-Monoalkylation of Sulfamate Esters: Benign Synthesis OfN-Alkyl Topiramate (Anticonvulsant Drug) Derivatives. J. Sulphur Chem. 2015, 36, 463–470. (27) Shirbin, S. J.; Boughton, B. A.; Zammit, S. C.; Zanatta, S. D.; Marcuccio, S. M.; Hutton, C. A.; Williams, S. J. Copper-Free Palladium-Catalyzed Sonogashira and Hiyama Cross- Couplings Using Aryl Imidazol-1-Ylsulfonates. Tetrahedron Lett. 2010, 51, 2971–2974. (28) Ackermann, L.; Barfüsser, S.; Pospech, J. Palladium-Catalyzed Direct Arylations, Alkenylations, and Benzylations through C-H Bond Cleavages with Sulfamates or Phosphates as Electrophiles. Org. Lett. 2010, 12, 724–726. (29) Ackermann, L.; Mehta, V. P. Palladium-Catalyzed Mono-α-Arylation of Acetone with Aryl Imidazolylsulfonates. Chemistry 2012, 18, 10230–10233. (30) Luo, Y.; Wu, J. Synthesis of Arylphosphonates via Palladium-Catalyzed Coupling Reactions of Aryl Imidazolylsulfonates with H-Phosphonate Diesters. Organometallics 2009, 28, 6823– 6826. (31) Ackermann, L.; Sandmann, R.; Song, W. Palladium- and Nickel-Catalyzed Aminations of Aryl Imidazolylsulfonates and Sulfamates. Org. Lett. 2011, 13, 1784–1786. (32) Wolfe, J. P.; Singer, R. A.; Yang, B. H.; Buchwald, S. L. Highly Active Palladium Catalysts for Suzuki Coupling Reactions. J. Am. Chem. Soc. 1999, 121, 9550–9561. (33) Chen, H.; Huang, Z.; Hu, X.; Tang, G.; Xu, P.; Zhao, Y.; Cheng, C.-H. Nickel-Catalyzed Cross-Coupling of Aryl Phosphates with Arylboronic Acids. J. Org. Chem. 2011, 76, 2338– 2344. (34) Guan, B.-T.; Lu, X.-Y.; Zheng, Y.; Yu, D.-G.; Wu, T.; Li, K.-L.; Li, B.-J.; Shi, Z.-J. Biaryl Construction through Kumada Coupling with Diaryl Sulfates as One-by-One Electrophiles under Mild Conditions. Org. Lett. 2010, 12, 396–399. 860