ORGANOMETALLIC CHEMISTRY PERTAINING TO MAIN GROUP ELEMENTS SILICON, GERMANIUM, TIN, AND BORON      By Aaron J. Baker            A DISSERTATION Submitted to Michigan State University in partial fulfillment of the requirements for the degree of  ChemistryDoctor of Philosophy 2016   ABSTRACT ORGANOMETALLIC CHEMISTRY PERTAINING TO MAIN GROUP ELEMENTS SILICON, GERMANIUM, TIN, AND BORON     By Aaron J. Baker  Double-decker silsesquioxane (DDSQ) cages closed with some end cap reagents were found to have degradations uncharacteristic for these cages. This could be blamed on the inefficient synthesis of the dichlorosilanes used as end cap reagents as well as possible degradations caused by side reactions involving trace palladium left over from the synthesis of end cap precursors. Work detailing methods of synthesizing end cap precursors without palladium, as well as evaluating palladium levels through the use of inductively coupled plasma  optical emission spectroscopy (ICP-OES) are disclosed.  Germanium is not as toxic as tin, but organometallic reactions involving germanium have been studied far less than tin. While research from our lab has shown that germanium can undergo an unusual coupling reaction with aryl iodides that inverts the stereochemistry, the mechanism is still largely unknown and optimizations are still ongoing. However, we have found which leads to the possibility of a one-pot process involving hydrogermylation and coupling due to the solvent required for the unique coupling reaction.  As previously stated, trialkyltin substrates are quite toxic, especially tributyltin hydride. Since trialkylvinyltin reagents are very useful for the Stille cross-coupling reaction, people have looked for alternative methods for synthesizing those tin reagents in selective and less toxic ways. Our group has shown that using poly(methylhydrosiloxane), or PMHS, as a reducing agent can provide the toxic tributyltin hydride in situ from tributyltin halides for palladium catalyzed hydrostannation. We have found that hydrostannations can be performed with tributyltin fluoride and PMHS to in situ create tributyltin hydride, which when reacted in situ with alkynes affords trialkylvinyltin in isomeric ratios similar to those synthesized using commercial tributyltin hydride in the same hydrostannations.  The Suzuki-Miyaura cross-coupling reaction has been used extensively by pharmaceutical companies to create carbon-carbon bonds due to its relative ease and lack of toxic byproducts, compared to other methods such as the Stille cross-coupling.  However, pharmaceutical companies would like to avoid the ubiquitous use of haloaromatics in the Suzuki-Miyaura reaction due to possible toxicity concerns in haloaromatics and haloaromatic equivalents, such as tosylates and triflates.  Imidazolyl sulfonates have previously been -Miyaura cross-couplings, so we extended their usage into one-pot processes with iridium catalyzed C-H borylation reactions and created our own imidazolyl sulfonates through similar borylations followed by oxidation with Oxone or photoredox catalysis.  Iridium catalyzed C-H borylation has been shown to be directed mostly by sterics, but there are other factors which can change the ratio of regiochemical isomers obtained in a borylation, including solvent, ligand, and possible directing groups on the arene to be borylated.  Fluorine, in particular, has both a small size and a large inductive effect that changes the ratios of products. In conjunction with Dow Chemical, we have looked at a cross-section of fluorinated arenes for the ratio of products obtained in C-H borylations in a variety of conditions, changing solvents, temperatures, and ligands to determine the changes in regioisomeric ratios of borylated products.                   Copyright by AARON J BAKER 2016 v                      I dedicate this dissertation to my wife Jessica  as well as my parents, sister, and the rest of my family vi  ACKNOWLEDGEMENTS   I would like to thank my advisor, Robert Maleczka, for all of his work in guiding me towards becoming a better scientist during my time here. Even as department chair he has always been available to ask questions the same day, and has helped me to be better at scientific writing, presenting, and also teaching once I realized my true passion for teaching chemistry during my time here. He sat in almost every lecture of CEM 252 that I was lecturing and provided constant feedback to help me become a better teacher and lecturer, and I hope to carry that forward as I continue in my independent academic career.  I would like to thank my second reader, William Wulff, for leading my committee and being available when I had questions to ask of him. I enjoyed working on the database and it helped me learn countless reactions in total syntheses and kept me involved in constantly reading the literature. Between that and CEM 850 and 852 that I took from you, I have a broad base of knowledge that I am looking forward to always expanding as I leave Michigan State, and I will not forget your overall kindness or the Macallan scotch you generously gave to me.  I would also like to thank committee members Aaron Odom, Kevin Walker, and Andre Lee for serving on my committee in one form or another over the years, and I have enjoyed the conversations I have had with all of you during my time here. I would like to thank Andre Lee and Mitch Smith for the collaborations with the boron and DDSQ projects, as I appreciate that both of you pushed me to become a better scientist and to think about problems in new and different ways.  I would like to thank my current and former group members, especially Rosario, Luis, Damith, Suzi, Jonathan, Gayanthi, Ruwi, David, Bani, Fangyi, and Hao for all of your help vii  getting started in the lab and then for continuing helpful discussions about chemistry, in addition to the boron group members Tim, Kristin, Behnaz, Buddha, and Dmitry for all of their help with the glovebox.  I would like to thank my wife, Jessica, for her constant love and moral support from graduate school orientation to thesis writing, as well as my family for their support as well.  I would also like to thank the friends I made at CCV, as we found a church home and friends in East Lansing even with our busy schedules. We will miss you all as we travel to Wooster for the start of my independent academic career.  viii  TABLE OF CONTENTS   x .. xi LIST OF SC... xvi KEY TO ABBREVI.... xix CHAPTER ... 1  1.1 Main Group Elements in Organometallic Chemistry             REFERENCES     2.1 Introduction to Double Decker Silsesquioxane (DDSQ) Cages   2.2 One-Pot Synthesis of DDSQ with Phenethynyl Side Chains   2.3 Syntheses of Side Chain Precursors by Palladium and Palladium-Free Routes   2.4 ICP-OES Analysis of Palladium Content of Side Chain and End-Cap Units   2.5 Experimental    2.5.1 Experimental for One-Pot Synthesis of DDSQ       2.5.2 Experimental for Syntheses of Side Chain Precursors    2.5.3 Experimental for ICP Analysis                   43   3.1 Introduction to Hydrogermylation/Coupling 43  3.2 Attempted Reduction of Bu3GeCl 7  3.3 Synthesis of Vinyl Germanes in Other Solvents and With Other Catalysts 7  3.4 One-Pot Hydrogermylation/Germyl Coupling 2  3.5 Experimental    3.5.1 Synthesis of Vinyl Germanes    3.5.2 One-Pot Synthesis              APPENDIX ...................................................................................................................... 62  REFERENCES 4   77  4.1 Introduction to PMHS Reductions in Organic Chemistry   4.2 PMHS Reductions of Tin Halides and Oxides   4.3 Hydrostannations of Alkynes Using PMHS and Tin Halides   4.4 Hydrostannations of Alkynes Using MoBI3 as a Catalyst 4  4.5 Hydrostannations of Alkynes Using PMHS and MoBI3  ix   4.6 Hydrostannations of Alkynes Using PMHS and Other Transition Metal Catalysts. 91  4.7 Conclu   4.8 Experimental 2    4.8.1 Preparation of Starting Materials 3    4.8.2 MoBI3-Catalyzed Hydrostannations 5     4.8.3 NiCl2(PPh3)2-Catalyzed Hydrostannation 3     4.8.4 CoCl2(PPh3)2-Catalyzed Hydrostannation ... 104             APPENDIX .................................................................................................................... 106   REFERENCES   143  5.1 The Need for Imidazolyl Sulfonate Coupling Reactions 143  5.2 Introduction to Photoredox Chemistry   5.3 Electron Rich Boronic Esters for Suzuki Reactions with Imidazolyl Sulfonates ... 149  5.4 Making Imidazolyl Sulfonates from Borylated Arenes   5.5 Conclusion   5.6 Experimental    5.6.1 Borylations  61   5.6.2 One-Pot Borylation/Suzuki Couplings .   5.6.3 Synthesis of Phenols from Oxidation of Boronic Esters    5.6.4 Synthesis of Imidazolyl Sulfonates ..             APPENDIX .................................................................................................................... 174  REFERENCES   . 199  6.1 Directing Groups for Borylation   6.2 Steric and Electronic Effects Determine Borylation Regiochemistry   -Methyl-Pyrrolidone (NMP)   6.4 Experimental 220    6.4.1 Ligand Synthesis 221     6.4.2 Well- 222     6.4.3 Well-Plate Reactions with NMP 253             APPENDIX .................................................................................................................... 265   R280   x  LIST OF TABLES  Table 4.1: MoBI3 Hydrostannation .. 88  Table 5.1: One-pot C-H Activation/Borylation/Suzuki Cross-Coupling of Disubstituted       Arenes by Perera ....................................................................................................... 150  Table 5.2: One-pot C-H Activation/Borylation/Oxidation/Imidazolyl Sulfonation of                    Disubstituted Arenes   Table 6.1: Borylation of 1-Chloro-3-fluoro-2-methylbenzene in Hünig's Base 210  Table 6.2: Borylation of 1-Chloro-2-ethoxy-3-fluorobenzene in Hünig's Base  211  Table 6.3: Borylation of 2-Chloro-6-fluoro-N,N-dimethylaniline in Hünig's Base 212  Table 6.4: Borylation of 1,2-Dichloro-3-fluorobenzene in Hünig's Base 213  Table 6.5: Borylation of 1-Chloro-2,3-difluorobenzene in Hünig's Base 214  Table 6.6: Borylation of 2-Chloro-6-fluorobenzonitrile in Hünig's Base 215  Table 6.7: Borylation Comparison Across Substrates of dtbpy in NMP vs. Hünig's Base  217  Table 6.8: Borylation Comparison Across Substrates of TMP in NMP vs. Hünig's Base 218  Table 6.9: Borylation Comparison Across Substrates of DPM in NMP vs. Hünig's Base 219  xi  LIST OF FIGURES   Figure 2.1: First Completely Condensed POSS Cage Synthesized, Me8T8  Figure 2.2: Polyimides, Poly(methylmethacralates), and Polyurethanes Are Examples of                     Thermosetting Polymers   Figure 2.3: An Example of Pendent-Like (left), Bead-Like (center), and "Beads on a Chain-                   Like" (right) Structures ..... 7                        Figure 2.4: DSC Results for DDSQ Made in Two Different Batches   Figure 2.5: Comparison of End Capped DDSQ Monomers, Commercial Dichlorosilane                     (Green Line) Shows No Weight Loss Prior to Complete Degradation   Figure 2.6: Air Force Material AFR-PE-4, with n = 4, with Weight Loss Prior to 400 °C   Figure 2.7: Structure of PEPA ............. 15  Figure 2.8: Two Solid-Supported Palladium Scavengers Used in This Study  22  Figure 2.9: 1H NMR of BPEP-DDSQ   Figure 2.10: 13C NMR of BPEP-DDSQ ..............................................................  Figure 2.11: 29Si NMR of BPEP-DDSQ ..............................................................  Figure 2.12: 1H NMR of 1-Bromo-4-iodobenzene ..............................................  Figure 2.13: 13C NMR of 1-Bromo-4-iodobenzene .............................................  Figure 2.14: 1H NMR of 1-Bromo-3-iodobenzene .............................................. 36  Figure 2.15: 13C NMR of 1-Bromo-3-iodobenzene .............................................  Figure 2.16: 1H NMR of Cleaned PEPA .............................................................  Figure 2.17: 13C NMR of Cleaned PEPA ............................................................  Figure 2.18: 1H NMR of PEPA Ester Acid .........................................................  Figure 2.19: 13C NMR of PEPA Ester Acid ........................................................  Figure 3.1: 1H NMR of Hydrogermylation of Alkyne 6 ..  Figure 3.2: 13C NMR of Hydrogermylation of Alkyne 6 .....  xii  Figure 3.3: 1H NMR of Hydrogermylation of Alkyne 6 in Water .  Figure 3.4: 1H NMR of Hydrogermylation of Alkyne 7 in Water.....................  Figure 3.5: 1H NMR of Hydrogermylation of Alkyne 7 in Water Expansion......................  Figure 3.6: 13C NMR of Hydrogermylation of Alkyne 7 in Water.....................  Figure 3.7: 1H NMR of One-pot Hydrogermylation/Coupling ...  Figure 3.8: 1H NMR of One-pot Hydrogermylation/Coupling Expansion...........  Figure 3.9: 13C NMR of One-pot Hydrogermylation/Coupling.  Figure 3.10: 1H NMR of New One-pot Hydrogermylation/Coupling...................  Figure 3.11: 1H NMR of New One-pot Hydrogermylation/Coupling Expansion............  Figure 4.1: Structure of PMHS   Figure 4.2: 1H NMR Spectra for Hydrostannation of Ethyl Propiolate with Bu3SnF (top) and                       Bu3SnH (bottom) 9  Figure 4.3: 1H NMR   Figure 4.4: 13C NMR 108  Figure 4.5: 1H NMR   Figure 4.6: 13C NMR of Starting Alkyne 13   Figure 4.7: 1H NMR of Starting Alkyne 15 ...............................111  Figure 4.8: 1H NMR of Starting Alkyne 15 Expansion .............112  Figure 4.9: 13C NMR of Starting Alkyne 15 ........................................................113  Figure 4.10: 1H NMR of Hydrostannation of Alkyne 16 ..............114  Figure 4.11: 13C NMR of Hydrostannation of Alkyne 16 ..........................................................115  Figure 4.12: 1H NMR of Hydrostannation of Alkyne 9 ..............116  Figure 4.13: 1H NMR of Hydrostannation of Alkyne 9 Expansion................................117  Figure 4.14: 13C NMR of Hydrostannation of Alkyne 9 .............118  Figure 4.15: 1H NMR of Hydrostannation of Alkyne 10 ....................119  xiii  Figure 4.16: 1H NMR of Hydrostannation of Alkyne 10 Expansion.......................................... 120  Figure 4.17: 13C NMR of Hydrostannation of Alkyne 10............121  Figure 4.18: 1H NMR of Hydrostannation of Alkyne 11 Conditions A .........................122  Figure 4.19: 1H NMR of Hydrostannation of Alkyne 11 Expansion Conditions A ..123  Figure 4.20: 13C NMR of Hydrostannation of Alkyne 11 Conditions A.124  Figure 4.21: 1H NMR of Hydrostannation of Alkyne 11 Conditions B ............................125  Figure 4.22: 1H NMR of Hydrostannation of Alkyne 11 Expansion Conditions B .................. 126  Figure 4.23: 13C NMR of Hydrostannation of Alkyne 11 Conditions B ......................127  Figure 4.24: 1H NMR of Hydrostannation of Alkyne 12 Conditions A ............128  Figure 4.25: 1H NMR of Hydrostannation of Alkyne 12 Expansion Conditions A ......129  Figure 4.26: 13C NMR of Hydrostannation of Alkyne 12 with Cobalt....130  Figure 4.27: 1H NMR of Hydrostannation of Alkyne 12 with Cobalt.........................131  Figure 4.28: 1H NMR of Hydrostannation of Alkyne 12 Expansion with Cobalt ..........132  Figure 4.29: 1H NMR of Hydrostannation of Alkyne 13..............133  Figure 4.30: 1H NMR of Hydrostannation of Alkyne 13 Expansion134  Figure 4.31: 13C NMR of Hydrostannation of Alkyne 13..............................................135  Figure 4.32: 1H NMR of Hydrostannation of Alkyne 14.............. 136  Figure 4.33: 1H NMR of Hydrostannation of Alkyne 14 Expansion......................137  Figure 4.34: 13C NMR of Hydrostannation of Alkyne 14............138  Figure 4.35: 1H NMR of Hydrostannation of Alkyne 15..............139  Figure 4.36: 1H NMR of Hydrostannation of Alkyne 15 Expansion. 140  Figure 4.37: 13C NMR of Hydrostannation of Alkyne 15............141  Figure 5.1: Triflates, Tosylates, and Mesylates Are Examples of Non-Halogen Electrophiles,                     but All Have Potential Issues ... 145  Figure 5.2: 1H NMR Spectra for the Borylation of 1,3-Dimethoxybenzene with dtbpy and                     TMP 151 xiv   Figure 5.3: 1H NMR of Borylation of Arene 16....................175  Figure 5.4: 1H NMR of Borylation of Arene 16 Expansion ..................176  Figure 5.5: 13C NMR of Borylation of Arene 16 .....................................................177  Figure 5.6: 1H NMR of Borylation of Arene 18 ................................................178  Figure 5.7: 13C NMR of Borylation of Arene 18 .....................................................179  Figure 5.8: 1H NMR of Suzuki Product 21 ................................................................................ 180  Figure 5.9: 13C NMR of Suzuki Product 21 ............................................181  Figure 5.10: 1H NMR of Phenol 24 .......................................................82  Figure 5.11: 13C NMR of Phenol 24 ............................................................................183  Figure 5.12: 1H NMR of Imidazolyl Sulfonate 28 ..............................184  Figure 5.13: 13C NMR of Imidazolyl Sulfonate 28 ................................185  Figure 5.14: 1H NMR of Imidazolyl Sulfonate 29  ..............................................186  Figure 5.15: 13C NMR of Imidazolyl Sulfonate 29 ............187  Figure 5.16: 1H NMR of Imidazolyl Sulfonate 32 ...........................188  Figure 5.17: 13C NMR of Imidazolyl Sulfonate 32 ..........189  Figure 5.18: 1H NMR of Imidazolyl Sulfonate 35 .........190  Figure 5.19: 13C NMR of Imidazolyl Sulfonate 35 ..........................................191  Figure 5.20: 1H NMR of Imidazolyl Sulfonate 38 ...........192  Figure 5.21: 13C NMR of Imidazolyl Sulfonate 38 ..............................193  Figure 5.22: 19F NMR of Imidazolyl Sulfonate 38 ........................................194  Figure 6.1: Kanai's Bipyridine Ligand with a Urea Group for Meta Borylation 203  Figure 6.2: 1H NMR of Dipyridylmethane Ligand .............................................  Figure 6.3: 13C NMR of Dipyridylmethane Ligand ............................................  Figure 6.4: 19F NMR of Borylation of Arene 42 with dtbpy ..............................  xv  Figure 6.5: 19F NMR of Borylation of Arene 42 with Box .................................  Figure 6.6: 19F NMR of Borylation of Arene 45 with dtbpy ..............................  Figure 6.7: 19F NMR of Borylation of Arene 45 with Box .................................  Figure 6.8: 19F NMR of Borylation of Arene 48 with dtbpy ..............................  Figure 6.9: 19F NMR of Borylation of Arene 48 with Box .................................  Figure 6.10: 19F NMR of Borylation of Arene 51 with dtbpy ................................  Figure 6.11: 19F NMR of Borylation of Arene 51 with Box ...................................  Figure 6.12: 19F NMR of Borylation of Arene 54 with dtbpy ....................................  Figure 6.13: 19F NMR of Borylation of Arene 54 with Box ...................................  Figure 6.14: 19F NMR of Borylation of Arene 57 with dtbpy ................................... 278  Figure 6.15: 19F NMR of Borylation of Arene 57 with Box ...................................   xvi  LIST OF SCHEMES   Scheme 1.1: Grignard Reagents and Organolithium Species Are Created Through Several                      Typical Organometallic Routes, such as Oxidative Addition and Metal-Halogen                        Exchange   Scheme 1.2: The Stille Cross-Coupling and Suzuki-Miyaura Cross-Coupling Are Two Examples                       of Transmetallations Performed with Main Group Elements  Scheme 2.1: Capping DDSQ Cages with a Capping Agent Gives Two Products if the            Dichlorosilane is Asymmetric    Scheme 2.2: Synthesis of PEPI-DDSQ in One-Pot   Scheme 2.3: One-Pot Procedure to Synthesize BPEP-DDSQ   Scheme 2.4: Multi-gram Scale of Palladium Catalyzed Sonagashira Coupling ..  Scheme 2.5: Nickel Catalyzed Sonagashira Coupling of Phenyl Acetylene with 1-bromo-4-                        iodobenzene   Scheme 2.6: Preparation of PEPA by Sonagashira Cross-Coupling, Followed by Ring Opening                          and Re-Closing   Scheme 2.7: Attempted Nickel-Catalyzed Synthesis of the Ester Acid Derived from PEPA ..... 19  Scheme 3.1: The Stille Reaction Cross-Couples Aryl and Vinyl Stannanes with Halides Very                       Effectively 43  Scheme 3.2: Can the Stille Cross-Coupling Be Reproduced with Germanium Instead of Tin?.. 44  Scheme 3.3: Reaction with Stille-Type Conditions Gives an Unexpected Product 45  Scheme 3.4: Proposed Mechanism 46  Scheme 3.5: Pd(PPh3)2Cl2 Hydrogermylates Faster Than Pd(PPh3)4 48  Scheme 3.6: Methylene Chloride and Acetonitrile/Water are Poor Solvents for                          Hydrogermylation 49  Scheme 3.7: Hydrogermylation Can Be Done with Water as the Solvent 50  Scheme 3.8: AIBN Catalyzed and Cobalt Catalyzed Hydrogermylations Failed to Provide Any                      Material50  Scheme 3.9: Hydrogermylation of 2-Phenylbut-3-yn-2-ol Works in Water As Well 51  xvii  Scheme 3.10: Diels-Alder Cyclization by Sharpless "On Water" 52  Scheme 3.11: One-pot Hydrogermylation/Coupling Compares Favorably to Two Step Process 53  Scheme 3.12: One-pot Hydrogermylation/Coupling with New Conditions Gives High Yield, but                         Still Lower Isomeric Ratio   Scheme 4.1: Transition Metal Catalyzed Reductions with PMHS   Scheme 4.2: Fluoride Assisted Reduction of an Ester with PMHS   Scheme 4.3: PMHS Reductions with Transition Metals and Halides    Scheme 4.4: One-pot Hydrostannation/Stille Cross-Coupling Catalytic in Tin  0  Scheme 4.5: Palladium Catalyzed Hydrostannations in situ with PMHS    Scheme 4.6: Radical Hydrostannations in situ with PMHS    Scheme 4.7: Anhydrous Bu3SnCl/PMHS/KF Method Also Provides the Internal Stannane                       with Ni(PPh3)2Cl2  3  Scheme 4.8: Cobalt Catalyzed Hydrostannations with Bu3SnCl/PMHS and Bu3SnH Give                      Similar Results   Scheme 4.9: Kazmaier Showed that MoBI3 is Effective for Making Internal Stannanes .... 85  Scheme 4.10: Proposed Mechanism by Kazmaier  .  Scheme 4.11: Bu3SnCl/PMHS/KF Method Also Provides the Internal Stannane with MoBI3 ... 87  Scheme 4.12: Potential Mechanism for Z-Isomer Formation ... 90  Scheme 4.13: 3,3-Dimethylbut-1-yne Gives the E-Isomer as the Major Product    Scheme 4.14: NiCl2(PPh3)2 Catalyzed Hydrostannations   Scheme 4.15: CoCl2(PPh3)2 Catalyzed Hydrostannations   Scheme 5.1: The Suzuki-Miyaura Cross-Coupling is an Efficient Route to Biaryl Systems .... 143  Scheme 5.2: Traditional Methods of Borylation 144  Scheme 5.3: Imidazolyl Sulfonates Decomposition Products Are Imidazole and Sulfuric Acid145  Scheme 5.4: C-H Borylation Provides a Route for Synthesizing Electrophiles Through Further                       Reactions 146 xviii   Scheme 5.5: Examples of Photoredox Chemistry by MacMillan, Stephenson, and Yoon . 147  Scheme 5.6: Ru(bpy)3Cl2 is a Versatile Photoredox Catalyst, Able to Reduce or Oxidize ..... 148  Scheme 5.7: Xiao's Previous Work Synthesizing Pyrrolo[2,1-a]isoquinolines Using                       Photoredox Catalysis 148  Scheme 5.8: Generic Conditions for One-pot Borylation/Suzuki Process .. 149  Scheme 5.9: Using DMF as the Primary Solvent Leads Only to Incomplete Conversion ........ 152  Scheme 5.10: Final Optimized Conditions for One-pot Process with 1,3-Dimethoxybenzene.. 153  Scheme 5.11: Making Phenols of Methyl 3-Chlorobenzoate with DMF and DMAc . 156  Scheme 5.12: Arenes with Two Different Electrophiles in the Suzuki Reaction Can Make                         Selective Additions Possible   Scheme 5.13: Multi-step Synthesis of an Imidazolyl Sul59  Scheme 6.1: Diagram of Several Methods for Ortho Borylation 200  Scheme 6.2: Borylation of 2-Substituted indoles Can Be Selective for the 3 or 7 Position                       Based on Conditions 200  Scheme 6.3: Anilines, Pyrroles, and Indoles Have Different Borylation Patterns with                       Protecting .  201  Scheme 6.4: Directed Ortho Borylation of Phenols Using Dimethylsilane  202  Scheme 6.5: Both of These Ligands Help to Direct Ortho to Substituents on the Arene, But                      in Different Ways 203                   Scheme 6.6: Electronic and Steric Effects Can Cause Mixtures of Regioisomers  205  Scheme 6.7: Steric and Electronic Products Are Shown Above 206  Scheme 6.8: Substrates to Study with Well-Plate Reactions 206  Scheme 6.9: Ligands Studied in the Well-Plate Reactions: dtbpy, TMP, DTBBM, DPM, and                         Box 207  Scheme 6.10: First Well-Plate Reaction: Hünig's Base, dtbpy, Room Temperature, 12 Hours..208  Scheme 6.11: Second Well-Plate Reaction: Hünig's Base, dtbpy, 60 °C, 6 Hours 209   xix  KEY TO ABBREVIATIONS   ACS   American Chemical Society  AFR-PE-4  Air Force polyimide oligomer  AIBN   azobisisobutyronitrile  B2Pin2   bis(pinacolato)diboron  Box   bis(oxazoline)  BPEP-DDSQ  bis(phenethynyl)phenyl-double decker silsesquioxane  Bu3GeCl  tributylgermanium chloride  Bu3GeH  tributylgermane  Bu3SnCl  tributyltin chloride  Bu3SnF  tributyltin fluoride  Bu3SnH  tributyltin hydride  (Bu3Sn)2O  bis(tributyltin) oxide  Bu6Sn2   hexabutylditin  CDCl3   deuterated chloroform  CH2Cl2  dichloromethane  Co(PPh3)2Cl2  dichlorobis(triphenylphosphine)cobalt(II)  DDSQ   double decker silsesquioxane  DMAc   N,N-dimethylacetamide  DMF   N,N-dimethylformamide  DPM   dipyridylmethane  DSC   differential scanning calorimetry  DTBBM  (S,S)--methylenebis(4-tert-butyl-2-oxazoline)  dtbpy   4--di-tert-butyl-2--bipyridine  E   entgegung, German for apart xx   GCI   Green Chemistry Institute  h   hour  HBPin   pinacol borane  ICP-OES  inductively coupled plasma/optical emission spectrometry  ICP-MS  inductively coupled plasma/mass spectrometry  Int   internal  KF   potassium flouoride  mg   milligrams  mL   milliliter  MLCT   metal to ligand charge transfer  mmol   millimole  MoBI3    Mo(CO)3(CNt-Bu)3  mp   melting point  N2   nitrogen  NASA   National Aeronautics and Space Administration  NiCl2(PPh3)2  dichlorobis(triphenylphosphine)nickel(II)  NMP   N-methyl pyrrolidinone  NMR   nuclear magnetic resonance  Pd   palladium  PdCl2(PPh3)2  dichlorobis(triphenylphosphine)palladium(II)  Pd(OAc)2  palladium acetate  Pd(PPh3)4  palladium tetrakis(triphenylphosphine)  PEPA   phenethynylphthalic anhydride  PEPI-DDSQ  phenethynylphthalic imide-double decker silsesquioxane  PDMS   polydimethylsiloxane xxi  PMHS   poly(methylhydrosiloxane)  PMR   polymerization of monomer reactants  POSS   polyhedral oligomeric silsesquioxanes  ppm   parts per million  rt   room temperature  Ru(bpy)3Cl2  t-bipyridyl)dichlororuthenium(II)  SCE   standard calomel electrode  Silica-SMAP-Ir silicon-constrained monodentate trialkylphosphine  TBAB   tetrabutylammonium bromide  TBAF   tetrabutylammonium bromide  Td   temperature of decomposition  Tg   glass transition temperature  TGA   thermogravimetric analysis  THF   tetrahydrofuran  TLC   thin layer chromatography  TMP   tetramethylphenanthroline  Z   zusammen, German for together 1  CHAPTER 1 1.1 Main Group Elements in Organometallic Chemistry  Organometallic chemistry is a branch of organic chemistry relating to materials which possess bonds between a carbon and a metal, usually a transition metal.1 However, organometallic chemistry is not restricted to carbon bonds to transition metals; it also includes carbon bonds to main group metals as well.  Main group elements are defined as anything in the s or p block of the periodic table, so alkali metals such as lithium and sodium are included, as well as p block elements such as boron, tin, and silicon.  Organometallic reactions with main group metals have a diverse chemistry that is predominantly affected by the group the metal is in on the periodic table.   For example, a magnesium addition to an organic halide to form a Grignard reagent (Scheme 1.1) is an example of an oxidative addition where the magnesium metal is oxidized from neutral (Mg0) to a positively charged species (Mg+2).  Additionally, an organometallic compound that has already been formed like n-butyl lithium can undergo a lithium-halogen exchange with an aryl halide to form the aryl lithium species and the corresponding n-butyl halide (Also Scheme 1.1).  In these ways, main group metals can perform many similar transformations with carbon as transition metals.  2   Perhaps the most common way main group semi-metals like boron, silicon, germanium, and tin are used is in transmetallations.  Transmetallation is the transfer of the organic group from one metal to another, and organotins,2 silanes,3 germanes,4 and boronic acids5 are all used in various cross-coupling reactions (Scheme 1.2). The organic group attached to the main group semi-metal is transferred onto a transition metal, usually palladium, and then is cross-coupled to another organic moiety.  This dissertation focuses on work involving four main group semi-metals and their reactions with organic molecules: silicon, germanium, tin, and boron.  While not all reactions are cross-coupling reactions, these reactions usually involve an additional transition metal that is used to catalyze either the formation of a new organic compound through cross-coupling or the formation of an organometallic compound for use in further studies.      3           REFERENCES         4  REFERENCES   1 Elschenbroich, C.; Salzer, A. Organometallics A Concise Introduction; VCH Publishers:    Weinheim, 1989.  2 Stille, J.K. Angew. Chem. Int. Ed. 1986, 25, 508524.   3 Hiyama, T. J. J. Organomet. Chem. 2002, 653, 5861.  4 Torres, N. M.; Lavis, J. M.; Maleczka, Jr., R. E. Tetrahedron Lett. 2009, 50, 44074410.  5 (a) Miyaura, N.; Yamada, K.; Suzuki, A. Tetrahedron Lett. 1979, 20, 34373440.  (b) Miyaura,     N.; Suzuki, A. J. Chem. Soc., Chem. Commun. 1979, 866867. 5  CHAPTER 2 2.1 Introduction to Double Decker Silsesquioxane (DDSQ) Cages  Organo-functionalized silsesquioxanes and their chemistries have become a topic of recent study in materials chemistry.  Silsesquioxanes are a class of silicon-based materials bearing the formula (RSiO1.5)n, where n is an integer and R is an organic group, either inert or able to be further functionalized.  While silsesquioxanes can be constructed in either random, ladder, or cage-like structures, our research focused in particular on cage-like structures called polyhedral oligomeric silsesquioxanes, also known as POSS.1  The first POSS cage was synthesized by Scott in 1946, and named Me8T8.2  It was called Me8T8 due to the eight methyl functional groups off of eight silicon atoms that are bonded three times to oxygen.3  This Me8T8 cage structure is shown below (Figure 2.1).   While the T8 is highly symmetrical, other structures have also been synthesized, ranging from n = 6 to n = 18.4  In any event, these POSS cages have drawn interest for their unique defined particle size (1-3 nm), as well as their ability to be used in applications that require unique inorganic/organic hybrid materials.  Examples of these applications range from liquid crystals to catalysis.5  The capability of these hybrid materials to also offer thermal stability and 6  solubility while maintaining a rigid silica based core provides the ability for these compounds to have thermal and mechanical properties that exceed fully organic materials.6  This stability allows for POSS cages to be introduced into polymer matrices to make hybrid inorganic/organic polymers.  The POSS cages provide the polymers with thermal, oxidative, and flammability resistance, as well as increased solubility and decreased viscosity.7  These POSS cages have been incorporated into a number of common classes of thermosetting polymers (Figure 2.2), such as polyimides,8 polyurethanes,9 poly(methylmethacrylates),10 polybenzoxazines,11 and poly (ethylene imines).12   Because of the advantages that POSS-containing polymers have over existing technology, the United States Air Force has done research on POSS-containing polymers as a thermoset material.  The National Aeronautics and Space Administration (NASA) have also looked into the potential of using these materials for their resistance to flammability and oxidation as film coatings during space missions.    Adding POSS to polymer moieties provides an increase to the temperature of decomposition (Td).  While the organic substituents of the cage may start to decompose, in burning they form a char-like substance on top of the cage, which prevents further breakdown.13  The organic substituents on each silicon atom also help with solubility in organic medium, and give the possibility of further functionalization of the substituents.  All of these intriguing 7  properties have led to over two decades of research into incorporating POSS cages into polymers to improve thermal and oxidative stability.  There have been three primary ways of incorporating POSS cages into polymers: pendant-like structures, bead-like structures,14 and beads on a chain.15  An example of each is shown below in Figure 2.3, but we have focused our research on the third type, beads on a chain.   -decker silsesquioxane, also known as DDSQ.  DDSQ is comprised of two decks of silsesquioxanes that have been stacked on top of each other, forming a cage-like structure.  The only commercially available DDSQ molecule available has phenyl groups as the organic side chains off the tetrasilanol structure, but the tetrasilanol structure allows for further modification of the DDSQ.  Recent work has centered on including functionalized DDSQ as monomeric units in polymeric structures.16    The tetrasilanols can also be closed with a dichlorosilane capping agent.  If the two other groups off of the dichlorosilane are symmetrical, there is only one product formed.  8  However, if the two groups are asymmetric, this causes the reaction to generate both cis and trans isomers of the DDSQ cage.  Since the isomers do not pack the same way, this causes the cis and trans isomers to have different physical properties, most important of which are differing melting points and solubilities, especially when synthesized together (Scheme 2.1).    Depending on the capping agents that are used, the DDSQ cages can be capped with groups such as vinyl groups, amines, and epoxides, among others, which all give further reactive moieties for further functionalization and polymerization.17  Because of the ability to functionalize and incorporate the DDSQ cages into a polymer, the ability to synthesize new capped DDSQ cages and develop a methodology to synthesize DDSQ cages efficiently opens up new possibilities in materials research with potentially new applications for the cages. 2.2 One-Pot Synthesis of DDSQ with Phenethynyl Side Chains   Polyimides are commercially available polymers that strengthen when heated, but cannot be remolded after they have been heated.  This class of polymers is called thermoset polymers, 9  which differ from thermoplastic polymers, which are re-malleable with additional heat.  Polyimides especially have been used because of their excellent thermal stability, and applications range from coatings for microelectronic equipment to high temperature applications for the Air Force and NASA.  However, the viscosity of polyimide polymers is typically high, and improvements to the polyimide polymer to lower the viscosity (without losing the excellent thermal properties of the polymer) have been looked at as a potential area of research.  Another potential issue with polyimides is the temperature at which it undergoes a solid to liquid phase transition (319-349 °C). The temperature is dangerously close to the temperature at which polyimides perform their curing reaction (350-371 °C), where the polyimide polymer chains cross-link and harden to their final thermoset structure.18    One method that has been investigated to solve these problems is using DDSQ as a backbone for polyimides.  The cage structures would disrupt the packing efficiency of the polymer, causing it to be lower in viscosity.  In addition, the glass transition temperature (Tg) is lowered from over 300 °C to 170 °C, also because of the intermolecular interactions that were broken. Thankfully, when the Tg was lowered by Lee and co-workers, the properties of the polyimide were maintained.19  In order to optimize these results, studies were undergone to make DDSQ cages functionalized with phenethynylphthalic anhydride (PEPA) to make PEPI-DDSQ (phenethynylphthalic imide-double decker silsesquioxane) oligoimides. When the DDSQ was end capped with silanes containing either a meta or para aniline group to make the fully condensed cages, a six isomer mixture was obtained, with the isomers a combination of both regioisomers (meta and para anilines) as well as stereoisomers (cis and trans isomers of the cage).20  Studies showed that this mixture and its lower packing efficiency produced a lower viscosity consistent with the goals in mind for the project.21 10   However, the synthesis of PEPI-DDSQ from the regioisomer mixture of meta- and para- aminophenyl methyldichlorosilanes and POSS tetrasilanol to final product required multiple purification steps, which caused a decrease in the overall yield.  While each step of the original procedure was 70% yield or higher, the three steps required reduce the overall yield to only 53%.  Combining all the steps into a one-pot procedure actually raises the yield to 69%, with the amount of time to synthesize the product cut in half.  The one-pot synthesis is shown below (Scheme 2.2).22   In addition to looking at polyimides, we also wanted to investigate the possibility of looking at similar fully condensed cages without the protected anilines. Without the polyimide functional group present, we could determine whether the imide was necessary to give us the necessary thermal and mechanical properties for our condensed DDSQ cages.  Oligomers and polymers with phenethynyl functionality within the chain undergo similar curing reactions, with chain extension, branching, and cross-linking giving polymers with good thermal stability.23  To start, we reacted 1-bromo-4-(phenethynyl)benzene with magnesium metal to make a Grignard reagent, which we added to methyltrichlorosilane. Incorporating the resulting 11  dichloro(methyl)(4-(phenylethynyl)phenyl silane with POSS tetrasilanol gave rise to the condensed BPEP-DDSQ (bis(phenethynyl)phenyl-double decker silsesquioxane) which could be tested with TGA (thermogravimetric analysis) and DSC (differential scanning calorimetry) to determine its performance versus the existing Air Force polyimide oligomer AFR-PE-424 (Scheme 2.3).      Based on the DSC results (Figure 2.4), it appears that even without the polyimide, the phenethynyl system has a Tg that is desirable, as well as a curing temperature that is similar to the polyimide curing temperatures.   12   However, as you see in Figure 2.5, there is some slight degradation of the material before 400 °C in the TGA, which appears to be caused by impurities that are contained in the DDSQ material.  It is proposed that since the addition of the Grignard reagent to the trichloromethylsilane does not cleanly form only the dichlorosilane, but also a mixture of the monochlorosilane and fully arylated silane, where the monochlorosilane potentially adds to one silanol of the POSS tetrasilanol and blocks addition to the other silanol.  Since the dichloro and monochloro products of the silylation of the Grignard reagent are a solid when not in solution and susceptible to hydrolysis, it is difficult to isolate the desired dichlorosilane through distillation, as other dichlorosilanes were previously prepared.  A route to cleanly prepare the dichlorosilane as a single product must be found to remove the possibility of monochlorosilyl impurities, as commercially purchased dichlorosilanes do not have the same degradations (also in Figure 2.5).    13   While a slight degradation was also present in the polyimide oligomer of the Air Force AFR-PE-4 (Figure 2.6), it could not be caused by the same issue. However, to study these two degradations, we would need considerably more 1-bromo-4-(phenethynyl)benzene and phenethynyl phthalic anhydride (PEPA) to make the necessary end cap reagents and a plan for testing certain variables that may cause these degradations. 14   2.3 Syntheses of Side Chain Precursors by Palladium and Palladium-Free Routes  In looking at the amount of 1-bromo-4-(phenethynyl)benzene required to make large amounts of the fully condensed DDSQ cages, it became clear that making it on a large scale would become an important goal.  1-Bromo-4-(phenethynyl)benzene is primarily made from the Sonagashira coupling of phenyl acetylene with 1-bromo-4-iodobenzene.  While we were looking to follow the previously defined route for the palladium catalyzed synthesis,25 it had originally only been done on a 10 mmol scale to obtain and 80% yield of the product.  Scaling the reaction to 20 mmol scale and 35 mmol scale showed no appreciable drop in yield of isolated material after column chromatography.  Finally, starting with 20 grams of 1-bromo-4-iodobenzene (70.6 15  mmol) provided a 78% yield of the Sonagashira coupled product, approximately 14 grams of material (Scheme 2.4).    The reaction appears to be scalable without any loss in yield or efficiency.  With the thought of potentially looking at regioisomers of 1-bromo-4-(phenethynyl)benzene, as well as showing that this Sonagashira reaction could extend to other possible substrates, 1-bromo-3-(phenethynyl)benzene was also synthesized in the same manner in similar yields.  However, one goal of this project was to determine if there was a synthesis for this material that did not involve the use of palladium.  Palladium is thought to be a potential cause of earlier than desired temperature weight loss degradation when AFR-PE-4 that contains the phenethynyl phthalic anhydride (PEPA) material is tested (Figure 2.7).    This premise has never been officially tested, so we set out with two goals in mind.  Firstly, we were interested in Sonagashira reactions that did not involve the use of palladium to avoid synthesizing materials for polymerization that contained palladium.  Secondly, we wanted 16  to quantify the actual amount of palladium that is contained in the materials, whether made by conventional palladium catalyzed cross-coupling or otherwise.  The amount of palladium in the material, and if it can be removed or reduced, is valuable information that to the best of our knowledge has never been ascertained.  The results of this second goal are in the next section of this chapter, but first we set out to determine possible alternate routes to 1-bromo-4-(phenethynyl)benzene and PEPA.    Palladium is used to catalyze many organometallic reactions due to its ease at changing oxidation states without losing catalytic activity, so doing a Sonagashira reaction without palladium was going to be a challenge.  Nickel is in the same group of the periodic table as palladium, and so its subsequent reactivity is similar to palladium.  There are some examples of nickel catalyzed Sonagashira reactions, and that is where our attention first focused.26  While determined to make enough of the 1-bromo-4-(phenethynyl)benzene for future studies, we also wanted to make it in a chemically useful preparation.  Early attempts to replace the previous palladium catalyzed system with a replicated synthesis with a combination of either a nickel(II) or nickel(II) and copper(I) iodide catalyst system in place of palladium did not provide us with much more than traces of the products.  No changes in heat, time, or catalyst loading up to 10 mol % gave the desired product as the major product.  In fact, the major product was a homocoupling of two phenyl acetylene molecules, structure confirmed by 13C NMR.  To prevent these unwanted products, a new synthesis would have to be devised.    Looking in the literature, a paper by Beletskaya and co-workers showed a number of aryl iodides could be coupled to phenyl acetylene by way of nickel catalysis.27  By adding copper iodide and potassium carbonate as the base instead of pyrrolidine in a mixture of dioxane and water to solubilize the carbonate gave high yields for a number of Sonagashira coupled products.  17  When refluxed overnight, the coupling was an overwhelming success: 97% yield of the product was obtained and was subsequently reproduced (Scheme 2.5).   Not only was this reaction successful, but it was more efficient than the palladium synthesis we had done previously.  While first done on a 10 mmol scale, this reaction was also scaled up to 20 mmol without a loss of yield.  Using 1-bromo-3-iodobenzene with the nickel and copper catalysis system was also successful, and gave an isolated yield of 67%.  Having success with the Sonagashira coupling of the bromo-iodobenzenes, attention was turned toward the synthesis of PEPA from 4-bromophthalic anhydride and phenyl acetylene.  Commercially it is synthesized using palladium catalysts using the bromide instead of the iodide due to availability and high cost of the 4-iodophthalic anhydride analog,28 and so an alternate route towards the synthesis without the use of palladium would give us the ability to compare the palladium content of the end cap reagents made with and without the use of palladium, and subsequently polyimide polymer performance.  One of the challenges associated with using the anhydride coupling partner is its susceptibility to hydrolysis.29  Most often, PEPA is made by a Sonagashira coupling, but then purposely opened to the phthalic acid derivative and recrystallized for easier purification.  This is followed by ring closure back to the anhydride with acetic anhydride, shown below in Scheme 2.6.  18    A direct synthesis of PEPA using either our palladium or nickel catalysis systems developed for the synthesis of 1-bromo-4-(phenethynyl)benzene was not possible due to the presence of water as a solvent.  Because of this, a different route would have to be found.  Since PEPA is opened in ethanol to form a phthalic ester acid for making oligoimides through in situ PMR (polymerization of monomer reactants),30 it was decided to attempt the coupling by first opening the anhydride to the ester acid, followed by a Sonagashira coupling of that ester acid with phenyl acetylene (Scheme 2.7).  The ester acid of 4-bromophthalic anhydride was obtained from refluxing in ethanol for 1 hour in quantitative yields.31 However, when doing the coupling, after filtering through a silica plug, only phenyl acetylene was recovered in low yields.  This suggests the possibility that the coupling took place, but in basic solution the carboxylate salt was unable to be removed from the silica gel.  Future reactions of this type must be re-acidified first to neutralize the solution, and then the product can be extracted.   19    In addition to the nickel catalyzed reactions, we have also thought about the palladium content in the palladium catalyzed reactions.  We have repeated those procedures and measuring the palladium content from our reactions following their procedure may give us the ability to test whether the commercial supplier of the material has done work in cleaning the material of palladium impurities, and we will do so by ICP-OES (Inductively Coupled Plasma/Optical Emission Spectrometry).  2.4 ICP-OES Analysis of Palladium Content of Side Chain and End-Cap Units  Inductively Coupled Plasma/Optical Emission Spectrometry, or ICP-OES, is one of the most widely used tools for analytical chemists to determine trace elemental content in a given sample.  First developed for use by Fassel and co-workers32 and Greenfield and co-workers33 in it was quickly adapted for use in commercial instrumentation.  The efficiency of ICP to generate ions quickly led to the addition of ICP-MS (Inductively Coupled Plasma/Mass Spectrometry) as well.34  An ICP works by creating a plasma of argon gas at very high temperatures, roughly 10,000 K at the core of the plasma, to effectively vaporize a stream of 20  liquid that has been nebulized into small droplets into the plasma.  When it is vaporized, these molecules are moving at high speeds and collide, causing them to form ions and reach excited states, releasing photons. For individual elements, there are known energy gaps between the excited states and their corresponding ground states.  These energies can be measured by collecting a portion of the photons with the use of a concave mirror.  The photons are redirected into a monochromator that converts energy into electrical energy through a photodetector.35  This electrical energy is processed by a computer to give data on the elemental content of a given solution.  Typically, for the determination of the content of one element, several wavelengths of photons will be detected, as there may be possible overlap in the emission spectra of one element with a contaminant.  This method allows for the possibility of detecting sub-ppm (parts per million) levels of most elements, and its applications are widespread.36  For my research, ICP-OES was a logical instrument to use based on the necessity of determining the possible trace palladium content in given samples for the Air Force.  To accurately determine palladium content, standards of known amounts of palladium must first be made.  Since palladium metal is a solid, and therefore unable to be nebulized alone, it must be dissolved into solution to be nebulized.  Typically acids are used to dissolve metals into solution, and nitric acid is an acceptable acid for dissolving palladium.  To make a stock solution of palladium, a known amount of palladium is added to concentrated nitric acid to dissolve into solution.  Once the stock solution has been prepared, one can measure out the volume of stock solution required to dilute the sample to 10 mL.  It is diluted with a 2% nitric acid in water solution, and all are tested against a blank sample, containing only 2% nitric acid in water with no palladium added.  After these have been completed, the standards can be tested on the ICP-OES and a calibration curve can be plotted.  Any unknown samples can be tested against this calibration curve to give accurate details to the palladium content.37 21   The first unknown sample that was tested was a sample of the commercially purchased phenethynyl phthalic anhydride (PEPA) provided by the Air Force.  After taking an NMR of the commercially provided PEPA to prove the material was clean and that the anhydride was intact, samples were made by treating the PEPA first with concentrated sulfuric acid and then diluting to 10 mL with 2% nitric acid solution.38  While the anhydride is not soluble in water or acid, any palladium that was contained in the solid matrix of the anhydride should be released and dissolved into the acid.  The product obtained was then filtered to prevent the solid aromatic material from entering the ICP nebulizer, which could clog the instrument and/or provide inaccurate data.  Each ICP-OES sample run is done in triplicate; the results on the PEPA material (unknown samples made twice for confirmation) showed that in fact there is approximately 1.2-1.3 ppm of palladium contained in the PEPA material, which comes out to approximately 1.3 mg Pd per gram of PEPA material (0.13% Pd by mass).  While it is not known at this time if that 1.2-1.3 ppm is the root cause of the degradation observed, studies can be done towards effectively proving whether or not that palladium level can be reduced or eliminated completely.   To see if the palladium could be reduced or eliminated, palladium scavengers were purchased and tested for their ability to remove palladium from the PEPA material.39  Two scavengers in particular were obtained, 3-(diethylenetriamino)propyl-functionalized silica gel and 3-mercaptopropyl-functionalized silica gel, shown in Figure 2.8 below.   Both silica gels were stirred vigorously with the commercial PEPA material, and then filtered off. ICP-OES samples were made with both the thiol and amine scavengers, and both 22  showed a considerable decrease in the palladium content of the commercial PEPA.  The amine scavenger showed approximately 0.2 ppm, while the thiol showed a 0.5 ppm palladium content.  Both of these are valuable, as we can study an approximate relationship between the palladium content of the PEPA and the performance in heat degradation studies of the polymeric material after the PEPA end caps complete the polyimide oligomers by TGA.    In addition to the PEPA end cap reagents, we also wanted to look at the palladium levels that would be contained both in our large scale palladium route and our palladium free nickel route for the synthesis of 1-bromo-4-(phenethynyl)benzene. As such, ICP-OES samples were made from the products of both routes, and subsequently we discovered that the 1-bromo-4-(phenethynyl)benzene made from our palladium route contained approximately 0.4 ppm of palladium in the solid material.  The palladium free route, however, showed that essentially no palladium (<0.02 ppm) was in the material that was synthesized from nickel/copper catalysis.    Future ICP-OES analysis will focus on the determination of palladium content from the synthesis of PEPA from a variety of synthetic routes, both with and without palladium, as well as measuring the palladium content of AFR-PE-4 made with differing levels of Pd in the PEPA after washing with scavengers.  This will help to determine whether the commercial PEPA product was put through a process to reduce palladium content by the manufacturer, as well giving more data points in terms of the heat degradation studies.  If we are able to synthesize PEPA without the use of palladium, we can definitively state whether or not palladium plays a role in the degradation.  At the time being, we can still run the commercial PEPA through scavengers to remove most of the palladium contained in the material and compare degradation results of the product oligomers to the oligomers formed with PEPA that has not been cleaned by us prior to use.  Future studies must be also be done on the nickel catalyzed systems to determine 23  what level of nickel incorporation there is in the products, and to determine whether it can be removed and if that nickel causes a similar degradation as the palladium. 2.5 Experimental All reactions were carried out either in glass vials or round-bottom flasks under nitrogen atmosphere unless specified otherwise.  All reactions were magnetically stirred and monitored by thin layer chromatography (TLC) unless otherwise indicated.  All commercial reagents were used as received without further purification.  All solvents were reagent grades.  Tetrahydrofuran and diethyl ether were distilled from sodium and benzophenone under nitrogen atmosphere.  POSS tetrasilanol purchased from Hybrid Plastics and used as received. Flash column chromatography was performed with silica gel 60 Å (particle size 230-400 mesh) purchased from Silicycle and monitored using TLC with UV light, potassium permanganate stain, or phosphomolybdic acid stain.  Yields refer to spectroscopically pure compounds unless specifically indicated.  1H NMR and 13C NMR data was taken on Varian VXR-500 (499.74 MHz for 1H and 125.67 MHz for 13C) and Varian automated 500 MHz NMR (499.70 MHz for 1H, 124.93 MHz for 13C, and for 29Si).  Chemical shifts are reported relative to the residue solvent peaks CDCl3 1H NMR and 77.0 for 13C NMR).  ICP-OES samples were run using a Varian 710-ES Axial ICP-OES. 2.5.1 Experimental for One-Pot Synthesis of DDSQ     24  (4-(phenylethynyl)phenyl)magnesium bromide (1): In a dry 100 mL round-bottom flask with a stir bar, 1-bromo-4-(phenylethynyl)benzene (3.5 g, 13.28 mmol) was added to a solution of tetrahydrofuran (THF) (10 mL) and magnesium turnings (350 mg, 13.28 mmol). The reaction was stirred under N2 atmosphere for 24 hours at room temperature. The Grignard reagent formed was taken on to the next step without further purification as in previous preparations.22    Dichloro(methyl)(4-(phenylethynyl)phenyl)silane (2): To a dry 100 mL round-bottom flask under N2 atmosphere was added trichloromethylsilane (1.4 mL, 11.95 mmol) and THF (10 mL). The (4-(phenylethynyl)phenyl)magnesium bromide solution in THF (3.8 g, 13.28 mmol Grignard in 10 mL THF) was added dropwise by syringe to the silane. The reaction was allowed to continue stirring at room temperature in N2 atmosphere for 48 hours.  The dichlorosilane was taken onto the next step without further purification as in previous preparations. 22    25  9,19-dimethyl-1,3,5,7,11,13,15,17-octaphenyl-9,19-bis(4-(phenylethynyl)phenyl)-2,4,6,8,10,12,14,16,18,20,21,22,23,24-tetradecaoxa-1,3,5,7,9,11,13,15,17,19-decasilapentacyclo[11.7.1.13,11.15,17.17,15]tetracosane (3, also will be referred to as BPEP): To a dry 100 mL round-bottom flask with a stir bar was added THF (25 mL), POSS tetrasilanol (7.1 g, 6.64 mmol, 1 equiv.), triethylamine (2.12 mL, 13.28 mmol, 4 equiv.), and dichloro(methyl)(4-(phenylethynyl)phenyl)silane (theoretical from previous reaction 3.48 g, 11.95 mmol, 0.9 equiv.). The reaction was stirred under N2 atmosphere for 48 hours at room temperature, after which the reaction was filtered and concentrated.  The reaction was then purified by flash chromatography (80:20 hexanes:CH2Cl2 gradient to 100% CH2Cl2) to afford the known DDSQ BPEP product as a white solid22 (1.5 g, 15% yield, mp = 210, 245 °C for mixture of two isomers by DSC). 1H NMR (500 MHz, CDCl3-7.84 (m, 58H). 13C-NMR (126 MHz, CDCl3-0.5, 89.5, 90.3, 123.3, 124.8, 127.6, 127.8, 127.9, 128.4, 130.3, 130.5, 130.9, 131.7, 133.4, 134.0, 134.1, 134.2, 134.2, 136.4. 29Si-NMR (100 MHz, CDCl3-31.1, -31.5, -77.4, -78.2, -79.0, -79.1, -79.6. Thermogravimetric Analysis: The parameter used for TGA testing is as follows: isothermal at 50 °C for 1 minute and then ramped to 700 °C with a rate of 20 °C/min in flowing N2 environment). Performed by Dr. Andre Lee, Michigan State University, Chemical Engineering.  2.5.2 Experimental for Syntheses of Side Chain Precursors   26   1-bromo-4-(phenylethynyl)benzene (4): In a dry 250 mL round-bottom flask with a stir bar was added 1-bromo-4-iodobenzene (20 g, 70.6 mmol), water (88 mL), pyrrolidine (29.2 mL, 352 mmol), and palladium(II) chloride (142 mg, 0.70 mmol). After 5 minutes of heating at 50 °C, phenyl acetylene (9.2 mL, 84.6 mmol) was added.  The reaction was stirred open to air for 48 hours at 50 °C. The product of the reaction was extracted with ethyl acetate, washed with water and brine, and concentrated. Flash chromatography (100% hexanes) was used to obtain the known product40 (14.1 g, 78% yield) as a white powdery solid (mp = 83-85 °C).  1H NMR (500 MHz, CDCl3J = 3.6 Hz, 2.0 Hz, 3H), 7.40 (d, J = 8.7 Hz, 2H), 7.50 (d, J = 8.7 Hz, 2H), 7.54 (dd, J = 3.6 Hz, 2.0 Hz, 2H). 13C-NMR (126 MHz, CDCl3122.9, 128.4, 128.5, 131.6, 131.6, 133.0.    1-bromo-3-(phenylethynyl)benzene (5): In a dry 100 mL round-bottom flask with a stir bar was added 1-bromo-3-iodobenzene (1.3 mL, 10 mmol), water (12.5 mL), pyrrolidine (4.15 mL, 50 mmol), and palladium(II) chloride (20 mg, 0.01 mmol). After 5 minutes of heating at 50 °C, phenyl acetylene (1.3 mL, 12 mmol) was added.  The reaction was stirred open to air for 48 hours at 50 °C. The product of the reaction was extracted with ethyl acetate, washed with water and brine, and concentrated. Flash chromatography (100% hexanes) was used to obtain the known product41 (2.44 g, 82% yield) as a light yellow oil. 1H NMR (500 MHz, CDCl327  1H, J = 7.5 Hz), 7.37 (m, 3H), 7.48 (m, 2H), 7.54 (m, 2H), 7.71 (s, 1H). 13C-NMR (126 MHz, CDCl31.4, 131.7, 134.3.      1-bromo-4-(phenylethynyl)benzene (4): In a dry 250 mL round-bottom flask with a stir bar was added 1-bromo-4-iodobenzene (2.83 g, 10 mmol), 1,4-dioxane (30 mL), water (10 mL), potassium carbonate (2.76 g, 20 mmol, 2 equiv.), copper iodide (190 mg, 1 mmol, 10 mol %) and bis(triphenylphosphine)nickel(II) dichloride (327 mg, 0.5 mmol, 5 mol %).  After 5 minutes of heating at 100 °C, phenyl acetylene (1.3 mL, 12 mmol) was added.  The reaction was stirred and refluxed at 100 °C for 16 h. The product of the reaction was eluted through a silica gel plug with ethyl acetate and concentrated. Flash chromatography (100% hexanes) was used to obtain the known product40 (2.87 g, 97% yield) as a white powdery solid (mp = 83-85 °C).  1H NMR (500 MHz, CDCl3J = 3.6 Hz, 2.0 Hz, 3H), 7.40 (d, J = 8.7 Hz, 2H), 7.50 (d, J = 8.7 Hz, 2H), 7.54 (dd, J = 3.6 Hz, 2.0 Hz, 2H). 13C-NMR (126 MHz, CDCl3122.9, 128.4, 128.5, 131.6, 131.6, 133.0.  28    1-bromo-3-(phenylethynyl)benzene (5): In a dry 250 mL round-bottom flask with a stir bar was added 1-bromo-3-iodobenzene (1.3 mL, 10 mmol), 1,4-dioxane (30 mL), water (10 mL), potassium carbonate (2.76 g, 20 mmol, 2 equiv.), copper iodide (190 mg, 1 mmol, 10 mol %) and bis(triphenylphosphine)nickel(II) dichloride (327 mg, 0.5 mmol, 5 mol %). After 5 minutes of heating at 100 °C, phenyl acetylene (1.3 mL, 12 mmol, 1.2 equiv.) was added.  The reaction was stirred and refluxed at 100 °C for 16 h. The product of the reaction was eluted through a silica gel plug with ethyl acetate and concentrated. Flash chromatography (100% hexanes) was used to obtain the known product41 (1.90 g, 64% yield) as a light yellow oil.  1H NMR (500 MHz, CDCl3J = 7.5 Hz, 1H), 7.37 (m, 3H), 7.48 (m, 2H), 7.54 (m, 2H), 7.71 (s, 1H). 13C-NMR (126 MHz, CDCl3125.3, 128.4, 128.6, 129.8, 130.1, 131.4, 131.7, 134.3.  2.5.3 Experimental for ICP Analysis Preparation of Stock Solution and Standards: In a 10 mL volumetric flask was added palladium(II) chloride (5 mg, 0.282 mmol) and 10 mL of concentrated nitric acid (0.0028 M Pd in the stock solution).  A blank was created by adding exactly 10 mL of 2% by volume nitric acid in water to a medium sized glass test tube and subsequent standard solutions of 10 mL each were also created.  To another clean 10 mL volumetric flask was added enough of the stock solution of rd 29  samples to be made, followed by dilution of each sample to 10 mL using 2% by volume nitric acid in water.  Each sample was placed in a medium sized glass test tube. Preparation of Solid Samples for ICP-OES: PEPA or 1-bromo-4-(phenylethynyl)benzene made with Ni or Pd catalysts (10 mg) was placed in a 10 mL volumetric flask and concentrated sulfuric acid (1 mL) was added.  This was further diluted with 2% by volume nitric acid in water until reaching 10 mL.  This solution was then filtered to prevent any solid organic material from entering the ICP-OES nebulizer and harming the instrument, and re-diluted to 10 mL with 2% by volume nitric acid in water if necessary. The sample was placed in a medium sized glass test tube.  Preparation of Solid Samples for ICP-OES with Palladium Scavengers: PEPA (10 mg) was placed in a 100 mL round-bottom flask with a stir bar and ethyl acetate (20 mL).  Palladium Scavenger 3-(diethylenetriamino)propyl-functionalized silica gel (100 mg, 1.2 mmol/g loading of scavenger, 0.12 mmol)  or 3-mercaptopropyl-functionalized silica gel (100 mg, 1.2 mmol/g loading of scavenger, 0.12 mmol)  was added to the solution and it was stirred vigorously for 1 hour at room temperature.  The solution was filtered through a medium pore size fritted funnel to remove the silica gel, and solvent was removed in vacuo.  The washed PEPA solid was then added to a clean 10 mL volumetric flask and treated with concentrated sulfuric acid (1 mL) and diluted to 10 mL with 2% by volume nitric acid in water. This solution was then filtered to prevent any solid organic material from entering the ICP-OES nebulizer and harming the instrument, and re-diluted to 10 mL with 2% by volume nitric acid in water if necessary. The sample was placed in a medium sized glass test tube.   30           APPENDIX     31   32   33   34   35   36   37   38        39   40   41  42           REFERENCES         43  REFERENCES   1 Harrison, P.G. J. Organomet. Chem. 1997, 542, 141183.  2 Scott, D. W. J. Am. Chem. Soc. 1946, 68, 356358.  3 Lee, D. W.; Kawakami, Y. Polym. J. 2007, 39, 230238.  4 (a) Agaskar, P. A. Inorg. Chem. 1993, 30, 27072708. (b) Agaskar, P. A.; Klemperer, W. G.     Inorg. Chim. Acta. 1995, 229, 355364. (c) Franco, R.; Kandalam, A. K.; Pandey, R.; Pernisz,      U. C. J. Phys. Chem. B. 2002, 106, 17091713.  5 (a) Cordes, D. B.; Lickiss, P. D.; Rataboul, F. Chem. Rev. 2010, 110, 20812173. (b)    Duchateau, R. Chem. Rev. 2002, 102, 35253542. (c) Pu, Y.; Yuang, M.; He, B.; Gu, Z.     Chinese Chemical Letters 2013, 24, 917920. (d) Li, Z.; Tan, B.; Jin, G.; Lia, K.; He, C.     Polym. Chem. 2014, 5, 67406753.  6 (a) Seino, M.; Hayakawa, T.; Ishida, Y.; Kakimoto, M. Macromolecules, 2006, 39, 34733475.      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Macromolecules 2004, 37, 89929004.  8 Huang, C.; He, C.; Xiao, Y.; Mya, K. Y.; Dai, J.; Siow, Y. P. Polymer 2003, 44, 44914499.  9 Liu, H.; Zheng, S.; Macromol. Rapid Commun. 2005, 26, 196200.  10 Costa, R.; Vasconcelos, W.; Tamaki, R.; Laine, R. Macromolecules 2001, 34, 53985407.  11 Liu, Y.; Zheng, S. J. Polym. Sci. Part A: Polym. Chem. 2006, 44, 11681181.  12 Zeng, K.; Liu, Y.; Zheng, S. Eur. Polym. J. 2008, 44, 39463956.  13 (a) Kuo, S. W.; Chang, F. C. Progress in Polymer Science 2011, 36, 16491696.  (b) Fina, A.;      Abbenhuis, H.; Tabuani, D.; Camino, G. Polym. Degrad. Stab. 2006, 91, 22752281.  14 Minton, T.; Wright, M.; Tomczak, S.; Marquez, S.; Shen, L.; Brunsvold, A.; Cooper, R.;      Zhang, J.; Vij, V.; Guenthner, A. J.; Petteys, B. J. ACS Applied Materials & Interfaces 2012,   44       4, 492502.  15 Wu, S.; Hayakawa, T.; Kakimoto, M.; Oikawa, H. Macromolecules 2008, 41, 34813487.  16 (a) Morimoto, Y.; Watanabe, K.; Ootake, N.; Inagaki, J.; Yoshida, K.; Ohguma, K.; Chisso       Corp., Jap. Pat. 024870, 2003. (b) Yandek, G. R.; Moore, B. M.; Ramirez, S. M.; Mabry, J. M.      J. Phys. Chem. C 2012, 116, 1675516765. (c) Vij, V.; Haddad, T. S.; Yandek, G. R.;     Ramirez, S. M.; Mabry, J. M. Silicon 2012, 4, 267280.       17 Dalton Trans.     2014, 43, 1320113207.  18 (a) Wu, S.; Hayakawa, T.; Kikuchi, R.; Grunzinger, S.; Kakimoto, M. Macromolecules 2007,      40, 56985705. (b) Weisenfeld, R. J. Org. Chem. 1986, 51, 24342436.      19 Seurer, B.; Vij, V.; Haddad, T.; Mabry, J. M.; Lee, A. Macromolecules 2010, 43, 93379347.  20 Schoen, B. W.; Holmes, D.; Lee, A.  Magn. Reson. Chem. 2013, 51, 490496.  21 (a) Schoen, B. W.; Lira, C. T.; Lee, A. J. Chem. Eng. Data 2014, 59, 14831493. (b) Schoen,      B. W. Aminophenyl Double Decker Silsesquioxanes: Spectroscopic Elucidation, Physical and      Thermal Characterization, and Their Applications. Ph. D. Dissertation, Michigan State       University. East Lansing, Michigan, 2013.  22 Attanayake, G. K. Study of Different Routes to Develop Asymmetric Double Decker      Silsesquioxane (DDSQ). M.S. Dissertation, Michigan State University. East Lansing,      Michigan, 2015.  23 Green, R.; Peed, J.; Taylor, J.; Blackburn, R.; Bull, S. Nature Protocol 2013, 8, 18901906.  24 Whitley, K. S.; Collins, T. J. American Institute of Aeronautics and Astronautics 2006, 113.  25 Liang, B.; Dai, M.; Chen, J.; Yang, Z. J. Org. Chem. 2005, 70, 391393.  26 (a) Vechorkin, O.; Barmaz, D.; Proust, V.; Hu, X. J. Am. Chem. Soc. 2009, 131, 1207812079.      (b) Yi, J.; Lu, X.; Sun, Y.; Xiao, B.; Liu, L. Angew. Chem. Int. Ed. 2013, 52, 1240912413.  27 Beletskaya, I. P.; Latyshev, G. V.; Tsvetkov, A. V.; Lukashev, N. V. Tetrahedron. Lett. 2003,      44, 50115013.  28 Hergenrother, P. M.; Smith Jr., J. G. Phenyl Phthalic Anhydride. U.S. Patent 5,681,967, 1997.  29 Wu, D. F.; Yang, M. J.; Wang, Y.; Gao, G. W.; Men, J. Chinese Chemical Letters 2011, 22,      159162.  30 Ryther, C. E. C. The Effect of Elevated Temperature on the Inelastic Deformation Behavior of      PMR-15 Solid Polymer. Ph. D. Dissertation, Air Force Institute of Technology, Wright-  45       Patterson Air Force Base. Dayton, Ohio, 2012.  31 Both regioisomers of the ester acid were obtained in a roughly 1:1 mixture, confirmed by 1H      NMR and 13C NMR. Spectral data are provided.  32 Wendt, R. H.; Fassel, V. A. Anal. Chem. 1965, 37, 920922.  33  Greenfield, S.; Jones, I. L.; Berry, C. T. Analyst 1964, 89, 713720.  34 Fassel, V. A. Fresenius Z. Anal. Chem. 1986, 324, 511518.    35 Hou, X.; Jones, B. T. Encyclopedia of Analytical Chemistry; Meyer, R. A. Ed., John Wiley &     Sons Ltd, Chichester. 2000, 94689485.  36 (a) Aceto, M.; Abollino, O.; Bruzzoniti, M. C.; Mentasti, E.; Sarzanini, C.; Malandrino, M.      Food Additives and Contaminants 2002, 19, 126133. (b) Boss, C. B.; Fredeen, K. J. Concept,     Instrumentation and Techniques in Inductively Coupled Plasma Optical Emission     Spectrometry, 2nd edition, Perkin-Elmer, Norwalk, CT, 1997. (c) Carey, J. M.; Caruso, J. A.     Crit. Rev. Anal. Chem. 1992, 23, 397439.  37 More detailed experimental information will be given at the end of the chapter as to the     volumes of stock solution added, as well as preparation of the unknown samples.  38 Adding nitric acid to some benzene derivatives can be explosive, so concentrated sulfuric acid      was added. Read more on this from Gaines, P. on Acid Digestions of Organic Samples Trace     Analysis Guide: Part 12 at https://www.inorganicventures.com/acid-digestions-organic-     samples.  39 Phillips, S.; Kauppinen, P. Platinum Metals Rev. 2010, 54, 6970.  40 Liang, B.; Dai, M.; Chen, J.; Yang, Z. J. Org. Chem. 2005, 70, 391393.  41 Chelucci, G.; Capitta, F.; Baldino, S. Tetrahedron 2008, 64, 1025010257. 43  CHAPTER 3 3.1 Introduction to Hydrogermylation/Coupling The Stille reaction, as introduced in Chapter 1, is a powerful cross-coupling reaction for the creation of carbon-carbon bonds.1  As shown in Scheme 3.1, it is a cross-coupling reaction that does not require a base like the Suzuki-Miyaura reaction or other coupling reactions like the Heck reaction.2  In addition to the mild conditions that tolerate a wide variety of functional groups, there is the ability to synthesize organostannane reagents ahead of time, as they are bench stable unlike other coupling precursors, such as Grignard reagents.  There are numerous methods for synthesizing organostannanes, and this makes it possible to synthesize almost any vinyl or aryl tin reagent that might be necessary.   44   While there are numerous advantages to using the Stille reaction, there are considerable drawbacks as well, which have severely limited their usage in industrial applications while the Suzuki-Miyaura cross-coupling has flourished.  For one, the reagents for synthesizing organostannanes, trialkyltin halides and trialkyltin hydrides, can be volatile, toxic materials (LD50 of Bu3SnCl = 117 mg/kg).3  In addition to the starting materials, the organostannanes that are synthesized are usually also toxic, as well as the byproduct, hexabutylditin.  Gallagher and co-workers discovered a potential route for limiting the usage of tin in the Stille coupling by making the reaction catalytic in tin with PMHS reduction of the organotin halide byproducts.4  Ideally though, finding a cross-coupling route with the ease of preparation and usage of the Stille reaction without the toxic effects of tin would be a desirable reaction and would allow for expanding the scope and advancing the knowledge of cross-coupling reactions, since this type of cross-coupling was unknown.  Hiyama cross-coupling reactions involving silicon are less toxic, but the silicon is relatively inert and must be activated with fluoride to cross-couple efficiently.5  Torres and co-workers surmised that using germanium as a tin replacement due to the lack of toxicity associated with germanium as opposed to tin (LD50 Bu3GeCl = 1970 mg/kg) as well as the possible enhanced reactivity going to germanium from silicon could make tributylgermanes a more environmentally friendly option if they provide a similar reactivity to tin (Scheme 3.2).6  There is literature precedence for being able to couple germanes,7 however a lack of viable substrates and stereospecificity hindered progress in germanium cross-couplings.  Kosugi and co-workers were coupling vinyl germatranes with aryl halides and palladium catalysts,8 similar to stannatranes.9  Oshima used TBAF to activate heteroaryl germanes for cross-couplings 45  to make biaryls, probably through hypervalent germanium species.10  Other work done by Wnuk,11 Kosugi,12 and Spivey13 have continued the advancement of germanium cross-coupling chemistry, with Spivey even applying the chemistry in the total synthesis of aspercyclide A.14 Because of these reports, the germanium cross-coupling looked promising.  Hydrogermylation with palladium gives primarily E vinyl germanes, with internal germanes becoming more common when the alkynes became less substituted and the steric hindrance that blocks the bulky germyl group is lessened.  For the first cross-coupling test, traditional Stille conditions gave an interesting result: while starting with the E vinyl germane, the Z cross-coupled product was the only one observed, albeit in low yield (Scheme 3.3).15    While trying to optimize this reaction for Stille conditions, it was found that no combination would give a better result than the first example.  Using Heck-like conditions as opposed to Stille-like conditions gave improvements in yield, with the continued inversion in the double bond geometry from E to Z.  The mechanism initially proposed for this interesting cross-coupling is shown below in Scheme 3.4.  46    The first step is an oxidative addition of the palladium into the aryl halide bond.  That is followed by an insertion of the palladium-phenyl species across the germylated alkene.  After a bond rotation, a -germyl elimination of palladium would give rise to the Z cross-coupled product, which is followed by a reductive elimination to reform the active palladium catalyst.  However, further studies done by Miller have shown that this proposed mechanism is probably not the actual mechanism.16 Having done hydrostannations of alkynes by making tributyltin hydride in situ using PMHS to reduce tin halides, we theorized that perhaps using similar conditions for hydrogermylations might provide a reasonable alternative for being able to hydrogermylate alkynes in situ using PMHS/KF/18-crown-6 and tributylchlorogermane.  Since there is no literature precedence for this type of reduction, some reductive conditions were tested.  The preliminary results of this investigation are discussed below, as well as some experiments to test if the hydrogermylation and cross-coupling could be done in a one-pot fashion.    47  3.2 Attempted Reduction of Bu3GeCl After working with making tin hydrides from tin halides in situ, we thought the logical next step would be to attempt to make germanes from chlorogermanes in situ using similar methods involving PMHS.  If these germanes could be synthesized using these conditions, then possibly hydrogermylation could be achieved using a similar methodology as the hydrostannation methods.  Unfortunately, there was not much success with this reaction.  Attempting to use the PMHS/KF/18-crown-6/TBAF methodology was unsuccessful.  Modifications to the temperature, time, and equivalents of PMHS and KF have not been successful.  The aqueous method without 18-crown-6 also proved to be unsuccessful.   3.3 Synthesis of Vinyl Germanes in Other Solvents and With Other Catalysts  The synthesis of the vinyl germane from 2-methyl-3-butyn-2-ol was reported by Torres with Pd(PPh3)4 in THF, but that palladium catalyst did not perform cross-coupling reactions of the type illustrated in Scheme 3.3.  We were curious about the nature of the cross-coupling reaction, and so we thought to investigate several catalyst systems for both the hydrogermylation and subsequent cross-coupling.  In the meantime, we also considered the possibility of being able to do both the hydrogermylation and the coupling with the same palladium catalyst.   Because of these goals, we also attempted several solvent systems to compare with our THF results, looking for a possible alternative, potentially providing us the possibility to do both reactions in the same pot.  To our surprise, Pd(PPh3)2Cl2 was a faster catalyst for the hydrogermylation than Pd(PPh3)4 in THF, but was still not efficient for the cross-coupling reaction.  As shown below, the hydrogermylation was complete in two hours with Pd(PPh3)2Cl2, whereas the Pd(PPh3)4 reaction took eight hours to go to completion (Scheme 3.5).  48    In addition to catalysts for the hydrogermylation, we thought of potential solvent systems for both the hydrogermylation reaction and the cross-coupling reaction.  While the hydrogermylation reaction in THF was efficient, we also wanted to improve the effectiveness of the cross-coupling reaction. We considered some Heck-type reactions that were done with water, using tetraalkylammonium salts similar to the ones used in our coupling reaction.17  We also considered some generic organic solvents, such as methylene chloride, but methylene chloride was a poor solvent for the hydrogermylation.  In addition, we thought about changing the solvent of the hydrogermylation to the solvent of the hydrogermylation, using the 10:1 acetonitrile to water ratio used by Torres to complete the Heck-like germyl coupling reaction.  Unfortunately, while it was useful for the coupling by Torres, it was a poor solvent for the hydrogermylation, with only 20% yield of the vinyl germane (Scheme 3.6). 49    Following these reaction failures, we tried using just water as the solvent for the hydrogermylation with Pd(PPh3)2Cl2.  While it is a slow and relatively nonselective (9:1 E:Z isomer ratio) reaction at room temperature even over 72 hours, we found that by raising the temperature to 65 °C, the yield was raised from 43% to 67% and the isomer ratio was much more selective (31:1 E:Z).  Going back to Pd(PPh3)4 actually increased the yield of the reaction even further to 85%, with only the E isomer observed by 1H NMR (Scheme 3.7).  A control experiment involving hydrogermylation with water as the solvent without the use of palladium showed only a small conversion (14% conversion by 1H NMR) and was not selective for either vinyl germane isomer (1:1 ratio of E:Z).  Radical hydrogermylation with AIBN as a radical initiator also proved to be an unsuccessful reaction, with only starting material observed after twelve hours at 70 °C.  While vinyl stannanes can be prepared with the use of other transition metal catalysts, 18 the use of Co(PPh3)2Cl2 proved ineffective in the synthesis of vinyl germanes. (Scheme 3.8). 50      This protocol can be extended to more substrates.  The hydrogermylation of 2-phenylbut-3-yn-2-ol is also efficient (Scheme 3.9). 51   Naturally, we were curious about how this unique hydrogermylation was taking place.  While 2-methyl-3-butyn-2-ol is miscible in water, the tributylgermane is a viscous oil that is not soluble in water, and it can be seen on top of the water.  In addition, Pd(PPh3)4 is a solid that is also not soluble in water.  When the reagents for the cross-coupling reaction (TBAB, potassium carbonate, etc.) were added along with the reagents for hydrogermylation, the hydrogermylation did not take place. As shown in Scheme 3.5, even using the acetonitrile and water mixture as a solvent gave poor results. We posbeen shown to accelerate certain organic reactions by Sharpless and co-workers, most notably reactions such as Claisen rearrangements and cycloadditions such as the Diels-Alder cyclization below (Scheme 3.10).19   He has found that it is not necessary for the reagents to be soluble in water, as the reaction occurs at the interface of the aqueous and organic layers of the solution.  Stirring the reaction often increases the surface area of the suspension, which often causes the reaction to proceed at a faster rate.  He also shows that the properties of water as the solvent are important; when running reactions the success of using water as a solvent for cyclizations,20 and the rate enhancement for the hydrogermylation, especially at elevated temperatures, must be caused by similar factors. 52    There are numerous advantages for us in switching to using water instead of THF for the hydrogermylation.  From a green chemistry/sustainability perspective, water is considered one of the most environmentally friendly solvents to use in organic synthesis, and its cost and safety considerations are also beneficial.  Furthermore, the workup procedure for isolating the product is relatively straightforward.  Since the product is not water soluble, an aqueous workup removes the water and product isolation is a straightforward procedure.  Lastly, the usage of water in the cross-coupling reaction involving the vinyl germane makes it possible to synthesize the vinyl germane and connect the hydrogermylation step with the cross-coupling in the hopes of making it a one-pot process.   3.4 One-Pot Hydrogermylation/Germyl Coupling  The solvent for the germyl cross-coupling reaction, a 10:1 ratio of acetonitrile to water, did not effectively form the vinyl germane in appreciable yields.  However, as we just showed, water alone was an effective solvent for the hydrogermylation of 2-methyl-3-butyn-2-ol.  Since the reaction was just as effective as the previous examples of hydrogermylation with THF, we considered the possibility that we may be able to avoid the isolation step of purifying the vinyl germane and directly add it into the cross-coupling reaction.  After running a hydrogermylation consistent with the conditions described above, the coupling conditions except for adding 53  additional palladium were followed and the reaction was refluxed for twelve hours.  Unfortunately, no coupled product was found, although the vinyl germane was still formed.  With this in mind, the same reaction was repeated, although the Pd(OAc)2 was added in between the hydrogermylation and the coupling, as Pd(PPh3)4 did not perform the coupling.  To our delight, a 64% yield of the product was obtained as a mixture of isomers (2:1:0.1 ratio of Z:E:Int) along with 16% recovery of the starting material.  While the isomeric ratio is not as pronounced as the ratio isolated by Torres (4.25:1 Z:E), the trend of forming the Z isomer as the major product is maintained, as well as an increase in the total yield of the reaction (64% vs. 47%).  This comparison of both the one-pot reaction and the original reaction by Torres is shown below (Scheme 3.11).    54   In conclusion, we have developed a one-pot synthesis for the hydrogermylation of alkynes to vinyl germanes and coupling of those vinyl germanes with aryl halides to form coupled styrenyl derivatused as the solvent for the reaction, which cleanly gives the vinyl germanes as clean products through a simple isolation.  This protocol compares favorably to traditional hydrogermylation methods done in conventional solvents, such as THF.  Future work is being done to optimize the coupling reaction by Miller and co-workers, and the most recent coupling conditions developed provided the one-pot coupled product with 86% conversion of starting material to the product, albeit with a Z:E ratio of 1.7:1 (Scheme 3.12).16    3.5 Experimental All reactions were carried out in round-bottom flasks under nitrogen atmosphere unless otherwise indicated.  All reactions were magnetically stirred and monitored by thin layer chromatography (TLC) unless otherwise indicated.  All commercial reagents were used as 55  received without further purification.  All alkynes used were either purchased from Aldrich or GFS Chemicals and used as received or synthesized.  All solvents were reagent grades.  Tetrahydrofuran and diethyl ether were distilled from sodium and benzophenone under nitrogen atmosphere.  Methylene chloride was distilled over calcium hydride under nitrogen atmosphere.  Flash column chromatography was performed with silica gel 60 Å (particle size 230-400 mesh) purchased from Silicycle and monitored using TLC with either UV light or phosphomolybdic acid stain.  Yields refer to spectroscopically pure compounds unless specifically indicated.  1H NMR and 13C NMR data was taken on Varian VXR-500 (499.74 MHz for 1H and 125.67 MHz for 13C), Varian Inova-600 (599.89 MHz for 1H and 150.84 MHz for 13C), and Varian automated 500 MHz NMR (499.70 MHz for 1H and 124.93 MHz for 13C).  Chemical shifts are reported relative to the residue solvent peaks CDCl3 ( 7.26 ppm for 1H NMR and 77.0 for 13C NMR). High-resolution mass spectra were acquired at the MSU Mass Spectrometry facility using a Waters GCT Premier GC/TOF instrument (EI, CI), a JEOL HX-110 double-focusing magnetic sector instrument (FAB), or a Waters QTOF Ultima mass spectrometer (APCI, ESI).  3.5.1 Synthesis of Vinyl Germanes   Preparation of 6a:  To an oven-dried 100 mL round-bottom flask were added THF (10 mL), 2-methyl-3-butyn-2-ol (0.1 mL, 1 mmol), and Bu3GeH (0.3 mL, 1.2 mmol, 1.2 equiv.) under nitrogen atmosphere at room temperature.  Pd(PPh3)4 (35 mg, 0.03 mmol, 3 mol %) was added 56  and the reaction was monitored by gas chromatography.  After 8 h, the reaction was deemed concentration to afford 9a.  The resulting oil was concentrated and purified by column chromatography (silica gel: methylene chloride) to afford 6a as a single isomer as a clear oil (230 mg, 70% yield).  Spectroscopic data are consistent with literature reports.6  Data for 6a: 1H-NMR (500 MHz, CDCl3J = 9.5 Hz, 1H), 6.01 (d, J = 9.5 Hz, 1H).  13C NMR (125 MHz, CDCl3122.5, 152.5.     Preparation of 6a:  To an oven-dried 100 mL round-bottom flask were added THF (10 mL), 2-methyl-3-butyn-2-ol (0.1 mL, 1 mmol), and Bu3GeH (0.3 mL, 1.2 mmol, 1.2 equiv.) under nitrogen atmosphere at room temperature.  PdCl2(PPh3)2 (21 mg, 0.03 mmol, 3 mol %) was added and the reaction was monitored by gas chromatography.  After 2 h, the reaction was followed by concentration to afford 6a.  The resulting oil was concentrated and purified by column chromatography (silica gel: methylene chloride) to afford a 6a as a clear oil (260 mg, 79% yield).  Spectroscopic data are consistent with literature reports.6  Data for 6a: 1H-NMR (500 MHz, CDCl3J = 9.5 Hz, 1H), 6.01 (d, J = 9.5 Hz, 1H).  13C NMR (125 MHz, CDCl3122.5, 152.5.    57     Preparation of 6a/6b:  To an oven-dried 100 mL round-bottom flask were added water (10 mL), 2-methyl-3-butyn-2-ol (0.1 mL, 1 mmol), and Bu3GeH (0.3 mL, 1.2 mmol, 1.2 equiv.) under nitrogen atmosphere at room temperature.  PdCl2(PPh3)2 (21 mg, 0.03 mmol, 3 mol %) was added and the reaction was monitored by gas chromatography.  After 72 h, the reaction was loride followed by concentration to afford 6a and 6b (isomeric ratio 6a:6b = 9:1).  The resulting mixture was concentrated and purified by column chromatography (silica gel: methylene chloride) to afford a mixture of 6a and 6b as a clear oil (142 mg, 43% yield).  Spectroscopic data are consistent with literature reports. 6 Data for 6a: 1H-NMR (500 MHz, CDCl3J = 9.5 Hz, 1H), 6.01 (d, J = 9.5 Hz, 1H).  13C NMR (125 MHz, CDCl326.3, 27.2, 71.8, 122.5, 152.5.  Data for 6b: 1H-NMR (500 MHz, CDCl3 0.8 (m, 15H), 1.23 (s, 6H), 1.32 (m, 12H), 5.09 (m, 1H), 5.64 (m, 1H).  13C NMR (125 MHz, CDCl316.4, 17.5, 26.0, 27.2, 67.7, 128.3, 132.0.  Preparation of 6a/6b:  To an oven-dried 100 mL round-bottom flask were added water (10 mL), 2-methyl-3-butyn-2-ol (0.1 mL, 1 mmol), and Bu3GeH (0.3 mL, 1.2 mmol, 1.2 equiv.) under 58  nitrogen atmosphere at 65 °C.  PdCl2(PPh3)2 (21 mg, 0.03 mmol, 3 mol %) was added and the silica plug with 60 mL methylene chloride followed by concentration to afford 6a and 6b (isomeric ratio 6a:6b = 31:1).  The resulting mixture was concentrated and purified by column chromatography (silica gel: methylene chloride) to afford a mixture of 6a and 6b as a clear oil (221 mg, 67% yield).  Spectroscopic data are consistent with literature reports. 6 Data for 6a: 1H-NMR (500 MHz, CDCl3J = 9.5 Hz, 1H), 6.01 (d, J = 9.5 Hz, 1H).  13C NMR (125 MHz, CDCl3122.5, 152.5.  Data for 6b: 1H-NMR (500 MHz, CDCl3 0.8 (m, 15H), 1.23 (s, 6H), 1.32 (m, 12H), 5.09 (m, 1H), 5.64 (m, 1H).  13C NMR (125 MHz, CDCl327.2, 67.7, 128.3, 132.0.   Preparation of 6a:  To an oven-dried 100 mL round-bottom flask were added water (10 mL), 2-methyl-3-butyn-2-ol (0.1 mL, 1 mmol), and Bu3GeH (0.3 mL, 1.2 mmol, 1.2 equiv.) under nitrogen atmosphere at 65 °C.  PdCl2(PPh3)2 (35 mg, 0.03 mmol, 3 mol %) was added and the reaction was monitored by gas chromatography.  After 8 h, the reaction was deemed complete by concentration to afford 6a.  The resulting mixture was concentrated and purified by column chromatography (silica gel: methylene chloride) to afford a 6a as a single isomer and as a clear oil (280 mg, 85% yield).  Spectroscopic data are consistent with literature reports. 6 Data for 6a: 1H-NMR (500 MHz, CDCl3J = 9.5 Hz, 59  1H), 6.01 (d, J = 9.5 Hz, 1H).  13C NMR (125 MHz, CDCl371.8, 122.5, 152.5.     Preparation of 7a/7b:  To an oven-dried 100 mL round-bottom flask were added water (10 mL), 2-phenylbut-3-yn-2-ol (146 mg, 1 mmol), and Bu3GeH (0.3 mL, 1.2 mmol, 1.2 equiv.) under nitrogen atmosphere at 65 °C.  Pd(PPh3)4 (35 mg, 0.03 mmol, 3 mol %) was added and the reaction was monitored by gas chromatography.  After 4 h, the reaction was deemed complete by concentration in vacuo to afford 7a and 7b (isomeric ratio 7a:7b = 15:1).  The resulting mixture was concentrated and purified by column chromatography (silica gel: methylene chloride) to afford a mixture of 7a and 7b as a clear oil (230 mg, 70% yield).  Data for 7a: IR (neat) 3418, 2955, 2922, 2870, 2854, 1601, 1456, 697 cm1; 1H-NMR (500 MHz, CDCl31.39 (m, 12H), 1.68 (s, 3H), 2.15 (bs, 1 H), 6.10 (d, J = 18.9 Hz, 1H), 6.29 (d, J = 18.9 Hz, 1H), 7.29 (d, J = 7.7 Hz, 1H), 7.37 (t, J = 9.1 Hz, 2H), 7.51 (d, J = 7.0 Hz, 2H).  13C NMR (125 MHz, CDCl312.9, 13.8, 26.5, 27.5, 29.4, 75.8, 124.8, 125.3, 126.8, 128.2, 146.8, 150.9.  HRMS (EI) 391.2051 H]-; calculated for C22H37GeO- 391.2056.  Data for 10b: IR (neat) 3418, 2955, 2922, 2870, 2854, 1601, 1456, 697  cm1; 1H-NMR (500 MHz, CDCl30.72 (m, 15H), 1.28 (m, 12H), 1.71 (s, 3H), 2.16 (bs, 1 H), 5.40 (s, 1H), 5.88 (s, 1H), 7.25 (d, J = 7.7 Hz, 1H), 7.34 (t, J = 9.1 Hz, 2H), 7.47 (d, J = 7.0 Hz, 2H).  13C NMR (125 MHz, CDCl313.7, 13.8, 26.6, 27.2, 30.6, 78.7, 127.7, 125.6, 126.7, 127.9, 146.9, 158.5. HRMS (EI) m/z 391.2051 H]-; calculated for C22H37GeO- 391.2056. 60  3.5.2 One-Pot Synthesis   Preparation of 8a/8b:  To an oven-dried 100 mL round-bottom flask were added water (10 mL), 2-methyl-3-butyn-2-ol (0.1 mL, 1 mmol), and Bu3GeH (0.3 mL, 1.2 mmol, 1.2 equiv.) under nitrogen atmosphere.  Pd(PPh3)4 (35 mg, 0.03 mmol, 3 mol %) was added and the reaction was monitored by gas chromatography.  After 8 hours, the reaction was deemed complete by GC and the following reagents were added: triphenylphosphine (47.3 mg, 0.2 mmol, 20 mol %), TBAB (322 mg, 1 mmol, 1 equiv.), potassium carbonate (345 mg, 2.5 mmol, 2.5 equiv.), acetonitrile (10 mL), Pd(OAc)2 (22.5 mg, 0.1 mmol, 10 mol %), and iodobenzene (0.22 mL, 2 mmol, 2 equiv.).  The resulting mixture was stirred under N2 atmosphere and heated to 70 °C overnight  purified by column chromatography (methylene chloride) to afford a mixture of isomers and starting material as a clear oil (130 mg, 64% yield + 16% vinyl germane, product isomer ratio = 2:1:0.1 Z:E:Int).  Spectroscopic data are consistent with literature reports.21 Data for 8a: 1H-NMR (500 MHz, CDCl3 (s, 6H), 5.76 (d, J = 13.1 Hz, 1H), 6.46 (d, J = 13.1 Hz, 1H), 7.20-7.40 (m, 5 H).  13C NMR (125 MHz, CDCl331.1, 72.0, 126.3, 128.0, 128.6, 128.9, 137.5, 139.3.  Data for 8b: 1H-NMR (500 MHz, CDCl3 1.36 (s, 6H), 6.35 (d, J = 16.0 Hz, 1H), 6.58 (d, J = 16.0 Hz, 1H), 7.20-7.40 (m, 5 H).  13C NMR (125 MHz, CDCl329.8, 70.9, 126.3, 127.3, 128.5, 136.9, 137.5.  61   Preparation of 8a/8b:  To an oven-dried 100 mL round-bottom flask were added water (10 mL), 2-methyl-3-butyn-2-ol (0.1 mL, 1 mmol), and Bu3GeH (0.3 mL, 1.2 mmol, 1.2 equiv.) under nitrogen atmosphere.  Pd(PPh3)4 (35 mg, 0.03 mmol, 3 mol %) was added and the reaction was monitored by gas chromatography.  After 8 hours, the reaction was deemed complete by GC and the following reagents were added: triphenylphosphine (47.3 mg, 0.2 mmol, 20 mol %), TBAB (322 mg, 1 mmol, 1 equiv.), potassium carbonate (345 mg, 2.5 mmol, 2.5 equiv.), acetonitrile (10 mL), and iodobenzene (0.22 mL, 2 mmol, 2 equiv.).  The solution is sparged with an oxygen balloon, after which Pd(OAc)2 (22.5 mg, 0.1 mmol, 10 mol %) is added at room temperature.  The reaction is stirred for 3 hours at room temperature, after which it is heated under oxygen atmosphere to 70 °C overnight (12 h).  The reaction was extracted with water and CH2Cl2, and the organic layer is column chromatography (methylene chloride) to afford a mixture of isomers and starting material as a clear oil (86% conversion, product isomer ratio = 1.7:1 Z:E by crude NMR).  Spectroscopic data are consistent with literature reports.21 Data for 8a: 1H-NMR (500 MHz, CDCl3J = 13.1 Hz, 1H), 6.46 (d, J = 13.1 Hz, 1H), 7.20-7.40 (m, 5 H).  13C NMR (125 MHz, CDCl3 126.3, 128.0, 128.6, 128.9, 137.5, 139.3.  Data for 8b: 1H-NMR (500 MHz, CDCl3 1.36 (s, 6H), 6.35 (d, J = 16.0 Hz, 1H), 6.58 (d, J = 16.0 Hz, 1H), 7.20-7.40 (m, 5 H).  13C NMR (125 MHz, CDCl39, 137.5.  62           APPENDIX       63   64   65   66   67   68   69   70   71   72   73  74           REFERENCES          75  REFERENCES  1 Stille, J.K. Angew. Chem. Int. Ed. 1986, 25, 508524.  2 Heck, R.F. J. Am. Chem. Soc. 1968, 90, 55185526.  3 Kimbrough, R. Environmental Health Perspectives 1976, 14, 5156.   4 (a) Gallagher, W. P.; Terstiege, I.; Maleczka Jr., R. E. J. Am. Chem. Soc. 2001, 123, 3194     3204.  (b) Maleczka Jr., R. E.; Gallagher, W. P. Org. Lett. 2001, 3, 41734176.  5 Hiyama, T. J. J. Organomet. Chem. 2002, 653, 5861.  6 Torres, N. M. Studies of the Stille Reaction Using 119 Tin NMR and Related Reactions. Ph. D.     Dissertation, Michigan State University. East Lansing, Michigan, 2010.  7 (a) Ikenaga, K.; Matsumoto, S.; Kikukawa, K.; Matsuda, T. Chem. Lett. 1990, 185188. (b)     Enokido, T.; Fugami, K.; Endo, M.; Kameyama, M.; Kosugi, M. Adv. Synth. Catal. 2004, 346,    16851688.  8 (a) Kosugi, M.; Tanji, T.; Tanaka, Y.; Yoshida, A.; Fugami, K.; Kameyama, K.; Migita, T. J.     Organomet. Chem.1996, 508, 255257. (b) Faller, J. W.; Kultyshev, R. G. Organometallics     2002, 21, 59115918. (c) Faller, J. W.; Kultyshev, R. G.; Parr, J. Tetrahedron Lett. 2003, 44,     451453.  9 Vedejs, E.; Haight, A. R.; Moss, W. O. J. Am. Chem. Soc. 1992, 114, 65566558.  10 (a) Nakamura, T.; Kinoshita, H.; Shinokubo, H.; Oshima, K. Org. Lett. 2002, 4, 31653167.      (b) Yorimitsu, H.; Oshima, K. Inorg. Chem. Commun. 2005, 8, 131142.  11 (a) Wnuk, S. F.; Garcia Jr., P. I.; Wang, Z.  Org. Lett. 2004, 6, 20472049.   12 Enokido, T.; Fugami, K.; Endo, M.; Kameyama, M.; Kosugi, M.  Adv. Synth. Catal. 2007,     349, 10251027.    13 (a) Spivey, A. C.; Gripton, C. J.; Hannah, J. P.; Tseng, C. C.; de Fraine, P.; Parr, N. J.;      Scicinski, J. J.  Appl. Organomet. Chem. 2007, 21, 572589. (b) Srikaran, R.; Kontorgiorgis,      C. A.; Warren, S. A.; Pisaneschi, F.; Spivey, A. C. Synlett. 2013, 24, 16631666.  14 Carr, J. L.; Sejberg, J. J. P.; Saab, F.; Holdom, M. D.; Davies, A. M.; White, A. J. P.;     Leatherbarrow, R. J.; Beavil, A. J.; Sutton, B. J.; Lindell, S. D.; Spivey, A. C. Org. Biomol.     Chem. 2011, 9, 68146824.  15 Torres, N. M.; Lavis, J. M.; Maleczka, Jr., R. E. Tetrahedron Lett. 2009, 50, 44074410.  16 Our manuscript on this is in preparation, more details of the work by Miller, S. L. to come      both in the manuscript and in the Ph.D. Dissertation by Miller, S. L. that is forthcoming.  76   17 (a) Jeffery, T. Tetrahedron 1996, 52, 1011310130. (b) Jeffery, T. Tetrahedron Lett. 1994, 35,      30513054.  18 Kikukawa, K.; Umekawa, H.; Wada, F.; Matsuda, T. Chem. Lett. 1988, 881884.  19 Narayan, S.; Muldoon, J.; Finn, M. G.; Fokin, V. V.; Kolb, H. C.; Sharpless, K. B. Angew.     Chem. Int. Ed. 2005, 44, 32753279.  20 Rodgman, A.; Wright, G. F. J. Org. Chem. 1953, 18, 465484.  21 Marko, I. E.; Leung, C. W. J. Am. Chem. Soc. 1994, 116, 371372. 77  CHAPTER 4 4.1 Introduction to PMHS Reductions in Organic Chemistry PMHS (poly(methylhydrosiloxane), Figure 4.1) has been used as a reducing agent for many years since its first reported synthesis by Sauer and co-workers in 1946.1 It is made commercially from methyldichlorosilane hydrolyzed by water to make cyclic siloxanes, which are thermally equilibrated to the linear chain polymer that is sold commercially by the inclusion of an end capping reagent, hexamethyldisiloxane.2,3  The siloxane reagent is air and moisture stable, which makes it preferable to alkali reducing agents such as lithium aluminum hydride, as well as other common reducing reagents, like boranes, due to the inherent hazards involved with using these other reducing agents.  In addition, PMHS is soluble in organic solvents and relatively inexpensive due to the fact that it is a coproduct made from the usual preparation of polydimethylsiloxane (PDMS).     While PMHS is usually not reactive as a reducing agent alone, the use of different catalysts alongside PMHS gives it the ability to reduce a wide variety of compounds.  There are two main classes of catalysts used for activation: metals and nucleophiles.  Transition metal catalysts, typically titanium, palladium, and zinc, mediate the reaction through corresponding hydrides.  These hydrides can be synthetically useful toward a variety of functional groups, such as amines through reductive amination,4 alcohols from carbonyls2, and the reduction of halides5. Examples of reductions using each of these metals are shown below in Scheme 4.1. 78    Nucleophiles, behave differently in their activating of PMHS. Nucleophiles will attack the silicon atoms to form hypercoordinate hydridosilicate species, which can directly transfer the hydrides to the molecule which is to be reduced.3  Fluoride anions are the best activators but other halogens, such as chlorides, as well as Triton® B (benzyltrimethylammonium hydroxide) have also been used (Scheme 4.2).6       Research has also been done concerning the use of a combination of transition metal catalysts with nucleophiles to activate PMHS.  Below in Scheme 4.3 are some examples from 79  Maleczka and co-workers of PMHS reductions of acid chlorides to aldehydes7 and nitro groups to amines8 mediated by the use of palladium and a fluoride source, as well as an example of the reduction of an amide to an amine with diethyl zinc and lithium chloride by Adolfsson and co-workers.9  4.2 PMHS Reductions of Tin Halides and Oxides  Alkyltin hydrides have been used to reduce alkyl halides for over fifty years.10  However, the preparation of those tin hydrides is not always trivial.  While originally created by reductions of organotin halides by lithium aluminum hydride or sodium borohydride, PMHS became a useful reducing reagent for the reduction of alkyltin oxides to their corresponding alkyltin hydrides in 1967.11  Not only is using PMHS safer than those stronger reducing agents, it is also more tolerant of other functional groups that may be present, since it is relatively inert without an activating agent.12 The separation of the desired alkyltin hydride from the byproducts is a simple distillation. A sigma-bond metathesis pathway with the transfer of the hydride from silicon to tin is proposed to be the mechanism for formation of the product.  Other silanes were tested for their 80  capability in doing this hydride transfer, but PMHS outperforms other silyl hydride donors, with trialkylsilanes being the weakest hydride donors.  Interestingly, this procedure does not work with alkyltin halides, as PMHS is not strong enough to reduce them.13 In 1999, it was reported by Maleczka and Terstiege that PMHS activated by aqueous KF could effectively reduce the organotin halides that were unable to be reduced by PMHS alone.14 In fact, after distillation to remove residual PMHS after an aqueous workup with sodium hydroxide, the reaction of PMHS/KF with Bu3SnCl gave an 82% yield of pure tributyltin hydride. This was a breakthrough for being able to create tributyltin hydride in situ, especially from trialkyltin halides.  Previously, the only two options for making tributyltin hydride would have been using PMHS and tin oxides, or using a stronger reducing agent (like sodium borohydride) with tributyltin halides.15  The second method will not tolerate functional groups like carbonyls and other groups susceptible to borohydride reductions.  This led to the Maleczka group showing several examples of in situ uses of tributyltin hydride. In the same paper, Terstiege and Maleczka showed dehalogenations, radical cyclizations, Stille couplings, and the -unsaturated aldehydes, all catalytic in the tin halide species, being reduced by PMHS and aqueous KF. Subsequent work by Maleczka and co-workers further developed the one-pot Stille/hydrostannation (Scheme 4.4),16 as well as carbonyl allylation/hydrostannation of an alkyne starting with allyltributyltin.17   81  4.3 Hydrostannations of Alkynes Using PMHS and Tin Halides  Vinyl stannanes are an important synthetic tool for a number of reactions and transformations.18  Vinyl stannanes have various preparations, but one of the more common ways is through the hydrostannation of alkynes.19  This is often done by use of a transition metal catalyst alongside tributyltin hydride.  However, use of tributyltin hydride has its own share of problems.  Tributyltin hydride is air-sensitive, and will react with oxygen in the air to form bis(tributyltin) oxide ((Bu3Sn)2O), which will not react in the same fashion as the hydride.  Another issue is that when reacted with transition metal catalysts, the hydride will form dimers, hexabutylditin (Bu6Sn2), which is problematic for two reasons: hexabutylditin is hard to separate from stannylated compounds, and its formation makes it necessary to use excess of the hydride to get full conversion of the alkyne.20    To try to eliminate some of these problems, our group has worked on using new methods to do the hydrostannations without having to use tributyltin hydride (Bu3SnH).  Our group used both aqueous and nonaqueous conditions to reduce tributyltin halides, such as tributyltin chloride (Bu3SnCl) and tributyltin fluoride (Bu3SnF), into Bu3SnH in situ.  The hydride can then be reacted with alkynes to do the hydrostannations in one pot.  On the next page are examples of the first reported hydrostannations using this method from our group under palladium catalysis (Scheme 4.5).  Using PMHS with either a combination of Bu3SnCl, aqueous KF (potassium fluoride), and TBAF (tetrabutylammonium fluoride) or with Bu3SnF and TBAF gave the desired hydrostannations in good yields.  Both methods primarily gave the E isomer of the stannylated alkene for most alkynes used, with a small amount of the internal (Int) isomer formed as a minor product.  These conditions proved to be tolerable to a number of functional groups, including alkyl halides and alcohols.21 82    It was further shown that aside from palladium, hydrostannations could be tolerated with non-transition metal catalysts.  In that same paper, our group tried using the in situ formation of tributyltin hydride to do radical hydrostannations with a radical initiator, such as AIBN. Below, in Scheme 4.6, are the general conditions for being able to do radical hydrostannations with either method.21   Once again, the E isomer of the stannylated alkene is the major isomer formed in this reaction.  These reactions prove that this tributyltin halide reduction with PMHS is amenable to a 83  variety of reaction conditions, both in terms of the radicals generated and in temperature stability.  Once again, we are reminded that the utility of this reaction created the possibility of being able to recycle the tin halide byproducts created in Stille cross-coupling reactions to perform a one-pot hydrostannation/Stille coupling that was catalytic in tin.16 It also meant that other transition metal catalysts that are used in hydrostannation reactions could be probed for their compatibility with the PMHS/tin halide method, and comparisons could be made to see the effectiveness of the method in place of the traditional tributyltin hydride methods.20   For this reason, other transition metal catalysts were explored for this reaction.  First using the PMHS/Bu3SnCl/aqueous KF method, it was found that the water used to dissolve the KF was inhibiting the reaction with other metals.  Because of this, an anhydrous method was developed to determine if the hydrostannation could proceed without water.  To do this, 18-crown-6 was added to the reaction mixture to capture potassium ions and help with the  solubility (Scheme 4.7).20 The first catalyst that was investigated was NiCl2(PPh3)2.22    Because of literature precedent, hydroquinone was added to inhibit any free radicals that may form during the reaction.23  The reactions gave yields that were comparable to the control reactions that simply used tributyltin hydride, and gave isomeric ratios of products that were slightly less selective, but still followed the same trend as the controls.20 After comparing our 2(PPh3)2 was explored.22  These reactions also could not be run 84  with aqueous KF, but were found to be effective if 18-crown-6 and heat were used.  Once again, isomeric ratios and yields were comparable to the tributyltin hydride control methods (Scheme 4.8).20    4.4 Hydrostannations of Alkynes Using MoBI3 as a Catalyst However, the results that are most pertinent to this thesis are the results of the reaction of PMHS/Bu3SnCl/KF/18-crown-6 with the MoBI3 catalyst.  MoBI3, which is Mo(CO)3(CNt-Bu)3, the dominant product.23  This catalyst was developed in part because of the work of Guibe with Mo(CO)6, which was shown to have the desired internal selectivity.24  The isocyanide ligands were added for several reasons.  The isocyanides were soluble in the solution as free ligands, to help with the lifetime of the catalyst.  The isocyanides were also thought to dissociate from molybdenum better than CO ligands, which would improve reactivity.  Finally, the size of the tert-butyl group on the nitrogen also provides steric bulk, which may also help with the observed regioselectivity of the reaction.   goal was to use these vinyl stannanes to do Claisen rearrangements, so he wanted to make allylic alcohols and alcohol derivatives with the vinyl tin proximal to the alcohol.  Because of this, all the substrates that he tested had some form of 85  propargylic oxygen, whether it was a carbonyl, alcohol, or ether.  substrates, the major product was the internal stannane with the E isomer as the minor product (Scheme 4.9).    Given those results, he proposed this mechanism for the hydrostannation (Scheme 4.10).23 The proposed mechanism starts with the addition of the molybdenum into the tin hydride bond.  Molybdenum then coordinates with the alkyne before insertion of the tin and molybdenum across the alkyne. Due to the steric strain, Kazmaier proposes that the larger group being added, the molybdenum catalyst, will add to the side of the alkyne with the smaller substituent, which causes the tin to be on the same side as the larger group.  This would give rise to the internal stannane following a reductive elimination that generates the product and regenerates the catalyst.23 Whether molybdenum prefers a molybdenum-hydride or molybdenum-tin addition across the alkyne is still unknown; while previously it was determined that palladium prefers a palladium hydride addition across the alkyne,16 this question has remained unanswered for molybdenum.  If molybdenum prefers a molybdenum-hydride addition, molybdenum would have to add opposite of the addition in Kazmaiachieve the high internal selectivity, which potentially could occur through chelation of the metal to a substituent on the more substituted side. 86   3 for hydrostannations led our group to see if the catalyst system would tolerate the Bu3SnCl/PMHS/KF method.  The goal was to see whether the method would give comparable results on Kazmaier as well as look into substrates that did not have a propargylic oxygen substituent.  What was found was a general agreement with the mechanistic pathway, with each internal stannane being the major product. This included the use of 3,3-dimethylbut-1-yne, which gave a 2.5:1 ratio of internal stannane to the E-stannane (Scheme 4.11)3SnH (Scheme 4.13), the E stannane was the major product, indicating that the reaction conditions may affect the regiochemical outcome of this reaction.20 In fact, when the Bu3SnF method was used for these MoBI3 reactions, the regioselectivity did not always follow the same trends as the Bu3SnCl method.  Because of this, we set out to look at hydrostannations with MoBI3, as well as some of the hydrostannations using CoCl2(PPh3)2 and NiCl2(PPh3)2 with the anhydrous Bu3SnF method.  87   4.5 Hydrostannations of Alkynes Using PMHS and MoBI3 First, we looked at the hydrostannation of some of the traditional substrates that Kazmaier had investigated as well as some alkynes without a propargyl oxygen substituent using our Bu3SnF/PMHS/TBAF method, which are included in Table 4.1 below.  For most of the oxygenated species, our results tend to follow the results obtained either by Kazmaier or by our own lab mirroring his Bu3SnH conditions.  The only exception to these results was with the reaction of ethyl propiolate (entry 3). Even with the addition of hydroquinone to quench possible radicals, the Z stannane was not only seen, but was the major product.  This did not change after fresh hydroquinone was purchased, which seems to indicate that the Z stannane in this case may not be produced by a radical pathway.  Stopping the reaction after 30 minutes instead of the typical 3 hours also did not give an appreciable change in isomeric ratio by NMR, which seems to rule out olefin isomerization after the hydrostannation is completed.   88   NMR spectra (Figure 4.2) detail the ratio change between the 1H NMR spectra for the hydrostannation using Bu3SnH and Bu3SnF. It is not known the reason for the change in ratios, but it is possible that as shown below in Scheme 4.12, the Z isomer is formed through initial addition of molybdenum and tin across the alkyne, followed by the formation of a ketene acetal-like intermediate which is trapped with molybdenum.  Reductive elimination gives the final Z isomer major product.25 89   90   Also of note is MoBI3 catalyzed hydrostannation of 3,3-dimethylbut-1-yne (Scheme 4.13). With the Bu3SnCl/PMHS/KF/18-crown-6 method, the internal product was the major product (Scheme 4.11), which is opposite to the ratio of products when using the Bu3SnF/PMHS in situ generated Bu3SnH method. Generally, while the Bu3SnF/PMHS/TBAF method gives comparable results to the MoBI3 catalyzed hydrostannations with pregenerated Bu3SnH, there are several advantages to using the Bu3SnF/PMHS/TBAF method. Reaction times are shorter as the Bu3SnF method usually takes about three hours to run to completion, whereas the Bu3SnH method typically takes twelve hours.  The loading of the tin hydride source is decreased in our method, going from three equivalents of Bu3SnH versus only 1.5 equivalents of Bu3SnF.26    91  Also, since Bu3SnF is a solid that is only slightly soluble in THF (as opposed to the soluble Bu3SnH), it helps lower the risk of accidental exposure to the toxic stannane.21,27 4.6 Hydrostannations of Alkynes Using PMHS and Other Transition Metal Catalysts  After looking at MoBI3 as a catalyst system for hydrostannation, we looked at some of the catalyst systems from our previous paper on the use of Bu3SnCl/PMHS/KF/18-crown-6.20   The first catalyst we examined was NiCl2(PPh3)2, due to its ability to be used in cross-couplings.28  Once again, our Bu3SnF conditions proved comparable to using Bu3SnH as described by Kikukawa.22 One example of this is shown below in Scheme 4.14.26     Next, we looked at the CoCl2(PPh3)2 catalyst which was also previously used by Kikukawa.22 Phenyl acetylene was reacted with the catalyst system using both the Bu3SnF and Bu3SnH methods.  Both methods gave comparable results, although the Bu3SnF method gave a larger portion of the internal stannane while the Bu3SnH method gave decidedly more Z stannane (Scheme 4.15).25 92   4.7 Conclusions In conclusion, I have shown that hydrostannations using various transition metal catalysts with Bu3SnF/PMHS/TBAF to make Bu3SnH in situ can give comparable results to the typical procedures that use ex situ Bu3SnH with those same catalysts, while being done in less time than a typical Bu3SnH hydrostannation and having to use fewer equivalents of the tin source.  Bu3SnF is also a safer tin reagent to use than Bu3SnH, due to the volatility of the hydride. MoBI3 gave a majority of the internal stannanes for most substrates, but those ratios seemed to be affected by steric bulk of the substituents and if those substituents were in conjugation with the alkyne.25    4.8 Experimental All reactions were carried out either in oven-dried pressure tubes or round-bottom flasks under nitrogen atmosphere.  All reactions were magnetically stirred and monitored by thin layer chromatography (TLC) unless otherwise indicated.  All commercial reagents were used as received without further purification.  Mo(CO)3(CNtBu)3 was synthesized from Mo(CO)6 using known protocols.29  All alkynes used were either purchased from Aldrich or GFS Chemicals and 93  used as received or synthesized.  All solvents were reagent grades.  Tetrahydrofuran and diethyl ether were distilled from sodium and benzophenone under nitrogen atmosphere.  Methylene chloride was distilled over calcium hydride under nitrogen atmosphere.  Flash column chromatography was performed with silica gel 60 Å (particle size 230-400 mesh) purchased from Silicycle and monitored using TLC with UV light, potassium permanganate stain, or phosphomolybdic acid stain.  Yields refer to spectroscopically pure compounds unless specifically indicated.  1H NMR and 13C NMR data was taken on Varian VXR-500 (499.74 MHz for 1H and 125.67 MHz for 13C), Varian Inova-600 (599.89 MHz for 1H and 150.84 MHz for 13C), and Varian automated 500 MHz NMR (499.70 MHz for 1H and 124.93 MHz for 13C).  Chemical shifts are reported relative to the residue solvent peaks CDCl3 ( 7.26 ppm for 1H NMR and 77.0 for 13C NMR).  High-resolution mass spectra were acquired at the MSU Mass Spectrometry facility using a Waters GCT Premier GC/TOF instrument (EI, CI), a JEOL HX-110 double-focusing magnetic sector instrument (FAB), or a Waters QTOF Ultima mass spectrometer (APCI, ESI).  4.8.1 Preparation of Starting Materials   Preparation of 3-(prop-2-yn-1-yloxy)prop-1-ene (Table 1, compound 10): Propargyl alcohol (0.64 mL, 11 mmol) was added drop-wise to a 50 mL round-bottom flask under nitrogen atmosphere containing a solution of sodium hydride (0.6 g, 25 mmol, 2.2 equiv.) in diethyl ether/DMF (20 mL, 10:1 ether:DMF).  The resulting solution was stirred for 1 h, followed by 94  drop-wise addition of allyl bromide in ether (0.82 mL, 9.5 mmol in 5 mL ether, 0.9 equiv.).  The resulting solution was stirred at 0° C for 12 h before being quenched with brine (50 mL).  The layers were separated and the organic layer was washed with water (50 mL) and dried over MgSO4.  The solution was then concentrated to afford the alkyne as a light brown oil (402 mg, 38% yield).  Spectroscopic data were consistent with literature reports.30  1H-NMR (500 MHz, CDCl32.45 (s, 1H), 4.11 (d, 2H), 4.19 (s, 2H), 5.31 (m, 2H), 5.94 (m, 1H).  13C NMR (125 MHz, CDCl3   Preparation of tert-butyldimethyl((4-methylpent-1-yn-3-yl)oxy)silane (Table 1, compound 13): To a dry 100 mL round-bottom flask were added methylene chloride (50 mL), TBSCl (4.15 g, 27.5 mmol, 1.1 equiv.), 4-methyl-1-pentyne-3-ol (2.75 mL, 25 mmol), and triethylamine (4.2 mL, 30 mmol, 1.2 equiv.).  The reaction mixture was stirred at room temperature for 20 h until judged complete by TLC analysis.  The resulting solution was rinsed with water (80 mL), 5% HCl(aq) (40 mL), water (40 mL), and 10% NaHCO3(aq) (40 mL) sequentially.  The organic layer was then dried over MgSO4 and concentrated to afford the alkyne as a yellow oil (4.13 g, 78% yield).  IR (neat) 2978 cm-1; 1H-NMR (500 MHz, CDCl3J = 1.8, 3.4 Hz, 6H), 1.85 (oct, J = 3.36 Hz, 1H), 2.40 (d, J = 1.1 Hz, 1H), 4.12 (dd, J = 1.8, 1.1 Hz, 1H).  13C NMR (125 MHz, CDCl3-3.7, 17.2, 17.9, 25.6, 34.1, 67.5, 73.4, 83.7.  HRMS (EI) m/z 155.0895 [M-Bu]+; calculated for C8H15OSi+ 155.0887.31  95   Preparation of tert-butyldimethyl(prop-2-yn-1-yloxy)silane (15):  To a dry 100 mL round-bottom flask were added methylene chloride (40 mL), propargyl alcohol (1.45 mL, 25 mmol), and imidazole (2.18 g, 37.5 mmol, 1.5 equiv.).  The resulting solution was stirred at 0° C while TBSCl (4.9 g, 32.5 mmol, 1.3 equiv.) was added slowly and allowed to warm up to room temperature over 1 h.  The reaction mixture was washed with water (50 mL) and brine (50 mL), after which the organic layer was dried over MgSO4 and concentrated to afford the desired alkyne as a dark yellow oil (3.8 g, 91% yield).  Spectroscopic data are consistent with literature reports.32  1H-NMR (500 MHz, CDCl3J=1.2 Hz, 1H), 4.29 (d, J=1.2 Hz, 2H).  13C NMR (125 MHz, CDCl3-5.2, 18.2, 25.6, 51.5, 72.8, 82.4.  4.8.2 MoBI3-Catalyzed Hydrostannations   Preparation of 16a/16b:  2-methyl-3-butyn-2-ol (0.1 mL, 1 mmol) was dissolved in THF (7 mL) in an oven-dried 50 mL sealed tube under nitrogen atmosphere.  Hydroquinone (10 mg, 0.1 mmol, 10 mol %), KF (174 mg, 3 mmol, 3 equiv.), and 18-crown-6 (793 mg, 3 mmol, 3 equiv.) were added to the solution, followed by MoBI3 (21.5 mg, 0.05 mmol, 5 mol %), Bu3SnCl (0.41 96  mL, 1.5 mmol, 1.5 equiv.), PMHS (0.1 mL, 1.5 mmol, 1.5 equiv.), and TBAF (2 drops of a 1 M solution in THF, ~0.01 mmol, 1 mol %).  The reaction was stirred and heated at 60° C for 24 h.  solution of 90/10 hexanes/ethyl acetate and concentrated to afford 16a and 16b (crude isomeric ratio 16a:16b = 3:1).  The mixture was subjected to column chromatography (silica gel: hexanes:ethyl acetate 9:1) to afford a partially separable mixture of 16a and 16b as clear oils (143 mg, 38% yield).  Spectroscopic data are consistent with literature reports.20 Data for 16a: 1H-NMR (500 MHz, CDCl31H), 5.75 (m, 1H).  13C NMR (125 MHz, CDCl3105.8, 120.9.  Data for 16b: 1H-NMR (500 MHz, CDCl36H), 1.52 (m, 6H), 5.98 (m, 2H).  13C NMR (125 MHz, CDCl331.6, 75.7, 105.8, 165.1. Representative Procedure for MoBI3-Catalyzed Hydrostannations with Bu3SnF To an oven-dried 50 mL sealed tube were added THF (7 mL), alkyne (1 mmol), hydroquinone (10 mg, 0.1 mmol, 10 mol %), Bu3SnF (464 mg, 1.5 mmol, 1.5 equiv.), PMHS (0.1 mL, 1.5 mmol, 1.5 equiv.), MoBI3 (8.6 mg, 0.02 mmol, 2 mol %), and TBAF (2 drops of a 1 M solution in THF, ~0.01 mmol, 1 mol %).  The reaction mixture is stirred under nitrogen atmosphere at 65 °C until complete by TLC analysis (~3 h).     97  Preparation of 9a/9b (Table 4.1, entry 1):  Propargyl acetate (0.1 mL, 1 mmol) was subjected 90/10 solution of hexanes/ethyl acetate followed by concentration afforded 9a and 9b (crude isomeric ratio 9a:9b = 17:1) as a brown oil.  The mixture was subjected to column chromatography (silica gel: hexanes/ethyl acetate 90/10) to afford a partially separable mixture of 9a and 9b as clear oils (233 mg, 60% yield).  Spectroscopic data are consistent with literature reports.23  Data for 9a: 1H-NMR (500 MHz, CDCl36H), 2.09 (s, 3H), 4.74 (m, 2H), 5.33 (m, 1H), 5.91 (m, 1H).  13C NMR (125 MHz, CDCl39.6, 13.7, 20.9, 27.3, 29.0, 71.2, 125.7, 149.1, 170.5.  Data for 9b: 1H-NMR (500 MHz, CDCl3): J = 2.5 Hz, 1H), 6.29 (d, J = 9 Hz, 1H).  13C NMR (125 MHz, CDCl3141.5, 170.5.   Preparation of 10a/10b (Table 4.1, entry 2):  (0.1 mL, 1 mmol) was subjected to the conditions hexanes/ethyl acetate followed by concentration afforded 10a and 10b (crude isomeric ratio 10a:10b = 10:1) as a brown oil.  Hexamethyldisiloxane (HMDS) was added to the 1H NMR as an internal standard (40% yield).  Spectroscopic data are consistent with literature reports.23 Data for 10a: 1H-NMR (500 MHz, CDCl30.82 (m, 9H), 0.89 (m, 6H), 1.24 (m, 6H), 1.43 (m, 6H), 3.88 (m, 2H), 4.01 (m, 2H), 5.14 (m, 1H), 5.24 (m, 2H), 5.88 (m, 2H).  13C NMR (125 MHz, 98  CDCl310b: 1H-NMR (500 MHz, CDCl30.82 (m, 9H), 0.89 (m, 6H), 1.24 (m, 6H), 1.43 (m, 6H), 3.92 (m, 2H), 4.17 (m, 2H), 5.24 (m, 1H), 5.88 (m, 2H), 6.00 (m, 1H), 6.16 (m, 1H).  13C NMR (125 MHz, CDCl3):    Preparation of 11a/11b/11c (Table 4.1, entry 3):  Ethyl propiolate (0.1 mL, 1 mmol) was mL of a 90/10 solution of hexanes/ethyl acetate followed by concentration afforded 11a, 11b, and 11c (crude isomeric ratio 11a:11b:11c = 1:1:5) as a light brown oil.  Hexamethyldisiloxane (HMDS) was added to the 1H NMR as an internal standard (75% yield).  Spectroscopic data is consistent with literature reports.22,33  Data for 11a: 1H-NMR (500 MHz, CDCl30.88 (m, 9H), 0.98 (m, 6H), 1.27 (t, J = 6.5 Hz, 3 H), 1.31 (m, 6H), 1.51 (m, 6H), 4.16 (q, J = 6.5 Hz, 2H), 5.89 (m, 1H), 6.89 (m, 1H).  13C NMR (125 MHz, CDCl3139.5, 170.1.  Data for 11b: 1H-NMR (500 MHz, CDCl30.88 (m, 9H), 0.98 (m, 6H), 1.27 (t, J=6.5 Hz, 3 H), 1.31 (m, 6H), 1.51 (m, 6H), 4.16 (q, J = 6.5 Hz, 2H), 6.29 (d, J = 10.1 Hz, 1H), 7.72 (d, J = 10.1 Hz, 1H).  13C NMR (125 MHz, CDCl3136.2, 151.9, 164.7.  Data for 11c: 1H-NMR (500 MHz, CDCl30.88 (m, 9H), 0.98 (m, 6H), 1.27 (t, J = 6.5 Hz, 3 H), 1.31 (m, 6H), 1.51 (m, 6H), 4.16 (q, J = 6.5 Hz, 2H), 6.7 (d, J = 6.6 Hz, 1H), 7.12 (d, J = 6.6 Hz, 1H).  13C NMR (125 MHz, CDCl3135.2, 156.7, 167.5.   99    Preparation of 12a/12b/12c (Table 1, entry 4):  Phenyl acetylene (0.1 mL, 1 mmol) was mL of a 90/10 solution of hexanes/ethyl acetate followed by concentration afforded 12a, 12b, and 12c (crude isomeric ratio 12a:12b:12c = 1:5:2) as a yellow oil.  Hexamethyldisiloxane (HMDS) was added to the 1H NMR as an internal standard (99% yield).  Spectroscopic data is consistent with literature reports.34,35  Data for 12a: 1H-NMR (500 MHz, CDCl31.17 (m, 6H), 1.53 (m, 6H), 1.74 (m, 6H), 5.6 (m, 1H), 6.2 (m, 1H), 7.74 (m, 5H).  13C NMR (125 MHz, CDCl312b: 1H-NMR (500 MHz, CDCl3 7.0 (m, 2H), 7.74 (m, 5H).  13C NMR (125 MHz, CDCl3137.8, 145.2.  Data for 12c: 1H-NMR (500 MHz, CDCl36H), 1.55 (m, 6H), 6.3 (m, 1H), 7.74 (m, 5H), 7.76 (m, 1H).  13C NMR (125 MHz, CDCl310.0, 13.7, 27.3, 29.1, 125.9, 126.1, 127.4, 128.4, 131.7, 145.8.     100  Preparation of 13a/13b (Table 1, entry 5):  tert-butyldimethyl((4-methylpent-1-yn-3-yl)oxy)silane (0.2 mL, 1 mmol) was subjected to the conditions above for 3 h.  Elution of the 13a, 13b, (crude isomeric ratio 13a:13b = 2.9:1) as a yellow oil.  Spectral data for 13a: IR (neat) 2964 cm1; 1H-NMR (500 MHz, CDCl30.00 (s, 6H), 0.810.93 (m, 30H), 1.221.37 (m, 6H), 1.391.55 (m, 7H), 3.73 (d, J = 6.9 Hz, 1H), 5.16 (m, 1H), 5.69 (m, 1H).  13C NMR (125 MHz, CDCl3)  (EI) m/z +; calculated for C20H43OSiSn+ 447.2100.  Data for 13b: IR (neat) 2939 cm1; 1H-NMR (500 MHz, CDCl30.00 (d, J = 8.9 Hz, 6H), 0.790.92 (m, 30H), 1.211.35 (m, 6H), 1.411.54 (m, 6H), 1.541.68 (m, 1H), 3.73 (t, J = 5.7 Hz, 1H), 5.786.08 (m, 2H); 13C NMR (125 MHz, CDCl3)  127.7, 150.5; HRMS (EI) m/z 4+; calculated for C20H43OSiSn+ 447.2100.31   Preparation of 14a/14b (Table 1, entry 6):  4-methyl-1-pentyne-3-ol (0.2 mL, 1 mmol) was mL of a 90/10 solution of hexanes/ethyl acetate followed by concentration afforded 14a and 14b (crude isomeric ratio 14a:14b = 3.7:1) as a yellow oil.  Hexamethyldisiloxane (HMDS) was added to the 1H NMR as an internal standard (40% yield).  Spectroscopic data is consistent with literature reports.20 Data for 14a: 1H-NMR (500 MHz, CDCl31.49 (m, 6H), 1.56 (d, J = 1.75Hz, 6H), 1.61 (m, 1H), 3.82 (m, 1H), 5.26 (m, 1H), 5.76 (m, 1H).  101  13C NMR (125 MHz, CDCl3for 14b: 1H-NMR (500 MHz, CDCl3J = 1.75Hz, 6H), 1.61 (m, 1H), 3.82 (m, 1H), 5.99 (dd, J = 9.6, 2.5 Hz, 1H), 6.13 (dd, J = 9.6, 0.6 Hz, 1H).  13C NMR (125 MHz, CDCl3149.7.    Representative Procedure for MoBI3-Catalyzed Hydrostannations with Bu3SnH To an oven-dried 50 mL sealed tube were added THF (7 mL), alkyne (1 mmol), hydroquinone (10 mg, 0.1 mmol, 10 mol %), and MoBI3 (4.3 mg, 0.01 mmol, 1 mol %).  The reaction mixture is heated to 55 °C and stirred under nitrogen atmosphere, followed by drop-wise addition of Bu3SnH (0.8 mL, 3 mmol, 3 equiv.).  The reaction mixture is heated for 12 h.    Preparation of 11a/11b/11c (Table 1, entry 3):  Ethyl propiolate (0.1 mL, 1 mmol) was 60 mL of a 90/10 solution of hexanes/ethyl acetate followed by concentration afforded 11a, 11b, and 11c (crude isomeric ratio 11a:11b:11c = 10:1:1.5) as a light brown oil.  Hexamethyldisiloxane (HMDS) was added to the 1H NMR as an internal standard (98% yield).  Spectroscopic data is consistent with literature reports.23,32  Data for 11a: 1H-NMR (500 MHz, CDCl30.88 (m, 9H), 0.98 (m, 6H), 1.27 (t, J = 6.5 Hz, 3 H), 1.31 (m, 6H), 1.51 (m, 6H), 4.16 102  (q, J = 6.5 Hz, 2H), 5.89 (m, 1H), 6.89 (m, 1H).  13C NMR (125 MHz, CDCl327.1, 28.8, 60.3, 115.9, 139.5, 170.1.  Data for 11b: 1H-NMR (500 MHz, CDCl30.88 (m, 9H), 0.98 (m, 6H), 1.27 (t, J = 6.5 Hz, 3 H), 1.31 (m, 6H), 1.51 (m, 6H), 4.16 (q, J = 6.5 Hz, 2H), 6.29 (d, J = 10.1 Hz, 1H), 7.72 (d, J = 10.1 Hz, 1H).  13C NMR (125 MHz, CDCl313.4, 27.2, 29.0, 60.1, 136.2, 151.9, 164.7.  Data for 11c: 1H-NMR (500 MHz, CDCl30.88 (m, 9H), 0.98 (m, 6H), 1.27 (t, J = 6.5 Hz, 3 H), 1.31 (m, 6H), 1.51 (m, 6H), 4.16 (q, J = 6.5 Hz, 2H), 6.7 (d, J = 6.6 Hz, 1H), 7.12 (d, J = 6.6 Hz, 1H).  13C NMR (125 MHz, CDCl313.3, 26.8, 29.8, 60.1, 135.2, 156.7, 167.5.     Preparation of 12a/12b/12c (Table 1, entry 4):  Phenyl acetylene (0.1 mL, 1 mmol) was 60 mL of a 90/10 solution of hexanes/ethyl acetate followed by concentration afforded 12a, 12b, and 12c (crude isomeric ratio 12a:12b:12c = 1:3.5:2) as a yellow oil.  Hexamethyldisiloxane (HMDS) was added to the 1H NMR as an internal standard (96% yield).  Spectroscopic data is consistent with literature reports.33,34  Data for 12a: 1H-NMR (500 MHz, CDCl31.10 (m, 9H), 1.17 (m, 6H), 1.53 (m, 6H), 1.74 (m, 6H), 5.6 (m, 1H), 6.2 (m, 1H), 7.74 (m, 5H).  13C NMR (125 MHz, CDCl312b: 1H-NMR (500 MHz, CDCl31.05 (m, 15H), 1.48 (m, 6H), 1.68 (m, 6H), 7.0 (m, 2H), 7.74 (m, 5H).  13C NMR (125 MHz, CDCl3137.8, 145.2.  Data for 12c: 1H-NMR (500 MHz, CDCl30.98 (m, 9H), 1.12 (m, 6H), 1.39 (m, 103  6H), 1.55 (m, 6H), 6.3 (m, 1H), 7.74 (m, 5H), 7.76 (m, 1H).  13C NMR (125 MHz, CDCl310.0, 13.7, 27.3, 29.1, 125.9, 126.1, 127.4, 128.4, 131.7, 145.8.    4.8.3 NiCl2(PPh3)2-Catalyzed Hydrostannation  Preparation of 15a/15b: To an oven-dried 50 mL sealed tube under nitrogen atmosphere were added THF (7 mL), tert-butyldimethyl(prop-2-yn-1-yloxy)silane (0.2 mL, 1 mmol), hydroquinone (10 mg, 0.1 mmol, 10 mol %), NiCl2(PPh3)2 (13.2 mg, 0.02 mmol, 2 mol %), PMHS (0.1 mL, 1.5 mmol, 1.5 equiv.), Bu3SnF (464 mg, 1.5 mmol, 1.5 equiv.), and TBAF (2 drops of a 1 M solution in THF, ~0.01 mmol, 1 mol %).  The reaction mixture was heated to 65 °hexanes/ethyl acetate.  The product was concentrated to afford a mixture of isomers 15a and 15b (crude isomeric ratio 15a:15b = 2.5:1) as a clear oil.  Hexamethyldisiloxane (HMDS) was added to the 1H NMR as an internal standard (40% yield).  Spectroscopic data is consistent with literature reports.22 Data for 15a: 1H-NMR (500 MHz, CDCl3 0.03 (s, 6H), 0.09 (m, 15H), 0.93 (s, 9H), 1.33 (m, 6H), 1.50 (m, 6H), 4.30 (m, 2H), 5.19 (m, 1H), 5.86 (m, 1H).  13C NMR (125 MHz, CDCl3-5.2, 9.6, 13.7, 26.1, 27.5, 29.2, 69.9, 122.0, 154.9.  Data for 15b: 1H-NMR (500 MHz, CDCl3 0.03 (s, 6H), 0.09 (m, 15H), 0.93 (s, 9H), 1.33 (m, 6H), 1.50 (m, 6H), 4.21 (m, 2H), 6.07 (m, 1H), 6.19 (m, 1H).  13C NMR (125 MHz, CDCl3-5.0, 10.1, 13.7, 26.0, 27.4, 29.2, 66.8, 126.9, 147.4.    104  4.8.4 CoCl2(PPh3)2-Catalyzed Hydrostannation  Preparation of 12a/12b/12c: To an oven-dried 50 mL sealed tube under nitrogen atmosphere were added THF (7 mL), phenyl acetylene (0.1 mL, 1 mmol), hydroquinone (10 mg, 0.1 mmol, 10 mol %), CoCl2(PPh3)2 (26 mg, 0.04 mmol, 4 mol %), PMHS (0.1 mL, 1.5 mmol, 1.5 equiv.), Bu3SnF (464 mg, 1.5 mmol, 1.5 equiv.), and TBAF (2 drops of a 1 M solution in THF, ~0.01 mmol, 1 mol %).  The reaction mixture was heated to 65 °C for 24 h, cooled, and eluted through f hexanes/ethyl acetate.  The product was concentrated to afford a mixture of isomers 12a, 12b, and 12c (crude isomeric ratio 12a:12b:12c = 1.5:4:1) as a yellow oil.  Hexamethyldisiloxane (HMDS) was added to the 1H NMR as an internal standard (99% yield).  Spectroscopic data is consistent with literature reports.33,34 Data for 12a: 1H-NMR (500 MHz, CDCl31.10 (m, 9H), 1.17 (m, 6H), 1.53 (m, 6H), 1.74 (m, 6H), 5.6 (m, 1H), 6.2 (m, 1H), 7.74 (m, 5H).  13C NMR (125 MHz, CDCl3126.3, 126.4, 126.8, 128.2, 146.6, 154.7.  Data for 12b: 1H-NMR (500 MHz, CDCl31.05 (m, 15H), 1.48 (m, 6H), 1.68 (m, 6H), 7.0 (m, 2H), 7.74 (m, 5H).  13C NMR (125 MHz, CDCl39.6, 13.7, 27.1, 29.2, 125.9, 127.4, 128.4, 131.7, 137.8, 145.2.  Data for 12c: 1H-NMR (500 MHz, CDCl30.98 (m, 9H), 1.12 (m, 6H), 1.39 (m, 6H), 1.55 (m, 6H), 6.3 (m, 1H), 7.74 (m, 5H), 7.76 (m, 1H).  13C NMR (125 MHz, CDCl3128.4, 131.7, 145.8.   105   Preparation of 12a/12b/12c:  To an oven-dried 50 mL sealed tube under nitrogen atmosphere were added THF (7 mL), phenyl acetylene (0.1 mL, 1 mmol), hydroquinone (10 mg, 0.1 mmol, 10 mol %), and CoCl2(PPh3)2 (26 mg, 0.04 mmol, 4 mol %). The reaction mixture is heated to 55 °C and stirred under nitrogen atmosphere, followed by drop-wise addition of Bu3SnH (0.4 mL, 1.5 mmol, 1.5 equiv.).  The reaction is heated for 12 h.  The reaction is cooled, followed by g with 60 mL of a 90/10 solution of hexanes/ethyl acetate followed by concentration afforded 12a, 12b, and 12c (crude isomeric ratio 12a:12b:12c = 1:4:2.5) as a yellow oil.  Hexamethyldisiloxane (HMDS) was added to the 1H NMR as an internal standard (94% yield).  Spectroscopic data is consistent with literature reports.33,34 Data for 12a: 1H-NMR (500 MHz, CDCl31.10 (m, 9H), 1.17 (m, 6H), 1.53 (m, 6H), 1.74 (m, 6H), 5.6 (m, 1H), 6.2 (m, 1H), 7.74 (m, 5H).  13C NMR (125 MHz, CDCl3126.3, 126.4, 126.8, 128.2, 146.6, 154.7.  Data for 12b: 1H-NMR (500 MHz, CDCl3 1.05 (m, 15H), 1.48 (m, 6H), 1.68 (m, 6H), 7.0 (m, 2H), 7.74 (m, 5H).  13C NMR (125 MHz, CDCl39.6, 13.7, 27.1, 29.2, 125.9, 127.4, 128.4, 131.7, 137.8, 145.2.  Data for 12c: 1H-NMR (500 MHz, CDCl30.98 (m, 9H), 1.12 (m, 6H), 1.39 (m, 6H), 1.55 (m, 6H), 6.3 (m, 1H), 7.74 (m, 5H), 7.76 (m, 1H).  13C NMR (125 MHz, CDCl3128.4, 131.7, 145.8.      106           APPENDIX 107   108  109  110   111  112   113   114  115  116   117   118   119   120   121   122  123   124   125   126   127   128   129   130   131   132   133   134   135   136   137   138   139  140  141  142           REFERENCES         143  REFERENCES   1 Sauer, R.O.; Scheiber, W. J.; Brewer, S. D. J. Am. Chem. Soc. 1946, 68, 962963.   2 Mimoun, H. J. Org. Chem. 1999, 64, 25822589.  3 Lawrence, N. J.; Drew, M. D.; Bushell, S. M. J. Chem. Soc. Perkin Trans. 1 1999, 33813391.  4 Menche, D.; Arikan, F.; Li, J.; Rudolph, S. Org. Lett. 2007, 9, 267270.  5 Pri-Bar, I.; Buchman, O. J. Org. Chem. 1986, 51, 734736.    6 Drew, M. D.; Lawrence, N. J.; Fontaine, D.; Sehkri, L.; Watson, W.; Bowles, S. A. Synlett     1997, 989991.  7 Lee, K.; Maleczka Jr., R. E. Org. Lett. 2006, 8, 18871888.  8 Rahaim Jr., R. J.; Maleczka Jr., R. E. Org. Lett. 2005, 7, 50875090.  9 Kovalenko, O. O.; Volkov, A.; Adolfsson, H. Org. Lett. 2015, 17, 446449.  10 VanderKirk, G. J. M.; Noltes, J. G.; Luitjen, J. G. A. J. Appl. Chem. 1957, 7, 366369.  11 Hayashi, K.; Iyoda, J.; Shiihara, I. J. Organomet. Chem. 1967, 10, 8194.  12 Deleuze, H.; Maillard, B. J. Organomet. Chem. 1995, 490, C14C17.  13 Matlin, S. A.; Gandham, P.S. J. Chem. Soc. Chem. Commun. 1984, 798799.  14 Terstiege, I.; Maleczka Jr., R. E. J. Org. Chem. 1999, 64, 342343.  15 Corey, E. J.; Suggs, J. W. J. Org. Chem. 1975, 40, 25542555.  16 (a) Gallagher, W. P.; Terstiege, I.; Maleczka Jr., R. E. J. Am. Chem. Soc. 2001, 123, 3194      3204. (b) Maleczka Jr., R. E.; Gallagher, W. P. Org. Lett. 2001, 3, 41734176.  17 Ghosh, B.; Amado- Sierra, M. R. I.; Holmes, D.; Maleczka, R. E., Jr., Org. Lett. 2014, 16,     23182321.  18 Farina, V.; Krishnamurthy, V.; Scott, W. Org. React. 1997, 50, 1652.  19 (a) Smith, N. D.; Mancuso, J.; Lautens, M.  Chem. Rev. 2000, 100, 32573282. (b) Zhang, H.;      Guibe, F.; Balavoine, G. Tetrahedron Lett. 1988, 29, 619622.  20 Ghosh, B.; Maleczka Jr., R. E. Tetrahedron Lett. 2011, 52, 52855287.   21 Maleczka Jr., R. E.; Terrell, L. R.; Clark, D. H.; Whitehead, S. L.; Gallagher, W. P.; Terstiege,      I.  J. Org. Chem. 1999, 64, 59585965. 144   22 Kikukawa, K.; Umekawa, H.; Wada, F.; Matsuda, T. Chem. Lett. 1988, 881884.  23 (a) Kazmaier, U.; Schauss, D.; Pohlman, M. Org. Lett. 1999, 1, 10171019.  (b) Kazmaier, U.;      Pohlman, M.; Schauss, D. Eur. J. Org. Chem. 2000, 27612766.  24 Zhang, H. X.; Guibe, F.; Balavoine, G. J. Org. Chem. 1990, 55, 18571867.  25 Ichinose, Y.; Oda, H.; Oshima, K.; Utimoto, K. Bull. Chem. Soc. Jpn. 1987, 60, 34683470.  26 Maleczka Jr., R. E.; Ghosh, B.; Gallagher, W. P.; Baker, A. J.; Muchnij, J. A.; Szymanski, A.      L.  Tetrahedron 2013, 69, 40004008.  27 Leibner, J. E.; Jacobus, J. J. Org. Chem. 1979, 44, 449450.  28 Negishi, E.  Acc. Chem. Res. 1982, 15, 340348.  29 Albers, M. O.; Singleton, E.; Coville, N. J. J. Chem. Educ. 1986, 63, 444447.  30 Gao, G. -L.; Niu, Y. -N.; Yan, Z. Y.; Wang, H. L.; Wang, G. W.; Shaukat, A.; Liang, Y.      M.  J. Org. Chem. 2010, 75, 13051308.   31 Mass Spec. and IR results taken by Bill Gallagher.  32 Wong, U.; Cox, R.  Angew. Chem. Int. Ed. 2007, 46, 49264929.  33 Gomez, A. M.; Lopez, J. C.; Fraser-Reid, B.  J. Chem. Soc., Perkin Trans. 1 1994, 16891695.   34 Darwish, A.; Lang, A.; Kim, T.; Chong, J. M.  Org. Lett. 2008, 10, 861864.  35 Rim, C.; Son, D. Y.  Org. Lett. 2003, 5, 34433445. 143  CHAPTER 5 5.1 The Need for Imidazolyl Sulfonate Coupling Reactions  The Suzuki-Miyaura coupling reaction (Scheme 5.1) is one of the most popular cross-coupling reactions in organic chemistry.1  It has become the primary way that the pharmaceutical industry forms aryl-aryl bonds. An analytic study of the reactions that are undergone to create potential drug candidates showed that 40% of all carbon-carbon bond forming reactions used in drug discovery are Suzuki-Miyaura couplings.2    The reaction is efficient, and as opposed to the Stille reaction where toxic byproducts from tin cross-coupling reactions are difficult to remove, Suzuki byproducts are relatively easy to remove.  However, the steps required to perform a Suzuki-Miyaura coupling still have 3 met with representatives from many of the major pharmaceutical companies, such as Pfizer, Merck, Johnson and Johnson, Eli Lilly, Schering-Plough, GlaxoSmithKline, and AstraZeneca to form the ACS Green Chemistry Institute Pharmaceutical Roundtable.4  In discussing challenges and solutions for implementing more green chemistry practices in the global pharmaceutical community, one of the biggest issues that came up was the use of haloaromatic compounds as a result of the widespread usage of cross-coupling reactions, like the Suzuki-Miyaura.5  The typical electrophile used in the cross-coupling, as shown in the Scheme above, is primarily a haloaromatic compound.  Oftentimes the boronic acid or ester coupling partner is also created 144  originally from a haloaromatic compound (Scheme 5.2), either by metal-halogen exchange followed by trapping with borates,6 or by the use of palladium cross-coupling of aryl halides with boronates, such as B2Pin2 (bis(pinacolato)diboron).7    There are several reasons why haloaromatics are not the preferred reagents. Firstly, some haloaromatics have toxicity concerns,8 which is a problem for the large scale production of a future pharmaceutical drugs.  The second problem is one of availability.  Most haloaromatics are made commercially through well-established Friedel-Crafts chemistry, which means that certain electronic patterns will be favored, while other regioisomers may be difficult to synthesize, and therefore more expensive. Knowing the prevalence of cross-coupling chemistry in the pharmaceutical industry, we looked for alternative ways to access nucleophilic and electrophilic coupling partners for the Suzuki-Miyaura coupling.  Electrophilic partners without halogens are known, but have potential problems associated with them as well.  Tosylates,9 mesylates,10 and triflates11 are three examples of coupling partners that are sulfonate derivatives and alternatives to traditional aryl bromides and iodides.  Triflates are quite reactive, but are often not bench stable.  Mesylates and tosylates tend to have better stability than triflates, but at a cost of poorer reactivity (Figure 5.1).   145   Additionally, new toxicology results have shown that aryl and alkyl sulfonates have potentially genotoxic effects that would require waste stream management.12  In fact, the HIV drug Viracept (nelfinavir) was recalled by Roche in the European Union in 2007 over the contamination of the drug with ethyl mesylates, which is known to be genotoxic.13  Seeking an alternative to these sulfonates, Albaneze-Walker and co-workers discovered that imidazolyl sulfonates are suitable electrophilic coupling partners for Suzuki-Miyaura reactions.14  The imidazolyl sulfonates exhibit greater reactivity than mesylates and tosylates, while still being bench stable compounds.  After hydrolysis, the byproducts of these coupling partners are sulfate and imidazole, both of which are nontoxic and considered environmentally benign (Scheme 5.3).    The success of this report has led others to use imidazolyl sulfonates for more than just Suzuki-Miyaura reactions;15 imidazolyl sulfonates have been used for Buchwald-Hartwig C-N couplings,16 C-H arylations,17 the synthesis of aryl phosphonates,18 and Sonagashira and Hiyama cross-couplings.19 146  For the nucleophilic coupling partners, C-H activation/borylation under iridium catalysis has made it possible to directly add a boronic ester moiety to an aryl ring, and can be used to synthesize cross-coupling nucleophiles without recourse to a haloaromatic like in Scheme 5.2.20  This method for installing boron onto an aromatic ring also gives us the opportunity to functionalize an aryl ring in many ways.  In addition to synthesizing the nucleophilic Suzuki coupling partners, electrophilic Suzuki coupling partners can be synthesized by first generating the boronic ester, which can be further functionalized to a number of chemically active electrophiles (Scheme 5.4).21    In this chapter, we will also discuss the oxidation of boronic esters to phenols, which can be transformed into the imidazolyl sulfonate electrophilic coupling partners for the Suzuki-Miyaura cross-coupling reaction. 5.2 Introduction to Photoredox Chemistry  Based on the goals in mind for this project, the green chemistry aspects of this work were always going to be a priority in terms of synthesizing the imidazolyl sulfonates.  One reagent that we do not always think of as a reagent is a light source.  Visible light photocatalysis is a sustainable resource that can be used to do powerful transformations (Scheme 5.5).22  MacMillan and co-workers have shown multiple examples of asymmetric alkylation of aldehydes using photoredox catalysis.23 Yoon and co-workers have shown examples of 2+2 cycloaddition of 147  enones,24 and Stephenson and co-workers have shown examples of reductive halogenations,25 just to name a few examples of recent chemistry using visible light catalysis.    Since most organic molecules do not absorb light in the visible light region, it is necessary to use a photoredox catalyst that will absorb photons in the visible region, and then through an electron or energy transfer react with the desired organic functionality to do the required transformation.  The most common example of a photoredox catalyst is the commercially available t-bipyridyl)dichlororuthenium, or Ru(bpy)3Cl2. Ru(bpy)3Cl2 is max for the catalyst is 452 nm, and when irradiated with light, the catalyst becomes excited (Ru(bpy)3Cl2*).  This happens through a process called metal to ligand charge transfer, or MLCT.  After this transfer has occurred, the catalyst species can be used as either a strong oxidant (1.29 V versus Standard Calomel Electrode, or SCE) or reductant (-1.33 V versus SCE), depending on conditions.26  This is shown below in Scheme 5.6. 148    Oxidation using these photoredox catalysts is possible, and there are reports of it within the literature.  Zen and co-workers oxidized sulfides to sulfoxides in 2003,27 and there are other examples since in synthesizing alcohols28 and oxidizing alcohols to aldehydes.29  Using molecular oxygen from the air as the primary oxidant to use with a photoredox catalyst would be desirable due to the abundance and renewability of oxygen and not needing to add a chemical to use as an oxidant to the reaction.  Xiao and co-workers used oxygen from air as the oxidant in a visible light induced oxidation/cycloaddition/aromatization protocol to synthesize pyrroloisoquinolines, as shown below (Scheme 5.7).30   149  5.3 Electron Rich Boronic Esters for Suzuki Reactions with Imidazolyl Sulfonates  Building on the past work by Albaneze-Walker and by the Smith and Maleczka group, we have developed a one-pot process involving arene borylation, followed by a Suzuki-Miyaura cross-coupling with an imidazolyl sulfonate (Scheme 5.8).    While the majority of the substrates for electron poor arenes and heterocycles were already completed by Perera, a selection of which can be seen in Table 5.1,31 we wanted to investigate the ability of our one-pot borylation/Suzuki protocol on electron rich arenes as well.  150   To do so, we selected a group of overall electron donating arenes to test. 1,3-Dimethoxybenzene was the first such substrate on the list.  Since electron rich arenes tend to be more difficult to borylate than electron poor arenes, the standard borylation conditions with dtbpy (4--di-tert-butyl-2--bipyridine) as the ligand did not borylate to completion.  After changing ligands to TMP (tetramethylphenanthroline) and raising the temperature to 80 °C, the borylation finally went to complete conversion as judged by 1H NMR (Figure 5.2).   151   Having found borylation conditions that allowed for full conversion, the next step was to find Suzuki cross-coupling conditions that would consistently give good yields with our imidazolyl sulfonate cross-coupling partner.  The standard conditions for the Suzuki reaction 152  were attempted first, but even after using the freeze-pump-thaw method for degassing the reaction, the reaction would not go past 70% conversion. Several modifications to the standard procedure were attempted, including addition of water, raising the temperature, extending the reaction time past 16 hours, and increased palladium loading from 10 mol % to 20 mol %.  However, none of these modifications helped the reaction (Scheme 5.9).   Switching the solvent to a combination of DMAc (N,N-dimethylacetamide) and water instead of using DMF (N,N-dimethylformamide) and raising the temperature to 80 °C from 60 °C gave improved results, and adding a slight excess of imidazolyl sulfonate (1.2 equivalents) finally gave consistent 90% conversions and greater than 70% isolated yields of the product.  It appears that in addition to being sluggish for the borylation, this substrate was also difficult for the Suzuki coupling.  In spite of the difficulties, we proved that optimization of the cross-coupling could still result in excellent conversions and isolated yields.  This success with electron rich arenes in combination with previous results with electron poor species establishes that reactions of imidazolyl sulfonates have good reaction scope.  Furthermore, both electron deficient and electron rich arenes can undergo borylation/cross-coupling in a one-pot fashion, as further shown by additional electron rich substrates below in Scheme 5.10.    153    5.4 Making Imidazolyl Sulfonates from Borylated Arenes  We also wanted to show ways of synthesizing the electrophilic partner, the imidazolyl sulfonate, via the C-H borylation chemistry.  The idea was to oxidize the borylated materials and then react the corresponding phenols with sulfonyl diimidazole to generate imidazolyl sulfonates.  Boronic ester oxidation to phenols through the use of Oxone® is a literature reaction.32  While we knew of its effectiveness for oxidizing boronic esters and acids very quickly, we also knew that 154  carrying through the Oxone® salt byproducts through a one-pot procedure could potentially cause problems.  In addition, the aqueous conditions required to perform an Oxone® oxidation would cause problems with sulfonyl diimidazole in the subsequent sulfonation of the phenol.  Hydrogen peroxide has also been shown to oxidize boronic esters and acids to phenols, but once again concerns over possible interactions of leftover peroxide and the presence of water had us look for an alternative.33   Because of this, we turned our attention to a paper by Xiao and co-workers involving the use of visible light photoredox catalysis.  As previously shown in Scheme 5.7, Xiao had done work in the area of using oxygen from the atmosphere as an oxidant.  Applying the knowledge that they were generating superoxide radical anions, they turned their attention to the synthesis of phenols from boronic acids.  Knowing that the boron has an empty p orbital that is Lewis acidic, the superoxide created by Ru(bpy)3Cl2 with air acts as a Lewis base, attacking the boronic ester.  This is followed by a subsequent rearrangement, transforming the boronic acid into a phenol.34  While they showed one example of a boronic ester, the rest of the substrates tested were boronic acids.  We thought that this procedure could be adapted for use in our one-pot procedures, due to the fact that our Suzuki reactions required the same solvent as the photoredox oxidation and that the Ru(bpy)3Cl2 photoredox catalyst system would be inert through the Suzuki-Miyaura cross-coupling reaction.      Our goal for substrate scope was to look at a variety of functional groups for tolerance to the photoredox oxidation, as well as to probe the electronics of the arenes to determine both the relative rates of reaction as well as overall success.  Methyl 3-chlorobenzoate was the first substrate that was made into an imidazolyl sulfonate by a one-pot process of borylation/photoredox/imidazolyl sulfonation.  It was synthesized in a 44% yield over three steps 155  (Table 5.2), which is approximately 76% yield per reaction step if done in a linear sequence with separations after each individual step.    156  The more electron withdrawing the substrate, the more easily it was oxidized to the phenol; the 1,3-bis(trifluoromethyl)benzene was the fastest to oxidize, only taking 24 hours for complete conversion.  Most other substrates took 48-72 hours to oxidize, but could be monitored to determine the loss of borylated starting material.  In any event, it shows that imidazolyl sulfonates can be synthesized through iridium catalyzed C-H borylation followed by photoredox oxidation and the addition of sulfonyl diimidazole. While the typical solvent for imidazolyl sulfonation is THF at room temperature,14 phenols can be transformed into imidazolyl sulfonates in DMF at mildly elevated temperatures, as shown in our one-pot process. In the case of 1,3-dimethoxybenzene, the Suzuki reaction became more efficient by going from DMF to DMAc, and so we wondered if switching between these two amide solvents would cause a change in the photoredox activity for our one-pot process to make imidazolyl sulfonates as well.  To test this question, two reactions were run, one in DMAc, and the other in DMF.  To get a direct comparison of the photoredox reactivities, reactions were quenched at the phenol stage and isolated without making imidazolyl sulfonates.  Based on our findings, it appears that whichever amide solvent you use makes little difference (Scheme 5.11) because the phenol was isolated in 72% yield from the reaction in DMAc and 67% yield from the reaction in DMF.    157  Since the choice of amide solvent appeared to make very little difference in the photoredox reaction, DMF was used as the solvent for all of the other oxidations to be consistent with the solvent of a majority of the Suzuki-Miyaura examples.  Isolated yields for the three step process from starting arene to imidazolyl sulfonate ranged from 44-65%, and the functional groups on the boronic esters appear to be well tolerated in the photoredox reaction.  The borylations are done in THF, so the THF and leftover pinacol borane (HBPin) when used in the borylation must be removed by rotary evaporation and a solvent swap must be performed. However, neither removal of the iridium catalyst nor isolation of the crude boronic esters has to take place for the reaction sequence to work. While it is understood that many of the substrates have halogens on them when we are trying to show a synthesis of biaryl systems that does not require halogenated products, there is still merit in looking at these substrates. First, halogenated arenes are widely commercial and it is important to note whether they are more or less reactive than the imidazolyl sulfonate during the Suzuki cross-coupling.  It was also important to note whether or not the halogens are affected by the photoredox reaction. We can definitively say they are not by their presence after isolation as determined by mass spectrometry and other spectroscopic methods.  Lastly, it may also be required to selectively arylate one carbon on a ring and then arylate with a different cross-coupling partner at a different carbon on the ring.  To do so selectively, one can create a competition where two different coupling moieties are on the starting molecule, but one significantly more reactive than the other.  This would cause the more reactive coupling to happen first, followed by the second arylation to get the final product.  By having chlorides and imidazolyl sulfonates on the same ring, multiple cross-couplings are possible (Scheme 5.12). 158   In addition to the imidazolyl sulfonates synthesized by photoredox catalysis, 3-chloroanisole was tested using Oxone® as the oxidant for synthesizing the phenol.  In that case, the phenol was isolated in 71% yield.  After the phenol was isolated, it was treated with sulfonyl diimidazole and the imidazolyl sulfonate of 3-chloroanisole was isolated in 73% yield.  These two isolation steps combined give a net overall yield of 52% from the starting anisole, comparable to the yield of the one-pot procedures using photoredox chemistry.  While the Oxone® route is not feasible for a one-pot procedure, and requires two separate isolations, it can still be used to obtain the product in equally high yield as the one-pot photoredox method and may be useful for substrates if they are unable to be oxidized by the photoredox method.  The full sequence is shown below in Scheme 5.13. 159   5.5 Conclusion  In conclusion, we have developed a one-pot procedure for the borylation/Suzuki-Miyaura cross-coupling of arenes with imidazolyl sulfonates.  In addition to this, we can create the electrophilic coupling partner of the Suzuki reaction by a borylation/photoredox oxidation/imidazolyl sulfonation sequence, either also in one-pot or in several sequential reactions with Oxone®. With the combination of these two reactions, we have made the Suzuki cross-coupling partner, lowering the amount of isolation steps that are necessary, and performing an oxidation with oxygen from the atmosphere as the main oxidant. 160  5.6 Experimental Iridium catalyzed borylations were prepared in a glove box.  All reactions were carried out oven/flame-dried glassware under an N2 atmosphere, unless otherwise noted. HBPin was purchased from Aldrich, and further purified by stirring with PPh3 to remove residual BH3, and vacuum transferred at room temperature to give the borane as a clear viscous liquid. All solvents were reagent grade. Cyclohexane and tetrahydrofuran (THF) were distilled over sodium/benzophenone under nitrogen atmosphere before use.  Dimethylformamide (DMF) was treated with calcium hydride, distilled, and stored over freshly activated 4Å molecular sieves. The freeze-pump-thaw method was the preferred technique for solvent degassing. 1,3-Bis(trifluoromethyl)benzene and 1,3-dichlorobenzene were distilled, dried over 4Å sieves, and vacuum transferred to an air free flask.  Unless otherwise specified all the imidazolyl sulfonates used were prepared by Dr. Jennifer Albaneze--di-tert--bipyridine (dtbpy) was purchased from Aldrich. [Ir(OMe)(COD)]2 was prepared according to literature procedures.35 Palladium catalyst PdCl2(dppf) and Ruthenium catalyst Ru(bpy)3Cl2 were purchased from Aldrich and used as received. Column chromatography was performed on 60 Å silica gel (230400 mesh). Yields refer to spectroscopically pure compounds unless specifically indicated.  1H NMR and 13C NMR data was taken on Varian VXR-500 (499.74 MHz for 1H and 125.67 MHz for 13C), Varian Inova-600 (599.89 MHz for 1H and 150.84 MHz for 13C), and Varian automated 500 MHz NMR (499.70 MHz for 1H and 124.93 MHz for 13C).  Chemical shifts are reported relative to the residue solvent peaks CDCl3 ( 7.26 ppm for 1H NMR and 77.0 for 13C NMR).  Melting points were recorded on a MEL-TEMP® capillary melting point apparatus and are uncorrected. High-resolution mass spectra were acquired at the MSU Mass Spectrometry facility using a Waters GCT Premier GC/TOF instrument (EI, CI), a JEOL HX-161  110 double-focusing magnetic sector instrument (FAB), or a Waters QTOF Ultima mass spectrometer (APCI, ESI). 5.6.1 Borylations General Procedure for Borylations (Procedure 5A) In a glove box, a Schlenk flask, equipped with a magnetic stirring bar, was charged with the corresponding substrate. Two separate test tubes were charged with [Ir(OMe)(COD)]2 and a ligand. HBPin or B2Pin2 was added to the [Ir(OMe)(COD)]2 containing test tube. Solvent was added to the ligand containing test tube in order to dissolve the ligand. That solution was then mixed with the [Ir(OMe)(COD)]2 and HBPin/B2Pin2 mixture. After mixing for one minute, the resulting solution was transferred to the Schlenk flask. Additional solvent was used to wash the test tubes and the washings were transferred to the Schlenk flask. The flask was stoppered, brought out of the glove box, and attached to the Schlenk line in a fume hood. The Schlenk flask was placed under N2 and the reaction was carried out at the specified temperature for the specified time. The reaction was monitored by GC-FID/MS. After completion of the reaction, the volatile materials were removed on a rotary evaporator.      2-(3,5-dimethoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (17): The general procedure for borylations (Procedure 5A) were carried out with the following amounts: HBPin (0.217 mL, 1.5 mmol, 1.5 equiv.), [Ir(OMe)(COD)]2 (19.8 mg, 0.03 mmol, 3 mol %), dtbpy 162  (16.0 mg, 0.06 mmol), 1,3-dimethoxybenzene (0.12 mL,1.0 mmol, 1 equiv.), and THF (2 mL). Borylation was carried out at 60 °C for 12 h. After the reaction was over, the reaction mixture was eluted through a silica plug with methylene chloride and the solvent was removed in vacuo to give a 66% conversion to the known boronic ester product36 by 1H NMR. 1H NMR (500 MHz, CDCl3, 6H), 6.58 (t, J = 2.7 Hz, 1H), 6.97 (d, J = 2.7 Hz, 2H). 13C NMR (126 MHz, CDCl3.      2-(3,5-dimethoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (17): The general procedure for borylations (Procedure 5A) were carried out with the following amounts: B2Pin2 (254 mg, 1.0 mmol), [Ir(OMe)(COD)]2 (6.6 mg, 0.01 mmol), TMP (5.8 mg, 0.02 mmol), 1,3-dimethoxybenzene (0.12 mL,1.0 mmol), and THF (2 mL). Borylation was carried out at 80 °C for 4 h. After the reaction was over, the reaction mixture was eluted through a silica plug with methylene chloride and the solvent was removed in vacuo to give the known product36 in full conversion by 1H NMR.  1H NMR (500 MHz, CDCl3, 6H), 6.58 (t, J = 2.7 Hz, 1H), 6.97 (d, J = 2.7 Hz, 2H). 13C NMR (126 MHz, CDCl3104.5, 111.6, 160.4.  163   2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (19): The general procedure for borylations (Procedure 5A) were carried out with the following amounts: HBPin (0.217 mL, 1.5 mmol, 2 equiv.), [Ir(OMe)(COD)]2 (19.8 mg, 0.03 mmol, 3.75 mol %), dtbpy (16.0 mg, 0.06 mmol, 7.5 mol %), 2,6-dichloropyridine (110 mg, 0.75 mmol), and THF (2 mL). Borylation was carried out at 60 °C for 1 h. After the reaction was over, the reaction mixture was eluted through a silica plug with methylene chloride and the solvent was removed in vacuo to obtain the known product37 (165 mg, 82% yield) as a white solid (mp = 118-119 °C).  1H NMR (500 MHz, CDCl3. 13C NMR (126 MHz, CDCl3, 85.2, 127.7, 150.2.   2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (19): The general procedure for borylations (Procedure 5A) were carried out with the following amounts: HBPin (0.217 mL, 1.5 mmol, 1.5 equiv.), [Ir(OMe)(COD)]2 (6.6 mg, 0.01 mmol, 1 mol %), dtbpy (5.3 mg, 0.02 mmol, 2 mol %), 2,6-dichlorppyridine (148 mg,1.0 mmol), and THF (2 mL). Borylation was carried out at 60 °C for 1 h. After the reaction was over, the reaction mixture was eluted through a silica plug with methylene chloride and the solvent was removed in vacuo to 164  obtain the known product37 (230 mg, 84% yield) as a white solid (mp = 118-119 °C).  1H NMR (500 MHz, CDCl313C NMR (126 MHz, CDCl3127.7, 150.2.  5.6.2 One-Pot Borylation/Suzuki Couplings    1-(3,5-dimethoxyphenyl)naphthalene (21): The general procedure for borylations (Procedure 5A) were followed with the following amounts: B2Pin2 (254 mg, 1.0 mmol), [Ir(OMe)(COD)]2 (6.6 mg, 0.01 mmol), TMP (5.8 mg, 0.02 mmol), 1,3-dimethoxybenzene (0.12 mL,1.0 mmol), THF (2 mL). Borylation was carried out at 80 °C for 4 h. After completion of the reaction, the volatile materials were removed on a rotary evaporator. Then, the Schlenk flask was charged with imidazole-1-sulfonatenapthalene (328.8 mg, 1.2 mmol, 1.2 equiv.), and potassium carbonate (276.4 mg, 2 mmol, 2 equiv.) in a DMAc/water mixture (5 mL : 0.5 mL). The reaction mixture was degassed three times by the freeze-pump-thaw degassing method. Next, (dppf)PdCl2 catalyst (73.2 mg, 0.10 mmol, 10 mol %) was added to the Schlenk flask under a nitrogen purge. Finally, the reaction was stirred at 80°C in an oil bath for 16 h and was cooled to room temperature and diluted with EtOAc and H2O. The layers were separated and aqueous phase was 165  washed with EtOAc (3x at 50 mL each). The combined organic extracts were washed with water (3x at 250 mL) and then brine (100 mL), dried over MgSO4, and concentrated.  Gradient column chromatography on silica eluting with hexanes to 7:3 hexane / CH2Cl2 as eluent gave 190 mg (72.0% yield) of known compound38 1-(3,5-dimethoxyphenyl)naphthalene as a colorless oil. 1H NMR (500 MHz, CDCl3J = 2.1 Hz 1H), 6.77 (d, J = 2.1 Hz, 2H), 7.55 (m, 4H), 7.93 (d, J = 7.9 Hz, 1H), 7.97 (d, J = 7.9 Hz, 1H), 8.08 (d, J = 8.5 Hz, 1H). 13C NMR (126 MHz, CDCl3142.9, 160.7.   5.6.3 Synthesis of Phenols from Oxidation of Boronic Esters    3-chloro-5-methoxyphenol (24): The general procedure for borylations (Procedure 5A) were followed with the following amounts: B2Pin2 (279.1 mg, 1.1 mmol, 1.1 equiv.), [Ir(OMe)(COD)]2 (9.9 mg, 0.015 mmol, 1.5 mol %), dtbpy (8.0 mg, 0.03 mmol, 3 mol %), 3-chloroanisole (0.12 mL, 1.0 mmol), THF (2 mL). Borylation was carried out at 60 °C for 12 h.  After completion of the reaction, the volatile materials were removed on a rotary evaporator. To the crude material were added acetone (3.2 mL), and an aqueous solution of Oxone® (615.0 mg, 1.0 mmol in 3.2 mL of H2O, 1 equiv.) that was added dropwise. The oxidation was stirred open to air and run for 30 minutes at room temperature. After complete consumption of the starting 166  boronic ester by GC, the reaction was quenched with aqueous NaHSO3. A layer of dark orange oil was observed. The reaction mixture was extracted three times with CH2Cl2. The combined organics were washed with brine (50 mL) followed by water (3x at 100 mL), and concentrated in vacuo, to afford the crude phenol. Gradient column chromatography on silica gel eluting with hexanes to 1:1 hexane / CH2Cl2 as eluent gave 112 mg (71% yield) of known 3-chloro-5-methoxyphenol32 as a white solid (mp = 94-96 °C). 1H NMR (500 MHz, CDCl34.85 (bs, 1H), 6.30 (dd, J = 1.8 and 2.1 Hz, 1H), 6.46 (dd, J = 1.8 and 2.1 Hz, 1H), 6.51 (dd, J = 1.8 and 2.1 Hz, 1H). 13C NMR (126 MHz, CDCl3161.3.    Methyl 3-chloro-5-hydroxybenzoate (27): The general borylation Procedure 5A was applied with the following amounts: B2Pin2 (254 mg, 1 mmol), [Ir(OMe)(COD)]2 (6.6 mg, 0.01 mmol), dtbpy (5.4 mg, 0.02 mmol), methyl 3-chlorobenzoate (0.12 mL, 1.0 mmol) and THF (2 mL). Borylation was carried out at 60 °C for 3 h. After completion of the reaction, the volatile materials were removed on a rotary evaporator. To a mixture of crude boronic ester was added Ru(bpy)3Cl22O (15.0 mg, 0.02 mmol, 2 mol %), iPr2NEt (0.35 mL, 2.0 mmol, 2 equiv.) and dry DMAc (10.0 mL).  The solution was stirred at room temperature below a 26-W compact fluorescent light bulb open to air (without bubbling air). The reaction was monitored by GC-MS/FID and once it was completed (48 h), the reaction mixture was cooled to 0  and quenched carefully by aqueous solution of HCl (10%, 10 mL). The resultant mixture was extracted with 167  ethyl acetate (3 x 10 mL). The combined organic layers were washed with brine (2 x 20 mL) and dried over MgSO4. After removal of the solvent in vacuo, the residue was purified by FC (silica gel, hexanes gradient to hexanes: ethyl acetate 4:1) to give the known desired product32 (134 mg, 72% yield) as a white solid (mp = 138-139 °C).  1H NMR (500 MHz, CDCl35.73 (bs, 1H), 7.08 (s, 1H), 7.47 (s, 1H), 7.60 (s, 1H). 13C-NMR (126 MHz, CDCl3115.0, 120.5, 122.0, 132.4, 135.2, 156.5, 166.1.   Methyl 3-chloro-5-hydroxybenzoate (27): The general borylation Procedure 5A was applied with the following amounts: B2Pin2 (254 mg, 1 mmol), [Ir(OMe)(COD)]2 (6.6 mg, 0.01 mmol), dtbpy (5.4 mg, 0.02 mmol), methyl 3-chlorobenzoate (0.12 mL, 1.0 mmol) and THF (2 mL). Borylation was carried out at 60 °C for 3 h. After completion of the reaction, the volatile materials were removed on a rotary evaporator. To a mixture of crude boronic ester was added Ru(bpy)3Cl22O (15.0 mg, 0.02 mmol, 2 mol %), iPr2NEt (0.35 mL, 2.0 mmol, 2 equiv.) and dry DMF (10.0 mL).  The solution was stirred at room temperature below a 26-W compact fluorescent light bulb open to air (without bubbling air). The reaction was monitored by GC-MS/FID and once it was completed (48 h), the reaction mixture was cooled to 0  and quenched carefully by aqueous solution of HCl (10%, 10 mL). The resultant mixture was extracted with ethyl acetate (3 x 10 mL). The combined organic layers were washed with brine (2 x 20 mL) and dried over MgSO4. After removal of the solvent in vacuo, the residue was purified by FC (silica gel, hexanes gradient to hexanes: ethyl acetate 4:1) to give the known desired product32 (125 mg, 168  67% yield) as a white solid (mp = 138-139 °C).  1H NMR (500 MHz, CDCl35.73 (bs, 1H), 7.08 (s, 1H), 7.47 (s, 1H), 7.60 (s, 1H). 13C-NMR (126 MHz, CDCl3115.0, 120.5, 122.0, 132.4, 135.2, 156.5, 166.1.  5.6.4 Synthesis of Imidazolyl Sulfonates   3-chloro-5-methoxyphenyl 1H-imidazole-1-sulfonate (28): The flask containing the phenol substrate (158.5 mg, 1 mmol) was charged with N--sulfonyldiimidazole (297.3 mg, 1.5 mmol, 1.5 equiv.) and Cs2CO3 (162.9 mg, 0.5 mmol, 0.5 equiv.) in THF (0.05 g/mL). The reaction was stirred at room temperature and monitored by GC-FID. After the starting phenol was completely consumed (16 h), the resulting crude imidazolylsulfonate was concentrated and EtOAc was added and cooled to 0 °C and saturated aqueous NH4Cl was added. The layers were separated and the aqueous layer was washed with EtOAc (3x 50 mL). The combined organic extracts were washed with water (2x 100 mL), followed by brine (1x 50 mL), dried with MgSO4, and concentrated. Gradient column chromatography on silica gel eluting with 1:1 hexane / CH2Cl2 as eluent gave 210 mg (73.0% yield) of 3-chloro-5-methoxyphenyl 1H-imidazole-1-sulfonate as a white solid (mp = 95-97 °C).  1H NMR (500 MHz, CDCl3J = 1.8 Hz, 1H), 6.58 (d, J = 1.8 Hz, 1H), 6.86 (s, 1H), 7.18 (s, 1H), 7.31 (s, 1H), 7.78 (s, 1H). 13C NMR (126 MHz, CDCl3169  161.0. IR: 3131, 1605, 1424 cm.-1 HRMS (EI) m/z 289.003 [M+1]+; calculated [M+1]+ for C10H9ClN2O4S+ 288.997.   Methyl 3-(((1H-imidazol-1-yl)sulfonyl)oxy)-5-chlorobenzoate (29): The general borylation Procedure 5A was applied with the following amounts: B2Pin2 (254 mg, 1 mmol, 1 equiv.), [Ir(OMe)(COD)]2 (6.6 mg, 0.01 mmol, 1 mol %), dtbpy (5.4 mg, 0.02 mmol, 2 mol %), methyl 3-chlorobenzoate (0.12 mL, 1.0 mmol) and THF (2 mL). Borylation was carried out for 3 h at 60 °C. After completion of the reaction, the volatile materials were removed on a rotary evaporator.  Crude boronic ester was transferred to a 100 mL round-bottom flask with the use of DMAc (10 mL), followed by addition of Ru(bpy)3Cl22O (15.0 mg, 0.02 mmol, 2 mol %), and iPr2NEt (0.35 mL, 2.0 mmol, 2 equiv.).  The solution was stirred at room temperature below a 26-W compact fluorescent light bulb open to air (without bubbling air). The reaction was monitored by GC-MS/FID and once it was completed (48 h), the crude reaction mixture was charged with N--sulfonyldiimidazole (297.3 mg, 1.5 mmol, 1.5 equiv.) and Cs2CO3 (162.9 mg, 0.5 mmol, 0.5 equiv.) and stirred at 60 °C for 16 h.  The reaction was cooled to room temperature and diluted with EtOAc and H2O. The layers were separated and aqueous phase was washed with EtOAc (3x at 50 mL each). The combined organic extracts were washed with water (3x at 250 mL) and then brine (100 mL), dried over MgSO4, and concentrated to obtain the methyl 3-(((1H-imidazol-1-yl)sulfonyl)oxy)-5-chlorobenzoate. After removal of the solvent in vacuo, the residue was 170  purified by FC (silica gel, hexanes:CH2Cl2 = 1:1) to give the desired product (140 mg, 44%) as a white solid (mp = 60-62 °C). 1H NMR (500 MHz, CDCl31H), 7.31 (d, J = 1.2 Hz, 1H), 7.48 (d, J = 1.2 Hz, 1H), 7.78 (s, 1H), 8.01 (s, 1H). 13C-NMR (126 MHz, CDCl33127, 1731, 1294 cm.-1 HRMS (EI) m/z 316.998 [M+1]+; calculated [M+1]+ for C11H9ClN2O5S+ 316.992.   3-chloro-5-methylphenyl 1H-imidazole-1-sulfonate (32): The general borylation Procedure 5A was applied with the following amounts: HBPin (0.29 mL, 2.5 mmol, 2.5 equiv.), [Ir(OMe)(COD)]2 (6.6 mg, 0.01 mmol, 1 mol %), dtbpy (5.4 mg, 0.02 mmol, 2 mol %), 3-chlorotoluene (0.12 mL, 1.0 mmol), and THF (2 mL). Borylation was carried out for 24 h at 60 °C. After completion of the reaction, the volatile materials were removed on a rotary evaporator. Crude boronic ester was transferred to a 100 mL round-bottom flask with the use of DMF (10 mL), followed by addition of Ru(bpy)3Cl22O (15.0 mg, 0.02 mmol, 2 mol %), and iPr2NEt (0.35 mL, 2.0 mmol, 2 equiv.).  The solution was stirred at room temperature below a 26-W compact fluorescent light bulb open to air (without bubbling air). The reaction was monitored by GC-MS/FID and once it was completed (80 h), the crude reaction mixture was charged with N--sulfonyldiimidazole (396 mg, 2 mmol, 2 equiv.) and Cs2CO3 (162.9 mg, 0.5 mmol, 0.5 equiv.) and stirred at 60 °C for 16 h.  The reaction then was cooled to room temperature and 171  diluted with EtOAc and H2O. The layers were separated and aqueous phase was washed with EtOAc (3x at 50 mL each). The combined organic extracts were washed with water (3x at 250 mL) and then brine (100 mL), dried over MgSO4, and concentrated to obtain the 3-chloro-5-methylphenyl 1H-imidazole-1-sulfonate. After removal of the solvent in vacuo, the residue was purified by FC (silica gel, hexanes:CH2Cl2 = 1:1) to give the desired product (120 mg, 44%) as a viscous oil.  1H NMR (500 MHz, CDCl37.19 (s, 1H), 7.31 (s, 1H), 7.78 (s, 1H). 13C-NMR (126 MHz, CDCl3120.1, 129.6, 131.4, 135.1, 137.5, 142.1, 148.8. IR: 3131, 2926, 1605, 1580 cm.-1 HRMS (EI) m/z 273.008 [M+1]+; calculated [M+1]+ for C10H9ClN2O3S+ 273.002.   3,5-dichlorophenyl 1H-imidazole-1-sulfonate (35): The general borylation Procedure 5A was applied with the following amounts: HBPin (0.219 mL, 2 mmol, 2 equiv.), [Ir(OMe)(COD)]2 (6.6 mg, 0.01 mmol, 1 mol %), dtbpy (5.8 mg, 0.02 mmol, 2 mol %), 1,3-dichlorobenzene (0.12 mL, 1.0 mmol), and THF (2 mL). Borylation was carried out for 4 h at 60 °C. After completion of the reaction, the volatile materials were removed on a rotary evaporator.  Crude boronic ester was transferred to a 100 mL round-bottom flask with the use of DMF (10 mL), followed by addition of Ru(bpy)3Cl22O (15.0 mg, 0.02 mmol, 2 mol %), and iPr2NEt (0.35 mL, 2.0 mmol, 2 equiv.).  The solution was stirred at room temperature below a 26-W compact fluorescent light bulb open to air (without bubbling air). The reaction was monitored by GC-MS/FID and once it 172  was completed (72 h), the crude reaction mixture was charged with N--sulfonyldiimidazole (396 mg, 2 mmol, 2 equiv.) and Cs2CO3 (162.9 mg, 0.5 mmol, 0.5 equiv.) and stirred at 60 °C for 16 h.  The reaction was then cooled to room temperature and diluted with EtOAc and H2O. The layers were separated and aqueous phase was washed with EtOAc (3x at 50 mL each).  The combined organic extracts were washed with water (3x at 250 mL) and then brine (100 mL), dried over MgSO4, and concentrated to obtain the 3,5-dichlorophenyl 1H-imidazole-1-sulfonate. After removal of the solvent in vacuo, the residue was purified by FC (silica gel, hexanes:CH2Cl2 = 1:1) to give the desired product (190 mg, 65%) as a viscous oil.  1H NMR (500 MHz, CDCl3):  13C NMR (126 MHz, CDCl3cm.-1 HRMS (EI) m/z 292.953 [M+1]+; calculated [M+1]+ for C9H6Cl2N2O3S+ 292.948.   3,5-bis(trifluoromethyl)phenyl 1H-imidazole-1-sulfonate (38): The general borylation Procedure 5A was applied with the following amounts: HBPin (0.217 mL, 1.5 mmol, 1.5 equiv.), [Ir(OMe)(COD)]2 (6.6 mg, 0.01 mmol, 1 mol %), dtbpy (5.4 mg, 0.02 mmol, 2 mol %), methyl 3-chlorobenzoate (0.12 mL, 1.0 mmol), and THF (2 mL). Borylation was carried out for 1 h at 60 °C. After completion of the reaction, the volatile materials were removed on a rotary evaporator.  Crude boronic ester was transferred to a 100 mL round-bottom flask with the use of DMF (10 mL), followed by addition of Ru(bpy)3Cl22O (15.0 mg, 0.02 mmol, 2 mol %), and iPr2NEt 173  (0.35 mL, 2.0 mmol, 2 equiv.).  The solution was stirred at room temperature below a 26-W compact fluorescent light bulb open to air (without bubbling air). The reaction was monitored by GC-MS/FID and once it was completed (24 h), the crude reaction mixture was charged with N--sulfonyldiimidazole (396 mg, 2 mmol, 2 equiv.) and Cs2CO3 (162.9 mg, 0.5 mmol, 0.5 equiv.) and stirred at 60 °C for 24 h.  The reaction was then cooled to room temperature and diluted with EtOAc and H2O. The layers were separated and aqueous phase was washed with EtOAc (3x at 50 mL each).  The combined organic extracts were washed with water (3x at 250 mL) and then brine (100 mL), dried over MgSO4, and concentrated to obtain the 3,5-bis(trifluoromethyl)phenyl 1H-imidazole-1-sulfonate. After removal of the solvent in vacuo, the residue was purified by FC (silica gel, hexanes: CH2Cl2 = 1:1) to give the desired product (200 mg, 56%) as a viscous oil.  1H NMR (500 MHz, CDCl32H), 7.81 (d, J = 7.8 Hz, 1H), 7.92 (d, J = 16.1 Hz, 1H). 13C NMR (126 MHz, CDCl3120.9, 122.5 (m), 123.1, 132.0, 134.1 (q, J = 42 Hz), 137.3, 149.0. 19F NMR (471 MHz, CDCl3): -63.3. IR: 3135, 3101, 1441, 1363 cm.-1 HRMS (EI) m/z 361.005 [M]+; calculated for C11H6F6N2O3S+ 361.000.        174           APPENDIX  175  176  177   178   179   180   181   182   183   184   185                                  186  187    188   189                190   191   192   193        194  195           REFERENCES          196  REFERENCES  1 (a) Miyaura, N.; Yamada, K.; Suzuki, A. Tetrahedron Lett. 1979, 20, 34373440. (b) Miyaura,     N.; Suzuki, A. J. Chem. Soc., Chem. Commun. 1979, 866867. (c) Miyaura, N.; Suzuki, A.    Chem. Rev. 1995, 95, 24572483. (d)  Han F-S.; Chem. Soc. 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R. J. Angew. Chem. Int. Ed. 2011,      50, 96559659. (c) Nguyen, J. D.;  M. R.; Stephenson, C. R. J.      Nature Chem. 2012, 4, 854859.  26 Narayanam, J. M. R.; Stephenson, C. R. J.  Chem. Soc. Rev. 2011, 40, 102113.  27 Zen, J.-M.; Liou, S.-L.; Kumar, A. S.; Hsia, M.-S. Angew. Chem. Int. Ed. 2003, 42, 577579.  28 Su, F.; Mathew, S. C.; Lipner, G.; Fu, X.; Antonietti, M.; Blechert, S.; Wang, X. J. Am. Chem.      Soc. 2010, 132, 1629916301. (b) Su, F.; Mathew, S. C.; Möhlmann, L.; Antonietti, M.;      Wang, X.; Blechert, S. Angew. Chem. Int. Ed. 2011, 50, 657660.  29 Zhang, M.; Chen, C.-C.; Ma, W.-H.; Zhao, J.-C. Angew. Chem. Int. Ed. 2008, 47, 97309733.  30 (a) Zou, Y.-Q.; Lu, L.-Q.; Fu, L.; Chang, N.-J.; Rong, J.; Chen, J.-R.; Xiao, W.J. Angew.     Chem. Int. Ed. 2012, 50, 71717175. (b) Xuan, J.; Cheng, Y.; An, J.; Lu, L.-Q.; Zhang, X.-X.;     Xiao, W.-J. Chem. Commun. 2011, 47, 83378339.  31 Our manuscript on this is in preparation, more details of the work by Perera to come both in      the manuscript and in the Ph.D. Dissertation by Perera, D. that is forthcoming.  32 (a) Maleczka, R. E., Jr.; Shi, F.; Holmes, D.; Smith, M. R., III.  J. Am. Chem. Soc. 2003, 125,      77927793. (b) Shi, F.; Smith, M. R., III; Maleczka, R. E., Jr. Org. Lett. 2006, 8, 14111414.      (c) Norberg, A. M.; Smith, M. R., III; Maleczka, R. E., Jr. Synthesis 2011, 857859.  33 Sasaki, I.; Taguchi, J.; Hiraki, S.; Hajime, I.; Ishiyama, T.; Chem. Eur. J. 2015, 21, 9236     9241.  34 Zou, Y.-Q.; Chen, J.-R.; Liu, X.-P.; Lu, L.-Q.; Davis, R. L.; Jørgensen, K.A.; Xiao. W.-J.      Angew. Chem. Int. Ed. 2012, 51, 784788.  35 (a) Crabtree, R. H.; Quirk, J. M.; Felkin, H.; Fillebeenkhan, T. Synth. React. Inorg. Met. Org.      Chem. 1982, 12, 407413. (b) Uson, R.; Oro, L. A.; Cabeza, J. A. Inorg. Synth. 1985, 23, 126     130.     36 Tse, M. K.; Cho, J. Y.; Smith, M. R., III. Org. Lett. 2001, 3, 28312833.  37 Cho, J. Y.; Tse, M. K.; Holmes, D.; Maleczka, R. E., Jr.; Smith, M. R., III. Science 2002, 295,      305308.  38 Song, C.; Ma, Y.; Chai, Q.; Ma, C.; Jiang, W.; Andrus, M. B. Tetrahedron 2005, 61, 7438     7446. 199  CHAPTER 6 6.1 Directing Groups for Borylation  Ever since 1999, when Iverson and co-workers published the first iridium-catalyzed C-H activation/borylation of an arene,1 people have been looking for ways to modify the reaction in ways to direct the borylation to occur at specific positions on the aromatic ring.  While there are inherent biases in the arene that can cause selectivity due to sterics or electronics (see section 6.2 for more details), researchers have also been looking at the use of directing groups attached to ligands or on the arene itself to direct borylations to occur in specific sites on the arene ring.2    There are several examples of using functional groups to effectively direct the borylation of a given arene.  If an atom with a lone pair such as oxygen or nitrogen can bind to the iridium metal center during the reaction, it can cause the C-H activation to happen in a chelating, hemi-labile fashion, usually ortho or meta to the directing group.3  However, even when there are no extra vacant sites available on iridium, it is possible that N-H and O-H bonds can direct not by chelation to iridium but by influencing external  (Scheme 6.1).4   For example, 2-substituted indoles can borylate at the three or seven position based on the conditions used.  Using a silica-supported iridium catalyst, called Silica-SMAP-Ir (silicon-constrained monodentate trialkylphosphine), Sawamura and co-workers were able to borylate in the three position of methyl 1H-indole-2-carboxylate effectively through a coordination of the Silica-SMAP-Ir to the ester, in only one hour with 90% yield.5 This method was applied for the direction of other heterocycles such as thiophenes, but all directed by esters. This method was extended further to more substrates,6 but when no directing groups are present, borylation occurs at the electronically favored and sterically most accessible 7 position instead (Scheme 6.2). 200     Through the use of a combination of outer sphere direction and chelation with conditions from Smith and Maleczka and co-workers, borylation occurs in the seven position in 87% yield.7  The two products are shown below in Scheme 6.2.   201  In addition to these examples of indoles, there are other examples of directed borylation by similar directing groups with lone pairs.  Clark and co-workers showed that benzylic amines can direct borylations with hemi-labile picolylamine ligands.8  Smith and Maleczka and co-workers also showed that using Boc (tert-butoxycarbonyl) or BPin groups as protecting groups on anilines, indoles, and pyrroles can direct the borylation to positions it would not normally borylate.9  For example, Boc protection of heterocycles such as pyrrole and indole directs borylation to the three position, when normally borylation would prefer the two position.  es provided the same effect with higher yields.10  The usage of the traceless technique with aniline, however, gave an interesting result: borylation was directed ortho to the aniline, with outer sphere direction by the leftover aniline N-H causing the directing effect.  These examples are all shown below in Scheme 6.3.  202   While amines and heterocycles have these directing effects which can be tuned by use of ligand and protecting group, silyl directing groups have also become commonplace for the direction of arenes and heterocycles.  Hartwig and co-workers developed this chemistry as early as 2008,11 and has since extended this work to include the direction of borylation in heterocycles,12 benzylic carbons,13 and unactivated alkyl chains.14  While typical iridium catalyzed conditions tended to give meta and para products, these hydrosilyl groups were effective in ortho direction whether they were benzyl hydrosilyl groups or substituted phenols and anilines.  An example of a procedure to move from phenol to ortho borylated phenol is shown below in Scheme 6.4.   Like Silica-SMAP-Ir, there are more examples of people adjusting the ligands on iridium to change the ability of the metal center to borylate at certain positions on the ring.  With -workers developed a silyl-phosphine directing ligand, which also borylated ortho to esters, amides, and anisoles.15  Lassaletta and co-workers also used hemi-labile ligands, in the form of substituted hydrazones to effectively borylate ortho to hydrazones for the purpose of synthesizing borylated aryl isoquinolines.16  Examples of each of these are below (Scheme 6.5). 203   Finally, Kanai in 2015 reported the synthesis of bipyridine ligands constructed with an extra aryl group containing a urea branching off of one side of the bipyridine core.17  This urea is an effective hydrogen bond donor with amides, esters, and phosphonates, which is a secondary interaction between the ligand and the substrate, causing the borylation to occur meta to the arene carbonyl.  Since the urea is far away from the metal center performing the C-H activation, this causes the borylation to occur meta instead of ortho to the carbonyl directing group. A picture of the ligand is below in Figure 6.1.  204  6.2 Steric and Electronic Effects Determine Borylation Regiochemistry  The need for directing groups in borylation chemistry stems from the inherent nature of the iridium catalyzed C-H borylation reaction, which is primarily sterically driven.  While boronic acids and esters can be made by lithium halogen exchange with halogens put in place from traditional electrophilic aromatic substitutions reactions,18 iridium catalyzed borylation can give access to substitution patterns that cannot be achieved by traditional methods without some difficulty.  Meta borylation and subsequent halogenation19 and meta borylation followed by oxidation to phenols20 are both possible through the use of borylation chemistry in simple two step protocols, preventing the challenging process of functional group manipulation to get the correct substitution.  While it was shown that often borylation follows a statistical preference of 67:33 meta:para ratio for simple monosubstituted arenes, not all examples will follow that trend.21 For example, heterocycles,22 like indole and thiophene, tend to borylate ortho to the heteroatom.23  While 1,3-disubstituted arenes typically will borylate in the 5 position, meta to both substituents due to sterics, a smaller, more electron withdrawing fluorine can cause problems in regioselectivity. The regioselectivity can oftentimes be a 1:1 mixture of ortho to the fluorine and meta to the fluorine isomers, which are difficult to separate (Scheme 6.6).24   205   These exceptions appear to prove that in some cases, while steric hindrance plays a role in selectivity, there are other electronic factors which cause some C-H bonds to be more acidic, and therefore more susceptible to C-H activation, than sterics alone would explain.  It would be to our benefit to fully detail some of the most common borylation ligands and see if their selectivities for either isomer can be improved one direction or the other by other substituents on the arene ring, which may increase or decrease the electronic induction of the overall arene. 6-Methyl-Pyrrolidone (NMP)  and N-methyl pyrrolidone (NMP) are effective solvents for borylations,25 we partnered with Dow Chemical to explore the full scope of borylations of 2-substituted 1-chloro-3-fluorobenzenes in terms of both the conversions as well as the ratio of borylated products obtained in  and NMP.  Borylated products where the boronic ester is meta to both halogens will be referred to product is mostly sterically driven away from the functional groups.  The product with the 206  boronic ester ortho to fluorine will be referred to occurs on the site where the C-H is most acidic due to the induction of fluorine, and therefore the borylation is electronically driven to that spot (Scheme 6.7).    We settled on looking at the six substrates shown below in Scheme 6.8.  These substrates give us a combination of both electron withdrawing and electron donating groups in the 2 position, which potentially could influence the overall electronics of the arene, thus changing the borylation isomeric ratio.     While the methyl, ethoxy, and dimethylamino groups are electron donating, the extra chlorine, fluorine, and cyano groups are inductively withdrawing.  It was postulated that the donating groups may afford a greater amount of steric products while the withdrawing groups would lead to more of the electronic products, due to the extra inductive effect on the hydrogen 207  ortho to fluorine.  To run all these substrates in a consistent fashion, we decided to run 24 well plate reactions, four of each substrate.  A stock solution of iridium catalyst, B2Pin2, and the ligand of choice was prepared with the given solvent for the borylation, and this stock solution was added to each substrate well evenly to ensure consistency.  In regards to the ligand, several common ligands were chosen to investigate.  In addition to control experiments with no ligand, we used the ligands below to determine ligand effects on the conversions and isomeric ratios of borylated products. (Scheme 6.9NMP as a solvent for some of the ligands we screened.  The results of these well plates are shown below.   The first well plate reaction used dtbpy26 as the are exactly what we expected based on one mmol scale reactions done in round-bottom flasks by Li,27 but conversions appeared to be depressed by about 10% from the exact same reaction run in a flask instead of the well plate.  Our explanation for this decrease in conversion is the relative lack of head space in the small vials for hydrogen gas that is produced in the borylation, which suppresses the rate of reaction.  In any event, the isomeric ratios are not affected by this slowing of the rate of reaction.  The electronic effect of the heteroatoms between chlorine and fluorine appears to favor the electronic products more than having either a methyl or a cyano group in between chlorine and fluorine. The results of this first well plate are shown in Scheme 6.10.   208   In addition to running each reaction with each ligand at room temperature for twelve hours, we also ran them at 60 °C for six hours to determine if there was any change in the conversions or isomeric ratios at higher temperature conditions.  While dtbpy shows almost the same conversions and isomeric ratios at room temperature and elevated temperatures (Scheme 6.11), most ligands had increased reactivity at higher temperatures.  The results of these are shown organized by substrate in Tables 6.1-6.6.  209    Based on these well plate studies, it appears that dtbpy is the most efficient ligand almost across the board in terms of total conversions and yields of both steric and electronic products However, it has poor selectivity for the electronic product.  While the Box ligand usually has the best selectivity for favoring the electronic products next to fluorine, the relative lack of conversion makes it difficult to observe the products in high yield.  In the case of DPM, addition of excess ligand (4 mol % instead of 2 mol %) depresses the rate of conversion, but does not change the isomeric ratio.    210    211   212   213   214   215     216  Since borylations run in NMP tbase, it is not surprising that the conversions over the same time periods for NMP tended to be dtbpy, DPM, and TMP tended to favor the steric product by roughly 5-15% more than they did  be seen from the data in Tables 6.7-6.9.    In conclusion, we have completed a comprehensive study of the borylation of 2-substituted 1-chloro-3-fluorobenzenes.  While they gave isomeric ratios consistent with 1 mmol scale reactions performed in a round-bottom flask, the conversions appear to be reduced due to the buildup of hydrogen gas in solution generated in the reaction.  With this in mind, we can accurately say that the Box ligand is the most selective for the electronic product, but that its relative lack of reactivity means that it underperforms in terms of total electronic product created versus the traditional dtbpy bipyridine ligand, which is more reactive overall.  Modifications to improve the overall efficiency of Box while retaining the isomeric ratio given would be desirable.   Most substituents that were added in between the chlorine and fluorine substituents held to what we expected, except for the cyano group, which was perhaps the most selective for the steric product despite its electron withdrawing character.  We concluded that while inductive for the position ortho to fluorine, it was also through resonance an electron withdrawing group to the hydrogen which was activated to form the steric product as well, making that the most accessible hydrogen for C-H activation.  More studies comparing the relative reaction rates of different substituents on substituted biaryl systems can answer some of the additional questions we have in terms of late stage functionalization and relative reaction rates and isomeric ratios for larger arenes, and is a project for further study.  217    218  219     220  6.4 Experimental Iridium catalyzed borylations were prepared in a glove box.  All reactions were carried out in 32 or 96 well plate reaction vessels under an N2 atmosphere unless otherwise noted. B2Pin2 was provided by BoroPharm, Inc. and used as received.  All solvents were reagent grade.   and N-methyl pyrrolidinone (NMP) was treated with calcium hydride, distilled, and stored over freshly activated 4Å molecular sieves. -di-tert--bipyridine (dtbpy), 3,4,7,8-tetramethylphenanthroline (TMP), bis(oxazoline) (Box), and  (S,S)--Methylenebis(4-tert-butyl-2-oxazoline) (DTBBM) were purchased from Aldrich and used as received. [Ir(OMe)(COD)]2 was prepared according to literature procedures.28  Yields refer to conversions recorded by 19F NMR unless specifically indicated.  1H NMR, 11B NMR, 19F NMR, and 13C NMR data was taken on Varian VXR-500 (499.74 MHz for 1H and 125.67 MHz for 13C), Varian Inova-600 (599.89 MHz for 1H and 150.84 MHz for 13C), and Varian automated 500 MHz NMR (499.70 MHz for 1H, 124.93 MHz for 13C, 96.29 MHz for 11B, and 470 MHz for 19F NMR).  Chemical shifts are reported relative to the residue solvent peaks CDCl3 ( 7.26 ppm for 1H NMR and 77.0 for 13C NMR).   General Procedure for Borylations (Procedure 6A) In a glove box, four well plate vials, equipped with a magnetic stirring bar, were charged with the corresponding substrate. A 10 mL stock solution of the given solvent was made in a volumetric flask, charged with B2Pin2, [Ir(OMe)(COD)]2 and a ligand of choice.  The stock solution of solvent and borylation reagents was added to each individual well plate vial of substrate with a given volume of the stock solution prepared (0.3 mL).  The well plate was sealed, brought out of the glove box, and set on a stirring hot plate in a fume hood to stir, either at room temperature or at 60 °C.  The reactions were carried out at the specified temperature for 221  the specified time.  After completion of the reaction, the well plate was unsealed and the individual reactions were taken up in CDCl3 to be observed by 19F NMR.27  6.4.1 Ligand Synthesis  Synthesis of Dipyridylmethane (DPM) ligand (41): To an oven-dried 500 mL three-necked flask was added 2-methylpyridine (3.9 mL, 40 mmol) and THF (50 mL).  The solution was cooled to -78 °C under N2 atmosphere and mechanically stirred. Once the flask was cold, n-BuLi (29 mL, 1.84 M solution in THF, 53 mmol, 1.3 equiv.) was added dropwise, stirred at -78 °C for 1 hour, and then the reaction was allowed to warm to room temperature slowly.  After the flask was at room temperature, 2-fluoropyridine (1.72 mL, 20 mmol, 0.5 equiv.) was added to the flask and it was heated to 60 °C for 1 hour.  The material was extracted with methylene chloride and water, and the organic layer was washed with water (50 mL 3x) and brine (50 mL), dried with magnesium sulfate, and filtered.  The organic layer was then concentrated and distilled through Kugelrohr distillation (100 °C, 0.1 torr), to yield a dark oil as the known final product (1.7 g, 50% yield).29  1H NMR (500 MHz, CDCl3 (dd, J = 6.7, 6.4 Hz, 2H), 7.06 (m, 2H), 7.21 (m, 2H), 7.54 (m, 2H), 8.49 (m, 2H).  13C NMR (126 MHz, CDCl347.3, 121.4, 123.5, 136.5, 149.4, 159.4.  222  6.4.2   Borylation of 1-chloro-3-fluoro-2-methylbenzene (43/44): Procedure 6A was followed with the following amounts: 1-chloro-3-fluoro-2-), B2Pin2 (635 mg, 0.075 mmol per well, 0.5 equiv.), dtbpy (22 mg, 0.0030 mmol per well, 2 mol %), [Ir(OMe)(COD)]2 (33 mg, 0.0015 mmol per well, 1 mol %10 mL).  The well plate was taken out of the glove box and stirred at room temperature for 12 hours.  After 12 hours, the well plate top was unsealed, and the vials containing the substrate were analyzed by 19F NMR to determine the conversion (70% conversion, 73%: 27% Steric: Electronic, averaged over 4 runs).  19F NMR (471 MHz, CDCl3): Steric i -114.3 (dd, J = 9.0, 3.7 Hz, 1 F).  -102.1 (sext, J = 3.0 Hz, 1 F) -113.1 (m, 1 F).   Borylation of 1-chloro-2-ethoxy-3-fluorobenzene (46/47): Procedure 6A was followed with the following amounts: 1-chloro-2-ethoxy-3-223  well), B2Pin2 (635 mg, 0.075 mmol per well, 0.5 equiv.), dtbpy (22 mg, 0.0030 mmol per well, 2 mol %), [Ir(OMe)(COD)]2 (33 mg, 0.0015 mmol per well, 1 mol %10 mL).  The well plate was taken out of the glove box and stirred at room temperature for 12 hours.  After 12 hours, the well plate top was unsealed, and the vials containing the substrate were analyzed by 19F NMR to determine the conversion (84% conversion, 51%: 49% Steric: Electronic, averaged over 4 runs).  19F NMR (471 MHz, CDCl3 -129.0 (d, J = 11.3 Hz, 1 F). -117.5 (d, J = 6.3 Hz, 1 F) -127.8 (dd, J = 9.5, 5.4 Hz, 1 F)   Borylation of 2-chloro-6-fluoro-N,N-dimethylaniline (49/50): Procedure 6A was followed with the following amounts: 2-chloro-6-fluoro-N,N-mmol per well), B2Pin2 (635 mg, 0.075 mmol per well, 0.5 equiv.), dtbpy (22 mg, 0.0030 mmol per well, 2 mol %), [Ir(OMe)(COD)]2 (33 mg, 0.0015 mmol per well, 1 mol %base (10 mL).  The well plate was taken out of the glove box and stirred at room temperature for 12 hours.  After 12 hours, the well plate top was unsealed, and the vials containing the substrate were analyzed by 19F NMR to determine the conversion (77% conversion, 57%: 43% Steric: Electronic, averaged over 4 runs).  19F NMR (471 MHz, CDCl3 -120.4 (dt, J = 224  11.8, 2.0 Hz, 1 F) -108.5 (t, J = 2.7 Hz, 1 F) -118.9 (undectet, J = 2.9 Hz, 1 F).   Borylation of 1,2-dichloro-3-fluorobenzene (52/53): Procedure 6A was followed with the following amounts: 1,2-dichloro-3-), B2Pin2 (635 mg, 0.075 mmol per well, 0.5 equiv.), dtbpy (22 mg, 0.0030 mmol per well, 2 mol %), [Ir(OMe)(COD)]2 (33 mg, 0.0015 mmol per well, 1 mol %10 mL).  The well plate was taken out of the glove box and stirred at room temperature for 12 hours.  After 12 hours, the well plate top was unsealed, and the vials containing the substrate were analyzed by 19F NMR to determine the conversion (84% conversion, 55%: 45% Steric: Electronic, averaged over 4 runs).  19F NMR (471 MHz, CDCl3 -111.2 (d, J = 8.0 Hz, 1 F). Electronic  -99.1 (d, J = 5.4 Hz, 1 F) -109.2 (ddd, J = 6.7, 5.4, 0.8 Hz, 1 F).  225   Borylation of 1-chloro-2,3-difluorobenzene (55/56): Procedure 6A was followed with the following amounts: 1-chloro-2,3-), B2Pin2 (635 mg, 0.075 mmol per well, 0.5 equiv.), dtbpy (22 mg, 0.0030 mmol per well, 2 mol %), [Ir(OMe)(COD)]2 (33 mg, 0.0015 mmol per well, 1 mol %10 mL).  The well plate was taken out of the glove box and stirred at room temperature for 12 hours.  After 12 hours, the well plate top was unsealed, and the vials containing the substrate were analyzed by 19F NMR to determine the conversion (91% conversion, 36%: 64% Steric: Electronic, averaged over 4 runs).  19F NMR (471 MHz, CDCl3 -136.1 (dd, J = 20.2, 9.8 Hz, 1 F),     -134.8 (dt, J = 20.3, 6.7 Hz, 1 F) -140.1 (ddd, J = 21.1, 5.4, 1.6 Hz, 1 F),     -125.4 (ddd, J = 21.1, 5.4, 1.6 Hz, 1 F) -138.8 (dtd, J = 20.7, 6.1, 1.8 Hz, 1 F), -135.1 (dddd, J = 20.7, 9.5, 5.4, 1.7 Hz, 1 F).   Borylation of 2-chloro-6-fluorobenzonitrile (58/59): Procedure 6A was followed with the following amounts: 2-chloro-6-), B2Pin2 (635 226  mg, 0.075 mmol per well, 0.5 equiv.), dtbpy (22 mg, 0.0030 mmol per well, 2 mol %), [Ir(OMe)(COD)]2 (33 mg, 0.0015 mmol per well, 1 mol %), a10 mL).  The well plate was taken out of the glove box and stirred at room temperature for 12 hours.  After 12 hours, the well plate top was unsealed, and the vials containing the substrate were analyzed by 19F NMR to determine the conversion (92% conversion, 69%: 31% Steric: Electronic, averaged over 4 runs).  19F NMR (471 MHz, CDCl3 -104.6 (d, J = 6.2 Hz, 1 F).  -92.2 (d, J = 5.7 Hz, 1 F) -103.1 (t, J = 6.3 Hz, 1 F).   Borylation of 1-chloro-3-fluoro-2-methylbenzene (43/44): Procedure 6A was followed with the following amounts: 1-chloro-3-fluoro-2-), B2Pin2 (635 mg, 0.075 mmol per well, 0.5 equiv.), dtbpy (22 mg, 0.0030 mmol per well, 2 mol %), [Ir(OMe)(COD)]2 (33 mg, 0.0015 mmol per well, 1 mol %10 mL).  The well plate was taken out of the glove box and stirred at 60 °C for 6 hours.  After 6 hours, the well plate top was unsealed, and the vials containing the substrate were analyzed by 19F NMR to determine the conversion (75% conversion, 73%: 27% Steric: Electronic, averaged over 4 runs).  19F NMR (471 MHz, CDCl3): -114.3 (dd, J = 9.0, 3.7 Hz, 1 F). Electronic -102.1 (sext, J = 3.0 Hz-113.1 (m, 1 F).  227   Borylation of 1-chloro-2-ethoxy-3-fluorobenzene (46/47): Procedure 6A was followed with the following amounts: 1-chloro-2-ethoxy-3-well), B2Pin2 (635 mg, 0.075 mmol per well, 0.5 equiv.), dtbpy (22 mg, 0.0030 mmol per well, 2 mol %), [Ir(OMe)(COD)]2 (33 mg, 0.0015 mmol per well, 1 mol %10 mL).  The well plate was taken out of the glove box and stirred at 60 °C for 6 hours.  After 6 hours, the well plate top was unsealed, and the vials containing the substrate were analyzed by 19F NMR to determine the conversion (78% conversion, 53%: 47% Steric: Electronic, averaged over 4 runs).  19F NMR (471 MHz, CDCl3): -129.0 (d, J = 11.3 Hz, 1 F). -117.5 (d, J -127.8 (dd, J = 9.5, 5.4 Hz, 1 F).   Borylation of 2-chloro-6-fluoro-N,N-dimethylaniline (49/50): Procedure 6A was followed with the following amounts: 2-chloro-6-fluoro-N,N-mmol per well), B2Pin2 (635 mg, 0.075 mmol per well, 0.5 equiv.), dtbpy (22 mg, 0.0030 mmol per well, 2 mol %), [Ir(OMe)(COD)]2 (33 mg, 0.0015 mmol per well, 1 mol %228  base (10 mL).  The well plate was taken out of the glove box and stirred at 60 °C for 6 hours.  After 6 hours, the well plate top was unsealed, and the vials containing the substrate were analyzed by 19F NMR to determine the conversion (75% conversion, 59%: 41% Steric: Electronic, averaged over 4 runs).  19F NMR (471 MHz, CDCl3): -120.4 (dt, J = -108.5 (t, J = 2.7 Hz, 1 -118.9 (undectet, J = 2.9 Hz, 1 F).   Borylation of 1,2-dichloro-3-fluorobenzene (52/53): Procedure 6A was followed with the following amounts: 1,2-dichloro-3-), B2Pin2 (635 mg, 0.075 mmol per well, 0.5 equiv.), dtbpy (22 mg, 0.0030 mmol per well, 2 mol %), [Ir(OMe)(COD)]2 (33 mg, 0.0015 mmol per well, 1 mol %10 mL).  The well plate was taken out of the glove box and stirred at 60 °C for 6 hours.  After 6 hours, the well plate top was unsealed, and the vials containing the substrate were analyzed by 19F NMR to determine the conversion (86% conversion, 57%: 43% Steric: Electronic, averaged over 4 runs).  19F NMR (471 MHz, CDCl3): -111.2 (d, J = 8.0 Hz, 1 -99.1 (d, J = 5.4 Hz, 1 -109.2 (ddd, J = 6.7, 5.4, 0.8 Hz, 1 F).  229   Borylation of 1-chloro-2,3-difluorobenzene (55/56): Procedure 6A was followed with the following amounts: 1-chloro-2,3-), B2Pin2 (635 mg, 0.075 mmol per well, 0.5 equiv.), dtbpy (22 mg, 0.0030 mmol per well, 2 mol %), [Ir(OMe)(COD)]2 (33 mg, 0.0015 mmol per well, 1 mol %10 mL).  The well plate was taken out of the glove box and stirred 60 °C for 6 hours.  After 6 hours, the well plate top was unsealed, and the vials containing the substrate were analyzed by 19F NMR to determine the conversion (93% conversion, 40%: 60% Steric: Electronic, averaged over 4 runs).  19F NMR (471 MHz, CDCl3): -136.1 (dd, J = 20.2, 9.8 Hz, 1 F), -134.8 (dt, J = -140.1 (ddd, J = 21.1, 5.4, 1.6 Hz, 1 F), -125.4 (ddd, J = 21.1, 5.4, 1.6 Hz, 1 F). -138.8 (dtd, J = 20.7, 6.1, 1.8 Hz, 1 F), -135.1 (dddd, J = 20.7, 9.5, 5.4, 1.7 Hz, 1 F).   Borylation of 2-chloro-6-fluorobenzonitrile (58/59): Procedure 6A was followed with the following amounts: 2-chloro-6-), B2Pin2 (635 230  mg, 0.075 mmol per well, 0.5 equiv.), dtbpy (22 mg, 0.0030 mmol per well, 2 mol %), [Ir(OMe)(COD)]2 (33 mg, 0.0015 mmol per well, 1 mol %10 mL).  The well plate was taken out of the glove box and stirred at 60 °C for 6 hours.  After 6 hours, the well plate top was unsealed, and the vials containing the substrate were analyzed by 19F NMR to determine the conversion (88% conversion, 67%: 33% Steric: Electronic, averaged over 4 runs).  19F NMR (471 MHz, CDCl3): -104.6 (d, J    -92.2 (d, J = 5.7 Hz, 1 -103.1 (t, J = 6.3 Hz, 1 F).   Borylation of 1-chloro-3-fluoro-2-methylbenzene (43/44): Procedure 6A was followed with the following amounts: 1-chloro-3-fluoro-2-), B2Pin2 (635 mg, 0.075 mmol per well, 0.5 equiv.), TMP (23.6 mg, 0.003 mmol well, 2 mol %), [Ir(OMe)(COD)]2 (33 mg, 0.0015 mmol per well, 1 mol %10 mL).  The well plate was taken out of the glove box and stirred at room temperature for 12 hours.  After 12 hours, the well plate top was unsealed, and the vials containing the substrate were analyzed by 19F NMR to determine the conversion (33% conversion, 73%: 27% Steric: Electronic, averaged over 4 runs).  19F NMR (471 MHz, CDCl3): -114.3 (dd, J = 9.0, 3.7 Hz, 1 F). -102.1 (sext, J = 3.0 Hz-113.1 (m, 1 F).  231   Borylation of 1-chloro-2-ethoxy-3-fluorobenzene (46/47): Procedure 6A was followed with the following amounts: 1-chloro-2-ethoxy-3-0.15 mmol per well), B2Pin2 (635 mg, 0.075 mmol per well, 0.5 equiv.), TMP (23.6 mg, 0.003 mmol well, 2 mol %), [Ir(OMe)(COD)]2 (33 mg, 0.0015 mmol per well, 1 mol %10 mL).  The well plate was taken out of the glove box and stirred at room temperature for 12 hours.  After 12 hours, the well plate top was unsealed, and the vials containing the substrate were analyzed by 19F NMR to determine the conversion (33% conversion, 47%: 53% Steric: Electronic, averaged over 4 runs).  19F NMR (471 MHz, CDCl3): -129.0 (d, J = 11.3 Hz, 1 F). -117.5 (d, J -127.8 (dd, J = 9.5, 5.4 Hz, 1 F).   Borylation of 2-chloro-6-fluoro-N,N-dimethylaniline (49/50): Procedure 6A was followed with the following amounts: 2-chloro-6-fluoro-N,N-mmol per well), B2Pin2 (635 mg, 0.075 mmol per well, 0.5 equiv.), TMP (23.6 mg, 0.003 mmol 232  well, 2 mol %), [Ir(OMe)(COD)]2 (33 mg, 0.0015 mmol per well, 1 mol %(10 mL).  The well plate was taken out of the glove box and stirred at room temperature for 12 hours.  After 12 hours, the well plate top was unsealed, and the vials containing the substrate were analyzed by 19F NMR to determine the conversion (55% conversion, 56%: 44% Steric: Electronic, averaged over 2 runs).  19F NMR (471 MHz, CDCl3): -120.4 (dt, J = -108.5 (t, J = 2.7 Hz, 1 -118.9 (undectet, J = 2.9 Hz, 1 F).   Borylation of 1,2-dichloro-3-fluorobenzene (52/53): Procedure 6A was followed with the following amounts: 1,2-dichloro-3-), B2Pin2 (635 mg, 0.075 mmol per well, 0.5 equiv.), TMP (23.6 mg, 0.003 mmol well, 2 mol %), [Ir(OMe)(COD)]2 (33 mg, 0.0015 mmol per well, 1 mol %), and Hün10 mL).  The well plate was taken out of the glove box and stirred at room temperature for 12 hours.  After 12 hours, the well plate top was unsealed, and the vials containing the substrate were analyzed by 19F NMR to determine the conversion (44% conversion, 52%: 48% Steric: Electronic, averaged over 3 runs).  19F NMR (471 MHz, CDCl3): -111.2 (d, J = 8.0 Hz, 1 F). -99.1 (d, J = 5.4 Hz, 1 -109.2 (ddd, J = 6.7, 5.4, 0.8 Hz, 1 F). 233   Borylation of 1-chloro-2,3-difluorobenzene (55/56): Procedure 6A was followed with the following amounts: 1-chloro-2,3-), B2Pin2 (635 mg, 0.075 mmol per well, 0.5 equiv.), TMP (23.6 mg, 0.003 mmol well, 2 mol %), [Ir(OMe)(COD)]2 (33 mg, 0.0015 mmol per well, 1 mol %10 mL).  The well plate was taken out of the glove box and stirred at room temperature for 12 hours.  After 12 hours, the well plate top was unsealed, and the vials containing the substrate were analyzed by 19F NMR to determine the conversion (65% conversion, 32%: 68% Steric: Electronic, averaged over 3 runs).  19F NMR (471 MHz, CDCl3): -136.1 (dd, J = 20.2, 9.8 Hz, 1 F), -134.8 (dt, J = 20.3, 6.7 -140.1 (ddd, J = 21.1, 5.4, 1.6 Hz, 1 F), -125.4 (ddd, J = 21.1, 5.4, -138.8 (dtd, J = 20.7, 6.1, 1.8 Hz, 1 F), -135.1 (dddd, J = 20.7, 9.5, 5.4, 1.7 Hz, 1 F).   Borylation of 2-chloro-6-fluorobenzonitrile (58/59): Procedure 6A was followed with the following amounts: 2-chloro-6-), B2Pin2 (635 234  mg, 0.075 mmol per well, 0.5 equiv.), TMP (23.6 mg, 0.003 mmol well, 2 mol %), [Ir(OMe)(COD)]2 (33 mg, 0.0015 mmol per well, 1 mol %10 mL).  The well plate was taken out of the glove box and stirred at room temperature for 12 hours.  After 12 hours, the well plate top was unsealed, and the vials containing the substrate were analyzed by 19F NMR to determine the conversion (61% conversion, 70%: 30% Steric: Electronic, averaged over 3 runs).  19F NMR (471 MHz, CDCl3): -104.6 (d, J = 6.2 Hz, 1 F). -92.2 (d, J = 5.7 Hz, 1 -103.1 (t, J = 6.3 Hz, 1 F).   Borylation of 1-chloro-3-fluoro-2-methylbenzene (43/44): Procedure 6A was followed with the following amounts: 1-chloro-3-fluoro-2- per well, 0.15 mmol), B2Pin2 (635 mg, 0.075 mmol per well, 0.5 equiv.), TMP (23.6 mg, 0.003 mmol well, 2 mol %), [Ir(OMe)(COD)]2 (33 mg, 0.0015 mmol per well, 1 mol %10 mL).  The well plate was taken out of the glove box and stirred at 60 °C for 6 hours.  After 6 hours, the well plate top was unsealed, and the vials containing the substrate were analyzed by 19F NMR to determine the conversion (47% conversion, 75%: 25% Steric: Electronic, averaged over 4 runs).  19F NMR (471 MHz, CDCl3): -114.3 (dd, J = 9.0, 3.7 Hz, 1 F). Electronic -102.1 (sext, J = 3.0 Hz-113.1 (m, 1 F).  235   Borylation of 1-chloro-2-ethoxy-3-fluorobenzene (46/47): Procedure 6A was followed with the following amounts: 1-chloro-2-ethoxy-3-well), B2Pin2 (635 mg, 0.075 mmol per well, 0.5 equiv.), TMP (23.6 mg, 0.003 mmol well, 2 mol %), [Ir(OMe)(COD)]2 (33 mg, 0.0015 mmol per well, 1 mol %10 mL).  The well plate was taken out of the glove box and stirred at 60 °C for 6 hours.  After 6 hours, the well plate top was unsealed, and the vials containing the substrate were analyzed by 19F NMR to determine the conversion (64% conversion, 54%: 46% Steric: Electronic, averaged over 4 runs).  19F NMR (471 MHz, CDCl3): -129.0 (d, J = 11.3 Hz, 1 F). -117.5 (d, J -127.8 (dd, J = 9.5, 5.4 Hz, 1 F).   Borylation of 2-chloro-6-fluoro-N,N-dimethylaniline (49/50): Procedure 6A was followed with the following amounts: 2-chloro-6-fluoro-N,N-mmol per well), B2Pin2 (635 mg, 0.075 mmol per well, 0.5 equiv.), TMP (23.6 mg, 0.003 mmol well, 2 mol %), [Ir(OMe)(COD)]2 (33 mg, 0.0015 mmol per well, 1 mol %236  (10 mL).  The well plate was taken out of the glove box and stirred at 60 °C for 6 hours.  After 6 hours, the well plate top was unsealed, and the vials containing the substrate were analyzed by 19F NMR to determine the conversion (49% conversion, 59%: 41% Steric: Electronic, averaged over 4 runs).  19F NMR (471 MHz, CDCl3): -120.4 (dt, J = 11.8, 2.0 Hz, 1 F). -108.5 (t, J = 2.7 Hz, 1 -118.9 (undectet, J = 2.9 Hz, 1 F).   Borylation of 1,2-dichloro-3-fluorobenzene (52/53): Procedure 6A was followed with the following amounts: 1,2-dichloro-3-), B2Pin2 (635 mg, 0.075 mmol per well, 0.5 equiv.), TMP (23.6 mg, 0.003 mmol well, 2 mol %), [Ir(OMe)(COD)]2 (33 mg, 0.0015 mmol per well, 1 mol %10 mL).  The well plate was taken out of the glove box and stirred at 60 °C for 6 hours.  After 6 hours, the well plate top was unsealed, and the vials containing the substrate were analyzed by 19F NMR to determine the conversion (63% conversion, 57%: 43% Steric: Electronic, averaged over 4 runs).  19F NMR (471 MHz, CDCl3): -111.2 (d, J = 8.0 Hz, 1    -99.1 (d, J = 5.4 Hz, 1 -109.2 (ddd, J = 6.7, 5.4, 0.8 Hz, 1 F).  237   Borylation of 1-chloro-2,3-difluorobenzene (55/56): Procedure 6A was followed with the following amounts: 1-chloro-2,3-), B2Pin2 (635 mg, 0.075 mmol per well, 0.5 equiv.), TMP (23.6 mg, 0.003 mmol well, 2 mol %), [Ir(OMe)(COD)]2 (33 mg, 0.0015 mmol per well, 1 mol %10 mL).  The well plate was taken out of the glove box and stirred 60 °C for 6 hours.  After 6 hours, the well plate top was unsealed, and the vials containing the substrate were analyzed by 19F NMR to determine the conversion (69% conversion, 39%: 61% Steric: Electronic, averaged over 4 runs).  19F NMR (471 MHz, CDCl3): -136.1 (dd, J = 20.2, 9.8 Hz, 1 F), -134.8 (dt, J = 20.3, 6.7 Hz, 1 -140.1 (ddd, J = 21.1, 5.4, 1.6 Hz, 1 F), -125.4 (ddd, J = 21.1, 5.4, 1.6 -138.8 (dtd, J = 20.7, 6.1, 1.8 Hz, 1 F), -135.1 (dddd, J = 20.7, 9.5, 5.4, 1.7 Hz, 1 F).   Borylation of 2-chloro-6-fluorobenzonitrile (58/59): Procedure 6A was followed with the following amounts: 2-chloro-6-), B2Pin2 (635 238  mg, 0.075 mmol per well, 0.5 equiv.), TMP (23.6 mg, 0.003 mmol well, 2 mol %), [Ir(OMe)(COD)]2 (33 mg, 0.0015 mmol per well, 1 mol %10 mL).  The well plate was taken out of the glove box and stirred at 60 °C for 6 hours.  After 6 hours, the well plate top was unsealed, and the vials containing the substrate were analyzed by 19F NMR to determine the conversion (70% conversion, 67%: 33% Steric: Electronic, averaged over 4 runs).  19F NMR (471 MHz, CDCl3): -104.6 (d, J    -92.2 (d, J = 5.7 Hz, 1 -103.1 (t, J = 6.3 Hz, 1 F).   Borylation of 1-chloro-3-fluoro-2-methylbenzene (43/44): Procedure 6A was followed with the following amounts: 1-chloro-3-fluoro-2-), B2Pin2 (635 mg, 0.075 mmol per well, 0.5 equiv.), Box (14 mg, 0.003 mmol per well, 2 mol %), [Ir(OMe)(COD)]2 (33 mg, 0.0015 mmol per well, 1 mol %10 mL).  The well plate was taken out of the glove box and stirred at 60 °C for 6 hours.  After 6 hours, the well plate top was unsealed, and the vials containing the substrate were analyzed by 19F NMR to determine the conversion (37% conversion, 34%: 66% Steric: Electronic, averaged over 2 runs).  19F NMR (471 MHz, CDCl3): -114.3 (dd, J = 9.0, 3.7 Hz, 1 F). Electronic -102.1 (sext, J = 3.0 Hz-113.1 (m, 1 F).  239   Borylation of 1-chloro-2-ethoxy-3-fluorobenzene (46/47): Procedure 6A was followed with the following amounts: 1-chloro-2-ethoxy-3-mmol per well), B2Pin2 (635 mg, 0.075 mmol per well, 0.5 equiv.), Box (14 mg, 0.003 mmol per well, 2 mol %), [Ir(OMe)(COD)]2 (33 mg, 0.0015 mmol per well, 1 mol %10 mL).  The well plate was taken out of the glove box and stirred at 60 °C for 6 hours.  After 6 hours, the well plate top was unsealed, and the vials containing the substrate were analyzed by 19F NMR to determine the conversion (28% conversion, 17%: 83% Steric: Electronic, averaged over 4 runs).  19F NMR (471 MHz, CDCl3): -129.0 (d, J = 11.3 Hz, 1 F). -117.5 (d, J -127.8 (dd, J = 9.5, 5.4 Hz, 1 F).   Borylation of 2-chloro-6-fluoro-N,N-dimethylaniline (49/50): Procedure 6A was followed with the following amounts: 2-chloro-6-fluoro-N,N-mmol per well), B2Pin2 (635 mg, 0.075 mmol per well, 0.5 equiv.), Box (14 mg, 0.003 mmol per well, 2 mol %), [Ir(OMe)(COD)]2 (33 mg, 0.0015 mmol per well, 1 mol %240  (10 mL).  The well plate was taken out of the glove box and stirred at 60 °C for 6 hours.  After 6 hours, the well plate top was unsealed, and the vials containing the substrate were analyzed by 19F NMR to determine the conversion (26% conversion, 28%: 72% Steric: Electronic, averaged over 4 runs).  19F NMR (471 MHz, CDCl3): -120.4 (dt, J = 11.8, 2.0 Hz, 1 F). -108.5 (t, J = 2.7 Hz, 1 -118.9 (undectet, J = 2.9 Hz, 1 F).   Borylation of 1,2-dichloro-3-fluorobenzene (52/53): Procedure 6A was followed with the following amounts: 1,2-dichloro-3-), B2Pin2 (635 mg, 0.075 mmol per well, 0.5 equiv.), Box (14 mg, 0.003 mmol per well, 2 mol %), [Ir(OMe)(COD)]2 (33 mg, 0.0015 mmol per well, 1 mol %), and 10 mL).  The well plate was taken out of the glove box and stirred at 60 °C for 6 hours.  After 6 hours, the well plate top was unsealed, and the vials containing the substrate were analyzed by 19F NMR to determine the conversion (42% conversion, 21%: 79% Steric: Electronic, averaged over 4 runs).  19F NMR (471 MHz, CDCl3): -111.2 (d, J = 8.0 Hz, 1     -99.1 (d, J = 5.4 Hz, 1 -109.2 (ddd, J = 6.7, 5.4, 0.8 Hz, 1 F).  241   Borylation of 1-chloro-2,3-difluorobenzene (55/56): Procedure 6A was followed with the following amounts: 1-chloro-2,3-), B2Pin2 (635 mg, 0.075 mmol per well, 0.5 equiv.), Box (14 mg, 0.003 mmol per well, 2 mol %), [Ir(OMe)(COD)]2 (33 mg, 0.0015 mmol per well, 1 mol %10 mL).  The well plate was taken out of the glove box and stirred 60 °C for 6 hours.  After 6 hours, the well plate top was unsealed, and the vials containing the substrate were analyzed by 19F NMR to determine the conversion (42% conversion, 12%: 88% Steric: Electronic, averaged over 4 runs).  19F NMR (471 MHz, CDCl3): -136.1 (dd, J = 20.2, 9.8 Hz, 1 F), -134.8 (dt, J = -140.1 (ddd, J = 21.1, 5.4, 1.6 Hz, 1 F), -125.4 (ddd, J = -138.8 (dtd, J = 20.7, 6.1, 1.8 Hz, 1 F), -135.1 (dddd, J = 20.7, 9.5, 5.4, 1.7 Hz, 1 F).   Borylation of 2-chloro-6-fluorobenzonitrile (58/59): Procedure 6A was followed with the following amounts: 2-chloro-6-), B2Pin2 (635 242  mg, 0.075 mmol per well, 0.5 equiv.), Box (14 mg, 0.003 mmol per well, 2 mol %), [Ir(OMe)(COD)]2 (33 mg, 0.0015 mmol per well, 1 mol %10 mL).  The well plate was taken out of the glove box and stirred at 60 °C for 6 hours.  After 6 hours, the well plate top was unsealed, and the vials containing the substrate were analyzed by 19F NMR to determine the conversion (53% conversion, 45%: 55% Steric: Electronic, averaged over 4 runs).  19F NMR (471 MHz, CDCl3): -104.6 (d, J    -92.2 (d, J = 5.7 Hz, 1 -103.1 (t, J = 6.3 Hz, 1 F).   Borylation of 1-chloro-3-fluoro-2-methylbenzene (43/44): Procedure 6A was followed with the following amounts: 1-chloro-3-fluoro-2-), B2Pin2 (635 mg, 0.075 mmol per well, 0.5 equiv.), DTBBM (21.9 mg, 0.003 mmol per well, 2 mol %), [Ir(OMe)(COD)]2 (33 mg, 0.0015 mmol per well, 1 mol %10 mL).  The well plate was taken out of the glove box and stirred at 60 °C for 6 hours.  After 6 hours, the well plate top was unsealed, and the vials containing the substrate were analyzed by 19F NMR to determine the conversion (2% conversion, 75%: 25% Steric: Electronic, averaged over 4 runs).  19F NMR (471 MHz, CDCl3): -114.3 (dd, J = 9.0, 3.7 Hz, 1 F). Electronic -102.1 (sext, J = 3.0 Hz-113.1 (m, 1 F).  243   Borylation of 1-chloro-2-ethoxy-3-fluorobenzene (46/47): Procedure 6A was followed with the following amounts: 1-chloro-2-ethoxy-3-well), B2Pin2 (635 mg, 0.075 mmol per well, 0.5 equiv.), DTBBM (21.9 mg, 0.003 mmol per well, 2 mol %), [Ir(OMe)(COD)]2 (33 mg, 0.0015 mmol per well, 1 mol %(10 mL).  The well plate was taken out of the glove box and stirred at 60 °C for 6 hours.  After 6 hours, the well plate top was unsealed, and the vials containing the substrate were analyzed by 19F NMR to determine the conversion (1% conversion, 66%: 34% Steric: Electronic, averaged over 4 runs).  19F NMR (471 MHz, CDCl3): -129.0 (d, J = 11.3 Hz, 1 F). -117.5 (d, J -127.8 (dd, J = 9.5, 5.4 Hz, 1 F).   Borylation of 2-chloro-6-fluoro-N,N-dimethylaniline (49/50): Procedure 6A was followed with the following amounts: 2-chloro-6-fluoro-N,N-mmol per well), B2Pin2 (635 mg, 0.075 mmol per well, 0.5 equiv.), DTBBM (21.9 mg, 0.003 244  mmol per well, 2 mol %), [Ir(OMe)(COD)]2 (33 mg, 0.0015 mmol per well, 1 mol %), and 10 mL).  The well plate was taken out of the glove box and stirred at 60 °C for 6 hours.  After 6 hours, the well plate top was unsealed, and the vials containing the substrate were analyzed by 19F NMR to determine the conversion (1% conversion, 76%: 24% Steric: Electronic, averaged over 4 runs).  19F NMR (471 MHz, CDCl3): -120.4 (dt, J = 11.8, 2.0 -108.5 (t, J = 2.7 Hz, 1 -118.9 (undectet, J = 2.9 Hz, 1 F).   Borylation of 1,2-dichloro-3-fluorobenzene (52/53): Procedure 6A was followed with the following amounts: 1,2-dichloro-3-), B2Pin2 (635 mg, 0.075 mmol per well, 0.5 equiv.), DTBBM (21.9 mg, 0.003 mmol per well, 2 mol %), [Ir(OMe)(COD)]2 (33 mg, 0.0015 mmol per well, 1 mol %10 mL).  The well plate was taken out of the glove box and stirred at 60 °C for 6 hours.  After 6 hours, the well plate top was unsealed, and the vials containing the substrate were analyzed by 19F NMR to determine the conversion (2% conversion, 64%: 36% Steric: Electronic, averaged over 3 runs).  19F NMR (471 MHz, CDCl3): -111.2 (d, J = 8.0 Hz, 1    -99.1 (d, J = 5.4 Hz, 1 -109.2 (ddd, J = 6.7, 5.4, 0.8 Hz, 1 F).  245   Borylation of 1-chloro-2,3-difluorobenzene (55/56): Procedure 6A was followed with the following amounts: 1-chloro-2,3-), B2Pin2 (635 mg, 0.075 mmol per well, 0.5 equiv.), DTBBM (21.9 mg, 0.003 mmol per well, 2 mol %), [Ir(OMe)(COD)]2 (33 mg, 0.0015 mmol per well, 1 mol %10 mL).  The well plate was taken out of the glove box and stirred 60 °C for 6 hours.  After 6 hours, the well plate top was unsealed, and the vials containing the substrate were analyzed by 19F NMR to determine the conversion (2% conversion, 51%: 49% Steric: Electronic, averaged over 4 runs).  19F NMR (471 MHz, CDCl3): -136.1 (dd, J = 20.2, 9.8 Hz, 1 F), -134.8 (dt, J = -140.1 (ddd, J = 21.1, 5.4, 1.6 Hz, 1 F), -125.4 (ddd, J = -138.8 (dtd, J = 20.7, 6.1, 1.8 Hz, 1 F), -135.1 (dddd, J = 20.7, 9.5, 5.4, 1.7 Hz, 1 F).   Borylation of 1-chloro-3-fluoro-2-methylbenzene (43/44): Procedure 6A was followed with the following amounts: 1-chloro-3-fluoro-2-), 246  B2Pin2 (635 mg, 0.075 mmol per well, 0.5 equiv.), DPM (39 mg, 0.006 mmol per well, 4 mol %), [Ir(OMe)(COD)]2 (33 mg, 0.0015 mmol per well, 1 mol %10 mL).  The well plate was taken out of the glove box and stirred at 60 °C for 6 hours.  After 6 hours, the well plate top was unsealed, and the vials containing the substrate were analyzed by 19F NMR to determine the conversion (10% conversion, 70%: 30% Steric: Electronic, averaged over 4 runs).  19F NMR (471 MHz, CDCl3): -114.3 (dd, J = 9.0, 3.7 Hz, 1 F). Electronic -102.1 (sext, J = 3.0 Hz-113.1 (m, 1 F).   Borylation of 1-chloro-2-ethoxy-3-fluorobenzene (46/47): Procedure 6A was followed with the following amounts: 1-chloro-2-ethoxy-3-well), B2Pin2 (635 mg, 0.075 mmol per well, 0.5 equiv.), DPM (39 mg, 0.006 mmol per well, 4 mol %), [Ir(OMe)(COD)]2 (33 mg, 0.0015 mmol per well, 1 mol %10 mL).  The well plate was taken out of the glove box and stirred at 60 °C for 6 hours.  After 6 hours, the well plate top was unsealed, and the vials containing the substrate were analyzed by 19F NMR to determine the conversion (19% conversion, 46%: 54% Steric: Electronic, averaged over 4 runs).  19F NMR (471 MHz, CDCl3): -129.0 (d, J = 11.3 Hz, 1 F). -117.5 (d, J -127.8 (dd, J = 9.5, 5.4 Hz, 1 F).  247   Borylation of 2-chloro-6-fluoro-N,N-dimethylaniline (49/50): Procedure 6A was followed with the following amounts: 2-chloro-6-fluoro-N,N-mmol per well), B2Pin2 (635 mg, 0.075 mmol per well, 0.5 equiv.), DPM (39 mg, 0.006 mmol per well, 4 mol %), [Ir(OMe)(COD)]2 (33 mg, 0.0015 mmol per well, 1 mol %base (10 mL).  The well plate was taken out of the glove box and stirred at 60 °C for 6 hours.  After 6 hours, the well plate top was unsealed, and the vials containing the substrate were analyzed by 19F NMR to determine the conversion (10% conversion, 58%: 42% Steric: Electronic, averaged over 4 runs).  19F NMR (471 MHz, CDCl3): -120.4 (dt, J = -108.5 (t, J = 2.7 Hz, 1 -118.9 (undectet, J = 2.9 Hz, 1 F).   Borylation of 1,2-dichloro-3-fluorobenzene (52/53): Procedure 6A was followed with the following amounts: 1,2-dichloro-3-), B2Pin2 (635 mg, 0.075 mmol per well, 0.5 equiv.), DPM (39 mg, 0.006 mmol per well, 4 mol %), 248  [Ir(OMe)(COD)]2 (33 mg, 0.0015 mmol per well, 1 mol %), and H10 mL).  The well plate was taken out of the glove box and stirred at 60 °C for 6 hours.  After 6 hours, the well plate top was unsealed, and the vials containing the substrate were analyzed by 19F NMR to determine the conversion (51% conversion, 55%: 45% Steric: Electronic, averaged over 4 runs).  19F NMR (471 MHz, CDCl3): -111.2 (d, J = 8.0 Hz, 1     -99.1 (d, J = 5.4 Hz, 1 -109.2 (ddd, J = 6.7, 5.4, 0.8 Hz, 1 F).   Borylation of 1-chloro-2,3-difluorobenzene (55/56): Procedure 6A was followed with the following amounts: 1-chloro-2,3-), B2Pin2 (635 mg, 0.075 mmol per well, 0.5 equiv.), DPM (39 mg, 0.006 mmol per well, 4 mol %), [Ir(OMe)(COD)]2 (33 mg, 0.0015 mmol per well, 1 mol %10 mL).  The well plate was taken out of the glove box and stirred 60 °C for 6 hours.  After 6 hours, the well plate top was unsealed, and the vials containing the substrate were analyzed by 19F NMR to determine the conversion (54% conversion, 33%: 67% Steric: Electronic, averaged over 4 runs).  19F NMR (471 MHz, CDCl3): -136.1 (dd, J = 20.2, 9.8 Hz, 1 F), -134.8 (dt, J = -140.1 (ddd, J = 21.1, 5.4, 1.6 Hz, 1 F), -125.4 (ddd, J = -138.8 (dtd, J = 20.7, 6.1, 1.8 Hz, 1 F), -135.1 (dddd, J = 20.7, 9.5, 5.4, 1.7 Hz, 1 F). 249   Borylation of 2-chloro-6-fluorobenzonitrile (58/59): Procedure 6A was followed with the following amounts: 2-chloro-6-), B2Pin2 (635 mg, 0.075 mmol per well, 0.5 equiv.), DPM (39 mg, 0.006 mmol per well, 4 mol %), [Ir(OMe)(COD)]2 (33 mg, 0.0015 mmol per well, 1 mol %10 mL).  The well plate was taken out of the glove box and stirred at 60 °C for 6 hours.  After 6 hours, the well plate top was unsealed, and the vials containing the substrate were analyzed by 19F NMR to determine the conversion (30% conversion, 60%: 40% Steric: Electronic, averaged over 4 runs).  19F NMR (471 MHz, CDCl3): -104.6 (d, J     -92.2 (d, J = 5.7 Hz, 1 -103.1 (t, J = 6.3 Hz, 1 F).   Borylation of 1-chloro-3-fluoro-2-methylbenzene (43/44): Procedure 6A was followed with the following amounts: 1-chloro-3-fluoro-2- per well, 0.15 mmol), B2Pin2 (635 mg, 0.075 mmol per well, 0.5 equiv.), DPM (19.5 mg, 0.003 mmol per well, 2 mol %), [Ir(OMe)(COD)]2 (33 mg, 0.0015 mmol per well, 1 mol %10 mL).  The 250  well plate was taken out of the glove box and stirred at 60 °C for 6 hours.  After 6 hours, the well plate top was unsealed, and the vials containing the substrate were analyzed by 19F NMR to determine the conversion (50% conversion, 65%: 35% Steric: Electronic, averaged over 4 runs).  19F NMR (471 MHz, CDCl3): -114.3 (dd, J = 9.0, 3.7 Hz, 1 F). Electronic -102.1 (sext, J = 3.0 Hz-113.1 (m, 1 F).   Borylation of 1-chloro-2-ethoxy-3-fluorobenzene (46/47): Procedure 6A was followed with the following amounts: 1-chloro-2-ethoxy-3-fluorobenzene (well), B2Pin2 (635 mg, 0.075 mmol per well, 0.5 equiv.), DPM (19.5 mg, 0.003 mmol per well, 2 mol %), [Ir(OMe)(COD)]2 (33 mg, 0.0015 mmol per well, 1 mol %10 mL).  The well plate was taken out of the glove box and stirred at 60 °C for 6 hours.  After 6 hours, the well plate top was unsealed, and the vials containing the substrate were analyzed by 19F NMR to determine the conversion (56% conversion, 47%: 53% Steric: Electronic, averaged over 4 runs).  19F NMR (471 MHz, CDCl3): -129.0 (d, J = 11.3 Hz, 1 F). -117.5 (d, J -127.8 (dd, J = 9.5, 5.4 Hz, 1 F).  251   Borylation of 2-chloro-6-fluoro-N,N-dimethylaniline (49/50): Procedure 6A was followed with the following amounts: 2-chloro-6-fluoro-N,N-dimethmmol per well), B2Pin2 (635 mg, 0.075 mmol per well, 0.5 equiv.), DPM (19.5 mg, 0.003 mmol per well, 2 mol %), [Ir(OMe)(COD)]2 (33 mg, 0.0015 mmol per well, 1 mol %base (10 mL).  The well plate was taken out of the glove box and stirred at 60 °C for 6 hours.  After 6 hours, the well plate top was unsealed, and the vials containing the substrate were analyzed by 19F NMR to determine the conversion (48% conversion, 56%: 44% Steric: Electronic, averaged over 4 runs).  19F NMR (471 MHz, CDCl3): -120.4 (dt, J = -108.5 (t, J = 2.7 Hz, 1 -118.9 (undectet, J = 2.9 Hz, 1 F).   Borylation of 1,2-dichloro-3-fluorobenzene (52/53): Procedure 6A was followed with the following amounts: 1,2-dichloro-3-), B2Pin2 (635 mg, 0.075 mmol per well, 0.5 equiv.), DPM (19.5 mg, 0.003 mmol per well, 2 mol %), 252  [Ir(OMe)(COD)]2 (33 mg, 0.0015 mmol per well, 1 mol %10 mL).  The well plate was taken out of the glove box and stirred at 60 °C for 6 hours.  After 6 hours, the well plate top was unsealed, and the vials containing the substrate were analyzed by 19F NMR to determine the conversion (88% conversion, 58%: 42% Steric: Electronic, averaged over 4 runs).  19F NMR (471 MHz, CDCl3): -111.2 (d, J = 8.0 Hz, 1    -99.1 (d, J = 5.4 Hz, 1 -109.2 (ddd, J = 6.7, 5.4, 0.8 Hz, 1 F).   Borylation of 1-chloro-2,3-difluorobenzene (55/56): Procedure 6A was followed with the following amounts: 1-chloro-2,3-), B2Pin2 (635 mg, 0.075 mmol per well, 0.5 equiv.), DPM (19.5 mg, 0.003 mmol per well, 2 mol %), [Ir(OMe)(COD)]2 (33 mg, 0.0015 mmol per well, 1 mol %10 mL).  The well plate was taken out of the glove box and stirred 60 °C for 6 hours.  After 6 hours, the well plate top was unsealed, and the vials containing the substrate were analyzed by 19F NMR to determine the conversion (86% conversion, 40%: 60% Steric: Electronic, averaged over 4 runs).  19F NMR (471 MHz, CDCl3): -136.1 (dd, J = 20.2, 9.8 Hz, 1 F), -134.8 (dt, J = -140.1 (ddd, J = 21.1, 5.4, 1.6 Hz, 1 F), -125.4 (ddd, J = 21.1, 5.4, 1.6 Hz, 1 F). -138.8 (dtd, J = 20.7, 6.1, 1.8 Hz, 1 F), -135.1 (dddd, J = 20.7, 9.5, 5.4, 1.7 Hz, 1 F). 253   Borylation of 2-chloro-6-fluorobenzonitrile (58/59): Procedure 6A was followed with the following amounts: 2-chloro-6-fluorobenzon), B2Pin2 (635 mg, 0.075 mmol per well, 0.5 equiv.), DPM (19.5 mg, 0.003 mmol per well, 2 mol %), [Ir(OMe)(COD)]2 (33 mg, 0.0015 mmol per well, 1 mol %), an10 mL).  The well plate was taken out of the glove box and stirred at 60 °C for 6 hours.  After 6 hours, the well plate top was unsealed, and the vials containing the substrate were analyzed by 19F NMR to determine the conversion (75% conversion, 63%: 37% Steric: Electronic, averaged over 4 runs).  19F NMR (471 MHz, CDCl3): -104.6 (d, J    -92.2 (d, J = 5.7 Hz, 1 -103.1 (t, J = 6.3 Hz, 1 F).  6.4.3 Well Plate Reactions with NMP  Borylation of 1-chloro-3-fluoro-2-methylbenzene (43/44): Procedure 6A was followed with the following amounts: 1-chloro-3-fluoro-2-), 254  B2Pin2 (635 mg, 0.075 mmol per well, 0.5 equiv.), DPM (19.5 mg, 0.003 mmol per well, 2 mol %), [Ir(OMe)(COD)]2 (33 mg, 0.0015 mmol per well, 1 mol %), and NMP (10 mL).  The well plate was taken out of the glove box and stirred at 60 °C for 6 hours.  After 6 hours, the well plate top was unsealed, and the vials containing the substrate were analyzed by 19F NMR to determine the conversion (10% conversion, 78%: 22% Steric: Electronic, averaged over 4 runs).  19F NMR (471 MHz, CDCl3): -114.3 (dd, J = 9.0, 3.7 Hz, 1 F). Electronic -102.1 (sext, J = 3.0 Hz-113.1 (m, 1 F).   Borylation of 1-chloro-2-ethoxy-3-fluorobenzene (46/47): Procedure 6A was followed with the following amounts: 1-chloro-2-ethoxy-3-well), B2Pin2 (635 mg, 0.075 mmol per well, 0.5 equiv.), DPM (19.5 mg, 0.003 mmol per well, 2 mol %), [Ir(OMe)(COD)]2 (33 mg, 0.0015 mmol per well, 1 mol %), and NMP (10 mL).  The well plate was taken out of the glove box and stirred at 60 °C for 6 hours.  After 6 hours, the well plate top was unsealed, and the vials containing the substrate were analyzed by 19F NMR to determine the conversion (11% conversion, 57%: 43% Steric: Electronic, averaged over 4 runs).  19F NMR (471 MHz, CDCl3): -129.0 (d, J = 11.3 Hz, 1 F). -117.5 (d, J -127.8 (dd, J = 9.5, 5.4 Hz, 1 F).  255   Borylation of 2-chloro-6-fluoro-N,N-dimethylaniline (49/50): Procedure 6A was followed with the following amounts: 2-chloro-6-fluoro-N,N-mmol per well), B2Pin2 (635 mg, 0.075 mmol per well, 0.5 equiv.), DPM (19.5 mg, 0.003 mmol per well, 2 mol %), [Ir(OMe)(COD)]2 (33 mg, 0.0015 mmol per well, 1 mol %), and NMP (10 mL).  The well plate was taken out of the glove box and stirred at 60 °C for 6 hours.  After 6 hours, the well plate top was unsealed, and the vials containing the substrate were analyzed by 19F NMR to determine the conversion (9% conversion, 70%: 30% Steric: Electronic, averaged over 4 runs).  19F NMR (471 MHz, CDCl3): -120.4 (dt, J = 11.8, 2.0 Hz, 1 F). -108.5 (t, J = 2.7 Hz, 1 -118.9 (undectet, J = 2.9 Hz, 1 F).   Borylation of 1,2-dichloro-3-fluorobenzene (52/53): Procedure 6A was followed with the following amounts: 1,2-dichloro-3-), B2Pin2 (635 mg, 0.075 mmol per well, 0.5 equiv.), DPM (19.5 mg, 0.003 mmol per well, 2 mol %), 256  [Ir(OMe)(COD)]2 (33 mg, 0.0015 mmol per well, 1 mol %), and NMP (10 mL).  The well plate was taken out of the glove box and stirred at 60 °C for 6 hours.  After 6 hours, the well plate top was unsealed, and the vials containing the substrate were analyzed by 19F NMR to determine the conversion (21% conversion, 64%: 36% Steric: Electronic, averaged over 4 runs).  19F NMR (471 MHz, CDCl3): -111.2 (d, J = 8.0 Hz, 1 -99.1 (d, J = 5.4 Hz, 1 -109.2 (ddd, J = 6.7, 5.4, 0.8 Hz, 1 F).   Borylation of 1-chloro-2,3-difluorobenzene (55/56): Procedure 6A was followed with the following amounts: 1-chloro-2,3-), B2Pin2 (635 mg, 0.075 mmol per well, 0.5 equiv.), DPM (19.5 mg, 0.003 mmol per well, 2 mol %), [Ir(OMe)(COD)]2 (33 mg, 0.0015 mmol per well, 1 mol %), and NMP (10 mL).  The well plate was taken out of the glove box and stirred 60 °C for 6 hours.  After 6 hours, the well plate top was unsealed, and the vials containing the substrate were analyzed by 19F NMR to determine the conversion (22% conversion, 45%: 55% Steric: Electronic, averaged over 4 runs).  19F NMR (471 MHz, CDCl3): -136.1 (dd, J = 20.2, 9.8 Hz, 1 F), -134.8 (dt, J = 20.3, 6.7 Hz, 1 -140.1 (ddd, J = 21.1, 5.4, 1.6 Hz, 1 F), -125.4 (ddd, J = 21.1, 5.4, 1.6 -138.8 (dtd, J = 20.7, 6.1, 1.8 Hz, 1 F), -135.1 (dddd, J = 20.7, 9.5, 5.4, 1.7 Hz, 1 F). 257   Borylation of 2-chloro-6-fluorobenzonitrile (58/59): Procedure 6A was followed with the following amounts: 2-chloro-6-), B2Pin2 (635 mg, 0.075 mmol per well, 0.5 equiv.), DPM (19.5 mg, 0.003 mmol per well, 2 mol %), [Ir(OMe)(COD)]2 (33 mg, 0.0015 mmol per well, 1 mol %), and NMP (10 mL).  The well plate was taken out of the glove box and stirred at 60 °C for 6 hours.  After 6 hours, the well plate top was unsealed, and the vials containing the substrate were analyzed by 19F NMR to determine the conversion (10% conversion, 64%: 36% Steric: Electronic, averaged over 4 runs).  19F NMR (471 MHz, CDCl3): -104.6 (d, J -92.2 (d, J = 5.7 Hz, 1 -103.1 (t, J = 6.3 Hz, 1 F).   Borylation of 1-chloro-3-fluoro-2-methylbenzene (43/44): Procedure 6A was followed with the following amounts: 1-chloro-3-fluoro-2- per well, 0.15 mmol), B2Pin2 (635 mg, 0.075 mmol per well, 0.5 equiv.), dtbpy (22 mg, 0.0030 mmol per well, 2 mol %), [Ir(OMe)(COD)]2 (33 mg, 0.0015 mmol per well, 1 mol %), and NMP (10 mL).  The well 258  plate was taken out of the glove box and stirred at 60 °C for 6 hours.  After 6 hours, the well plate top was unsealed, and the vials containing the substrate were analyzed by 19F NMR to determine the conversion (45% conversion, 72%: 28% Steric: Electronic, averaged over 4 runs).  19F NMR (471 MHz, CDCl3): -114.3 (dd, J = 9.0, 3.7 Hz, 1 F). Electronic -102.1 (sext, J = 3.0 Hz-113.1 (m, 1 F).   Borylation of 1-chloro-2-ethoxy-3-fluorobenzene (46/47): Procedure 6A was followed with the following amounts: 1-chloro-2-ethoxy-3-fluorobenzene well), B2Pin2 (635 mg, 0.075 mmol per well, 0.5 equiv.), dtbpy (22 mg, 0.0030 mmol per well, 2 mol %), [Ir(OMe)(COD)]2 (33 mg, 0.0015 mmol per well, 1 mol %), and NMP (10 mL).  The well plate was taken out of the glove box and stirred at 60 °C for 6 hours.  After 6 hours, the well plate top was unsealed, and the vials containing the substrate were analyzed by 19F NMR to determine the conversion (44% conversion, 59%: 41% Steric: Electronic, averaged over 4 runs).  19F NMR (471 MHz, CDCl3): -129.0 (d, J = 11.3 Hz, 1 F). -117.5 (d, J -127.8 (dd, J = 9.5, 5.4 Hz, 1 F).  259   Borylation of 2-chloro-6-fluoro-N,N-dimethylaniline (49/50): Procedure 6A was followed with the following amounts: 2-chloro-6-fluoro-N,N-mmol per well), B2Pin2 (635 mg, 0.075 mmol per well, 0.5 equiv.), dtbpy (22 mg, 0.0030 mmol per well, 2 mol %), [Ir(OMe)(COD)]2 (33 mg, 0.0015 mmol per well, 1 mol %), and NMP (10 mL).  The well plate was taken out of the glove box and stirred at 60 °C for 6 hours.  After 6 hours, the well plate top was unsealed, and the vials containing the substrate were analyzed by 19F NMR to determine the conversion (46% conversion, 67%: 33% Steric: Electronic, averaged over 4 runs).  19F NMR (471 MHz, CDCl3): -120.4 (dt, J = 11.8, 2.0 Hz, 1 F). -108.5 (t, J = 2.7 Hz, 1 -118.9 (undectet, J = 2.9 Hz, 1 F).   Borylation of 1,2-dichloro-3-fluorobenzene (52/53): Procedure 6A was followed with the following amounts: 1,2-dichloro-3-fluorobenzene (), B2Pin2 (635 mg, 0.075 mmol per well, 0.5 equiv.), dtbpy (22 mg, 0.0030 mmol per well, 2 mol %), 260  [Ir(OMe)(COD)]2 (33 mg, 0.0015 mmol per well, 1 mol %), and NMP (10 mL).  The well plate was taken out of the glove box and stirred at 60 °C for 6 hours.  After 6 hours, the well plate top was unsealed, and the vials containing the substrate were analyzed by 19F NMR to determine the conversion (36% conversion, 62%: 38% Steric: Electronic, averaged over 4 runs).  19F NMR (471 MHz, CDCl3): -111.2 (d, J = 8.0 Hz, 1 -99.1 (d, J = 5.4 Hz, 1 -109.2 (ddd, J = 6.7, 5.4, 0.8 Hz, 1 F).   Borylation of 1-chloro-2,3-difluorobenzene (55/56): Procedure 6A was followed with the following amounts: 1-chloro-2,3-), B2Pin2 (635 mg, 0.075 mmol per well, 0.5 equiv.), dtbpy (22 mg, 0.0030 mmol per well, 2 mol %), [Ir(OMe)(COD)]2 (33 mg, 0.0015 mmol per well, 1 mol %), and NMP (10 mL).  The well plate was taken out of the glove box and stirred 60 °C for 6 hours.  After 6 hours, the well plate top was unsealed, and the vials containing the substrate were analyzed by 19F NMR to determine the conversion (40% conversion, 31%: 69% Steric: Electronic, averaged over 3 runs).  19F NMR (471 MHz, CDCl3): -136.1 (dd, J = 20.2, 9.8 Hz, 1 F), -134.8 (dt, J = 20.3, 6.7 Hz, 1 -140.1 (ddd, J = 21.1, 5.4, 1.6 Hz, 1 F), -125.4 (ddd, J = 21.1, 5.4, 1.6 -138.8 (dtd, J = 20.7, 6.1, 1.8 Hz, 1 F), -135.1 (dddd, J = 20.7, 9.5, 5.4, 1.7 Hz, 1 F). 261   Borylation of 2-chloro-6-fluorobenzonitrile (58/59): Procedure 6A was followed with the following amounts: 2-chloro-6-), B2Pin2 (635 mg, 0.075 mmol per well, 0.5 equiv.), dtbpy (22 mg, 0.0030 mmol per well, 2 mol %), [Ir(OMe)(COD)]2 (33 mg, 0.0015 mmol per well, 1 mol %), and NMP (10 mL).  The well plate was taken out of the glove box and stirred at 60 °C for 6 hours.  After 6 hours, the well plate top was unsealed, and the vials containing the substrate were analyzed by 19F NMR to determine the conversion (9% conversion, 91%: 9% Steric: Electronic, averaged over 4 runs).  19F NMR (471 MHz, CDCl3): -104.6 (d, J -92.2 (d, J = 5.7 Hz, 1 -103.1 (t, J = 6.3 Hz, 1 F).   Borylation of 1-chloro-3-fluoro-2-methylbenzene (43/44): Procedure 6A was followed with the following amounts: 1-chloro-3-fluoro-2-), B2Pin2 (635 mg, 0.075 mmol per well, 0.5 equiv.), TMP (23.6 mg, 0.003 mmol well, 2 mol %), [Ir(OMe)(COD)]2 (33 mg, 0.0015 mmol per well, 1 mol %), and NMP (10 mL).  The well plate 262  was taken out of the glove box and stirred at 60 °C for 6 hours.  After 6 hours, the well plate top was unsealed, and the vials containing the substrate were analyzed by 19F NMR to determine the conversion (31% conversion, 89%: 11% Steric: Electronic, averaged over 3 runs).  19F NMR (471 MHz, CDCl3): -114.3 (dd, J = 9.0, 3.7 Hz, 1 F)-102.1 (sext, J = 3.0 Hz, 1 F). Starting -113.1 (m, 1 F).   Borylation of 1-chloro-2-ethoxy-3-fluorobenzene (46/47): Procedure 6A was followed with the following amounts: 1-chloro-2-ethoxy-3-well), B2Pin2 (635 mg, 0.075 mmol per well, 0.5 equiv.), TMP (23.6 mg, 0.003 mmol well, 2 mol %), [Ir(OMe)(COD)]2 (33 mg, 0.0015 mmol per well, 1 mol %), and NMP (10 mL).  The well plate was taken out of the glove box and stirred at 60 °C for 6 hours.  After 6 hours, the well plate top was unsealed, and the vials containing the substrate were analyzed by 19F NMR to determine the conversion (34% conversion, 65%: 35% Steric: Electronic, averaged over 2 runs).  19F NMR (471 MHz, CDCl3): -129.0 (d, J = 11.3 Hz, 1 F). -117.5 (d, J -127.8 (dd, J = 9.5, 5.4 Hz, 1 F).  263   Borylation of 2-chloro-6-fluoro-N,N-dimethylaniline (49/50): Procedure 6A was followed with the following amounts: 2-chloro-6-fluoro-N,N-mmol per well), B2Pin2 (635 mg, 0.075 mmol per well, 0.5 equiv.), TMP (23.6 mg, 0.003 mmol well, 2 mol %), [Ir(OMe)(COD)]2 (33 mg, 0.0015 mmol per well, 1 mol %), and NMP (10 mL).  The well plate was taken out of the glove box and stirred at 60 °C for 6 hours.  After 6 hours, the well plate top was unsealed, and the vials containing the substrate were analyzed by 19F NMR to determine the conversion (29% conversion, 81%: 19% Steric: Electronic, averaged over 1 run).  19F NMR (471 MHz, CDCl3): -120.4 (dt, J = 11.8, 2.0 Hz, 1 F). Electronic -108.5 (t, J = 2.7 Hz, 1 -118.9 (undectet, J = 2.9 Hz, 1 F).   Borylation of 1,2-dichloro-3-fluorobenzene (52/53): Procedure 6A was followed with the following amounts: 1,2-dichloro-3-), B2Pin2 (635 mg, 0.075 mmol per well, 0.5 equiv.), TMP (23.6 mg, 0.003 mmol well, 2 mol %), [Ir(OMe)(COD)]2 (33 mg, 0.0015 mmol per well, 1 mol %), and NMP (10 mL).  The well plate 264  was taken out of the glove box and stirred at 60 °C for 6 hours.  After 6 hours, the well plate top was unsealed, and the vials containing the substrate were analyzed by 19F NMR to determine the conversion (41% conversion, 44%: 56% Steric: Electronic, averaged over 2 runs).  19F NMR (471 MHz, CDCl3): -111.2 (d, J = 8.0 Hz, 1 -99.1 (d, J = 5.4 Hz, 1 -109.2 (ddd, J = 6.7, 5.4, 0.8 Hz, 1 F).              265           APPENDIX      266  267  268  269  270  271   272  273  274  275  276  277  278  279  280           REFERENCES          281  REFERENCES   1 Iverson, C. N.; Smith, M. R., III. J. Am. Chem. 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