RITTER ENABLED CATALYTIC ASYMMETRIC HALOAMIDATION AND MECHANISTIC STUDIES FOR INTERMOLECULAR HALOFUNCTIONALIZATION By Daniel C. Steigerwald A DISSERTATION Submitted to Michigan State University in partial fulfillment of the requirements for the degree of Chemistry—Doctor of Philosophy 2021 ABSTRACT RITTER ENABLED CATALYTIC ASYMMETRIC HALOAMIDATION AND MECHANISTIC STUDIES FOR INTERMOLECULAR HALOFUNCTIONALIZATION By Daniel C. Steigerwald This thesis presents the development of an efficient catalytic asymmetric olefin haloamidation method and mechanistic investigations of intermolecular halofunctionalization reactions. It guides the reader through the challenges of catalytic asymmetric olefin halofunctionalization and presents how our group has used a mechanistically conscious approach to solve these problems to achieve high enantiocontrol over a stereodefined carbon-halogen bond. Chapter 1 focuses on the development of a catalytic asymmetric Ritter-type haloamidation of olefins. The stereodefined vicinal haloamine moiety is highly valuable; however, catalytic asymmetric variations have not realized the same success as analogous haloetherification and dihalogenation reactions. We utilize Halenium Affinity to examine the core difficulties of haloaminations and design a competent nucleophile for this transformation. Chapter 2 gives the reader a more accurate mechanistic understanding of intermolecular olefin halofunctionalizations. This reaction is often depicted as a stepwise mechanism with the formation of a haliranium ion that is then intercepted by a nucleophile to provide the difunctionalized product. Preliminary mechanistic evidence suggests a spectrum of concerted vs. stepwise mechanisms dependent on the alkene, halenium ion, halenium donor, and nucleophile. ACKNOWLEDGMENTS I am extremely thankful for my time spent at Michigan State University. I want to thank my advisor, Professor Babak Borhan, for his endless support. He was fully invested in my development as a researcher and knew how to motivate me to reach my full potential. He matched my enthusiasm for my science and was always excited to discuss new results and mechanistic theories. He encouraged us to work on the projects we wanted to and to think for ourselves, a freedom that I enjoyed. I am grateful for the lab environment that he fostered, a place that is both scientifically rigorous and socially enjoyable, which allowed us to enjoy our path of development. During my graduate studies, I was fortunate to have an outstanding committee comprised of Professor William Wulff, Professor Jetze Tepe, and Professor Milton Smith. Each of my committee members brought an area of expertise that was valuable for me and the further development of my research. Their willingness to assist with career advice or fellowship opportunities is something that I will always value. The world-class facilities at Michigan State were essential in allowing me to explore my research to the furthest extent. These facilities are led by experts Dr. Daniel Holmes (NMR) and Dr. Richard Staples (Crystallography), both were eager to assist me. Michigan State is lucky to have these people. I am thankful for the support and friendship of my fellow lab mates and co-workers: Dr. Calvin Grant, Dr. Nastaran Salehi, Dr. Yi Yi, Dr. Elizabeth Santos, Dr. Jun Zhang, Dr. Wei Sheng, Dr. Xin Liang Ding, Dr. Arita Sarkar, Dr. Aliakbar Mohammadlou, Dr. Saeedeh iii Torabi Kohlbouni, Dr. Rahele Esmatpour, Dr. Debarshi Chakraborty, Soham Maity, Ankush Chakraborty, Medhi Moemeni, Emily Dzurka, Aria Vahdani, Behrad Masoudi, Jiaojiao Wang, Mitchell Maday, Ishita Chandra, and my undergrad assistants Cecilia Morgenstern and Jayden Elliot. I specifically want to thank Dr. Bardia Soltanzadeh, Dr. Hadi Gholami, and Dr. Chrysoula Vasileiou for their leadership in our lab. Each one was an outstanding role model and mentor. I am incredibly lucky to have such a supportive family. As a young kid, my parents and siblings (Jon and Leanne) spent countless hours helping me learn outside of the classroom. While they invested a significant amount of time in my studies, I never felt any pressure from them to succeed. I believe this was critical to my success and has molded me into the scientist I am today. Lastly, I want to thank Julie. Her positive influence on my graduate studies cannot be understated. From proofreading a manuscript, to coming to campus for an evening walk when I am stressed out, she wanted to do everything she could for me to be happy with my research and life. iv TABLE OF CONTENTS LIST OF TABLES .………………………………………………………………………………ix LIST OF FIGURES ……………………………………………………………………………...x KEY TO SYMBOLS AND ABBREVIATIONS .……………………………………………...xvii Chapter I Ritter Enabled Catalytic Asymmetric Chloroamidation of Olefins .................. 1 I-1 Introduction ........................................................................................................... 1 I-2 Racemization Processes of Halonium Ions .......................................................... 2 I-2-1 Racemization via Olefin to Olefin Halenium Transfer .................................... 3 I-2-2 Isomerization to the b-Halocarbenium Ion ..................................................... 6 I-3 Mechanistic Comprehension of Halofunctionalizations......................................... 7 I-3-1 Halenium Affinity ............................................................................................ 7 I-3-2 Nucleophile Assisted Alkene Activation ....................................................... 10 I-3-2-1 Experimental Evidence for Nucleophile Assisted Alkene Activation .... 12 I-4 Development of Catalytic Asymmetric Halofunctionalizations ............................ 16 I-4-1 Intramolecular Catalytic Asymmetric Halofunctionalizations ....................... 16 I-4-2 Intermolecular Catalytic Asymmetric Halofunctionalizations ....................... 17 I-5 Catalytic Asymmetric Haloamination of Olefins .................................................. 21 I-5-1 Literature Precedent for Intramolecular Catalytic Asymmetric Haloamination Reactions................................................................................................................ 23 I-5-1-1 Halocyclization of Unsaturated Sulfonamides with a Thio-Carbmate Catalyst ………………………………………………………………………………...24 I-5-1-2 Catalyst Controlled Bromolactamization of Sulfonylimides .................. 25 I-5-1-3 Catalytic Asymmetric Intramolecular Iodoamination of Alkenes ........... 27 I-5-2 General Approach of Previous Intermolecular Halenium Induced Haloamination Reactions........................................................................................ 28 I-5-2-1 Enantioselective 𝜶-Halogenation of Enecarbamates ........................... 29 I-5-2-2 Enantioselective Bromoamination of Allylic Alcohols ........................... 31 I-5-2-3 Haloazidation of Allylic Alcohols ........................................................... 32 I-5-2-4 Nucleophile Induced Asymmetric Haloamination of Olefins ................. 34 I-5-3 Design of an Unmasked Nitrogen Nucleophile for Halofunctionalizations ... 36 I-5-3-1 Seminal Ritter Reaction ........................................................................ 38 I-5-3-2 Halo-Ritter Reaction from Halohydrins ................................................. 38 I-5-3-3 Halenium Induced Ritter Reaction with Alkenes................................... 39 I-5-3-4 Lewis acid Catalyzed Bromo-Ritter Reaction and Total Synthesis of Oseltamivir .......................................................................................................... 40 I-5-3-5 Lewis Base Catalyzed Chloroamidation of Olefins ............................... 43 I-5-3-6 Stoichiometric Chiral Promoter Asymmetric Thio-Ritter Reaction ........ 44 I-6 Catalytic Asymmetric Ritter-Type Reaction ........................................................ 44 I-6-1 Optimization Investigations .......................................................................... 44 v I-6-2 Optimization of Amide Functional Handle.................................................... 47 I-6-3 Alternative Functional Handles .................................................................... 48 I-6-4 Substrate Scope of the Ritter-Type Asymmetric Chloroamidation Reaction 49 I-6-5 Preliminary Efforts to Improve Diastereoselectivity in the Asymmetric Chloroamidation Aryl Substituted Ally-Amides ....................................................... 53 I-6-6 Varied Nitrile Nucleophiles........................................................................... 59 I-6-7 Catalyst Loading Study for Less Reactive Allyl-Amide I-70v ....................... 59 I-6-8 Structural Determination of Ritter Trapped Product..................................... 61 I-6-8-1 Computational details for NMR calculations ......................................... 64 I-6-9 Catalyst Control of Product Formation......................................................... 65 I-6-10 Redirecting Nitrilium Ion Trap to Provide Precious Diamine Products......... 66 I-6-11 Optimization of Dichloramine-T Chloroamidations ...................................... 68 I-6-12 Dichloramine-T Mediated Chloroamidination Scope ................................... 69 I-6-13 Elaborations of Chlorosulfonylamidines....................................................... 69 I-7 Conclusion .......................................................................................................... 70 I-8 Experimental Section .......................................................................................... 71 I-8-1 Materials and General Instrumentations ...................................................... 71 I-8-2 General procedure for the catalytic asymmetric chloroamidation of unsaturated amides with DCDMH to yield vicinal chloroamides ............................ 72 I-8-3 Procedure for the catalytic asymmetric chloroamidation of 1a with DCDMH and 10 equivalents of acetonitrile to yield vicinal chloroamides ............................. 73 I-8-4 Procedure for the chloroamidation of allyl-phthalimide 1j and allyl-ester 1k substrates ............................................................................................................... 74 I-8-5 Procedure for the 1 mmol scale catalytic asymmetric chloroamidation of unsaturated amides with DCDMH to yield vicinal chloroamides ............................ 75 I-8-6 General procedure for the chloroamidation of allyl-amides with different nitrile solvents .................................................................................................................. 76 I-8-7 General procedure for the catalytic asymmetric chloroamidination of unsaturated amides with dichloramine-T as the chlorinating reagent to yield vicinal chlorosulfonylamidines ........................................................................................... 77 I-8-8 Procedure for the synthesis of enantiomeric mixtures of chloroamide compounds for HPLC separations.......................................................................... 78 I-8-9 Procedure for the synthesis of enantiomeric mixtures of chloroamidine compounds for HPLC separations.......................................................................... 79 I-8-10 Procedure for the Determination of the Absolute and Relative Stereochemistry of Vicinal Chlorosulfonylamidine Products ............................................................. 80 I-9 Analytical Data .................................................................................................... 82 I-9-1 Analytical Data for Chloroamide Products ................................................... 82 I-9-2 Analytical data for vicinal chloroamidine products ..................................... 110 I-9-3 Analytical data for derivatives .................................................................... 114 I-9-4 Analytical data for miscellaneous products/byproducts ............................. 119 I-9-5 Analytical Data for Starting Materials......................................................... 123 REFERENCES ........................................................................................................ 130 Chapter II Bromenium and Chlorenium Mechanistic Divergence ............................... 137 vi II-1 Catalytic Bromenium and Chlorenium Induced Reactions................................ 137 II-2 Bromenium Reaction Divergence ..................................................................... 137 II-2-1 Kinetic Competition Studies for Catalyzed Halofunctionalizations ............ 139 II-2-1-1 Nucleophile Dependent Kinetic Competition Study ............................ 140 II-2-1-2 Halenium Dependent Kinetic Competition Study................................ 141 II-2-2 Catalytic Asymmetric Bromoamidation Optimization ................................. 142 II-2-3 Nucleophile Assisted Alkene Activation in Catalytic Bromofunctionalization Reactions.............................................................................................................. 146 II-2-4 Eyring Analysis of Competitive Reactions ................................................. 147 II-2-4-1 Eyring Analysis of Varied Nucleophiles .............................................. 148 II-2-4-2 Eyring Analysis of Varied Bromenium Sources .................................. 151 II-2-5 Conclusion ................................................................................................. 153 II-3 Intermolecular Nucleophile Assisted Alkene Activation in Bromenium and Chlorenium Induced Halofunctionalizations…………………………………………… 153 II-3-1 Challenges Unique to Intermolecular Nucleophile Assisted Alkene Activation ………………………………………………………………………………. 154 II-3-2 Influence of Bromenium Donor HalA on Product Distribution .................... 157 II-3-3 Computational Exploration of Product Distribution Relative to Halenium Reagent ................................................................................................................ 158 II-3-4 Product Distribution with Electronically Unbiased Regiochemistry ............ 159 II-3-5 Influence of Alkene Electronics on Product Distribution ............................ 162 II-3-6 Eyring Analysis of Various Bromenium Sources ....................................... 163 II-3-7 Order of Methanol with Different Bromenium Sources .............................. 165 II-3-8 Literature Precedent for Order Relative to an Internal Clock Reaction ..... 166 II-3-8-1 Determination of Methanol Order with Different Bromenium Sources 169 II-3-8-2 Literature Precedent for Hydrogen Bonding Nucleophilic Enhancement in Halofunctionalization ......................................................................................... 172 II-3-9 Influence of Sterics on Product Distribution ............................................... 173 II-3-10 Influence of Acid Additives on Product Distribution................................ 176 II-3-11 Divergent Reaction Pathways for DBDMH and N-Bromosaccharine ..... 178 II-3-12 Modulation of Reaction Pathways via Alkene HalA ............................... 180 II-4 Diastereoselectivity in Intermolecular Halofunctionalizations ........................... 183 II-4-1 Eyring Analysis of Diastereoselectivity ...................................................... 186 II-4-2 Influence of Chlorenium Donor HalA on Diastereoselectivity .................... 187 II-4-3 Influence of Bromenium Donor HalA on Diastereoselectivity .................... 189 II-5 Mechanistic dissimilarities of intermolecular bromo and chlorofunctionalizations ………………………………………………………………….. 191 II-5-1 Influence of Chlorenium Donor HalA on Product Distribution .................... 191 II-5-2 Competitive Eyring Analysis of Chlorofunctionalizations and Bromofunctionalizations ....................................................................................... 192 II-5-3 Influence of Sterics on Product Distribution with Bromo and Chlorofunctionalizations ....................................................................................... 196 II-5-4 Rationalization of Divergent Bromenium and Chlorenium Halofunctionalization Mechanisms. ...................................................................... 198 vii II-6 Conclusion ...................................................................................................... 200 II-7 Experimental Section ........................................................................................ 201 II-7-1 Materials and General Instrumentations .................................................... 201 II-7-2 General Procedure for the screening of Catalytic Asymmetric Bromoamadination of II-1 to Yield Vicinal Bromoamadine II-14 ........................... 202 II-7-3 Procedure for the Eyring Analysis of the Catalytic Asymmetric Bromoamidation of II-1 With Acetonitrile .............................................................. 203 II-7-4 Procedure for the Eyring Analysis of the Catalytic Asymmetric Bromoamadination of II-1 With Dimethylcyanamide............................................. 204 II-7-5 Procedure for Eyring Analysis of Haloetherification Reactions With Various Bromenium Reagents ........................................................................................... 205 II-7-6 Procedure for Product Ratio as a Function of Nucleophile Concentration 206 II-7-7 Procedure for Acid Additive Influence of Product Ratio ............................. 206 II-7-8 Procedure for Product Ratio as a Function of Nucleophile Size ................ 207 II-7-9 Procedure for Eyring Analysis With Alkenes of Varied Halenium Affinity . 208 II-7-10 Procedure of Eyring Analysis of Diastereoselectivity in Chlorofunctionalization ......................................................................................... 209 II-7-11 Procedure for Halenium Affinity Diastereoselectivity Studies of Chlorofunctionalizations ....................................................................................... 209 II-7-12 Procedure for the Study of the Influence of Chlorenium Donor HalA on Product Distribution .............................................................................................. 210 II-7-13 Procedure for Eyring Analysis with N-Chlorosaccharine........................ 211 II-7-14 Procedure for Nucleophile Size Study with N-Chlorosaccharine ........... 212 II-8 Analytical Data .................................................................................................. 212 REFERENCES ........................................................................................................ 222 viii LIST OF TABLES Table I-1: 1H and 13C resonances of Z-styrylic alkene upon modulation of electronic of a remotely tethered nucleophile........................................................................................ 14 Table I-2: Catalyst control of regiochemistry for haloetherification reactions ................ 19 Table I-3: Enantioselective chloroamidation optimization .............................................. 45 Table I-4: Amide functional handle optimization ............................................................ 47 Table I-5: Attempt to improve diastereoselectivity by modulating HalA of the chlorenium donor.............................................................................................................................. 56 Table I-6: Solvent polarity and diastereoselectivity........................................................ 58 Table I-7: Experimental (I-162a, I-162b, and I-165) and calculated 13C-NMR values for potential Ritter intermediates ......................................................................................... 64 Table I-8: Catalyst Control over product formation ........................................................ 65 Table I-9: Optimization of Dichloramine-T Chloroamidations ........................................ 68 Table II-1: Catalytic bromoamidation optimization ....................................................... 143 Table II-2: Influence of HalA on product distribution .................................................... 157 Table II-3: Computational data for reaction divergence ............................................... 158 Table II-4: Influence of bromenium source on product distribution with electronically unbiased regiochemistry. ............................................................................................. 161 Table II-5: Influence of alkene electronics on product distribution ............................... 162 Table II-6: Competitive H2 transfer and alcohol addition reactions. ............................. 166 Table II-7: Influence of HalA on diastereoselectivity in chloroetherifications ............... 189 Table II-8: Influence of bromenium donor HalA on bromoetherifications .................... 190 ix LIST OF FIGURES Figure I-1: Natural products containing stereodefined carbon halogen bonds…………... 1 Figure I-2: Racemization processes for haliranium ions (a) Olefin to olefin halenium transfer (b) Opening of the haliranium in to the β-halocarbenium ion (c) Enhanced problematic nature of haliranium ions in asymmetric intermolecular functionalizations… 3 Figure I-3: a) Mechanistic overview of olefin-to-olefin transfer as a racemization process (b) Propensity of bromonium ions to racemize in the presence of excess olefin (c) Stereochemical stability of chloronium in the presence of excess olefin…………………. 5 Figure I-4: (a) The propensity of long lived haliranium ions to open to the β-halocarbenium ion with diastereomeric consequences (b) Potential rearrangements associated with haliranium ions………………………………………………………………………………….. 6 Figure I-5: Racemization via β-Halocarbenium Ion…………………………………………. 7 Figure I-6: (a) 1H NMR of NCS (b) 1H NMR of succinimide anion (c) 1H NMR of DCDMH (d) 1H NMR of succinimide anion DCDMH mixture that results in the abstraction of chlorenium to form NCS……………………………………………………………………….. 9 Figure I-7: Predictive ability of Halenium affinity in chemoselectivity (a) Aromatic ring with high halenium affinity undergoing chlorination (b) Aromatic ring with attenuated halenium affinity undergoes a carbocyclization……………………………………………………….. 10 Figure I-8: (a) Contrasting classical and nucleophile assisted halofunctionalizations (b) Reaction pathway for a classical halofunctionalization and the halenium affinity of the alkene in this mechanism (c) Reaction pathway for a NAAA halofunctionalization and HalA in this mechanism………………………………………………………………………. 11 Figure I-9: Influence of nucleophilicity on reaction rate……………………………………. 12 Figure I-10: 13C natural abundance KIE studies of chlorolactonizations………………… 15 Figure I-11: (a) Catalytic asymmetric chlorolactonization with proposed mechanism (b) Catalytic asymmetric amide halocyclizations………………………………………………. 16 Figure I-12: (a) Catalytic asymmetric intermolecular chloroetherification scope (b) Catalytic asymmetric intermolecular bromoetherification scope…………………………. 18 x Figure I-13: (a) Transfer of chlorenium from DCDMH to (DHQD)2PHAL to form chiral halenium source (b) KIE experiment suggesting a concerted nucleophile assisted mechanism…………………………………………………………………………………….. 20 Figure I-14: (a) Biologically significant molecules that contain a chiral vicinal chloramine (b) Stereodefined amines in small molecule pharmaceuticals……………………………. 21 Figure I-15: (a) Sampling of potential nucleophiles for halofunctionalizations (b) The role of halenium affinity in the control of the reaction pathway………………………………… 22 Figure I-16: General strategy for the intramolecular catalytic asymmetric haloamidation of alkenes……………………………………………………………………………………........ 24 Figure I-17: Thiocarbamate catalyzed bromocyclization………………………………….. 24 Figure I-18: (a) Catalyst control of reaction pathway to preference nitrogen nucleophiles (b) Substrate scope of bromolactamization……………………………………………….... 26 Figure I-19: (a) Substrate scope for alkene iodoamination for the synthesis of chiral ureas (b) Product elaboration to NK1 inhibitor…………………………………………………….. 28 Figure I-20: General mechanism for traditional intermolecular catalytic asymmetric haloamidation…………………………………………………………………………………. 29 Figure I-21: (a) Enantioselective bromoamidation (b) Enantioselective iodoamination (c) Enantioselective chloroamination (d) Proposed mechanism for the enantioselective bromoamidation………………………………………………………………………………. 30 Figure I-22: Substrate scope for bromoamidation of allylic-alcohols (b) Proposed activation mode for thiourea catalysts………………………………………………………. 31 Figure I-23: Haloazidation of allylic alcohols……………………………………………….. 32 Figure I-24: Regiodivergent behavior between Z and E alkenes. (a) Regioselectivity of E olefin. (b) Regioselectivity of Z olefin………………………………………………………... 33 Figure I-25: Feng’s Lewis acid approach to haloamidation of Michael acceptors. (a) Chloramidation (b) Bromoamidation (c) Idodoamination (d) Mechanistic approach to enable to enable the construction of haloamine products with electron poor alkyl systems………………………………………………………………………………………… 35 Figure I-26: Summary of approaches to intermolecular halofunctionalizations (a) Display of the problematic nature of amines in halofunctionalization reactions. (b) Stepwise pro- xi nucleophile haloamination (c) Concerted haloetherification reactions. (d) Proposal of a concerted haloamidation via the attenuation of HalA……………………………………… 37 Figure I-27: Seminal Ritter reaction (a) Reaction mechanism (b) Reaction scope…..... 38 Figure I-28: Halo-Ritter reaction (a) Reaction mechanism (b) Reaction scope….……... 39 Figure I-29: Halenium induced Ritter reaction of alkenes (a) Reaction Mechanism (b) Reaction scope………………………………………………………………………………... 40 Figure I-30: (a) Reaction scope of Ritter-type haloamidations. (b) Proposed reaction mechanism. (c) Synthesis of Oseltamivir with haloamidation as a key step……………. 42 Figure I-31: (a) Substrate scope for base catalyzed chloroamidation (b) Proposed mechanism for selenium catalysis…………………………………………………………... 43 Figure I-32: Asymmetric Ritter reaction with stoichiometric chiral promoter……………. 44 Figure I-33: Exploration of alternative functional handles for enantioselective chloroamidation reactions……………………………………………………………………. 48 Figure I-34: Aliphatic substrate scope of allyl amides for chloroamidation……………… 49 Figure I-35: Aromatic substrate scope for allyl-amide chloroamidation………………….. 51 Figure I-36: Divergent reactivity in electron rich aromatic systems (a) Halo-Ritter chemistry (b) Attempt of halo Ritter chemistry on highly electron rich system (c) Haloetherification chemistry with highly electron rich systems (d) Stereochemical result of asymmetric chlorocyclization………………...………………..………………………….. 52 Figure I-37: Correlation between alkene HalA and diastereoselectivity of halo-Ritter product…………………………………………………………………………………………. 54 Figure I-38: (a) NAAA explanation for reduction of diastereoselectivity in halofunctionalizations (b) Potential methods to modulate Halenium affinity of the donor to favor pathway 1……………………………………………………………………………….. 55 Figure I-39: Proposed transition state for enantio-selective chloroetherification of allyl- amides…………………………………………………………………………………………. 57 Figure I-40: Effort to improve diastereoselectivity by employing a nonpolar cosolvent.. 58 Figure I-41: Substrate Scope with varied nitrile nucleophiles….…………………………. 59 xii Figure I-42: (a) Influence of catalyst loading on I-70v relative to I-70s. (b) Catalyst incubation study………………………………………………………………………………. 60 Figure I-43: HalA of quinoline ring…………………………………………………………… 61 Figure I-44: Potential Ritter intermediates……………………...…………………………... 62 Figure I-45: Hypothesis of rotomeric equilibria of a single intermediate…………………. 63 Figure I-46: Complexation of DCH with (DHQD)2PHAL………………………….……….. 66 Figure I-47: (a) Hydrolysis of tertiary amidine products to provide amides. (b) Redirection of nitrilium intermediate to provide useful products………………………………………… 67 Figure I-48: Dichloramine-T mediated chloroamidination scope…………………………. 69 Figure I-49: Chloroamidine elaborations to precious enantiopure chiral diamine products………………………………………………………………………………………... 70 Figure I-50: General procedure for the catalytic asymmetric chloroamidation of unsaturated amides with DCDMH to yield vicinal chloroamides.………………………….72 Figure I-51: Procedure for the catalytic asymmetric chloroamidation of 1a with DCDMH and 10 equivalents of acetonitrile to yield vicinal chloroamides………………………….. 73 Figure I-52: Procedure for the chloroamidation of allyl-phthalimide 1j and allyl-ester 1k substrates……..………………………………………………………………………………. 74 Figure I-53: Procedure for the 1 mmol scale catalytic asymmetric chloroamidation of unsaturated amides with DCDMH to yield vicinal chloroamides…………….…………… 75 Figure I-54: General procedure for the chloroamidation of allyl-amides with different nitrile solvents………………………………………………………………………………………… 76 Figure I-55: General procedure for the catalytic asymmetric chloroamidination of unsaturated amides with dichloramine-T as the chlorinating reagent to yield vicinal chlorosulfonylamidines………………………………………………………………….….… 77 Figure I-56: Procedure for the synthesis of enantiomeric mixtures of chloroamide compounds for HPLC separations……………………………………………………..……. 78 Figure I-57: Procedure for the synthesis of enantiomeric mixtures of chloroamidine compounds for HPLC separations…………………………………………………………... 79 Figure I-58: Chemical transformations to determine the absolute stereochemistry of chlorosulfonylamidines……………………………………………………………………….. 81 xiii Figure I-59: HPLC trace of I-173a and ent- I-173a……………………………………..….. 81 Figure I-60: HPLC trace of I-173a following procedure for the chlorosulfonylamidation of allyl amides……………………………………………………………………………………. 81 Figure I-61: HPLC trace of I-173a obtained from derivatization of I-122a’………….….. 82 Figure II-1: Divergent reaction paths observed with chlorenium and bromenium reagents……………………………………………………………………………………… 139 Figure II-2: (a) Hydrogen bond assisted bromenium transfer (b) Halogen bond assisted bromenium transfer…………………………………………………………………………. 139 Figure II-3: Nucleophile dependent kinetic competition study………………………….. 141 Figure II-4: Bromenium and chlorenium kinetic competition…………………………….. 142 Figure II-5: Potential roles of HFIP in redirecting catalytic bromofunctionalizations. (a) Quinuclidine activating the amide providing II-7 (b) Quinuclidine functioning as a Lewis base for chlorenium transfer (c) HFIP attenuating the nucleophilicity of the amide carbonyl………………………………………………………………………………………. 145 Figure II-6: (a) Classical reaction pathway which electrophile and nucleophile should have no influence on product distribution. (b) Mechanism with sensitivity to electrophile and nucleophile…………………………………………………………………………………… 146 Figure II-7: Modified condition to yield Ritter product with acetnitrile………………..….. 148 Figure II-8: (a) Eyring analysis with dimethylcyanamide. (b) Eyring analysis with acetonitrile. (c) Eyring Plots of data in (a) and (b)…………….………………….……….. 150 Figure II-9: (a) Eyring analysis data for bromenium reagent temperature product ratio analysis. (b) Eyring plot of NBP, DBDMH and NBSac experiments…………………….. 152 Figure II-10: Traditional mechanistic view of halofunctionalization……………...……… 154 Figure II-11: (a) Stepwise intramolecular halofunctionalization. (b) Concerted Intramolecular . (c) Kinetic variables of stepwise vs. concerted intramolecular halofunctionalization. (d) Kinetic variables of stepwise vs. concerted intermolecular halofunctionalization………………………………………………………………………… 156 Figure II-12: Competitive reaction proceeding through a traditional stepwise mechanism..…………………………………………………………………………………. 157 Figure II-13: (a) Transition state charges in electronically biased alkene II-1 (b) Transition state charges in electronically unbiased alkene II-42…………………………………….. 160 xiv Figure II-14: (a) Eyring Analysis of product ratios with varied bromenium donors. (b) Eyring Plot……………………………………………………………………………………..165 Figure II-15: Trapping experiment with benzyne intermediates…………………………. 168 Figure II-16: Influence of methanol concentration on product distribution……………… 169 Figure II-17: Comparison of (a) monomer and (b) dimer nucleophilicities…….……….. 170 Figure II-18: Proton donor assisted bromenium source activation……………………… 171 Figure II-19: Literature precedent for base assisted nucleophilic enhancement. (a) Chlorolactonizations (b) Bromoetherifications……………………………………………. 173 Figure II-20: Influence of alcohol size with different bromenium sources…….…...........175 Figure II-21: Influence of protic additives on product distribution…………….…………. 176 Figure II-22: Proton assisted pathways……………………………………………………. 177 Figure II-23: Enthalpic and Entropic Pathways for bromoetherifications (a) DBDMH (b) N- bromosaccharine……………………………………………………………………………. 180 Figure II-24: Eyring analysis of varied alkenes……………………………………………. 182 Figure II-25: Divergent bromoetherification molecularity with electron poor and electron rich alkenes…………………………………………………………………………………... 183 Figure II-26: (a) Traditional explanation for diastereoselectivity (b) Diastereoselectivity in chloroetherifications (c) explanation for diastereoselectivity……………………………. 185 Figure II-27: Eyring analysis of diastereoselectivity……………...………………………. 186 Figure II-28: Reagent controlled approach to improve diastereoselectivity……………. 188 Figure II-29: (a) Influence of chlorenium donor HalA on product distribution. (b) Potential mechanism for chlorofunctionalizations…………………………………………………… 193 Figure II-30: Eyring analysis of bromo and chloroetherifications………………………... 195 Figure II-31: Sensitivity to alcohol size for bromo and chloroetherifications……………. 197 xv Figure II-32: (a) Comparison of the bromine and chlorine halogen bond alkene activation (b) Proposed mechanism for bromofunctionalizations (c) Proposed mechanism for chlorofunctionalizations…………………………………………………………………….. 200 Figure II-33: General procedure for the screening of catalytic asymmetric bromoamadination of II-1 to yield vicinal bromoamadine II-14………………………….. 202 Figure II-34: Procedure for the Eyring Analysis of the catalytic asymmetric bromoamidation of II-1 with acetonitrile……………………………………..…………….. 203 Figure II-35: Procedure for the Eyring Analysis of the catalytic asymmetric bromoamadination of II-1 with dimethylcyanamide………………………………………. 204 Figure II-36: Procedure for Eyring Analysis of haloetherification reactions with various bromenium reagents ………………………………………………..……………………… 205 Figure II-37: Procedure for product ratio as a function of nucleophile concentration.… 206 Figure II-38: Procedure for acid additive influence of product ratio.…………………… 206 Figure II-39: Procedure for product ratio as a function of nucleophile size…………… 207 Figure II-40: Procedure for Eyring Analysis with alkenes of varied halenium affinity…. 208 Figure II-41: Procedure of Eyring Analysis of diastereoselectivity in chlorofunctionalization……………………………………………………………………… 209 Figure II-42: Procedure for halenium affinity diastereoselectivity studies of chlorofunctionalizations…………………………………………………………………….. 210 Figure II-43: Procedure for the study of the influence of chlorenium donor HalA on product distribution……………………………………………………………………………………. 210 Figure II-44: Procedure for Eyring Analysis with N-Chlorosaccharine……….…………. 211 Figure II-45: Procedure for nucleophile size study with N-Chlorosaccharine.…………. 212 xvi KEY TO SYMBOLS AND ABBREVIATIONS ‡ Transition State [α] Specific Rotation °C Degree Celsius ∆ Change 1° Primary Å Angstrom Ar Aryl BINOL 1,1′-Bi-2-naphthol cal Calorie CDCl3 Deuterated Chloroform CHCl3 Chloroform Cs2CO3 Cesium Carbonate d Days DBDMH 1,3-Dibromo-5,5-Dimethylhydantoin DCDMH 1,3-Dichloro-5,5-Dimethylhydantoin DCM Dichloromethane DHQ Dihydroquinine DHQD Dihydroquinidine DMAP 4-Dimethylaminopyridine DMC Dimethylcyanamide xvii DMSO Dimethylsulfoxide dr Diastereomeric Ratio ee Enantiomeric Excess ent Enantiomer es Enantiospecificity ESI Electrospray Ionization Et Ethyl EtOAc Ethyl Acetate EtOH Ethanol g Gram H Enthalpy h Hour HalA Halenium Affinity HCl Hydrochloric Acid HFIP 1,1,1,3,3,3-Hexafluoro-propan-2-ol HOMO Highest Occupied Molecular Orbital HRMS High Resolution Mass Spectrometry Hz Hertz i-Pr Isopropyl J Coupling Constant K Kelvin kcal Kilocalorie xviii KIE Kinetic Isotope Effect LiCl Lithium Chloride ln Natural Logarithm LUMO Lowest Unoccupied Molecular Orbital M Molar Me Methyl MeCN Acetonitrile MeOH Methanol mg Milligram MHz Megahertz min Minutes mL Milliliter mmol Millimole MS Molecular Sieves Na2S2O3 Sodium Thiosulfate Na2SO4 Sodium Sulfate NAAA Nucleophile Assisted Alkene Activation NAPH Naphthalene NBA N-bromoacetamide NBP N-bromophthalimide NBS N-bromosuccinimide NBSac N-bromosaccharin xix NCP N-chlorophthalimide NCS N-chlorosuccinimide NCSac N-chlorosaccharin NEt3 Triethylamine NIS N-iodosuccinimide NK1 Neurokinin 1 NO2 Nitro Ns Nosyl PHAL phthalazinediyl q quartet Rf Retention Factor rr Regioisomeric Ratio RT Retention Time rt Room Temperature S Entropy SiO2 Silicon Dioxide t Time TBSCl Tert-Butyldimethylsilyl Chloride tBu Tert-Butyl TCCA Trichloroisocyanuric Acid TFE 2,2,2-Trifluoroethan-1-ol THF Tetrahydrofuran xx TLC Thin Layer Chromatography δ Chemical Shift µL Microliter xxi Chapter I Ritter Enabled Catalytic Asymmetric Chloroamidation of Olefins I-1 Introduction Br Br H H Cl Cl Br O O Br Cl Br O Cl Br Br Cl H Br Halomon Obtusin Anverene OH OH O O Cl Cl NH Cl Cl H O Br Cl O Cl OH H O Telfairine Chlorochrymorin Dichlorolissoclimide OH O Cl Cl Cl OSO3 Cl Cl HO OSO3 O C6H13 7 Cl Cl Cl Danicalipan A Napyradiomycin A1 Figure I-1: Natural products containing stereodefined carbon halogen bonds The carbon carbon double bond is one of the most important motifs in organic chemistry. The olefin’s importance stems from its versatility; the olefin is a slate for key reactions, such as epoxidation,1-4 aziridination,4-5 dihydroxylation,6 aminohydroxylation,7- 9 hydrogenation,10-11 and more. It is important to note that within these difunctionalization reactions, there is the potential for the generation of two new stereocenters and that asymmetric methodology has been developed for the aforementioned reactions. The asymmetric variations of such reactions have been a useful starting point to install chirality 1 for asymmetric total syntheses.12 Interestingly, halofunctionalizations, which are among the first reactions introduced in sophomore organic chemistry, had not succumbed to catalytic asymmetric variations until the last decade. The realization of asymmetric halofunctionalization can establish a starting point in the synthesis of complex molecules as the stereodefined carbon halogen bond is prevalent in valuable natural products (Figure I-1)13-16 and can serve as a lynchpin for downstream functionalizations.17 The incorporation of a stereodefined heteroatom vicinal to the halogen provides an additional layer of versatility with the potential to incorporate oxygen, halogen, nitrogen, and carbon nucleophiles. I-2 Racemization Processes of Halonium Ions The mechanistic comprehension of halofunctionalization mechanisms is critical to the design of novel halofunctionalization reactions, especially intermolecular enantioselective halofunctionalizations. The traditional stepwise mechanistic hypothesis for halofunctionalizations suggests reactions proceed through a haliranium ion such as I- 1 which incites racemization processes such as olefin to olefin halenium transfer (Figure I-2a) and the opening to the beta-halocarbenium ion I-4 (Figure I-2b). Thus, the face selectivity for the initial halenium transfer to the alkene is not necessarily the face selectivity observed in the difunctionalized product. The configurational and chemical stability of these intermediates is even more problematic with intermolecular 2 halofunctionalizations, which do not benefit from proximity-driven rate enhancement which may result in longer lived haliranium ions (Figure I-2c). a H R1 R2 H R2 X H H R2 R1 H X X R1 H H R2 I-1 I-3 R1 H I-2 b X R2 X X H R2 R1 H R1 H H I-1 I-4 c X X X X Intramolecular Intermolecular Fast Nu Slow Nu Nu H Nu H I-5 I-6 I-7 I-8 Shorter Lifetime Longer Lifetime Figure I-2: Racemization processes for haliranium ions (a) Olefin to olefin halenium transfer (b) Opening of the haliranium in to the β- halocarbenium ion (c) Enhanced problematic nature of haliranium ions in asymmetric intermolecular functionalizations I-2-1 Racemization via Olefin to Olefin Halenium Transfer Early studies by Brown18 demonstrated the existence of olefin-to-olefin halonium ion transfer and, in 2010, Denmark19 investigated olefin to olefin bromenium transfer as a potential racemization process (Figure I-3). This study hinged on the formation of enantioenriched bromiranium ions and the products' stereospecificity when trapped by a nucleophilic partner. They were able to generate the C2 symmetric bromiranium ion I-10 in-situ via the anchimerically assisted ionization of I-9. With no excess olefin in solution (Figure I-3b), the bromiranium ion is trapped by the acetate ion to provide I-11 with full 3 enantiospecificity. This indicates stereospecific formation of the bromonium ion and with no racemization events occurring without additional olefin. However, under the same reaction conditions but with one equivalent of I-12, I-11 is formed with a significant loss of enantiospecificity (30% es) (Figure I-3b). This experiment displays the intrinsic difficulties involved with enantioselective bromofunctionalizations. The analogous experiments with chloronium ions were also performed and yielded orthogonal results to the bromonium experiments (Figure I-3c). The process of ionization to form the chloronium ion as well as the trapping with acetate proceeded with full enantiospecificity, indicating that olefin to olefin racemization is not present in this system. Though proceeding through a chloronium ion intermediate may appear to be an appealing process to obviate racemization, the authors did note that the chloroacetate products were produced in reduced yields. The authors attribute this inverse relationship between chemical and stereochemical stability via bromine and chlorine's relative electronegativities. The greater electronegativity of chlorine leads to more positive charge on the carbon, leaving it more susceptible to nucleophilic attack as well as elimination reactions. Conversely, bromine's greater positive charge facilitates the π-complex required for olefin-to-olefin transfer. This data serves as an example that enantioselective halofunctionalizations initiated by different halenium ions will provide unique challenges. 4 a OTs OAc C 3H 7 HFIP n-Bu4NOAc C 3H 7 C 3H 7 C 3H 7 C 3H 7 C 3H 7 Br Br Br I-9 I-10 I-11 (4R,5S) C 3H 7 C 3H 7 I-12 OAc C3H7 n-Bu4NOAc C 3H 7 C 3H 7 Br C 3H 7 Br ent I-10 I-11 (4S,5R) b OTs HFIP OAc C 3H 7 2 equiv n-Bu4NOAc 0 equiv of I-12 C 3H 7 C 3H 7 C 3H 7 C 3H 7 C 3H 7 100% es rt 1 equiv of I-12 Br Br 30% es I-9 I-12 I-11 c OTf HFIP OAc C 3H 7 2 equiv n-Bu4NOAc 0 equiv of I-12 C 3H 7 C 3H 7 C 3H 7 C 3H 7 C 3H 7 100% es rt 1 equiv of I-12 Cl Cl 100% es I-13 I-12 I-14 Figure I-3: a) Mechanistic overview of olefin-to-olefin transfer as a racemization process (b) Propensity of bromonium ions to racemize in the presence of excess olefin (c) Stereochemical stability of chloronium in the presence of excess olefin 5 a Br Br SbF5-SO2 Br or Br -60 to -80 °C F F 70% 30% I-15 I-16 I-17 I-18 Thermodyanmic Equilibrium Br Br bond rotation Br Br I-17 I-19 I-20 I-18 b Br Br -40 °C Br 70% 30% I-21 I-17 I-18 Br Br Br Methyl Shift Hydride Shift Br I-17 I-22 I-23 I-24 Figure I-4: (a) The propensity of long lived haliranium ions to open to the β-halocarbenium ion with diastereomeric consequences (b) Potential rearrangements associated with haliranium ions I-2-2 Isomerization to the b-Halocarbenium Ion Olah’s use of super acids20 to generate various halonium ions shed light on other potential issues involved with haliranium ion pathways. Upon exposure of either bromo- fluoride diastereomer I-15 or I-16 with SbF5-SO2 they obtained the same 70%-30% ratio of I-17 : I:18 (Figure I-4a). While the authors explicitly stated that the non-stereospecific solvolysis might generate the haliranium ion, they also suggested that this might result from the opening to the b-halocarbenium ion I-19 with ensuing bond rotation and closure to form haliranium ion I-18, the diastereomer of I-17. Further displaying the instability of bromiranium ions, upon warming to -40 °C, both I-17 and I-18 underwent hydride and methyl sifts to yield I-24 (Figure I-4b). Ohta and co-workers21 observed similar b- 6 halocarbenium ions and alkyl shifts in their NMR studies of deuterated halogenated substrates. Not only will b-halocarbenium ions lead to deteriorated yields and diastereoselectivity due to rearrangement, but they may also lead to a lowered enantioselectivity due to two successive openings with bond rotations (Figure I-5). X R2 R2 bond rotation X R1 R1 R1 R1 R2 R2 X X I-25 I-26 I-27 I-28 R2 bond rotation R1 R1 R1 R2 R2 X X X I-29 I-30 I-31 Figure I-5: Racemization via β-Halocarbenium Ion I-3 Mechanistic Comprehension of Halofunctionalizations I-3-1 Halenium Affinity The synthetic utility and ubiquitous nature of carbon halogen bonds makes electrophilic halofunctionalization a key tool in organic synthesis. While this chemistry is widely employed, much of the progress relies on trial and error. In the context of the synthesis of more complex molecules, there are often multiple potential halenium acceptors. This translates into difficulties in predicting chemoselectivity, which can complicate synthetic strategies. In order to address this limitation, our lab introduced the Halenium Affinity (HalA)22 concept as a quantitative descriptor of the thermodynamic affinity of various functional groups to halenium ions. This method was demonstrably successful in providing the correct prediction of halenium acceptor HalA. The equations for the calculation of a neutral acceptor (equation 1) or anionic acceptor (equation 2) are displayed below. 7 Neutral acceptor: ∆Hrxn(X+ + :LB → X-LB+) Equation 1 Anion acceptor: ∆Hrxn(X+ + :LB– → X-LB) Equation 2 The HalA values discussed in this text are in kcal/mol at T = 298.15 K as derived computationally in equation 3. * 𝐻𝑎𝑙𝐴 = − ∆𝐸("#"$) − ∆𝑍𝑃𝐸 − ∆𝐸 & ('()) + + 𝑅𝑇 Equation 3 With a computational method in hand, the halenium affinities of various chlorenium donors were calculated and compared to each other to probe the validity of HalA. HalA predicts that a Lewis base with the higher HalA will abstract a chlorenium ion from a donor with a lower HalA (of its corresponding Lewis base). An NMR competition experiment between tetra-n-butyammonium succinimidate acceptor (Figure I-6b, HalA (Cl) = 194.0) and DCDMH donor (Figure I-6c HalA (Cl) of Lewis base = 181.1 kcal/mol) was performed to probe the validity of the HalA calculations. The succinimide anion possesses a higher halenium affinity than the chlorohydantoin anion and thus should abstract the chlorenium ion from the DCDMH donor. This proposition is supported by the chemical shifts of the 1:1 mixture of DCDMH and tetrabutylammonium succimidate (Figure I-6d) in which the methylene protons of the succimidate (Ha) which would lie at about 2.3 ppm if anionic (Figure I-6b) shift upfield to the same chemical shift of NCS (Figure I-6a). Consequently, 8 the methyl protons of the DCDMH donor experience a upfield shift indicating transfer of the chlorenium ion. a. Ha O Ha N Cl Ha = ~ 2.9 ppm O NCS b. Ha O N(nBu)4 Ha N Ha = ~ 2.2 ppm HalA (Cl) = 194.0 kcal/mol O succinimide anion c. H 3C O CH3 = ~ 1.5 ppm H 3C 3 N Cl N Cl 1 HalA (Cl) of DCDMH O anion (N3) = 181.1 kcal/mol DCDMH d. H 3C O Ha O H 3C Ha succinimide anion + DCDMH N N(nBu)4 + N Cl N Cl O O CH3 = ~ 1.3 ppm Ha = ~ 2.9 ppm Figure I-6: (a) 1H NMR of NCS (b) 1H NMR of succinimide anion (c) 1H NMR of DCDMH (d) 1H NMR of succinimide anion DCDMH mixture that results in the abstraction of chlorenium to form NCS The comprehension of HalA in the context of a molecule with multiple competitive Lewis basic functionalities enables the prediction of chemoselectivity of reactions (Figure I-7). For example, molecule I-32 contains two potential sites for halogenation: the aromatic ring (HalA = 181.5 kcal/mol), which leads to the chlorination of the aromatic ring, or the aryl alkene (HalA = 179.3 kcal/mol), which leads to the carbocyclization product. As predicted by HalA, exposure of I-32 to chlorenium source DCDMH yields the electrophilic aromatic chlorination reaction product I-33. Modification of the electronic nature of the aromatic ring via the removal of methoxy electron donors led to the attenuation of the HalA of the aromatic ring in substrate I-34 (HalA = 164.5 kcal/mol, about 9 15 kcal/mol less than the alkene) thus rendering the alkene the functionality with the highest HalA within the molecule and providing the carbocyclization product I-35.22 a HalA: 181.5 Ts Cl Ts 1.2 equiv DCDMH MeO N MeO N 5 mol% DABCO 9:1 DCE:HFIP MeO 0° C, 4h MeO OMe Ph OMe Ph HalA: 179.3 I-32 I-33 b HalA: 164.5 Ts Ts 1.2 equiv DCDMH N N 5 mol% DABCO 9:1 DCE:HFIP MeO 0° C, 4h MeO Cl Ph Ph (±) HalA: 179.3 I-34 I-35 HalA (Cl) values in Kcal/mol (B3LYP/6-31G*) Figure I-7: Predictive ability of Halenium affinity in chemoselectivity (a) Aromatic ring with high halenium affinity undergoing chlorination (b) Aromatic ring with attenuated halenium affinity undergoes a carbocyclization I-3-2 Nucleophile Assisted Alkene Activation Recently our group disclosed studies on the intramolecular Nucleophile Assisted Alkene Activation (NAAA).23 This is a mechanistic revelation that challenges the traditional stepwise halofunctionalization mechanism by asserting, with strong experimental evidence, that intramolecular halofunctionalizations often proceed through an asynchronous concerted mechanism driven by an interaction between the HOMO of the nucleophile and LUMO of the alkene, thus increasing the HalA to the extent that transfer of the halenium ion to the alkene can occur. This is demonstrated via the conformer dependent HalAs of I-45 (Figure 1-8a). In the stepwise reaction path 10 proceeding through a carbocation (Figure I-8b) the halenium affinity of the unactivated I- 45 alkene is 167.4 Kcal/mol. Conversely, in the nucleophile assisted reaction pathway C (Figure I-8C) the HalA of I-45 is increased to 173.3 kcal/mol. Thus, with a higher HalA, the coiled conformer I-45 reacts faster. Additionally, viewed in the context of an asymmetric halofunctionalization, a concerted addition of both the nucleophile and halenium ion in NAAA circumvents racemization processes involved with haliranium ions. a D X X X ! X Nuc D X Y Classical NAAA Y Mechanism Mechanism ! Nuc I-38 I-37 I-36 I-39 I-40 b A X Path A -AH HO2C HalA: 167.4 kcal/mol H Y X (Chloroform B3LYP 6-31G*) X A I-42 H Y A I-44Y extended conformer I-41 X unactivated -AH I-45 Path B H Y I-43 c δ ‡ O A H! δ X X O HalA: 173.3 kcal/mol Path C A X -AH (Chloroform B3LYP 6-31G*) Y ! Y Y H Y H H δ δ coiled conformer I-41 I-46 I-47 I-44 activated I-45 Figure I-8: (a) Contrasting classical and nucleophile assisted halofunctionalizations (b) Reaction pathway for a classical halofunctionalization and the halenium affinity of the alkene in this mechanism (c) Reaction pathway for a NAAA halofunctionalization and HalA in this mechanism 11 I-3-2-1 Experimental Evidence for Nucleophile Assisted Alkene Activation Dr. Kumar Ashtekar’s elegant experiments provided support for NAAA. The next section will be a brief discussion of the most convincing experiments supporting this controversial mechanism. While the following experiments provide evidence for the existence of NAAA, it is critical to recognize that it is a mechanistic spectrum of O Cl Cl N Rxn time Nuc N Cl Ph CH3Cl, rt Nuc Ph O Activation I-48 DCDMH II-49 energya O OH 72 h Classical Intermediates O 27.7 Ph RDS prior to Nuc Attack O Ph I-48a A Cl Cl I-49a O Nuc 12 h 16.7 OH Ph Ph I-48b Cl or I-49b O A O H N 20 min Ph O 14.3 Cl O Ph I-48a + quinuclidine Cl Nuc I-49a O O <2 min NBu4 O 8.8 Ph O Ph I-48c Cl I-49a Nucleophile Assisted Alkene Activation ‡ A! ! nucleophile induced Cl Nucleophile pre-polarization participation in Nuc RDS ! Nuc ! Figure I-9: Influence of nucleophilicity on reaction rate 12 possibilities, both the NAAA and traditional stepwise reaction pathways can occur depending on the olefin, halenium donor, and nucleophile. The traditional halofunctionalization mechanism depicts the rate-determining step as the haliranium ion formation. This implies the nucleophile plays no role, therefore if the nucleophile is not involved in the rate-determining step, then modulation of the nucleophilicity should have no effect on the reaction rate (Figure I-8b). To explore the possibility of a nucleophile assisted mechanism, Dr. Ashtekar synthesized substrates with tethered nucleophiles possessing a range of nucleophilicities (Figure I-9). Carboxylic acid I-48a is the weakest nucleophile, therefore it provides the least assistance and the most sluggish reaction. Progression to stronger nucleophiles such as alcohol I-48b or basic additives with I-48a correlate with an increased reaction rate, indicating that the nucleophile is involved in the rate-determining step. The variation of reaction rates is supported with computational data indicating a lower activation energy with a stronger nucleophile. NMR spectroscopy probed the possibility of an asynchronous transition state via a pre-polarized nucleophile. Here, the tethered nucleophiles that displayed varied reaction rates were synthesized and their respective NMR spectra were observed (Table I-I). In line with rate observation, stronger nucleophiles, such as I-50c, provided more shielding (electron density) to Ha while deshielding Hb. The enhanced electron density of the alkene results from the HOMO of the nucleophile interacting with the LUMO of the alkene. This raises the halenium affinity of the alkene and increases the reaction rate. 13 Table I-1: 1H and 13C resonances of Z-styrylic alkene upon modulation of electronic of a remotely tethered nucleophile Ha δ δ Hb Ph Nuc I-50 Ha Hb Ha Hb Ha Hb O Ha Hb CO2H CH2OH O H N CO2 NBu4 Ph Ph Ph Ph I-50a I-50b I-50a + quinuclidine I-50c Entry Substrate δ 1Ha (ppm) δ 1Hb (ppm) δ 13C-Ha (ppm) δ 13C-Hb (ppm) 1 I-50a 6.48 5.62 130.4 129.8 2 I-50b 6.44 5.66 129.4 132.0 3 I-50a + quinuclidine 6.34 5.66 128.6 132.6 4 I-50c 6.30 5.73 127.8 133.7 Kinetic isotope effects were critical in differentiating between potential mechanistic pathways (Figure I-10). If proceeding through a stepwise fashion, the halolactonizations of I-51 and I-53 are expected to proceed through the tertiary benzylic halocarbenium ion.22 If the formation of this intermediate is the rate determining step, then no 13C is expected at the benzylic carbon. The chlorolactonization of I-51 displays a KIE of 1.011 indicating hybridization state change of that carbon in the transition state and thus the nucleophile's involvement in the rate determining step. To display the 13C KIE of a stepwise pathway electron rich I-53 was subjected to the same conditions and yielded a KIE of 1.001 at the benzylic center, indicating a carbocationic reaction pathway without assistance from the nucleophile. This difference in KIE between these two substrates is a direct observation of an NAAA in an alkene with lower HalA (I-51) requiring NAAA to enable the abstraction of a halenium ion and a non-NAAA pathway with an electron-rich alkene that does not 14 require further HalA enhancement from the nucleophile to abstract the halenium ion from the donor. O 1.000 DCDMH 1.002 OH O Ph O Ph 1.011 1.008 Cl 1.016 I-51 1.013 I-52 O 1.000 DCDMH 1.002 OH O Ar O Ar 1.001 1.010 Cl 1.008 I-53 1.012 I-54 Ar = 4-OMe-C6H4 Figure I-10: 13C natural abundance KIE studies of chlorolactonizations 15 I-4 Development of Catalytic Asymmetric Halofunctionalizations I-4-1 Intramolecular Catalytic Asymmetric Halofunctionalizations Cognizant of the intrinsic chemical and confirmational instabilities haliranium ions pose, our group first explored catalytic asymmetric halocyclization. The proximity-driven rate enhancement or NAAA would limit the haliranium ion lifetime, thus lessening the potential for racemization processes. In 2010 Dr. Whitehead disclosed the first catalytic a O (DHQD)2PHAL (10 mol%) DCDPH (1.1 equiv.) OH O Ar Benzoic Acid (1 equiv.) Ar O CH3Cl:Hex (1:1), -40°C Cl I-55 I-56 9 examples Yield: 61-99% ee: 5-90% N N O ‡ Cl N Cl N O O O Ph O O O H N N N N N O R H (DHQD)2PHAL I-57 b Ar (DHQD)2PHAL (2 mol%) H DCDPH (1.1 equiv.) N Ar O N Ar TFE, -30°C Ar O Cl I-58 I-59 15 examples Yield: 72-97% ee: 55-98% Ar R2 O (DHQD)2PHAL (2 mol%) DCDPH (1.1 equiv.) O N R1 N Ar R2 H TFE, -30°C R1 Cl I-60 I-61 R1, R2 = Aryl or alkyl 14 examples Yield: 52-99% ee: 20-99% Figure I-11: (a) Catalytic asymmetric chlorolactonization with proposed mechanism (b) Catalytic asymmetric amide halocyclizations 16 asymmetric chlorolactonization employing cinchona alkaloid dimer (DHQD)2PHAL as a catalyst and N-halohydantoins as halenium sources (Figure I-11A).24 This reaction is tolerant of most electronic perturbations of the aryl ring of I-55, providing enantioselectivities in excess of 80% ee for the majority of substrates. Highly electron rich substrates such as the 4-methoxy phenyl substrate provides severely deteriorated enantioselectivity. The reduction in enantiocontrol is attributed to the substrate's high halenium affinity that possibly does not require NAAA or the catalyst to transfer the chlorenium ion to the alkene. Mechanistic studies suggest an NAAA mechanism for the catalytic reaction with the quinuclidine of (DHQD)2PHAL functioning to activate the acid nucleophile. Dr. Jaganathan expanded this chemistry to include amide halocyclizations (Figure I-11B). By altering the substituents on the alkene, both the 5-exo (I-58) and 6- endo (I-60) products were attainable. Like the chlorolactonizations, this reaction was highly tolerant to most alkenes but suffered a reduction of enantioselectivity with the most electron-rich substrates.25-26 I-4-2 Intermolecular Catalytic Asymmetric Halofunctionalizations In 2015 Dr. Soltanzadeh disclosed the stereoselective intermolecular haloetherification of allyl-amides(Figure I-12).27 Employment of (DHQD)2PHAL, DCDMH, and a methanol nucleophile proved to be optimal in the highly enantioselective transformation of Z and E olefins of aliphatic and aromatic substitution to their corresponding chloro-ether products (Figure I-12a). This methodology was not limited to chlorenium reagents as NBS provided the bromoether product in high yield and enantioselectivity (Figure I-12b).28 17 This work expanded the prior art in the field as it provided strong regiochemical catalyst control over unactivated alkenes that contain minimal electronic bias (Table I-2). Relative to halocyclization reactions, control of regioselectivity is more challenging in intermolecular haloetherifications that do not benefit from regioselective bias due to ring closure kinetics. Dr. Soltanzadeh discovered that (DHQD)2PHAL is significant in determining the regiochemical outcome of the reaction, improving the regio-isomeric ratio (I:65 to I:66) to 24:1 for the catalyzed reaction as opposed to 4:1 without the catalyst. Interestingly, (DHQD)2NAPH reversed the regio-isomeric ratio back to 4:1 (Table I-2). a (DHQD)2PHAL (10 mol%) R2 O R2 O DCDMH (2.0 equiv.) R 3O R1 N Ar N Ar Nucleophile:MeCN (3:7) R1 H H (0.01 M), -30 °C Cl I-62 I-63a R1, R2 = aryl or alkyl 22 examples R3 = alkyl, H, or acyl Yield: 49-93% ee: 50-99% b (DHQD)2PHAL (10 mol%) R2 O R2 O NBS (2.0 equiv.) R 3O R1 N Ar N Ar Nucleophile:MeCN (3:7) R1 H H (0.01 M), -30 °C Br I-62 I-63b R1, R2 = alkyl 4 examples R3 = Me or H Yield: 51-92% ee: 70-99% Figure I-12: (a) Catalytic asymmetric intermolecular chloroetherification scope (b) Catalytic asymmetric intermolecular bromoetherification scope 18 This may be attributed to substrate phthalazine hydrogen bonding through the N-H of the amide or enhancing structural rigidity of the catalyst. Table I-2: Catalyst control of regiochemistry for haloetherification reactions catalyst (10 mol%) Cl OMe H 2.0 equiv DCDMH H + C H H N Ar C 3H 7 N Ar 3 7 N Ar MeOH:MeCN (3:7) C 3H 7 O 0.01 M, rt, 3 h OMe O Cl O I-64 I-65 I-66 Entry Catalyst rr (I-65:I-66) N N 1 None 4:1 O O 2 (DHQD)2PHAL 24:1 O O 3 (DHQD)2NAPH 4:1 N N (DHQD)2NAPH Mechanistic studies led by Dr. Sarkar elucidated an unorthodox catalytic transformation. The order of each reagent was determined through detailed Reaction Progress Kinetic Analysis and Variable Time Normalized Analysis developed by Blackmond and Burns. The elucidation of the order of each reagent sheds light on the rate-determining step and off-cycle processes of the catalytic cycle. It was determined that the reaction was first order in substrate and methanol nucleophile suggesting that it is involved in the rate-determining step and zeroth order in DCDMH. The zeroth-order suggests saturation with the chlorohydantoin and the catalyst. Interestingly, the reaction was also zeroth order in the catalyst at molar equivalents greater than 0.01, indicating that the catalyst is not involved in the rate-determining step. Considering the observed orders, Dr. Sarkar proposed a catalytic cycle with the rate-determining pre-catalytic step to form the activated alkene with complexation of the substrate with methanol. Once in this reactive conformation, the substrate reacts with the chiral DCDMH (DHQD)2PHAL 19 complex to provide the chloro-ether product in high yield, regioselectivity, and enantioselectivity. The transfer of from chlorenium to DCDMH and (DHQD)2PHAL to form I-67 presents a catalytic system with potentially broad applicability as a chiral source of chlorenium. Additionally, kinetic data elucidating a first order of methanol and an inverse KIE support a concerted mechanism (Figure I-13b). A concerted mechanism obviates racemization processes and allows for the inclusion of unactivated alkenes in an intermolecular halofunctionalization process. a (DHQD)2PHAL Polar Protic Solvent DCDMH Cl N R H I-67 Catalytic Chiral Halenium Source N N O O O O N N N N (DHQD)2PHAL b H O H OMe O C 3H 7 N Ar C 3H 7 N Ar H Standard Condition H I-68 Cl 80% Conversion I-69 D O D OMe O C 3H 7 N Ar C 3H 7 N Ar H H Cl I-68D I-69D 1:1 ratio of isotopomers KH/KD = 0.89 Inverse KIE Figure I-13: (a) Transfer of chlorenium from DCDMH to (DHQD)2PHAL to form chiral halenium source (b) KIE experiment suggesting a concerted nucleophile assisted mechanism 20 I-5 Catalytic Asymmetric Haloamination of Olefins The catalytic asymmetric haloamination of olefins is a desirable tool for synthetic chemists. The installation of the enantiopure carbon halogen bond provides a ubiquitous moiety found in many natural products and an important handle for downstream stereospecific reactions (Figure I-14a). Additionally, the stereodefined carbon nitrogen bond is common in many compounds of biological and synthetic significance (Figure I- 14b). a (-)-Palau’amine (-)-Virantmycin Clindamycin NH2 HOOC Cl S Cl H 3N HN NH O OH NH HO H HO H NH2 OMe HN O OH H N Cl Me N NH N O N Me Me b Sensipar Tamiflu CF3 O O O HN HN NH2 O Figure I-14: (a) Biologically significant molecules that contain a chiral vicinal chloramine (b) Stereodefined amines in small molecule pharmaceuticals While this reaction's desire is clear, intermolecular asymmetric haloamination reactions have not afforded the same success that related halofunctionalization reactions with halogen and oxygen nucleophiles provide. The key difference between these nucleophilic species is their respective halenium affinities. A sampling of halenium 21 affinities is shown in the table below (Figure I-15a). The halenium affinity of alcohols, representative of oxygen nucleophiles, falls below the range of alkenes and, as a result, does not compete with alkene I-70 for halenium ions permitting the formation of haloether product I-71. Conversely, amines have a halenium affinity higher than alkenes and under analogous haloamination conditions the amine nucleophile out competes the alkene I-70 for the capture of the halenium ion.22 This results in the retainment of the allyl-amide starting material and the formation of I-73 and I-74 as a kinetic trap via hydrogen halogen exchange between the two nitrogen atoms. a Alkenes Primary Amines Alcohols HalA ranges (kcal/mol): 140-170 140-180 110-140 b C 3H 7 O N Ph H I-70a R O (DHQD)2PHAL (DHQD)2PHAL Cl Me Me OH R NH2 H H O N Ph N N R H DCDMH DCDMH R Cl R O I-71a 79% yield I-72a 99% ee H H O N O Cl O N O N R N N Cl H Cl I-73 I-74 DCDMH Retained starting material! Figure I-15: (a) Sampling of potential nucleophiles for halofunctionalizations (b) The role of halenium affinity in the control of the reaction pathway Many groups have leveraged an elegant “pro-nucleophile” approach to construct vicinal haloamines utilizing a nitrogen-based halenium source (Section I-5-2). While this is a clever method to circumvent the quenching of the halenium source by the nucleophile, 22 it hinges on the olefin's capability to fully abstract the halenium ion from the halenium source. This subsequently produces a haliranium or β-halocarbenium ion that is trapped by the nitrogen-based counter anion to yield the difunctionalized product. The drawback to this chemistry is that a halenium ion's abstraction via the olefin to form putative haliranium or β-halocarbenium ion intermediates is a kinetically difficult stepwise process. This often requires either a highly reactive alkene, halenium source, or catalyst. These procedures frequently employ bromenium or iodenium reagents as their respective haliranium intermediates are more stable to mitigate the chemical instability of these high- energy intermediates. This stepwise pro-nucleophile mechanistic pathway differs from other halofunctionalizations that enable an NAAA pathway that helps assist the transfer of halenium ions to unactivated olefins. I-5-1 Literature Precedent for Intramolecular Catalytic Asymmetric Haloamination Reactions As with many reactions within the family of halofunctionalization, catalytic halocyclizations piloted catalytic asymmetric haloamination chemistry. The intramolecular nature of the reactions circumvents many problematic features of haliranium ions and enable a less entropically challenged route to nucleophile assisted alkene activation. These methods are precious due to the ubiquitous nature of nitrogen-containing chiral heterocycles in natural products. To avoid halenium ion deactivation via exchange with the nitrogen nucleophile, most groups avoided using basic nitrogen nucleophiles that possess a higher halenium affinity and employed sulfonylimides or nosylsulfonamides, which possess a much lower halenium affinity. It is also possible that with the basic 23 catalysts (cinchona alkaloid or amidine) employed in these reactions, the amine nucleophile I-75 is deprotonated, thus generating I-76, a stronger nucleophile for the reaction. R R R N H LB Catalyst* N H X+ Donor N LB Catalyst* X I-75 I-76 I-77 R = EWG Figure I-16: General strategy for the intramolecular catalytic asymmetric haloamidation of alkenes I-5-1-1 Halocyclization of Unsaturated Sulfonamides with a Thio- Carbmate Catalyst In 2011, Yeung and coworkers disclosed the catalytic asymmetric halocyclization of unsaturated sulfonamides with an amino-thiocarbamate catalyst I-79 yielding pyrrolidine products with high yields and high ee (Figure I-17).29 Selection of the proper amine protecting group was critical to yield, ee, and reaction time with 4-Ns in I-78 providing the optimized result in nearly every category. The authors suggest that the 4- Ns group provided the ideal steric bulk and acidity to enable interaction with the catalyst's quinuclidine moiety. While a broad range of substrates were displayed, only H N S R I-79 (10 mol%) O H N(4-Ns) N N R (4-Ns) NBS, CHCl3, -62 °C O R I-78 Br N R = Ar, Alkyl, H I-80 16 examples I-79 61-99% yield R = 2,6-(EtO)2C6H3 10 -99% ee Figure I-17: Thiocarbamate catalyzed bromocyclization 24 aryl disubstituted alkenes yielded products with enantiomeric excess greater than 46%. Additionally, alkenes with high electron density such as 4-MeOC4H6 suffered from reduced enantioselectivity (19%). I-5-1-2 Catalyst Controlled Bromolactamization of Sulfonylimides In 2015 Yeung and coworkers disclosed the bromolactamization of sulfonylimides.30 This reaction presents an additional challenge of nucleophile chemoselectivity with the imide's oxygen presenting a competitive nucleophile. The authors suggest that the catalyst I-84 hydrogen bonds through the imide substrate's tautomer. The hydrogen bonding confirmation makes it difficult for oxygen to behave as a nucleophile in the reaction thus yielding I-82a in preference to I-83a (Figure I-18A). This method was efficient and provided 22 products with high yield and enantiomeric excess. Unlike similar work that yielded pyrrolidines, this reaction was more tolerable of electron- poor and electron-rich substrates. Additionally, 1,2 disubstituted systems cleanly provides 25 products in high yield and enantioselectivity. Unfortunately, this reaction was limited to indole substrates which hinders its broad applicability and yielded bromination at the 3- position of the indole (Figure I-17b). a Br Br O NTs CONHTs Catalyst, NBS, CH2Cl2 NTs O N N N CH2Cl2, -78 °C Br Br I-81a I-82a I-83a Entry Catalyst I-82a:I-83a 1 I-84 100:0 2 PPh3 60:40 3 Ph3PS 60:40 4 BF3-THF 60:40 CF3 CF3 CF3 O O N CF3 N O O H Br N N H TsN N OMe H O I-84 I-85 b Br O CONHR3 I-84 (10 mol%), NBS NR3 N N R2 R1 Chloroform/Toluene (2:1) R2 -78 °C R1 Br I-81 I-82 R1 = Alkyl, Aryl, H 22 examples R2 = Alkyl, H 62-98% yield R3 = Ts, Ns 64-97% ee Figure I-18: (a) Catalyst control of reaction pathway to preference nitrogen nucleophiles (b) Substrate scope of bromolactamization 26 I-5-1-3 Catalytic Asymmetric Intramolecular Iodoamination of Alkenes In 2018 Johnston and coworkers disclosed the catalytic asymmetric intramolecular iodoamination of alkenes via amine isocyanate capture (Figure I-19).31 The sulfonyl isocyanate employed forms the reactive sulfonylimine in solution. Like Yeung's work, this reaction can preferentially yield the nitrogen nucleophile in preference to the oxygen nucleophile. This reaction was heavily reliant on aryl alkenes, with most aryl alkenes providing enantiomeric excess near 90% and alkyl systems providing enantiomeric excess less than 50%. Regardless, this method utilizes the substitution of the alkene with subsequent carbocationic stability of haliranium to dictate the product's regiochemistry. The authors are able to leverage this to yield the five-membered cyclic urea I-87 with 1,1 disubstituted systems and the six-membered cyclic urea I-89 with the 1,2 disubstituted compounds (Figure I-18A). The utility of the carbon halogen bond is displayed in the further elaboration of the urea product to NK1 inhibitor I-91 after 4 steps from the haloamine product I-87a. 27 a NIS, 5 mol% I-90 O Ts H Ts N C O I N N N PMP R PMP toluene, (0.05 M), -50 °C R Ph Ph H H I-86 HN NH R = Aryl, Alkyl, H I-87 12 examples 15-97% yield N N N N 29-92% ee O Ts N C O R R R R H Ts PMP R1 N NIS, 5 mol% I-90 N N PMP toluene, (0.05 M), -50 °C I-90 R2 R1 R = OMe R2 I I-88 R1 = Aryl, Me I-89 R2 = Aryl, Me, H 5 examples 31-93% yield 63-94% ee b CF3 NIS, 5 mol% I-90 O 4 steps CF3 Ts O H Ts N C O N I N pFC 6H 4 PMP N PMP O HN toluene, (0.05 M), -50 °C NH pFC 6H 4 pFC I-86a 6H 4 I-87a 90% yield I-91 89% ee NK1 Inhibitor Figure I-19: (a) Substrate scope for alkene iodoamination for the synthesis of chiral ureas (b) Product elaboration to NK1 inhibitor I-5-2 General Approach of Previous Intermolecular Halenium Induced Haloamination Reactions As discussed at the beginning of Section I-5, most early examples of intermolecular haloamination (both asymmetric and achiral methods) utilized the counter anion of a nitrogen-based halogenating source as a pro-nucleophile in haloamination reactions. This mechanistic pathway proceeds in stepwise mechanism (Figure I-20), often forming a high-energy haliranium (or β-halocarbenium) ion intermediate I-93 via the halogenation of I-92 with a nitrogen halenium donor. The nitrogen donor adds back in to the haliranium 28 ion to yield the difunctionalized product I-94. A reaction pathway proceeding through haliranium intermediate I-93 is suspectable to racemization processes as well as competing decomposition reactions. To mitigate side reactions and render a more kinetically suitable pathway, olefins with high halenium affinities are often employed, enabling a more chemical and configurationally stable haliranium ion. This requirement is a significant limitation on the olefin scope as aliphatic substrates are less tolerant to these high-energy intermediates. O O O N Chiral Catalyst R2 R2 R1 + N R2 R1 X R1 O X O X N I-92 I-93 I-94 O Figure I-20: General mechanism for traditional intermolecular catalytic asymmetric haloamidation I-5-2-1 Enantioselective 𝜶-Halogenation of Enecarbamates In 2012 Masson and co-workers elegantly reported the enantioselective 𝜶- halogenation of E ene-carbamates with NBS and a BINOL derived chiral phosphoric acid catalyst (Figure I-20a).32 They propose that the chiral phosphoric acid catalyst acts as a bifunctional catalyst by simultaneously activating the NBS and ene-carbamate I-95 via hydrogen bonding I-98. The subsequent β-halo-iminium ion is trapped by the succinimidate ion to provide the difunctionalized product I-97a. The hydrogen bond stabilization of these high-energy intermediates allows for the smooth production of 13 unique vicinal bromo amines. In 2016 this strategy was expanded to include both iodination (Figure I-20b) and chlorination chemistry (Figure I-21c).33 This methodology's 29 success originates from the high halenium affinity of the ene-carbamate substrate that can abstract a halenium ion with no nucleophile assistance. a iPr NBS, I-96a (1 mol %) R1O2HCN Br iPr R1O2CHN toluene, RT O N R2 iPr R2 I-95 O O O P I-97a O OH R1 = aryl, alkyl R2 = alkyl 13 examples iPr Yields 46-99% ee 84-97% iPr iPr b I-96a NIS, I-96a (1 mol %) R1O2CHN I R1O2CHN toluene, RT O N R2 R2 I-95 O R1 = aryl, alkyl I-97b R2 = alkyl 8 examples Yields 44-80% O O ee 84-97% P O O Ca c 2 NCS, I-96b (1 mol %) R1O2CHN Cl R1O2CHN toluene, RT O N R2 R2 I-96b I-95 O R1 = aryl, alkyl I-97c R2 = alkyl 5 examples Yields 42-60% ee 64-92% d iPr iPr iPr COR1 N O O H P R2 O O H iPr O Br N iPr iPr O I-98 Figure I-21: (a) Enantioselective bromoamidation (b) Enantioselective iodoamination (c) Enantioselective chloroamination (d) Proposed mechanism for the enantioselective bromoamidation 30 I-5-2-2 Enantioselective Bromoamination of Allylic Alcohols A similar strategy to Masson's work was reported in 2014 by Zhou (Figure I-22).34 This method employs a cinchona-derived thiourea catalyst I-100 as a hydrogen bond donor in the activation of N,N-dibromo-4-nitrobenzene-sulfonamide to assist in the asymmetric transfer of bromenium to the aryl-substituted E alkene I-99. Following the bromenium ion transfer, the counter anion attacks the putative bromonium or β- halocarbenium ion. While moderately activated, aryl substituted alkenes do not possess halenium affinities as high as ene-carbamates; however, the use of the highly reactive nosyl-sulfonamide permits the transfer of bromenium to this less reactive species. It should be noted that the alcohols were protected with TBSCl upon reaction completion to yield the protected alcohol I-101. The reaction was also limited to trans alkenes, potentially limiting the susceptibility to reduce strain by opening the β-bromocarbenium ion, which would reduce diastereoselectivity. a 1) I-100 (10 mol%), NsNBr2 (1.2 equiv.) OMe NHNs CH2Cl2/Toluene (2:3), -35 °C, 120h N Ar OH Ar OTBS 2) TBSCl, imidazole, CH2Cl2, rt, 2h Br NH I-99 I-101 N 17 examples S NH Yield 16-71% R ee 46-95% R = 4-Tritral-C6H4 I-100 b S R R N N H H O O S Br N Br NO2 I-102 Figure I-22: Substrate scope for bromoamidation of allylic-alcohols (b) Proposed activation mode for thiourea catalysts 31 I-5-2-3 Haloazidation of Allylic Alcohols Burns and coworkers' work is slightly different but is derived from the same pro- nucleophile strategy to synthesize haloazides I-107a and I-107B from allylic alcohol I-103 (Figure I-23).35 Like previous work achieved by this group, they rely on reactive species' coordination to a titanium center in a catalytic chiral ligand accelerated approach.36-39 The work is inspired by Sharpless' regioselective ring opening of epoxides with the in-situ titanium azide complex that releases the azide upon coordination with the epoxy alcohol.40 activated electrophile activated nucleophile R3 R3 X R3 TiN3(Oi-Pr)3, hexane R O R4 X R1 OH 1 R1 O R4 NBS or t-BuOCl Ti Ti R2 I-104 (10-30%), -20 °C R2 N3 L n* R2 N3 L n* I-103 I-105 I-106 R1 = Alkyl, H R4 = Succinimidate or t-BuO R4 = Succinimidate or t-BuO R2 = Alkyl, Aryl, H R3 = Alkyl, H t-Bu R3 X R3 N3 HO R1 OH R1 OH OH or N N3 R2 X R2 Ph t-Bu Ph I-107a I-107b 14 examples I-104 44-92% yield 87-99% ee Figure I-23: Haloazidation of allylic alcohols Burns and coworkers' adaptation of this chemistry is reliant on the titanium to play multiple roles in the reaction: 1. The titanium acts as a Lewis acid to activate the halenium source. 2. Upon transfer of the halenium ion, the increased electron density on titanium provided by the counter anion of the halenium ion activates the azide for N-3 (I- 108B) transfer to open the haliranium ion. 32 3. Though formally an intermolecular molecular transformation, the chelation of all three components in I-106 renders an intramolecular transition state and short lived haliranium ion. 4. The intramolecular nature of haliranium capture obviates many of the racemization and side reaction pathways (Figure I-23). This comes with the ability to reverse regioselectivity via ring closure kinetics/substrate control with Z olefins to yield regioisomer I-107b in preference to Markovnikov regioisomer 1-107c (Figure I-23). While this might be a useful synthetic property of this method, it renders the opposite diastereomer unattainable (Figure I-24). a X Reaction Conditons R OH R OH N3 I-103a I-107a b N3 OH Reaction Conditons X OH R R I-103b X I-107b R OH N3 I-107C unattainable diastereomer Figure I-24: Regiodivergent behavior between Z and E alkenes. (a) Regioselectivity of E olefin. (b) Regioselectivity of Z olefin Unlike other methods proceeding through a pro-nucleophile mechanism, this work is compatible with unactivated aliphatic alkenes. There are two potential explanations for this tolerance of less reactive alkenes: 1. The titanium center is highly activating for the halenium source, this allows for the halenium transfer to occur without NAAA or 2. Though 33 the nucleophilicity of the titanium coordinated azide is highly attenuated, it can still assist in the transfer of the bromenium via the distal nitrogen. This work is groundbreaking since unactivated alkenes lead to vicinal haloamine products. It also earns high recognition for its use of allylic alcohols; however, the high catalyst loadings and the stoichiometric equivalent of titanium are limitations of this chemistry. I-5-2-4 Nucleophile Induced Asymmetric Haloamination of Olefins While the groups of Masson, Zhou, and Burns employed an olefin with high halenium affinity or a highly reactive halenium source, Feng’s strategy was notably different (Figure I-25).41 Feng’s work leverages Michael acceptors I-108 as highly electrophilic olefins that undergo 1,4 addition with imides or sulfonyl amides. A halenium ion traps the subsequent enolate to provide the haloamine products I-109a. Although this transformation was initially proposed to proceed through a haliranium ion pro-nucleophile mechanism, considerations of the high energy nature of haliranium ion on an electron- poor alkene prompted the authors to revise their proposal to a Michael type mechanism (Figure I-25d).42 This Lewis acid catalyzed pathway relies upon the Lewis acid to lower the pKa of the bound sulfonamide, thus activating it through deprotonation for nucleophilic attack of the alkene while simultaneously activating the Michael acceptor. This stereodefined environment fostered by the chiral ligand provides high yield across a broad range of 𝜶-β unsaturated carbonyl compounds. This chemistry has been further developed to enable the enantioselective construction of bromoamide (Figure I-25b) and iodoamide (Figure I-25c) products.42 34 a I-109a-[Sc(OTf)3] (0.05 mol%) Cl R1 O TsNH2 (0.6 eq), TsNCl2 (0.6 eq) R1 O O N N O R2 20 mg 4 Å MS, 35 °C, CH2Cl2 O O NH R2 N H H N Ts R I-108 R I-110a R1 = H, Me, Ar, COOAr, COOAlk 44 examples I-109a R2 = Ar 61-99% yield R = 1-adamantyl 21-99% ee b I-109b—[Sc(OTf)3] (0.05 mol%) Br R1 O TsNH2 (1.1 eq), NBS (1.2 eq) R1 O O N N O R2 40 mg 4 Å MS, 35 °C, CH2Cl2 O O NH R2 N H H N Ts R R I-108 I-110b 31 examples I-109b R1, R2 = Ar R = CH2CH2Ph 68-99% yield 95-99% ee c I-109b—[Sc(OTf)3] (0.05 mol%) I R1 O TsNH2 (1.2 eq), NIS (1.2 eq) R1 O R2 30 mg 4 Å MS, 35 °C, CH2Cl2 NH R2 Ts I-108 I-110c R1 = H, Me, Ar, COOAr, COOAlk 32 examples R2 = Ar 75-97% yield 95-99% ee d Proposed Mechansim Nucleophile formation TsNH2 + TsNCl2 2 TsNHCl 2 TsNCl + 2 H I-111a I-111b I-111c Ar L-PiAd Ar L-PiAd O Sc O Sc Cl S S O O NCl NCl Ar O O O NH Ar Ts Cl N Cl Ts I-112a I-112b I-110a Figure I-25: Feng’s Lewis acid approach to haloamidation of Michael acceptors. (a) Chloramidation (b) Bromoamidation (c) Idodoamination (d) Mechanistic approach to enable to enable the construction of haloamine products with electron poor alkyl systems 35 I-5-3 Design of an Unmasked Nitrogen Nucleophile for Halofunctionalizations Well aware of the difficulties involved with high halenium affinity nucleophiles (Figure I-26a) and substrate limitations of pro-nucleophile approaches (Figure I-26b), we sought to design a method with a higher tolerance to less reactive alkenes. We were inspired by our intermolecular haloetherification and dihalogenation reactions that were widely successful on a broad range of aliphatic and aromatic substitutions. The extension of this chemistry to aliphatic substrates is partially attributed to the ability for these nucleophiles to participate in a concerted mechanism I-120 (Figure I-26c) or, as a solvent, quickly capture the haliranium ion before racemization or decomposition pathways can take place. This enables the inclusion of less reactive alkenes and obviates conformational and chemical instabilities involved with the haliranium ion I-118. While other intermolecular haloamination processes deserve high recognition, their stepwise pathways to circumvent the halenium affinity of alkenes requires harsh reaction conditions or limited substrate scope. We envisioned employing a nitrogen nucleophile that can assist in the transfer of halenium to the alkene or, if proceeding through a stepwise reaction, immediately capture a haliranium ion. Cognizant of the relatively similar halenium affinities of alkenes and nitrogen atoms, we sought to attenuate the halenium affinity of a nitrogen nucleophile to a lower value than that of the alkene, so that it will not compete for the halenium ion to provide kinetic trap I-117 (Figure I-26a). We found that acetonitrile, which had actually seen success in racemic alkene haloamination reactions, has a halenium affinity lower than that of alkenes. This reaction is what is known as a 36 Ritter-type process (Figure I-25d). We became highly interested in the development of a Amines HalA: 140-185 Outcompete alkenes for halenium ion H NH X R N X R NH2 R NH2 R X R N H Cl R R R X-D H-D X-D H H-D D I-117 I-113 D Kinetic Trap I-115 I-114 I-116 HalA: 140-170 Alkene Retained b Pro-Nucleophile Haloamination R2 R3 X X N X R3 N Stepwise Mechanism R1 R2 R1 R2 N R1 Incompatiable with unactived alkenes I-113 R3 I-119 High energy Intermediates susceptible I-118 to racemization and decomposition High energy intermediate c Alcohols HalA: 110-140 HalA lower than alkenes! React slowly with halenium source H ‡ R O X H H X-D, ROH H H H O N Ar N Ar N R C 3H 7 O (DHQD)2PHAL R O R O X Ar D I-70 I-120 I-71 Concerted NAAA Mechanism Compatible With Unactivated Alkenes d Nitriles HalA: 120 HalA lower than alkenes! Potentially competent nitrogen nucleophile Ritter-Type reactivity R ‡ N X H H H O N N Ar N Ar X-D, R-CN H H H (DHQD)2PHAL N C 3H 7 O R R O R O X Ar D I-70 I-121 I-122 Concerted NAAA Mechanism Compatible With Unactivated Alkenes Figure I-26: Summary of approaches to intermolecular halofunctionalizations (a) Display of the problematic nature of amines in halofunctionalization reactions. (b) Stepwise pro- nucleophile haloamination (c) Concerted haloetherification reactions. (d) Proposal of a concerted haloamidation via the attenuation of HalA 37 this method when we noticed that there are no known asymmetric Ritter reactions.43 I-5-3-1 Seminal Ritter Reaction In 1948 Ritter and coworkers disclosed what is known as the Ritter reaction (Figure I-27).44 This reaction proceeds through the protonation of alkene I-123 with sulfuric acid. The resulting carbocation I-124 is trapped with a nitrile to form nitrilium ion I-125 that is then hydrolyzed to form the corresponding amide product I-126. The relative carbocationic stability is responsible for the Markovnikov regioselectivity. Due to the low stability of carbocationic intermediates, the substrate scope is limited to substrates that offer either benzylic or trisubstituted carbocation. This reaction is tolerant to various nitriles, providing practical yields with various aliphatic and aromatic nitriles. a Sulfuric Acid Nitrile Hydrolysis H N O NH H H I-123 I-124 I-125 I-126 b R4 R1 R4-CN, Acetic Acid O NH R3 R2 Sulfuric Acid R1 H R2 R3 I-127 I-128 R1 = Ar or alkyl, R2 = alkyl or H 21 examples R3 = alkyl or H, R4 = Ar, alkyl, nitrogen Yields: 12-90% Figure I-27: Seminal Ritter reaction (a) Reaction mechanism (b) Reaction scope I-5-3-2 Halo-Ritter Reaction from Halohydrins The first resemblance of a halo-Ritter reaction was reported by Ritter in 1950 and relied on the ability to form the haliranium ion in-situ by subjecting the corresponding halohydrin to sulfuric acid (Figure I-28).45 Upon solvolysis of the alcohol with sulfuric acid, the β-halocarbenium ion I-130 or haliranium ion I-131 forms and then is opened by a 38 nitrile nucleophile to provide I-133 following hydrolysis. Reminiscent of the proton induced reactions, the substrate scope was limited to substituents that can effectively stabilize a carbocationic (or haliranium ion) intermediate. a R4 OH Sulfuric Acid Nitrile Hydrolysis X X or N O NH X X X I-129 I-130 I-131 I-132 I-133 R4 b OH R4-CN, Acetic Acid O NH R1 X R2 Sulfuric Acid R1 X R3 R2 R3 I-134 R1 = Ar or alkyl, R2 = alkyl or H I-135 R3 = alky or H, R4 = Ar, alkyl, nitrogen 8 examples X = Br or Cl Yields: 40-92% Figure I-28: Halo-Ritter reaction (a) Reaction mechanism (b) Reaction scope I-5-3-3 Halenium Induced Ritter Reaction with Alkenes In 1952 Cairns and co-workers disclosed the first halenium induced Ritter reaction (Figure I-29).46 An advancement from the Ritter report, which relied upon the in-situ formation of a haliranium ion of a pre-functionalized starting material, enabling the direct incorporation of both the halogen and nitrogen from a simple olefin starting material I-127. Their report utilized chlorine gas as the electrophile to form β-halocarbenium ion I-130 or haliranium ion I-131. The nitrilium ion I-132 reacts with a chloride ion to form a Vilsmeier type intermediate I-136 which they isolated. They reported relatively modest yields maximizing at 58%. It is uncertain if this due to an inefficient reaction or unstable product formation. The authors mention that the dichlorination product is a side product. 39 a R4 Cl2 Chloride Nitrile Attack Cl N Cl or N Cl Cl Cl I-123 I-130 I-131 I-132 I-136 R4 b R1 R4-CN, Cl2 Cl N R3 R2 R1 Cl R2 R3 I-127 I-137 R1 = Ar or alkyl, R2 = alkyl or H 12 examples R3 = alky or H, R4 = Ar OR alkyl Yields: 11-58% Figure I-29: Halenium induced Ritter reaction of alkenes (a) Reaction Mechanism (b) Reaction scope I-5-3-4 Lewis acid Catalyzed Bromo-Ritter Reaction and Total Synthesis of Oseltamivir Corey and coworkers’ Lewis acid-catalyzed halo-Ritter reactions offered a distinguished improvement over previous work and displayed the utility of vicinal haloamine products.47 Utilizing Cairns' strategy, they employed an alkene and a halogenating source as an electrophile in a halenium induced Ritter reaction (Figure I- 30a). Their conditions proved to be compatible for to provide bromoamides (I-139a), chlooamides(I-139b), and iodoamides (I-139c), reporting yields in excess of 90% for each reaction. This reaction showed to be broadly applicable, with high yields of aliphatic substrates. The broad applicability is likely due to the Lewis acid activation of the halenium source I-142, creating a potent halenium donor that is able to transfer to an unactivated alkene. The widespread success of stereoselective bromoamidation reactions on functionalized starting materials allowed for the incorporation of this chemistry in a more 40 complex synthesis. This success is further elaborated in the total synthesis of oseltamivir.48 41 a AcHN Br BF3 · OEt2 (40 mol%) BF3 · OEt2 (40 mol%) AcHN I CH3CONHBr I2 MeCN, 0°C MeCN, 0°C I-138 I-139a I-139c 91% yield 98% yield BF3 · OEt2 (40 mol%) NCS, MeCN, 0°C AcHN Cl I-139b 90% yield b Lewis Acid Catalyst (40 mol%) CH3CONHBr AcHN Br R1 R2 MeCN, 0°C R1 R2 I-140 I-141 10 examples 40-85% yield F3B O O BF3 · OEt2 R1 R2 Br MeCN Br Br N N H H R1 R2 I-142 I-143 activated bromenium source N Br Hydrolysis AcHN Br R1 R2 R1 R2 I-144 I-141 c H Ph Ph N O B NTf2 H 7 steps O-tol OCH2CF3 OEt CO2CH2CF3 10 mol %, 23 °C, BocHN 30 h, 97% yield O O I-145 I-146 I-147 I-148 >97% ee NHAc O 5 mol% SnBr4 Br AcHN 3 steps CH3CONHBr OEt OEt -40 °C, 4h, MeCN BocHN H 3N 75% O O H2PO4 1-141a Oseltamivir Figure I-30: (a) Reaction scope of Ritter-type haloamidations. (b) Proposed reaction mechanism. (c) Synthesis of Oseltamivir with haloamidation as a key step 42 I-5-3-5 Lewis Base Catalyzed Chloroamidation of Olefins In 2013, Yeung and co-workers displayed an alternative catalytic method utilizing a diphenyl selenide Lewis base for the halenium induced halo-ritter reaction of alkenes (Figure I-31).49 They propose this reaction to proceed through the Lewis base interaction with NCS that transfers the chlorenium ion to the diphenyl selenide to form I-153 which then transfers the halenium ion to the 1-149. After transfer of the chlorenium ion to the alkene, the same nitrile interception proposed in above reactions occurs to provide I-150. This reaction was most successful with chlorenium sources as analogous bromenium sources provided products with a lower yield. a R3 Cl NCS, Ph2Se (20 mol%) R1 R3 H2O, MeCN, 25 °C R1 R2 AcHN R2 I-149 R1, R2 = H, Alkyl I-150 13 examples R3 = Alkyl, Aryl 40-89% yield NHAc OBz Cl Cl Cl NHAc NHAc I-150a I-150b I-150c 65% yield 76% yield 65% yield b O O Ph Ph Ph Se + Cl N Se Cl N Se Cl Ph Ph Ph O O I-151 NCS I-152 I-153 Figure I-31: (a) Substrate scope for base catalyzed chloroamidation (b) Proposed mechanism for selenium catalysis 43 I-5-3-6 Stoichiometric Chiral Promoter Asymmetric Thio-Ritter Reaction In 1994 Pasquato and co-workers disclosed a single example of an asymmetric thiiranium Ritter-type reaction (Figure I-32).50 This reaction relied on a preformed stoichiometric chiral promoter to deliver the thiiranium ion enantioselectively to an olefin. The enantioenriched C2 symmetric intermediate is then subjected to an acetonitrile-water mixture that opens the thiiranium ion to yield the difunctionalized product I-156 in 90% yield and 86% ee. SMe Et Me Me S S Et MeCN/H2O S Et Et S -78 °C, 2 hours Et Et SbCl6 NHAc SbCl6 80% yield 86% ee I-154 I-155 I-156 Figure I-32: Asymmetric Ritter reaction with stoichiometric chiral promoter I-6 Catalytic Asymmetric Ritter-Type Reaction I-6-1 Optimization Investigations Our prior success in employing cinchona alkaloid dimers in the catalytic asymmetric intra- and intermolecular halofunctionalization of allyl amides prompted the following investigation for developing a process for haloamidations. The study was initiated with substrate I-70a, which had previously shown excellent results in delivering enantioenriched 1,2-chloroethers.27 Early exploration of the reaction with acetonitrile, catalytic (DHQD)2PHAL, and 1,3-dichloro-5,5-dimethylhydantoin (DCDMH) revealed the presence of Ritter-type products. Nonetheless, unlike the product of a classical Ritter- 44 reaction that yields the corresponding amide by trapping of the nitrilium ion intermediate with water,43, 47, 51 the observed product was the result of the hydantoin anion trap of the nitrilium ion intermediate as indicated by the mass spectrum of the crude product (see I- 122a’, Table I-3). Mild acid workup hydrolyzed the amidine product I-122a’ to provide the vicinal chloroamide I-122a. Interestingly, without the presence of (DHQD)2PHAL, the Table I-3: Enantioselective chloroamidation optimization MeCN (0.05 M) (DHQD)2PHAL C 3H 7 O C 3H 7 O additive, –30 ºC N Ar Cl+ source (2 equiv) O N N Ar H acid workup H H I-70a Cl Ar = pNO2-C6H4 I-122a O C 3H 7 O N N N Ar HCl (aq) H HN Cl O I-122a’ Entry Additive (equiv) Cl+ source (DHQD)2PHAL (mol%) Time (h) Yield (%)a ee (%)b 1 none DCDMH 10 72 68 96 2 HFIP (2) DCDMH 10 0.5 71 99 3 HFIP (10) DCDMH 10 0.5 78 99 4c HFIP (10) DCDMH 10 0.5 78 98 5c HFIP (10) NCS 10 96 70 98 6 HFIP (10) TCCA 10 0.5 42 98 7d HFIP (10) DiCh-T 10 0.5 12 99 8 HFIP (10) DCDMH 1 0.5 76 99 9 TFE (10) DCDMH 1 5 67 96 10 PhCO2H (10) DCDMH 1 2 29 97 11e HFIP (10) DCDMH 1 4 53 99 aNMR yield on a 0.05 mmol scale. bEnantiomeric excess determined by chiral HPLC. cReaction completed at room temperature. dMajor product was the incorporation of the p-tolyl sulfonamide from DiCh-T (see I-173a for structure). eReaction completed in dichloromethane (0.10 M) with 10 equiv of acetonitrile. nitrilium ion is trapped by water, as indicated by direct amide formation that yields I-122a. The control over product formation suggests that the catalyst is not innocent in the addition of the hydantoin ion to the nitrilium ion. This divergent pathway hints towards an associative complex between (DHQD)2PHAL and DCDMH.24 45 Table I-3 illustrates the optimization of the reaction under various conditions with the Z aliphatic substrate I-70a. The reaction proceeds to yield a 68% yield of I-122a (96% ee), however, requiring 72 h to reach completion (entry 1, Table I-3). In our previously reported studies on asymmetric halofunctionalization reactions, had observed an increased performance, both in terms of rate of reaction and yield of products, when a fluorinated alcohol additive was employed.25-28 Presumably, the acidic nature of the alcohol, and its attenuated nucleophilicity, are good combinations that lead to rate acceleration without nucleophilic participation in the reaction.52-53 There is also evidence that protonation of cinchona alkaloid dimeric catalysts could lead to altered conformations.54 An early screening of solvents showed that the addition of 1,1,1,3,3,3,- hexafluoroisopropanol (HFIP) improved the enantiomeric excess of I-122a, while tremendously increasing the rate of the reaction (entries 2-3, Table I-3). DCDMH proved to be the optimal chlorenium source as the less active N-chlorosuccinimide (NCS) (entry 5) was sluggish and gave slightly lower ee, while the more active chlorenium trichloroisocyanuric acid (TCCA) (entry 6) gave a lower yield. Use of dichloramine-T returned the product in high ee, although in low yields. Interestingly, the mass balance was identified as the p-tolyl sulfonylamidine product I-173a (addition of the p-tolyl sulfonamide to the Ritter intermediate, yielding a stable product, vide infra). Lowering the catalyst loading (entry 8) led to a negligible change in reaction proficiency, and thus 1 mol% (DHQD)2PHAL was chosen as standard for ensuing reactions. Less reactive substrates required increased catalyst loading to achieve optimal proficiency (See I-8-6). A quick screen of acidic additives (entries 9 and 10) proved HFIP’s superiority and was thus maintained as part of the standard reaction condition. Decreasing nucleophile equivalents (entry 11) provided slightly lower yield and longer reaction times but retained high enantioselectivity for I-122a. 46 I-6-2 Optimization of Amide Functional Handle Next, we examined the nature of the amide on the performance of the reaction (Table I-4). Comparing to the standard substrate I-70a, electronic perturbations to the aryl of the amide group did not alter the course or results of the reactions, delivering products I-122b to I-122f in good yields and high enantioselectivity (entries 1-6, Table-4). The acetamide substrate I-70g, though sluggish, provided the chloroamidation product I-122g with good enantiocontrol (94% ee). Nonetheless, the results were inferior in terms of yield, enantiopurity of product, and time to completion of the reaction in comparison to arylamide substrates 1a- 1f. Interestingly, the E aliphatic substrate 1h was nonreactive without HFIP, but reacted under the standard condition to yield product 2h in good yield and high enantioselectivity (entry 8). Table I-4: Amide functional handle optimization R2 O (DHQD)2PHAL (1 mol%) AcHN R2 O MeCN (0.05 M) R3 N R1 R3 N R1 H DCDMH (2 equiv) H Cl I-70a - I-70i HFIP (10 equiv), –30 °C acid workup I-122a - I-122i Entry prd time (h) R1 R2 R3 Yield (%)a ee (%)b 1 I-122a 0.5 pNO2-C6H4 C 3H 7 H 90 99 2 I-122b 2.0 Ph C 3H 7 H 81 98 3c I-122c 0.5 pOMe-C6H4 C 3H 7 H 89 99 4 I-122d 0.5 pF-C6H4 C 3H 7 H 85 99 5 I-122e 0.5 pt-Bu-C6H4 C 3H 7 H 79 99 6 I-122f 0.5 pNO2-C6H4 C 3H 7 H 91 99 7 I-122g 18 Me C 3H 7 H 58 94 8 I-122h 5 pNO2-C6H4 H C 3H 7 81 97 9c I-122i 5 pNO2-C6H4 H C 3H 7 59 95 aIsolated yield on a 0.1 mmol scale. bEnantiomeric excess determined by chiral HPLC. cAbsolute stereochemical determination was verified by x-ray crystal analysis. Diastereoselectivity was >20:1 for all examples 47 I-6-3 Alternative Functional Handles The requirement for a secondary amide substrate was briefly examined (Figure I-33) with the analogous imide I-70j, ester I-70k, and N-methylated tertiary amide I-70l (Scheme 1). Substrates I-70j and I-70k yielded their respective chloroamide products I-122j and I-122k, respectively, albeit with less enantiocontrol than the aryl amide substrates, while requiring a higher catalyst loading (10 mol%). The anticipated chloroamide product was not observed upon treatment of I-70l under slightly modified conditions (10 mol% catalyst instead of 1 mol%, and 0 ºC instead of -30 ºC), but instead chloroester I-122l’’ was isolated in good yield. As depicted in Scheme 1, I-122l’’ is presumably obtained from the hydrolysis of the postulated intermediate I-122l’. Taken together, these results not only indicate the need for a hydrogen bonding element supplied by the 2º amide, C 3H 7 O C 3H 7 O (DHQD)2PHAL (10 mol%) N MeCN (0.05 M) AcHN N Cl O DCDMH (2 equiv) O I-70j HFIP (10 equiv), 0 °C 72 hrs, then acid workup I-122j 67% yield 29% ee C 3H 7 O C 3H 7 O (DHQD)2PHAL (10 mol%) MeCN (0.05 M) AcHN O O DCDMH (2 equiv) Cl HFIP (10 equiv), 0 °C I-122k NO2 I-70k NO2 72 hrs, then acid workup 68% yield 60% ee C 3H 7 O (DHQD)2PHAL (10 mol%) C 3H 7 O MeCN (0.05 M) N AcHN N DCDMH (2 equiv) Cl NO2 HFIP (10 equiv), 0 °C NO2 I-70l I-122l C 3H 7 C 3H 7 H 2O Cl N Cl N H Ar O O Ar I-122l’’ O I-122l’ 80% , 19% ee Ar = pNO2-C6H4 Ar = pNO2-C6H4 Figure I-33: Exploration of alternative functional handles for enantioselective chloroamidation reactions but also the amide confirmation presumably plays a significant role in the success of these asymmetric catalytic reactions. The modest result from allyl-ester I-70k 48 serves as a potential new substrate to explore with previous chemistry as esters offer facile deprotection to the corresponding alcohol. I-6-4 Substrate Scope of the Ritter-Type Asymmetric Chloroamidation Reaction Figure I-34 illustrates the results of the substrate scope for E and Z aliphatic allyl-amides. In all cases, the minor diastereomer was not observed. Z-olefins reacted smoothly to yield the corresponding chloroamide products in high yields, enantioselectivities (99% ee for all examples), and regioselectivities. This was true of the less electronically biased examples I-70o and I-70p, which often result in lower performance due to inductive changes in polarity, leading to regioisomeric products.55-56 The extended reaction time required for I-70p led to the over- chlorinated product I-122p’ (resulting from the α-chlorination of the acetamide moiety) in ~2:1 ratio (I-122p’:I-122p). R1 O (DHQD)2PHAL (1 mol%) AcHN R1 O MeCN (0.05 M) R2 N Ar R2 N Ar H DCDMH (2 equiv) H Cl I-70a, I-70h, I-70m-r HFIP (10 equiv), –30 °C I-122a, I-122h, I-122m-r Ar = pNO2-C6H4 acid workup Ar = pNO2-C6H4 NHAc O NHAc O NHAc O NHAc O NHAc O BnO C 3H 7 N Ar C6H13 N Ar C 2H 5 N Ar TBDPSO N Ar N Ar H H H H H Cl Cl Cl Cl Cl I-122a I-122m I-122n I-122o I-122pb 90% (83%)a yield 79% yield 73% yield 62% yield 69% yieldc 99% ee 99% ee 99% ee 99% ee 99% eed NHAc O NHAc O O NHAc O NHAc O AcHN C 3H 7 N Ar C6H13 N Ar N Ar C 3H 7 N Ar C 3H 7 N Ar H H H H H Cl Cl Cl Cl Cl I-122h I-122q I-122r ent-I-122ae ent-I-122he 81% yield 83% yield 79% yield 87% yield 87% yield 96% ee 94% ee 99% ee 99% ee 97% ee Unless otherwise noted, reactions are isolated yields on 0.1 mmol scale. Enantiomeric Excess determined by chiral HPLC aIsolated yield on a 1.0 mmol scale. b15 mol% (DHQD)2PHAL was added over the course of the reaction (3 days), maintaining the temperature at 0 °C. cCombined yield of the acetamide product and the alpha-chlorinated acetamide product. dBoth acetamide and alpha-chlorinated acetamide were obtained with 99% ee.eReaction performed with quasi-enantiomeric (DHQ)2PHAL. Figure I-34: Aliphatic substrate scope of allyl amides for chloroamidation 49 The same success was observed for the corresponding E-isomeric substrates, providing the chloroamide products with slightly less enantiocontrol (≥94% ee) and excellent yields of products I-122h and I-122q. The tri-substituted allyl amide I-70r was also not problematic, providing the product 2r in high yield as well as high ee (entry 8). The quasi-enantiomeric (DHQ)2PHAL catalyst gave comparable results for the Z and E isomeric substrates 1a and 1h, yielding ent I- 122a and ent I-122h, in 99% ee and 97% ee, respectively. Aryl substituted allyl amide substrates proved more problematic, leading to diastereomeric products, presumably as a result of carbocationic stabilization afforded by the aromatic group (Figure I-35).27-28 As expected, the more electron rich systems, having the ability to stabilize the benzylic carbocation, resulted in lower selectivity for products I-122s, I-122t, and I-122u while the electron deficient pCF3-Ph substituent I-70v restored the high diastereomeric selectivity observed with the alkyl systems I-122v. Similar to I-70p, the extended reaction time required for full conversion of I-70v to the product led to a-chlorination of the acetamide functionality as the major product (~5:1 I-122v’:I-122v). Nonetheless, while the chloroamidation of electron rich aryls led to low drs, each diastereomer wasisolated in high enantiomeric excess, suggesting the olefinic face selectivity is not reduced. 50 Neither the E-substituted alkene I-70w, nor the trisubstituted alkene I-70x were immune to the observed diminished diastereoselectivity, although in both cases high enantioselectivity of their products were maintained. The reduced yield for product I-122w was attributed to competing intramolecular halocyclization, not observed with Z alkenes. The quasi-enantiomeric (DHQ)2PHAL provided ent-I- 122s and ent-I-122w with similar efficiencies in all categories. R1 O (DHQD)2PHAL (1 mol%) AcHN R1 O MeCN (0.05 M) R2 N Ar R2 N Ar H DCDMH (2 equiv) H Cl HFIP (10 equiv), –30 °C I-70s-I-70x acid workup I-122s-I-122x Ar = pNO2-C6H4 Ar = pNO2-C6H4 NHAc O NHAc O NHAc O N Ar N Ar N Ar H H H Cl Cl Cl Me Cl I-122u I-122s I-122t 78% yield 95% yield 92% yield 50:50 dr 65:35 dr 66:34 dr 99% ee for both diastereomers 99% ee for both diastereomers 98% ee minor 97% ee major NHAc O Me NHAc O NHAc O N Ar N Ar N Ar H H Cl Cl H Cl CF3 I-122x I-122w I-122va 53% yield 57% yield 78% yieldb 74:26 dr 61:39 dr 93% ee minor 99% ee major 99% ee minor 97% ee major >20:1 dr 89% eec Ar NHAc O NHAc O O N N Ar N Ar H H Cl Cl Cl MeO ent-I-122sd ent-I-122wd 84% yield 66% yield I-122y 63:37 dr 70:30 dr 55% yielde 99% ee for both diastereomers 93% ee minor 99% ee major 94% ee Isolated yields on a 0.1 mmol scale. Diastereomeric ratio determined by NMR. Enantiomeric excess determined by chiral HPLC. a 15 mol% (DHQD) PHAL was added over the course of the reaction, maintaining the temperature at 23 °C. b Combined 2 yield of acetamide product and αalpha-chlorinated acetamide product. c The alpha-chlorinated acetamide product had enantiomeric excess of 87%. d Reaction performed with quasi-enantiomeric (DHQ)2PHAL. e No trace of Ritter product Figure I-35: Aromatic substrate scope for allyl-amide chloroamidation 51 We were surprised to discover that when subjected to haloamidation conditions, the 4-methoxy substituted phenyl ring I-70y yielded the 6-endo halocyclization product and no Ritter-product (Figure I-36). The reaction proceeded with decent enantioselectivity and yield. The relative stereochemistry of the major diastereomer was confirmed via x-ray crystallography as formally a syn addition of a NHAc O O (DHQD)2PHAL (1 mol%) MeCN (0.05 M) N Ar N Ar H Cl H DCDMH (2 equiv) R HFIP (10 equiv), –30 °C I-70s I-122s- Major Diastereomer acid workup Ar = pNO2-C6H4 95% yield 65:35 dr 99% ee for both diastereomers b OMe Ar O N (DHQD)2PHAL (1 mol%) O MeCN (0.05 M) N Ar DCDMH (2 equiv) Cl H MeO R HFIP (10 equiv), –30 °C I-70y acid workup I-122y Major Diastereomer Ar = pNO2-C6H4 57% yield 94% ee c OMe OMe O (DHQD)2PHAL (10 mol%) O MeOH MeCN (3:7) (0.01 M) N Ar H N Ar DCDMH (2 equiv), –30 °C Cl MeO R H I-70y Ar = pNO2-C6H4 I-71y 80% yield 50 : 50 dr 96% ee d Ar (DHQD)2PHAL (2 mol%) O N O TFE (0.05M) N Ar DCDPH (1.1 equiv), –30 °C Cl H MeO S MeO I-70z I-122z Ar = pBr-C6H4 >20:1 dr 84% yield 20% ee Figure I-36: Divergent reactivity in electron rich aromatic systems (a) Halo-Ritter chemistry (b) Attempt of halo Ritter chemistry on highly electron rich system (c) Haloetherification chemistry with highly electron rich systems (d) Stereochemical result of asymmetric chlorocyclization 52 the chlorenium and oxygen nucleophiles. The absolute stereochemistry matches the chlorenium olefin face selectivity of the Ritter products. This is the opposite face selectivity observed for the (DHQD)2PHAL catalyzed halocyclization of E allyl amides providing I-122z (Figure I-36d).26 It should also be recognized that 4- methoxy phenyl substituted alkenes are known to proceed via a carbocation intermediate.23 Both Z and E allyl amides providing the same major diastereomer for the 6 endo cyclization suggest that they both proceed via a carbocation and Z substrate’s intermediate is susceptible to bond rotation to the less strained intermediate to minimize gauche interactions. These observations suggest that the reaction is proceeding through a mechanism similar to the Ritter-type reaction for chlorenium transfer, yet acetonitrile is not incorporated in the product. Further research in this area is ongoing. I-6-5 Preliminary Efforts to Improve Diastereoselectivity in the Asymmetric Chloroamidation Aryl Substituted Ally-Amides Reminiscent to other intermolecular halofunctionalizations originating in our laboratory, we suffered from deteriorated diastereoselectivity with electron-rich substrates, possessing diastereomeric ratios as poor as 1:1 (Figure I-37).23 The deterioration of diastereoselectivity was well correlated with the alkene's HalA, with I-70u possessing a HalA of 142.8 kcal/mol that is approaching the HalA of DCDMH of 150.0 kcal/mol. We hypothesized that the correlation of diastereoselectivity results from two separate competing mechanisms shown as pathway 1 and pathway 2 below (Figure I-38A). Pathway 1 is a concerted NAAA addition and preferences that anti-product through transition state. We rationalize that this is the pathway for electron-poor alkenes that do not possess a high enough HalA to abstract the chlorenium ion from the chlorenium donor without a nucleophile's assistance in a concerted mechanism. Conversely, for electron rich alkenes, the 53 HalA is high enough to abstract the chlorenium ion without the nucleophile's assistance and proceeds through a classical stepwise mechanism with a carbocation intermediate. The subsequent carbocation may be attacked from either face, leading to a reduction in diastereoselectivity. We noticed that our diastereoselectivities for the Ritter-product were lower than those observed for haloetherification reactions.25 Recognizing that a 3:7 co- solvent methanol acetonitrile mixture is employed in the reaction, we postulated R (DHQD)2PHAL (1 mol%) NHAc O MeCN (0.05 M) N Ar O DCDMH (2 equiv) H HFIP (10 equiv), –30 °C Cl R N Ar acid workup H I-70s-I70v I-122s-I-122v Ar = pNO2-C6H4 Ar = pNO2-C6H4 R = Me, H, Cl, CF3 R = Me, H, Cl, CF3 NHAc O NHAc O NHAc O NHAc O N Ar N Ar N Ar N Ar H H H H Cl Cl Cl Cl Me Cl CF3 I-122u I-122s I-122t I-122va HalA = 142.8 kcal/mol HalA = 138.6 kcal/mol HalA = 137.1 kcal/mol HalA = 131.5 kcal/mol 50:50 dr 65:35 dr 66:34 dr >20:1 dr Higher Halenium Affinity Lower Halenium Affinity Lower Diastereoselectivity Higher Diastereoselectivity Figure I-37: Correlation between alkene HalA and diastereoselectivity of halo-Ritter product 54 a ! ! Nuc Cl Nuc H Pathway 1 AcHN N Ar A B A Cl H H H H H H Ph N O N O Ph O ! Cl Ar A Ar I-157 A BH3 A ! I-122s BH3 Pre-polarization A Major diastereomer H of olefin I-158 N Ar Concerted TS Ph O I-70s Ar = p-NO2-Ph Cl Cl H H H H H AcHN N Ar AcHN N Ar N MeCN Ph O Pathway 2 O O Cl Ar2 A ! A I-159 I-122s I-122s Stepwise Halenium Transfer Minor diastereomer Major diastereomer Hypothesis The higher the propensitity of A-Cl to donate Cl+ (lower HalA) the more likely pathway 2 b Cl O O N Cl More Stable Counter Anion N N Less NAAA Needed? Cl N Cl Decreased Diastereoselectivity? O O DCDMH DCDMH Anion HalA: 150.0 kcal/mol O Cl O Less Stable Counter Anion N Cl N More NAAA Needed? Increased Diastereoselectivity? O O NCP NCP Anion HalA: 158.2 kcal/mol O CF3 Cl O CF3 H H O CF3 O CF3 Cl Cl N N More Stable Counter Anion N Cl N Less NAAA Needed? Decreased Diastereoselectivity? O O DCDMH HFIP Complex DCDMH HFIP Complex Anion HalA: 145.7 kcal/mol Figure I-38: (a) NAAA explanation for reduction of diastereoselectivity in halofunctionalizations (b) Potential methods to modulate Halenium affinity of the donor to favor pathway 1 55 that methanol is a stronger nucleophile, and this stronger nucleophile might, in fact, play in role in improved diastereoselectivity making pathway 1 (Figure I-38a) more likely. As discussed earlier, we hypothesized that the major diastereomer (anti- addition) results from a concerted pathway minor diastereomer might be the result of a carbocationic stepwise pathway that is more likely with a weaker nucleophile such as acetonitrile. We postulated that a less potent chlorenium source would be more likely to proceed through a NAAA pathway (Figure I-38b). The summary of our initial efforts is displayed in Table I-5. In an effort to induce a nucleophile assisted concerted mechanism, we employed the less reactive NCP (N- chlorophthalimide) (HalA 158.2 kcal/mol) as a chlorenium donor (entry 2-3). To our displeasure, the reaction with the less reactive NCP actually provided a lower diastereoselectivity than the more reactive DCDMH. It should be noted that the sluggish nature of this reaction required slightly elevated temperatures to reach completion. Recognizing that proton donors can stabilize the chlorenium donor's Table I-5: Attempt to improve diastereoselectivity by modulating HalA of the chlorenium donor (DHQD)2PHAL (1 mol%) O Ph O O Ph O Ph O MeCN (0.05 M), HFIP (x equiv.) N N Ar N N Ar N Ar Temperature, Cl+ (2 equiv.) H H H Cl H H then acid workup Cl I-70s I-122s I-122s Diastereomer Ar = p-NO2-Ph Entry Temperature °C HFIP (equiv.) Cl+ d.ra 1 -30 10 DCDMH 65:35 2 23 10 NCP 63:37 3 -30 100 NCP 61:39 4 -30 2 DCDMH 66:34 5 -30 100 DCDMH 63:37 a. Determined by crude NMR counteranion, tweaking the proton source's ability to stabilize the chlorenium donor's counteranion can modify the donor's halenium affinity. This effect is seen is with the halenium affinity of DCDMH decreased by 4.3 kcal/mol via hydrogen bonding with HFIP (Figure I-38b). In theory, this hydrogen bonding can temper the propensity to proceed via a stepwise pathway. Additionally, HFIP possesses a 56 lower pKa than methanol, rendering it superior at activating the chlorenium source than methanol, suggesting that the large excess of HFIP might be responsible for the reduction in diastereoselectivity in chloroamidations relative to chloroetherifications. Modifying equivalents of HFIP proved to be unfruitful (entries 4-5), proving nearly the same diastereoselectivity. While we were displeased with the inability to improve diastereoselectivity via alteration of chlorenium donor halenium affinity, this observation matches the studies performed by Dr. Sarkar on catalytic asymmetric chloroetherifications. He suggested that the halenium ion is transferred to the (DHQD)2PHAL catalyst when protic solvents are present and is then transferred to the alkene. This mechanistic picture provides the same terminal halenium source (quinuclidine) rendering the identity of the initial chlorenium donor a non-participant in transfer of the chlorenium ion to the alkene in transition state I-160 (Figure I-39). R ‡ O H N N H N O Me O O H R Cl O O N N N N N (DHQD)2PHAL R H I-160 R = (DHQD)2PHAL Figure I-39: Proposed transition state for enantio- selective chloroetherification of allyl-amides 57 NAAA Mechanism Classical Mechanism ! Nuc H H H I-122s H H H N N MeCN Mixture of Ph O Major diastereomer Ph O diastereomers Cl Ar Cl Ar2 A BH3 D ! A BH4 D A I-158 I-159 Concerted TS Stepwise Rxn Less Polar Transition State More Polar Transition State Favored in a non-polar solvent? Favored in a Polar Solvent? Figure I-40: Effort to improve diastereoselectivity by employing a nonpolar cosolvent We next directed our attention to the possibility that the reaction is proceeding through the same mechanism regardless of chlorenium source. We hypothesized that if the pathway to the minor diastereomer was due to a non-NAAA pathway, we could disfavor this highly polarized transition state by employing a non-polar co-solvent (Figure I-40). Non-polar cosolvents dichloromethane and hexane were added in an attempt to improve diastereoselectivity (Table I-6). We observed no notable changes in diastereoselectivity correlated with the polarity or ratio of the cosolvent employed. Table I-6: Solvent polarity and diastereoselectivity Ph O (DHQD)2PHAL (1 mol%) O Ph O O Ph O MeCN:Cosolvent (0.05 M), -30 °C N Ar N N Ar N N Ar H HFIP (10 equiv), DCDMH (2 equiv.) H H H H then acid workup Cl Cl I-70s Ar = p-NO2-Ph I-122s I-122s Diastereomer Entry Cosolvent MeCN:Cosolvent dra 1 none NA 65:35 2 DCM 9:1 65:35 3 DCM 7:3 63:37 4 Hexaneb 9:1 67:33 5 Hexaneb 7:3 66:34 a Diastereomeric ratio determined by crude NMR. b Acetonitrile hexane mixtures are not miscible at low temperature 58 I-6-6 Varied Nitrile Nucleophiles The next variable examined was the nitrile nucleophile, yielding different amide products (Figure I-41). Reactions of I-70a proceeded smoothly with propionitrile (I-122aa), benzonitrile (I-122ab), and the bulky pivalonitrile (I-122ac). Although the latter two reactions required slightly higher temperatures (0 °C and 23 °C, respectively) to accommodate the higher melting points of their respective nitrile solvents, we did not observe erosion in enantioselectivities. The versatility in choosing different nitrile nucleophiles enables the assembly of more complex amide structures. O (DHQD)2PHAL (1 mol%) R NH O C 3H 7 O R-CN (0.05 M) C 3H 7 N Ar N Ar DCDMH (2 equiv) H H Cl HFIP (10 equiv), temp I-70a I-122a, I-122aa, I-122ab, I-122ac Ar=pNO2-C6H4 Ar= pNO2-C6H4 O O O O Me NH O Et NH O Ph NH O tBu NH O C 3H 7 N Ar C 3H 7 N Ar C 3H 7 N Ar C 3H 7 N Ar H H H H Cl Cl Cl Cl I-122a I-122aa I-122ab I-122ac 90% yield 88% yield 87% yield 86% yield 99% ee 99% ee 99% ee 99% ee Figure I-41: Substrate Scope with varied nitrile nucleophiles I-6-7 Catalyst Loading Study for Less Reactive Allyl-Amide I-70v 59 a R R 23 °C, MeCN (0.05 M), O O (DHQD)2PHAL (X mol %) NO2 NO2 NH HFIP (10 equiv), DCDMH (2 equiv.) NH NH Cl O I-70v I-122v Entry R (DHQD)2PHAL (mol %) ee (%) 1 H 1 99 2 CF3 1 54 3 CF3 5 90 4 CF3 10 93 b O -30 °C, MeCN (0.05 M), NO2 O (DHQD)2PHAL (X mol %) NH NO2 C 3H 7 C 3H 7 NH HFIP (10 equiv), DCDMH (2 equiv.) NH Cl I-70a O I-122a catalyst/DCDMH Entry (DHQD)2PHAL % exposure time Yield (%) ee 1 1 None 76 99 2 1 48 h 48 1 3 0 NA 0 NA Figure I-42: (a) Influence of catalyst loading on I-70v relative to I-70s. (b) Catalyst incubation study Optimization studies for I-70a showed no decrease in enantioselectivity when the catalyst loading was decreased from 10 mol% to 1 mol%. Many aryl-substituted substrates (I-70s, I-70u, I-70w, I-70x) were compatible with these conditions and returned products with enantiomeric excess greater than 90%. When these reaction conditions were extended to the less reactive substrate II-70v, the enantiomeric excess decreased to 53% and the rate of the reaction decreased significantly relative to the other aryl substrates (48 h relative to 6 h). When catalyst loading was increased to 5 mol%, modest levels of enantioselectivity were restored. We hypothesized that the decrease in enantiocontrol may be the result of catalyst degradation under reaction conditions. To test this hypothesis, we subjected (DHQD)2PHAL to reaction conditions for 48 h at room temperature. After 48 h, the reaction mixture was cooled to –30 °C and I-70a was added 60 (note I-70a leads to the product I-122a in 99% ee under optimized conditions). These conditions provided nearly racemic product (entry 2). Nonetheless, the catalyst is still necessary to form the product as no reaction was observed without catalyst (entry 3). We speculate that the catalyst degradation is occurring via chlorination of the quinoline moiety as the C5 position has a halenium affinity of 165.9 kcal/mol (Figure I-43).22 N N N O O O O MeO N N N N HalA = 165.9 kcal/mol (DHQD)2PHAL Figure I-43: HalA of quinoline ring I-6-8 Structural Determination of Ritter Trapped Product Early studies of reaction conditions on I-70a revealed that the transformation was not proceeding through a traditional Ritter-type pathway, which would undergo a nitrilium trap by water and provide I-122a. Interestingly, mass spectrometry revealed the reaction was undergoing a nitrilium trap by 3-chloro-5,5-dimethylhydantoin, the residue left after chlorenium transfer. The 1H NMR spectrum was complicated, hinting at multiple products, none of which were identified as I-122a. This trapped product underwent hydrolysis to provide the amide products previously described. This observation leads to ambiguity of which potential nucleophilic center or centers on the chlorenium donor attacked the 61 nitrilium cation as it could be the nitrogen atom, or either of the carbonyl oxygen atoms (see structures I-162a, I-163, and I-164 in Figure I-43). LB N O C 3H 7 O (DHQD)2PHAL (1 mol%), Cl MeCN 0.05 M, –30°C C 3H 7 O I-162a or H3 O+ NH O I-163 or N Ar HFIP (10 equiv), I-164 H N Ar C 3H 7 N Ar DCDMH (2 equiv) H H Ar=p-NO2-Ph Cl I-70a I-161 I-122a potential Ritter intermediates observed in mass spec Cl Cl Cl N N N O N O O O O O N N attack via attack via nitrogen oxygen 1 attack via oxygen 2 HN NH HN O O O N O N N O O N O N O N O C 3H 7 N Ar C 3H 7 N Ar C 3H 7 N Ar H H H Cl Cl Cl I-162a I-163 I-164 Figure I-44: Potential Ritter intermediates The acid lability of the Ritter intermediate obtained from acetonitrile made analysis of the intermediate challenging. The Ritter intermediate formed when pivalonitrile was employed as a nucleophile was stable under column chromatography (SiO2/EtOAc– Hexanes gradient) and provided two products that could be isolated and analyzed by NMR. These two products were determined to be in equilibrium with each other as 30 min after initial isolation, the formerly pure products began to interconvert back to being the original mixture. This led to the hypothesis that a single product with two roto-isomeric structures such as I-162a and I-162b were isolated. Interestingly, I-165, obtained from the reaction of I-70a with pivalonitrile, with NCS as the chlorenium source exhibits only 62 one rotomeric product, owing to its symmetrical nature (Figure I-45). This provides further proof that the mixture obtained above is in fact due to rotomeric equilibria, and not the result of having a mix of products as a result of nitrogen and oxygen atoms as nucleophiles. Two products Single product observed by NMR observed by NMR HN NH O O O O O N O N N t-Bu N O t-Bu N O t-Bu N O C 3H 7 N Ar C 3H 7 N Ar C 3H 7 N Ar H H H Cl Cl Cl I-162a I-162b I-165 Figure I-45: Hypothesis of rotomeric equilibria of a single intermediate To conclusively determine the structure of the Ritter intermediates, experimentally observed 13C resonances were compared to those obtained for I-165 and also computationally calculated chemical shifts anticipated for all scenarios. Comparison of the observed 13C NMR to a computationally generated (EDF2-6-31g*) NMR of simplified substrates (I-162a analog, I-162b analog, I-163 analog, and I-164 analog) were used to predict the structure of the Ritter intermediate. The oxygen atom attack analogs (I-163 and I-164), lead to resonances that do not fit the observed chemical shifts for I-162 or I- 162a. The validity of the computed chemical shifts was corroborated with examples from the literature for accuracy. The computed chemical shift for C3 in the I-163-analog (190.2 ppm) is much further downfield as compared to other carbonyl carbons in the series investigated. Fortuitously, a similarly situated carbonyl carbon shown in structure I-166 has a chemical shift in the same range,57 thus corroborating the calculations. The 63 experimentally observed resonances for I-165, along with the calculated chemicals shifts for I-162 analogs fit well with the observed chemical shifts for I-162a and I-162b, thus suggesting that not only the nitrogen atom is the nucleophilic participant, but also, the observed mixture is, as described above, a consequence of a rotomeric equilibrium. I-6-8-1 Computational details for NMR calculations All calculations presented in this article were performed using the Spartan’18 (Spartan 18; Wavefunction Inc.: Irvine, CA) software package. NMR calculations for I- 162a/b-analog, I-163-analog, and I-164-analog commenced with finding optimum geometry using a MonteCarlo search function. The best conformer was then subject to DFT optimization at the B3LYP/6-31G* level. The geometry optimized structures were then recalculated with EDF2-6-31G* to obtain NMR values. Table I-7: Experimental (I-162a, I-162b, and I-165) and calculated 13C-NMR values for potential Ritter intermediates HN NH 2 3 3 3 O N O O N 2 O O N 2 O HN NH HN t-Bu 1 N O t-Bu 1 N O t-Bu 1 N O 3 O 3 2 O 3 O N 2 O N O N 2 O C 3H 7 N Ar C 3H 7 N Ar C 3H 7 N Ar H H H 1 N 1 N 1 N Cl Cl Cl I-162a I-162b I-165 I-162a/b analog I-163 analog I-164 analog 13C-resonances (ppm) C1 155.4 155.3 156.5 151.7 153.3 151.7 C2 175.3 153.5 175.1 173.5 176.3 179.0 C3 154.9 177.0 176.6 155.6 190.2 166.0 outlier chemical shifts O 176.8 NH O 190.7 N O I-166 known chemical shifts see reference 2 64 I-6-9 Catalyst Control of Product Formation Table I-8: Catalyst control over product formation NH O O O N t-Bu NH O t-Bu N O C 3H 7 N Ar C 3H 7 N Ar H H Cl (DHQD)2PHAL (X mol%) Cl C 3H 7 O Pivalonitrile (0.05 M) H2O (x equiv) I-162a/b I-122ac N Ar DCDMH (2 equiv), 23 °C H C 3H 7 O Ar I-70a Ar = p-NO2-Ph N Cl I-167 Entry Catalyst loading (mol %) H2O (equiv) I-162:I-122ac:I-167 1 10 0 83:6:11 2 0 0 0:37:63 As discussed in Section I-6-8, under standard reaction conditions the Lewis base of the chlorenium donor traps the nitrilium ion intermediate (Table I-8 entry 1) to yield I- 122a’ before acid workup. However, when I-70a was exposed to pivalonitrile and DCDMH without (DHQD)2PHAL (entry 2), I-162a/b was not observed. In fact, Ritter product 1- 122ac, the result of trapping the nitrilium ion by water, along with the cyclized I-168, the product of the non-Ritter intramolecular pathway was isolated. This divergent reaction path hints at an associative complex between the (DHQD)2PHAL and DCDMH. This associative complex was first observed in seminal halo-lactonization reactions. Subjection of (DHQD)2PHAL with benzoic acid and dichlorohydantoin (Figure I-46) resulted in diastereotopic splitting of the methylene hydrogens (HA and HB) of dichlorohydantoin. As an achiral molecule, the diastereotopic splitting indicates that the hydantoin is in the chiral pocket of the catalyst as either complex I-168 or I-169. 65 Preliminary studies by Dr. Sarkar suggest that the chlorenium ion transfers to the quinuclidine in polar solvents.24 Interestingly, this catalyst control was not observed with dichloramine-t initiated Ritter reactions which provided the counteranion trapped product with and without the catalyst (Section I-6-10). I-168 I-169 Et Et Cl O N R R O (DHQD)2PHAL (1 equiv) N N H N H Cl H or H H Cl PhCO2H (2 equiv) O CDCl3, -40 °C O (500 MHz NMR) N 4.35 ppm, s Cl N N Cl O N Cl DCH HA O HB HB HA N N 4.30 ppm, AB quartet O O (JAB = 16.5 Hz) O O N N N N (DHQD)2PHAL Figure I-46: Complexation of DCH with (DHQD)2PHAL I-6-10 Redirecting Nitrilium Ion Trap to Provide Precious Diamine Products The tertiary amidine intermediate I-122a’ that is directly formed in the DCDMH induced Ritter reaction underwent facile hydrolysis to provide the vicinal chloroamide product I-122. We sought to redirect the nitrilium intermediate in our Ritter reactions to directly provide a synthetically useful product. The employment of a 1° amine chlorenium source enables straightforward downstream synthesis of synthetically useful and biologically significant moieties such as enantiopure imidazolines I-171 and diamines I-172 (Figure I-47b) through the intramolecular SN2 displacement of the stereodefined chlorine.58-59 The success of catalytic 66 enantioselective diamination chemistry is limited (relative to dihydroxylation, epoxidation, aziridination etc.) as diamination products lead to product inhibition a Cl N O N Cl H Rxn O Rxn Cl N Ar Conditions O N Cl Workup H H H O N N Ar Cl N N N Ar C 3H 7 O H N N Ar C 3H 7 O O C 3H 7 O R O I-70 I-161 I-122’ I-122 3° amadine not particularly useful b acidic proton R R Cl N H NH H H N Ar acid H H N N N Ar base N O N N Ar Ts Cl R N O C 3H 7 O C 3H 7 C 3H 7 O Cl I-170 I-171 I-172 Dichloramine-T chiral imidazoline chiral “triamine” Commercially available HalA: 273.3 kcal/mol 2° amadine downstream chemistry! Figure I-47: (a) Hydrolysis of tertiary amidine products to provide amides. (b) Redirection of nitrilium intermediate to provide useful products via chelation with metal catalysts. Recent publications report groundbreaking catalytic asymmetric advancements providing direct synthesis of diamine products from alkenes60-68 however, the substrate scope is often limited to styrenyl alkenes. An orthogonal approach to these valuable molecules is high interest. We were led to this work when upon the employment of dichloramine-T as a chlorenium source for the chloroamide products (see Table I-3, entry 7). Although reaction conversion was high, analysis of the reaction products led to the identification of the corresponding chlorosulfonylamidine, which results from the capture of the nitrilium ion intermediate with the sulfonylamadine generated upon transfer of the halogen. 67 I-6-11 Optimization of Dichloramine-T Chloroamidations A quick screen led to a slight modification from conditions used in the Ritter- type reactions with DCDMH (Table I-9). Standard conditions used with DCDMH led to a 5.4:1 173h:174h ratio (entry 1). Not surprisingly, increasing equivalents of HFIP worsened the selectivity (entry 2). As illustrated in entry 3, however, omission of HFIP to eliminate the side product 1-174h reduces the enantioselectivity of I- 173h, similar to reactions that employed DCDMH as the chlorenium source. Interestingly, increased equivalents of dichloramine-T greatly enhanced the Table I-9: Optimization of Dichloramine-T Chloroamidations CF3 (DHQD)2PHAL Ts (X mol%) N CF3 O O MeCN (0.05 M) C 3H 7 N Ar dichloramine-T HN O N O H HFIP C H N Ar I-70h –30 °C, 30 min 3 7 C 3H 7 N Ar Ar = pNO2-C6H4 H H Cl Cl I-173h I-174h Entry (DHQD)2PHAL (mol %) DiCh-T (equiv.) HFIP (equiv.) Yield I-173h (%)a I-173h:I-174hb ee (%)c I-173h 1 1 1.00 10 43 5.4:1 94 2 1 2.00 20 39 2.6:1 94 3 1 2.00 0 45 NA 62 4 1 3.00 10 49 16:1 92 5 1 1.25 10 50 2.6:1 95 6 5 2.00 10 59 >20:1 96 aNMR yield on a 0.05 mmol scale bRatios determined by crude NMR. cEnantiomeric Excess determined by chiral HPLC product ratio (16:1, 173h:174h), while maintaining high ee (entry 4). Further verification of the latter was the observed diminution of the same ratio (2.6:1) when 1.25 equivalent of dichloramine-T was employed (entry 5). Alternatively, increase in the amount of catalyst (from 1 mol% to 5 mol%), without increasing dichloramine- T (2 equivalents), led to the same high product ratio (entry 6). It is likely that 4h originates from the trap of the nitrilium intermediate, as incubation of I-173h in neat HFIP over a prolonged period did not return any I-174h. 68 I-6-12 Dichloramine-T Mediated Chloroamidination Scope Figure I-48 lists a short survey of substrates that highlights a similar level of efficiency for the dichloramine-T mediated reaction that yield the Ts N H R1 O (DHQD)2PHAL (5 mol%) N R1 O MeCN (0.05 M) R2 N Ar R2 N Ar H Dichloramine-T (2.0 equiv) H Cl HFIP (10 equiv), –30 °C I-70 I-173 Ar= pNO2-C6H4 Ar= pNO2-C6H4 Ts Ts Ts Ts N N N N H H H H N O N O N O N O C 3H 7 N Ar C 3H 7 N Ar BnOH2C N Ar Ph N Ar H H H H Cl Cl Cl Cl I-173a I-173h I-173p I-173s 71% yield 65% yield 71% yield 71% yielda >20:1 dr >20:1 dr >20:1 dr >61:39 dr 99% ee 95% ee 96% ee 99% ee major 97% ee minor Isolated yields yield on a 0.10 mmol scale. dr are obtained from NMR of crude reaction mixture. Enantiomeric excess determined by chiral HPLC. (a) NMR yield on 0.05 mmol scale Figure I-48: Dichloramine-T mediated chloroamidination scope chlorosulfonylamidines as compared to the chloroamides obtained with DCDMH. Z and E aliphatic allyl amides I-70a and I-70h are converted to their corresponding products 3a and 3h in good yields and high enantiomeric excess (99% and 95%, respectively). The benzyl protected allylic alcohol I-70p also returned product I- 173p with no observable evidence for regio-isomeric products, in high enantiomeric excess (entry 3). As previously detailed, the aryl substituted olefin I-70s was more problematic, leading to diastereomeric products, although with high ee for each isomer. I-6-13 Elaborations of Chlorosulfonylamidines The utility of the sulfonylamide product I-173a was demonstrated via its cyclization to form the imidazoline I-175a (Figure I-49). This product was then easily hydrolyzed to the chiral tri-amine I-176a upon treatment with dilute HCl, 69 yielding the orthogonally protected triamine product with two contiguous chiral centers. This could be of synthetic value, as there are few known methods to deliver chiral triamines,18 in addition, this allows for orthogonal protection. Also illustrated in Figure, is the conversion of I-70a to I-177a, using dimethylcyanimide as the nucleophile, en route to the cyclic guanidine I-178a. The enantioselectivity obtained in the asymmetric transformation is maintained in subsequent reaction for both sequences described below. Ts N R MeCN:1 M HCl, 4:1 Cs2CO3 23 ºC, 30 min, (2 equiv) C 3H 7 NH HN (0.57 mmol), 99% R MeCN, 23 ºC 24 h, C 3H 7 N N NTs O H (0.1 mmol), 57% Cl NH I-173a (99% ee) I-175a R R = pNO2-C6H4-CO- C 3H 7 N H NHTs I-176a (99% ee) (DHQD)2PHAL Ts R N C 3H 7 (1 mol%), –40°C C 3H 7 NH HFIP (10 equiv) 80 ºC R Me2N NH N H Me2N N R DMF N NTs C 3H 7 N (0.05 mmol) DiCh.T (1.25 equiv), H 62% Cl NMe2 I-70a (0.1 mmol) I-177a R = pNO2-C6H4-CO- 4Å MS, 82% (98% ee) I-178a Figure I-49: Chloroamidine elaborations to precious enantiopure chiral diamine products I-7 Conclusion The stereodefined carbon nitrogen bond is important in synthesis and biology. Unfortunately, it is largely inaccessible via alkene halofunctionalization. The historic limitations of halenium induced amination reactions are derived from the high halenium affinity of the nitrogen atom which out competes the alkene for the halenium ion. We employed the HalA scale to identify acetonitrile as a potential nucleophile in this chemistry due to its attenuated halenium affinity which falls below the range of alkenes. We 70 envisioned this reaction proceeding through a Ritter-type pathway, enabling a nucleophile assisted pathway that can tolerate electron poor unactivated alkenes. While other haloamination reactions exist, many of them proceed through a stepwise “pro- nucleophile” pathway that necessitates alkenes with high halenium affinity. Furthermore, we were able to display the versatility of the nitrilium ion by intercepting it with alternative chlorenium donors which led to the synthesis of precious diamine products with high enantioselectivity. We hope that this example will enable scientists to design difunctionalization reactions with a comprehension of the affinity an electrophile might have for a nucleophile in a three-component reaction. Additionally, this is the first example of a Ritter-type reaction in the literature, thus expanding the toolbox to forge stereodefined carbon nitrogen bonds. I-8 Experimental Section I-8-1 Materials and General Instrumentations Commercially available reagents were purchased from Sigma-Aldrich or Alfa- Aesar and used as received. CH2Cl2 and acetonitrile were freshly distilled over CaH2 prior to use. THF was distilled over sodium-benzophenone ketyl. All other solvents were used as purchased. DCDMH was purified by recrystallization in chloroform. Dichloramine-T was purchased from TCI and used without further purification. Enantiomeric excess for all products was determined by HPLC analysis using DAICEL Chiralcel® OJ-H and OD- H or Chiralpak® IA, AD-H, and AS-H columns. Optical rotations of all products were measured in chloroform. All substrates prior to section I-6 were synthesized in the cited work. Allyl amides I-70a, I-70f, I-70h, I-70i, I-70m-p, I-70r, I-70s, I-70u, I-70v were 71 synthesized as reported previously and analytical data matched reported values.27 Substrates I-70b-e, I-70g, I-70k, I-70l, I-70q, I-70t, I-70u, I-70x were synthesized by the same procedure described for substrates above, and provided overall yields ranging from 40-60%. Analytical data for the new substrates can be found below in Section I-9. I-8-2 General procedure for the catalytic asymmetric chloroamidation of unsaturated amides with DCDMH to yield vicinal chloroamides (DHQD)2PHAL (1 mol%) O R2 O AcHN R2 MeCN (0.05 M) R3 N R1 R3 N R1 DCDMH (2 equiv) H H HFIP (10 equiv), –30 °C Cl I-70a-i, I-70m-x acid workup I-122a-i, I-122m-x Figure I-50: General procedure for the catalytic asymmetric chloroamidation of unsaturated amides with DCDMH to yield vicinal chloroamides The substrate (I-70a-i, I-70m-x) (0.1 mmol, 1.0 equiv) and (DHQD)2PHAL (0.8 mg, 1 mol%) were suspended in acetonitrile (2 mL) in a test tube with a magnetic stir bar and capped with a rubber septa. HFIP (105 µL, 1.0 mmol, 10 equiv) was added via syringe. The resulting suspension was cooled to –30 °C in an immersion cooler. After stirring for 10 min, DCDMH (39.4 mg, 0.2 mmol, 2 equiv) was added. The reaction was monitored by TLC and upon competition was quenched by the addition of saturated Na2S2O3 (2 mL). The reaction was concentrated to remove acetonitrile and the resultant aqueous layer was extracted with DCM (3 x 5 mL). The combined organics were concentrated. To the concentrated vial with a stir bar, acetonitrile (1 mL) and a solution of HCl (1 M, 0.2 mL) were added and stirred for 5 min. Water (3 mL) was added and the solution was concentrated in vacuo and extracted with DCM (3 x 5 mL). The combined organic layers 72 were dried with anhydrous Na2SO4 and concentrated. Column chromatography (SiO2/EtOAc–Hexanes gradient) provided the desired product (2a-i, 2m-x). I-8-3 Procedure for the catalytic asymmetric chloroamidation of 1a with DCDMH and 10 equivalents of acetonitrile to yield vicinal chloroamides O C 3H 7 O (DHQD)2PHAL (1 mol%) DCM (0.10 M), MeCN (10 equiv.) NH O N H DCDMH (2 equiv) C 3H 7 N NO2 HFIP (10 equiv), –30 °C H Cl acid workup NO2 I-70a I-122a Figure I-51: Procedure for the catalytic asymmetric chloroamidation of 1a with DCDMH and 10 equivalents of acetonitrile to yield vicinal chloroamides The substrate I-70a (12.4. mg, 0.05 mmol, 1.0 equiv) and (DHQD)2PHAL (0.4 mg, 1 mol%) were suspended in dichloromethane (0.5 mL) in a test tube with a magnetic stir bar and capped with a rubber septa. HFIP (50 µL, 0.50 mmol, 10 equiv) and acetonitrile (26 µL, 0.50 mmol, 10 equiv) were added via syringe. The resulting suspension was cooled to – 30 °C in an immersion cooler. After stirring for 10 min, DCDMH (19.7 mg, 0.10, mmol, 2 equiv) was added. The reaction was monitored by TLC and upon competition was quenched by the addition of saturated Na2S2O3 (2 mL). The resultant aqueous layer was extracted with DCM (3 x 5 mL). The combined organics were concentrated. To the concentrated vial with a stir bar, acetonitrile (1 mL) and a solution of HCl (1 M, 0.2 mL) were added and stirred for 15 min. Water (3 mL) was added and the solution was concentrated in vacuo and extracted with DCM (3 x 5 mL). The combined organic layers were dried with anhydrous Na2SO4 and concentrated. Column chromatography 73 (SiO2/EtOAc–Hexanes gradient) provided the desired product I-122a (53% yield with triphenylmethane NMR standard, 99% ee). I-8-4 Procedure for the chloroamidation of allyl-phthalimide 1j and allyl-ester 1k substrates (DHQD)2PHAL (10 mol%) NHAc C 3H 7 MeCN (0.05 M) C 3H 7 R R DCDMH (2 equiv) HFIP (10 equiv), 0 °C Cl I-70j; R = Phthalimide acid workup I-122j; R = Phthalimide I-70k; R = p-NO2 Benzoate I-122k; R = p-NO2 Benzoate Figure I-52: Procedure for the chloroamidation of allyl- phthalimide 1j and allyl-ester 1k substrates The substrate (I-70j, I-70k) (0.1 mmol, 1.0 equiv) and (DHQD)2PHAL (7.8 mg, 10 mol%) were suspended in acetonitrile (2 mL) HFIP (105 µL, 1.0 mmol, 10 equiv) was added via a syringe. The resulting suspension was cooled to 0 °C in an immersion cooler. After stirring for 10 min, DCDMH (39.4 mg, 0.2 mmol, 2 equiv) was added. Upon completion, the reaction was quenched by the addition of saturated Na2S2O3 (2 mL). The reaction was concentrated to remove the acetonitrile and the resultant aqueous layer was extracted with DCM (3 x 5 mL). The combined organics were concentrated. To the concentrated product in the vial with a stir bar, acetonitrile (1 mL) and a solution of HCl (1 M, 0.2 mL) were added and stirred for 15 min. Water (3 mL) was added and the solution was concentrated and extracted with DCM (3 x 4 mL). The combined organic layers were dried with anhydrous Na2SO4 and concentrated. Column chromatography (SiO2/EtOAc– Hexanes gradient) provided the desired product (I-122j, I-122k). 74 I-8-5 Procedure for the 1 mmol scale catalytic asymmetric chloroamidation of unsaturated amides with DCDMH to yield vicinal chloroamides O C 3H 7 O (DHQD)2PHAL (1 mol%) MeCN (0.05 M) NH O N H DCDMH (2 equiv) C 3H 7 N NO2 HFIP (10 equiv), –30 °C H Cl acid workup NO2 I-70a I-122a Figure I-53: Procedure for the 1 mmol scale catalytic asymmetric chloroamidation of unsaturated amides with DCDMH to yield vicinal chloroamides The substrate I-70a (248.0 mg, 1.0 mmol, 1.0 equiv) and (DHQD)2PHAL (7.8 mg, 1 mol%) were suspended in acetonitrile (20 mL) in a test tube with a magnetic stir bar and capped with a rubber septa. HFIP (1.05 mL, 10.0 mmol, 10 equiv) was added via syringe. The resulting suspension was cooled to –30 °C in an immersion cooler. After stirring for 10 min, DCDMH (394.0 mg, 2 mmol, 2 equiv) was added. The reaction was monitored by TLC and upon competition was quenched by the addition of saturated Na2S2O3 (10 mL). The reaction was concentrated to remove acetonitrile and the resultant aqueous layer was extracted with DCM (3 x 10 mL). The combined organics were concentrated. To the concentrated vial with a stir bar, acetonitrile (5 mL) and a solution of HCl (1 M, 1 mL) were added and stirred for 15 min. Water (3 mL) was added and the solution was concentrated in vacuo and extracted with DCM (3 x 5 mL). The combined organic layers were dried with anhydrous Na2SO4 and concentrated. Column chromatography (SiO2/EtOAc– Hexanes gradient) provided the desired product I-122a (282.0 mg, 83% yield, 99% ee). 75 I-8-6 General procedure for the chloroamidation of allyl-amides with different nitrile solvents O C 3H 7 O (DHQD)2PHAL (1 mol%) R-CN (0.05 M) R NH O N H DCDMH (2 equiv) C 3H 7 N NO2 HFIP (10 equiv), Temp H Cl acid workup NO2 I-70a I-122aa, I-122ab, I-122ac Figure I-54: General procedure for the chloroamidation of allyl- amides with different nitrile solvents The substrate I-70a (24.8 mg, 0.1 mmol, 1.0 equiv) and (DHQD)2PHAL (0.8 mg, 1 mol%) were suspended in a nitrile solvent (2 mL) in a test tube with a magnetic stir bar and capped with a rubber septa. HFIP (105 µL, 1.0 mmol, 10 equiv) was added via syringe. The reaction mixtures were then cooled to a temperature to accommodate the freezing point of the solvent (I-122aa: –30 °C, I-122ab: 0 °C, I-122ac: 23 °C). After stirring for 10 min, DCDMH (39.4 mg, 0.2 mmol, 2 equiv) was added. The reaction was monitored by TLC and upon competition was quenched by the addition of saturated Na2S2O3 (2 mL). The resultant aqueous layer was extracted with DCM (3 x 5 mL). The combined organics were concentrated. To the concentrated vial with a stir bar, acetonitrile (1 mL) and a solution of HCl (1 M, 0.2 mL) were added and stirred for 15 min. Water (3 mL) was added and the solution was concentrated in vacuo and extracted with DCM (3 x 5 mL). The combined organic layers were dried with anhydrous Na2SO4 and concentrated. Column chromatography (SiO2/EtOAc–Hexanes gradient) provided the desired product (I-122aa, I-122ab, I-122ac). 76 I-8-7 General procedure for the catalytic asymmetric chloroamidination of unsaturated amides with dichloramine-T as the chlorinating reagent to yield vicinal chlorosulfonylamidines (DHQD)2PHAL (5 mol%) Ts N H R1 O MeCN (0.05 M) N R1 O R2 N Ar Dichloramine-T (2.0 equiv) R2 N Ar H HFIP (10 equiv), –30 °C H Cl I-70a, I-70h, I-70p, I-70s Ar = p-NO2Ph I-173a, I-173h, I-173p, I-173s Ar = p-NO2Ph Figure I-55: General procedure for the catalytic asymmetric chloroamidination of unsaturated amides with dichloramine-T as the chlorinating reagent to yield vicinal chlorosulfonylamidines The substrate (I-70a, I-70h, I-70p, I-70s) (0.1 mmol, 1.0 equiv) and (DHQD)2PHAL (3.9 mg, 5 mol%) were suspended in acetonitrile (2 mL) in a test tube with a magnetic stir bar and capped with a rubber septa. HFIP (105 µL, 1.0 mmol, 10 equiv) was added via syringe. The resulting suspension was cooled to –30 °C in an immersion cooler. After stirring for 10 min dichloramine-T (48.0 mg, 0.2 mmol, 2 equiv) was added. The reaction was monitored by TLC and upon completion was quenched by the addition of saturated Na2S2O3 (2 mL). The reaction was concentrated to remove acetonitrile and the resultant aqueous layer was extracted with DCM (3 x 5 mL). The combined organic layers were dried with anhydrous Na2SO4 and concentrated. Column chromatography (SiO2/EtOAc– Hexanes gradient) provided the desired product (I-173a, I-173h, I-173p, I-173s). 77 I-8-8 Procedure for the synthesis of enantiomeric mixtures of chloroamide compounds for HPLC separations (DHQD)2PHAL (2 mol%) (DHQ)2PHAL (2 mol%) O H R2 O R4—CN, (0.05 M) N R2 O R4 R3 X R1 DCDMH (2.0 equiv) R3 X R1 HFIP (5.0 equiv), 0 °C Cl X = O, NH, NMe, imide acid workup I-70 (+/-) I-122 Figure I-56: Procedure for the synthesis of enantiomeric mixtures of chloroamide compounds for HPLC separations The enantiomeric mixtures used for HPLC analysis in determining enantiopurity were synthesized as follows by using the quasi-enantiomeric cinchona alkaloid dimers. The substrate (1a-1x, 0.05 mmol, 1.0 equiv), (DHQD)2PHAL (0.8 mg, 2 mol%), and (DHQ)2PHAL (0.8 mg, 2 mol%) were placed in a test tube with a magnetic stir bar and dissolved in the nitrile solvent of choice (1 mL), capped with a rubber septa. HFIP (25 µL, 0.25 mmol, 5 equiv) was added via a syringe. The resulting suspension was cooled to 0 ºC in an immersion cooler. After stirring for 10 min, DCDMH (19.7 mg, 0.1 mmol, 2 equiv) was added. The reaction was monitored by TLC and upon competition was quenched by the addition of saturated Na2S2O3 (2 mL). The reaction was concentrated to remove acetonitrile and the resultant aqueous layer was extracted with DCM (3 x 5 mL). The combined organics were concentrated under reduced pressure. To the concentrated vial with a stir bar, acetonitrile (1 mL) and a solution of HCl (1 M, 0.2 mL) were added and stirred for 5 min. Water (3 mL) was added and the solution was concentrated in vacuo and extracted with DCM (3 x 5 mL). The combined organic layers were dried with anhydrous Na2SO4 and concentrated. Column chromatography (SiO2/EtOAc–Hexanes 78 gradient) provided the desired products as mixture of enantiomers (I-122a-x, I-122aa, I- 122ab, I-122ac). I-8-9 Procedure for the synthesis of enantiomeric mixtures of chloroamidine compounds for HPLC separations (DHQD)2PHAL (2 mol%) (DHQ)2PHAL (2 mol%) TsN H R1 O R3—CN, (0.05 M) N R1 O R2 N Ar R3 Dichloramine-T (2.0 equiv) R2 N Ar H HFIP (5.0 equiv), 0 °C H Cl (+/-) I-70a, I-70h, I-70p, I-70s I-173a, I-173h, I-173p, I-173s Ar = p-NO2Ph Ar = p-NO2Ph Figure I-57: Procedure for the synthesis of enantiomeric mixtures of chloroamidine compounds for HPLC separations The enantiomeric mixtures used for HPLC analysis in determining enantiopurity were synthesized as follows by using the quasi-enantiomeric cinchona alkaloid dimers. The substrate (I-70a, I-70h, I-70p, I70s, (0.05 mmol, 1.0 equiv), (DHQD)2PHAL (0.8 mg, 2 mol%), and (DHQ)2PHAL (0.8 mg, 2 mol%) were placed in a test tube with a magnetic stir bar and dissolved in the nitrile solvent of choice (1 mL), capped with a rubber septa. HFIP (25 µL, 0.25 mmol, 5 equiv) was added via syringe. The resulting suspension was cooled to 0 ºC in an immersion cooler. After stirring for 10 min, Dichloramine-T (24.0 mg, 0.1 mmol, 2 equiv) was added. The reaction was monitored by TLC and upon competition was quenched by the addition of saturated Na2S2O3 (2 mL). The reaction was concentrated to remove acetonitrile and the resultant aqueous layer was extracted with DCM (3 x 5 mL). The combined organic layers were dried with anhydrous Na2SO4 and concentrated. Column chromatography (SiO2/EtOAc–Hexanes gradient) provided the desired products as mixture of enantiomers (I-173a, I-173h, I-173p, I-173s, I-177a). 79 I-8-10 Procedure for the Determination of the Absolute and Relative Stereochemistry of Vicinal Chlorosulfonylamidine Products The absolute and relative stereochemistry of chloroamide products 2c and 2i were determined by single crystal X-ray diffraction. The stereochemistry of other chloroamide products were inferred. We were unable to obtain crystals for vicinal chlorosulfonylamidine products and resorted to chemical transformations. We observed that the Ritter intermediate I-122a’ obtained from the hydantoin mediated reaction could be converted to the sulfonylamidine product I-173a with the addition of para-toluene sulfonamide (10 equiv) in a stereoretentive reaction. The HPLC trace for I-173a obtained by the procedure described in Section I-8-7 and the HPLC trace of presumed I-173a, obtained via the derivatization of I-122a’ matched, and thus confirmed the absolute stereochemistry of I-173a as illustrated. The relative and absolute stereochemistries of I- 173h, I-173p, I-173s, I-174h, I-175a, I-176a, I-177a, and I-178a were inferred as a result of this observation. 80 O 9:1 ACN: 1 M HCl NH O HN C 3H 7 N Ar O N O H Cl C 3H 7 O (DHQD)2PHAL (1 mol%), I-122a MeCN 0.05 M, –30°C N O Stereoretentive Absolute stereochemistry N Ar HFIP (10 equiv), reactions inferred by analogy to I-122c H DCDMH (2 equiv) C 3H 7 N Ar Ar=p-NO2-Ph H I-70a Cl Ts N I-122a’ NH O 10 equiv. TsNH2 C 3H 7 N Ar H Cl Ts I-173a N O (DHQD)2PHAL (5 mol%), NMR and HPLC data C 3H 7 O match I-122a MeCN 0.05 M, –30°C NH O NH O N Ar HFIP (10 equiv), H TsNCl2 (2.0 equiv) C 3H 7 N Ar C 3H 7 N pOMe-Ph H H Ar=p-NO2-Ph Cl Cl I-70a 2c - x-ray structure I-173a Figure I-58: Chemical transformations to determine the absolute stereochemistry of chlorosulfonylamidines Figure I-59: HPLC trace of I-173a and ent- I-173a Figure I-60: HPLC trace of I-173a following procedure for the chlorosulfonylamidation of allyl amides 81 Figure I-61: HPLC trace of I-173a obtained from derivatization of I-122a’ I-9 Analytical Data I-9-1 Analytical Data for Chloroamide Products O NH O C 3H 7 N H Cl NO2 I-122a, N-((2R,3R)-3-acetamido-2-chlorohexyl)-4-nitrobenzamide Compound I-122a (30.7 mg, 90% yield, 99% ee) was synthesized following the procedure detailed in Section I-8-2 using I-70a (24.8 mg, 0.10 mmol) as starting material. Rf: 0.14 (60% EtOAC/Hex) 1H NMR (500 MHz, CDCl3) δ 8.35 – 8.27 (m, 3H), 8.08 (d, J = 8.6 Hz, 2H), 5.72 (d, J = 9.3 Hz, 1H), 4.38 – 4.25 (m, 2H), 4.13 (ddd, J = 11.0, 5.2, 1.7 Hz, 1H), 2.93 (ddd, J = 13.7, 11.0, 4.3 Hz, 1H), 2.15 (s, 3H), 1.67 (dtd, J = 13.8, 8.6, 6.7 Hz, 1H), 1.61 – 1.52 (m, 1H), 1.41 – 1.32 (m, 2H), 0.90 (t, J = 7.3 Hz, 3H). 13C NMR (126 MHz, CDCl3) δ 172.2, 164.8, 149.7, 139.2, 128.4, 123.9, 61.2, 49.4, 42.6, 34.7, 23.3, 19.3, 13.7. Resolution of enantiomers: DAICEL Chiralpak®, AD-H 10% IPA/Hexane 1ml/min, 254 nm, RT 1 (major)=10.6 min, RT 2 (minor) =12.6 min. 82 HRMS analysis (ESI): calculated for [M+H]+: C15H21ClN3O4: 342.1221; Found: 342.1223 Optical activity: [α]D20 = -35.2 (c = 0.4, CHCl3, 99% ee) O NH O C 3H 7 N H Cl I-122b, N-((2R,3R)-3-acetamido-2-chlorohexyl)benzamide Compound I-122b (24.1 mg, 81% yield, 98% ee) was synthesized following the procedure detailed in Section I-8-2 using I-70b (20.3 mg, 0.10 mmol) as starting material. Rf: 0.16 (50% EtOAC/Hex) 1H NMR (500 MHz, CDCl3) δ 8.00 (dd, J = 8.7, 4.5 Hz, 1H),7.92 (d, J = 7.0 Hz, 2H), 7.51 (t, J = 7.3 Hz, 1H), 7.46 (t, J = 7.4 Hz, 2H), 5.69 (d, J = 9.4 Hz, 1H), 4.43 – 4.22 (m, 2H), 4.15 (ddd, J = 10.8, 5.1, 1.7 Hz, 1H), 2.93 (ddd, J = 13.6, 10.8, 4.5 Hz, 1H), 2.14 (s, 3H), 1.69 – 1.60 (m, 1H), 1.54 (dtd, J = 13.6, 7.9, 5.5 Hz, 1H), 1.36 (dq, J = 15.0, 7.6 Hz, 2H), 0.90 (t, J = 7.4 Hz, 3H). 13C NMR (126 MHz, CDCl3) δ 171.8, 167.0, 133.7, 131.7, 128.6, 127.1, 61.7, 49.2, 42.5, 34.8, 23.2, 19.2, 13.7. Resolution of enantiomers: DAICEL Chiralpak®, AD-H 10% IPA/Hexane 1ml/min, 254 nm, RT 1 (major)=8.8 min, RT 2 (minor) =10.2 min. HRMS analysis (ESI): calculated for [M+H]+: C15H22ClN2O2: 297.1370; Found: 297.1369 Optical Activity: [α]D20 = -31.2 (c = 0.40, CHCl3, 98% ee) O NH O C 3H 7 N H Cl OMe 83 I-122c, N-((2R,3R)-3-acetamido-2-chlorohexyl)-4-methoxybenzamide Compound I-122c (29.0 mg, 89% yield, 99% ee) was synthesized following the procedure detailed in Section I-8-2 using I-70c (22.3 mg, 0.10 mmol) as starting material. Rf: 0.12 (50% EtOAC/Hex) 1H NMR (500 MHz, CDCl3) δ 7.93 – 7.81 (m, 3H), 6.95 (d, J = 8.9 Hz, 2H), 5.58 (d, J = 9.5 Hz, 1H), 4.38 – 4.24 (m, 2H), 4.14 (ddd, J = 10.8, 5.2, 1.7 Hz, 1H), 3.85 (s, 3H), 2.90 (ddd, J = 13.7, 10.8, 4.5 Hz, 1H), 2.14 (s, 3H), 1.68 – 1.60 (m, 1H), 1.54 (dtd, J = 13.7, 7.9, 5.5 Hz, 1H), 1.37 (ddd, J = 15.0, 8.0, 6.4 Hz, 2H), 0.90 (t, J = 7.4 Hz, 3H). 13C NMR (126 MHz, CDCl3) δ 171.8, 166.6, 162.3, 129.0, 126.0, 113.8, 61.8, 55.4, 49.2, 42.4, 34.8, 23.3, 19.3, 13.7. Resolution of enantiomers: DAICEL Chiralpak®, IA 10% IPA/Hexane 1ml/min, 254 nm, RT 1 (major)=13.9 min, RT 2 (minor) =17.8 min. HRMS analysis (ESI): calculated for [M+H]+: C16H24ClN2O3: 327.1476; Found: 327.1475 Optical activity: [α]D20 = -19.8 (c = 0.10, CHCl3, 99% ee) Single colorless needle-shaped crystals of I-122c were obtained from a mixture of methanol and hexanes by slow evaporation in a silicone coated NMR tube. 84 O NH O C 3H 7 N H Cl F I-122d, N-((2R,3R)-3-acetamido-2-chlorohexyl)-4-fluorobenzamide Compound I-122d (26.7 mg, 85% yield, 99% ee) was synthesized following the procedure detailed in Section I-8-2 using I-70d (22.1 mg, 0.10 mmol) as starting material. Rf: 0.25 (50% EtOAC/Hex) 1H NMR (500 MHz, CDCl3) δ 8.01 (dd, J = 8.6, 4.4 Hz, 1H), 7.93 (dd, J = 8.8, 5.3 Hz, 2H), 7.13 (t, J = 8.6 Hz, 2H), 5.69 (d, J = 9.4 Hz, 1H), 4.35 – 4.25 (m, 2H), 4.13 (ddd, J = 10.9, 5.1, 1.7 Hz, 1H), 2.90 (ddd, J = 13.6, 10.9, 4.4 Hz, 1H), 2.14 (s, 3H), 1.70 – 1.59 (m, 1H), 1.60 – 1.49 (m, 1H), 1.41 – 1.30 (m, 2H), 0.90 (t, J = 7.4 Hz, 3H). 13C NMR (126 MHz, CDCl3) δ 171.9, 165.9, 164.9 (d, J = 251.8 Hz). 129.9 (d, J = 3.0 Hz), 129.5 (d, J = 9.0 Hz), 115.7 (d, J = 21.9 Hz), 61.5, 49.2, 42.5, 34.8, 23.3, 19.3, 13.7. 19F NMR (470 MHz, CDCl3) δ -108.06. Resolution of enantiomers: DAICEL Chiralpak®, IA 5% IPA/Hexane 1ml/min, 254 nm, RT 1 (major)=20.9 min, RT 2 (minor) =22.1 min. HRMS analysis (ESI): calculated for [M+H]+: C15H21ClN2O2: 315.1276; Found: 315.1274 Optical Activity: [α]D20 = -23.9 (c = 0.10, CHCl3, 99% ee) O NH O C 3H 7 N H Cl tBu I-122e, N-((2R,3R)-3-acetamido-2-chlorohexyl)-4-(tert-butyl)benzamide 85 Compound I-122e (27.8 mg, 79% yield, 99% ee) was synthesized following the procedure detailed in Section I-8-2 using I-70e (25.9 mg, 0.10 mmol) as starting material. Rf: 0.21 (70% EtOAC/Hex) 1H NMR (500 MHz, CDCl3) δ 7.92 (s, 1H), 7.84 (d, J = 8.6 Hz, 2H), 7.47 (d, J = 8.6 Hz, 2H), 5.59 (s, 1H), 4.37 – 4.24 (m, 2H), 4.19 – 4.05 (m, 1H), 2.91 (ddd, J = 13.6, 10.8, 4.5 Hz, 1H), 2.13 (s, 3H), 1.68 – 1.58 (m, 1H), 1.53 (dtd, J = 13.6, 7.9, 5.5 Hz, 1H), 1.38-1.32 (m, 2H), 1.32 (s, 9H), 0.89 (t, J = 7.3 Hz, 3H). 13C NMR (126 MHz, CDCl3) δ 171.7, 166.9, 155.1, 130.9, 127.0, 125.6, 61.8, 49.2, 42.4, 34.9, 34.9, 31.2, 23.3, 19.3, 13.7. Resolution of enantiomers: DAICEL Chiralpak®, IA 10% IPA/Hexane 1ml/min, 254 nm, RT 1 (major)=8.2 min, RT 2 (minor) =11.7 min. HRMS analysis (ESI): calculated for [M+H]+: C19H30ClN2O2: 353.1996; Found: 353.1989 Optical activity: [α]D20 = -27.1 (c = 0.10, CHCl3, 99% ee) O NH O C 3H 7 N H Cl Br I-122f, N-((2R,3R)-3-acetamido-2-chlorohexyl)-4-bromobenzamide Rf: 0.21 (50% EtOAC/Hex) Compound I-122f (34.2 mg, 91% yield, 99% ee) was synthesized following the procedure detailed in Section I-8-2 using I-70f (28.2 mg, 0.10 mmol) as starting material. 1H NMR (500 MHz, CDCl3) δ 8.04 (dd, J = 8.6, 4.7 Hz, 1H), 7.78 (d, J = 8.5 Hz, 2H), 7.59 (d, J = 8.5 Hz, 2H), 5.65 (d, J = 9.4 Hz, 1H), 4.29 (ddd, J = 13.7, 8.8, 5.2 Hz, 2H), 4.12 (ddd, J = 10.9, 5.1, 1.7 Hz, 1H), 2.90 (ddd, J = 13.5, 10.9, 4.4 Hz, 1H), 2.14 (s, 3H), 1.70 86 – 1.59 (m, 1H), 1.54 (dtd, J = 13.6, 7.8, 5.5 Hz, 1H), 1.36 (h, J = 7.5 Hz, 2H), 0.90 (t, J = 7.3 Hz, 3H). 13C NMR (126 MHz, CDCl3) δ 171.9, 166.0, 132.5, 131.9, 128.8, 126.5, 61.5, 49.2, 42.5, 34.8, 23.3, 19.3, 13.7. Resolution of enantiomers: DAICEL Chiralpak®, AD-H 15% IPA/Hexane 1ml/min, 254 nm, RT 1 (major)=6.1 min, RT 2 (minor) =7.6 min. HRMS analysis (ESI): calculated for [M+H]+: C15H21BrClN2O2: 375.0475; Found: 375.0473 Optical activity: [α]D20 = -13.2 (c = 0.40, CHCl3, 99% ee) O NH O C 3H 7 N H Cl I-122g, N,N'-((2R,3R)-2-chlorohexane-1,3-diyl)diacetamide Compound I-122g (13.6 mg, 58% yield, 94% ee) was synthesized following the procedure detailed in Section I-8-2 using I-70g (14.1 mg, 0.10 mmol) as starting material. 1H NMR (500 MHz, CDCl3) δ 6.93 (s, 1H), 5.57 (d, J = 9.5 Hz, 1H), 4.25 (tdd, J = 9.2, 5.6, 1.5 Hz, 1H), 4.07 – 3.90 (m, 2H), 2.85 – 2.68 (m, 1H), 2.07 (s, 3H), 2.00 (s, 3H), 1.67 – 1.57 (m, 1H), 1.58 – 1.48 (m, 1H), 1.36 (h, J = 7.4 Hz, 2H), 0.92 (t, J = 7.3 Hz, 3H). 13C NMR (126 MHz, CDCl3) δ 171.4, 170.4, 61.9, 49.0, 42.39, 35.9, 23.3, 23.2, 19.2, 13.7. Resolution of enantiomers: DAICEL Chiralcel®, OD-H 8% IPA/Hexane 1 ml/min, 214 nm, RT 1 (minor)=10.5 min, RT 2 (major) =11.6 min. HRMS analysis (ESI): calculated for [M+H]+: C10H20ClN2O2: 235.1213; Found: 235.1208 Optical activity: [α]D20 = -22.3 (c = 0.10, CHCl3, 94% ee) 87 O NH O C 3H 7 N H Cl NO2 I-122h, N-((2R,3S)-3-acetamido-2-chlorohexyl)-4-nitrobenzamide Compound I-122h (27.7 mg, 81% yield, 97% ee) was synthesized following the procedure detailed in Section I-8-2 using I-70h (24.8 mg, 0.10 mmol) as starting material. Rf: 0.16 (50% EtOAC/Hex) 1H NMR (500 MHz, C2D6SO) δ 9.05 (t, J = 5.7 Hz, 1H), 8.33 (d, J = 8.8 Hz, 2H), 8.06 (d, J = 8.8 Hz, 2H), 7.98 (d, J = 8.4 Hz, 1H), 4.23 (dt, J = 8.3, 4.9 Hz, 1H), 4.08 – 3.99 (m, 1H), 3.70 (dt, J = 14.0, 5.2 Hz, 1H), 3.48 (ddd, J = 14.3, 8.4, 6.1 Hz, 1H), 1.85 (s, 3H), 1.61 (dddd, J = 12.9, 9.6, 6.7, 2.9 Hz, 1H), 1.51 – 1.41 (m, 1H), 1.41 – 1.32 (m, 1H), 1.29 – 1.13 (m, 1H), 0.86 (t, J = 7.3 Hz, 3H). 13C NMR (126 MHz, C2D6SO) δ 169.5, 164.8, 149.1, 149.8, 128.7, 123.7, 64.8, 50.6, 43.2, 30.8, 22.5, 18.8, 13.7. Resolution of enantiomers: DAICEL Chiralpak®, AD-H 10% IPA/Hexane 1ml/min, 254 nm, RT 1 (minor)=10.8 min, RT 2 (major) =12.0 min. (97% ee) HRMS analysis (ESI): calculated for [M+H]+: C15H21ClN3O4: 342.1221; Found: 342.1220. Optical activity: [α]D20 = +63.3 (c = 0.4, CHCl3, 97% ee) O NH O C 3H 7 N H Cl Br I-122i, N-((2R,3S)-3-acetamido-2-chlorohexyl)-4-bromobenzamide 88 Compound I-122i (22.1 mg, 59% yield, 95% ee) was synthesized following the procedure detailed in Section I-8-2 using I-70i (28.2 mg, 0.10 mmol) as starting material. Rf: 0.23 (70% EtOAC/Hex) 1H NMR (500 MHz, DMSO-d6) δ 8.80 (t, J = 5.7 Hz, 1H), 7.97 (d, J = 8.4 Hz, 1H), 7.78 (d, J = 8.7 Hz, 2H), 7.70 (d, J = 8.5 Hz, 2H), 4.22 (dt, J = 8.1, 5.0 Hz, 1H), 4.06 – 3.97 (m, 1H), 3.68 (dt, J = 14.0, 5.3 Hz, 1H), 3.44 (ddd, J = 14.2, 8.2, 6.1 Hz, 1H), 1.85 (s, 3H), 1.62 (dddd, J = 12.8, 9.5, 6.6, 2.9 Hz, 1H), 1.51 – 1.42 (m, 1H), 1.36 (dd, J = 6.5, 3.1 Hz, 1H), 1.28 – 1.18 (m, 1H), 0.7 (t, J = 7.3 Hz, 3H). 13C NMR (126 MHz, DMSO-d6) δ 169.5, 165.5, 133.3, 131.4, 129.3, 125.1, 64.9, 50.5, 43.0, 30.8, 22.5, 18.8, 13.7. Resolution of enantiomers: DAICEL Chiralpak®, ad-h 10% IPA/Hexane 1ml/min, 254 nm, RT 1 (major)=8.1 min, RT 2 (minor) =10.2 min. HRMS analysis (ESI): calculated for [M+H]+: C15H21BrClN2O2: 375.0475; Found: 375.0477 Optical activity: [α]D20 = +32.8 (c = 0.1, CHCl3, 96% ee) Single colorless needle-shaped crystals of I-122i were recrystallized from a mixture of dichloromethane and hexanes by slow evaporation in a silicone coated NMR tube. 89 O NH O C 3H 7 N Cl O I-122j, N-((2R,3R)-2-chloro-1-(1,3-dioxoisoindolin-2-yl)hexan-3-yl)acetamide Compound I-122j (19.1 mg, 67% yield, 29% ee) was synthesized following the procedure detailed in Section I-8-4 using I-70j (22.9 mg, 0.10 mmol) as starting material. Rf: 0.21 (50% EtOAC/Hex) 1H NMR (500 MHz, CDCl3) δ 7.87 (dd, J = 5.4, 3.1 Hz, 2H), 7.74 (dd, J = 5.5, 3.0 Hz, 2H), 5.61 (d, J = 9.7 Hz, 1H), 4.58 (ddd, J = 10.2, 4.2, 1.8 Hz, 1H), 4.43 (dddd, J = 10.1, 8.2, 5.9, 1.8 Hz, 1H), 4.02 (dd, J = 14.5, 10.2 Hz, 1H), 3.91 (dd, J = 14.5, 4.2 Hz, 1H), 2.10 (s, 3H), 1.67 – 1.53 (m, 2H), 1.44 – 1.33 (m, 2H), 0.94 (t, J = 7.3 Hz, 3H). 13C NMR (126 MHz, CDCl3) δ 170.1, 168.0, 134.2, 131.8, 123.5, 63.0, 49.7, 42.5, 35.8, 23.4, 19.0, 13.8. Resolution of enantiomers: DAICEL Chiralpak®, AD-H 10% IPA/Hexane 1 ml/min, 230 nm, RT 1 (minor)=13.0 min, RT 2 (major) = 15.8 min. HRMS analysis (ESI): calculated for [M+H]+: C16H20ClN2O3: 323.1162; Found: 323.1162 Optical activity: [α]D20 = +2.1 (c = 0.10, CHCl3, 29% ee) O NH O C 3H 7 O Cl NO2 I-122k, (2S,3R)-3-acetamido-2-chlorohexyl 4-nitrobenzoate Compound I-122k (23.3 mg, 68% yield, 60% ee) was synthesized following the procedure detailed in Section I-8-4 using I-70k (24.9 mg, 0.10 mmol) as starting material. 90 Rf: 0.23 (50% EtOAC/Hex) 1H NMR (500 MHz, CDCl3) δ 8.31 (d, J = 8.9 Hz, 2H), 8.25 (d, J = 9.0 Hz, 2H), 5.50 (d, J = 9.7 Hz, 1H), 4.57 – 4.43 (m, 3H), 4.35 (ddd, J = 7.6, 6.5, 1.8 Hz, 1H), 2.05 (s, 3H), 1.71 – 1.52 (m, 2H), 1.44 – 1.35 (m, 2H), 0.95 (t, J = 7.3 Hz, 3H). 13C NMR (126 MHz, CDCl3) δ 169.9, 164.1, 150.7, 135.0, 131.0, 123.7, 66.1, 62.0, 48.7, 35.3, 23.3, 19.1, 13.8. Resolution of enantiomers: DAICEL Chiralcel®, OD-H 15% IPA/Hexane 1 ml/min, 254 nm, RT 1 (major)=11.6 min, RT 2 (minor) =15.9 min. HRMS analysis (ESI): calculated for [M+H]+: C15H20ClN2O5: 343.1061; Found: 343.1058 Optical activity: [α]D20 = +3.0 (c = 0.1, CHCl3, 60% ee) O NH O C6H13 N H Cl NO2 I-122m, N-((2R,3R)-3-acetamido-2-chlorononyl)-4-nitrobenzamide Rf: 0.22 (50% EtOAC/Hex). Compound I-122m (30.3 mg, 79% yield, 99% ee) was synthesized following the procedure detailed in Section I-8-2 using I-70m (29.0 mg, 0.10 mmol) as starting material. 1H NMR (500 MHz, CDCl3) δ 8.33 – 8.23 (m, 3H), 8.08 (d, J = 8.8 Hz, 2H), 5.58 (d, J = 9.4 Hz, 1H), 4.34 (ddd, J = 13.8, 8.8, 5.2 Hz, 1H), 4.26 (tdd, J = 8.7, 5.7, 1.7 Hz, 1H), 4.13 (ddd, J = 11.1, 5.2, 1.7 Hz, 1H), 2.92 (ddd, J = 13.7, 11.0, 4.3 Hz, 1H), 2.15 (s, 3H), 1.71 – 1.54 (m, 2H), 1.36 – 1.16 (m, 8H), 0.84 (t, J = 7.4 Hz, 3H). 13C NMR (126 MHz, CDCl3) δ 172.0, 164.8, 149.7, 139.2, 128.4, 123.9, 61.1, 49.7, 42.5, 32.8, 31.5, 28.9, 26.0, 23.3, 22.5, 14.0. 91 Resolution of enantiomers: DAICEL Chiralpak®, AD-H 4% IPA/Hexane 1 ml/min, 254 nm, RT 1 (major)=28.1 min, RT 2 (major) =31.0 min. HRMS analysis (ESI): calculated for [M+H]+: C18H27ClN3O4: 384.1690; Found: 384.1688 Optical activity: [α]D20 = -35.3 (c = 0.20, CHCl3, 99% ee) O NH O C 2H 5 N H Cl NO2 I-122n, N-((2R,3R)-3-acetamido-2-chloropentyl)-4-nitrobenzamide Compound I-122n (23.3 mg, 73% yield, 99% ee) was synthesized following the procedure detailed in Section I-8-2 using I-70n (23.4 mg, 0.10 mmol) as starting material. Rf: 0.16 (50% EtOAC/Hex) 1H NMR (500 MHz, CDCl3) δ 8.35 – 8.27 (m, 3H), 8.10 (d, J = 9.0 Hz, 2H), 5.62 (d, J = 9.3 Hz, 1H), 4.35 (ddd, J = 13.8, 8.8, 5.1 Hz, 1H), 4.23 – 4.09 (m, 2H), 2.94 (ddd, J = 13.6, 11.0, 4.3 Hz, 1H), 2.17 (s, 3H), 1.78 – 1.58 (m, 2H), 0.96 (t, J = 7.4 Hz, 3H). 13C NMR (126 MHz, CDCl3) δ 172.2, 164.8, 149.7, 139.2, 128.4, 123.9, 60.8, 51.3, 42.5, 25.9, 23.3, 10.6. Resolution of enantiomers: DAICEL Chiralpak®, AD-H 15% IPA/Hexane 1 ml/min, 214 nm, RT 1 (major)=7.8 min, RT 2 (minor) =9.4 min. HRMS analysis (ESI): calculated for [M+H]+: C14H19ClN3O4: 328.1064; Found: 328.1061 Optical activity: [α]D20 = -40.5 (c = 0.2, CHCl3, 99% ee) O NH O TBDPSO N H Cl NO2 92 I-122o, N-((2R,3R)-3-acetamido-5-((tert-butyldiphenylsilyl)oxy)-2-chloropentyl)-4- nitrobenzamide Compound I-122o (36.1 mg, 62% yield, 99% ee) was synthesized following the procedure detailed in Section I-8-2 using I-70o (48.8 mg, 0.10 mmol) as starting material. Rf: 0.36 (50% EtOAC/Hex) 1H NMR (500 MHz, CDCl3) δ 8.49 (dd, J = 8.9, 4.2 Hz, 1H), 8.25 (d, J = 8.9 Hz, 2H), 8.09 (d, J = 8.8 Hz, 2H), 7.51-7.55 (m, J = 9.7, 6.7, 1.5 Hz, 4H), 7.45 – 7.39 (m, 2H), 7.39-7.34 (m, 4H), 5.61 (d, J = 9.3 Hz, 1H), 4.77 (dtd, J = 8.9, 6.9, 1.7 Hz, 1H), 4.40 (ddd, J = 13.9, 8.9, 5.1 Hz, 1H), 4.17 (ddd, J = 11.2, 5.1, 1.7 Hz, 1H), 3.76 – 3.58 (m, 2H), 2.93 (ddd, J = 13.7, 11.2, 4.2 Hz, 1H), 2.11 (s, 3H), 1.84 (q, J = 6.4 Hz, 2H), 0.89 (s, 9H). 13C NMR (126 MHz, CDCl3) δ 172.2, 164.7, 149.7, 139.1, 135.5, 135.4, 133.0, 133.0, 129.8, 129.8, 128.4, 127.8, 127.8, 123.8, 61.5, 59.5, 46.4, 42.4, 35.6, 26.7, 23.3, 19.0. Resolution of enantiomers: DAICEL Chiralcel®, OD-H 7% IPA/Hexane 1ml/min, 254 nm, RT 1 (minor)=21.5 min, RT 2 (major) =26.4 min. HRMS analysis (ESI): calculated for [M+H]+: C30H37ClN3O5Si: 582.2191; Found: 582.2188 Optical activity: [α]D20 = -173.2 (c = 0.05, CHCl3, 99% ee) O NH O BnO N H Cl NO2 I-122p, N-((2R,3R)-3-acetamido-4-(benzyloxy)-2-chlorobutyl)-4-nitrobenzamide The substrate I-70p (32.6 mg, 0.1 mmol, 1.0 equiv) and (DHQD)2PHAL (1.6 mg, 2 mol%) were suspended in acetonitrile (1 mL) in a test tube with a magnetic stir bar and capped 93 with a rubber septa. HFIP (105 µL, 1.0 mmol, 10 equiv) was added via a syringe. The resulting suspension was stirred at 23 °C. After stirring for 10 min DCDMH (39.4 mg, 0.2 mmol, 2 equiv) was added. The reaction was monitored by TLC and (DHQD)2PHAL (1.6 mg, 2 mol%) was added every 12 h until the reaction reached completion. Upon completion, the reaction was quenched by the addition of saturated Na2S2O3 (2 mL). The reaction was concentrated to remove the acetonitrile and the resultant aqueous layer was extracted with DCM (3 x 4 mL). The combined organics were concentrated. To the concentrated product in the vial with a stir bar, acetonitrile (1 mL) and a solution of HCl (1 M, 0.2 mL) were added and stirred for 15 min. Water (3 mL) was added and the solution was concentrated and extracted with DCM (3 x 4 mL). The combined organic layers were dried with anhydrous Na2SO4 and concentrated. Column chromatography (SiO2/EtOAc– Hexanes gradient) provided the desired product I-122p in a 23 % yield (9.7 mg, 99% ee) Rf: 0.10 (50% EtOAC/Hex) 1H NMR (500 MHz, CDCl3) δ 8.31 (d, J = 8.8 Hz, 2H), 8.19 – 8.12 (m, 1H), 8.08 (d, J = 8.9 Hz, 2H), 7.38 – 7.27 (m, 5H), 5.73 (d, J = 9.2 Hz, 1H), 4.62 – 4.44 (m, 3H), 4.38 – 4.25 (m, 2H), 3.59 (d, J = 6.8 Hz, 2H), 3.00 (ddd, J = 15.2, 12.1, 4.5 Hz, 1H), 2.14 (s, 3H). 13C NMR (126 MHz, CDCl3) δ 172.3, 164.8, 149.7, 139.2, 137.2, 128.6, 128.4, 128.1, 127.9, 123.8, 73.5, 69.3, 58.5, 49.4, 42.2, 23.3. Resolution of enantiomers: DAICEL Chiralcel®, OD-H 10% IPA/Hexane 1 ml/min, 254 nm, RT 1 (major)=42.7 min, RT 2 (minor) =66.8 min. HRMS analysis (ESI): calculated for [M+H]+: C20H23ClN3O5: 420.1326; Found: 420.1328 Optical activity: [α]D20 = -21.5 (c = 0.1, CHCl3, 99% ee) 94 O Cl NH O BnO N H Cl NO2 I-122p’, N-((2R,3R)-4-(benzyloxy)-2-chloro-3-(2-chloroacetamido)butyl)-4- nitrobenzamide The substrate I-70p (32.6 mg, 0.1 mmol, 1.0 equiv) and (DHQD)2PHAL (1.6 mg, 2 mol%) were suspended in acetonitrile (1 mL) in a test tube with a magnetic stir bar and capped with a rubber septa. HFIP (105 µL, 1.0 mmol, 10 equiv) was added via a syringe. The resulting suspension was stirred at 23 °C. After stirring for 10 min DCDMH (39.4 mg, 0.2 mmol, 2 equiv) was added. The reaction was monitored by TLC and (DHQD)2PHAL (1.6 mg 2 mol%) was added every 12 h until the reaction reached completion. Upon completion, the reaction was quenched by the addition of saturated Na2S2O3 (2 mL). The reaction was concentrated to remove the acetonitrile and the resultant aqueous layer was extracted with DCM (3 x 4 mL). The combined organics were concentrated. To the concentrated product in the vial with a stir bar, acetonitrile (1 mL) and a solution of HCl (1 M, 0.2 mL) were added and stirred for 15 min. Water (3 mL) was added and the solution was concentrated and extracted with DCM (3 x 4 mL). The combined organic layers were dried with anhydrous Na2SO4 and concentrated. Column chromatography (SiO2/EtOAc– Hexanes gradient) provided product I-122p’ in a 20.8 mg yield (46% yield, 99% ee). Rf: 0.35 (50% EtOAC/Hex) 1H NMR (500 MHz, CDCl3) δ 8.31 (d, J = 8.9 Hz, 2H), 8.04 (d, J = 8.8 Hz, 2H), 7.77 (dd, J = 8.1, 4.6 Hz, 1H), 7.38 – 7.29 (m, 5H), 6.78 (d, J = 9.3 Hz, 1H), 4.61 – 4.51 (m, 3H), 95 4.40 (ddd, J = 10.2, 5.6, 2.0 Hz, 1H), 4.26 (ddd, J = 13.9, 8.2, 5.7 Hz, 1H), 4.17 (d, J = 1.9 Hz, 2H), 3.65 (d, J = 6.7 Hz, 2H), 3.09 (ddd, J = 13.9, 10.2, 4.8 Hz, 1H). 13C NMR (126 MHz, CDCl3) δ 168.0, 164.9, 149.8, 139.1, 137.1, 128.6, 128.4, 128.1, 127.8, 123.9, 73.6, 69.0, 58.2, 50.0, 42.4, 42.4. Resolution of enantiomers: DAICEL Chiralpak®, IA 20% IPA/Hexane 1ml/min, 254 nm, RT 1 (major)=11.8 min, RT 2 (minor) =15.9 min. HRMS analysis (ESI): calculated for [M+H]+: C20H22Cl2N3O5: 454.0937; Found: 454.0938 Optical activity: [α]D20 = +15.1 (c = 0.1, CHCl3, 99% ee) O NH O C6H13 N H Cl NO2 I-122q, N-((2R,3S)-3-acetamido-2-chlorononyl)-4-nitrobenzamide Rf: 0.28 (70% EtOAC/Hex) Compound I-122q (31.7 mg, 83% yield, 94% ee) was synthesized following the procedure detailed in Section I-8-2 using I-70q (29.0 mg, 0.10 mmol) as starting material. 1H NMR (500 MHz, C2D6SO) δ 9.04 (t, J = 5.7 Hz, 1H), 8.33 (d, J = 8.9 Hz, 2H), 8.05 (d, J = 8.8 Hz, 2H), 7.99 (d, J = 8.4 Hz, 1H), 4.22 (dt, J = 8.3, 4.9 Hz, 1H), 4.10 – 3.89 (m, 1H), 3.69 (dt, J = 14.1, 5.2 Hz, 1H), 3.48 (ddd, J = 14.3, 8.4, 6.1 Hz, 1H), 1.85 (s, 3H), 1.60-1.68 (m, 1H), 1.53 – 1.40 (m, 1H), 1.37 – 1.15 (m, 8H), 0.84 (t, J = 7.4 Hz, 3H). 13C NMR (126 MHz, C2D6SO) δ 170.0, 165.3, 149.6, 140.2, 129.2, 124.1, 65.2, 51.3, 43.5, 31.6, 29.2, 28.9, 25.9, 22.9, 22.5, 14.4. Resolution of enantiomers: DAICEL Chiralcel®, OD-H 5% IPA/Hexane 1 ml/min, 254 nm, RT 1 (major)=17.1 min, RT 2 (minor) =23.0 min. 96 HRMS analysis (ESI): calculated for [M+H]+: C18H27ClN3O4: 384.1690; Found: 384.1689 Optical activity: [α]D20 = +72.1 (c = 0.20, CHCl3, 95% ee) O NH O N H Cl NO2 I-122r, (R)-N-(3-acetamido-2-chloro-3-methylbutyl)-4-nitrobenzamide Compound I-122r (25.9 mg, 79% yield, 99% ee) was synthesized following the procedure detailed in Section I-8-2 using I-70r (23.4 mg, 0.10 mmol) as starting material. Rf: 0.13 (70% EtOAC/Hex) 1H NMR (500 MHz, CDCl3) δ 8.31 (d, J = 8.8 Hz, 2H), 7.96 (d, J = 8.8 Hz, 2H), 6.79 (s, 1H), 5.54 (s, 1H), 4.90 (dd, J = 9.5, 3.2 Hz, 1H), 4.21 – 4.10 (m, 1H), 3.57 – 3.47 (m, 1H), 1.98 (s, 3H), 1.54 (s, 3H), 1.50 (s, 3H) 13C NMR (126 MHz, CDCl3) δ 170.3, 165.5, 149.7, 139.6, 128.2, 123.9, 66.6, 56.6, 42.9, 24.5, 24.4, 24.0. Resolution of enantiomers: DAICEL Chiralpak®, AD-H 10% IPA/Hexane 1 ml/min, 254 nm, RT 1 (major)=17.5 min, RT 2 (minor) =22.6 min. HRMS analysis (ESI): calculated for [M+H]+: C14H19ClN3O4: 328.1064; Found: 328.1064 Optical activity: [α]D20 = +62.4 (c = 0.10, CHCl3, 99 % ee) O NH O N H Cl NO2 I-122s, N-((2R,3R)-3-acetamido-2-chloro-3-phenylpropyl)-4-nitrobenzamide Compound I-122s (35.6 mg, 95% yield, 65:35 dr, 99% ee) was synthesized following the procedure detailed in Section I-8-2 using I-70s (28.2 mg, 0.10 mmol) as starting material. 97 Rf: 0.11 (50% EtOAC/Hex) 1H NMR (500 MHz, CDCl3) δ 8.32 (d, J = 8.7 Hz, 2H), 8.11 (m, 3H), 7.42 – 7.36 (m, 2H), 7.36 – 7.29 (m, 3H), 6.29 (d, J = 9.7 Hz, 1H), 5.63 (dd, J = 9.6, 1.8 Hz, 1H), 4.56 (ddd, J = 10.5, 5.4, 1.8 Hz, 1H), 4.39 (ddd, J = 13.8, 8.3, 5.4 Hz, 1H), 3.14 (ddd, J = 13.8, 10.5, 4.7 Hz, 1H), 2.25 (s, 3H). 13C NMR (126 MHz, CDCl3) δ 171.8, 165.0, 149.8, 139.1, 137.1, 128.8, 128.4, 128.3, 126.6, 123.9, 61.2, 52.2, 43.0, 23.4. Resolution of enantiomers: DAICEL Chiralcel®, OD-H 20% IPA/Hexane 1 ml/min, 254 nm, RT 1 (major)=12.1 min, RT 2 (minor) = 16.9 min. HRMS analysis (ESI): calculated for [M+H]+: C18H19ClN3O4: 376.1064; Found: 376.1057. Optical activity: [α]D20 = -33.5 (c = 0.2, CHCl3, 99% ee) O NH O N H Cl Cl NO2 I-122t, N-((2R,3R)-3-acetamido-2-chloro-3-(4-chlorophenyl)propyl)-4-nitrobenzamide Compound I-122t (37.6 mg, 92% yield, 64:36 dr, 97% ee) was synthesized following the procedure detailed in Section I-8-2 using I-70t (31.6 mg, 0.10 mmol) as starting material. Rf: 0.08 (50% EtOAC/Hex) 1H NMR (500 MHz, CDCl3) δ 8.32 (d, J = 8.8 Hz, 2H), 8.09 (d, J = 8.8 Hz, 2H), 8.01 (dd, J = 8.0, 4.7 Hz, 1H), 7.39 – 7.32 (m, 2H), 7.29 – 7.23 (m, 2H), 6.29 (d, J = 9.7 Hz, 1H), 5.61 (dd, J = 9.8, 1.9 Hz, 1H), 4.52 (ddd, J = 10.3, 5.5, 1.9 Hz, 1H), 4.35 (ddd, J = 13.8, 8.1, 5.4 Hz, 1H), 3.14 (ddd, J = 13.9, 10.3, 4.8 Hz, 1H), 2.25 (s, 3H). 98 13C NMR (126 MHz, CDCl3) δ 171.7, 165.1, 149.8, 138.9, 135.6, 134.2, 129.0, 128.4, 128.1, 123.9, 61.0, 51.7, 43.0, 23.4. Resolution of enantiomers: DAICEL Chiralpak®, IA 20% IPA/Hexane 1 ml/min, 254 nm, RT 1 (minor)=10.8 min, RT 2 (major) =17.6 min. HRMS analysis (ESI): calculated for [M+H]+: C18H18Cl2N3O4: 410.0674; Found: 410.0668. Optical activity: [α]D20 = -28.2 (c = 0.2, CHCl3, 97% ee) O NH O N H Cl Cl NO2 I-122t-Diastereomer, N-((2R,3S)-3-acetamido-2-chloro-3-(4-chlorophenyl)propyl)-4- nitrobenzamide Rf: 0.15 (70% EtOAC/Hex) 1H NMR (500 MHz, CDCl3) δ 8.31 (d, J = 8.7 Hz, 2H), 8.01 (d, J = 8.7 Hz, 2H), 7.55 (dd, J = 8.3, 3.9 Hz, 1H), 7.36 (d, J = 8.6 Hz, 2H), 7.30 (d, J = 8.5 Hz, 2H), 6.26 (d, J = 8.7 Hz, 1H), 5.23 (t, J = 8.5 Hz, 1H), 4.46 – 4.37 (m, 2H), 3.34 (ddd, J = 15.4, 5.9, 3.8 Hz, 1H), 2.07 (s, 3H). 13C NMR (126 MHz, CDCl3) δ 170.6, 165.6, 149.7, 139.4, 136.1, 134.7, 129.3, 128.9, 128.3, 123.9, 62.0, 55.6, 42.7, 23.4. Resolution of enantiomers: DAICEL Chiralcel®, OJ-H 8% IPA/Hexane 1 ml/min, 254 nm, RT 1 (major)=22.2 min, RT 2 (minor) =31.9 min. HRMS analysis (ESI): calculated for [M+H]+: C18H18Cl2N3O4: 410.0674; Found: 410.0666. Optical activity: [α]D20 = +90.8 (c = 0.2, CHCl3, 98% ee) 99 O NH O N H Cl NO2 I-122u, N-((2R,3R)-3-acetamido-2-chloro-3-(p-tolyl)propyl)-4-nitrobenzamide Compound I-122u (30.3 mg, 78% yield, 50:50 dr, 99% ee) was synthesized following the procedure detailed in Section I-8-2 using I-70u (29.6 mg, 0.10 mmol) as starting material. Rf: 0.08 (50% EtOAC/Hex) 1H NMR (500 MHz, CDCl3) δ 8.31 (d, J = 8.8 Hz, 2H), 8.13 (dd, J = 8.3, 4.8 Hz, 1H), 8.09 (d, J = 8.8 Hz, 2H), 7.19 (s, 4H), 6.27 (d, J = 9.7 Hz, 1H), 5.57 (d, J = 9.7 Hz, 1H), 4.52 (ddd, J = 10.5, 5.4, 1.9 Hz, 1H), 4.37 (ddd, J = 13.8, 8.3, 5.4 Hz, 1H), 3.11 (ddd, J = 13.8, 10.5, 4.7 Hz, 1H), 2.34 (s, 3H), 2.23 (s, 3H). 13C NMR (126 MHz, CDCl3) δ 171.7, 165.0, 149.8, 139.1, 138.1, 134.0, 129.5, 128.4, 126.5, 123.9, 61.3, 52.0, 43.0, 23.4, 21.0. Resolution of enantiomers: DAICEL Chiralpak®, IA 15% IPA/Hexane 1 ml/min, 254 nm, RT 1 (minor)=17.6 min, RT 2 (major) = 23.6 min. HRMS analysis (ESI): calculated for [M+H]+: C19H21ClN3O4: 390.1221; Found: 390.1214. Optical activity: [α]D20 = +157.3 (c = 0.1, CHCl3, 99% ee) O NH O N H Cl NO2 I-122u-Diastereomer, N-((2R,3R)-3-acetamido-2-chloro-3-(p-tolyl)propyl)-4- nitrobenzamide Rf: 0.22 (70% EtOAC/Hex) 100 1H NMR (500 MHz, CDCl3) δ 8.32 (d, J = 8.8 Hz, 2H), 8.05 (d, J = 8.8 Hz, 2H), 7.65 (d, J = 8.1 Hz, 1H), 7.27 – 7.17 (m, 4H), 6.00 (d, J = 8.4 Hz, 1H), 5.19 (t, J = 8.7 Hz, 1H), 4.50 (ddd, J = 14.5, 8.9, 3.5 Hz, 1H), 4.43 (ddd, J = 8.5, 4.7, 3.5 Hz, 1H), 3.37 (ddd, J = 14.6, 4.7, 3.7 Hz, 1H), 2.37 (s, 3H), 2.07 (s, 3H). 13C NMR (126 MHz, CDCl3) δ 170.7, 165.5, 149.7, 139.6, 138.8, 134.6, 129.8, 128.4, 127.3, 123.8, 62.2, 56.1, 42.5, 23.4, 21.2. Resolution of enantiomers: DAICEL Chiralcel®, OJ-H 5% IPA/Hexane 1 ml/min, 254 nm, RT 1 (major)=39.7 min, RT 2 (minor) =49.4 min. HRMS analysis (ESI): calculated for [M+H]+: C19H21ClN3O4: 390.1221; Found: 390.1212. Optical activity: +80.1 (90% ee) (c = 0.1, CHCl3, 99% ee) O NH O N H Cl CF3 NO2 I-122v, N-((2R,3R)-3-acetamido-2-chloro-3-(4-(trifluoromethyl)phenyl)propyl)-4- nitrobenzamide The substrate I-70v (0.1 mmol, 1.0 equiv) and (DHQD)2PHAL (1.6 mg, 2 mol%) were suspended in acetonitrile (1 mL) in a test tube with a magnetic stir bar and capped with a rubber septa. HFIP (105 µL, 1.0 mmol, 10 equiv) was added via a syringe. The resulting suspension was stirred at 23 °C. After stirring for 10 min DCDMH (39.4 mg, 0.2 mmol, 2 equiv) was added. The reaction was monitored by TLC and (DHQD)2PHAL (1.6 mg 2 mol%) was added every 12 h until the reaction reached completion. Upon completion, the reaction was quenched by the addition of saturated Na2S2O3 (2 mL). The reaction was concentrated to remove the acetonitrile and the resultant aqueous layer was extracted 101 with DCM (3 x 4 mL). The combined organics were concentrated. To the concentrated product in the vial with a stir bar, acetonitrile (1 mL) and a solution of HCl (1 M, 0.2 mL) were added and stirred for 15 min. Water (3 mL) was added and the solution was concentrated and extracted with DCM (3 x 4 mL). The combined organic layers were dried with anhydrous Na2SO4 and concentrated. Column chromatography (SiO2/EtOAc– Hexanes gradient) provided the desired product I-122v (5.1 mg, 12% yield, 89% ee). Rf: 0.28 (50% EtOAC/Hex) 1H NMR (500 MHz, CDCl3) δ 8.34 (d, J = 8.9 Hz, 2H), 8.11 (d, J = 8.8 Hz, 2H), 7.95 (t, J = 6.8 Hz, 1H), 7.66 (d, J = 8.2 Hz, 2H), 7.46 (d, J = 8.1 Hz, 2H), 6.27 (d, J = 9.9 Hz, 1H), 5.71 (d, J = 9.8 Hz, 1H), 4.58 (ddd, J = 10.3, 5.5, 1.8 Hz, 1H), 4.39 (ddd, J = 13.8, 8.2, 5.5 Hz, 1H), 3.17 (ddd, J = 13.7, 10.3, 4.8 Hz, 1H), 2.28 (s, 3H). 13C NMR (126 MHz, CDCl3) δ 171.7, 165.1, 149.9, 140.6, 138.5, 130.8 (q, JCF = 31.25 Hz), 128.4, 127.1, 125.7 (q, JCF = 3.75 Hz), 123.8 (q, JCF = 145.00 Hz), 124.0, 60.9, 51.9, 43.1, 23.5. 19F NMR (470 MHz, CDCl3) δ -62.72. Resolution of enantiomers: DAICEL Chiralcel®, IA 20% IPA/Hexane 1 ml/min, 254 nm, RT 1 (minor)=8.4 min, RT 2 (major) =15.1 min. HRMS analysis (ESI): calculated for [M+H]+: C19H18ClF3N3O4: 444.0938; Found: 444.0932. Optical activity: [α]D20 = -18.2 (c = 0.1, CHCl3, 89% ee) 102 O Cl NH O N H Cl CF3 NO2 I-122v’, N-((2R,3R)-2-chloro-3-(2-chloroacetamido)-3-(4-(trifluoromethyl)phenyl)propyl)- 4-nitrobenzamide The substrate I-70v (0.1 mmol, 1.0 equiv) and (DHQD)2PHAL (1.6 mg, 2 mol%) were suspended in acetonitrile (1 mL) in a test tube with a magnetic stir bar and capped with a rubber septa. HFIP (105 µL, 1.0 mmol, 10 equiv) was added via a syringe. The resulting suspension was stirred at 23 °C. After stirring for 10 min DCDMH (39.4 mg, 0.2 mmol, 2 equiv) was added. The reaction was monitored by TLC and (DHQD)2PHAL (1.6 mg 2 mol%) was added every 12 h until the reaction reached completion. Upon completion, the reaction was quenched by the addition of saturated Na2S2O3 (2 mL). The reaction was concentrated to remove the acetonitrile and the resultant aqueous layer was extracted with DCM (3 x 4 mL). The combined organics were concentrated. To the concentrated product in the vial with a stir bar, acetonitrile (1 mL) and a solution of HCl (1 M, 0.2 mL) were added and stirred for 15 min. Water (3 mL) was added and the solution was concentrated and extracted with DCM (3 x 4 mL). The combined organic layers were dried with anhydrous Na2SO4 and concentrated. Column chromatography (SiO2/EtOAc– Hexanes gradient) provided the desired product I-122v’ (30.5 mg, 64% yield, 87% ee). Rf: 0.54 (50% EtOAC/Hex) 1H NMR (500 MHz, CDCl3) δ 8.32 (d, J = 8.7 Hz, 2H), 8.06 (d, J = 8.7 Hz, 2H), 7.67 (d, J = 8.2 Hz, 2H), 7.65 – 7.58 (m, 1H), 7.46 (d, J = 8.4 Hz, 3H), 5.67 (d, J = 9.7 Hz, 1H), 4.62 103 (ddd, J = 8.8, 6.1, 2.1 Hz, 1H), 4.27 (d, J = 5.0 Hz, 2H), 4.26 – 4.19 (m, 1H), 3.34 (ddd, J = 14.3, 9.3, 5.3 Hz, 1H). 13C NMR (126 MHz, CDCl3) δ 167.4, 165.2, 149.9, 140.6, 138.8, 130.8 (q, JCF = 31.25 Hz), 128.4, 127.0, 126.0 (q, JCF = 3.75 Hz), 124.3 (q, JCF = 145.00 Hz), 124.0, 61.2, 52.7, 43.4, 42.6. 19F NMR (470 MHz, CDCl3) δ -62.8. Resolution of enantiomers: DAICEL Chiralcel®, OD-H 15% IPA/Hexane 1 ml/min, 254 nm, RT 1 (major)=22.2 min, RT 2 (minor) =29.9 min. HRMS analysis (ESI): calculated for [M+H]+: C19H17Cl2F3N3O4: 478.0548; Found: 478.0558. Optical activity: [α]D20 = -14.3 (c = 0.1, CHCl3, 87% ee) O NH O N H Cl NO2 I-122w, N-((2R,3S)-3-acetamido-2-chloro-3-phenylpropyl)-4-nitrobenzamide Compound I-122w (19.8 mg, 53% yield, 74:26 dr, 99% ee) was synthesized following the procedure detailed in Section I-8-2 using I-70w (28.2 mg, 0.10 mmol) as starting material. Rf: 0.19 (70% EtOAC/Hex) 1H NMR (500 MHz, CDCl3) δ 8.31 (d, J = 8.8 Hz, 2H), 8.04 (d, J = 8.8 Hz, 2H), 7.68 (dd, J = 8.7, 3.7 Hz, 1H), 7.44 – 7.31 (m, 5H), 6.16 (d, J = 8.5 Hz, 1H), 5.23 (t, J = 8.6 Hz, 1H), 4.54 – 4.39 (m, 2H), 3.47 – 3.30 (m, 1H), 2.08 (s, 3H). 13C NMR (126 MHz, CDCl3) δ 170.7, 165.5, 149.7, 139.6, 137.6, 129.2, 128.9, 128.4, 127.5, 123.8, 62.1, 56.3, 42.5, 23.4. 104 Resolution of enantiomers: DAICEL Chiralcel®, OJ-H 10% IPA/Hexane 1 ml/min, 254 nm, RT 1 (major)=18.7 min, RT 2 (minor) =23.5 min. HRMS analysis (ESI): calculated for [M+H]+: C18H19ClN3O4: 376.1064; Found: 376.1057. Optical activity: [α]D20 = +86.8 (c = 0.1, CHCl3, 99% ee) O HN CH3 O N H Cl NO2 I-122x, N-((2R,3S)-3-acetamido-2-chloro-3-phenylbutyl)-4-nitrobenzamide Rf: 0.23 (70% EtOAC/Hex) Compound I-122x (22.2 mg, 57% yield, 61:39 dr, 97% ee) was synthesized following the procedure detailed in Section I-8-2 using I-70x (29.6 mg, 0.10 mmol) as starting material. Following column chromatography (SiO2/EtOAc–Hexanes gradient), though inseparable by column chromatography, the diastereomers were able to be separated by HPLC (IA, 10% IPA/Hexanes). 1H NMR (500 MHz, CDCl3) δ 8.21 (d, J = 8.8 Hz, 2H), 7.68 (d, J = 8.8 Hz, 2H), 7.43 (d, J = 7.3 Hz, 2H), 7.31 (t, J = 7.8 Hz, 2H), 7.24 – 7.18 (m, 1H), 6.71 (t, J = 5.8 Hz, 1H), 6.13 (s, 1H), 4.90 (dd, J = 8.0, 5.2 Hz, 1H), 3.85 (ddd, J = 14.5, 6.3, 5.2 Hz, 1H), 3.49 (ddd, J = 14.2, 8.0, 6.0 Hz, 1H), 2.14 (s, 3H), 1.93 (s, 3H). 13C NMR (126 MHz, CDCl3) δ 170.1, 165.2, 149.6 (HMBC correlation), 140.5, 139.2, 128.6, 128.1, 127.7, 125.9, 123.7, 67.4, 61.6, 43.5, 29.7, 24.5. Resolution of enantiomers: DAICEL Chiralcel®, IA 10% IPA/Hexane 1 ml/min, 254 nm, RT 1 (major)=15.8 min, RT 2 (minor) =18.0 min. HRMS analysis (ESI): calculated for [M+H]+: C19H21ClN3O4: 390.1221; Found: 390.1215. 105 Optical activity: [α]D20 = -19.2 (c = 0.1, CHCl3, 97% ee) O HN CH3 O N H Cl NO2 I-122x-Diastereomer-, N-((2R,3R)-3-acetamido-2-chloro-3-phenylbutyl)-4- nitrobenzamide Rf: 0.23 (70% EtOAC/Hex) 1H NMR (500 MHz, CDCl3) δ 8.27 (d, J = 8.8 Hz, 2H), 7.82 (d, J = 8.8 Hz, 2H), 7.50 – 7.45 (m, 2H), 7.39 (dd, J = 8.6, 7.0 Hz, 2H), 7.34 – 7.29 (m, 1H), 6.32 (t, J = 5.4 Hz, 1H), 6.24 (s, 1H), 4.73 (dd, J = 9.2, 3.5 Hz, 1H), 3.92 (ddd, J = 14.4, 6.6, 3.5 Hz, 1H), 3.39 (ddd, J = 14.5, 9.3, 5.3 Hz, 1H), 2.04 (s, 3H), 1.97 (s, 3H). 13C NMR (126 MHz, CDCl3) δ 169.4, 165.4, 149.8, 141.2, 139.2, 128.8, 128.2, 128.1, 126.0, 123.9, 68.7, 61.4, 42.7, 24.4, 20.3. Resolution of enantiomers: DAICEL Chiralcel®, IA 10% IPA/Hexane 1 ml/min, 254 nm, RT 1 (major)=22.1 min, RT 2 (minor) =28.1 min. HRMS analysis (ESI): calculated for [M+H]+: C19H21ClN3O4: 390.1221; Found: 390.1187. Optical activity: [α]D20 = -35.6 (c = 0.05, CHCl3, 97% ee) MeO O Cl NO2 N I-122y (5R,6S)-5-chloro-6-(4-methoxyphenyl)-2-(4-nitrophenyl)-5,6-dihydro-4H-1,3- oxazine 106 1H NMR (500 MHz, CDCl3) δ 8.23 (d, J = 8.9 Hz, 2H), 8.13 (d, J = 8.9 Hz, 2H), 7.31 (d, J = 8.7 Hz, 2H), 6.97 (d, J = 8.7 Hz, 2H), 5.21 (d, J = 7.8 Hz, 1H), 4.22 (td, J = 7.9, 4.8 Hz, 1H), 4.05 (dd, J = 17.4, 4.8 Hz, 1H), 3.87 – 3.78 (m, 4H). 13C NMR (126 MHz, CDCl3) δ 160.3, 153.6, 149.3, 138.4, 128.6, 128.4, 128.1, 123.4, 114.2, 80.8, 55.4, 53.6, 50.3. Resolution of enantiomers: DAICEL Chiralpak®, AD-H 10% IPA/Hexane 1 ml/min, 254 nm, RT 1 (minor)=17.6 min, RT 2 (major) =20.8 min. O C 2H 5 NH O C 3H 7 N H Cl NO2 I-122aa, N-((2R,3R)-2-chloro-3-propionamidohexyl)-4-nitrobenzamide Compound I-122aa (31.2 mg, 88% yield, 99% ee) was synthesized following the procedure detailed in Section I-8-6 using I-70a (24.8 mg, 0.10 mmol) as starting material. Rf: 0.29 (50% EtOAC/Hex) 107 1H NMR (500 MHz, CDCl3) δ 8.36 – 8.25 (m, 3H), 8.09 (d, J = 9.0 Hz, 2H), 5.56 (d, J = 9.3 Hz, 1H), 4.40 – 4.22 (m, 2H), 4.13 (ddd, J = 11.0, 5.2, 1.7 Hz, 1H), 2.89 (ddd, J = 13.6, 11.0, 4.3 Hz, 1H), 2.36 (q, J = 7.6 Hz, 2H), 1.71 – 1.61 (m, 1H), 1.61 – 1.51 (m, 1H), 1.41 – 1.32 (m, 2H), 1.24 (t, J = 7.6 Hz, 3H), 0.90 (t, J = 7.4 Hz, 3H). 13C NMR (126 MHz, CDCl3) δ 176.0, 164.8, 149.7, 139.2, 128.4, 123.9, 61.2, 49.0, 42.5, 34.8, 29.9, 19.3, 13.7, 10.2. HRMS analysis (ESI): calculated for [M+H]+: C16H23ClN3O4: 356.1377; Found: 356.1378. Resolution of enantiomers: DAICEL Chiralpak®, AS-H 10% IPA/Hexane 1 ml/min, 254 nm, RT 1 (minor)=13.5 min, RT 2 (major) = 28.7 min. Optical Activity: [α]D20 = -40.8 (c = 0.40, CHCl3, 99% ee) O Ph NH O C 3H 7 N H Cl NO2 I-122ab, N-((2R,3R)-3-benzamido-2-chlorohexyl)-4-nitrobenzamide Compound I-122ab (35.0 mg, 86% yield, 98% ee) was synthesized following the procedure detailed in Section I-8-6 using I-70a (24.8 mg, 0.10 mmol) as starting material. Rf: 0.65 (50% EtOAC/Hex) 1H NMR (500 MHz, CDCl3) δ 8.44 – 8.36 (m, 1H), 8.33 (d, J = 8.9 Hz, 2H), 8.15 (d, J = 8.9 Hz, 2H), 7.86 – 7.81 (m, 2H), 7.62 – 7.57 (m, 1H), 7.55 – 7.48 (m, 2H), 6.23 (d, J = 9.4 Hz, 1H), 4.53 (tdd, J = 9.2, 5.4, 1.7 Hz, 1H), 4.35 (ddd, J = 13.8, 8.7, 5.2 Hz, 1H), 4.24 (ddd, J = 10.9, 5.2, 1.7 Hz, 1H), 3.00 (ddd, J = 13.7, 10.9, 4.4 Hz, 1H), 1.81 (dtd, J = 14.0, 8.5, 6.6 Hz, 1H), 1.74 – 1.63 (m, 1H), 1.49 – 1.39 (m, 2H), 0.93 (t, J = 7.3 Hz, 3H). 108 13C NMR (126 MHz, CDCl3) δ 169.3, 164.9, 149.7, 139.2, 133.2, 132.4, 129.0, 128.4, 128.0, 123.9, 61.5, 50.0, 42.7, 34.9, 19.4, 13.7. Resolution of enantiomers: DAICEL Chiralcel®, OD-H 15% IPA/Hexane 1 ml/min, 254 nm, RT 1 (minor)=15.4 min, RT 2 (major) =30.0 min. HRMS analysis (ESI): calculated for [M+H]+: C20H23ClN3O4: 404.1377; Found: 404.1383. Optical activity: [α]D20 = -119.2 (c = 0.39, CHCl3), 98% ee) O t-Bu NH O C 3H 7 N H Cl NO2 I-122ac, N-((2R,3R)-2-chloro-3-pivalamidohexyl)-4-nitrobenzamide Compound I-122ac (33.0 mg, 86% yield, 99% ee) was synthesized following the procedure detailed in Section I-8-6 (heated to 80 °C during hydrolysis) using I-70a (24.8 mg, 0.10 mmol) as starting material. Rf: 0.65 (30% EtOAC/Hex) 1H NMR (500 MHz, CDCl3) δ 8.39 – 8.27 (m, 3H), 8.11 (d, J = 9.0 Hz, 2H), 5.72 (d, J = 9.3 Hz, 1H), 4.38 – 4.25 (m, 2H), 4.14 (ddd, J = 11.0, 5.1, 1.7 Hz, 1H), 2.81 (ddd, J = 13.6, 11.0, 4.3 Hz, 1H), 1.75 – 1.65 (m, 1H), 1.61 – 1.52 (m, 1H), 1.37 (dt, J = 15.0, 7.5 Hz, 2H), 1.29 (s, 9H), 0.91 (t, J = 7.3 Hz, 3H). 13C NMR (126 MHz, CDCl3) δ 180.7, 164.8, 149.7, 139.3, 128.4, 123.9, 61.5, 48.7, 42.6, 39.2, 34.8, 27.7, 19.3, 13.7. Resolution of enantiomers: DAICEL Chiralpak®, IA 7% IPA/Hexane 1 ml/min, 254 nm, RT 1 (minor)=8.9 min, RT 2 (major) = 10.6 min. HRMS analysis (ESI): calculated for [M+H]+: C18H27ClN3O4: 384.1690; Found: 384.1683. 109 Optical activity: [α]D20 = -38.9 (c = 0.2, CHCl3) (99% ee) I-9-2 Analytical data for vicinal chloroamidine products Ts N HN O C 3H 7 N H Cl NO2 I-173a, N-((2R,3R)-2-chloro-3-N'-tosylacetimidamido)hexyl)-4-nitrobenzamide Compound I-173a (35.1 mg, 71% yield, 99% ee) was synthesized following the procedure detailed in Section I-8-7 using I-70a (24.8 mg, 0.10 mmol) as starting material. Rf: 0.26 (50% EtOAC/Hex) 1H NMR (500 MHz, CDCl3) δ 1H NMR (500 MHz, CDCl3) δ 8.28 (d, J = 8.8 Hz, 2H), 8.21 (d, J = 8.8 Hz, 2H), 8.00 (t J=6.2 Hz, 1H), 7.71 (d, J = 8.2 Hz, 2H), 7.25 (d, J = 8.2 Hz, 2H), 5.63 (d, J = 9.1 Hz, 1H), 4.54 (td, J= 9.1, 5.5 Hz, 1H), 4.28 – 4.20 (m, 2H), 3.06 (ddd, J = 14.5, 12.2, 5.1 Hz, 1H).2.41 (s, 3H), 2.41 (s, 3H), 1.69 (dtd, J = 15.2, 9.0, 7.1 Hz, 1H), 1.60 – 1.52 (m, 1H), 1.31 (q, J = 7.5 Hz, 2H), 0.86 (t, J = 7.3 Hz, 3H). 13C NMR (126 MHz, CDCl3) δ 168.0, 165.6, 149.8, 143.3, 139.1, 138.5, 129.7, 128.9, 126.4, 123.7, 60.8, 51.2, 43.3, 34.6, 21.5, 20.9, 19.1, 13.5. Resolution of enantiomers: DAICEL Chiralpak®, IA 15% IPA/Hexane 1 ml/min, 254 nm, RT 1 (major)=13.6 min, RT 2 (minor) =19.6 min. HRMS analysis (ESI): calculated for [M+H]+: C22H28ClN4O5S: 495.1469; Found: 495.1473. Optical activity: [α]D20 = +39.7 (c = 0.2, CHCl3) (99% ee) 110 Ts N HN O C 3H 7 N H Cl NO2 I-173h, N-((2R,3S)-2-chloro-3-N'-tosylacetimidamido)hexyl)-4-nitrobenzamide Rf: 0.10 (50% EtOAC/Hex) Compound I-173h (32.1 mg, 65% yield, 95% ee) was synthesized following the procedure detailed in Section I-8-7 using I-70h (24.8 mg, 0.10 mmol) as starting material. 1H NMR (500 MHz, CDCl3) δ 8.25 (d, J = 8.8 Hz, 2H), 8.01 (d, J = 8.8 Hz, 2H), 7.71 (d, J = 8.3 Hz, 2H), 7.23 (d, J = 8.0 Hz, 2H), 7.13 (dd, J = 7.0, 4.8 Hz, 1H), 5.99 (d, J = 8.7 Hz, 1H), 4.37 (tt, J = 10.3, 8.4, 3.1 Hz, 1H), 4.24 (q, J = 5.7 Hz, 1H), 4.14 (ddd, J = 13.7, 7.8, 5.6 Hz, 1H), 3.49 (ddd, J = 14.3, 6.1, 4.5 Hz, 1H), 2.39 (s, J = 1.8 Hz, 6H), 1.81 (dddd, J = 13.6, 9.8, 6.8, 2.9 Hz, 1H), 1.56 (dtd, J = 14.6, 10.1, 4.6 Hz, 1H), 1.45 – 1.32 (m, 1H), 1.32-1.22 (m, 1H), 0.89 (t, J = 7.3 Hz, 3H). 13C NMR (126 MHz, CDCl3) δ 166.9, 166.1, 149.7, 142.9, 139.7, 139.3, 129.5, 128.5, 126.3, 123.8, 62.5, 53.3, 42.9, 31.8, 21.5, 21.2, 19.0, 13.7. Resolution of enantiomers: DAICEL Chiralpak®, IA 15% IPA/Hexane 1 ml/min, 254 nm, RT 1 (minor)=11.4 min, RT 2 (major) =17.3 min. HRMS analysis (ESI): calculated for [M+H]+: C22H28ClN4O5S: 495.1469; Found: 495.1470. Optical activity: [α]D20 = -15.8 (c = 0.1, CHCl3, 95% ee) NTs NH O BnO N H Cl NO2 111 I-173p, N-((2R,3R)-4-(benzyloxy)-2-chloro-3-(N'-tosylacetimidamido)butyl)-4- nitrobenzamide The substrate I-70p (0.1 mmol, 1.0 equiv) and (DHQD)2PHAL (3.9 mg, 5 mol%) were suspended in acetonitrile (2 mL) in a test tube with a magnetic stir bar and capped with a rubber septa. HFIP (105 µL, 1.0 mmol, 10 equiv) was added via syringe. The resulting suspension was cooled to 0 °C in an immersion cooler. After stirring for 10 min Dichloramine-T (48.0 mg, 0.2 mmol, 2 equiv) was added. The reaction was monitored by TLC and upon completion was quenched by the addition of saturated Na2S2O3 (2 mL). The reaction was concentrated to remove acetonitrile and the resultant aqueous layer was extracted with DCM (3 x 5 mL). The combined organic layers were dried with anhydrous Na2SO4 and concentrated. Column chromatography (SiO2/EtOAc–Hexanes gradient) provided the desired product I-173p in a 65% yield (34.3 mg, 96% ee). Rf: 0.10 (50% EtOAC/Hex) 1H NMR (500 MHz, CDCl3) δ 8.27 (d, J = 8.8 Hz, 2H), 8.20 (d, J = 8.8 Hz, 2H), 7.93 (dd, J = 7.6, 5.1 Hz, 1H), 7.71 (d, J = 8.3 Hz, 2H), 7.32 – 7.28 (m, 3H), 7.26 – 7.20 (m, 4H), 5.79 (d, J = 8.8 Hz, 1H), 4.78 (dtd, J = 8.6, 6.7, 1.5 Hz, 1H), 4.51 – 4.42 (m, 2H), 4.37 (ddd, J = 11.0, 4.7, 1.5 Hz, 1H), 4.22 (ddd, J = 13.6, 7.5, 4.8 Hz, 1H), 3.60 (qd, J = 10.0, 6.6 Hz, 2H), 3.13 (ddd, J = 13.7, 10.9, 5.1 Hz, 1H), 2.40 (s, 3H), 2.39 (s, 3H). 13C NMR (126 MHz, CDCl3) δ 168.3, 165.6, 149.8, 143.3, 138.9, 138.6, 136.9, 129.7, 128.9, 128.6, 128.2, 127.8, 126.5, 123.7, 73.4, 69.3, 58.1, 51.2, 43.1, 21.5, 20.9. Resolution of enantiomers: DAICEL Chiralcel®, OD-H 17.5% IPA/Hexane 1 ml/min, 254 nm, RT 1 (major)=27.1 min, RT 2 (minor) =42.8 min. 112 HRMS analysis (ESI): calculated for [M+H]+: C27H30ClN4O6S: 573.1575; Found: 573.1577. Optical activity: [α]D20 = +29.5 (c = 0.1, CHCl3, 95% ee) Ts N HN O Ph N H Cl NO2 I-173s, N-((2R,3S)-2-chloro-3-phenyl-3-((N'-tosylacetimidamido)propyl)-4- nitrobenzamide Rf: 0.20 (50% EtOAC/Hex) Compound I-173s (17.2 mg, 54% yield, 99% ee) was synthesized following the procedure detailed in Section I-8-7 using I-70s (14.1 mg, 0.05 mmol) as starting material. 1H NMR (500 MHz, CDCl3) δ 8.28 (d, J = 8.9 Hz, 2H), 8.20 (d, J = 8.9 Hz, 2H), 8.00 – 7.88 (m, 1H), 7.72 (d, J = 8.3 Hz, 2H), 7.43 – 7.31 (m, 3H), 7.31 – 7.22 (m, 4H), 6.13 (d, J = 9.3 Hz, 1H), 5.82 (d, J = 9.0 Hz, 1H), 4.68 (ddd, J = 10.8, 4.9, 1.5 Hz, 1H), 4.28 (ddd, J = 13.7, 7.1, 4.9 Hz, 1H), 3.25 (ddd, J = 13.8, 10.7, 5.3 Hz, 1H), 2.51 (s, 3H), 2.40 (s, 3H). 13C NMR (126 MHz, CDCl3) δ 167.4, 165.8, 149.8, 143.4, 138.9, 138.5, 136.2, 129.7, 129.0, 128.9, 128.7, 126.7, 126.5, 123.8, 60.6, 53.9, 43.8, 21.5, 21.3. Resolution of enantiomers: DAICEL Chiralpak®, IA 20% IPA/Hexane 1 ml/min, 254 nm, RT 1 (major)=32.0 min, RT 2 (minor) =41.3 min. HRMS analysis (ESI): calculated for [M+H]+: C25H26ClN4O5S: 529.1312; Found: 592.1312. Optical activity: [α]D20 = +120.2 (c = 0.1, CHCl3, 99% ee) 113 Ts N HN O Ph N H Cl NO2 I-173s-Diastereomer, N-((2R,3R)-2-chloro-3-phenyl-3-(N'-tosylacetimidamido)propyl)-4- nitrobenzamide Rf: 0.12 (50% EtOAC/Hex) 1H NMR (500 MHz, CD3CN) δ 8.27 (d, J = 8.9 Hz, 2H), 7.97 (d, J = 8.9 Hz, 2H), 7.59 (d, J = 8.2 Hz, 2H), 7.56 – 7.47 (m, 2H), 7.46 – 7.34 (m, 5H), 7.26 (d, J = 8.0 Hz, 2H), 5.44 (dd, J = 8.4, 6.5 Hz, 1H), 4.70 (td, J = 6.8, 4.6 Hz, 1H), 3.91 (dt, J = 14.4, 5.4 Hz, 1H), 3.51 (dt, J = 14.3, 6.4 Hz, 1H), 2.38 (s, 3H), 2.37 (s, 3H). 13C NMR (126 MHz, CDCl3) δ 166.0, 165.8, 149.8, 142.7, 139.6, 139.0, 136.2, 129.4, 129.0, 128.9, 128.4, 127.7, 126.4, 123.8, 61.6, 57.8, 43.2, 21.5, 21.3. Resolution of enantiomers: DAICEL Chiralpak®, IA 22% IPA/Hexane 1 ml/min, 254 nm, RT 1 (minor)=11.9 min, RT 2 (minor) =35.3 min HRMS analysis (ESI): calculated for [M+H]+: C25H26ClN4O5S: 529.1312; Found: 592.1312. Optical activity: [α]D20 = +54.2 (c = 0.1, CHCl3, 97% ee) I-9-3 Analytical data for derivatives N N Ts C 3H 7 NH NO2 O I-175a, N-(((4R,5S)-2-(methyl)-4-propyl-1-tosyl-4,5-dihydro-1H-imidazol-5-yl)methyl)-4- nitrobenzamide 114 To a solution of I-73a (49.4 mg, 0.1 mmol, 1 equiv) in acetonitrile (1 mL) at room temperature, Cs2CO3 was added and allowed to stir for 48 h. The reaction was quenched with the addition of water (3 mL) and extracted with DCM (3 x 4 mL). The combined organic layers were dried with anhydrous Na2SO4 and concentrated in vacuo. Column chromatography (SiO2/EtOAc–Hexanes gradient) gave the desired product I-175a in a 57% yield (26.2 mg). Rf: 0.55 (60% EtOAC/Hex) 1H NMR (500 MHz, CDCl3) δ 8.31 (d, J = 8.9 Hz, 2H), 8.09 (d, J = 8.8 Hz, 2H), 7.70 (d, J = 8.4 Hz, 2H), 7.55 – 7.47 (m, 1H), 7.39 – 7.32 (m, 2H), 4.18 (ddd, J = 11.2, 8.3, 2.7 Hz, 1H), 3.81 (ddd, J = 13.9, 6.4, 2.7 Hz, 1H), 3.46 – 3.35 (m, 1H), 3.27 (ddd, J = 14.2, 11.3, 3.0 Hz, 1H), 2.45 (s, 3H), 2.37 (d, J = 2.2 Hz, 3H), 1.62 – 1.46 (m, 2H), 1.38 – 1.28 (m, 2H), 0.90 (t, J = 7.0 Hz, 3H). 13C NMR (126 MHz, CDCl3) δ 165.7, 155.7, 149.7, 145.4, 139.6, 135.6, 130.5, 128.4, 126.7, 123.9, 67.6, 62.4, 39.8, 31.3, 21.7, 20.9, 17.9, 14.0. HRMS analysis (ESI): calculated for [M+H]+: C22H27N4O5S: 459.1702; Found: 459.1700. Optical activity: [α]D20 = +183.2 (c = 0.5, CHCl3, 99% ee) O HN O C 3H 7 N H NHTs NO2 I-176a, N-((2S,3R)-3-acetamido-2-((4-methylphenyl)sulfonamido)hexyl)-4- nitrobenzamide Rf: 0.25 (60% EtOAC/Hex) 115 Imidazoline I-175a (26.2 mg, 0.57 mmol), acetonitrile (1 mL) and a solution of HCl (1 M, 0.2 mL) were added to a vial and stirred for 15 min. Water (3 mL) was added and the solution was concentrated in vacuo and extracted with DCM (3 x 4 mL). The combined organic layers were dried with anhydrous Na2SO4 and concentrated. Column chromatography (SiO2/EtOAc–Hexanes gradient) provided the desired product I-176a in a 99% yield (27.1 mg, 99% ee). 1H NMR (500 MHz, CDCl3) δ 8.31 (d, J = 8.8 Hz, 2H), 8.05 (d, J = 8.8 Hz, 2H), 7.86 (d, J = 8.3 Hz, 2H), 7.77 (s, 1H), 7.34 (d, J = 8.5 Hz, 2H), 6.66 (d, J = 6.6 Hz, 1H), 5.66 (d, J = 7.8 Hz, 1H), 3.69 (dq, J = 8.7, 4.4 Hz, 1H), 3.60 (dd, J = 10.7, 6.6 Hz, 1H), 3.35 – 3.17 (m, 2H), 2.43 (s, 3H), 2.00 (s, 3H), 1.63-1.57 (m, 1H), 1.44 – 1.33 (m, 1H), 1.23 – 1.13 (m, 2H), 0.77 (t, J = 7.3 Hz, 3H). 13C NMR (126 MHz, CDCl3) δ 172.6, 166.3, 149.8, 143.9, 139.0, 136.8, 129.9, 128.4, 127.3, 123.9, 57.6, 52.3, 40.5, 33.6, 23.1, 21.6, 19.3, 13.4. Resolution of enantiomers: DAICEL Chiralpak®, AD-H 15% IPA/Hexane 1 ml/min, 254 nm, RT 1 (minor)=15.2 min, RT 2 (major) =22.8 min HRMS analysis (ESI): calculated for [M+H]+: C22H29ClN4O5S: 477.1808; Found: 477.1804. Optical activity: [α]D20 = +65.2 (c = 0.2, CHCl3, 99% ee) Ts NH C 3H 7 O N N N H Cl NO2 116 I-177a, N-((2R,3R)-2-chloro-3-(((Z)-(dimethylamino)((4-methylphenyl)sulfonamido) methylene)amino)hexyl)-4-nitrobenzamide The substrate I-70a (24.8 mg, 0.1 mmol, 1.0 equiv), (DHQD)2PHAL (0.8 mg, 1 mol%), and MS4Å (20 mg) were suspended in dimethylcyanamide (1 mL) in a test tube with a magnetic stir bar and capped with a rubber septa. HFIP (105 µL, 1.0 mmol, 10 equiv) was added via syringe. The resulting suspension was cooled to 0 °C in an immersion cooler. After stirring for 10 min dichloramine-T (48.0 mg, 0.2 mmol, 2 equiv) was added. The reaction was monitored by TLC and upon completion was quenched by the addition of saturated Na2S2O3 (2 mL). The reaction was concentrated to remove acetonitrile and the resultant aqueous layer was extracted with DCM (3 x 5 mL). The combined organic layers were dried with anhydrous Na2SO4 and concentrated. Column chromatography (SiO2/EtOAc–Hexanes gradient) provided the desired product I-177a in an 82% yield (42.9 mg, 98% ee). Rf: 0.35 (70% EtOAC/Hex) 1H NMR (500 MHz, CDCl3) δ 8.66 – 8.54 (m, 1H), 8.25 (d, J = 8.9 Hz, 2H), 8.17 (d, J = 8.9 Hz, 2H), 7.72 (d, J = 8.3 Hz, 2H), 7.20 (d, J = 8.3 Hz, 2H), 5.09 (d, J = 9.9 Hz, 1H), 4.67 – 4.54 (m, 1H), 4.33 – 4.18 (m, 2H), 3.30 (ddd, J = 13.3, 10.1, 4.9 Hz, 1H), 3.05 (s, 6H), 2.37 (s, 3H), 1.67 – 1.53 (m, 2H), 1.42 – 1.29 (m, 1H), 1.28 – 1.17 (m, 1H), 0.88 (t, J = 7.4 Hz, 3H). 13C NMR (126 MHz, CDCl3) δ 165.8, 156.7, 149.6, 142.1, 141.8, 139.1, 129.3, 128.9, 125.4, 123.6, 61.5, 53.7, 42.7, 39.3, 36.3, 21.4, 19.1, 13.7. 117 Resolution of enantiomers: DAICEL Chiralpak®, IA 16% IPA/Hexane 1ml/min, 254 nm, RT 1 (major)=43.8 min, RT 2 (minor) =51.9 min. HRMS analysis (ESI): calculated for [M+H]+: C23H31N5O5S: 524.1735; Found: 524.1732. Optical activity: [α]D20 = -31.9 (c = 0.50, CHCl3) (98% ee) NMe2 N N Ts C 3H 7 NH NO2 O I-178a, N-(((4R,5S)-2-(dimethylamino)-4-propyl-1-tosyl-4,5-dihydro-1H-imidazol-5- yl)methyl)-4-nitrobenzamide I-177a (26.2 mg, 0.05 mmol) was added to a 10 mL test tube with a magnetic stir bar. DMF (0.5 mL) was added via syringe. The reaction was heated to 80 °C and monitored by TLC. After the reaction reached competition reaction, it was cooled, quenched with water (5 mL) and extracted with dichloromethane (3x 5 mL). The combined organic layers were dried with anhydrous Na2SO4 and concentrated in vacuo. Column chromatography (SiO2/EtOAc–Hexanes gradient) provided the desired product I-178a in a 62% yield (15.1 mg). Rf: 0.30 (100% EtOAC) 1H NMR (500 MHz, CDCl3) δ 8.32 (d, J = 8.5 Hz, 2H), 8.10 (d, J = 8.4 Hz, 2H), 7.73 (d, J = 8.0 Hz, 2H), 7.48 (t, J = 4.5 Hz, 1H), 7.37 (d, J = 8.0 Hz, 2H), 3.87 (dt, J = 11.1, 2.9 Hz, 1H), 3.59 (ddd, J = 13.9, 5.8, 3.3 Hz, 1H), 3.38 (ddd, J = 14.2, 11.0, 3.5 Hz, 1H), 3.25 (ddd, J = 8.8, 6.1, 2.2 Hz, 1H), 2.92 (s, 6H), 2.46 (s, 3H), 1.20 – 0.93 (m, 2H), 0.63 (t, J = 7.3 Hz, 3H), 0.57 (ddd, J = 16.5, 9.0, 5.3 Hz, 1H), -0.16 (dtd, J = 14.0, 9.6, 5.1 Hz, 1H). 118 13C NMR (126 MHz, CDCl3) δ 165.6, 156.0, 149.6, 145.5, 139.6, 133.3, 130.0, 128.4, 127.9, 123.9, 66.6, 64.5, 44.7, 41.6, 38.0, 21.6, 18.9, 13.7. HRMS analysis (ESI): calculated for [M+H]+: C23H30N5O5S: 488.1968; Found: 488.1978. Optical activity: [α]D20 = +40.2 (c = 0.25, CHCl3) I-9-4 Analytical data for miscellaneous products/byproducts Cl C 3H 7 O (DHQD)2PHAL (10 mol%) N MeCN (0.05 M) H N O O DCDMH (2 equiv) NO2 HFIP (10 equiv), 0 °C 2l” 1l NO2 I-122l”, N-((2R,3R)-3-chloro-2-hydroxyhexyl)-N-methyl-4-nitrobenzamide I-70l (0.1 mmol, 1.0 equiv) and (DHQD)2PHAL (7.8 mg, 10 mol%) were suspended in acetonitrile (2 mL) in a test tube with a magnetic stir bar and capped with a rubber septa. HFIP (105 µL, 1.0 mmol, 10 equiv) was added via a syringe. The resulting suspension was cooled to 0 °C in an immersion cooler. After stirring for 10 min, DCDMH (39.4 mg, 0.2 mmol, 2 equiv) was added. Upon completion, the reaction was quenched by the addition of saturated Na2S2O3 (2 mL). The reaction was concentrated to remove the acetonitrile and the resultant aqueous layer was extracted with DCM (3 x 5 mL). The combined organics were concentrated. The combined organic layers were dried with anhydrous Na2SO4 and concentrated. Column chromatography (SiO2/EtOAc–Hexanes gradient) provided I-122l” (25.1 mg, 80% yield, 19% ee). Rf 0.68 (20% EtOAC/Hex) 1H NMR (500 MHz, CDCl3) δ 8.32 (d, J = 9.0 Hz, 2H), 8.27 (d, J = 9.0 Hz, 2H), 5.68 (td, J = 6.2, 2.2 Hz, 1H), 4.30 (ddd, J = 8.2, 5.8, 2.2 Hz, 1H), 3.31 (dd, J = 6.1, 1.7 Hz, 2H), 119 3.01 (s, 3H), 1.84 – 1.69 (m, 2H), 1.69 – 1.55 (m, 2H), 1.56 – 1.42 (m, 1H), 0.94 (t, J = 7.3 Hz, 3H). 13C NMR (126 MHz, CDCl3) δ 163.8, 150.8, 134.9, 131.1, 123.7, 73.5, 66.2, 61.6, 53.7, 37.0, 19.8, 13.4. Resolution of enantiomers: DAICEL Chiralpak®, AD-H 5% IPA/Hexane 1 ml/min, 254 nm, RT 1 (minor)=6.6 min, RT 2 (major) =7.9 min. HRMS analysis (ESI): calculated for [M+H]+: C14H20ClN2O4: 315.1111; Found: 315.1108 CF3 CF3 O N O C 3H 7 N H Cl NO2 I-174h, 1,1,1,3,3,3-hexafluoropropan-2-yl-N-((2R,3S)-2-chloro-1-(4-nitrobenzamido) hexan-3-yl)acetimidate Rf: 0.39 (25% EtOAC/Hex) 1H NMR (500 MHz, CDCl3) δ 8.32 (d, J = 8.8 Hz, 2H), 7.96 (d, J = 8.8 Hz, 2H), 6.54 (s, 1H), 6.34 (hept, J = 6.5 Hz, 1H), 4.32 – 4.21 (m, 2H), 3.69 (dt, J = 9.2, 4.0 Hz, 1H), 3.34 (ddd, J = 13.8, 9.6, 4.0 Hz, 1H), 2.08 (s, 3H), 1.75 (tdd, J = 10.1, 6.2, 3.0 Hz, 1H), 1.64 (ddt, J = 18.7, 9.6, 5.0 Hz, 1H), 1.34 – 1.17 (m, 2H), 0.94 (t, J = 7.3 Hz, 3H). 13C NMR (126 MHz, CDCl3) δ 165.5, 158.7, 149.8, 139.6, 128.2, 124.0, 65.5, 62.5, 42.3, 35.9, 19.4, 14.7, 13.9 (note the trifluoromethyl carbons and the methine of the HFIP addition are not listed since they could not be assigned with confidence, presumably due to their splitting, which led to small intensity in the NMR spectrum. 19F NMR (470 MHz, CDCl3) δ -73.01 – -73.10 (m), -73.29 – -73.44 (m). 120 HRMS analysis (ESI): calculated for [M+H]+: C18H21ClF6N3O4: 492.1125, found: 492.1110 Optical activity: [α]D20 = 27.9 (c = 0.20, CHCl3) NH O N O t-Bu N O N H Cl NO2 I-162a/b, N-((2R,3R)-2-chloro-3-((( 1-(4,4-dimethyl-2,5-dioxoimidazolidin-1-yl)-2,2- dimethylpropylidene)amino)hexyl)-4-nitrobenzamide Less polar rotamer Rf: 0.25 (30% EtOAC/Hex) 1H NMR (500 MHz, CDCl3) δ 8.25 (d, J = 8.8 Hz, 2H), 8.09 (d, J = 8.8 Hz, 2H), 7.77 (t, 1H, J = 7.5 Hz), 6.23 (s, 1H), 4.20 (ddd, J = 9.8, 4.8, 1.9 Hz, 1H), 4.15 – 4.04 (m, 1H), 3.45 (ddd, J = 9.2, 5.1, 1.9 Hz, 1H), 3.35 (ddd, J = 13.4, 9.9, 5.1 Hz, 1H), 1.89 (dtd, J = 13.2, 9.3, 4.4 Hz, 1H), 1.56 (s, 3H), 1.48 (s, 3H), 1.27 (s, 9H), 1.32-1.11 (m, 3H), 0.85 (t, J = 7.2 Hz, 3H). 13C NMR (126 MHz, CDCl3) δ 175.5, 165.5, 155.4, 154.9, 149.3, 139.6, 128.8, 123.6, 60.1, 60.0, 59.4, 43.4, 41.3, 34.3, 28.4, 25.4, 25.3, 18.8, 14.0. I-162a/b, More polar rotamer Rf: 0.25 (30% EtOAC/Hex) 1H NMR (500 MHz, CDCl3) δ 8.29 (d, J = 8.9 Hz, 2H), 8.05 (d, J = 8.8 Hz, 2H), 7.29 (t, J = 6.3 Hz, 1H), 5.79 (s, 1H), 4.22 (ddd, J = 8.9, 5.7, 2.2 Hz, 1H), 3.98 (ddd, J = 13.7, 6.8, 121 5.7 Hz, 1H), 3.48 (td, J = 8.7, 4.5 Hz, 1H), 3.35 (td, J = 5.6, 2.7 Hz, 1H), 1.96 – 1.85 (m, 1H), 1.68 (s, 3H), 1.52 (s, 3H), 1.41 – 1.28 (m, 3H), 1.25 (s, 9H), 0.85 (t, J = 7.2, 3H). 13C NMR (126 MHz, CDCl3) δ 177.0, 165.6, 155.3, 153.5, 149.6, 139.5, 128.6, 123.6, 60.6, 59.7, 59.7, 43.5, 41.2, 33.5, 28.4, 25.6, 25.2, 18.7, 13.8. HRMS analysis (ESI): calculated for [M+H]+: C23H33ClN5O5: 494.2170; Found: 494.2149 Optical activity: [α]D20 = +40.2 (c = 0.25, CHCl3) O N O t-Bu N O N H Cl NO2 I-165, N-((2R,3R)-2-chloro-3-(((1-(2,5-dioxopyrrolidin-1-yl)-2,2- dimethylpropylidene)amino)hexyl)-4-nitrobenzamide Rf: 0.20 (30% EtOAC/Hex) 1H NMR (500 MHz, CDCl3) δ 8.29 (d, J = 8.8 Hz, 2H), 8.02 (d, J = 8.8 Hz, 2H), 7.16 – 7.09 (m, 1H), 4.19 (ddd, J = 8.2, 6.4, 2.2 Hz, 1H), 3.85 (dt, J = 13.9, 6.4 Hz, 1H), 3.57 (ddd, J = 13.8, 8.0, 5.7 Hz, 1H), 3.24 (ddd, J = 8.0, 5.4, 2.3 Hz, 1H), 2.97 – 2.62 (m, 4H), 1.94 – 1.81 (m, 1H), 1.33 – 1.23 (m, 3H), 1.21 (s, 9H), 0.84 (t, J = 7.1 Hz, 3H). 13C NMR (126 MHz, CDCl3) δ 176.6, 175.1, 165.4, 156.5, 149.6, 139.5, 128.5, 123.7, 61.3, 60.3, 43.6, 40.8, 33.6, 28.7, 28.7, 28.4, 18.7, 13.9. HRMS analysis (ESI): calculated for [M+H]+: C22H30ClN4O5: 465.1905; Found; 465.1907 Optical activity: [α]D20 = +63.8 (c = 0.35, CHCl3) 122 I-9-5 Analytical Data for Starting Materials C 3H 7 O N H I-70b, (Z)-N-(hex-2-en-1-yl)benzamide Rf: 0.26 (20% EtOAC/Hex) 1H NMR (500 MHz, CDCl3) δ 7.81-7.76 (m, 2H), 7.53 – 7.47 (m, 1H), 7.46-7.41 (m, 2H), 6.06 (s, 1H), 5.64 (dtt, J = 10.3, 7.4, 1.4 Hz, 1H), 5.53 (dtt, J = 10.7, 7.0, 1.5 Hz, 1H), 4.11 (t, J = 6.1 Hz, 2H), 2.13 (q, J = 7.4 Hz, 2H), 1.43 (dt, J = 14.8, 7.4 Hz, 2H), 0.94 (t, J = 7.3 Hz, 3H). 13C NMR (126 MHz, CDCl3) δ 167.5, 134.7, 134.3, 131.5, 128.7, 127.0, 125.3, 37.3, 29.6, 22.8, 13.9. HRMS analysis (ESI): calculated for [M+H]+: C13H18NO: 204.1388; Found: 204.1386 C 3H 7 O N H OMe I-70c, (Z )-N-(hex-2-en-1-yl)-4-methoxybenzamide Rf: 0.38 (20% EtOAC/Hex) 1H NMR (500 MHz, CDCl3) δ 7.74 (d, J = 8.9 Hz, 2H), 6.93 (d, J = 8.9 Hz, 2H), 5.94 (s, 1H), 5.63 (dtt, J = 10.4, 7.3, 1.4 Hz, 1H), 5.56 – 5.46 (m, 1H), 4.10 (, J = 6.1 Hz, 2H), 3.86 (s, 3H), 2.13 (q, J = 6.7 Hz, 2H), 1.43 (h, J = 7.4 Hz, 2H), 0.94 (t, J = 7.4 Hz, 3H). 13C NMR (126 MHz, CDCl3) δ 166.9, 162.1, 134.0, 128.6, 126.9, 125.2, 113.7, 55.4, 37.1, 29.4, 22.7, 13.7. HRMS analysis (ESI): calculated for [M+H]+: C14H20NO2: 234.1494; Found: 234.1490 123 C 3H 7 O N H F I-70d, (Z)-4-fluoro-N-(hex-2-en-1-yl)benzamide Rf: 0.15 (10% EtOAC/Hex) 1H NMR (500 MHz, CDCl3) δ 7.78 (dd, J = 8.6, 5.3 Hz, 2H), 7.09 (t, J = 8.6 Hz, 2H), 6.11 (s, 1H), 5.67 – 5.56 (m, 1H), 5.56 – 5.46 (m, 1H), 4.08 (t, J = 6.1 Hz, 2H), 2.11 (q, J = 7.4 2H), 1.41 (h, J = 7.3 Hz, 2H), 0.92 (t, J = 7.4 Hz, 3H). 13C NMR (126 MHz, CDCl3) δ 166.4, 164.7 (d, J = 251.8 Hz), 134.2, 130.7 (d, J = 3.3 Hz), 129.2 (d, J = 9.0 Hz), 124.9, 115.6 (d, J = 21.9 Hz), 37.3, 29.4, 22.6, 13.7. 19F NMR (470 MHz, CDCl3) δ -108.40. HRMS analysis (ESI): calculated for [M+H]+: C13H17FNO: 222.1294; Found: 222.1287 C 3H 7 O N H t-Bu I-70e, (Z )-4-(tert-butyl)-N-(hex-2-en-1-yl)benzamide Rf: 0.33 (20% EtOAC/Hex) 1H NMR (500 MHz, CDCl3) δ 7.71 (d, J = 8.5 Hz, 2H), 7.45 (d, J = 8.5 Hz, 2H), 5.99 (s, 1H), 5.63 (dtt, J = 10.4, 7.3, 1.4 Hz, 1H), 5.57 – 5.48 (m, 1H), 4.11 (t, J = 6.1 Hz, 2H), 2.13 (q, J = 7.6, 2H), 1.43 (h, J = 7.3 Hz, 2H), 1.34 (s, 9H), 0.94 (t, J = 7.3 Hz, 3H). 13C NMR (126 MHz, CDCl3) δ 167.3, 154.9, 134.1, 131.7, 126.7, 125.5, 125.2, 37.1, 34.9, 31.2, 29.4, 22.7, 13.7. HRMS analysis (ESI): calculated for [M+H]+: C17H26NO: 260.2014; Found: 260.2011 124 C 3H 7 O N H I-70g, (Z )-N-(hex-2-en-1-yl)acetamide Rf: 0.23 (70% EtOAC/Hex) 1H NMR (500 MHz, CDCl3) δ 5.56 (dtt, J = 10.6, 7.5, 1.6 Hz, 1H), 5.46 (s, 1H), 5.40 (dtt, J = 10.8, 7.0, 1.6 Hz, 1H), 3.88 (t, J = 6.0 Hz, 2H), 2.04 (q, J = 7.6 Hz, 2H), 1.98 (s, 3H), 1.38 (h, J = 7.3 Hz, 2H), 0.90 (t, J = 7.4 Hz, 3H). 13C NMR (126 MHz, CDCl3) δ 169.9, 133.8, 125.1, 36.8, 29.3, 23.3, 22.6, 13.7. HRMS analysis (ESI): calculated for [M+H]+: C8H16NO: 142.1232; Found: 142.1229. C 3H 7 O N O I-70j, (Z )-2-(hex-2-en-1-yl)isoindoline-1,3-dione Rf: 0.17 (10% EtOAC/Hex) 1H NMR (500 MHz, CDCl3) δ 7.84 (dd, J = 5.4, 3.1 Hz, 2H), 7.70 (dd, J = 5.4, 3.0 Hz, 2H), 5.64 – 5.55 (m, 1H), 5.47 (dtd, J = 10.8, 7.0, 1.5 Hz, 1H), 4.32 (d, J = 7.0 Hz, 2H), 2.24 (q, J = 7.4 Hz, 2H), 1.44 (p, J = 7.3 Hz, 2H), 0.95 (t, J = 7.4 Hz, 3H). 13C NMR (126 MHz, CDCl3) δ 168.1, 134.4, 133.9, 132.3, 123.2, 123.0, 34.9, 29.3, 22.6, 13.8. HRMS analysis (ESI): calculated for [M+H]+: C14H16NO2: 230.1181; Found: 230.1181 C 3H 7 O O NO2 I-70k, (Z)-hex-2-en-1-yl 4-nitrobenzoate 125 THF, 0 °C to 23 °C, C 3H 7 O C 3H 7 DMAP, NEt3, O OH 4-nitrobenzoyl chloride I 1k NO2 Alcohol I (400 mg, 4.0 mmol, 1.0 equiv) was placed in an oven-dried round bottom flask with stir bar under argon. THF (20 mL) and DMAP (12 mg, 0.1 mmol, 0.05 equiv) was added and the reaction was cooled to 0 °C, after which, 4-nitrobenzoyl chloride (814 mg, 4.4 mmol, 1.1 equiv) was added. Reaction progress was monitored by TLC and quenched at 2 h by the addition of water (5 mL). The reaction was concentrated in vacuo to remove THF. The aqueous phase was extracted with dichloromethane (3 x 10 mL). The combined organic layers were dried with anhydrous Na2SO4 and concentrated. Column chromatography (SiO2/EtOAc–Hexanes gradient) provided 1j in a 91% yield (909 mg). Rf: 0.33 (10% EtOAC/Hex) 1H NMR (500 MHz, CDCl3) δ 8.29 (d, J = 9.1 Hz, 2H), 8.22 (d, J = 9.0 Hz, 2H), 5.75 (dtt, J = 11.0, 7.1, 1.0 Hz, 1H), 5.67 (dtt, J = 11.0, 6.9, 1.3 Hz, 1H), 4.92 (d, J = 6.4 Hz, 2H), 2.21 – 2.11 (m, 2H), 1.44 (h, J = 7.4 Hz, 2H), 0.93 (t, J = 7.4 Hz, 3H). 13C NMR (126 MHz, CDCl3) δ 164.6, 150.5, 136.3, 135.7, 130.7, 123.5, 122.7, 61.7, 29.6, 22.5, 13.7. C 3H 7 O N NO2 I-70l, (Z )-N-(hex-2-en-1-yl)-N-methyl-4-nitrobenzamide C 3H 7 O C 3H 7 O DMF, 0 °C, NaH N N H iodomethane NO2 NO2 I-70a I-70l 126 I-70a (124 mg, 0.5 mmol, 1.0 equiv) was added to a flame dried round bottom flask with stir bar under argon. Distilled DMF (5 mL) was added and the reaction was cooled to 0 °C. After stirring for 5 min, iodomethane (0.047 mL, 0.75 mmol, 1.5 equiv) was added via syringe and the reaction was slowly warmed to room temperature. The reaction was monitored by TLC and reached completion at 1 h. It was again cooled to 0 °C. Water (1 mL) was added dropwise to quench the reaction. After the exotherm was complete, water (10 mL) and dichloromethane (5 mL) were added, and the organic layer was separated. The organics were washed with water (3 x 5 mL) and then concentrated. Column chromatography (SiO2/EtOAc–Hexanes gradient) provided I-70l in a 88% yield (121.8 mg). I-70l exists as two rotamers in chloroform at room temperature in a ratio of 0.56:0.44. Major rotamer: 1H NMR (500 MHz, CDCl3) δ 8.27 (d, J = 8.0 Hz, 2H), 7.58 (d, J = 8.6 Hz, 2H), 5.61 (dd, J = 12.5, 5.9 Hz, 1H), 5.37 (dt, J = 11.0, 6.6 Hz, 1H), 3.83 (d, J = 6.6 Hz, 2H), 3.08 (s, 3H), 1.85 (q, J = 7.4 Hz, 2H), 1.33 (q, J = 7.4 Hz, 2H), 0.84 (t, J = 7.4 Hz, 3H). Minor rotamer: 1H NMR (500 MHz, CDCl3) δ 8.27 (d, J = 8.0 Hz, 2H), 7.58 (d, J = 8.6 Hz, 2H), 5.72 (q, J= 8.3 Hz, 1H), 5.47 (dd, J = 10.0, 7.5 Hz, 1H), 4.23 (d, J = 7.1 Hz, 2H), 2.87 (s, 3H), 2.14 (t, J = 7.4 Hz, 2H), 1.44 (q, J = 7.4 Hz, 2H), 0.94 (t, J = 7.4 Hz, 3H). Carbon NMR of the mixture is not reported since it was not possible to assign peaks to the major and minor components with confidence. HRMS analysis (ESI): calculated for [M+H]+: C14H20N2O3: 263.1396; Found: 263.1406 127 O C6H13 N H NO2 I-70q, (E)-4-nitro-N-(non-2-en-1-yl)benzamide Rf: 0.53 (40% EtOAc/Hex) 1H NMR (500 MHz, CDCl3) δ 8.30 (d, J = 8.8 Hz, 2H), 7.95 (d, J = 8.8 Hz, 2H), 6.15 (s, 1H), 5.78-5.71 (m, 1H), 5.60 – 5.51 (m, 1H), 4.06 (t, J = 6.6 Hz, 2H), 2.06 (q, J = 8.1, 7.5 Hz, 2H), 1.38 (q, J = 7.2, 6.7 Hz, 2H), 1.35 – 1.24 (m, 6H), 0.89 (t, J = 7.4 Hz, 3H) 13C NMR (126 MHz, CDCl3) δ 165.1, 149.6, 140.2, 135.3, 128.1, 124.7, 123.9, 42.4, 32.3, 31.7, 29.0, 28.9, 22.6, 14.1. HRMS analysis (ESI): calculated for [M+H]+: C16H23N2O3: 291.1709; Found: 291.1706. Cl O N H NO2 1-70t, (Z)-N-(3-(4-chlorophenyl)allyl)-4-nitrobenzamide Rf: 0.25 (30% EtOAC/Hex) 1H NMR (500 MHz, CDCl3) δ 8.29 (d, J = 8.8 Hz, 2H), 7.90 (d, J = 8.7 Hz, 2H), 7.34 (d, J = 8.5 Hz, 2H), 7.21 (d, J = 8.4 Hz, 2H), 6.62 (d, J = 11.5 Hz, 1H), 6.25 (s, 1H), 5.78 (dt, J = 11.5, 6.7 Hz, 1H), 4.36 (ddd, J = 7.0, 5.5, 1.9 Hz, 2H). 13C NMR (126 MHz, CDCl3) δ 165.3, 149.7, 139.8, 134.4, 133.4, 131.3, 130.0, 128.7, 128.1, 127.6, 123.9, 38.6. HRMS analysis (ESI): calculated for [M+H]+: C16H14ClN2O3: 317.0693; Found: 317.0693. 128 Me O Ph N H NO2 I-70x, (E)-4-nitro-N-(3-phenylbut-2-en-1-yl)benzamide Rf: 0.43 (40% EtOAC/Hex) 1H NMR (500 MHz, CDCl3) δ 8.31 (d, J = 8.7 Hz, 2H), 7.96 (d, J = 8.8 Hz, 2H), 7.46 – 7.40 (m, 2H), 7.39 – 7.32 (m, 2H), 7.32 – 7.28 (m, 1H), 6.22 (s, 1H), 5.88 (td, J = 7.1, 1.5 Hz, 1H), 4.31 (t, J=6.3 2H), 2.18 (s, 3H). 13C NMR (126 MHz, CDCl3) δ 165.4, 149.6, 142.5, 140.1, 139.7, 128.4, 128.1, 127.6, 125.8, 123.9, 122.3, 38.9, 16.2. 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D.; Roy, S.; Phukan, P., A Metal-Free Protocol for Aminofunctionalization of Olefins Using TsNBr2. J. Org. Chem. 2016, 81, 5423- 32. 63. Lykke, L.; Carlsen, B. D.; Rambo, R. S.; Jorgensen, K. A., Catalytic asymmetric synthesis of 4-nitropyrazolidines: an access to optically active 1,2,3-triamines. J. Am. Chem. Soc. 2014, 136, 11296-9. 64. Ingalls, E. L.; Sibbald, P. A.; Kaminsky, W.; Michael, F. E., Enantioselective Palladium-Catalyzed Diamination of Alkenes Using N-Fluorobenzenesulfonimide. J. Am. Chem. Soc. 2013, 135, 8854-8856. 65. Cardona, F.; Goti, A., Metal-catalysed 1,2-diamination reactions. Nat. Chem. 2009, 1, 269-275. 66. Du, H. F.; Zhao, B. G.; Shi, Y., Catalytic asymmetric allylic and homoallylic diamination of terminal olefins via formal C-H activation. J. Am. Chem. Soc. 2008, 130, 8590. 67. Jiang, H.; Nielsen, J. B.; Nielsen, M.; Jorgensen, K. A., Organocatalysed asymmetric beta-amination and multicomponent syn-selective diamination of alpha,beta- unsaturated aldehydes. Chemistry (Easton) 2007, 13, 9068-9075. 68. Du, H. F.; Yuan, W. C.; Zhao, B. G.; Shi, Y. A., Catalytic asymmetric diamination of conjugated dienes and triene. J. Am. Chem. Soc. 2007, 129, 11688. 136 Chapter II Bromenium and Chlorenium Mechanistic Divergence II-1 Catalytic Bromenium and Chlorenium Induced Reactions Halofunctionalization reactions serve as one of the early transformations introduced in sophomore organic chemistry. The mechanism of this family of reactions is often portrayed in a simplified manner that does not satisfy observed reactivity reflected in the dependence on both the halenium donor and the nucleophile; furthermore, little effort explored dissimilarities between different halenium ions, halenium sources, and nucleophiles in their roles in dictating reaction pathways. We were particularly drawn to dissecting differences between bromenium and chlorenium induced reactions with allyl amides when we discovered a divergent reaction with the chlorenium reagent providing the intermolecular chloroamide product and the analogous bromenium reagent yielding the bromocyclization product (Figure II-1). To the best of our knowledge, this is the first halenium dependent divergent reaction. Through investigation of nucleophile and electrophile reactivity, we were able to redirect the bromenium induced reactions to provide a strong preference for the intermolecular bromoamide product II-14 (Table II-1). Mechanistic analysis through Eyring plots examine the enthalpic and entropic variables as a function of nitrile nucleophile and bromenium sources. Taken together, this hints at a concerted mechanism for intermolecular bromofunctionalizations. II-2 Bromenium Reaction Divergence The stereodefined carbon bromine bond is a highly valuable functionality in organic chemistry. Recent advancements display its utility in downstream synthesis and its 137 increased ability to halogen bond is structurally significant and unique to chlorine. While chlorenium has served as the primary halogen electrophile in previous alkene halofunctionalizations, we were delighted that the intermolecular enantioselective halofunctionalizations previously developed within our laboratory were highly compatible with both chlorenium and bromenium induced reactions. This enabled the construction of stereodefined vicinal bromoethers (II-5)1 and bromochlorides (II-6)2 with efficiency similar to their chlorine analogs (Figure II-2). To our surprise, the extension of our halo-Ritter chemistry3 is incompatible with dibromodimethyl hydantoin (DBDMH), the bromenium equivalent of DCDMH. Interestingly, this reaction condition cleanly provided oxazoline (II- 7) in 75% enantiomeric excess with no trace of the Ritter product. The use of NBS, the bromenium source of choice for dihalogenation and bromoetherification reactions, provided only a trace of the intermolecular product (~2% intermolecular product). While background reactions for both bromo and chlorofunctionalization reactions can lead to cyclization, conditions for the bromoamidation yield the cyclization product in 75% ee; thus, under these conditions, the cyclization product is indeed a catalyzed process. To the best of our knowledge, this reaction is the first report of a halenium dependent divergent reaction. This focus of this section is to elucidate the origin of the observed divergence in catalytic halofunctionalization reaction. 138 OMe O OMe O DCDMH, MeOH NBS, MeOH C 3H 7 N Ar C 3H 7 N Ar H (DHQD)2PHAL (DHQD)2PHAL H Cl Br II-2 II-5 87% yield, 99% ee 92% yield, 98% ee C 3H 7 O Cl O Cl O N Ar C 3H 7 N Ar DCDMH, LiCl H NBS, LiCl C 3H 7 N Ar H (DHQD)2PHAL II-1 H Cl (DHQD)2PHAL Br II-3 Ar = pNO2C6H4 II-6 91% yield, 98% ee 97% yield, 99% ee NHAc O Br O Ar C 3H 7 N Ar DCDMH, MeCN DBDMH, MeCN H (DHQD)2PHAL (DHQD)2PHAL C 3H 7 N Cl II-4 II-7 90% yield, 99% ee 82% yield, 75% ee Figure II-1: Divergent reaction paths observed with chlorenium and bromenium reagents II-2-1 Kinetic Competition Studies for Catalyzed Halofunctionalizations a b Br Br R R N N O O O O H H N Br Br N Br O O O O Br Br N N Br N N Br O O Br N N Br N N Br O O O O II-8 II-9 II-10 II-11 Figure II-2: (a) Hydrogen bond assisted bromenium transfer (b) Halogen bond assisted bromenium transfer We performed comparative kinetic studies in a preliminary effort to probe the origin of the observed reaction divergence for the bromenium and chlorenium induced reactions. The competition reactions serve as a gauge of the relative reaction rates, as well as probe hydrogen (Figure II-2a)4 and/or halogen bond (Figure II-2b)5-6 as the potential origin of 139 the reaction divergence. These studies lay the groundwork for the development of an enantioselective bromoamidation of alkenes. II-2-1-1 Nucleophile Dependent Kinetic Competition Study The divergent reaction paths illustrated in Figure II-1 suggest that the nucleophile plays a role in the ultimate fate of the reaction. Acetonitrile, the weakest nucleophile tested, is the only one that failed to provide the intermolecular product. While nucleophilicity appears to function as the determining factor in the reaction pathway, each reaction is performed in a different protic medium. This is significant as proton donors are known to function in different roles for catalytic asymmetric halofunctionalization ranging from activation of halenium ion sources (Figure II-2a)7-9 to modulating the confirmation of cinchona alkaloid catalysts.10 Cognizant of the fact that different proton donors with different polarities have been employed as solvents in bromoetherification (methanol cosolvent) and bromochlorination (trifluoroethanol solvent), we sought to compare a successful nucleophile with an unsuccessful nucleophile in the same reaction medium. If nucleophilicity plays a role in dictating the product distribution, then there should be a preference for the stronger nucleophile to appear in the product. We viewed a 1:1 molar ratio of methanol with acetonitrile as the ideal medium to study as methanol reacts cleanly to provide the intermolecular product and acetonitrile only provides the cyclized product. We observed exclusive formation of II-2 (Figure II-3a), hence displaying methanol's nucleophilic superiority. To support the proposal that enhanced nucleophilicity modulates the reaction pathway as opposed to the nucleophile’s ability to function as a hydrogen bond donor, we 140 employed a 1:1 molar concentration of acetonitrile and dimethylcyanamide (DMC) in dichloramine-T initiated chloroamidation (Figure II-3b). The dimethylcyanamide nucleophile outcompeted acetonitrile yielding an 8:1 ratio of the two corresponding products. This displays the ability of a stronger nitrile nucleophile to redirect the reaction. a 10 Mol% (DHQD)2PHAL OMe O C 3H 7 NH 2 equiv. NCP, Ar C 3H 7 N Ar MeCN:MeOH 1:1 , RT H O Cl II-1 II-2 Ar=pNO2-Ph Exclusive Product b NTs NTs 1 mol% (DHQD)2PHAL C 3H 7 O 1.25 equiv. TsNCl2 N NH O NH O N Ar MeCN:DMC 1:1 H C 3H 7 N Ar C 3H 7 N Ar 0.05 M, -30°C H H 10.0 equiv. HFIP Cl Cl II-1 II-12 II-13 DMC Ratio of II-12:II-13~8:1 Me2N N Figure II-3: Nucleophile dependent kinetic competition study II-2-1-2 Halenium Dependent Kinetic Competition Study The use of competition reactions between analogous chlorenium and bromenium reagents probes the relative rates of chlorenium and bromenium induced halofunctionalizations and potential for halogen bonding (Figure II-2b) to redirect the reaction pathway.5-6 Subjecting II-1 to a solution of a 1:1 molar ratio of N- chlorophthalimide (NCP) and N-bromophthalimide (NBP) provided the bromocyclized product II-7 with no trace of chlorofunctionalization or Ritter products (Figure II-4). This 141 result indicates the increased reaction rate for bromofunctionalizations relative to chlorofunctionalizations. 10 mol% (DHQD)2PHAL 1.5 equiv NBP 1.5 equiv. NCP, Br O Ar C 3H 7 NH Ar N MeCN, RT, 5.0 equiv. HFIP C 3H 7 O II-1 II-7 Ar=pNO2-Ph Exclusive Product Figure II-4: Bromenium and chlorenium kinetic competition The results of the nucleophile competition reactions prompted efforts to redirect the reaction pathway and provide a catalytic asymmetric bromo Ritter product. Comparing acetonitrile and methanol, methanol was significantly faster. The effect of nucleophilicity was also apparent in the competitive reaction between DMC and acetonitrile. Additionally, between analogous chlorenium (NCP) and bromenium (NBP) sources, bromenium reacted faster than chlorenium. The results of the studies suggest the use of a stronger nitrile nucleophile and a less potent (i.e., higher HalA) bromenium source could lead to a successful enantioselective bromo Ritter reaction. II-2-2 Catalytic Asymmetric Bromoamidation Optimization With guiding principles discussed in Section II-2-1 in hand, we aspired to develop an intermolecular bromoamidation reaction. The optimization of this reaction is shown in Table II-1. As previously mentioned, we hypothesized that a stronger nitrile nucleophile could potentially outcompete the cyclization reaction and provide the bromo Ritter product. We viewed DMC’s enhanced nucleophilicity as the ideal mode to test to this hypothesis having already displayed its nucleophilic superiority (Figure II-3b). Gratifyingly, the employment of DMC (entry 2) greatly improved the yield, providing a 39% yield of II-8. An 142 increase in hexafluoroisopropanol (HFIP) equivalents (entry 3) proved advantageous, further improving the yield of the intermolecular product. Next, we compared different bromonium sources and their ability to modulate the reaction pathway. The potent halenium donor N-bromosaccharine (HalA of 112.2 kcal/mol in polar solvent) completely reverted selectivity to produce the cyclization product II-7 (entry 5). Additionally, under these conditions, II-7 was racemic. Use of weaker bromenium sources (based on their HalA values) led to improved II-7:II-14 ratios. For example, the use of N- bromophthalimide (HalA of 131.3 kcal/mol in polar solvent) offered improved selectivity favoring the Ritter product in preference to cyclization in roughly a ~ 4:1 ratio. Further optimization displayed that HFIP positively affects the reaction with 100 equivalents providing the optimal results. Table II-1: Catalytic bromoamidation optimization CF3 Temperature Ar CF3 O (DHQD)2PHAL (10 mol%) C 3H 7 O O Nitrile Solvent 0.1 M Me2N N O N + N Ar HFIP, Br+ source Br H C 3H 7 N Ar II-1 then acid workup H C 3H 7 Br Ar=pNO2-C6H4 II-7 II-14 Entry Solvent Temp °C HFIP Equiv. Br+ Source Ratio II-7:II-14a Yield (II-14)b ee (II-14)c 1 ACN -30 10 DBDMH 100:0d 0d NA 2 DMC -40 10 DBDMH 45:55 39 99% 3 DMC -40 20 DBDMH 42:58 47 99% 4 DMC -40 20 NBSAC 100:0 0 NA 5 DMC -40 20 N-Bromophthalimide 19:81 69 99% 6 DMC -40 100 N-Bromophthalimide 6:94 79 99% MeCN DMC NBSAC DBDMH N-Bromophthalimide O O O O S Br N Me N N N Br N N Br Br N O O O HalA: 112.2 kcal/mol HalA: 123.8 kcal/mol HalA: 131.3 kcal/mol a Ratio determined by NMR of crude reaction mixture b NMR yield with triphenylmethane standard c enantiomeric excess determined by chiral HPLC. d There was no yield for the respective Ritter product 143 As indicated by the enantiomeric excess of both II-7 and II-14, one can deduce that each reaction is efficiently catalyzed by (DHQD)2PHAL, yet the selectivity can be inverted through the use of a large excess of HFIP. While the exact role of HFIP is uncertain at this time, protic additives are known to serve multiple roles in (DHQD)2PHAL catalyzed halofunctionalizations. Two behaviors are particularly relevant to the divergent reactivity: 1) Protic additives are known to induce confirmational changes in (DHQD)2PHAL upon protonation of the quinuclidine nitrogen atom. A modified catalyst conformation may catalyze one reaction in preference of the other. 2) While (DHQD)2PHAL was employed as the catalyst in both halolactonization and intermolecular halofunctionalizations, mechanistic investigations suggest different roles for the quinuclidine nitrogen atom. In halolactonization reactions, the quinuclidine nitrogen atom acts as a base to enhance the nucleophilicity of the carboxylic acid. Conversely, in the case of haloetherification reactions, the polar protic solvent aids in the halogenation of the quinuclidine, which then transfers the halenium ion to the alkene. We speculate that HFIP might be playing a similar role in the divergent catalytic reactivity seen in Table II-2. The less of the protic additive used, the more likely the quinuclidine exists as a free base which can hydrogen bond with the amide; thus, enhancing the nucleophilicity for halocyclization (Figure II-5a, II-15). Additionally, HFIP functions as a 144 a ‡ Br O C 3H 7 O DBDMH N (DHQD)2PHAL N H N N Br II-7 N Ar O H H R H O C 3H 7 Ar II-1 II-15 Ar = pNO2-C6H4 R = (DHQD)2PHAL N N O O O O N N N N (DHQD)2PHAL b O H N N Br O BDMH O HC3H7 Br N Nuc N Br Br N II-1, Nuc Br N II-14 Polar Protic Solvent O R H O R (DHQD)2PHAL N H H DBDMH Ar II-16 II-17 R = (DHQD)2PHAL R = (DHQD)2PHAL c O CF3 H C 3H 7 O C 3H 7 O CF3 HFIP N Ar N Ar H H II-1 II-1 complex Ar = pNO2-C6H4 Attenuated Carbonyl Nucleophilicity? Figure II-5: Potential roles of HFIP in redirecting catalytic bromofunctionalizations. (a) Quinuclidine activating the amide providing II-7 (b) Quinuclidine functioning as a Lewis base for chlorenium transfer (c) HFIP attenuating the nucleophilicity of the amide carbonyl catalyst to lead to II-16, which has served as a key intermediate in intermolecular haloetherification reactions. It is reasonable to speculate that these two reactions are operating under different catalytic mechanisms with the same catalyst. One with less HFIP, that leads to the amide cyclization 145 through II-15, and an alternative mechanism with more HFIP that yields II- 16 leading to the intermolecular product. It should also be noted that HFIP’s ability to hydrogen bond may attenuate the nucleophilicity of the amide oxygen, leading to less II-7. (Figure II-5c). II-2-3 Nucleophile Assisted Alkene Activation in Catalytic Bromofunctionalization Reactions a CF3 Ar CF3 O O Me2N N O N II-7‡ Br C 3H 7 N Ar II-14‡ C 3H 7 H Br II-7 II-14 D SM Br H II-7 N Ar II-14 H N Ar C 3H 7 O Product distribution would be C 3H 7 O II-18 independent of bromenium source in a stepwise halofunctionalization II-1 pNO2-C6H4 Rate independent of nucleophile Product distribution independent of electrophile NMe2 b II-7 ‡ Ar N II-14 ‡ NH O C 3H 7 H H H H H N C 3H 7 O Br II-7 Br Ar SM D II-14 D H N Ar II-7‡ II-14‡ C 3H 7 O II-1 pNO2-C6H4 Product distribution would be dependent on bromenium source in a concerted halofunctionalization Figure II-6: (a) Classical reaction pathway which electrophile and nucleophile should have no influence on product distribution. (b) Mechanism with sensitivity to electrophile and nucleophile The main challenge of bromoamidation optimization (Table II-1) was the improvement of the ratio of the intermolecular product II-14 to the cyclization product II-7. 146 We discovered a high sensitivity to the bromenium donor with NBP providing a 4:1 ratio in preference of product II-14 (entry 5) while N-bromosaccharine only provided the intramolecular product II-7 (entry 3). This contradicts the classical reaction pathway (Figure II-6a) that proceeds through the formation of haliranium ion II-18, in which the selectivity determining step does not involve the bromenium donor's counteranion and therefore, product ratios should be independent of the donor. Alternatively, the dependence of the bromenium donor on product distribution suggests that it is involved in the selectivity determining step of the bromofunctionalization. This led us to the initial hypothesis that the intermolecular bromoamidation is a concerted addition of the bromenium and nucleophile to the alkene. The next set of experiments is focused on the relative entropic and enthalpic barriers to activation leading to products II-7 and II-14 and how a catalytic and concerted mechanism would affect those variables. II-2-4 Eyring Analysis of Competitive Reactions We employed Eyring analysis to elucidate the mechanistic variables dictating the preference of II-7 and II-14 in terms of nucleophile and electrophile.11 Considering that both intramolecular and intermolecular reactions are irreversible, the product ratios directly reflect the relative Gibbs free energies of the two selectivity determining step (or ∆∆G‡). It is important to recognize that ∆G‡ is comprised of enthalpy (∆H‡) and entropy (∆S‡) (∆G‡ = ∆H‡-T∆S‡), and therefore, the significance of the entropic barrier is scaled by temperature. This has enabled the elucidation of ∆H‡ and ∆S‡ by studying the effect of temperature on reaction rate. We sought to apply this in a comparative context between 147 II-7 and II-14 to probe the relative enthalpic and entropic factors leading each product to understand factors that lead to the divergent reaction behavior. II-2-4-1 Eyring Analysis of Varied Nucleophiles The importance of nucleophilicity in delivering the intermolecular product is evident in entries 1 and 2 (Table II-1). We investigated the enthalpic and entropic differences between acetonitrile and DMC as nucleophiles, which required the use of alternative reaction conditions to provide a measurable quantity of bromo-Ritter product with acetonitrile. We were delighted to discover that with a large excess of HFIP (100 equiv.), a ~1:3 ratio of intermolecular acetonitrile bromo-Ritter product II-19 to II-7 was produced. This condition is similar to entry 6 (Table II-1), allowing for both Eyring analyses with DMC and acetonitrile to be completed under similar reaction conditions. This enables a fair comparison between the two Eyring analyses as they share II-7 as a common internal clock, and acetonitrile and DMC have a similar dielectric constant (36.6 and 37.2, respectively). CF3 Ar (DHQD)2PHAL (10 mol%) CF3 O H N Ar Nitrile Solvent:HFIP 1:1 (0.05 M) O N + Br N O C 3H 7 O NBP, 25 °C C 3H 7 C 3H 7 N Ar H Br II-1 II-7 II-19 pNO2-C6H4 Ratio II-7:II-19 ~ 3:1 Figure II-7: Modified condition to yield Ritter product with acetonitrile 148 Competitive Eyring analysis of intermolecular reactions yielding II-14 (Figure II-9a) and II-19 (Figure II-8b) indicate lower enthalpic barrier (-3.9 and -2.6 kcal/mol, respectively) relative to the amide cyclization product II-7. The DMC's enhanced nucleophilicity provides a 1.3 kcal/mol lower enthalpic activation barrier for the intermolecular product, which helps redirect to favor the Ritter product. The relative entropic barriers favoring II-7 relative to II-14 and II-19 indicate an increase in molecularity for the intermolecular reaction. While these values only differ by 0.6 cal/molK, we were intrigued that acetonitrile, with its lower molecular weight and thus higher molarity relative to DMC (6.2 M for DMC, 9.6 M for acetonitrile), did not provide a lower entropic barrier than DMC (each reaction employed 0.5 mL of nucleophilic solvent and 0.5 mL of HFIP). This might be due to more pre-association of the DMC’s higher energy HOMO with the alkene’s LUMO.12 At the moment, this is purely a speculative hypothesis, and more studies will continue; however, in terms of enthalpy, there is a clear correlation between nucleophile strength and a decreased enthalpy of activation. 149 a (DHQD)2PHAL (10 mol %) C 3H 7 C 3H 7 O CF3 NMe2C3H7 O 1:1 Me2N-CN HFIP (0.05M) + Br N N Ar CF3 O N N Ar H temperature, NBP (2 equiv.) H O Br MS4Å Ar II-1 II-7 II-14 Ar = pNO2-C6H4 Temperature °C Ratio II-14/II-7a Eyring Analysis Data 56 2.00:1.00 ∆∆H‡ = -3.9 kcal/mol 3.66:1.00 ∆∆S‡ = -10.6 cal/molK 25 3 6.88:1.00 -20 11.91:1.00 a Product ratios determinted by crude NMR b (DHQD)2PHAL (10 mol %) C 3H 7 C 3H 7 O CF3 Me C 3H 7 O 1:1 MeCN HFIP (0.05M) + Br N N Ar temperature, NBP (2 equiv.) CF3 O N N Ar H H O Br Ar II-19 II-7 II-1 Ar = pNO2-C6H4 Temperature °C Ratio II-19/II-7a Eyring Analysis Data 47 0.22:1.00 ∆∆H‡ = -2.6 kcal/mol 25 0.34:1.00 ∆∆S‡ = -11.2 cal/molK 7 0.42:1.00 -22 0.72:1.00 a Product ratios determinted by crude NMR. c Nuclephile Varied Eyring Analysis 3 NBP DMC 2 ln (II-14/II-7) NBP ACN 1 y = 1985x - 5.333 0 R² = 0.997 y = 1341x - 5.652 -1 R² = 0.9883 -2 0.003 0.0032 0.0034 0.0036 0.0038 0.004 1/T °K Figure II-8: (a) Eyring analysis with dimethylcyanamide. (b) Eyring analysis with acetonitrile. (c) Eyring Plots of data in (a) and (b) 150 II-2-4-2 Eyring Analysis of Varied Bromenium Sources Reaction screening indicated the importance of both the nucleophile and electrophile in product distribution. In an attempt to probe the role of the bromenium counter anion and relate it to the halenium affinity, and thus the potency of the bromenium source, we explored Eyring analysis for three brominating reagents with HalAs (B3LYP- 6-31G* polar solvent) ranging from 131.3 kcal/mol in the case of NBP to 112.2 kcal/mol for N-bromosaccharine. The results of this study are summarized below in Figure II-9. While the nucleophilic strength affected the ∆∆H‡ for both reaction paths, the bromenium source affected both the ∆∆H‡ and ∆∆S‡. The general trend bromenium strength shows that the more potent donor favors the intermolecular product II-19 enthalpically but had the highest entropic penalty for the intermolecular product. Our current hypothesis for the correlation between HalA and ∆∆H‡ and ∆∆S‡ is that since each reagent provides high ee for II-19, all are catalyzed. However, for more reactive bromenium sources, such as NBSac, the reaction to yield II-7 is noncatalyzed as indicated by the 0% ee for II-7 (Table II-1 entry 4, it is important to note that a reaction providing 0% ee can still be catalyzed process). This provides a significant difference between ∆∆H‡ and ∆∆S‡ as a catalyzed process is enthalpically favored but entropically disfavored. Alternatively, the ee obtained for both products with less reactive sources suggests that both pathways are at least partially catalyzed. This provides less of an 151 enthalpic and entropic barrier of the intermolecular reaction relative to the cyclization reaction. (a) (DHQD)2PHAL (10 mol %) C 3H 7 C 3H 7 O CF3 Me C 3H 7 O 1:1 MeCN HFIP (0.05M) + Br N N Ar CF3 O N N Ar H temperature, Br+ Source (2 equiv.) H O Br Ar II-1 II-19 II-7 Ar = pNO2-C6H4 N-Bromopthalimide Dibromodimethylhydantoin N-Bromosaccharine HalA: 131.3 kcal/mol HalA: 123.8 kcal/mol HalA: 112.6 kcal/mol ∆∆H‡ = -2.6 kcal/mol ∆∆H‡ = -3.6 kcal/mol ∆∆H‡ = -5.0 kcal/mol ∆∆S‡ = -10.6 cal/molK ∆∆S‡ = -21.0 cal/molK ∆∆S‡ = -16.6 cal/molK Temperature °C Ratio II-19:II-7 Temperature °C Ratio II-19:II-7 Temperature °C Ratio II-19:II-7 0.22:1.00 51 0.07:1.00 51 0.07:1.00 47 25 0.34:1.00 23 0.13:1.00 23 0.10:1.00 7 0.42:1.00 0 0.25:1.00 0 0.39:1.00 -22 0.72:1.00 -27 0.39:1.00 -27 0.70:1.00 (b) Catalyzed Bromenium Donor Variable 0 y = 1341.6x - 5.6523 R² = 0.9883 -0.5 y = 1846.4x - 8.3607 ln (II-19/II-7) -1 R² = 0.9863 y = 2529.1x - 10.57 R² = 0.9675 -1.5 -2 NBP -2.5 DBDMH NBSac -3 0.003 0.0035 0.004 1/T °K Figure II-9: (a) Eyring analysis data for bromenium reagent temperature product ratio analysis. (b) Eyring plot of NBP, DBDMH and NBSac experiments 152 II-2-5 Conclusion Intrigued by an unprecedented divergent reactivity, which depends on the halenium ion (Figure II-1), we investigated the factors preferencing the intermolecular reaction relative to the intramolecular reaction. This led to the optimization of catalytic asymmetric bromo Ritter reaction via the use of a less reactive bromenium source and a stronger nitrile nucleophile. Though many aspects of the optimization of catalytic bromoamidation suggest that the reaction divergence could be operating under NAAA, Eyring analysis coupled with the enantioselectivity of halofunctionalization products indicated catalyst control of product distribution is likely with highly reactive bromenium sources such as N- bromosaccharine offering noncatalyzed pathways to II-7. II-3 Intermolecular Nucleophile Assisted Alkene Activation in Bromenium and Chlorenium Induced Halofunctionalizations Introductory chemistry courses depict halofunctionalization reactions as a stepwise mechanism. This mechanism proceeds through the rate-determining formation of haliranium ion II-21 that is subsequently opened by the nucleophile furnishing the difunctionalized product II-22. For this mechanistic picture to be true, the nucleophile should not affect the reaction rate and the halenium source should not affect product distribution. Our work examining the nucleophile's role in intramolecular reactions challenged the traditional mechanistic viewpoint and suggests a concerted addition of both nucleophile and halenium ion across the double bond for intramolecular halofunctionalizations.12 153 While nucleophile assisted halocyclization reactions have been studied in-depth, entropically challenged intermolecular halofunctionalizations have yet to see the same attention. A more complete understanding of this will enable control of reaction pathways via the selection of nucleophile and electrophile. Additionally, the ability to invoke a NAAA type concerted mechanism enables the potential to improve diastereoselectivity with electron rich alkenes that are prone to erosion of diastereoselectivity due to β- halocarbenium stability. X R2 D R1 R2 II-21 X D R1 Nuc R2 II-20 R1 X II-22 Figure II-10: Traditional mechanistic view of halofunctionalization II-3-1 Challenges Unique to Intermolecular Nucleophile Assisted Alkene Activation Nucleophile assisted halofunctionalization for intramolecular transformations have been experimentally supported through KIE, spectroscopic, and competition studies (Section I-3-2). In the case of the chlorolactonization of 4-phenylpent-4-enoic acid, the HalA of the alkene computed for the traditional stepwise mechanism (Figure II-11a) 167.4 kcal/mol. Alternatively, the concerted mechanism (Figure II-11b), proceeding through transition state II-28, employs the tethered nucleophile to assist in transfer to the alkene, 154 raising the HalA of the alkene to 173.3 kcal/mol in conformer II-29. This example displays the lower enthalpic barrier for the concerted NAAA mechanism (Figure II-11c). Conceptually, the intermolecular adaptation of a concerted halofunctionalization (Figure II-11d) lowers the enthalpic reaction barrier for II-33 relative to II-31, analogous to intramolecular transition states II-28 and II-24. However, the increased entropic burden of a trimolecular transition state relative to the bimolecular stepwise mechanism renders the intermolecular adaptation of this reaction mechanism non-trivial. 155 a HO2C A HalA: 167.4 kcal/mol X X (Chloroform B3LYP 6-31G*) X D -DH Y H Y extended conformer H Y unactivated II-23 II-24 II-25 II-26 b δ ‡ O D H! δ X X O HalA: 173.3 kcal/mol D X -DH (Chloroform B3LYP 6-31G*) Y ! Y Y H Y H H δ δ coiled conformer II-23 II-27 II-28 II-25 activated II-29 c ‡ ! D D X X X -DH D X D X -DH X Y Classical NAAA Y Y Mechanism H Y Mechanism H! H Y II-25 II-24 II-23 II-28 II-25 Stepwise Mechanism Nucleophile Assisted Enthalpically Disfavored Enthalpically Favored d ‡ ! D D X X X -DH D X X D X -DH Y Classical NAAA Y H Y Mechanism H Y Mechanism H Y ! II-32 II-31 II-30 II-33 II-32 Stepwise Mechanism Nucleophile Assisted Enthalpically Disfavored Enthalpically Favored Entropically Favored Entropically Disfavored Figure II-11: (a) Stepwise intramolecular halofunctionalization. (b) Concerted Intramolecular . (c) Kinetic variables of stepwise vs. concerted intramolecular halofunctionalization. (d) Kinetic variables of stepwise vs. concerted intermolecular halofunctionalization 156 II-3-2 Influence of Bromenium Donor HalA on Product Distribution Table II-2: Influence of HalA on product distribution MeOH (0.05M), rt C 3H 7 C 3H 7 O C 3H 7 O X+ reagent (2 equiv) + X N N Ar MeO N Ar H H O X II-1 ± ± Ar Ar = pNO2C6H4 II-35 II-36 Entry X+ reagent HalA (Br)a Ratio II-35:II-36b 1 NBSac 112.2 2.20 : 1.0 2 DBDMH 123.8 0.53 : 1.0 3 NBS 133.8 0.47 : 1.0 4 NBA 150.3 0.40 : 1.0 5 DCDMH NA 2.96 : 1.0 a HalA polar solvent. b Determined by crude NMR We subjected Allyl-amide II-1 to various bromenium reagents and a chlorenium reagent (DCDMH) in methanol (Table II-2). Under these conditions, the alkene can undergo two reactions: an intermolecular haloetherification to yield halo-ether II-35, or an amide cyclization to yield oxazoline II-36. If proceeding through the haliranium intermediate II-34, the counteranion of the halenium donor should have little effect on the product distribution. (Figure II-12) Interestingly, the product distribution for the two reaction pathways was sensitive to the halenium donor, following a trend of HalA13 with the lower HalA donors favoring the intermolecular product (Table II-2). Additionally, the C 3H 7 O MeOH MeO N Ar H X C 3H 7 O C 3H 7 O ± X-LB II-35 N Ar RDS N Ar H X H C 3H 7 LB Cyclization X N ± II-1 II-34 O Ar = pNO2C6H4 Ar ± II-36 Figure II-12: Competitive reaction proceeding through a traditional stepwise mechanism 157 chlorenium donor DCDMH (entry 5) provides the highest preference for the intermolecular product II-35. The dependence on halenium counter-ion and product distributions leads to the interrogation of the traditional stepwise haliranium ion pathway that predicts the same product distribution regardless of the halenium counter anion. Table II-3: Computational data for reaction divergence O O X+ source X Acetonitrile NH O N + N Ph O Ph H N Ph H X II-37 ± ± II-38 II-39 Entry Halogenating Reagent HalA(Br) kcal/mol ∆H‡ II-38 (kcal/mol) ∆H‡ II-39 (kcal/mol) ∆∆H‡ (kcal/mol) 1 DCDMH NA 9.3 16.4 7.1 2 NBS 133.8 17.3 20.9 3.6 3 BCDMH 123.2 12.4 16.8 4.4 II-3-3 Computational Exploration of Product Distribution Relative to Halenium Reagent Dr. Aritra Sarkar performed preliminary computational experiments (gas phase B3LYP-6-31G*) of the enthalpic energies of activation to probe the dependence of the halenium ion counteranion on the reaction pathway for allyl-amides (Table II-3). This study utilized allyl-amide II-37 and calculated the ∆H‡ for reaction pathways leading to the Ritter-product II-38 and the halocyclization product II-39. Three mechanistically significant findings were apparent: 1. No reactions proceed through a haliranium or β-halo carbenium pathway. 2. Chlorenium reagents provide more of an enthalpic bias to intermolecular transformations. 158 3. Halenium donors with a lower halenium affinity yield a higher enthalpic bias in favor of intermolecular product. Each of these conclusions is in agreement with our previous publications or the experimental results of product distribution (Table II-2). The lower enthalpic barrier for the intermolecular product is due to the electron withdrawing nature of the amide biasing the etherification reaction due to the Markovnikov-like regiochemistry of II-38. This justifies the trend of ∆∆H‡ correlating with the electrophilicity of the halenium source. Chlorenium reagents are more electrophilic than their bromenium counterparts, thus, they induce a larger positive charge on the alkene during halenium transfer. This scenario leads to more carbocationic character distal to the electron withdrawing group, the site at which acetonitrile adds. We propose a similar explanation for the correlation between the bromenium donor and the ∆∆H‡ favoring the intermolecular product (entry 2 vs. 3). BCDMH is more electrophilic than NBS, thus it generates more of a partial positive on the alkene carbon which the distal carbon, leading to a higher preference for the intermolecular product II-38. II-3-4 Product Distribution with Electronically Unbiased Regiochemistry We hypothesized that the electron withdrawing nature of the allyl-amide in substrate II-1 generated a biased alkene. This enabled the production of II-35 with Markovnikov like regiochemistry, and as the result the structural rigidity of Z alkenes, limited halocyclization to the 5-exo anti-Markovnikov selectivity. This results in the 159 sensitivity to bromenium sources observed in table II-2. The correlation between product and center of carbocationic character is depicted in Figure II-13a. The more electrophilic the bromenium source, the more carbocationic character induced on the alkene in the transition state. This justifies the transition state preference of II-40 with more electrophilic halenium sources which provide carbocationic character distal to the electron withdrawing amide. To confirm that the electronic bias plays a role in dictating in the reaction outcome, a b C 3H 7 O O N Ar Ph N Ar H H II-1 II-42 Ar = pNO2-C6H4 Ar = pNO2-C6H4 H Ar H Ar Me O NH Me O NH !+ O !+ O Ph H H Ph H H H H C 3H 7 H N C 3H 7 N O O H !+ H H !+ Br Ar Br X Ar X D D D D II-43 II-45 II-40 II-41 Ar C 3H 7 OMe O C 3H 7 O O N X N Ph N Ar MeO N Ar H H O Br Ph X Ar Br ± ± ± ± II-35 II-36 II-44 II-46 Partial Charges on Different Carbon Center Partial Charges on Same Carbon Center Electronic Bias Favors Intermolecular Product No Electronic Bias in Alkene Figure II-13: (a) Transition state charges in electronically biased alkene II-1 (b) Transition state charges in electronically unbiased alkene II-42 we selected alkene II-42 (Figure II-13b) with E alkene geometry. This enables the 6-endo 160 Table II-4: Influence of bromenium source on product distribution with electronically unbiased regiochemistry O OMe O MeOH (0.05 M), 23 °C O N Ph N Ar + Ph N Ar bromenium source (2 equiv.) H H Br Ph Br II-42 ± Ar = 4-NO2-C6H4 ± II-44 II-46 Entry Bromenium Source HalA(Br)a Ratio II-44 : II-46b 1 NBS 133.8 0.26 : 1.00 2 NBP 131.3 0.26 : 1.00 3 DBDMH 123.8 0.26 : 1.00 4 NBSac 112.2 1.00 : 1.00 aB3LYP/6-31G* polar solvent b Ratio determined by crude NMR cyclization, allowing both intermolecular and intramolecular nucleophiles attack the same carbon center with Markovnikov like regiochemistry to provide products II-44 and II-46 (Figure II-13). This results in transition states (II-43 and II-45) with the same carbocationic site. We hypothesized that alkene II-42 would not possess any correlation between the HalA of the donor and product distribution. A sampling of bromenium sources (Table II-4) with a range of HalA provided the same ratio of intermolecular product II-44 to intramolecular II-46 with less reactive bromenium sources such as NBS, NBP, and DBDMH (entries 1-3). However, the more reactive N-bromosaccharine (entry 4) provided a 1.00 : 1.00 ratio of II-44 and II-46. The identical product ratios provided by the three weaker halenium sources (Table II-4, entries 1-3) suggest that differences in product ratios (Table-II-2, entries 2-4) might be a result of the polarization of the alkene; however, the 1.00 : 1.00 ratio provided by N-bromosaccharine hints that there is a mechanistic break at some point between DBDMH and N-bromosaccharine that provides a stronger preference for the intermolecular product. 161 II-3-5 Influence of Alkene Electronics on Product Distribution We hypothesized that the regioselectivity and intermolecular bias observed with halenium reagents results from the amide’s inductive effect. This notion was supported Table II-5: Influence of alkene electronics on product distribution DBDMH (2 equiv.) OMe Br O MeOH (0.05M), rt Br O + O R N Ar Ar H R N Ar R N H ± ± II-47a-c II-48a-c II-49a-c Ar = pNO2-C6H4 Entry Substrate R HalA(Br) kcal/mola Ratio II-48:II-49b 1 II-47a H 108.4 11.9 : 1 2 II-47b Cl 106.8 7.1 : 1 3 II-47c CF3 101.7 2.6 : 1 a HalA (polar solvent B3LYP 6-31G*) b Product ratio determined by crude NMR. by the correlation of bromenium HalA and product distribution (Section II-3-2/II-3-4) and computational enthalpies of activation (Section II-3-3). We sought to more vigorously test this hypothesis by modulating the HalA of the alkene and measuring the subsequent effects on product distribution. If this hypothesis were to be functional, a more electron rich styrenyl alkene will prefer the transition state providing II-48 due to the enhanced stability of the benzylic carbocation. Alternatively, a less electron rich styrenyl system would have contributions from II-49 due to the decreased stability of the benzylic carbocation. We probed the effect of alkene HalA on product distribution by subjecting three alkenes of varied HalA to product distribution studies (Table II-5). The most electron donating substrate, II-47a (entry 1), provided the highest II-48:11:49 ratio while the most electron withdrawing, substrate II-47c (entry 3), yielded the lowest II-48:11-49 ratio. These results validate the olefin's polarization as a significant mode of control in the ratio of intermolecular haloetherifications and halocyclizations. 162 II-3-6 Eyring Analysis of Various Bromenium Sources Product distribution in kinetic competition studies and computational studies guided us towards a HalA dependent reaction divergence governed by the ∆∆H‡ of different reaction paths. This thought originates from the idea that each bromenium source induces the same reaction mechanism and the inductive effect of the amide provides an increased enthalpic bias for the intermolecular product with more potent halenium donors. We performed Eyring analysis on the selectivity determining step by measuring the product ratios to probe the relative enthalpic barriers as a function of bromenium donor HalA (Figure II-14). To our surprise, Eyring analysis yielded a result contradictory to our initial hypothesis and computational data. N-Bromosaccharine (Entry 1), possessing the lowest HalA and the strongest preference for the intermolecular product II-50, counterintuitively had the smallest relative enthalpic barrier (-1.92 cal/molK) in favor of II-50. To compensate for this, N-Bromosaccharine had the lowest relative entropic barrier for II-50 relative to II-51, thus posessing the highest preference for the intermolecular product. This study clearly demonstrates that increased HalA of the bromenium donor leads to larger relative entropic barrier to yield II-50. Presumably, the observed correlation of ∆∆H‡ and ∆∆S‡ with HalA and its contradiction to computational transition state energies are evidence for intermolecular NAAA (Figure II-11d). Relative to the classical stepwise mechanism, intermolecular NAAA requires a more highly ordered transition state, which results in a higher entropic barrier. While more highly ordered, a concerted transition state raises the HalA of the alkene, thus decreasing the enthalpic activation barrier. This is displayed in the ∆∆H‡ (-2.96 to -2.83 kcal/mol) and 163 ∆∆S‡ (-15.1 to -14.6 cal/molK) for high HalA bromenium reagents (i.e., DBDMH and NBS) that require assistance via NAAA to enable bromenium transfer. Conversely, bromenium donors with a lower HalA such as N-bromosaccharine require less NAAA, exhibiting lower ∆∆H‡ (-1.92) and ∆∆S‡ (-6.77). Furthermore, only N-bromosaccharine initiated reaction provided traces of the Ritter product, displaying its tolerance to a less weaker nucleophile. 164 II-3-7 Order of Methanol with Different Bromenium Sources In the previous section there was a clear correlation between the HalA of the bromenium reagent and the relative entropy of activation leading to products II-50 and II- 7. This, coupled with the contradiction of the computationally predicted enthalpic a OMe O N C 3H 7 O 3:7 MeOH : MeCN (0.05 M) Ar C 3H 7 N Ar + C 3H 7 O N Ar H temperature, Br+ Reagent (2 equiv.) H Br Br II-1 ± ± Ar = pNO2-C6H4 II-50 II-7 HalA = 103.0 kcal/mola,b Entry Br+ Reagent HalA Br II-50:II-7 II-50:II-7 II-50:II-7 II-50:II-7 ∆∆H‡ ∆∆S‡ kcal/mola (-28 °C)c (-7 °C)c (25 °C)c (51 °C)c (kcal/mol) (cal/mol °K) 1 NBSac 112.2 1.65 :1.00 1.35 :1.00 0.84 :1.00 0.65 :1.00 -1.92 -6.77 2 DBDMH 123.8 0.28 :1.00 0.16 :1.00 0.10 :1.00 0.06 :1.00 -2.96 -14.6 3 NBS 133.8 0.16 :1.00 0.11 :1.00 0.06 :1.00 0.04 :1.00 -2.83 -15.1 aB3LYP/6-31G* polar solvent bHalA calculated on alcohol analog cRatio determined by crude NMR b Bromenium Eyring y = 968.4x - 3.407 1 R² = 0.988 y = 1491x - 7.364 0 R² = 0.990 ln(II-50/II-7) -1 y = 1423.2x - 7.611 R² = 0.998 -2 NBSac -3 DBDMH -4 NBS 0.003 0.0033 0.0036 0.0039 0.0042 1/T °K Figure II-14: (a) Eyring Analysis of product ratios with varied bromenium donors. (b) Eyring Plot activation energies, suggest a weaker bromenium reagent requires more NAAA and a stronger bromenium reagent is less reliant on NAAA. To further examine this mechanistic 165 possibility and rule out alternative pathways unrelated to methanol that could induce different entropic barriers, we studied the effect of methanol concentration on product distribution. Inspired by Hoye’s study of HDDA reactions14 and Dr. Soltanzadeh’s studies of diastereoselectivity, we sought to elucidate the order of methanol with different bromenium reagents. II-3-8 Literature Precedent for Order Relative to an Internal Clock Reaction In 2014 Hoye and coworkers disclosed a study elucidating the mechanistic divergence of benzyne trapping events with alcohols.14 This study was spurred by the initial observation of a cyclohexanol concentration dependent divergent reaction. They Table II-6: Competitive H2 transfer and alcohol addition reactions n-Pr OH n-Pr n-Pr O TMS TMS TMS 85 °C O O O II-51 II-52 II-53 n-Pr H TMS O H O II-54 II-55 Entry [Cyclohexanol] II-53:II-54 1 9.5 M (neat) 12:1 2 0.013 (in CDCl3) 1:17 166 noticed when II-51 is subjected to hexadehydro Diels-Alder (HDDA) reaction conditions with high concentrations of cyclohexanol, they primarily obtained the aryl ether product II- 53 via oxygen trapping of the benzyne intermediate II-52 (Table II-6 entry 1), and with low cyclohexanol concentrations they obtained II-54 via transfer hydrogenation. Considering both products II-53 and II-54 are the result of the alcoholic trapping of benzyne II-52, the authors were curious of the origin of the selectivity inversion of this post rate determining step. Suspicious that the concentration of alcohol played a role in the selectivity determining step, they cleverly designed substrate II-56 which contains an aromatic ring functioning as an intramolecular benzyne trap of that is independent of alcohol concentration in product II-58. They subjected this substrate to HDDA conditions and measured the aryl ether (II-59) and hydrogenation product (II-60) ratios at different isopropanol concentrations relative to clock reaction product. The slopes of the ln[i-Pr] vs ln(II-59/II-58) or ln(II-60/II-58) provide the order of isopropanol for the respective products. This yielded an isopropanol order of two for II-59 and one for II-60. Complementary computational experiments suggest that dimeric isopropanol functions as a nucleophile to react with the benzyne and yield the aryl ether product in a transition state similar to II- 61 while the hydrogenation is hydrogen transfer from the monomeric alcohol to the benzyne. 167 i-PrOH R R R CDCl3 68 °C N N N Ts Ts Ts II-56 II-57 II-58 Ph Ph R O R N N Ts Ts II-59 II-60 ‡ H O H O II-61 Figure II-15: Trapping experiment with benzyne intermediates 168 II-3-8-1 Determination of Methanol Order with Different Bromenium Sources Inspired by Hoye’s technique,14 we employed a similar clock method to determine the relative order of methanol for the formation. This method determines the order of methanol for II-50 relative to clock reaction II-7, which is presumably independent of methanol concentration, by measuring the II-50:II-7 ratio as a function of methanol concentration. The slope of the graph ln[MeOH] vs. ln(II-50/II-7) provides the order of C 3H 7 O C 3H 7 C 3H 7 O Br+ Source (2 equiv.), 23 °C MeO N Ar + Br N N Ar MeOH:Nitromethane (0.05M) H H O Br 1 Ar (±) (±) Ar=pNO2-Ph II-50 II-7 [MeOH] NBS Ratio (II-50:II-7)a DBDMH Ratio (II-50:II-7)a NBSac Ratio (II-50:II-7)a 3.84 1.00 : 28.5 1.00 : 19.4 1.00 : 1.83 5.45 1.00 : 19.4 1.00 : 15.1 1.00 : 1.46 9.31 1.00 : 9.25 1.00 : 8.30 1.00 : 1.05 14.96 1.00 : 5.48 1.00 : 4.03 1.00 : 0.83 aRatio determined by crude NMR ln[MeOH]bulk vs. ln(II-50/II-7) 1 0.5 NBSac y = 0.74x - 1.68 0 R² = 0.965 ln(II-50/II-7 ) -0.5 -1 DBDMH y = 1.39x - 5.13 -1.5 R² = 0.9947 -2 -2.5 NBS y = 1.43x - 5.43 R² = 0.9887 -3 -3.5 1.6 2.6 ln[MeOH]bulk Figure II-16: Influence of methanol concentration on product distribution 169 methanol for II-50 relative to II-7. As anticipated, there was a notable change in sensitivity of methanol concentration with less reactive sources (NBS, DBDMH). The aforementioned method provided a relative methanol order of about 1.4 for NBS and DBDMH and 0.74 for the more reactive N-bromosaccharine. The higher order of methanol for less reactive bromenium sources justifies the higher relative entropic activation barrier displayed in Eyring analysis (Section II-3-6). The values of ~1.4 obtained for the less reactive bromenium sources suggest a competitive reaction pathway that employs two molecules of methanol to yield II-50. There are two potential explanations for the requirement of two methanol molecules in a haloetherification reaction: 1. Dimeric Methanol is functioning as a nucleophile. Similar to what Hoye observed with II-53 and II-59. Dimeric alcohol is more nucleophilic than the corresponding monomer. The enhanced nucleophilicity can more effectively assist the alkene in the abstraction of the bromenium ion from a b Monomer Nucleophile Dimer Nucleophile More Cationic Character Less Cationic Character Weaker Nucleophile Stronger Nucleophile O H H H O O ! ! H H H H H H N N C 3H 7 O C 3H 7 O Br Ar Br Ar ! ! N O N O O O N N Br Br II-62 II-63 Figure II-17: Comparison of (a) monomer and (b) dimer nucleophilicities the weaker donor (Figure II-17). Similar phenomena have been observed 170 with intramolecular halofunctionalizations. (This will be explained in further detail in Section II-3-8.) 2. Methanol is functioning as a protic activator of the bromenium source. Hydrogen bonding is known to activate imide donors in electrophilic alkene difunctionalizations. The bromenium sources with lower HalA require the assistance of a proton donor to stabilize the formation of a negative charge on the donor in the transition state (Figure II-18). Alternatively, the more potent donors have a more stable counteranion and do not require the external bromenium source stabilization via a protic donor. (This will be explained in further detail in Section II-3-10.) a Free Donor b Proton Assisted Donor H H O O ! ! H H H H H H N N C 3H 7 C 3H 7 O O More Anionic Character Less Anionic Character Less Potent Donor Br Ar More Potent Donor Br Ar ! ! N O N O O O H N N O Br Br II-64 II-65 Figure II-18: Proton donor assisted bromenium source activation The following sections are a deeper investigation to elucidate the role of the second equivalent of methanol. 171 II-3-8-2 Literature Precedent for Hydrogen Bonding Nucleophilic Enhancement in Halofunctionalization The enhancement of nucleophilicity via hydrogen bonding is a known mode of activation14 and has been hypothesized to exist in the context of halofunctionalization. This behavior has been leveraged by our group in the quinuclidine catalyzed chlorolactonization of alkene II-66 to yield II-67 (Figure II-19a).10 The employment of a quinuclidine base offers increased reaction rates relative to the free carboxylic acid II-66 through enhancement of nucleophilicity via hydrogen bonding. The proposed transition state is displayed as II-68. The effect of the rate is substantial with the reaction reaching completion in 20 minutes with quinuclidine as opposed to 72 hours without. Brown observed similar behavior in the intramolecular bromoetherification of II-69 to II-70 (Figure II-18b).15 In this case, the reaction is second order with respect to II-69. With no clear mechanism for protic activation of the adamantylideneadamantane bromenium source II- 71, the authors propose that a second molecule of II-69 functions as a base in the reaction mechanism. The authors propose II-72 and II-73 as two possible junctions in which the alcohol could function as a base to catalyze the reaction. In II-72, the alcohol enhances the nucleophilicity of another molecule of alcohol leading to the opening of the bromiranium ion. Alternatively, in II-73, the alcohol functions as a base to deprotonate the oxonium ion and provide II-70. 172 a O OH DCDMH Ph O 72 h Quinuclidine Catalysis O Ph II-66 ‡ Cl II-67 O N H O O O H N DCDMH Ph O 20 min Cl O Ph II-66 + quinuclidine Cl D II-67 II-68 b Ad Ad Br OHTf II-71 O Second Order in II-69! HO Br II-69 II-70 Br O Ad Ad H R OTf O Br II-72 H II-71 O HO Br II-69 II-70 O H R Br O II-73 H Figure II-19: Literature precedent for base assisted nucleophilic enhancement. (a) Chlorolactonizations (b) Bromoetherifications II-3-9 Influence of Sterics on Product Distribution In the previous section, we proposed participation of methanol as a dimeric nucleophile for DBDMH initiated reactions and as a monomer for N-bromosaccharine initiated reactions. To further probe this hypothesis, we tested the steric influence of the alcohol on product distribution. The increase in steric interactions should disrupt the formation of the dimeric alcohol, and therefore, the proposed DBDMH transition state II- 74, should be more sensitive to the sterics of the alcohol than N-bromosaccharine, which 173 presumably favors transition state II-75 (Figure II-20a). The variation of nucleophile size has a significant effect on the product distribution for reactions utilizing DBDMH (Figure II-19b), with methanol providing a 1:6.5 ratio of II-50 to II-7 and isopropanol providing a 1.0:31 ratio of II-50b to II-7. Alternatively, the more reactive N-bromosaccharine is much less sensitive to the size of the alcohol nucleophile with the intermolecular to intramolecular ratio ranging only from 1.0:1.2 with methanol to 1.0:2.2 with isopropanol. The plot of alcohol size vs. ln(II-50/II-7) for DBDMH and N-bromosaccharine quantifies the relative magnitude of sensitivity to nucleophile size for each bromenium source with a slope of -0.31 for N-bromosaccharine and -0.78 for DBDMH. While the effect of alcohol size is clear for each reagent, the influence is greater with the less reactive DBDMH. We hypothesize that this is due to the necessity for alcohol dimerization to generate a stronger nucleophile required for the less reactive DBDMH, suggesting it proceeds through a transition state similar to II-74, while N-bromosaccharine proceeds through monomeric transition state II-75 which is less sensitive to alcohol size. It should be noted that size 174 can affect an alcohol's ability to activate the bromenium source through hydrogen bonding (Figure I-17). This possibility is explored in Section II-3-10. a Steric Interactions? Less Steric Interaction? Fewest Steric Intereactions! Non NAAA Pathway O H H H O O ! ! H H ! H H H H N H H H N C 3H 7 O N C 3H 7 O C 3H 7 O Br Ar Br Ar Br Ar ! ! ! N O N O N O O O O N N N Br Br Br II-74 II-75 II-76 b C 3H 7 C 3H 7 O C 3H 7 O Br+ Source, 23 °C + Br N N Ar ROH (150 equiv) : Nitromethane (0.05M) RO N Ar H H O Br Ar ± ± II-1 II-7 II-50, II-50a, II-50b Ar=pNO2-C6H4 (intermolecular product) Alcohol Product # of carbons NBSac Ratio (II-50:II-7)a DBDMH Ratio (II-50:II-7)a MeOH II-50 1 1.00 :1.22 1.00 : 6.57 EtOH II-50a 2 1.00 :1.68 1.00 : 15.0 i-PrOH II-50b 3 1.00 : 2.24 1.00 : 31.1 aDetermined by crude NMR. Steric Effects on Product Distribution 0 y = -0.3088x + 0.1129 R² = 0.9984 -0.5 y = -0.778x - 1.1213 -1 R² = 0.9986 ln (II-50/II-7) -1.5 NBSac -2 DBDMH -2.5 -3 -3.5 -4 0.5 1 1.5 2 2.5 3 3.5 Number Of Carbons Figure II-20: Influence of alcohol size with different bromenium sources 175 II-3-10 Influence of Acid Additives on Product Distribution Hydrogen bond donors such as ureas and phosphoric acids are common catalysts in halofunctionalization reactions.4, 16-17 They often function by stabilizing the halenium donor's counteranion, subsequently lowering HalA of the halenium donor. We sought to rule out the possibility that the higher order of methanol with DBDMH and NBS is the result of hydrogen bond activation of the bromenium donor. To examine this, we performed parallel reactions with common halofunctionalization protic additives hexafluoroisopropanol (HFIP) and trifluoroethanol (TFE) and measured their influence on H H H O O O H ! H H H ! H H H H H N N N C 3H 7 O C 3H 7 O C 3H 7 O Br Ar Br Ar Br Ar ! ! ! N O N O N O O O O H N H N H N O O O Br Br Br CF3 CF3 CF3 II-64 II-77 II-78 Weaker Acid Stronger Acid More Partial Negative Less Partial Negative C 3H 7 O C 3H 7 O C 3H 7 MeOH:Toluene 1:4 (0.05 M) + N Ar Acid additive (20 equiv.) MeO N Ar Br N H H 23°C, DBDMH (2 equiv.) Br O 1 Ar=pNO2-Ph Ar ± ± II-50 II-7 Entry Acid Additive Ratio II-50:II-7 CF3 OH 1 None 1.0:8.2 TFE 2 TFE 1.0:8.7 CF3 CF3 OH 3 HFIP 1.0:7.6 HFIP Figure II-21: Influence of protic additives on product distribution product ratios. It is important to note that each of the acids, including methanol, can 176 behave as a proton donor and activate the bromenium source; however, methanol (pKa = 15.5) is a much weaker acid than HFIP (pKa = 9.3), and thus the methanol assisted transition state II-64 a much less activated as compared to the HFIP assisted transition state II-77 (Figure II-21). We anticipated that if the additional molecule of methanol functions as a proton donor to preference the intermolecular product II-50, then TFE and HFIP should be even more efficient at this than methanol and provide more II-50. These reactions were performed in toluene as a cosolvent to lessen the equivalents of methanol and lower the polarity of the solvent, which will enhance the need for a proton donor to stabilize a negative charge.18-19 Proton Assisted Bromoetherification Proton Assisted Bromocyclization O H H Ar O ! NH H H H C 3H 7 O N C 3H 7 O H H !+ Br Ar Br ! O N! N O O H O O H N O N Br Br II-79 II-80 Figure II-22: Proton assisted pathways We did not observe a strong correlation between acid strength and product distribution of II-50 and II-7 (Figure II-21) with each condition providing similar ratios. This does not rule out the possibility that methanol is behaving as a proton donor; rather, it supports the fact that it does not account for the difference in the entropic barrier or order of the solvent between the two reaction pathways leading to products II-50 and II-7. It is important to note that both the Eyring analysis (Section II-3-6) and the order of methanol (Section II-3-7) studies are relative to the cyclization reaction. Protic assistance for 177 halenium transfer to the alkene for inter and intramolecular pathways are likely present in both. For example, transition states depicted in Figure II-22 (II-79 and II-80) are proton assisted; however, II-79 has two additional molecules of methanol in the transition state. II-3-11 Divergent Reaction Pathways for DBDMH and N- Bromosaccharine Preliminary studies exploring the effect of the HalA of the bromenium donor and product distribution with starting material II-1 displayed a strong correlation between the bromenium donor and the II-50:II-7 product ratios, with lower HalA donors yielding more II-50. This challenges the classical stepwise mechanism that suggests each reaction proceeding through a convergent bromiranium intermediate II-18 (Figure II-6). This should yield similar product ratios regardless of the donor. Initially we hypothesized the possibility that a concerted mechanism is operational and the correlation between HalA and product distribution is the result of the inductive effect of the amide producing an enthalpic bias for II-50 that generates carbocationic character distal to the withdrawing group in the transition state. Computational studies further support this hypothesis, suggesting that the bromenium sources with a lower HalA (i.e. N-bromosaccharine) will provide more of an enthalpic preference for product II-50. Contradictory to the hypothesis, Eyring analysis indicated that less reactive bromenium sources (DBDMH and NBS) provided a lower relative enthalpic barrier for II-50 than lower HalA (less reactive) bromenium N-bromosaccharine. Additionally, Eyring analysis indicated the relative entropic barrier for intermolecular haloetherification product II-50 was lower for N- bromosaccharine than DBDMH, hinting at differing mechanisms for II-50 with different 178 bromenium sources. We further investigated methanol's role, elucidating a relative order of 1.4 for methanol with DBDMH and 0.74 for N-bromosaccharine, indicating a mechanistic switch is likely related to methanol. This led us to hypothesize that the reaction pathway yielding II-50 with DBDMH is a dimeric in methanol, while a monomeric methanol is a sufficient nucleophile for N-bromosaccharine mediated reactions. Further studies exploring the relative effects of alcohol sterics and acid additives support this claim. The rationalization for this mechanistic switch is derived from the relative contribution of NAAA required for the transfer of the bromenium ion from the bromenium source to the alkene; an NAAA pathway lowers the enthalpic barrier but raises the entropic barrier, which is observed, shifting from N-bromosaccharine to DBDMH. Our current hypothesis is that the bromenium sources such as DBDMH that possess a higher HalA require “more NAAA”. This decreased reactivity enables two competitive reaction pathways with DBDMH leading to II-50, an enthalpic dimeric nucleophile pathway through transition state II-81 and an entropically favored monomeric pathway through transition state II-82 (Figure II-23a). Alternatively, the more reactive N-bromosaccharine requires less nucleophilic assistance to transfer the bromenium ion to the alkene and primarily 179 proceeds through the monomeric pathway II-83, justifying the change in the relative entropic activation barriers (Figure II-23b). a H b O H O H O H ! H H N ! H H H C 3H 7 H ! O N O H H H C 3H 7 O N Br Ar ! C 3H 7 O Br Ar H H H H N A Br Ar C 3H 7 O O D! II-81 II-82 D ! Br Ar D! H ! H H N II-84 C 3H 7 O D! II-83 A Br Ar ΔH‡ D II-86 ΔH‡ ΔH‡ ΔH‡ -TΔS‡ -TΔS‡ -TΔS‡ -TΔS‡ H ! H H N II-1 C 3H 7 O II-1 D= DBDMH D= NBSac A Br Ar II-50 D II-50 II-50 II-50 Enthalpic Pathway Entropic Pathway Enthalpic Pathway II-85 Entropic Pathway Br Br O O O O N Br N N Br N N N Br S S Br O O O O O O DBDMH HalA 123.8 kcal/mol N-bromosaccharine HalA 112.2 kcal/mol Figure II-23: Enthalpic and Entropic Pathways for bromoetherifications (a) DBDMH (b) N-bromosaccharine II-3-12 Modulation of Reaction Pathways via Alkene HalA In previous sections, we observed an apparent change in mechanistic pathways via the modulation of the bromenium donor’s HalA. We hypothesized that when the HalA of the bromenium donor became closer to the HalA of the alkene, less nucleophilic assistance was required to transfer the bromenium ion to the alkene. We desired to explore this hypothesis further by keeping the bromenium source constant but modulating alkene HalA. We hypothesize that this should function in the same manner as bromenium 180 donor modulation; therefore, alkenes with higher HalA should require less nucleophile assistance than alkenes with lower HalA. We employed three styrenyl allyl amides (II- 47a-c) with a range of alkene HalA (-101.7 to -108.4) in a comparative Eyring analysis study to test this hypothesis (Figure II-24). Eyring analysis exhibited that with alkenes with higher HalA yield lower relative enthalpic and entropic activation barriers for II-48 products relative to intramolecular II-49 products. The entropic variance ranging from -2.86 kcal/molK with II-47a to -7.84 kcal/molK with II-47c is rationalized by the relative HalA of the alkenes probed. II-47a possesses a higher HalA (-108.4 kcal/mol) than II-47c (-101.7 kcal/mol) therefore II-47a requires less assistance from an external nucleophile (methanol) to enable the transfer of bromenium from DBDMH to the alkene and provide II-48a. The 181 enthalpic variance favoring II-48 follows the same trend, with II-47a providing the highest relative enthalpic barrier in favor of II-48 (-2.31 kcal/mol) and II-47c the lowest enthalpically favoring of II-48 (-1.78 kcal/mol). We rationalize II-48a proceeding with less NAAA (as measured by relative entropy of activation) than II-47b,c but a lower relative enthalpic barrier due to the stabilities of the benzylic carbocation in the respective MeOH (0.05M) OMe Br O DBDMH (2 equiv.) Br O O Ar R N Ar Temperature H R N Ar R N II-47a-c H Ar = pNO2-C6H4 II-48a-c II-49a-c II-47a II-47b II-47c R=H R = Cl R = CF3 HalA = -108.4 kcal/mol HalA = -106.8 kcal/mol HalA = -101.7 kcal/mol ∆∆H‡ = -2.31 kcal/mol ∆∆H‡ = -2.21 kcal/mol ∆∆H‡ = -1.78 kcal/mol ∆∆S‡ = -2.86 cal/molK ∆∆S‡ = -3.59 cal/molK ∆∆S‡ = -7.84 cal/molK Temperature °C Ratio II-48c:II-49c Temperature °C Ratio II-48b:II-49b Temperature °C Ratio II-48a:II-49a -15 22.0 : 1.00 -4 10.2 : 1.00 6 0.49 : 1.00 0 16.5 : 1.00 6 9.10 : 1.00 24 0.38 : 1.00 24 11.9 : 1.00 25 7.09 : 1.00 40 0.33 : 1.00 51 8.68 : 1.00 40 5.80 : 1.00 55 0.30 : 1.00 56 4.81 : 1.00 4 Alkene Eyring y = 1164.1x - 1.4392 3 R² = 0.998 ln (II-48/II-49) y = 1116.8x - 1.8083 2 R² = 0.9964 y = 895.78x - 3.9479 1 R² = 0.9909 0 Ph -1 4-Cl Ph -2 4-CF3 Ph 0.003 0.00325 0.0035 0.00375 0.004 1/T °K Figure II-24: Eyring analysis of varied alkenes 182 transition states. We envision a divergent mechanistic pathway for electron poor alkenes such as II-47c, requiring more nucleophile assistance and proceeding through more entropically challenged transition states II-87 and II-88. Alternatively, electron rich alkenes such as II-47a require less HalA will proceed through less entropically challenged transition states such as II-89 and II-90 (Figure II-25). Ar is Electron Poor Ar is Electron Rich Higher Entropic Barrier Lower Entropic Barrier II-47c II-47a H O H O H O H ! H H N H ! H H Ar O H ! Ar N O O H H H N Br Ar Ar O Br Ar H ! H H N A Br Ar H D! Ar O O II-87 D! II-88 Br Ar D! H ! H H II-90 N Ar O D! II-89 A Br Ar D II-92 H ! H H N SM Ar O SM D= DBDMH D= DBDMH A Br Ar II-48c II-48c II-48a D II-48a II-91 Figure II-25: Divergent bromoetherification molecularity with electron poor and electron rich alkenes II-4 Diastereoselectivity in Intermolecular Halofunctionalizations Control of diastereoselectivity is a critical facet of alkene difunctionalizations. Generally, only one diastereomer is desired and thus any loss in diastereoselectivity results in a 183 reduced yield. Intermolecular halofunctionalizations are especially prone to erosion of diastereoselectivity. Classically, this is rationalized by the propensity for the haliranium ion intermediate II-93 to open to the β-halocarbenium ion II-94, which as a carbocation, provides little stereocontrol leading to diastereomeric products (Figure II-26a). At first approximation, the β-halocarbenium ion pathway appears to be a reasonable justification for diastereoselectivity trend observed with chloroetherifications1 and chloroamidations3 of II-47 (Figure II-26b); however, deeper investigation into the structure the haliranium addition to styrenyl indicates a significant thermodynamic favoring of II-94 in comparison to II-93 with all styrenyl alkenes.13 Additionally, the recent mechanistic reevaluation, NAAA, hints that the major diastereomer (anti addition) results from NAAA II-99 and the minor diastereomer the result of the classical β-halocarbenium ion pathway II-94 (Figure II-26c). The NAAA hypothesis for erosion of diastereoselectivity suggests that when the HalA of the alkene becomes closer to the HalA of the chlorenium donor DCDMH then non NAAA pathway II-94 becomes operative. Utilizing the mechanistic observations obtained in Section II-3, we sought to improve diastereoselectivity for chloroetherifications by employing a chlorenium source with a higher HalA that will require more nucleophile assistance from methanol and lead to a stronger preference for the anti-product. 184 a X X Me Me II-93 II-94 ROH H RO ROH OR OR X X Me Me II-95 II-96 Anti-Addition Syn-Addition b H N Ar 10 mol% (DHQD)2PHAL R R 2.0 equiv DCDMH Cl Cl O H H N Ar + N Ar MeOH:MeCN (3:7) -30 °C, 0.01 M OMe O OMe O R II-97a-d II-98a-d II-47a-d Anti-Addition Syn-addition Ar = pNO2-C6H4 R = H, Me, OMe, CF3 Entry Substrate R σ HalAa dr (II-97:II-98)b 1 II-48d OMe -0.27 150.2 1:1 2 II-48a CH3 -0.14 142.8 1.3:1 3 II-48b H 0 138.6 3.3:1 4 II-48c CF3 0.53 131.5 >20:1 a. HalA calculated with alcohol analog b.dr determined by crude NMR c NAAA Mechanism Stepwise Mechanism ! MeO H H H H H Ph Me II-95 Ph Me MeOH Mix of II-95 and II-96 Cl Cl A BH3 D ! ABH4 D A II-99 II-94 Concerted TS β-halocarbenium ion Figure II-26: (a) Traditional explanation for diastereoselectivity. (b) Diastereoselectivity in chloroetherifications (c) explanation for diastereoselectivity 185 II-4-1 Eyring Analysis of Diastereoselectivity The correlation between electronic perturbations of II-47 and diastereoselectivity of haloetherification products has led to discussions on the origin of diastereoselectivity. We hypothesized that the major diastereomer II-97 is the result of a nucleophile assisted transition state similar to II-99 and the minor diastereomer II-98 is the result of a stepwise DCDMH (2 equiv.) OMe OMe Ph O MeOH (0.05M) Cl Cl Ph O Ar Ph O + Ph O + N Ar N H N Ar N Ar Cl H H II-47a II-97a II-98a II-100 Ar = pNO2-C6H4 Temperature (°C) II-97a II-98a II-100 56 59.7 27.7 12.7 40 61.1 26.6 12.3 24 64.1 24.6 11.3 10 65.3 23.8 10.9 II-97a vs II-98a II-97a vs. II-100 II-98a vs. II-100 ∆∆H‡ Kcal/mol -1.02 -1.03 -0.01 ∆∆S‡ cal/molK -1.58 -0.08 1.50 DR and Cyclization Eyring y = 515.18x - 0.7992 2 R² = 0.9767 1.8 y = 6.3814x + 0.7566 1.6 R² = 0.1 1.4 y = 521.56x - 0.0427 1.2 R² = 0.9726 ln Ratio 1 0.8 ln II-86a/II-89 0.6 0.4 ln II-87a/II-89 0.2 ln II-86a/II-87a 0 0.003 0.0031 0.0032 0.0033 0.0034 0.0035 0.0036 1/T °K Figure II-27: Eyring analysis of diastereoselectivity 186 mechanism. We anticipated enthalpic and entropic consequences to these two reaction pathways, with NAAA like pathway II-99 possessing a lower enthalpic barrier but a higher entropic barrier relative to stepwise pathway II-94. We sought to probe the entropic and enthalpic differences between both reaction pathways of the selectivity determining step via Eyring analysis in hopes of acquiring an improved comprehension of diastereoselectivity in intermolecular chloroetherifications. As anticipated, the reaction pathway leading to the major diastereomer II-97a is enthalpically favored (by 1.02 kcal/mol) and entropically disfavored (by 1.58 cal/molK) relative to the minor diastereomer II-98a (Figure II-26), indicative of a nucleophile assisted transition state. Eyring analysis of both diastereomers relative to 6-endo chlorocyclization side product II-100 led to peculiar relative entropic barriers to activation. To our surprise, we discovered that the relative entropy of activation for II-97a to II-100 was relatively low (0.08 cal/molk) and the minor diastereomer II-98a was entropically favored relative to II- 100 by 1.50 cal/mol. This suggests that the reaction pathway leading to II-100 has a moderate entropic barrier to activation, potentially via the adoption of a NAAA transition state. Regardless, we were intrigued to observe such a similar entropy of activation for the II-97a and II-100 reaction pathways which is different than what was observed in Section II-3-12. II-4-2 Influence of Chlorenium Donor HalA on Diastereoselectivity As previously discussed, diastereoselectivity is a pertinent issue in halofunctionalization. The correlation between alkene HalA and diastereoselectivity of the halofunctionalization product hints that the major diastereomer is the result of a concerted 187 NAAA like transition state and the minor diastereomer is the result of a non-NAAA β- halocarbenium ion pathway. We were curious as to whether the modulation of chlorenium donor to a lower HalA could increase the requirement for a nucleophile assisted transfer of chlorenium to the alkene, thus, mitigating the β-halocarbenium pathway and improving diastereoselectivity via reagent control (Figure II-27). This hypothesis was emboldened by Eyring analysis of bromofunctionalizations which displayed the ability to control the requisite for a NAAA concerted pathway by modulating the HalA of the bromenium donor or the alkene. Further Eyring studies related to the diastereoselectivities of chlorofunctionalizations of II-47a supported the hypothesis that the major diastereomer II-97a is the result of NAAA transition state II-101 and the minor diastereomer II-98a is the result of a classical stepwise reaction through II-102. NAAA Mechanism Classical Mechanism ! MeO H H H H H H H N (±) N Ar O Ar O MeOH II-97a (±) (±) Ar Cl Ar2 II-97a II-98a Cl A BH3! A DBH4 D II-101 A II-102 Stepwise Rxn Concerted TS Favored with an electron withdrawing Ar Favored with an electron donating Ar Favored with a weak donor? Favored with a potent donor? Destabalize ABH4 disfavor II-102? Improve dr??? D Figure II-28: Reagent controlled approach to improve diastereoselectivity The summarization of diastereoselectivity studies with varied chlorenium sources is displayed in Table II-7. To our dismay, use of less reactive chlorenium sources did not improve diastereoselectivity (II-97a:II-98a ratio). The least reactive NCS (entry 1) and the 188 most reactive TCCA (entry 4) provided the same diastereoselectivities despite TCCA’s HalA being lower 5.5 kcal/mol than of II-47a and NCS being 22.2 kcal/mol higher. While the independence of chlorenium donor HalA and diastereoselectivity insinuate that the reactions proceed through a stepwise intermediate, there are examples in the literature that propose a syn-concerted addition of the halenium ion and nucleophile to the alkene.20-21 Table II-7: Influence of HalA on diastereoselectivity in chloroetherifications Ph O OMe O OMe O Ph O Ar MeOH (0.05 M), rt Ph N Ar + Ph N Ar + N Ar Cl+ Source (2 equiv.) N H H H Cl Cl Cl II-47a (±) II-97a (±) II-98a (±) II-100 Ar = pNO2-C6H4 HalA (Cl)a,b = 138.6 kcal/mol Entry Cl+ source HalA (Cl) kcal/mola Ratio II-97a:II-98a:II-100c drc 1 NCS 160.8 70 : 30 : 0 1:2.4 2 DCDMH 150.0 64 : 25 : 11 1:2.6 3 NCSac 138.7 64 : 27 : 9 1:2.4 4 TCCA 133.1 64 : 27 : 9 1:2.4 a. Calculated by B3LPY/6-31G* (polar solvent). b. HalA caclulation on alcohol analog c. Determined by crude NMR II-4-3 Influence of Bromenium Donor HalA on Diastereoselectivity While we were surprised by the inability to improve diastereoselectivity by selecting a less reactive chlorenium source, we recognized that our Eyring studies detailing the relative entropies of activation with different halenium sources and alkenes all employed bromenium electrophiles. This led us to explore the possibility that bromenium and chlorenium induced are mechanistically distinct and perhaps there will be a correlation between bromenium donor HalA and diastereoselectivity. Gratifyingly we observed that highly reactive allyl-amide II-47e, the diastereoselectivity was sensitive to bromenium 189 donor HalA with DBDMH (entries 1 and 3), providing a higher dr than N-bromosaccharine (entries 2 and 4) (Table II-8). Table II-8: Influence of bromenium donor HalA on bromoetherifications OMe O N Ar H O Br Me Ar II-48e 1:3 MeOH:Cosolvent (0.05M) NH OMe O Br+ source (2 equiv.), rt N Ar Me H II-47e Br Me Ar = pNO2C6H4 II-103 HalA (Br) = 112.2 kcal/mola,b Entry Br+ source HalA (Br) kcal/mola Cosolvent drc 1 DBDMH 123.7 MeCN 1:6.5 2 NBSac 112.2 MeCN 1:3.4 3 DBDMH 123.7 None 1:13.6 4 NBSac 112.2 None 1:8.4 a. HalA calculated in polar solvent (B3LYP/6-31G*) b. HalA of alcohol analog c. dr measured from crude NMR The correlation between the HalA of the bromenium donor and diastereoselectivity suggests with low HalA donors such as N-bromosaccharine, II-47e requires less NAAA to transfer the bromenium ion and can potentially proceed through a β-halo carbenium intermediate leading to an erosion of diastereoselectivity. This pathway can be suppressed by selecting the less reactive bromenium source DBDMH which will provide a higher diastereoselectivity. We were curious as to why chlorenium induced halofunctionalizations display different HalA sensitivities than the bromenium analogs. This subject is addressed in future sections. 190 II-5 Mechanistic Dissimilarities of Intermolecular Bromo and Chlorofunctionalizations A multitude of studies suggested that bromenium induced haloetherifications proceed through a concerted nucleophile assisted mechanism. We observed that through the modulation of alkene and bromenium donor HalA, we can tune the requirement for nucleophile assistance. We hypothesized that we could improve diastereoselectivity for problematic chloroetherifications by employing a less reactive chlorenium source that would require nucleophile assistance to transfer the chlorenium ion to the alkene. To our surprise, we did not observe any correlation between the chlorenium donor HalA and diastereoselectivity; however, reinvestigation with bromenium reagents displayed HalA dependent reagent controlled diastereoselectivity for bromoetherifications. In an effort to elucidate the origin mechanistic divergence between bromenium and chlorenium reagents, we repeated many experiments in section II-3 with chlorenium analogs. II-5-1 Influence of Chlorenium Donor HalA on Product Distribution The high sensitivity to the HalA of the bromenium donor and product distribution described in Section II-3-2 challenges the traditional stepwise mechanism that predicts minimal influence of bromenium donor on product distribution. Alternatively, a concerted intermolecular halofunctionalization reaction pathway was suggested as the explanation to these results (Figure II-29b). Reexamination of this experiment with various chlorenium sources yielded different results (Figure II-29a). We discovered that the product ratio is independent of the chlorenium source HalA, with NCP (entry 1, HalA = 158.2 kcal/mol) providing similar product ratios of II-104 and II-105 as TCCA (entry 5, HalA = 133.1 191 kcal/mol). This observation is in agreement with the diastereoselectivity observed for chloroetherifications (section II-4-2) that displays no correlation between donor HalA and product distribution. The lack of sensitivity for the chlorenium source for both of these reactions suggest that the selectivity determining step for chlorofunctionalization reactions is independent of the chlorenium donor; thus, chlorofunctionalizations could be proceeding through a common intermediate (Figure II-28c). Following the formation of the haliranium intermediate II-109, the selectivity determining step leading to products II-104 and II-105 occurs with no sensitivity for the counterion of the chlorenium donor. II-5-2 Competitive Eyring Analysis of Chlorofunctionalizations and Bromofunctionalizations The observed divergent halenium source sensitivity for bromo and chlorofunctionalizations led to the hypothesis that bromofunctionalizations proceed through a nucleophile assisted transfer of bromenium (Figure II-29b) to the alkene and chlorofunctionalizations proceed through a stepwise mechanism involving a haliranium or β-halocarbenium intermediate (Figure II-29c). We anticipate that these mechanisms would have different enthalpic and entropic barriers to activation in the selectivity determining step. If proceeding through a nucleophile assisted concerted mechanism, the 192 a MeOH (0.05M), rt C 3H 7 C 3H 7 O C 3H 7 O Cl+ reagent (2 equiv) MeO N Ar + Cl N N Ar O H H Cl Ar II-1 Ar = pNO2-C6H4 (±) II-104 (±) II-105 HalA (Cl)a,b = 129.9 kcal/mol Entry Cl+ reagent HalA (Cl) kcal/mola Ratio II-104:II-105c 1 NCP 158.2 3.0:1 2 DCDMH 150.0 3.1:1 3 Dichloramine-T 144.3 3.0:1 4 NCSac 138.7 3.0:1 5 TCCA 133.1 3.2:1 a Calculated by B3LPY/6-31G* (polar solvent). b HalA caclulation on alcohol analog .c Determined by crude NMR c b Ar H Ar H ! O O H H H NH2 N NH2 ! C 3H 7 O O ! H H O ! H H H C 3H 7 ! H C 3H 7 N N C 3H 7 O Cl Ar H H C 3H 7 O H H Br Ar Cl Cl Ar D! Br D D ! D D! II-108 II-110 II-111 II-106 II-107 II-106 II-107 Rate Determining II-108 Selectivity Step Determining Step II-110 II-111 H ! H H N C 3H 7 O II-1 Cl Ar D= Bromenium Donor D II-7 II-50 II-109 II-1 D= Chlorenium Donor Pdts Figure II-29: (a) Influence of chlorenium donor HalA on product distribution. (b) Potential mechanism for chlorofunctionalizations intermolecular transition state II-107 that yields bromoether II-50 should possess a higher entropy of activation relative to the transition state for cyclization II-106; however, assisting the transfer of bromenium should lower the enthalpic barrier to activation relative to II-106. Conversely, if chlorofunctionalizations proceed through a stepwise mechanism 193 with the formation of the highly reactive haliranium intermediate II-109, there will be smaller differences in enthalpic and entropic barriers in transition states II-110 and II-111. We viewed competitive Eyring analysis as the ideal tool to probe the proposed divergent reaction mechanisms. In this set of experiments, we were able to extract the relative enthalpic and entropic barriers of activation for the selectivity determining step. As predicated, N-chlorosaccharine provided a smaller relative enthalpic and entropic activation barriers (-0.68 kcal/mol for ∆∆H‡ and -0.04 cal/molK for ∆∆S‡) in comparison to N-bromosaccharine (-1.32 kcal/mol for ∆∆H‡ and -2.94 cal/molK for ∆∆S‡) (Figure II-29). This result, in conjunction with divergent results for bromenium and chlorenium related to the sensitivity of the halenium donor support alternative mechanisms for bromo and chlorofunctionalizations. If proceeding through a chloriranium ion, we would expect this highly reactive intermediate to have a low enthalpic barrier to open to the respective difunctionalized products. 194 a MeOH (0.05 M), Temperature C 3H 7 C 3H 7 O C 3H 7 O NCSac (0.6 equiv) + Cl N N Ar MeO N Ar H H O Cl Ar II-1 (±) II-104 (±) II-105 Ar = pNO2-C6H4 Entry Temperature °C Ratio II-104:II-105a ∆∆H‡ = -0.68 kcal/mol 1 -22 3.85 : 1.00 ∆∆S‡ = -0.04 cal/molK 2 -10 3.70 : 1.00 3 8 3.32 : 1.00 4 23 3.13 : 1.00 5 41 2.96 : 1.00 aDetermined by crude NMR b MeOH (0.05 M), Temperature C 3H 7 C 3H 7 O C 3H 7 O NBSac (2.0 equiv) + Br N N Ar MeO N Ar H H O Br Ar II-1 (±) II-50 (±) II-7 Ar = pNO2-C6H4 Entry Temperature °C Ratio II-50:II-7a ∆∆H‡ = -1.32 kcal/mol 1 -30 3.46 : 1.00 ∆∆S‡ = -2.94 cal/molK 2 2 2.58 : 1.00 3 23 2.17 : 1.00 4 50 1.73 : 1.00 aDetermined by crude NMR c Bromenium vs. Chlorenium Eyring 1.4 ln(Ether/Oxazoline) 1.2 y = 344.85x - 0.0178 1 R² = 0.9913 y = 664.97x - 1.4809 0.8 R² = 0.9941 NBSac NCSac 0.6 0.4 0.003 0.0033 0.0036 0.0039 0.0042 1/T K Figure II-30: Eyring analysis of bromo and chloroetherifications 195 II-5-3 Influence of Sterics on Product Distribution with Bromo and Chlorofunctionalizations Inspired by the sensitivity for the size of the alcohol with different bromenium reagents (section II-3-9), we examined the sensitivity to sterics with N-chlorosaccharine relative to its bromenium analog N-bromosaccharine. If the nucleophile plays less role in assisting the alkene to abstract the chlorenium ion (proposal based on results discussed in Sections II-3-2, II-4-1 and II-4-2), then we anticipate less sensitivity relative to the size of the alcohol with chlorofunctionalizations. Employing methanol, ethanol, and isopropanol we were able to test a range of steric effects on product distribution (II-Figure- 31). As expected, the chlorenium reagent N-chlorosaccharine (Figure II-31b) was much less sensitive to the sterics of the nucleophile than N-bromosaccharine (Figure II-31a), supporting a different mechanistic pathway for bromo and chlorofunctionalizations. To gain a quantitative measurement of the sensitivity, the number of carbons vs ln(intermolecular/intramolecular) to get a sense of the relative sensitivity. This delivered a slope of -0.21 for chlorenium induced reactions and -0.31 for bromenium. This displays that with even N-bromosaccharine, the bromenium electrophile least sensitive to size, it is still more sensitive than N-chlorosaccharine and likely proceeds through more of a nucleophile assisted mechanism than its chlorenium counterpart. If proceeding through a chlorenium intermediate, a weaker and more sterically hindered nucleophile will be at less of a disadvantage. 196 a C 3H 7 C 3H 7 O C 3H 7 O NBSac (2.0 equiv.), 23 °C + Br N N Ar ROH (150 equiv) : Nitromethane (0.05M) RO N Ar H H O Br Ar II-1 (±) II-50, II-50a, II-50b (±) II-7 Ar=pNO2-C6H4 (intermolecular product) Alcohol Product # of carbons Ratio (II-50:II-7)a MeOH II-50 1 1.00 :1.22 EtOH II-50a 2 1.00 :1.68 i-PrOH II-50b 3 1.00 : 2.24 aDetermined by crude NMR. b C 3H 7 C 3H 7 O C 3H 7 O NCSac (0.6 equiv.), 23 °C + Cl N N Ar ROH (150 equiv) : Nitromethane (0.05M) RO N Ar H H O Cl Ar II-1 Ar=pNO2-Ph (±) II-104, II-104a, II-104b (±) II-105 Alcohol Product # of carbons Ratio (II-104:II-105)a MeOH II-93 1 1.00 :0.90 EtOH II-93a 2 1.00 :1.11 i-PrOH II-93b 3 1.00 : 1.37 aDetermined by crude NMR. Nucleophile Steric Effects Bromine Vs. Chlorine 0.2 y = -0.2095x + 0.3138 ln (intermolecular/intramolecular) R² = 1 0 y = -0.3088x + 0.1129 R² = 0.9984 -0.2 -0.4 NBSac NCSac -0.6 -0.8 -1 0.5 1 1.5 2 2.5 3 3.5 Number of Carbons Figure II-31: Sensitivity to alcohol size for bromo and chloroetherifications 197 II-5-4 Rationalization of Divergent Bromenium and Chlorenium Halofunctionalization Mechanisms Considering the slower reaction rates of chlorofunctionalizations and decreased stabilities of chloriranium ions relative to their bromenium counterpart, we initially hypothesized that chlorenium induced halofunctionalizations were more likely to require an NAAA like concerted mechanism than bromenium induced halofunctionalization. We were surprised that mechanistic studies comparing the halenium donor’s influence on product ratios and diastereoselectivity with allyl-amides suggested that bromenium induced reactions proceed through a concerted mechanism and chlorenium induced reactions through a stepwise pathway. This raises the obvious question as to why this mechanistic divergence is occurring. If the nucleophile-induced pre-polarization of the alkene (Figure I-9) occurs, we do not anticipate this reaction pathway to be present with in bromofunctionalizations and absent in chlorofunctionalizations. This provoked a reevaluation of this mechanistic hypothesis with allyl-amide II-1 to consider bromine and chlorine atoms' varied properties and envision how they might modify reaction paths. This led us to contemplate the relative ability of bromenium and chlorenium reagents to halogen bond with Lewis bases as the divergent factor with these reactions. Halogen bonding is an intermolecular force that has been leveraged in crystal engineering, drug design, and catalysis.6 This attractive force increases in strength with the polarizability of the halogen (I > Br > Cl > F) and thus is more viable activation mode with bromenium sources (II-112) than chlorenium sources (II-113) (Figure II-32a). We envision that bromofunctionalizations with II-1 are initiated by reversible halogen bonding of the 198 bromenium donor with π-system of the alkene to generate II-112. The halogen bonding increases the electrophilicity of the alkene, thus activating it for attack by the nucleophile and subsequent cleavage of the bromine donor bond (Figure II-31b).4, 22 The lower the HalA the bromenium donor, the less nucleophilic assistance to cleave the bond from the bromenium ion to the bromenium donor.4 Chlorenium reagents do not possess the same aptitude for halogen bonding and cannot adequately activate the alkene while bound to the chlorenium donor. Thus, chlorenium donors must transfer the chlorenium ion to the alkene, forming the chloriranium ion II-109. This chloriranium ion pathway will be independent of the chlorenium donor in the selectivity determining step. It is also possible to envision that the “chloriranium ion” like intermediate II-114 is still weakly bound to the donor, but not enough to modulate the electronics of the alkene and the subsequent reaction path. We believe that the common chloriranium ion intermediate hypothesis satisfies observations included in this chapter. 199 II-6 Conclusion a ! ! H H H H H H N N C 3H 7 O vs. C 3H 7 O A Br Ar A Cl Ar D! D! II-112 II-113 Bromine is a better halogen bond donor More of a partial positive on the alkene in II-112 II-113 is an inadequate mode of activation b H ! O H H H N ! H H H H H C 3H 7 O MeOH H N N C 3H 7 O C 3H 7 O Br D A Br Ar Ar Br Ar II-1 D! ! Ar = pNO2-C6H4 II-112 D II-107 Amide Cyclization C 3H 7 Ar C 3H 7 O NH2 Br N O C 3H 7 ! MeO N Ar O H H H Br Ar (±) Br (±) II-50 II-7 ! D II-106 c ! H H H C 3H 7 O N C 3H 7 O MeOH MeO N Ar A Cl Ar H Cl D (±) II-104 H H H II-109 N or C 3H 7 O Cl D ! Ar H H H N II-1 C 3H 7 O C 3H 7 Ar = pNO2-C6H4 A Cl Ar Amide Cyclization Cl N O D! Ar II-114 (±) II-105 Figure II-32: (a) Comparison of the bromine and chlorine halogen bond alkene activation (b) Proposed mechanism for bromofunctionalizations (c) Proposed mechanism for chlorofunctionalizations Bromenium and chlorenium sources are often portrayed as mechanistically identical electrophiles regardless of the identity of the halenium ion or halenium donor. We were first enticed by the divergent nature of catalytic bromenium and chlorenium 200 induced reactions that provided a halocyclization with bromenium and intermolecular halo-Ritter reaction with chlorenium. We were delighted that with proper selection of bromenium reagent and nitrile nucleophile we were able to yield the bromo-Ritter product. Mechanistic studies hinted that the sensitivity to bromenium source might be the result of catalyst control. This led us to investigate the mechanistic divergence in the non-catalyzed haloetherifications. Multiple studies displayed a high sensitivity to bromenium donor as a determining factor in product distribution; however, analogous chlorofunctionalization studies displayed little or no dependence on the chlorenium donor. This initiated a mechanistic hypothesis that chlorenium induced difunctionalization reactions proceed through a stepwise mechanism and bromenium induced difunctionalization reactions proceed through a concerted addition of bromenium and nucleophile to the alkene. We hope this sparks appreciation to the complexity of halofunctionalization mechanisms and how one can leverage properties of an alkene, halenium ion, or halenium donor to induce an intended result. I hope people feel comfortable challenging my hypothesizes and look to explore this mechanism further. II-7 Experimental Section II-7-1 Materials and General Instrumentations Commercially available reagents were purchased from Sigma-Aldrich, Alfa-Aesar, or TCI and used as received. Acetonitrile was freshly distilled over CaH2 prior to use. All other solvents were used as purchased. NBS was purified by recrystallization in water. N-bromosaccharine was purchased from TCI and used without further purification. 201 Enantiomeric excess for all products was determined by HPLC analysis using DAICEL Chiralcel® OJ-H and OD-H or Chiralpak® IA, AD-H, and AS-H columns. Allyl amides II- 1, II-42, II-47a-c, II-47e, were synthesized as reported previously and analytical data matched reported values.1, 3 Spectral data for halofunctionalization products II-7, II-50, II- 97a, II-97b, II-104, II-104a, II-105 match reported values. Analytical data for the new substrates can be found below in Section II-8. II-7-2 General Procedure for the Screening of Catalytic Asymmetric Bromoamadination of II-1 to Yield Vicinal Bromoamadine II-14 CF3 (DHQD)2PHAL (10 mol %) N CF3 O C 3H 7 O 1:1 DMC : HFIP (0.05 M), 4ÅMS Ar C 3H 7 O + Me2N N N Ar O H -40 °C, Br+ Reagent (2 equiv.) Br C 3H 7 N Ar H II-1 Br Ar = pNO2-C6H4 II-7 II-14 Figure II-33: General procedure for the screening of catalytic asymmetric bromoamadination of II-1 to yield vicinal bromoamadine II-14 The substrate II-1 (12.4 mg, 0.1 mmol, 1.0 equiv) and (DHQD)2PHAL (3.9 mg, 10 mol%) were suspended in dimethyl cyanamide (0.5 mL) in a test tube with a magnetic stir bar and capped with a rubber septa. HFIP (variable quantity) was added via syringe and 15mg of powder MS4Å was added. The resulting suspension was cooled to –40 °C in an immersion cooler. After stirring for 10 min, the bromenium reagent (0.1 mmol, 2 equiv) was added. Upon completion the reaction was quenched by the addition of saturated Na2S2O3 (2 mL). The reaction was concentrated to remove acetonitrile and the resultant aqueous layer was extracted with DCM (3 x 5 mL). The combined organic layers were 202 dried with anhydrous Na2SO4 and concentrated. Yields were determined by crude NMR with 10 second relaxation delay and a triphenylmethane standard. Column chromatography (SiO2/EtOAc–Hexanes gradient) provided the desired product (II-14). II-7-3 Procedure for the Eyring Analysis of the Catalytic Asymmetric Bromoamidation of II-1 With Acetonitrile CF3 N CF3 O (DHQD)2PHAL (10 mol %) Ar C 3H 7 O 1:1 MeCN : HFIP (0.05 M) C 3H 7 + O N O N Ar temperature, NBSac (2 equiv.) Br H C 3H 7 N Ar H Br II-7 II-19 II-1 Ar = pNO2-C6H4 Figure II-34: Procedure for the Eyring Analysis of the catalytic asymmetric bromoamidation of II-1 with acetonitrile A stock solution of the substrate (II-1) (62.0 mg, 0.25 mmol, 1.0 equiv), (DHQD)2PHAL (19.5 mg, 10 mol%), acetonitrile (2.5 mL), and HFIP (2.5 mL) were combined in a 20 mL vial. 1 mL aliquots were transferred via syringe to 10 mL test tubes with stir bars. Test tubes were heated (via oil bath) or cooled (via immersion cooler) to their respective temperature (47 °C, 25 °C, 7 °C, or -22 °C). After allowing 15 min to equilibrate, reactions were initiated by the addition of N-Bromophthalimide (22.6 mg, 0.1 mmol, 2 equiv.). Upon completion, the reaction was quenched by the addition of saturated Na2S2O3 (2 mL). The reaction was concentrated to remove solvent and the resultant aqueous layer was extracted with DCM (3 x 5 mL). To the concentrated vial with a stir bar, acetonitrile (1 mL) and a solution of HCl (1 M, 0.2 mL) were added and stirred for 5 min. Water (3 mL) was added and the solution was concentrated in vacuo and extracted 203 with DCM (3 x 5 mL). The combined organic layers were dried with anhydrous Na2SO4 and concentrated. Yields and ratios were determined by crude NMR with 10 second relaxation delay and a triphenylmethane standard. Further analysis of product II-19 was on the hydrolyzed product. Hydrolysis procedure is as follows: To the concentrated vial with a stir bar, acetonitrile (1 mL) and a solution of HCl (1 M, 0.2 mL) were added and stirred for 5 min. Water (3 mL) was added and the solution was concentrated in vacuo and extracted with DCM (3 x 5 mL). The combined organic layers were dried with anhydrous Na2SO4 and concentrated to provide amide xy. II-7-4 Procedure for the Eyring Analysis of the Catalytic Asymmetric Bromoamadination of II-1 With Dimethylcyanamide CF3 N CF3 O (DHQD)2PHAL (10 mol %) Ar C 3H 7 O C 3H 7 + 1:1 DMC : HFIP (0.05 M), 4ÅMS O Me2N N O N Ar Temperature, NBP (2 equiv.) Br H C 3H 7 N Ar H Br II-1 II-7 Ar = pNO2-C6H4 II-14 Figure II-35: Procedure for the Eyring Analysis of the catalytic asymmetric bromoamadination of II-1 with dimethylcyanamide A stock solution of the substrate (II-1) (62.0 mg, 0.25 mmol, 1.0 equiv), (DHQD)2PHAL (19.5 mg, 10 mol%), acetonitrile (2.5 mL), and HFIP (2.5 mL) were combined in a 20 mL vial. 1 mL aliquots were transferred via syringe to 10 mL test tubes with stir bars. Test tubes were heated (via oil bath) or cooled (via immersion cooler) to their respective temperature (Figure II-9). After allowing 15 min to equilibrate, reactions were initiated by the addition of the bromenium reagent (0.1 mmol, 2 equiv.). Upon completion, the reaction 204 was quenched by the addition of saturated Na2S2O3 (2 mL). The reaction was concentrated to remove solvent and the resultant aqueous layer was extracted with DCM (3 x 5 mL). The combined organic layers were dried with anhydrous Na2SO4 and concentrated. Ratios of II-7 to II-19 were determined by crude NMR with 10 second relaxation delay and a triphenylmethane standard. II-7-5 Procedure for Eyring Analysis of Haloetherification Reactions with Various Bromenium Reagents OMe O N C 3H 7 O 3:7 MeOH : MeCN (0.05 M) Ar C 3H 7 N Ar + C 3H 7 O N Ar H temperature, Br+ Reagent (2 equiv.) H Br Br II-1 ± ± Ar = pNO2-C6H4 II-7 II-50 Figure II-36: Procedure for Eyring Analysis of haloetherification reactions with various bromenium reagents A stock solution of the substrate (II-1) (161.4 mg, 0.65 mmol, 1.0 equiv.), acetonitrile (9.1 mL), and methanol (3.9 mL) were combined in a 20 mL vial. 1 mL aliquots were transferred via syringe to 10 mL test tubes with stir bars. Test tubes were heated (via oil bath) or cooled (via immersion cooler) to their respective temperature (51 °C, 25 °C, - 7 °C, -28 °C) After allowing 15 min to equilibrate, reactions were initiated by the addition of the bromenium reagent (0.1 mmol, 2 equiv.). The reaction was monitored by TLC and upon completion was quenched by the addition of saturated Na2S2O3 (2 mL). The reaction was concentrated to remove acetonitrile and the resultant aqueous layer was extracted with DCM (3 x 5 mL). The combined organic layers were dried with anhydrous Na2SO4 and concentrated. Product ratios (II-50:II-7) were determined by crude NMR with 10 second relaxation delay. 205 II-7-6 Procedure for Product Ratio as a Function of Nucleophile Concentration C 3H 7 C 3H 7 O OMe O Br+ Source, 23 °C + Br N N Ar MeOH:Nitromethane (0.05M) C 3H 7 N Ar H H O Br Ar II-1 ± ± Ar = pNO2-C6H4 II-50 II-7 Figure II-37: Procedure for product ratio as a function of nucleophile concentration Stock solutions of methanol nitromethane mixtures were made providing methanol molar concentrations of 3.84, 5.45, 9.31, and 14.96. The substrate (II-1) (12.4 mg, 0.05 mmol, 1 equiv.) was added to a test tube with stir bar. 1 mL of the methanol nitromethane mixture was added to the test tube and it was allowed to stir for 5 minutes at room temperature. Reactions were initiated by the addition of the bromenium reagent (0.1 mmol, 2 equiv.). The reaction was monitored by TLC and upon completion was quenched by the addition of saturated Na2S2O3 (2 mL). The reaction was concentrated to remove the solvent and the resultant aqueous layer was extracted with DCM (3 x 5 mL). The combined organic layers were dried with anhydrous Na2SO4 and concentrated. Product ratios were determined by crude NMR with 10 second relaxation delay. II-7-7 Procedure for Acid Additive Influence of Product Ratio C 3H 7 C 3H 7 O OMe O MeOH:Toluene 1:4 (0.05 M) + Br N N Ar Acid additive (20 equiv.) C 3H 7 N Ar H H O 23°C, DBDMH (2 equiv.) Br Ar II-1 ± ± Ar = pNO2-C6H4 II-50 II-7 Figure II-38: Procedure for acid additive influence of product ratio 206 A stock solution of the substrate (II-1) (49.6 mg, 0.2 mmol, 1.0 equiv.), toluene (3.2 mL), and methanol (0.8 mL) were combined in a 20 mL vial. 1 mL aliquots were transferred via syringe to 10 mL test tubes with stir bars. Acid additives (TFE or HFIP) (0.8 mmol, 20 equiv.) were added to their respective test tube via glass syringe. After allowing 5 min to equilibrate, reactions were initiated by the addition of the DBDMH (28.5 mg, 0.1 mmol, 2 equiv.). The reaction was monitored by TLC and upon completion was quenched by the addition of saturated Na2S2O3 (2 mL). The reaction was concentrated to remove the solvent and the resultant aqueous layer was extracted with DCM (3 x 5 mL). The combined organic layers were dried with anhydrous Na2SO4 and concentrated. Product ratios were determined by crude NMR with 10 second relaxation delay. II-7-8 Procedure for Product Ratio as a Function of Nucleophile Size C 3H 7 C 3H 7 O OR O Br+ Source, 23 °C + Br N N Ar ROH (150 equiv) : Nitromethane (0.05M) C 3H 7 N Ar H H O Br Ar II-1 ± Ar = pNO2-C6H4 ± II-50, II-50a, II-50b II-7 Figure II-39: Procedure for product ratio as a function of nucleophile size Stock Solutions of alcohol nucleophile (7.5 mmol, 150 equiv.) and nitromethane (supplemented to enable a 0.05M concentration of II-1). The substrate (II-1) (12.4 mg, 0.05 mmol, 1 equiv.) was added to a test tube with stir bar. 1 mL of the alcohol nitromethane mixture was added to the test tube and it was allowed to stir for 5 minutes at room temperature. Reactions were initiated by the addition of the bromenium reagent (0.1 mmol, 2 equiv.). Upon completion the reactions were quenched by the addition of 207 saturated Na2S2O3 (2 mL). The reaction was concentrated to remove the alcohol/nitromethane solvent and the resultant aqueous layer was extracted with DCM (3 x 5 mL). The combined organic layers were dried with anhydrous Na2SO4 and concentrated. Product ratios were determined by crude NMR with 10 second relaxation delay. II-7-9 Procedure for Eyring Analysis With Alkenes of Varied Halenium Affinity DBDMH (2 equiv.) OMe Br O MeOH (0.05M), rt Br O + O R N Ar Ar H R N Ar R N H ± ± II-47a-c II-48a-c II-49a-c Ar = pNO2-C6H4 Figure II-40: Procedure for Eyring Analysis with alkenes of varied halenium affinity A stock solution of the substrate (II-47a, II-47b, or II-47c) (0.25 mmol, 1.0 equiv.) and methanol (5 mL) were combined in a 20 mL vial. 1 mL aliquots were transferred via syringe to 10 mL test tubes with stir bars. Test tubes were heated (via oil bath) or cooled (via immersion cooler) to their respective temperature. After allowing 15 min to equilibrate, reactions were initiated by the addition of the DBDMH (28.5 mg, 0.1 mmol, 2 equiv.). The reaction was monitored by TLC and upon completion was quenched by the addition of saturated Na2S2O3 (2 mL). The reaction was concentrated to remove methanol and the resultant aqueous layer was extracted with DCM (3 x 5 mL). The combined organic layers were dried with anhydrous Na2SO4 and concentrated. Product ratios of the intermolecular 208 product (II-48) to intramolecular product (II-49) were determined by crude NMR with 10 second relaxation delay. II-7-10 Procedure of Eyring Analysis of Diastereoselectivity in Chlorofunctionalization Ph O OMe O OMe O Ph O Ar MeOH (0.05 M) Ph N Ar + Ph N Ar + N Ar temperature, N H H H Cl DCDMH (2 equiv.) Cl Cl II-47a (±) (±) (±) Ar = pNO2-C6H4 II-97a II-98a II-100 Figure II-41: Procedure of Eyring Analysis of diastereoselectivity in chlorofunctionalization A stock solution of the substrate (II-47a) (70.5 mg, 0.25 mmol, 1.0 equiv.) and methanol (5 mL) were combined in a 20 mL vial. 1 mL aliquots were transferred via syringe to 10 mL test tubes with stir bars. Test tubes were heated (via oil bath) or cooled (via immersion cooler) to their respective temperature (56 °C, 40 °C, 24 °C, 10 °C) After allowing 15 min to equilibrate, reactions were initiated by the addition of the DBDMH (28.5 mg, 0.1 mmol, 2 equiv.). The reaction was monitored by TLC and upon completion was quenched by the addition of saturated Na2S2O3 (2 mL). The reaction was concentrated to remove methanol and the resultant aqueous layer was extracted with DCM (3 x 5 mL). The combined organic layers were dried with anhydrous Na2SO4 and concentrated. Product ratios were determined by crude NMR with 10 second relaxation delay. II-7-11 Procedure for Halenium Affinity Diastereoselectivity Studies of Chlorofunctionalizations 209 Ph O OMe O OMe O Ph O Ar MeOH (0.05 M), rt N Ar Ph N Ar + Ph N Ar + H Cl+ Source (2 equiv.) H H N Cl Cl Cl II-47a (±) (±) (±) Ar = pNO2-C6H4 II-97a II-98a II-100 Figure II-42: Procedure for halenium affinity diastereoselectivity studies of chlorofunctionalizations A stock solution of the substrate (II-47a) (70.5 mg, 0.25 mmol, 1.0 equiv.) and methanol (5 mL) were combined in a 20 mL vial. 1 mL aliquots were transferred via syringe to 10 mL test tubes with stir bars at room temperature. The reactions were initiated by the addition of the chlorinating reagent (0.1 mmol, 2 equiv.). The reaction was monitored by TLC and upon completion was quenched by the addition of saturated Na2S2O3 (2 mL). The reaction was concentrated to remove methanol and the resultant aqueous layer was extracted with DCM (3 x 5 mL). The combined organic layers were dried with anhydrous Na2SO4 and concentrated. Product ratios were determined by crude NMR with 10 second relaxation delay. II-7-12 Procedure for the Study of the Influence of Chlorenium Donor HalA on Product Distribution MeOH (0.05M), rt C 3H 7 OMe O C 3H 7 O Cl+ reagent (2 equiv) + Cl N C 3H 7 N Ar N Ar H O H Cl Ar ± ± II-1 II-105 Ar = pNO2-C6H4 II-104 Figure II-43: Procedure for the study of the influence of chlorenium donor HalA on product distribution A stock solution of the substrate (II-1) (74.4 mg, 0.3 mmol, 1.0 equiv.) and methanol (6 mL) were combined in a 20 mL vial. 1 mL aliquots were transferred via syringe to 10 mL 210 test tubes with stir bars at room temperature. The reactions were initiated by the addition of the chlorinating reagent (0.1 mmol, 2 equiv.). The reaction was monitored by TLC and upon completion was quenched by the addition of saturated Na2S2O3 (2 mL). The reaction was concentrated to remove methanol and the resultant aqueous layer was extracted with DCM (3 x 5 mL). The combined organic layers were dried with anhydrous Na2SO4 and concentrated. Product ratios were determined by crude NMR with 10 second relaxation delay. II-7-13 Procedure for Eyring Analysis with N-Chlorosaccharine MeOH (0.05M), rt C 3H 7 OMe O C 3H 7 O NCSac (0.6 equiv) + Cl N C 3H 7 N Ar N Ar H O H Cl Ar II-1 ± ± Ar = pNO2-C6H4 II-104 II-105 Figure II-44: Procedure for Eyring Analysis with N- Chlorosaccharine A stock solution of the substrate II-1 (74.4 mg, 0.30 mmol, 1.0 equiv.) and methanol (6 mL) were combined in a 20 mL vial. 1 mL aliquots were transferred via syringe to 10 mL test tubes with stir bars. Test tubes were heated (via oil bath) or cooled (via immersion cooler) to their respective temperature (41 °C, 23 °C, 8 °C, -10 °C, -22 °C) After allowing 15 min to equilibrate, reactions were initiated by the addition of the NCSac (6.5 mg, 0.03 mmol, 0.6 equiv.). The reaction was quenched by the addition of saturated Na2S2O3 (2 mL). The reaction was concentrated to remove methanol and the resultant aqueous layer was extracted with DCM (3 x 5 mL). The combined organic layers were dried with anhydrous Na2SO4 and concentrated. Product ratios were determined by crude NMR with 10 second relaxation delay. 211 II-7-14 Procedure for Nucleophile Size Study with N- Chlorosaccharine C 3H 7 C 3H 7 O OR O NCSac (0.6 equiv.), 23 °C + Cl N N Ar ROH (150 equiv) : Nitromethane (0.05M) C 3H 7 N Ar H H O Cl Ar II-1 Ar = pNO2-C6H4 ± ± II-104, II-104a, II-104b II-105 Figure II-45: Procedure for nucleophile size study with N-Chlorosaccharine Stock Solutions of alcohol nucleophile (7.5 mmol, 150 equiv.) and nitromethane. The substrate (12.4 mg, 0.05 mmol, 1 equiv.) was added to a test tube with stir bar. 1 mL of the alcohol nitromethane mixture was added to the test tube and it was allowed to stir for 5 minutes at room temperature. Reactions were initiated by the addition of the bromenium reagent (0.1 mmol, 2 equiv.). The reaction was quenched with saturated Na2S2O3 (2 mL). The reaction was concentrated to remove acetonitrile and the resultant aqueous layer was extracted with DCM (3 x 5 mL). The combined organic layers were dried with anhydrous Na2SO4 and concentrated. Product ratios were determined by crude NMR with 10 second relaxation delay. II-8 Analytical Data Br O NO2 C 3H 7 N II-7, (R)-5-((R)-1-bromobutyl)-2-(4-nitrophenyl)-4,5-dihydrooxazole 1H and 13C NMR data match previous publications Resolution of enantiomers: DAICEL Chiralpak®, IA 98.5% IPA/Hexane 1ml/min, 254 nm, RT 1 (major)=21.8 min, RT 2 (minor) =24.4 min. 212 CF3 CF3 O Me2N N O C 3H 7 N H Br NO2 II-14, 1,1,1,3,3,3-hexafluoropropan-2-yl N'-((2R,3R)-2-bromo-1-(4- nitrobenzamido)hexan-3-yl)-N,N-dimethylcarbamimidate 1H NMR (500 MHz, CDCl3) δ 8.32 (d, J = 8.7 Hz, 2H), 7.95 (d, J = 8.8 Hz, 2H), 6.70 (s, 1H), 4.30 (dt, J = 9.5, 3.3 Hz, 1H), 4.12 (ddd, J = 14.4, 7.3, 3.5 Hz, 1H), 3.80 (td, J = 6.5, 2.8 Hz, 1H), 3.52 – 3.41 (m, 1H), 2.89 (s, 6H), 1.76 – 1.61 (m, 1H), 1.48 (ddt, J = 16.4, 14.3, 7.1 Hz, 1H), 1.36 – 1.28 (m, 2H), 0.95 (t, J = 7.3 Hz, 3H). 13C NMR (126 MHz, CDCl3) δ 165.3, 150.2, 149.7, 139.7, 128.1, 123.9, 60.8, 57.0, 44.9, 39.6, 36.5, 18.9, 14.0. 19F NMR (470 MHz, CDCl3) δ -73.06 (p, J = 8.2 Hz), -73.40. Resolution of enantiomers: DAICEL Chiralpak®, IA 97.5% IPA/Hexane 1ml/min, 254 nm, RT 1 (minor)=18.9 min, RT 2 (major) =22.3 min. CF3 CF3 O N O C 3H 7 N H Br NO2 II-19, 1,1,1,3,3,3-hexafluoropropan-2-yl N-((2R,3R)-1-(argioformamido)-2-bromohexan- 3-yl)acetimidate Rf: 0.32 (30% EtOAC/Hex) 213 1H NMR (500 MHz, CDCl3) δ 8.33 (d, J = 8.9 Hz, 2H), 7.96 (d, J = 8.9 Hz, 2H), 6.61 (s, 1H), 6.43 (hept, J = 6.5 Hz, 1H), 4.28 (ddd, J = 10.0, 4.4, 3.1 Hz, 1H), 4.15 (ddd, J = 14.4, 7.5, 2.9 Hz, 1H), 3.51 (dt, J = 8.7, 4.3 Hz, 1H), 3.32 (ddd, J = 14.4, 10.0, 4.4 Hz, 1H), 2.08 (s, 3H), 1.72 (dddd, J = 14.2, 10.4, 6.1, 4.5 Hz, 1H), 1.67 – 1.49 (m, 1H), 1.30 – 1.18 (m, 2H), 0.94 (t, J = 7.4 Hz, 3H). 13C NMR (126 MHz, CDCl3) δ 165.5, 157.8, 149.8, 139.5, 128.2, 124.0, 60.8, 60.2, 44.5, 36.3, 19.0, 14.9, 13.9. 19F NMR (470 MHz, CDCl3) δ -73.15 (p, J = 8.0 Hz), -73.35 (p, J = 8.1 Hz). Resolution of enantiomers: DAICEL Chiralpak®, IA 96% IPA/Hexane 1ml/min, 254 nm, RT 1 (minor)=9.9 min, RT 2 (major) =10.7 min. O NH O C 3H 7 N H Br NO2 II-19-Hydrolyzed N-((2R,3R)-3-acetamido-2-bromohexyl)-4-nitrobenzamide 1H NMR (500 MHz, CDCl3) δ 8.38 (dd, J = 7.9, 3.3 Hz, 1H), 8.32 (d, J = 8.8 Hz, 2H), 8.09 (d, J = 8.8 Hz, 2H), 5.58 (d, J = 9.3 Hz, 1H), 4.42 (ddd, J = 13.8, 8.8, 5.1 Hz, 1H), 4.22 (ddd, J = 11.3, 5.1, 1.8 Hz, 1H), 4.15 (tdd, J = 9.0, 5.4, 1.8 Hz, 1H), 3.05 (ddd, J = 13.7, 11.3, 4.3 Hz, 1H), 2.16 (s, 3H), 1.67 (dtd, J = 13.9, 8.5, 6.7 Hz, 1H), 1.58 – 1.49 (m, 1H), 1.40 – 1.33 (m, 2H), 0.91 (t, J = 7.3 Hz, 3H). 13C NMR (126 MHz, CDCl3) δ 172.0, 164.7, 149.7, 139.2, 128.4, 123.9, 55.5, 49.0, 43.1, 36.3, 23.3, 19.2, 13.7. 214 Resolution of enantiomers: DAICEL Chiralpak®, AD-H 10% IPA/Hexane 1ml/min, 254 nm, RT 1 (major)=28.0 min, RT 2 (minor) =30.4 min. OMe O N H Br NO2 II-44, (±) N-((2R,3S)-2-bromo-3-methoxy-3-phenylpropyl)-4-nitrobenzamide Rf: 0.28 (30% EtOAC/Hex) 1H NMR (500 MHz, CDCl3) δ 8.31 (d, J = 8.9 Hz, 2H), 7.92 (d, J = 9.0 Hz, 2H), 7.48 – 7.33 (m, 5H), 6.97 (s, 1H), 4.58 (d, J = 5.2 Hz, 1H), 4.36 (dd, J = 10.9, 5.0 Hz, 1H), 4.11 (ddd, J = 14.5, 6.5, 4.6 Hz, 1H), 3.71 (ddd, J = 14.6, 6.1, 4.5 Hz, 1H), 3.39 (s, 3H). 13C NMR (126 MHz, CDCl3) δ 165.2, 149.7, 139.9, 137.5, 128.8, 128.8, 128.2, 127.1, 123.9, 86.7, 58.2, 55.1, 42.7. O Br NO2 N II-46, (±) (5R,6S)-5-bromo-2-(4-nitrophenyl)-6-phenyl-5,6-dihydro-4H-1,3-oxazine Rf: 0.55 (30% EtOAC/Hex) 1H NMR (500 MHz, CDCl3) δ 8.23 (d, J = 9.0 Hz, 2H), 8.13 (d, J = 8.9 Hz, 2H), 7.48 – 7.41 (m, 3H), 7.42 – 7.36 (m, 2H), 5.37 (d, J = 8.0 Hz, 1H), 4.33 (td, J = 8.0, 4.8 Hz, 1H), 4.11 (dd, J = 17.6, 4.8 Hz, 1H), 3.96 (dd, J = 17.6, 8.1 Hz, 1H). 215 13C NMR (126 MHz, CDCl3) δ 153.6, 149.4, 138.4, 137.0, 129.4, 128.9, 128.3, 126.8, 123.4, 81.3, 50.6, 44.7. OMe O N H Br NO2 II-48a, N-((2R,3R)-2-bromo-3-methoxy-3-phenylpropyl)-4-nitrobenzamide Rf: 0.20 (30% EtOAC/Hex) 1H NMR (500 MHz, CDCl3) δ 8.29 (d, J = 8.9 Hz, 1H), 7.89 (d, J = 8.8 Hz, 1H), 7.45 – 7.32 (m, 5H), 6.66 (s, 1H), 4.44 (d, J = 5.0 Hz, 1H), 4.37 (ddd, J = 7.8, 5.0, 4.3 Hz, 1H), 3.35 (s, 3H) 13C NMR (126 MHz, CDCl3) δ 165.3, 149.7, 139.6, 137.3, 128.8, 128.7, 128.2, 127.4, 123.9, 85.0, 57.4, 57.4, 44.3. OMe O N H Br Cl NO2 II-48b, (±) N-((2R,3R)-2-bromo-3-(4-chlorophenyl)-3-methoxypropyl)-4-nitrobenzamide Rf: 0.18 (30% EtOAC/Hex) 1H NMR (500 MHz, CDCl3) δ 8.31 (d, J = 8.8 Hz, 2H), 7.91 (d, J = 8.8 Hz, 2H), 7.39 (d, J = 8.5 Hz, 2H), 7.31 (d, J = 8.5 Hz, 1H), 6.68 (t, J = 5.2 Hz, 1H), 4.43 (d, J = 4.5 Hz, 1H), 4.33 (dt, J = 8.4, 4.3 Hz, 1H), 4.08 (ddd, J = 14.5, 6.8, 4.1 Hz, 1H), 3.65 (ddd, J = 14.5, 8.1, 4.8 Hz, 1H), 3.34 (s, 3H). 216 13C NMR (126 MHz, CDCl3) δ 165.4, 149.8, 139.5, 135.8, 134.7, 128.9, 128.7, 128.2, 124.0, 84.0, 57.5, 57.2, 44.3. OMe O N H Br CF3 NO2 II-48c, (±) N-((2R,3R)-2-bromo-3-methoxy-3-(4-(trifluoromethyl)phenyl)propyl)-4- nitrobenzamide Rf: 0.20 (30% EtOAC/Hex) 1H NMR (500 MHz, CDCl3) δ 8.31 (d, J = 8.8 Hz, 1H), 7.92 (d, J = 8.8 Hz, 1H), 7.68 (d, J = 8.5 Hz, 2H), 7.51 (d, J = 8.0 Hz, 2H), 4.53 (d, J = 4.0 Hz, 1H), 4.37 (dt, J = 8.1, 4.0 Hz, 1H), 4.15 (ddd, J = 14.4, 6.8, 4.0 Hz, 1H), 3.68 (ddd, J = 14.4, 8.2, 4.8 Hz, 1H), 3.38 (s, 3H). 13C NMR (126 MHz, CDCl3) δ 165.5, 149.8, 141.4, 139.5, 130.9 (q, J = 32.5 Hz), 128.2, 127.8, 126.8 (q, J = 271.8 Hz), 125.6 (q, J = 3.8 Hz), 124.0, 83.9, 57.7, 57.0, 44.5. 19F NMR (470 MHz, CDCl3) δ -62.63. OMe O N H Br Me NO2 II-48e, (±) N-((2R,3R)-2-bromo-3-methoxy-3-(p-tolyl)propyl)-4-nitrobenzamide Rf: 0.25 (30% EtOAC/Hex) 1H NMR (500 MHz, CDCl3) δ 8.30 (d, J = 8.8 Hz, 2H), 7.89 (d, J = 8.8 Hz, 2H), 7.27 – 7.20 (m, 4H), 6.61 (s, 1H), 4.40 (d, J = 5.3 Hz, 1H), 4.36 (dt, J = 7.5, 4.8 Hz, 1H), 4.00 217 (ddd, J = 14.4, 6.6, 4.4 Hz, 1H), 3.67 (ddd, J = 14.4, 7.6, 4.9 Hz, 1H), 3.34 (s, 3H), 2.38 (s, 3H). 13C NMR (126 MHz, CDCl3) δ 165.2, 149.7, 139.7, 138.8, 134.2, 129.4, 128.1, 127.3, 123.9, 85.0, 57.4, 57.3, 44.3, 21.3. Br O NO2 N II-49a, (R)-5-((R)-bromo(phenyl)methyl)-2-(4-nitrophenyl)-4,5-dihydrooxazole Rf: 0.23 (30% EtOAC/Hex) 1H NMR (500 MHz, CDCl3) δ 8.31 (d, J = 9.0 Hz, 1H), 8.18 (d, J = 8.8 Hz, 2H), 7.50 – 7.44 (m, 1H), 7.43 – 7.32 (m, 2H), 5.26 (dt, J = 9.9, 6.9 Hz, 1H), 5.02 (d, J = 6.6 Hz, 1H), 4.12 (dd, J = 15.8, 9.9 Hz, 1H), 3.88 (dd, J = 15.8, 7.0 Hz, 1H). 13C NMR (126 MHz, CDCl3) δ 162.1, 149.6, 137.1, 132.8, 129.4, 129.3, 129.1, 128.3, 123.6, 82.8, 58.8, 54.9. (Assisted by HSQC and HMBC NMR) Br O NO2 Cl N II-49b, (±) (R)-5-((R)-bromo(4-chlorophenyl)methyl)-2-(4-nitrophenyl)-4,5-dihydrooxazole 1H NMR (500 MHz, CDCl3) δ 8.31 (d, J = 9.0 Hz, 2H), 8.14 (d, J = 8.9 Hz, 2H), 7.43 (d, J = 8.6 Hz, 2H), 7.37 (d, J = 8.6 Hz, 2H), 5.18 (dt, J = 10.1, 6.6 Hz, 1H), 4.99 (d, J = 6.1 Hz, 1H), 4.14 (dd, J = 15.9, 9.9 Hz, 1H), 3.88 (dd, J = 15.8, 6.9 Hz, 1H). 13C NMR (126 MHz, CDCl3) δ 161.8, 149.8, 135.9, 135.1, 132.8, 129.6, 129.3, 129.2, 123.7, 82.4, 59.2, 51.7 218 Br O NO2 CF3 N II-49c, (±) (R)-5-((R)-bromo(4-(trifluoromethyl)phenyl)methyl)-2-(4-nitrophenyl)-4,5- dihydrooxazole Rf: 0.24 (30% EtOAC/Hex) 1H NMR (500 MHz, CDCl3) δ 8.31 (d, J = 8.8 Hz, 2H), 8.14 (d, J = 8.8 Hz, 2H), 7.67 (d, J = 8.4 Hz, 2H), 7.63 (d, J = 8.3 Hz, 2H), 5.19 (ddd, J = 9.9, 6.9, 5.7 Hz, 1H), 5.05 (d, J = 5.7 Hz, 1H), 4.18 (dd, J = 15.8, 9.9 Hz, 1H), 3.92 (dd, J = 15.8, 6.9 Hz, 1H). 13C NMR (126 MHz, CDCl3) δ 161.8, 149.7, 141.3, 132.8, 131.3 (q, J = 32.9 Hz), 129.3, 128.8, 127.3 (q, J = 290.6 Hz), 126.0 (q, J = 3.8 Hz), 123.7, 82.1, 59.1, 53.6. 19F NMR (470 MHz, Chloroform-d) δ -62.85. O O C 3H 7 N H Br NO2 II-50a, (±) N-((2R,3R)-2-bromo-3-ethoxyhexyl)-4-nitrobenzamide Rf: 0.36 (30% EtOAC/Hex) 1H NMR (500 MHz, CDCl3) δ 8.32 (d, J = 8.8 Hz, 2H), 7.96 (d, J = 8.8 Hz, 2H), 6.99 (s, 1H), 4.36 (ddd, J = 8.0, 5.1, 3.0 Hz, 1H), 4.17 (ddd, J = 14.3, 6.4, 5.1 Hz, 1H), 3.72 (ddd, J = 14.3, 7.7, 4.7 Hz, 1H), 3.65 (qd, J = 7.0, 2.3 Hz, 2H), 3.52 (ddd, J = 7.9, 5.0, 3.0 Hz, 1H), 1.81 – 1.71 (m, 1H), 1.68 – 1.59 (m, 1H), 1.51 – 1.34 (m, 2H), 1.23 (t, J = 7.0 Hz, 3H), 0.98 (t, J = 7.3 Hz, 3H). 13C NMR (126 MHz, Chloroform-d) δ 165.2, 149.7, 139.8, 128.2, 123.9, 81.5, 66.0, 54.3, 44.1, 33.1, 19.1, 15.6, 14.0. 219 O O C 3H 7 N H Br NO2 II-50b, (±) N-((2R,3R)-2-bromo-3-isopropoxyhexyl)-4-nitrobenzamide Rf: 0.44 (30% EtOAC/Hex) 1H NMR (500 MHz, CDCl3) δ 8.32 (d, J = 8.7 Hz, 2H), 7.96 (d, J = 8.8 Hz, 2H), 7.05 (s, 1H), 4.33 (ddd, J = 8.4, 5.6, 3.0 Hz, 1H), 4.15 (dt, J = 14.2, 5.8 Hz, 1H), 3.79 – 3.67 (m, 2H), 3.62 (dt, J = 8.0, 4.0 Hz, 1H), 1.86 – 1.76 (m, 1H), 1.57 – 1.43 (m, 2H), 1.41 – 1.30 (m, 1H), 1.20 (t, J = 5.9 Hz, 6H), 0.98 (t, J = 7.3 Hz, 3H). 13C NMR (126 MHz, Chloroform-d) δ 165.1, 149.7, 139.8, 128.2, 123.9, 79.3, 71.3, 53.7, 43.7, 32.6, 23.0, 22.6, 19.2, 14.0. OMe O N H Br NO2 II-103, (±) N-((2R,3S)-2-bromo-3-methoxy-3-(p-tolyl)propyl)-4-nitrobenzamide Rf: 0.21 (30% EtOAC/Hex) 1H NMR (500 MHz, CDCl3) δ 8.31 (d, J = 8.8 Hz, 2H), 7.92 (d, J = 8.8 Hz, 2H), 7.27 – 7.19 (m, 4H), 6.97 (s, 1H), 4.55 (d, J = 5.2 Hz, 1H), 4.34 (q, J = 5.1 Hz, 1H), 4.10 (ddd, J = 14.7, 6.5, 4.7 Hz, 1H), 3.72 (ddd, J = 14.5, 5.9, 4.4 Hz, 1H), 3.37 (s, 3H), 2.37 (s, 3H). 13C NMR (126 MHz, CDCl3) δ 165.1, 149.6, 140.0, 138.7, 134.5, 129.5, 128.1, 127.0, 123.9, 86.7, 58.1, 55.2, 42.7, 21.2. 220 O O C 3H 7 N H Cl NO2 II-104b, (±) N-((2R,3R)-2-chloro-3-isopropoxyhexyl)-4-nitrobenzamide Rf: 0.39 (30% EtOAC/Hex) 1H NMR (500 MHz, CDCl3) δ 8.32 (d, J = 8.8 Hz, 2H), 7.96 (d, J = 8.9 Hz, 2H), 7.00 (s, 1H), 4.23 (ddd, J = 8.2, 5.3, 3.2 Hz, 1H), 4.11 (ddd, J = 14.1, 6.2, 5.3 Hz, 1H), 3.75 (hept, J = 6.0 Hz, 1H), 3.66 – 3.58 (m, 2H), 1.83 – 1.64 (m, 1H), 1.55 – 1.45 (m, 2H), 1.43 – 1.30 (m, 1H), 1.20 (dd, J = 6.1, 3.5 Hz, 6H), 0.98 (t, J = 7.3 Hz, 3H). 13C NMR (126 MHz, CDCl3) δ 165.3, 149.8, 139.9, 128.2, 123.9, 79.6, 71.4, 60.4, 43.4, 32.0, 22.7, 19.0, 14.0 221 REFERENCES 222 REFERENCES 1. 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