SELECTIVE SYNTHESIS OF AROMATIC AND SATURATED ORGANOBORON COMPOUNDS By Timothy Michael Shannon A DISSERTATION Submitted to Michigan State University in partial fulfillment of the requirements for the degree of Chemistry – Doctor of Philosophy 2019 ABSTRACT SELECTIVE SYNTHESIS OF AROMATIC AND SATURATED ORGANOBORON COMPOUNDS By Timothy Michael Shannon C-H borylation (CHB) is a method to functionalize C-H bonds. The development of CHB has taken many years but is getting to the point of well-established chemistry. The directed CHB is possible for a variety of differing substrates and differing loctions of direction. A new method for ortho directed CHB of esters amides and ketones was developed through the use of pyridine based monodentate ligands. Using 4-cyano-2-methoxypyridine as a ligand iridium catalyzed CHB of esters ketones and amides were performed. The mechanism of CHB in this process likely operates through a different rate-determining step than the other C-H borylation methods used as it was found that the kinetic isotope effect data did not clearly support C-H activation as rate-determining. The development of sp3 C-H borylation is not as advanced as sp2 CHB; a 2-step process to generate the same products could be equally desirable. Utilizing a borylation- hydrogenation process the selectivity that have already been developed for sp2 C-H borylation can be used to generate the sp3 carbon boron bond at the desired location. This process has been developed and limitations of it have been investigated. Philip Lucasse and Kristin Shannon iii ACKNOWLEDGMENTS Thank you Dr. Milton R Smith III for your time and patience. I came to graduate school hoping to learn how to identify a chemical problem and figure out a possible solution. Without a doubt you helped to teach me that. While we fundmentally think about things differently, your scientific approach is amazing and I am thankful and beyond greatful to have worked with you. Dr. Malezcka, special thanks for all of the years of guideance and for steping into the role of 2nd reader in the last few weeks. Dr. Odom and Dr. Jackson, I will always be thankful for the indepth questions while serving on my committee. Graduate school would not hve been survivable without the great pears that I worked with along the way: Dr. Sean, Don, Dr. Buddhadeb, Dr. Behnaz, Dr. Dimity, Dr. Olivia, Dr. Yu-ling, PoJen, Alex, Ryan, Seokjoo, Mona, Reza, Dr. Suzi, Dr. Aaron, Dr. Hao Li, Dr. Ruwi , Jonathan, Fang Yi, and Pepe. Thank you for always being there to have a conversation about crazy ideas inside or outside of our group meetings. Drs. Tanner, Corey, Travis, Matt, Kristen, Josh, Dan, Hammed, Brennan, Kelly, and Tyler being able to chat about ideas, chemistry, our advisors, or students made for a great time. Dr. Staples, Dr. Holmes thanks you for your guidance and mentoring throughout my time at MSU. Dr. Azadnia, and Dr. Vassilou, ti was great to work with you as TA for several semesters. My friends and family that are not in chemistry I made a promise to myself to not let graduate school change our relationships in negative way. I cnnot say with any iv confidence that I fulfilled that promise, and I am beyond appreciative for all of your support even when I missed life events or was not available as much as I wished. Dr. Kristin… There is nothing I write on paper that would do justice to all the support you have shown me. Finding you at MSU made the 10 to 14 hour days, weekends, stress induced migranes, and failiures all worthwhile. There is no amount of joy I get from chemistry, science experiments or teaching that will ever compare to the joy I get to spend every day of the rest of my life with you. I love you and thank you for always being there for me. v TABLE OF CONTENTS LIST OF TABLES ......................................................................................................... viii LIST OF FIGURES ......................................................................................................... ix LIST OF SCHEMES ..................................................................................................... xvi KEY TO ABBREVIATIONS ..................................................................................... xviii Chapter 1. Formation of Carbon-Boron Bonds ............................................................. 1 1.1 Importance of Boron Containing Compounds in Synthetic Chemistry. ................... 1 1.2 C-H functionalization ................................................................................................ 3 1.3 Early C-H Borylation ................................................................................................ 6 1.4 Mechanistic Investigations into Iridium Catalyzed C-H borylation ......................... 9 1.5 Selectivity of CHB .................................................................................................. 12 1.6 Ortho-Directed C-H borylation ............................................................................... 13 1.7 Meta-Directed CHB ................................................................................................ 18 1.8 Para-Directed C-H Borylation ................................................................................ 20 1.9 Aliphatic C-B Bond Formation ............................................................................... 22 1.10 sp3 C-H borylation ................................................................................................ 23 1.11 Conclusions and Future Work .............................................................................. 26 Chapter 2. Hydrogenation of Aromatic and Heteroaromatic Organoboronic Esters and Organosilicon Compounds ..................................................................................... 27 2.1 A Brief History of Hydrogenation Chemistry ........................................................ 27 2.2 Hydrogenation of Borylated Olefins ....................................................................... 30 2.3 Hydrogenation of Borylated Arenes ....................................................................... 32 2.4 Additives for Hydrogenation of Borylated 6-Membered Heterocycles. ................. 33 2.5 Additives Free Hydrogenation of Borylated 6-Membered Heterocycles. .............. 39 2.6 Hydrogenation of Borylated 5-Membered Heterocycles ........................................ 42 2.7 Hydrogenation of Borylated Arenes ....................................................................... 44 2.8 Silylated heterocycles ............................................................................................. 45 2.9 Chiral Resolution of a reduced borylated piperidine .............................................. 48 2.10 Hydrogenation Conclusion ................................................................................... 50 Chapter 3. Pyridine Ligands for ortho-Directed C-H Borylation .............................. 51 3.1 Chelate Directed ortho C-H Borylation .................................................................. 51 3.2 Hemi-Labile Ligand Systems ................................................................................. 52 3.3 L-X type Ligand Systems for Chelate Directed ortho-Borylation .......................... 55 3.4 Monodentate Ligand Systems ................................................................................. 57 3.5 Further Challenges in Chelate Directed ortho-Borylation ...................................... 60 3.6 Pyridine Ligand Screens for ortho Selectivity ........................................................ 61 3.7 Investigation into Substrate Scope .......................................................................... 68 3.8 Insights into mechanism of pyridine ligated iridium systems for ortho borylation 73 vi 3.9 Selectivity Dependence on Concentration of the Catalyst ...................................... 78 3.10 Combined Mechanism for Pyridine Ligated Iridium CHB ................................... 80 3.11 Pyridine Ligands for ortho CHB Conclusions ...................................................... 81 Chapter 4. Experimental ................................................................................................ 82 4.1 General Considerations ........................................................................................... 82 4.2 Experimental Information for Chapter 2 ................................................................. 83 4.3 Experimental information for Chapter 3 ............................................................... 114 APPENDICES ............................................................................................................... 137 APPENDIX A: NMR Spectra ..................................................................................... 138 APPENDIX B: Crystal Structure Data ....................................................................... 270 REFERENCES .............................................................................................................. 273 vii LIST OF TABLES Table 1. Heterogeneous catalyst screen for hydrogenation of 2a ..................................... 35 Table 2. Solvent Screen for the Hydrogenation of 2a ...................................................... 36 Table 3. Bronsted acid additives for the hydrogenation of 2a by rhodium on carbon ..... 37 Table 4. Lewis Acid Screen for the Rhodium on carbon hydrogenation of 2a ................ 38 Table 5. Hydrogenation of 6-membered heterocyclesa,b ................................................... 40 Table 6. Heterogeneous Hydrogenation of 5-membered Heterocycles ............................ 43 Table 7. Hydrogenation of borylated arenesa,b .................................................................. 45 Table 8. Hydrogenation of silylated heterocycles............................................................. 46 Table 9. Screen of pyridine ligands for ortho borylation of methyl benzoate with one equivalent of diboron ........................................................................................................ 63 Table 10. Screen of pyridine ligands for ortho-borylation of methyl benzoate with half an equivalent of diboron ........................................................................................................ 65 Table 11. Ligand Screen for ortho-Borylation of Cyclopropyl Phenylketone.................. 66 Table 12. Electronic effects of 4-substituted-2-methoxypyridines for ortho-borylation of cyclopropyl phenylketone ................................................................................................. 67 Table 13. ortho C-H borylation of aryl esters and amides using a monodentate pyridine ligand................................................................................................................................. 69 Table 14. ortho C-H borylation of aryl ketones using a monodentate pyridine ligand .... 70 Table 15. ortho-borylation on complex substrates ............................................................ 72 Table 16. Pyridine to iridium ratio impact on reactivity ................................................... 73 Table 17. Underlying data for Figure 16 ........................................................................ 135 Table 18. Underlying data for Figure 17 ........................................................................ 136 Table B1 Crystal data for compound 2e ......................................................................... 271 Table B2 Crystal structure data for 2za .......................................................................... 272 viii LIST OF FIGURES Figure 1. Transformations of C-B bonds ............................................................................ 2 Figure 2. Proposed Relay-directed ortho CHB transition state ........................................ 13 Figure 3. Electrostatic directed ortho CHB transition state .............................................. 14 Figure 4. Hydrogen bonding directed ortho CHB of aniline32.......................................... 15 Figure 5. Chelate directed ortho CHB .............................................................................. 17 Figure 6. Thioether directed ortho CHB ........................................................................... 17 Figure 7. Hydrogen bond-directed meta-borylation ......................................................... 18 Figure 8. Imine directed meta borylation .......................................................................... 19 Figure 9. Ion pairing interactions for meta-directed CHB ................................................ 20 Figure 10. Directed para borylation of aryl esters ............................................................ 22 Figure 11. Homogeneous hydrogenation catalysts.9-12 ..................................................... 29 Figure 12. Hydrogenation of 2a yielding borylated and deborylated product .................. 34 Figure 13. Crystal Structure of Compound 2e .................................................................. 41 Figure 14. 1H NMR signal from the TMS group on 2u .................................................... 47 Figure 15. Crystal Structure of Compound 2za ................................................................ 50 Figure 16. C-H Activation in Chelate Directed ortho-Borylation .................................... 51 Figure 17. General catalytic cycle for chelate directed ortho-borylation ......................... 52 Figure 18. Selectivity vs concentration of catalyst in iridium catalyzed ortho borylation of methyl benzoate. ............................................................................................................... 78 Figure 19. Selectivity of ortho-Borylation of Methyl Benzoate With no Added Ligand . 79 Figure 20. 400 MHz 1H-NMR of pinacol in D2O ............................................................. 87 Figure 21. gCOSY of compound 2l .................................................................................. 95 Figure 22. NOE between protons on 2l showing cis stereochemistry 3.9ppm irradiated . 96 ix Figure 23. NOE between protons on 2l showing cis stereochemistry 3.7ppm irradiated . 97 Figure 24. NOE between the major species of 2q showing cis stereochemistry ............ 100 Figure 25. NOE between the major species of 2r showing cis stereochemistry ............ 102 Figure 26. NOE between the major species of 2s showing cis stereochemistry ............. 104 Figure 27. NOE between the major species of 2t showing cis stereochemistry ............. 106 Figure 28. gHMQC for assignments of 3ba an 3bb. ..................................................... 131 Figure 29. gHMBCAD for assignments of 3ba an 3bb.................................................. 132 Figure 30. gCOSY for assignments of 3ba an 3bb. ....................................................... 133 Figure A1. 500 MHz 1H NMR of 2b in D2O .................................................................. 139 Figure A2. 500 MHz 1H NMR of 2b in D2O from 3.9 to 1.0 ppm ................................. 140 Figure A3. 125 MHz 13C NMR of 2b in D2O ................................................................. 141 Figure A4. 125 MHz 13C NMR of 2b in D2O from 85 to 15 ppm .................................. 142 Figure A5. 500 MHz 1H NMR of 2c in D2O .................................................................. 143 Figure A6. 500 MHz 1H NMR of 2c in D2O from 3.6 to 0.6 ppm ................................. 144 Figure A7. 125 MHz 13C NMR of 2c in D2O ................................................................. 145 Figure A8. 125 MHz 13C NMR of 2c in D2O from 85 to 15 ppm .................................. 146 Figure A9. 160 MHz 11B NMR of 2c in D2O ................................................................. 147 Figure A10. 500 MHz 1H NMR of 2d′′′′ in CDCl3 ........................................................... 148 Figure A11. 160 MHz 11B NMR of 2d′′′′ in D2O .............................................................. 149 Figure A12. 500 MHz 1H NMR of 2d in D2O ................................................................ 150 Figure A13. 125 MHz 13C NMR of 2d in D2O ............................................................... 151 Figure A14. 125 MHz 13C NMR of 2d in D2O from 60 to 15 ppm ................................ 152 Figure A15. 160 MHz 11B NMR of 2d in D2O ............................................................... 153 Figure A16. 500 MHz 1H NMR of 2e′′′′ in CDCl3 ............................................................ 154 Figure A17. 125 MHz 13C NMR of 2e′′′′ in CDCl3 ........................................................... 155 x Figure A18. 160 MHz 11B NMR of 2e′′′′ in CDCl3 ........................................................... 156 Figure A19. 500 MHz 1H NMR of 2e in D2O ................................................................ 157 Figure A20. 500 MHz 1H NMR of 2e in D2O from 3.8 to 1.0 ppm ............................... 158 Figure A21. 125 MHz 13C NMR of 2e in D2O ............................................................... 159 Figure A22. 160 MHz 11B NMR of 2e in D2O ............................................................... 160 Figure A23. 500 MHz 1H NMR of 2f in CDCl3 ............................................................ 161 Figure A24. 160 MHz 11B NMR of 2f in CDCl3 ............................................................ 162 Figure A25. 500 MHz 1H NMR of 2g′′′′ in CDCl3 ............................................................ 163 Figure A26. 500 MHz 1H NMR of 2g in CDCl3............................................................. 164 Figure A27. 500 MHz 1H NMR of 2g in CDCl3 from 4.0 to 0.9 ppm ............................ 165 Figure A28. 125 MHz 13C NMR of 2g in CDCl3 ........................................................... 166 Figure A29. 125 MHz 13C NMR of 2g in CDCl3 from 85 to 15 ppm ............................. 167 Figure A30. 160 MHz 11B NMR of 2g in CDCl3 ........................................................... 168 Figure A31. 500 MHz 1H NMR of 2h in CDCl3 ............................................................ 169 Figure A32. 160 MHz 11B NMR of 2h in CDCl3 ........................................................... 170 Figure A33. 500 MHz 1H NMR of 2l in C6D6 ................................................................ 171 Figure A34. 500 MHz 1H NMR of 2l in C6D6 from 2.3ppm to 0.9ppm ......................... 172 Figure A35. 500 MHz 1H NMR of 2l in C6D6 from 4.1ppm to 3.5ppm ......................... 173 Figure A36. 125 MHz 13C NMR of 2l in C6D6 ............................................................... 174 Figure A37. 125 MHz 13C NMR of 2l in C6D6 from 43ppm to 18 ppm ......................... 175 Figure A38. 160 MHz 11B NMR of 2l in C6D6 ............................................................... 176 Figure A39. 500 MHz 1H NMR of 2o in CDCl3............................................................. 177 Figure A40. 125 MHz 13C NMR of 2o in CDCl3 ........................................................... 178 Figure A41. 160 MHz 11B NMR of 2o in CDCl3 ........................................................... 179 Figure A42. 500 MHz 1H NMR of 2p in D2O ................................................................ 180 xi Figure A43. 160 MHz 11B NMR of 2p in D2O ............................................................... 181 Figure A44. 500 MHz 1H NMR of 2q in CDCl3 ............................................................ 182 Figure A45. 500 MHz 1H NMR of 2q in CDCl3 ............................................................ 183 Figure A46. 125 MHz 13C NMR of 2q in CDCl3 ........................................................... 184 Figure A47. 125 MHz 13C NMR of 2q in CDCl3 from 44 to 22 ppm ............................ 185 Figure A48. 470 MHz 19F NMR of 2q in CDCl3 ............................................................ 186 Figure A49. 500 MHz 1H NMR of 2r in C6D6 ............................................................... 187 Figure A50. 125 MHz 13C NMR of 2r in C6D6 .............................................................. 188 Figure A51. 160 MHz 11B NMR of 2r in C6D6 .............................................................. 189 Figure A52. 500 MHz 1H NMR of 2s in C6D6 ............................................................... 190 Figure A53. 500 MHz 1H NMR of 2s in C6D6 from 2.5 to 0.4 ppm ............................... 191 Figure A54. 125 MHz 13C NMR of 2s in C6D6 .............................................................. 192 Figure A55. 160 MHz 11B NMR of 2s in C6D6 .............................................................. 193 Figure A56. 500 MHz 1H NMR of 2t in C6D6 ................................................................ 194 Figure A57. 500 MHz 1H NMR of 2t in C6D6 from 3.6 to 0.7 ppm ............................... 195 Figure A58. 500 MHz 1H NMR of 2t in C6D6 from 3.45 to 2.5 ppm ............................. 196 Figure A59. 125 MHz 13C NMR of 2t in CDCl3 ............................................................ 197 Figure A60. 160 MHz 11B NMR of 2t in CDCl3 ............................................................ 198 Figure A61. 500 MHz 1H NMR of 2u in CDCl3 ............................................................ 199 Figure A62. 500 MHz 1H NMR of 2u in CDCl3 from 3.8 to 0.0 ppm ............................ 200 Figure A63. 125 MHz 13C NMR of 2u in CDCl3 ........................................................... 201 Figure A64. 125 MHz 13C NMR of 2u in D2O from 60 to 18 ppm ................................ 202 Figure A65. 500 MHz 1H NMR of 2v in D2O ................................................................ 203 Figure A66. 500 MHz 1H NMR of 2v in D2O from 4.4 to -0.2ppm ............................... 204 Figure A67. 125 MHz 13C NMR of 2v in D2O ............................................................... 205 xii Figure A68. 470 MHz 19F NMR of 2v in D2O ............................................................... 206 Figure A69. 500 MHz 1H NMR of 2w in C6D6 .............................................................. 207 Figure A70. 125 MHz 13C NMR of 2w in C6D6 ............................................................. 208 Figure A71. 500 MHz 1H NMR of 2x in CDCl3............................................................. 209 Figure A72. 125 MHz 13C NMR of 2x in CDCl3 ........................................................... 210 Figure A73. 500 MHz 1H NMR of 2y in C6D6 ............................................................... 211 Figure A74. 125 MHz 13C NMR of 2y in CDCl3 ........................................................... 212 Figure A75. 99 MHz 29Si NMR of 2y in CDCl3 ............................................................. 213 Figure A76. 500 MHz 1H NMR of 2za in C6D6 ............................................................. 214 Figure A77. 500 MHz 1H NMR of 2za in C6D6 from 3.0 to 0.3 ppm ............................ 215 Figure A78. 125 MHz 13C NMR of 2za in C6D6 ............................................................ 216 Figure A79. 125 MHz 13C NMR of 2za in C6D6 from 36 to 6 ppm ............................... 217 Figure A80. 160 MHz 11B NMR of 2za in C6D6 ............................................................ 218 Figure A81. 500 MHz 1H NMR of 2zb in C6D6 ............................................................. 219 Figure A82. 500 MHz 1H NMR of 2zb in C6D6 ............................................................. 220 Figure A83. 125 MHz 13C NMR of 2zb in C6D6 ............................................................ 221 Figure A84. 125 MHz 13C NMR of 2zb in C6D6 from 85 to 5 ppm ............................... 222 Figure A85. 160 MHz 11B NMR of 2zb in C6D6 ............................................................ 223 Figure A86. 500 MHz 1H NMR of 3z in CDCl3 ............................................................. 224 Figure A87. 500 MHz 1H NMR of 3z in CDCl3 from 9.0 to 6.5 ppm ............................ 225 Figure A88. 500 MHz 1H NMR of 3aa in CDCl3........................................................... 226 Figure A89. 500 MHz 1H NMR of 3aa in CDCl3 from 9.0 to 6.5 ppm .......................... 227 Figure A90. 160 MHz 11B NMR of 3aa in CDCl3 ......................................................... 228 Figure A91. 500 MHz 1H NMR of 3ab′′′′ in CDCl3 ......................................................... 229 Figure A92. 500 MHz 1H NMR of 3ab′′′′ in CDCl3 from 9.0 to 6.5 ppm ........................ 230 xiii Figure A93. 125 MHz 13C NMR of 3ab′′′′ in CDCl3 ........................................................ 231 Figure A94. 125 MHz 13C NMR of 3ab′′′′ in CDCl3 from 150 to 110 ppm...................... 232 Figure A95. 470 MHz 19F NMR of 3ab′′′′ in CDCl3 ......................................................... 233 Figure A96. 500 MHz 1H NMR of 3ab in CDCl3 .......................................................... 234 Figure A97. 500 MHz 1H NMR of 3ab in CDCl3 from 8.4 to 7.0 ppm ......................... 235 Figure A98. 125 MHz 13C NMR of 3ab in CDCl3 ......................................................... 236 Figure A99. 125 MHz 13C NMR of 3ab in CDCl3 from 168 to 108 ppm ...................... 237 Figure A100. 470 MHz 19F NMR of 3ab in CDCl3 ........................................................ 238 Figure A101. 160 MHz 11B NMR of 3ab in CDCl3 ....................................................... 239 Figure A102. 500 MHz 1H NMR of 3ac in CDCl3 ......................................................... 240 Figure A103. 500 MHz 1H NMR of 3ac in CDCl3 from 7.9 to 7.2 ppm ........................ 241 Figure A104. 500 MHz 1H NMR of 3ad in CDCl3 ........................................................ 242 Figure A105. 160 MHz 11B NMR of 3ad in CDCl3 ....................................................... 243 Figure A106. 500 MHz 1H NMR of 3ae in CDCl3 ......................................................... 244 Figure A107. 500 MHz 1H NMR of 3ae in CDCl3 from 8.0 to 7.35 ppm ...................... 245 Figure A108. 125 MHz 13C NMR of 3ae in CDCl3 ........................................................ 246 Figure A109. 160 MHz 11B NMR of 3ae in CDCl3 ........................................................ 247 Figure A110. 500 MHz 1H NMR of 3af in CDCl3 ......................................................... 248 Figure A111. 500 MHz 1H NMR of 3af in CDCl3 from 7.85 to 7.40 ppm .................... 249 Figure A112. 125 MHz 13C NMR of 3af in CDCl3 ........................................................ 250 Figure A113. 160 MHz 11B NMR of 3af in CDCl3 ........................................................ 251 Figure A114. 500 MHz 1H NMR of 3ah in CDCl3 ........................................................ 252 Figure A115. 500 MHz 1H NMR of 3ah in CDCl3 from 7.50 to 7.00 ppm ................... 253 Figure A116. 125 MHz 13C NMR of 3ah in CDCl3 ....................................................... 254 Figure A117. 470 MHz 19F NMR of 3ah in CDCl3 ........................................................ 255 xiv Figure A118. 160 MHz 11B NMR of 3ah in CDCl3 ....................................................... 256 Figure A119. 500 MHz 1H NMR of 3ai in CDCl3 ......................................................... 257 Figure A120. 500 MHz 1H NMR of 3ao in CDCl3......................................................... 258 Figure A121. 500 MHz 1H NMR of 3ao in CDCl3 from 9.0 to 6.8 ppm ........................ 259 Figure A122. 125 MHz 13C NMR of 3ao in CDCl3 ....................................................... 260 Figure A123. 470 MHz 19F NMR of 3ao in CDCl3 ........................................................ 261 Figure A124. 160 MHz 11B NMR of 3ao in CDCl3 ....................................................... 262 Figure A125. 500 MHz 1H NMR of 3az in CDCl3 ......................................................... 263 Figure A126. 500 MHz 1H NMR of 3az in CDCl3 from 9.0 to 6.5 ppm ........................ 264 Figure A127. 125 MHz 13C NMR of 3az in CDCl3 ........................................................ 265 Figure A128. 500 MHz 1H NMR of 3ba and 3bb in CDCl3 .......................................... 266 Figure A129. 500 MHz 1H NMR of 3ba and 3bb in CDCl3 between 2.0ppm and 1.0ppm ......................................................................................................................................... 267 Figure A130. 500 MHz 1H NMR of 3ba and 3bb in CDCl3 between 8.0ppm and 6.4ppm ......................................................................................................................................... 268 Figure A131. 125 MHz 13C NMR of 3ba and 3bb in CDCl3 ......................................... 269 xv LIST OF SCHEMES Scheme 1. Chiral hydroboration/oxidation of 2,3-dihydrofuran3 ....................................... 1 Scheme 2. First cross coupling of an aryl boronic acid with an aryl halide5 ...................... 2 Scheme 3. Lithiation-borylation chemistry......................................................................... 3 Scheme 4. Carbonylation of 1-diphenylmethanimine using octacarbonyldicobalt17.......... 4 Scheme 5. ortho Carbon-hydrogen bond activation by nickelocene19 ................................ 5 Scheme 6. Ruthenium C-H bond activation equilibrium reported by Chatt and Davidson20 ............................................................................................................................................. 5 Scheme 7. Iridium complex oxidative addition to cyclohexane21 ...................................... 6 Scheme 8. First thermal catalytic C-H silylation22 ............................................................. 6 Scheme 9. First isolated thermal catalytic CHB23 .............................................................. 7 Scheme 10. Comparison between Rhodium and Iridium precatalysts for CHB ................. 8 Scheme 11. Iridium catalyzed borylation of iodobenzene .................................................. 9 Scheme 12. Proposed mechanism of iridium CHB25,27–29 ................................................ 12 Scheme 13. Enantioselective CHB through relay silyl-directed borylation ..................... 14 Scheme 14. Hydrogen bond directed ortho diborylation33 ............................................... 16 Scheme 15. Steric directed para-borylation of bulky monosubstituted arenes ................. 21 Scheme 16. Aluminum/iridium co-catalysts for para-directed CHB of esters and pyridines ........................................................................................................................................... 21 Scheme 17. Octane CHB using a rhodium catalyst .......................................................... 24 Scheme 18. CHB of saturated cyclic ethers ...................................................................... 24 Scheme 19. Pyridine directed triborylation of primary C-H bonds .................................. 25 Scheme 20. Palladium catalyzed sp3 CHB directed by amides55...................................... 25 Scheme 21. First enantioselective CHB of a sp3 carbon ................................................... 26 Scheme 22. Platinum oxide catalyst for hydrogenation.3 ................................................. 27 xvi Scheme 23. Hydrogenation of Fluorinated Arenes.13 ....................................................... 29 Scheme 24. First reported hydrogenation of a borylated olefin23 ..................................... 30 Scheme 25. First reported hydrogenation of a vinyl boronic ester.24 ............................... 31 Scheme 26. Hydrogenation of n-Boc-2-pyrrolyl-boronic aicd.31 ..................................... 32 Scheme 27. Homogeneous hydrogenation of fluorinated aryl boronic esters.13 ............... 33 Scheme 28. sp3 CHB of tetrahydrofuran.37 ....................................................................... 42 Scheme 29. Chiral resolution of 2b through chiral amide formation ............................... 49 Scheme 30. Lassaletta Hemi-Labile ortho-Directed Borylation.4 .................................... 53 Scheme 31. Picolylamine for ortho-Directed CHB of Benzylamines and Benzylphosphines.15.......................................................................................................... 54 Scheme 32. ortho-Borylation of Aryl-DMG Using Phosphine-Silane Based Ligands.19 . 55 Scheme 33. ortho-Borylation of Aryl-DMG Using Nitrogen-Boron Based Ligands.7 ..... 56 Scheme 34. Supported Phosphine Catalysts for ortho CHB ............................................. 58 Scheme 35. Homogeneous ortho CHB with Excess Ligand ............................................. 59 Scheme 36. Homogeneous electron poor monodentate phosphine ligand for ortho CHB 59 Scheme 37. Intermolecular Kinetic Isotope Effects of CHB on Cyclopropyl Phenylketone ........................................................................................................................................... 74 Scheme 38. Intramolecular kinetic isotope effects of CHB on cyclopropyl phenylketone ........................................................................................................................................... 75 Scheme 39. sp3 CHB of Electron Rich 4-N,N-dimethyl-2-methoxypyridine ................... 75 Scheme 40. Competition reactions for ortho CHB of ketones vs esters ........................... 76 Scheme 41. Competition reaction between methyl benzoate and N,N-dimethylbenzamide ........................................................................................................................................... 76 Scheme 42. Competition of electronically different methyl benzoates ............................ 77 Scheme 43. Proposed catalytic cycle of py′ ligand ortho borylation ................................ 80 xvii B2pin2 HBpin Boc CHB Cp Cp* COD Ind dtbpy NMR TMS KEY TO ABBREVIATIONS Bis(pinacolato)diboron Pinacolborane tert-butyloxycarbonyl C-H Borylation Cyclopentadienyl Pentamethylcyclopentadienyl Cyclooctadiene Indenyl 4,4′-di-tert-butylbipyridine Nuclear magnetic resonance Trimethylsilyl gHMBC gradiednt Heteronuclear Multiple Bond Coherance xviii Chapter 1. Formation of Carbon-Boron Bonds 1.1 Importance of Boron Containing Compounds in Synthetic Chemistry. Carbon-boron bonds have a diverse and rich chemistry of chemical transformations. As such organoboron compounds have been heavily utilized in organic chemistry. One of the first transformations that was utilized to a large extent was the use of boranes to produce anti-Markovnikov alcohols via one pot hydroboration/oxidation chemistry.1 By using chiral boranes, chiral alcohols were synthesized.2 This chemistry was mainly pioneered by H.C. Brown, who won a Nobel prize for his development of this chemistry. Scheme 1. Chiral hydroboration/oxidation of 2,3-dihydrofuran3 In 1979, the first catalytic cross coupling of an organoboron compound with a organohalide to generate a carbon-carbon bond was reported by Miyaura, Yamada and Suzuki.4 While the first few reactions demonstrated the ability of alkenyl boronic esters to transform from a C-B bond into a C-C bond further papers demonstrated the power that could be developed by using aryl carbon-boron bonds to generate carbon-carbon bonds via palladium coupling.5 Since then, the Suzuki coupling has become one of the most widely utilized reactions for synthesis of carbon-carbon bonds.6 1 Scheme 2. First cross coupling of an aryl boronic acid with an aryl halide5 Carbon-boron bonds can be transformed into carbon-nitrogen bonds through the use of a Chan-Lam coupling.7 Transformations converting carbon-boron bonds into carbon bonded to chlorine,8,9 bromine,8,9 iodide,8 and finally fluorine10 have also been reported. This expansion of transformations of organoboron compounds continued and now includes the likes of cyanation,11 trifluormethylation,12,13 thiolations,14 stereospecific conversions to carbon-carbon bonds,15 and others. Figure 1. Transformations of C-B bonds 2 The variety of transformations, especially in the development in aryl functionalizations resulted in research into synthesis of carbon-boron bonds.16 While carbon-boron bonds could be generated through lithiation or a Grignard reagent followed by quenching with a borate these boronic acid synthesis generated large quantities of salt waste. Another challenge of stoichiometric metalation chemistry is that they tend to require cryogenic temperatures. This can be a challenge in scaled up processes. Scheme 3. Lithiation-borylation chemistry A step forward was by the report of the Miyaura coupling, which used a palladium catalyst to convert a carbon-bromine or carbon-iodide bond into a carbon- boron bond. All of this was incredibly helpful to the chemical industry and the use of carbon boron bonds continued to expand in discovery chemistry. However, this did little to limit the amount of salt waste generated. As such, further development of methods into C-H functionalization/borylation were needed. 1.2 C-H functionalization Carbon-hydrogen bonds are pervasive in chemicals. As such for atom economical synthesis, a direct functionalization of these bonds is necessary. As discussed in the previous section the transformations of carbon boron bonds are incredibly useful. As such, the catalytic synthesis of carbon-boron bonds through carbon-hydrogen borylation (CHB) 3 would be incredibly useful. Through CHB the direct transformation of any C-H bond into a large range of functionalities could be accomplished through a two-step process. Murahashi reported in 1955 a carbonylation of Schiff bases to generate phthalimide. This resulted from a reaction of dicobaltoctacarbonyl under 100-200 atm of carbon monoxide at 220-230 °C.17 While the mechanism was unknown, a Friedel-Crafts type mechanism could have been possible with hydride transfer to rearomatize the arene and form the product. This possibility is why this reaction is not considered the first metal mediated C-H activation. Scheme 4. Carbonylation of 1-diphenylmethanimine using octacarbonyldicobalt17 In 1962 Chatt and Watson showed that metal complexes of osmium, and ruthenium reacted with sodium naphthalide to produce a C-H functionalization of the naphthlene shown in scheme 5.18 They did not report the structure of the metal hydride complex discussed but said investigations were still ongoing. This was the first mention of what turned out to be C-H activation. This was followed by the activation of azobenzene by Kleiman and Dubeck with nickelocene which resulted in a C-H activation of one of the C(sp2)-H bonds.19 This was the first isolated complex with a formal C-H activation. However, the metal hydride was 4 not observed or isolated. As a result, the definitive evidence of metal activated C-H cleavage occurring was not shown. Scheme 5. ortho Carbon-hydrogen bond activation by nickelocene19 The first definitive metal hydride formation from the reaction of a metal complex and a C-H bond was reported by Chatt and Davidson in 1965 when they showed that a ruthenium(0) complex with two dmpe ligands on it would have an equilibrium between a coordinated naphthalene and a C-H activated metal hydride and naphthalyl lignd.20 They also showed that in the absence of naphthalene, C-H activation from the methyl on the dimethylphosphinoethane (dmpe) occurred and was also reversible. Scheme 6. Ruthenium C-H bond activation equilibrium reported by Chatt and Davidson20 One of the first reported intermolecular C-H activations of non-activated carbon- hydrogen bonds was demonstrated by Bergman in 1982.21 They showed that a Cp*Ir(PMe3)H2 catalyst would undergo UV light mediated oxidative addition of unactivated hydrocarbons such as cyclohexane, isopentane and an aromatic compound benzene. This result demonstrated that intermolecular C-H activation was possible with unactivated C-H bonds. 5 Scheme 7. Iridium complex oxidative addition to cyclohexane21 C-H silylation, which has many similarities to CHB was first reported by Curtis and co-workers in 1982, when they showed that when heated at 100 °C for 49 days in a closed container, Vaska’s complex catalyzed the hydrosilylation of benzene with (CH3)3SiOSi(CH3)2H.22 The reaction proceeded with a 50% conversion to Ph- Si(CH3)2OSi(CH3)3 and disilylated unidentified isomers. They calculated that there were 13.4 turnovers per catalyst. Scheme 8. First thermal catalytic C-H silylation22 1.3 Early C-H Borylation In 1995, Hartwig and co-workers reported the first CHB of using an iron complex with UV light to activate the reaction.21 They were able to demonstrate the potential for transforming C-H bonds of sp2 carbons into carbon-boron bonds. This UV-based functionalization was further expanded with the switch to a tungsten catalyst, which resulted in better yields, that was also able to functionalize alkyl C-H bonds.22 However, neither of these two systems were catalytic. The metal complexes that underwent the stoichiometric transformations could be regenerated through a multi-step recovery 6 process. The failure of these complexes to turnover and provide catalysis was a major drawback from their use. A metal boryl complex that could result in C-H functionalization catalytically would be a major improvement. While today there are many UV-Vis reactors that utilize flow chemistry, in 1999 that was not well established. As such a reaction that operated through thermal energy was desired. In 1999 Iverson and Smith published the first thermal catalytic CHB reaction.23 This opened the door to a lot of chemistry to convert a carbon-hydrogen bond into a carbon-boron bond. This first CHB reaction used an iridium Cp* chair complex with excess borane run in neat benzene. The reaction used was analogous to the complex (Cp*Ir(PMe3)H2) used by Bergman for the first intermolecular C-H activation.21 Shown in Scheme 9 this reaction generated a little over 3 turnovers. Scheme 9. First isolated thermal catalytic CHB23 Further development of CHB quickly followed. In 2000 Hartwig reported a rhodium catalyst for borylation of alkanes and benzene in high yields at 150 °C (Scheme 19).51 Cho, Iverson and Smith used similar iridium chair structures with phosphine ligands to look into the CHB of various arenes.24 What they found was that the CHB of arenes was largely stericly driven. The iridium catalyst was also more selective for C-H activation over C-F activation with only 4% of C-F bond activation. While the rhodium catalyst, Cp*Rh(η4-C6Me6), resulted in 16% of C-F bond activation. The rhodium catalyst 7 that was first developed by Hartwig and co-workers for the borylation of alkanes was a much faster catalyst but this showed early indications that iridium would be a more selective catalyst. Scheme 10. Comparison between Rhodium and Iridium precatalysts for CHB In 2002, Maleczka, Smith and co-workers demonstrated that using (Ind)Ir(COD) and (η6-mesitylene)Ir(Bpin)3 as precatalysts with combination of bisphosphine ligands resulted in a very selective catalyst for steric control of the product formation. This was the first report of bidentate ligands for CHB. An important finding from this paper was the selectivity for the meta position on 1,3 disubstituted arenes. Of particular note was the borylation of iodobenzene. Using (η6-mesitylene)Ir(Bpin)3 as a precatalyst and di(phenyl)phosphine ethane as a ligand they were able to borylate iodobenzene in 77% yield with a 79:21 meta to para selectivity. This was important as it illustrated the incredible halogen tolerance of the system. They showed how this system could be 8 combined with Suzuki couplings in the first one pot borylation-suzuki coupling to make complex molecules or even synthesis of polymers of aryl compounds.27 Scheme 11. Iridium catalyzed borylation of iodobenzene In 2002 Ishiyama, Hartwig, Miyuara and co-workers reported use of 4,4′′′′-di-tert- butyl 2,2′′′′-bipyridine(dtbpy) with [Ir(Cl)COD]2 for CHB of arenes. They found that this combination of precatalyst and ligand worked incredibly efficiently at room temperature or 80 °C with high turnovers.25 They followed this with an investigation into precatalysts and different bipyridines to help determine the best combination of iridium precatalysts and ligands.26 They found that the best combination of ligands and precatalysts were electron rich bipyridines with [Ir(OMe)COD]2. 1.4 Mechanistic Investigations into Iridium Catalyzed C-H borylation Maleczka and Smith first started the process of determining the reaction mechanism of iridium catalyzed CHB in 2002.27 They looked into two possible mechanisms; one operating via an iridium (I/III) cycle and the other through a (III/V) cycle. To investigate this, they isolated two different iridium complexes. First was Ir(III)(PMe)3(Bpin)3 and the other was Ir(I)(Bpin)(PMe3)4. Using these metal complexes they performed the CHB of iodobenzene. The differences in reactivity between the two 9 catalysts was telling. It was found that the Ir(I)(Bpin)(PMe3)4 failed to make any C6H4IBpin product while the Ir(III)(PMe)3(Bpin)3 yielded 54% of the borylated iodobenzene. This was consistent with the previous reaction (Scheme 11) showing that the iridium CHB would tolerate iodide in the reaction. This experiment suggested that an iridium (I/III) cycle would likely not have tolerance for iodides. As such they proposed that the iridium CHB operated through an iridium (III/V) cycle. In 2002, submitted shortly after the Maleczka and Smith paper27, Ishiyama, Hartwig and co-workers reported the isolation of an iridium (III) trisboryl bipyridine complex by using cyclohexene to trap it in a six coordinate 18-electron complex.25 Upon loss of cyclooctene this complex was a potential intermediate in the CHB mechanism. Using this complex, they showed that it could transfer all three boryl ligands to benzene in minutes. Sakaki computed the transition states for the CHB using iridium trisboryl catalyst. They were able to calculate the transition states for a variety of different possibilities and concluded that the most likely mechanism was through an Ir(III/V) species. Their results also supported the proposed mechanism by Maleczka and Smith. They also calculated the rate determining step to be C-H functionalization with an activation barrier just under 25 kcal/mol. In 2005, Hartwig and co-workers reported the mechanistic study of iridium catalyzed CHB, using dtbpy as a ligand.28 They isolated a trisboryl(dtbpy)Ir(COE) complex that they used for the study along with performing in-situ generated reactions. They found that iridium CHB was first order in arene concentration and zero order in boron concentration. They also found that increased COE concentration acted as an 10 inhibitor to the reaction. From this data they were able to state that the rate-determining step was C-H activation, which was similar to the computational results of Sakaki. They also determined from their data that the iridium CHB system likely operated through an iridium III/V cycle, which supported the results of the experiments performed by Maleczka, Smith, and co-workers. In 2015 Maleczka, Smith, and co-workers investigated at the mechanism of CHB using phosphine ligands.29 Using phosphine ligands they were able to isolate and identify several different hydride intermediates in the CHB catalytic reaction cycle. They were able to identify 4 different iridium hydride states of the catalyst and show their interconversion through additions of HBpin or H2. They then demonstrated that each of the hydride species that contained an iridium-boryl bond were competent for CHB. They also showed that under catalytically relevant conditions the different hydride species would all potentially be operational for differing CHB catalytic cycles. From these previous papers a general catalytic cycle can be proposed depending on the nature of the ligand as shown in Scheme 12. From the precatalyst of [Ir(OMe)cod]2 with a bidentate nitrogen-based ligand and boron source an iridium(III)trisboryl complex is formed (1a). Oxidative addition of an aryl or heteroaryl C-H bond results in a 7-coordinate iridium (V) species shown as 1b. This complex undergoes reductive elimination to generate an iridium hydride species 1c. Oxidative addition of either B2pin2 or HBpin results in a 7-coordinate, iridium(V) complex 1d. Reductive elimination of either HBpin or H2 respectively, based on the boron source, results in regeneration of the resting state of the catalyst (1a). 11 When a bidentate phosphorus-base ligand is used the catayst undergoes a similar process, however, the generation of 1b′′′′ results in an iridium (III) species, instead of an iridium (V) intermediate, due to the η2 coordination of a pinacolborane. 1b′′′′ then follows a similar path through the rest of the catalytic cycle through reductive elimination to generate 1c. With bisphosphines addition of pinacol borane results in a η2 –binding of hydrogen to make 1d′′′′. Reductive elimination results in regeneration of 1a. Scheme 12. Proposed mechanism of iridium CHB25,27–29 1.5 Selectivity of CHB Without a specific interaction that results in a directed borylation, CHB reactions are mostly directed by steric interactions. Maleczka, Smith and co-workers first noted the selectivity of substituted arenes in 2000 when they were comparing the reaction of iridium and rhodium complexes for CHB.24 This was followed by observations from Hartwig25,26 and publication in a 2002 science paper by Maleczka Smith and co-workers where they described the selective meta borylation of 1,3 disubstituted benzenes.24 Up to that point in chemistry most aromatic functionalizations operated through either 12 electrophilic or nucleophilic conditions. With CHB the electronics had a much less impact on the selectivity of the catalyst. 1.6 Ortho-Directed C-H borylation Through the years there have been several methods of generating ortho-selective CHB. The different methods have been proposed to accomplish this through generating a silicon-iridium covalent bond to the iridium center,30 an “outer-sphere” type interaction with the ligands on the iridium catalyst through a hydrogen bond interaction,31–33 electrostatic interactions,34 or a chelating interaction with an open coordination site on the iridium center.35 Figure 2. Proposed Relay-directed ortho CHB transition state First reported by Hartwig and coworkers,30 relay directed borylation covalently binds the substrate to the homogeneous iridium catalyst by first undergoing a Si-H oxidative addition to the iridium center (Figure 2). Reductive elimination of HBpin, the catalyst shown in Figure 2 is generated. This directs the C-H activation at the ortho position relative to the silyl group. The relay directed C-H borylation was expanded to generate chiral centers through CHB differentiation of substituents.36 By hydrosilylation of benzophenone compounds followed by use of a chiral ligand on the catalyst to 13 generate the C-B bond formation on the aromatic ring (Scheme 13). Relay direction provides incredible control of the selectivity of borylation, however, this is a substrate- controlled direction method that requires an auxiliary to be added to the substrate. Because of this it is limited to phenols, ketones, or substrates with benzylic positions that can undergo addition of a silane or generation of a benzylic silane through synthesis. Scheme 13. Enantioselective CHB through relay silyl-directed borylation A second type of ortho direction used in CHB is an electrostatic interaction between the substrate and the bidentate ligand. This direction method was reported by Maleczka and Smith and co-workers for phenols37 and anilines.38 Figure 3. Electrostatic directed ortho CHB transition state Starting from a phenol or an aniline treatment with the boron source used for CHB generates a borate protecting group. The substrate that is generated has electron density on the borate that interacts with a partial positive charge on the bipyridine ligand. 14 This electrostatic interaction directs borylation to the ortho position of the phenol or aniline. This interaction may seem weak but, as the authors note, a 2.7 kcal/mol difference at 25 °C is needed to generate 99:1 selectivity.37 The majority of the substrate scope contained para substitutions. However, when moving from a pinacol boronate to an ethylene glycol boronate the authors found that the interaction was enhanced and the selectivity was greatly improved. The limitations of this system are similar, but fewer, than the limitations of the relay directed ortho borylation by Hartwig. Both systems require the substrate to react with something that before the directing effect occurs. Both systems result in this protecting or directing group to be sacrificed after the reaction is complete. However, the boron directed system allows for use of the same reagent as will be used to replace the C-H bond., This new type of interaction shows promise and indicates that other electron rich type systems might be possible to interact with a bidentate ligand to generate selective borylations. Figure 4. Hydrogen bonding directed ortho CHB of aniline32 There have been two distinct types of directed ortho borylation in the literature generated by a hydrogen bond interaction between the substrate and the catalyst. In both cases they take advantage of the oxygen atoms on the boryl ligands to act as the hydrogen bond acceptor. In one method reported by Maleczka, Smith, and co-workers anilines, 15 protected by either a Boc group32 or a boronate,39 can result in a hydrogen bond interaction that generates ortho selectivity. The limitation to this chemistry is that it requires that the aniline not be fully substituted. Also during the course of their investigations it was discovered that 2-substituted anilines did not borylate effectively at the ortho position due to a steric interaction between the substitution and the protecting group of the aniline resulting in the N-H bond angling away from the open ortho position on the ring. Scheme 14. Hydrogen bond directed ortho diborylation33 Another type of ortho borylation using a hydrogen bond interaction was reported by Suginome and co-workers where they used a pyrazolylaniline as the protecting group on a boron (Scheme 14).33 The resulting borylation of these compounds was ortho di- borylated substrates with differing boron substructures that can undergo orthogonal chemistry or be converted to the Bpin as shown in Scheme 14. In the absence of ligand, [Ir(OMe)cod]2 catalyzed the CHB in high yield and high selectivity. 16 Figure 5. Chelate directed ortho CHB Chelate-directed CHB will be discussed in more detail in Chapter 3. As shown in Figure 5, chelate directed CHB operates through opening up an extra coordination site on the iridium catalyst. In this extra site a directing group, containing a lone electron pair, coordinates to the iridium center and promotes C-H activation to proceed ortho to the directing group. This chelate directed borylation has been the most widely used method for ortho borylation and as such there are more differing methods for this process than other types of ortho borylation. Kanai and co-workers demonstrated that a Lewis acid could be used to direct CHB. They followed methods that were developed first in meta directed CHB to put a Lewis acid off of the side of a bipyridine. This allowed a thioether to coordinate to the Lewis acid, in this case a boronic ester, and direct the CHB to the ortho position. Figure 6. Thioether directed ortho CHB 17 1.7 Meta-Directed CHB There have been three reported methods of directed meta borylation. This is defined as borylation that is not controlled by steric effects but on mono or sparsely substituted arenes or heteroarenes where a specific interaction dictates the CHB result at the meta position. The first example of this was reported by Kanai and co-workers.40 He found that by attaching a urea moiety off of the side of a bipyridine ligand the selectivity of the borylation for aryl and heteroaryl compounds with functional groups that contained an adjacent carbonyl such as esters, ketones, amides, phosphates and others could be controlled. It was found that by switching the solvent from hexane to p-xylene the selectivity was able to be increased from 8.3:1 m:p to 17:1. Figure 7. Hydrogen bond-directed meta-borylation The second example of meta borylation was published by Chattopadhyay and Bisht.41 They showed that generation of imines in-situ from aldehydes could result in formal borylation of aldehydes upon workup. The borylation was selective for the meta position upon use of methyl amine as the nitrogen for the imine source. Using bulkier amines resulted in poorer selectivity. By reducing the steric hindrance around the imine center they proposed that the imine would coordinate to the open p-orbital of the boronic 18 ester on the catalyst and that would result in greater meta-direction. This reaction proceeded better with more electron donating ligands. 3,4,7,8-Tetramethyl-1,10- phenanthroline (TMP) resulted in the greatest amount of meta-directed CHB of benzaldehyde at 97:3 m:(o+p) ratio when methyl amine was used to form the imines. No heteroaromatics were reported for meta directed borylation using this method. Figure 8. Imine directed meta borylation The final method for meta directed borylation was developed by Phipps and co- workers.42 Phipps used ion pairing to direct the borylation. Using a sulfate ion dangling off of a bipyridine the interaction with benzyl ammonium tosylate ions created a directed borylation that resulted in meta borylation. Phipps followed this up with two other papers on meta-directed borylation of tethered amines43 and of tethered ammonium salts.44 While this is similar to the electrostatic interaction there is formally a full charge on each ligand and substrate, while the borylation by Maleczka, Smith and co-workers was partial build-up of electron density. 19 Figure 9. Ion pairing interactions for meta-directed CHB As of yet, nobody has flipped the ion pair such that the positive charge is on the ligand and the negative charge on the substrate. While a negatively charged substrate might result in difficult interactions with the iridium, other lone pair type interactions with a positively charged ion might be a potential for directed borylation. 1.8 Para-Directed C-H Borylation There have been three methods of para-directed borylation reported. The first method is the use of steric interactions between the substrate and the ligand to generate para selectivity. In 2015 Itami and co-workers demonstrated that by using a xylyl- methoxy-BIPHEP ligand they could achieve 9:1 para:meta selectivity with 94% yield in hexane.45 They found that para selectivity could be obtained for a variety of arenes with quaternary carbons and silanes as substituents. When they switched to an isopropyl group the selectivity dropped to 58:42 and when they tested the borylation of ethylbenzene using the catalyst the selectivity reverted to a near statistical distribution of 31:68 para:meta. 20 Scheme 15. Steric directed para-borylation of bulky monosubstituted arenes In 2017, Nakao and co-workers demonstrated how to use cooperative catalysis in CHB reactions.46 Use of a large aluminum complex acts as a Lewis acid and blocks half of the substrate. Using dtbpy as a ligand, the CHB was directed to the para position. CHB of pyridines, amides, and phosphonates with examples more than 20:1 para selective. The solvent choice was important as use of a polar solvent would result in lower interaction between substrate and the aluminate co-catalyst. This use of a co-catalyst is a unique technique for CHB and was a creative way to solve the challenge of para selectivity for a wider range of substrates than Itami and co-workers. Scheme 16. Aluminum/iridium co-catalysts for para-directed CHB of esters and pyridines Shortly after the report by Nakao and co-workers, Chattopadhyay and co-workers published a para-directed CHB utilizing an L-shaped ligand to interact with the 21 substrate.47 They designed a ligand similar in concept to that used by Kanai for meta- directed borylation by adding 2-quinone as side chain to a bipyridine ligand. What they found was that through the addition of potassium tert-butoxide they were able to generate up to 33:1 para-selective borylation of ethyl esters. This was demonstrated on ethyl benzoates as well as on esters on pyridines. 5-membered rings resulted in C2-borylation selectively and failed to show differences from other bipyridine-based borylation.48 Figure 10. Directed para borylation of aryl esters 1.9 Aliphatic C-B Bond Formation There have been a few different routes to synthesizing sp3-carbon-boron bonds. One route that has been around for quite some time is by the use of hydroboration of alkenes.3 When an alkyl halide is usd as a starting material generation of a lithium or Grignard reagent followed by quenching the product with a borate can be used.49 When an activated substrate is around lithiation and quenching with a borate is an established route.49 All of these methods have been used to generate chiral sp3-carbon-boron bonds. Like all chemistry they both have drawbacks to general use. Selectivity of hydroboration is mainly sterically driven but has some electronic components. However, when there is 22 not a significant difference in steric size between different sides of an olefin selectivity can be problematic. As mentioned earlier Grignard reagents and lithiation chemistry can have issues with chemoselectivity and some functional groups are not tolerated in these processes. Use of this metalation/borylation process is dependent on the selectivity for halogenations. Without a halogen present lithiation needs to be at the most acidic position or directed in order to be effective. A different route to synthesizing aliphatic carbon boron bonds was demonstrated by Ito and co-workers. They demonstrated that through dearomative borylation they could enantioselectively borylate the 3-position of piperidines.50 1.10 sp3 C-H borylation One of the more enticing routes to sp3 C-B bonds is metal catalyzed CHB. Since 1999, there have been a few different reactions that have been developed for this transformation. However, each of them has specific limitations that prevent it from becoming a general reaction for use. The first example of a transition metal catalyzed CHB of an sp3 carbon-hydrogen bond was, a photocatalytic example using a rhenium complex to catalyzed CHB of octane by Hartwig and co-workers. The found when irradiating a solution of CpRe(CO)3 they were able to borylate alkanes at the terminal position selectively.51 The further studied the CHB of alkane when They found that by using RhCp*(C2H4)2 as a precatalyst with B2pin2 as a boron source resulted in borylation of the primary carbon of n-octane in 84% yield over 5 hours at 150 °C.52 This was preformed without the use of photocatalytic 23 process. These were incredible reactions as they were selective for the primary carbon- hydrogen bond in the presence of all of the other secondary C-H bonds. Scheme 17. Octane CHB using a rhodium catalyst Years later, Hartwig and co-workers expanded the use of CHB on sp3 centers with the selective CHB of cyclic ethers. The CHB of cyclic ethers was selective for borylation at the 3-position. This reaction was counter to many different C-H functionalizations of cyclic ethers prior to that which functionalized the 2-position. However, the CHB resulted in a very similar selectivity to the products generated by hydroboration of an alkene in a similar position. This represented the first use of iridium for CHB on an sp3 center.53 Scheme 18. CHB of saturated cyclic ethers Sato and Michigami used a pyridyl directing group to triborylate a primary sp3 C- H center. They did this with using 3.5 equivalents of B2pin2, or 1.2 equivalents of B2pin2 24 for every borylation. The reaction they ran was quite hot at 150 °C, similar to the octane borylation by Hartwig, however the reaction was complete in only 12 minutes when the 4-position contains an ether off of it. The triborylation was a very unique result that was not repeated with a different system until years later when Chirik and coworkers performed it with a nickel catalyst.54 Scheme 19. Pyridine directed triborylation of primary C-H bonds The directed ortho borylation of saturated cyclic centers was reported by Yu and co-workers. Using an electron deficient amide system shown in Scheme 20.55 Yu borylated primary and secondary sp3 centers as well as aromatic compounds. They did this through the use of a palladium catalyst and a catalytic cycle that was significantly different than that of iridium CHB. The result was the ability to direct borylation selectively using a quinoline based ligand on the palladium. Scheme 20. Palladium catalyzed sp3 CHB directed by amides55 25 Yu and co-workers followed that work with a report of the enantioselective borylation of sp3 centers. They used a very similar catalyst as their work in 2016 but with a chiral ligand as shown in Scheme 21.56 This was the first example of an enantioselective CHB reaction. Scheme 21. First enantioselective CHB of a sp3 carbon 1.11 Conclusions and Future Work Carbon-boron bonds are important intermediates in synthetic chemistry. They have the ability to be transformed through a variety of different methods. The synthesis of carbon-boron bonds has become incredibly selective with methods developed for every position on arenes. The advancement of CHB into aliphatic CHB represents the next major area of research and selective synthesis of borylated saturated cyclic compounds is an important future step. Enantioselective CHB has been demonstrated and future work will continue to push for more selective routes to install boron on saturated substrates. 26 Chapter 2. Hydrogenation of Aromatic and Heteroaromatic Organoboronic Esters and Organosilicon Compounds 2.1 A Brief History of Hydrogenation Chemistry Heterogeneous hydrogenation has been a staple in synthetic chemistry dating back to when Sabatier and Senderens made important discoveries in 1897.57 In the first report by Senderens and Sabatier, ethylene was reduced with a dispersed nickel catalyst. Further experimentation by Senderens and Sabatier found that a nickel catalyst could hydrogenatate aromatic compounds such as phenol and aniline.58 For these advancements in reduction chemistry Sabatier won the Nobel prize in 1912. Since that time, heterogeneous hydrogenation has expanded to a variety of different metals and catalysts. Voorhees and Adams found that the reports in the literature of platinum metal for hydrogenations generated mixed results.59 Consequently, they sought a repeatable synthesis of a platinum catalyst for hydrogenation. They synthesized platinum oxide by fusion of chloroplatinic acid with sodium nitrate at 320 °C. This platinum oxide was then used to hydrogenate ketones, aldehydes, and esters to alcohols, as well as hydrogenation of phenol to cyclohexanol.59 It became known as Adam’s catalyst and it is often used with addition of glacial acetic acid. Scheme 22. Platinum oxide catalyst for hydrogenation.59 27 In 1925 and 1927 Raney was issued two different patents for the development of a porous nickel catalyst. First, Raney synthesized a silicone/nickel alloy and then treated it with sodium hydroxide.60 The resulting nickel was the most active catalyst for hydrogenation of seed oil under high pressure and temperature at that time. Raney followed that by making a 1:1 nickel/aluminum alloy that he treated with sodium hydroxide to generate the nickel catalyst.61 This nickel/aluminum starting material was found to be incredibly active and up to five times as active of a catalyst as was available for hydrogenation at that time. This porous nickel catalyst became known as Raney nickel. The use of rhodium as a hydrogenation catalyst was first reported by Beeck in 1945. He illustrated that the rhodium was the fastest of the metals he tested for hydrogenation of ethylene.62 The first example found in the literature of hydrogenation chemistry utilizing rhodium on carbon was reported in 1952 by Dunworth and Noord looked at the reactivity of rhodium on carbon.63 Dunworth and Noord found that rhodium on carbon was an effective catalyst for the hydrogenation of olefins, carbonyls, aldehydes, nitro groups and quinones with addition of acid. Freifender and co-workers looked at the reactivity of different supports of rhodium in hydrogenation chemistry. They found that rhodium was more active and less prone to poisoning when hydrogenating pyridine on a carbon based support than an alumina-based support.64 These reports and many others also showed the chemoselectivity of rhodium tolerated esters, ethers, alcohols and amines. 28 Figure 11. Homogeneous hydrogenation catalysts.65-68 Homogeneous hydrogenations took off with the development of metal complexes that catalyzed reduction of alkenes. Wilkinson developed a tris(triphenylphosphine)rhodium (I)chloride for the use as a hydrogenation catalyst (Figure 11 A).65 It operated by dissociation of a triphenylphosphine to open up a coordination site and allow for hydrogenation to occur. This work was advanced by Osborn and Schrock.66 They synthesized the cationic rhodium complex B shown in Figure 11. This Osborn and Schrock catalyst was able to selectively hydrogenate dienes to mono-alkenes and generated more turnovers than Wilkinson’s catalyst.67 Taking the cationic complex formation further, Crabtree and co-workers develop an iridium-based catalyst for hydrogenation of tri and tetrasubstituted alkenes. While tetrasubstituted alkenes were able to be reduced using Crabtree’s catalyst, C in Figure 11, Wilkinson’s and Osborn’s catalysts were unable to reduce highly substituted alkenes.68 Scheme 23. Hydrogenation of Fluorinated Arenes.69 29 More recently, homogeneous hydrogenations have been extended to asymmetric hydrogenations of heteroaromatic compounds such as pyridines70, indoles71–73, pyrroles,74 furans,75,76 and others.77 Homogeneous hydrogenation has typically struggled with non-heterocylic hydrogenations. Illustrated by Scheme 23, one of the most recent developments was the hydrogenation of fluorinated benzenes to generate fluorinated cyclohexanes by Glorius and co-workers.69.This process, while using a homogeneous precatalyst, was reported to likely be a heterogeneous catalyst. Using this same system, Glorius also reported the first hydrogenation of arylboronic esters.69 Previously there existed only a single other report of fluorine being maintained through the hydrogenation of an arene.78 In the hydrogenation of fluorobenzene by Blum and co-workers it was reported to result in only 39 % fluorocyclohexane with the rest being defluorinated compound. 2.2 Hydrogenation of Borylated Olefins The hydrogenation of borylated olefins has been reported in literature since 1965 when Clark and co-workers patented a process of synthesizing diethyl chloroborane from chlorodivinylborane79 The hydrogenation occurred over palladium on carbon using hydrogen gas as the hydrogen source. The loss of hydrochloric acid during the reaction gave the desired product (Scheme 24). Scheme 24. First reported hydrogenation of a borylated olefin79 30 Quickly following that patent, 2-vinyl-4,4,6-trimethyl-1,3,2-dioxaborinane was reported to be hydrogenated over a platinum catalyst by Woods and coworkers.80 This first report of a oxaborinane being hydrogenated paved the way for hydrogenation of other boronic esters. Scheme 25. First reported hydrogenation of a vinyl boronic ester.80 The first asymmetric hydrogenation of a vinyl boronic ester was performed by Morgan and Morken in 2003.81 The hydrogenation of 1,2- bis(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)styrene yielded the saturated compound in 85% yield with 93% e.e. This was a big step in organoboron chemistry because it illustrated how to create a borylated stereocenter without the use of asymmetric hydroboration. Since the report by Morken, several examples of asymmetric hydrogenation have been performed by Andersson82, Pfaltz83, and others to yield enantiopure organoboron compounds. Hydrogenation of borylated olefins extended to other protecting groups on boron as well. In 2007, Molander and co-workers reported the hydrogenation of a vinyl potassium trifluoroborate salt in methanol with palladium on carbon.84 Hydrogenation of vinyl MIDA boronate was performed by Burke in 2010 with hydrogenation of an alkynyl MIDA boronate.85 In 2010 Suiginome and co-corkers hydrogenated a diaminonaphthalene boronic ester (Bdan) on an olefin with palladium on carbon.86 Overall a wide variety of boron containing olefins have been shown to be stable in 31 alcoholic, or polar solvents for hydrogenation using palladium on carbon, platinum metal, and a variety of rhodium and iridium homogeneous catalysts. 2.3 Hydrogenation of Borylated Arenes Arenes and heteroarenes are a bigger challenge for hydrogenation than that of olefins. The challenges are varied but the large barrier required to breaking the aromaticity is the largest challenge. As such, there have been a few examples reported in literature where aromatic or heteroaromatic organoboron compound has been hydrogenated. The first was in 1993 by Kelly and co-workers where n-Bocpyrrole was subjected to a lithiation/borylation to yield the boronic acid at the 2-position. They followed this by hydrogenating the pyrrole to the pyrrolidine using palladium on carbon. They were able to isolate the product in 97% yield.87 Scheme 26. Hydrogenation of n-Boc-2-pyrrolyl-boronic aicd.87 The next example, was recently reported by Glorius and co-workers when they showed the hydrogenation of borylated fluorobenzenes could be performed using a homogeneous catalyst.69 They reported three examples of arylboronic esters being reduced to the cyclohexanes. 32 Scheme 27. Homogeneous hydrogenation of fluorinated aryl boronic esters.69 These two examples showed that a general method for the hydrogenation of borylated arenes and heteroarenes could be made. As discussed in Chapter 1, the methods for producing saturated cyclic organoboron compounds are limited to hydroboration or sp3 CHB. The recent advances in sp3 CHB are important; however, a simpler route to synthesizing these compounds would be extremely helpful. It would be beneficial to utilize the past 19 years of thermal catalytic CHB research to generate selectivities for the saturated cyclic compounds that are currently challenging to make. 2.4 Additives for Hydrogenation of Borylated 6-Membered Heterocycles. Many hydrogenations of heteroaromatics are performed with the use of an acid additive. One major concern was that the borylated heteroaromatic compounds would deborylate during the hydrogenation. To screen for conditions that would limit deborylation a sample substrate of 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)pyridine (2a) was used. The reduction of 2a was attempted using hydrochloric acid as an additive and the hydrogenation was attempted over a variety of metal catalysts. Upon workup the product distribution was determined by analyzing the 1H-NMR spectra An example spectrum is shown below in Figure 12. 33 O B O N H2 700 psi 5% Rh/C 10 mg HCl excess Solvent, rt, time O B O N H2 A Cl N H2 B Cl Figure 12. Hydrogenation of 2a yielding borylated and deborylated product The catalyst screen results were summarized in Table 1. It was found that 5% rhodium on carbon performed the best. It resulted in the least amount of deborylated product and it was faster than the other catalysts. Rhodium on alumina also had comparable deborylation to product formation but the reaction was slower. Palladium on carbon failed to hydrogenate the 2a. Platinum oxide showed slower hydrogenation and an increased rate of deborylation as compared to that of the rhodium catalysts. Rhodium on carbon is the catalyst that tends to have the most functional group tolerance while at the same time operates at the lowest temperature of the metals on solid supports. Catalysts available on more exotic support systems or metal alloys were not tested for the hydrogenation of borylated compounds. Raney nickel was not tested under these conditions as an attempt to use Raney nickel with a borylated arene resulted in complete 34 deborylation; while the use of rhodium on carbon does not result in deborylation under similar conditions. Table 1. Heterogeneous catalyst screen for hydrogenation of 2a Entry 1 2 Catalyst 5% Rh/Cb 5% Rh/Al2O3 Product A (%)a Product B (%) Starting Material 72 50 28 15 0 35 PtO2 3 4 5 36 100 38 a) 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.25 mmol), hydrochloric acid (1 mmol), hydrogen gas (700 psi), ethanol (2 mL), catalyst (10 mg), rt, 2 hours. Conversion % based on 1H-NMR b) 1 hour 10% Pd/C 10% Pt/C 32 0 24 32 0 38 After determining that rhodium on carbon was the best option for a catalyst, a solvent screen was run. It was found that by switching from a potentially nucleophilic solvent such as ethanol to a non-nucleophilic polar solvent, dioxane, no reduction of the deborylation occurred. In fact, the deborylation that occurred in dioxane was actually greater than the amount of deborylation that occurred in ethanol. DCM showed complete deborylation over 36 hours and THF also showed more deborylation than ethanol as well. These results were summarized in Table 2. 35 Table 2. Solvent Screen for the Hydrogenation of 2a Entry Solvent Time (hours) Product A Product B 2a (%)a 75 0 0 47 65 75 (%)a 25 0 100 53 35 25 Ethanolb 1 2 3 4 5 6 Dichloromethane Dichloromethane 0 100 0 0 0 0 a) 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.25 mmol), hydrochloric acid (1 mmol), hydrogen gas (700 psi), solvent (2 mL), 5% Rh/C (10 mg), rt. Conversion % based on 1H-NMR 16 4 36 7 7 2 Dioxane Tetrahydrofruan Methanol The amount of deborylation was not found to be significantly different between reactions the proceeded for 16 hours or reactions that were stopped after 1 hour. This was observed when comparing the use of rhodium on carbon in ethanol in Table 2 to that same use in Table 1. Between hours 1 and 16 the compound is fully hydrogenated in the ethanol run of Table 2. However, there is no increased deborylation during the extra time. This implies that the saturated compound is stable under these conditions to deborylation. The deborylation that is occurring must therefore happen while the organoboron compound is either still aromatic or during the process of reduction. 36 Table 3. Bronsted acid additives for the hydrogenation of 2a by rhodium on carbon Entry Additive (1 equivalent) Time (hours) Product A Product B (%)a (%)a 1 2 3 4 5 6 7 8 9 HClb HCl (dry) HCl + 1 mL H2O MeSO3H NH4Cl PO4H3 2,6-dichloropyridine Sulfuric Acid Triflic acid 16 1 1 2 24 2 36 2 2 75 72 71 63 0 58 38 39 52 25 28 28 37 70 42 62 61 48 2a (%) 0 0 1 0 30 0 0 0 0 a)Conversion percentages determined by 1H-NMR. 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)pyridine (0.25 mmol), Additive (0.25 mmol), Hydrogen gas (700 psi), Ethanol (2 mL), 5% Rh/C (10 mg), rt. The reaction was tested with the addition of 1 mL of H2O in an effort to determine if a failure to properly dry the solvent was a cause of deborylation. The deborylation was very similar to that of using dry solvent. Other acids with less nucleophilic conjugate bases were tested as well. Methanesulfonic acid resulted in a 2:1 ratio between desired product and that of the deborylated reduced product. Phosphoric acid, sulfuric acid, and triflic acid all saw significantly greater quantities of deborylation than that of hydrochloric acid. Entry 7 was 37 an attempt to generate hydrochloric acid in-situ. The dichloropyridine would generate 2 equivalents of hydrochloric acid over time instead of being added all at once. However this process resulted in more deborylation compared to simple addition of hydrochloric acid. Table 4. Lewis Acid Screen for the Rhodium on carbon hydrogenation of 2a Entry Additive (1 equiv) Product Aa,b (%) Product Ba,b (%) 1 2 3 4 5 6 7 8 9 Cerium (III) chloride Magnesium chloride Copper sulfate Potassium Iodide Zinc chloride Iron powder (rusted) Magnesium sulfate Trimethyl borate 3Å molecular sieves (activated) 0 0 20 16 0 0 0 0 0 100 30 18 42 15 15 17 11 19 2aa,b 0 70 62 42 85 85 83 89 81 a) Conversion percentages determined by GCMS comparing piperidine to starting material. Pyridine was not seen by GC/MS. b) 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.1 mmol), Additive (0.1 mmol), Hydrogen gas (700 psi), Ethanol (1 mL), 5% Rh/C (10 mg), rt. An attempt was made to hydrogenate 2a in the presence of a Lewis acid to help facilitate the isolation of the product away from that of the deborylated side product. 38 However, these were largely unsuccessful. The results are summarized in Table 4, which show that only copper sulfate and potassium iodide resulted in any hydrogenated product. As these reactions were run in ethanol, a few of the compounds likely reacted with the solvent. Overall the Lewis acids that did show some reduction were slow and also showed equal or greater amounts of deborylation. Based on these screens, the best conditions for hydrogenation of pyridines or other heterocycles were determined to be with 5% rhodium on carbon in ethanol with hydrochloric acid as an additive. Rhodium on carbon was the quickest and most tolerated catalyst and should be used for all substrates due to its affinity to hydrogenate a wide variety of arenes and heteroarenes. These conditions were used in an attempt to hydrogenate a variety of differing pyridines, however, isolations proved to be difficult. To start with the hydrogenation of 2a under conditions labeled above was attempted and after filtration of the rhodium on carbon through Celite and removal of solvents a sticky residue remained. Selective crystallization was unsuccessful. Attempts were made to isolate amides or carbamates by reaction with chloroformates or acid chlorides. However, in those attempts more deborylation occurred. 2.5 Additives Free Hydrogenation of Borylated 6-Membered Heterocycles. Some six-membered heterocycle substrates tested hydrogenated without the addition of acid. For the most part they fell into one of two classes of compounds. Either they contained steric bulk around the nitrogen or they contained a halogen in the molecule that was eliminated during the hydrogenation to generate an acid that facilitated 39 the hydrogenation reaction. The hydrogenation under these conditions did not result in any observable deborylation. Table 5 summarizes the results of these hydrogenations. Table 5. Hydrogenation of 6-membered heterocyclesa,b a) standard conditions 0.5 mmol substrate, 25 mg 5% Rh/C, H2 (700 psi), EtOH (5 mL), rt, 16 h b) relative stereochemistry shown c) Isolated as a mixture with deborylated product Starting from 2-Br-6-Bpin-pyridine compound 2b was synthesized in 99% yield. This was a surprise as elimination is possible from the two positions of heteroaromatics. No deborylation was observed in this reaction. Compound 2b is incredibly useful as two- substituted piperidines are a common motif in pharmaceutical chemistry. Overall the formation of 2b, 2c, and 2d are important as this provides a clean and quick method for the formation of borylated piperidine in any position desired. Each of them started from 40 the heteroaryl halides. Compound 2c was unable to be separated from a mixture of deborylated product. Other methods for synthesizing borylated piperidines are limited. Borylation at the two position has been synthesized through the use of pyridyl directed CHB,88,89 and lithiation/borylation of boc-piperidine.90 The 3-borylated piperidine is accessible through some very nice chemistry by Ito and coworkers using a broylative reduction of pyridines to generate the partially saturated piperidine.91 The 4-borylated piperidine is also available through Miyaura borylation.92 The relative stereochemistry generated from this type of transformation follows that of other reductions of pyridines by rhodium on carbon, as illustrated by compound 2e. Figure 13. Crystal Structure of Compound 2e 41 Compounds 2f is important in that it does not contain a halogen that eliminated during the hydrogenation. 2f has steric bulk near the nitrogen that helps to prevent poisoning of the catalyst through the hydrogenation. 2.6 Hydrogenation of Borylated 5-Membered Heterocycles Furans, indoles, pyrroles and thiophenes all have well developed CHB chemistry. They have been well studied and various papers have included methods of borylating those 5-membered heterocycles at different positions of sp2 carbon centers. The CHB of these reduced heterocycles has not been reported except for tetrohydrofuran.93 Unfortunately the CHB of tetrahydrofurans mimics the selectivity from a similar hydroboration of the 2,3 dihydrofurans.94 Shown in Scheme 28, this selectivity means that there is limited use of those methods for generating the desired product. The use of CHB on a furan or benzofuran results in borylation at the 2-position. Upon hydrogenation this results in complementary selectivity to that of hydroboration of sp3 CHB. Scheme 28. sp3 CHB of tetrahydrofuran.93 42 Table 6. Heterogeneous Hydrogenation of 5-membered Heterocycles Heterocycle (0.5 mmol), 10% Pd/C(25 mg), EtOH (5 mL), rt, 16h Unfortunately, but not unexpectedly, thiophene was unable to be hydrogenated. Both sulfur containing compounds 2j and 2n were unable to be formed through hydrogenation. This is not unexpected as the hydrogenation of thiophenes have been a challenge in the literature and thiophene is known to be a poison to catalysts. This is also the case with unsubstituted indoles and pyrroles. Addition of acid to the hydrogenation of borylated pyrroles resulted in polymerization and deborylation of the pyrrole. The 2- position of N-Boc-pyrrole had previously been borylated via lithiation/borylation and hydrogenated to yield the borylated N-Boc-pyrrolidine but using CHB of N-Boc-pyrrole the 3-boryl pyrrolidine was able to be generated. An interesting study was 2m and 2m´ as the borylation at the 2 position on indole resulted in the reaction failing to generate the saturated cyclic product either protected by a Boc group or without protection. With 2m´ addition of acid resulted in deborylation either prior to or concurrently with hydrogenation. This was slightly surprising. Addition of acid to the reaction mixture 43 resulted in deborylation. The MIDA boronate of N-methylindole failed to hydrogenate likely due to insolubility in compatible solvents. 2-Bpin-benzofuran also failed to generate 2k when palladium on carbon was used for hydrogenation. The use of rhodium on carbon resulted the complete reduction of the compound to generate the 2-borylated octahydrobenzofuran. This was noted by stopping the hydrogenation early and seeing that no build up of 2,3-dihydro-2-Bpin-benzofuran was observed. Without any build up of the 2,3 dihydrobenzofuran this likely means that when rhodium on carbon is used the hydrogenation of the arene occurs first, followed by the hydrogenation of the furan. The hydrogenation of 6 benzene rings are slower than that of heterocycles even when in a fuse system. The hydrogenation of the 5 membered ring were occurring first there would be a build up of that 2,3 dihydrobenzofurn. As there is not, the hydrogenation therefore likely begins with the hydrogenation of the benzene ring. 2.7 Hydrogenation of Borylated Arenes Using rhodium on carbon the hydrogenation of borylated arenes was demonstrated. The result was generation of borylated cyclohexanes. Unlike the heteroarenes, the arenes resulted in a mixture of cis and trans products. Functional groups such as methoxide, esters or alcohols survived hydrogenation. The diastereoselectivity was determined by 1D-NOE experiments. A positive NOE was seen between the proton on the geminal position on the substituent and that of the geminal position to the boron. This indicated a cis relationship between all of the major isomers. More electron rich substituents such as esters and methoxides that could have interactions with the rhodium 44 surface resulted in greater selectivity for the cis isomer. The results for the hydrogenations of borylated arenes are summarized in Table 7. Table 7. Hydrogenation of borylated arenesa,b a) Relative stereochemistry shown. b) Substrate (0.5 mmol), 5% Rh/C (25 mg), H2 (700 psi), EtOH (5 ml), rt, 16 h 2.8 Silylated heterocycles Similar to borylated compounds, carbon-silicon bonds are very versatile in their synthetic transformations. Going a step beyond boron, they are more often used in materials chemistry as silicone polymers show incredible thermal and chemical resistance. This variety in uses makes the research into development of new organosilicon compounds important. It was found that using the same methods of silylation via lithiation or C-H silylation followed by hydrogenation new compounds containing carbon-silicon bonds could be generated. Similar to organoboron compounds, hydrogenation of silylated compound were previously restricted to that of olefins and 45 arenes. Hydrogenation of a silylated heteroarene had not been accomplished. Applying the methodology developed in reduction of the organoboron compounds, the reduction of organosilicon heterocycles was achieved. Table 8. Hydrogenation of silylated heterocycles . Standard conditions: 0.5 mmol substrate, 25 mg 5%Rh/C, EtOH (5 ml), rt, 16 h The hydrogenation of 2u resulted in seeing double the normal number of carbons. At first this was thought to be because of de-silylation, however upon looking at the proton NMR the silane peak was split into 2 different silicone resonances. This leads to the conclusion that the diastereomeric peaks are visible. 46 Figure 14. 1H NMR signal from the TMS group on 2u The hydrogenation of 2v resulted in a 12:1 selectivity between cis and trans. This was the only heteroaromatic that showed mixtures of relative stereochemistry. The spectrum of 2v also showed the differences by NMR of the axial and equatorial positions of the substituents. The size of a TMS group and that of a CF3 group were found to be similar. As such there is little difference in energy between which substituent is in the axial position and which substituent is in the equatorial position. Compound 2w illustrates that when a borylated compound failed to hydrogenate the possibility exists for complex synthesis using a silyl group instead. While compound 2k was unable to be synthesized by hydrogenation and only the fully hydrogenated compound could be seen the reduction of the 2,3 bond was possible when silylated. The reaction was clean and the reduction of the 2,3 bond to generate 2w was performed by palladium on carbon to prevent reduction of the benzene ring. 47 Compound 2x shows the possibility for divergent synthesis. Generating a compound with cis-relative stereochemistry that could be used for multiple functionalizations using orthogonal chemistry. One handle being the boronic ester and the other being the silane multiple variations can be synthesized using a scaffold containing these two substituents. While silylated arenes had been hydrogenated before, the hydrogenation of a trialkoxysilylarene or heteroarene had not been demonstrated. By hydrogenating the triethoxyphenylsilane in ethanol formation of silicone polymers, based on 29Si-NMR, were made. However, when the solvent was switched to hexane only one product was formed by silicon NMR carbon and proton NMR is also consistent with the previously reported synthesis of 2y via hydrosilylation. The importance that the formation of 2y shows is that the process of hydrogenation over rhodium on carbon can generate the siloxy-cyclohexane compound. This could then be used in more advanced materials synthesis. 2.9 Chiral Resolution of a reduced borylated piperidine The resolution of a saturated borylated compound was performed as a way to illustrate how this work could be used to generate enantiopure compounds. There were several failed attempts at the isolation of an enantioenriched compound by crystallization of chiral salts. It was found that the use of chiral carboxylic acids such as tartaric acid were not able to result in a chiral resolution. The attempts then moved on to the use of menthyl chloroformate. However, the products were unable to be separated by column 48 chromatography. The other issue with the menthol carbamate that was formed was that it was hard to visualize by GCMS. From there, the attempts turned to the use of (S)-2-methylbutyricanhydride to form a chiral amide. These products could be separated via column chromatography and different peaks with the appropriate mass were observed by GCMS. As shown in Scheme 29, 2-borylated piperidine could be separated into its enantiomeric components using this route. The crystal structure of isomer A was found to be the (S,R) isomer shown in Figure 15. Scheme 29. Chiral resolution of 2b through chiral amide formation 49 Figure 15. Crystal Structure of Compound 2za 2.10 Hydrogenation Conclusion A two-step process for synthesis of saturated cyclic borylated and silylated compounds was developed. The use of rhodium on carbon limits the amount of deborylation that occurs during the hydrogenation process. Utilizing chiral amide formation, chiral resolution of the saturate cyclic organoboron piperidine was shown to be a viable route to enantiopure organoboron compounds. Further research into the use of asymmetric hydrogenation catalysts for asymmetric reduction of heteroaromatic organoboron compounds is necessary to continue to develop important chiral intermediates for synthesis. 50 Chapter 3. Pyridine Ligands for ortho-Directed C-H Borylation 3.1 Chelate Directed ortho C-H Borylation One of the most well studied methods of directed C-H borylation is the chelate directed borylation using directed metalation group (DMG) such as ketones, esters, amides, carbonates, carbamates, imines, pyridyl...etc. The chelate direction method utilizes a generated open coordination site on the active catalyst to coordinate a lewis base to the metal center. The proximity and ring size of the transition state favors the C-H activation occurring at the ortho position relative to the directing group from the substrate. Dissociation of the borylated product turns over the catalyst Figure 16. C-H Activation in Chelate Directed ortho-Borylation There are three general methods for generating an open coordination site on Ir(III) complexes for chelate-directed CHB. First, by the use of a monodentate ligand with only one coordinated ligand on each metal center when the catalyst is active 3a.95–97 Second is through the use of a hemi-labile bidentate ligand were one of the binding sites of a ligand will oscillate on and off to allow for the substrate chelation and CHB 3b.98,99 The third method is through the use of an L type and X type bidentate ligand 3c.100,101 All of these methods result in a 14/16-electron iridium (III/V) catalytic cycle (Figure 17). This is 51 different than the iridium (III/V) 16/18 electron cycle when using L,L-type bidentate ligands which tend to favor steric based selectivity.102,103 When isolated from excess ligands the spatially open iridium (III) 14/16 electron catalytic system has been found to be incredibly active.95,104–107 Figure 17. General catalytic cycle for chelate directed ortho-borylation The active catalyst for ortho borylation contains 3 x-type ligands that have been reported as either boryl or silyl groups. With one L-type ligand in on the catalyst when the reaction begins this generates the 14 electron 4-coordinate iridium (III) shown as 3d. The catalyst coordinates a substrate through a DMG to generate 3e. Oxidative addition of the C-H bond generates complex 3f, which is a heptacoordinate iridium (V) complex. Reductive elimination of the catalyst followed by oxidative addition of B2pin2 and reductive elimination of HBpin regenerates 3d. 3.2 Hemi-Labile Ligand Systems Lassaletta and co-workers generated a method of chelate directed borylation using a pyridyl-imine bidentate catalyst system that is proposed to dissociate the imine arm of 52 the catalyst before borylation.98 This was used to preform the CHB using pyridyl, quinolyl, and imine directing groups. Ortho-borylation is achieved in high yields at 80 °C in a 1:1 ratio of boron source to substrate. Lassaletta further developed this catalyst system to include the borylation of hydrazones that could be generated from various aryl aldehydes.108 Lasseletta demonstrated how a ligand system could be used to help stabilize the catalyst in a resting state and yet still allow it to provide the ortho selectivity desired. Scheme 30. Lassaletta Hemi-Labile ortho-Directed Borylation.98 Clark and co-workers used pyridin-2-ylmethanamine as a ligand to ortho-borylate benzylic amines (Scheme 31).109 Clark further explored this work by investigating the bite angle of the amine-pyridine combination. What they found was that the smaller bite angle of a 2-aminopyridine was a better catalyst for ortho-borylation of benzylicamines.110 They further expanded this work to include ortho-borylation of benzylic phosphines with using the benzylphosphines as their own ligand.111 53 Scheme 31. Picolylamine for ortho-Directed CHB of Benzylamines and Benzylphosphines.109 All of these catalysts systems had the drawback of requiring substrates with strong donors as the directing group. This is because the substrate needs to out compete the pendent side of the ligand for coordination to the catalyst. Without a strong donor it is much more likely that the reactant dissociates from the catalyst before the borylation at the ortho position can occur. This would likely lead to a loss of selectivity for weaker donating directing groups such as ketones, esters or amides. This is also likely why there has yet to be a publication using these ligands for the ortho borylation of one of these substrates. More recently, Chattopadhyay and co-worker used 8-aminoquinoline for borylation ortho to pre-generated imines.112 They directly compared their ligand to Lassaletta and co-worker’s ligand to show that while the Lassaletta ligand generated good selectivity, 8-aminoquinoline used as a ligand generated a more active catalyst. Chattopadhyay borylated the ortho position on imines generated in-situ from aldehydes and isolated the aldehydes upon working up the reaction. The amines used for in-situ generation of imines were methyl, isopropyl and tert-butyl. Interestingly, only the tert- butyl group resulted in ortho borylation in significant quantities in comparison to the other sites. Chattopadhyay argued that this is because the excess bulk was needed to generate an open coordination site. 54 3.3 L-X type Ligand Systems for Chelate Directed ortho-Borylation Smith, Maleczka and co-workers developed a system for ortho-borylation113 that took advantage of a use of the necessity for iridium to be iridium (III) as the resting state of the catalyst. They used an L-X type bidentate ligand such that one phosphine and one silyl group were attached to the catalyst center. The use of an X-type ligand resulted in only two boryl ligands being on the iridium center as well as the one X-type ligand resulting in a 14-electron iridium (III) tetra coordinate complex with two open coordination sites. This catalyst design was inspired by Hartwig and coworkers use of silane-directed ortho borylation,114 but by including the silane on the ligand the selectivity became catalyst controlled and not substrate controlled. This P-Si ligand was used for ortho-borylation using directing groups of esters, amides, methoxides, carbamates and pyridines. By changing from a phosphine-silane to a quinoline-silane ligand the reactivity for ortho-borylation was significantly increased. Scheme 32. ortho-Borylation of Aryl-DMG Using Phosphine-Silane Based Ligands.113 In an effort to improve upon this type of L-X type bidentate system, Yu and co- workers exchanged the silyl group for a boryl group.115 The reasoning behind this exchange was that a boryl group could be more electron donating than a silyl group on a 55 metal. Thus if an N,B-bidentate ligand could be used, they envisioned a catalyst that would be more reactive than the quinoline-silyl ligand used by Smith, Maleczka and co- workers. They synthesized a ligand dimer that contained a boron-boron bond that would be broken apart upon oxidative addition to the metal. However Yu and co-workers found that this resulted in a catalyst system that contained two N,B bidentate ligands on it. This resulted in a system that generated steric-influenced borylation.115 Scheme 33. ortho-Borylation of Aryl-DMG Using Nitrogen-Boron Based Ligands.101 In an attempt to generate a catalyst system with only one bidentate ligand on it Yu and co-workers synthesized a ligand that contained a boron-silyl bond (Scheme 33).101 Using this ligand resulted in a catalyst that performed ortho-borylation of esters, ketones, carbamates, amines, imines, and pyridyl groups. However, this catalyst did not operate under conditions that were an improvement from Maleczka, Smith, and co- workers. There were a few potential reasons for the lowered reactivity of the catalyst used by Yu and co-workers. The first possibility was that the silyl group was still bound to the metal resulting in a less electron rich catalyst that slowed the reaction. The second reason is that the bite angle of the ligand is more acute than that of the quinoline silyl ligand generated. This could result in less orbital overlap and less electron donation to the 56 metal. The last possibility is that the general premise that any boryl ligand will be a better donor than any silyl ligand is inherently false. A real possibility exists that the diazaboryl ligands are worse donors than that of the dioxaboryl ligands. However, that would run counter to previous calculations on boryl donor strength by Marder and co-workers.116 However, the computation energy levels calculated by Marder are not all that different from each other and Yu’s ligand is very different than that of the ligands computed. As such there could still be a question to which ligand is more donating. 3.4 Monodentate Ligand Systems Discussion to this point has focused on bidentate ligands for ortho-directed borylation. However, 14-electron iridium (III) catalysts that contain two open coordination sites could be generated with monodentate ligands. There are two general methods for generating these types of catalysts. The first method is through isolating a metal center on a solid support.95,104-107 The second is through use of stoichiometric, steric or electronic factors that result in coordination of only one ligand per metal center.96,97 57 Scheme 34. Supported Phosphine Catalysts for ortho CHB Sawamura an co-workers first used a caged monodentate phosphine ligand bound to silica (Silica-SMAP) to isolate the iridium catalysts sites on one phosphine ligand.95 The surface of the silica was passivized with trimethylsilyl groups to prevent the surface hydroxyl groups from interfering in the catalysis. The resulting catalyst system was incredibly active, functioning well at low temperatures and low catalyst loading. Silica-SMAP has been used for the ortho borylation of phenol derivatives,104 sp3 centers using rhodium105 as well as esters,16 amides,95 and even produced ortho-borylation of aryl chlorides.95 These CHB’s were at room temperature or slightly above. The isolated catalyst resulted in a very controlled reaction environment. The caged nature of the phosphine resulted in minimal steric bulk around the catalyst that results in a highly active catalyst. The problem with silica-SMAP is that the ligand is very challenging to synthesize. 58 Scheme 35. Homogeneous ortho CHB with Excess Ligand Shortly after silica-SMAP was reported a new method for ortho-directed CHB was developed by Ishiyama, Miyaura and co-workers. They took advantage of the inability of electron poor ligands to stay bound to a catalyst. They generated an open coordination site using large electron poor monophosphines96 and triphenylarsine.97 Shown in Scheme 35, the electron-poor and sterically bulky nature of these systems lends itself to generate equilibrium between proposed intermediates 2 and 3. Intermediate 2 is a 14-electron complex with two open coordination sites due to the loss of a ligand that allows for ortho CHB. Intermediate 3 contains two monodentate ligands and is a 16- electron Iridium (III) complex that results in sterically driven borylation. Scheme 36. Homogeneous electron poor monodentate phosphine ligand for ortho CHB 59 This was the first method to generate ortho borylated aryl esters2 and ketones3 using easily purchasable ligands. However, this ligand required higher reaction temperatures, 80-120 °C, and had greater limitations in substrate scope than silica-SMAP. Another issue with this system developed was the need for excess substrate in an order of 5:1 to boron source in order to prevent diborylation. However, these were the first homogeneous ligand system for ortho-CHB of esters and ketones. 3.5 Further Challenges in Chelate Directed ortho-Borylation Overall, these methods for directed ortho CHB generated desired product; however, there were issues of selectivity, availability or reactivity depending on the catalyst. After observing how bipyridine systems worked better for steric directed CHB compared to bis-phosphine systems Dmitry Shabahov set out to determine if monodentate pyridine systems could work better than the corresponding phosphine system reported by Ishyama, Miyuara and co-workers. From his preliminary results it was apparent that by changing the sterics or electronics of the pyridine ligands, ortho- borylation could be accomplished. The benefit of using pyridines as ligands for ortho-borylation was the vast number of different commercially available pyridines. This allowed for the fine-tuning of the catalyst system to control the equilibrium between 2 and 3 from Scheme 35. The use of a sterically encumbered pyridine should generate a weaker bond to the metal and shift the equilibrium towards 2. However, using a pyridine with too much bulk around the nitrogen could result in a slower catalyst by either steric hinderance of substraight- catalyst inerctions or inhibition of ligation. 60 The other route to take is the use of electronic poor pyridines. This is similar to the use of triphenylarsine. It results in a lower ability for the ligands to have multiple monodentate ligands on a single metal center due to the lower bond strength to the metal center. This would also result an electronically poor catalyst. The last controllable variable was the amount of ligand added. By using just one equivalent of pyridine per iridium, a greater amount of complex 2 could be formed. This was supported from literature when Ishiyama, Miyuara and co-workers.96 They used a 2:1 ratio of pyridine to iridium metal. This combination favored formation of complex 3. The result was borylation of methyl benzoate in 7% yield at 80 °C over 16 hours. The selectivity was poor, 1:4:2 ortho:meta:para. This result, rather than discouraging, caused us to think carefully about using more electronically poor and sterically encumbered ligands. 3.6 Pyridine Ligand Screens for ortho Selectivity A ligand screen was performed to test a variety of monodentate pyridine ligands against ortho-borylation of esters. GC/FID was used to determine the ratios between ortho CHB to meta+para CHB. The results of this screen are illustrated in Table 9. The initial ligand screen was performed under catalytically relevant conditions. It was found with a 1:1 ratio of B2pin2 to methyl benzoate that a combination of a 2-methoxypyridine worked quite well as a ligand for ortho-borylation. One challenge that was shown was that use of 3g resulted in 20% diborylation based on methyl benzoate. Other ligands that worked well were electron-poor pyridines such as 3o and 3s. However, these 61 trifluoromethylated compounds were more expensive and more challenging to modify than a 2-methoxypyridine. While it was apparent that the electronics play a large role as shown by the trifluoromethyl pyridines 3j, 3o, and 3s if the steric bulk near the nitrogen of the pyridine is too great (3j) then the borylation significantly slowed. One concern about the use of 2-methoxypyridine as a ligand was that it could be borylated during the CHB reaction. To this end, other substituentions were added to then 2-methoxypyridine scaffold. A trifluoromethyl group in the 5-position (3t) resulted in high conversions, a reduction in the amount of diborylation, and improved selectivity. However, the overall yield was not as high as 3g and 3t is much more expensive than 3g. 62 Table 9. Screen of pyridine ligands for ortho borylation of methyl benzoate with one equivalent of diboron a) All numbers are GC/FID conversions compared to a naphthalene internal standard b) Reaction conditions: methyl benzoate (136 mg, 1 mmol), [Ir(OMe)cod]2 (6.6 mg, 0.01 mmol), py′′′′ (0.02 mmol), B2pin2 (254 mg, 1 mmol), THF (2 mL) 80 °C 14 h. c) diborylation reported as combined diborylated isomers. From this initial ligand screen a major concern that arose was the significant amount of diborylation. This was shown to be an issue with nearly every ligand that resulted in high conversions and reported in Table 9 as the combined diborylated isomers. When diborylation, that was not di-ortho, it is impossible to know which CHB location was first. To determine how the selectivity was impacted with no diborylation, a second 63 ligand screen was performed with a 0.5:1 B2pin2 to substrate ratio. This resulted in less boron for the use in diborylation of the substrate. With the lower amount of boron in solution, the yields and selectivities were all reduced. Some of the ligands selectivities changed more significantly than others. The trifluormethylated pyridines, which had great ortho selectivity at a 1:1 ratio of B2pin2 to substrate, performed worse when there was less B2pin2 present. This gave a stronger argument for the use of 2-methoxypyridine as the backbone of further optimization. The other important finding of the ligand screen in Table 10 was the complete lack of any substrate to exceed 50% yield. This caused us to believe that the catalyst system was incapable of using pinacolborane as the boron source. Follow-up studies attempting borylation with only pinacolborane confirmed that pinacolborane was not a viable boron source for use in this catalyst system. 64 Table 10. Screen of pyridine ligands for ortho-borylation of methyl benzoate with half an equivalent of diboron a) All numbers are GC/FID conversions compared to a naphthalene internal standard . b) Reaction conditions: methyl benzoate (136 mg, 1 mmol), [Ir(OMe)cod]2 (6.6 mg, 0.01 mmol), py′′′′ (0.02 mmol), B2pin2 (127 mg, 0.5 mmol), THF (1.5 mL) 80 °C 14 h 3v was significant in that moving the methoxy group further from the pyridine resulted in a complete loss of reactivity and a change in selectivity. This indicated that the methoxy group from 3g is either hemilabile or not binding to the iridium center during the rection. When 3v is used the methoxy group has a greater chance of binding to the iridium center due to the larger bite angle of the pendant ligand. This appears to shut the reaction down and adds evidence that the active catalyst contains only one L-type ligand 65 bound to the metal. A control experiment was tested without a ligand and resulted in very little CHB. To see if the same selectivity holds up with a different substrate Dmitry Shababshov ran the same ligands used in Table 10 against cyclopropyl phenyl ketone as a substrate. The results from this screen followed a lot of the same trends as seen in the ligand screen of the esters. From this screen there are two significant results worth mentioning that were different. First, the result of using no ligand had 22% conversion and nearly perfect selectivity for the ortho borylated product. The second was that across the whole ligand subset the conversions were higher against the ketone substrate than the ester substrate. The only ligand that faired worse than not using a ligand was 3v that showed catalyst inhibition. Table 11. Ligand Screen for ortho-Borylation of Cyclopropyl Phenylketone a) All reactions performed by Dmitry Shabashov b) All numbers are GC/FID conversions. c) Reaction conditions: cyclopropyl phenylketone (1 mmol), [Ir(OMe)cod]2 (6.6 mg, 0.01 mmol), py′′′′ (0.02 mmol), B2pin2 (127 mg, 0.5 mmol), THF (1.5 mL) 80°C 14 h 66 From the result of these ligand screens Dimitry Shabashov tested two different electronic variations of 2-methoxypyridine as the ligand. The first was 2-methoxy-4- cyanopyridine (3y) and the second was 2-methoxy-4-(dimethylamino)pyridine (3x). Compound 3y was found to have much higher selectivity as well as a greater yield than that of 3x. This result was counter to conventional thought on CHB’s because 3y is more electron poor than 3x. Table 12. Electronic effects of 4-substituted-2-methoxypyridines for ortho-borylation of cyclopropyl phenylketone a) Reactions performed by Dmitry Shabashov. b) Isolated yields relative to B2pin2 c) B2pin2 (508 mg, 2 mmol), cyclopropyl phenylketone (380 mg, 2.6 mmol), THF(3 mL), [Ir(OMe)cod]2 (13.2 mg, 0.02 mmol) 67 3.7 Investigation into Substrate Scope After it was found that the 3x worked best as a ligand for ortho-borylation of cyclopropyl phenylketone, a variety of other substrates were tested to determine the functional tolerance and the selectivity for the catalyst system. It was found to have a fairly wide functional group tolerance as shown in Tables 13 and Table 14. Table 13 illustrate that this system was selective for esters, amides, and ketones. Benzamide, not shown, was not viable for CHB under this catalyst-ligand system. Halogen tolerance was demonstrated for fluorides, chlorides, and bromides. Under the conditions used for CHB in Tables 13 and 14 it was found that the diborylation of the substrate was observed when methyl esters were used, entries 1 and 5, as shown in in Table 13. Diborylation could be mitigated by changing the methyl ester to a tert-butyl ester as shown in entries 1 vs 4. After the initial borylation of the substrate an increased interaction from a tert-butyl ester and the pinacol group likely reduces the ability for the second ortho CHB. When the ester substrates contain a substitution at the ortho position such as entries 8 and 9 in Table 13 the borylation is still viable at the 6- position on the substrate. 68 Table 13. ortho C-H borylation of aryl esters and amides using a monodentate pyridine ligand O R B2pin2, 1.2 mmol [Ir(OMe)(cod)]2 1 mol % 3y 2 mol % THF, 70 °C, 16 h Y E R = OMe, O-t-Bu, NMe2 E = CH, N Y = CF3, F, Me ,Br, NMe2 BPin O R Y E OMe 3z 55b,c 8 yield (%)a entry substrate product Bpin O yield (%) O F O O-t-Bu O-t-Bu 3ah 46b,g F Bpin O NMe2 3aa 77 9 OMe CH3 OMe 3ai 71 CH3 OMe 3ab 72d 10h MeO OMe MeO OMe 3aj O O O O O-t-Bu 3ac 83 Me2N 11h OMe Me2N O O OMe 3ad 65b,c 12h H3C OMe H3C 65 73 61 13l:13m = 1.9:1 Bpin O OMe 3ak Bpin O OMe 2al Bpin Bpin O Bpin O OMe 3am H3C H3C OMe 3an 15 Bpin product Bpin O Bpin O Bpin O CF3 Bpin O Bpin O Bpin O CH3 O entry substrate O O OMe NMe2 OMe F F CF3 O O O-t-Bu O O OMe OMe CH3 O N F3C Br Br Br F3C Br Br 1 2 3 4 5 6 7 OMe 3ae 21e 3af 37e OMe BPin CH3 Bpin O N 3ag 51f 13 O OMe Bpin O F N F N OMe 3ao 84 a) Arene (1 mmol), B2pin2 (1.2 mmol), [Ir(OMe)(cod)]2 (0.01 mmol), py′′′′ (0.02 mmol), THF (2 mL) at 70 °C, for 16 h yields reported are isolated yields relative to arene b) B2pin2 (1.0 mmol) c) <5% of diborylated product observed by but not isolated. d) 19:1 ratio of 2 to 6 borylated isomers by 19F-NMR. e) Isolated yields from the same reaction. 29% starting material also recovered. f) Arene (1 mmol), B2pin2 (2.2 mmol), [Ir(Cl)(cod)]2 (0.01 mmol), py′ (0.02 mmol), THF (1.5 mL), 28 h g) other isomers were present in the crude reaction mixture in low quantities but only the major product was isolated. h) Performed by Dmitry Shabashov 69 Table 14. ortho C-H borylation of aryl ketones using a monodentate pyridine ligand entry substratea O 2.6 mmol O 2.6 mmol O O 1.3 mmol O Me 1 2 3 4 O R B2pin2, 1.0 mmol [Ir(Cl)(cod)]2 1 mol % 3y 2mol % THF, 70 °C BPin O R Y Y = CF3, OR, alkyl yieldb (%), time entry substrate 3ap 87, 11 h 5c O F3C 1.5 mmol Y 1.3-2.0 mmol product Bpin O Bpin O Bpin O O Bpin O 3aq 71, 14 h 3ar 68, 5 h Me 3as 7 45, 16 h product Bpin O yieldb,d (%), time O Bpin F3C F3C O Bpin O 6c MeO 2.0 mmol O Bpin MeO MeO O Me Bpin O Me 3ax 1.3 mmol 3at 3au 3av 3aw 62, 8 h 13e:13f = 1.5:1 61, 6 h 13g:13h = 1.9:1 94, 16 h a) The reactions were carried out using Arene (1.3 mmol), B2pin2 (1.0 mmol), [Ir(μ-Cl)(cod)]2 (0.01 mmol), py′′′′ (0.02 mmol), THF (1.5 mL) at 70 °C. b) Isolated yields shown are relative to B2pin2. c) B2pin2 (0.75 mmol) d) All reactions in Table 14 performed by Dmitry Shabashov Ketone substrates shown in Table 14 showed some interesting selectivity. The CHB of substituted benzophenones occurred more often on the substituted phenyl group regardless of electronic influences of the substrate. Phthalimides and other constrained 5- membered rings with ketones such as fluoren-9-one were not viable for ortho CHB under these conditions (not shown). This is likely a geometric argument as the distance from the ketone lone pair electrons to the ortho C-H bond is different when it is tied back than when it is free. More complex substrates were tested for ortho CHB that contained multiple potential sites for CHB (Table 15). In entry 1 there are multiple potential directing groups such as methoxides as well as cyclic ethers. However, the selectivity is perfect for the borylation ortho to the ketone. For entry 2 the borylation occurs selectively, however, 70 significant reduction of the ester was also observed during the reaction. The mechanism of the reduction is not known at this time, but potential formation of an N-B bond22 on the secondary nitrogen could provide a Lewis acid for coordination and a potential reduction pathway for the ester. Entry 3 shows the ortho-borylation on fenofibrate. The borylation is not completely selective and the product was isolated as a mixture of isomers in a 5:1 ratio. The assignments were accomplished through gHMBC and gCOSY NMR experiements. The assignment of 3ba was based on a resonance between the ipso carbon on the chlorine to the singlet of the proton adjacent to the boron. The other isomer 3bb was the minor isomer and contained a correlation between the ipso carbon of the ether and a smaller singlet in the aromatic range. 71 Table 15. ortho-Borylation on complex substrates a) Arene (1.3 mmol), B2pin2 (1.0 mmol), [Ir(Cl)(cod)]2 (0.01 mmol). 3y (0.02 mmol), THF (1.5 mL) 70 °c, 11 h. b) Arene (1.0 mmol), B2pin2 (0.6 mmol), [Ir(OMe)(cod)]2 (0.01 mmol). 3y (0.02 mmol), THF (2.0 mL) 85 °c, 16 h c) Arene (1.0 mmol), B2pin2 (0.9 mmol), [Ir(OMe)(cod)]2 (0.01 mmol). 3y (0.02 mmol), THF(2.0 mL) 85 °c, 16 h d) performed by Dmitry Shabashov 72 3.8 Insights into mechanism of pyridine ligated iridium systems for ortho borylation An investigation into the mechanism of the ortho borylation was performed. Initially an investigation into the ligand to metal ratio was performed using tert-butyl benzoate as a substrate. The results were summarized in Table 16. As Expected, the borylation failed to significantly proceed without a ligand; yielding only 7% conversion after 7h. Increasing the ligand to half an equivalent was found to accelerate ortho CHB. When the amount of ligand to iridium reached 1:1 the reaction was found to be nearly complete after 7 hours. Moving beyond 1:1 ligand:iridium resulted in a decrease in catalytic activity. When 4 equivalents of ligand were added, the result was a complete inhibition of the ortho-CHB of tert-butyl benzoate over a span of 4 hours. This suggests that an increase in the ligand concentration could result in multiple ligations of the catalyst and a species that could be completely inactive. Table 16. Pyridine to iridium ratio impact on reactivity B2pin2, 1.2 mmol [Ir(µ-OMe)(cod)]2 1 mol% 3y 0-8 mol % THF, 70 °C O O-t-Bu Bpin O O-t-Bu 1.0 mmol % conversiona [3y]:[Ir] 0:1 0.5:1 1:1 2:1 4:1 3h 2 54 65 <1 <1 5h 5 71 82 5 <1 7h 7 76 90 47 <1 a) Conversions determined by GC/FID relative to the ester 73 To determine the rate-determining step, Dmitry Shabashov performed a kinetic isotope effect (KIE) study. He made the deuterated versions of cyclopropyl phenylketone for the study. He found that the intermolecular KIE was 1.8 (Scheme 37). Scheme 37. Intermolecular Kinetic Isotope Effects of CHB on Cyclopropyl Phenylketone Reaction performed by Dmitry Shabashov The intramolecular KIE was found to be 1.5 (Scheme 38). These KIE values are inconsistent with C-H activation being the rate-determining step. Previously it has been shown that KIE values of 3.5 to 6.7 indicate C-H bond cleavage being the rate- determining step.118 As a result of this discrepancy, it is quite possible that this CHB system is the first CHB with a definitively different rate-determining step in its mechanism. While other C-H functionalization techniques such as C-H silylation or arylation have different catalyst systems in place that proceed through differing mechanisms this is less common in CHB. 74 Scheme 38. Intramolecular kinetic isotope effects of CHB on cyclopropyl phenylketone Reaction performed by Dmitry Shabashov An effort was made by Dimitry Shabashov to isolate important catalytic intermediates. Mixing trisboryl iridium(III)mesetylene with the monodentate pyridine ligands resulted in different outcomes (Scheme 39). When mixed with 4-(N,N′-dimethyl)- 2-methoxypyridine, the only product observed was that of the C-H borylation on the primary center of the methoxy group. However, when Shabashov, using 4-cyano-2- methoxypyridine, attempted this same experiment no intermolecular borylation of the ligand was observed. This result illustrated why the electron poorer pyridine was the better ligand for ortho CHB. Scheme 39. sp3 CHB of Electron Rich 4-N,N-dimethyl-2-methoxypyridine Performed by Dmitry Shabashov 75 Scheme 40. Competition reactions for ortho CHB of ketones vs esters Several intermolecular competition reactions were performed to determine which substrates performed better for ortho-CHB. It was found that in an intermolecular competition reaction between tert-butyl benzoate and cyclopropyl phenylketone the ketone was borylated 62% compared to only 10% borylation for the ester in 3 hours. Scheme 41. Competition reaction between methyl benzoate and N,N-dimethylbenzamide Performed by Dmitry Shabashov 76 Dimitry Shabashov tested the reaction of the methyl benzoate vs. N,N- dimethylbenzamide. It was found that the combined borylation of the methyl ester was 28% while the borylation of the carbamate was 46% over 10 hours. Scheme 42. Competition of electronically different methyl benzoates Performed by Dmitry Shabashov Lastly, in order to determine the better functionalization to have on the substrate an intermolecular reaction was performed comparing dimethyl isophthalate to methyl 3- (dimethylamino)benzoate. The dimethylisophthalate was found to perform better than the methyl 3-(dimethylamino)benzoate. This test determined if an electron poorer or electron richer ring system would be a better substrate for ortho CHB using pyridine ligands. Similar to other CHBs electron-poor substrates reacted faster for ortho CHB. 77 3.9 Selectivity Dependence on Concentration of the Catalyst While investigating the mechanism of ortho borylation an interesting observation was made. The selectivity of the reaction for ortho borylation was directly related to the catalyst concentration. When lower loadings of catalyst were used, the reaction proceeded with much greater ortho selectivity (Figure 18). p + m : o 30 25 20 15 10 5 0 0 0.01 0.02 0.03 0.04 0.05 [Ir(COD)OMe]2 mols/L a) Reaction conditions: methyl benzoate (0.2 mmol), [L]/[Ir] (1:1), B2pin2 (0.2 mmol), 80 °C, 16 hours. Figure 18. Selectivity vs concentration of catalyst in iridium catalyzed ortho borylation of methyl benzoate. This behavior was seen for both the systems with ligand included as well as when just the precatalyst was used without ligand (Figure 19). However, in comparing figure 78 18 to figure 19, the resulting reaction with 4-cyano-2-methoxy pyridine had less of a change in selectivity than that of the pre-catalyst without ligand. This indicates that the ligand stabilized the ability to perform ortho-borylation even as the catalyst concentrations increase. While it is possible that the increased ortho selectivity is simply due to the equilibrium of a mono-ligated catalyst (3be) and a di-ligated catalyst (3bh) the exact cause of this selectivity has yet to be determined. 45 40 35 30 p + m : o 25 20 15 10 5 0 0 0.01 0.02 0.03 0.04 0.05 [Ir(COD)OMe]2 mols/L a) Methyl benzoate (0.2 mmol), [Ir(OMe)cod]2 (0.0025M-0.04M), B2pin2 (0.2 mmol), THF(0.4 mL), 80 °C, 16 hours. Figure 19. Selectivity of ortho-Borylation of Methyl Benzoate With no Added Ligand 79 3.10 Combined Mechanism for Pyridine Ligated Iridium CHB Scheme 43. Proposed catalytic cycle of py′ ligand ortho borylation The mechanism of the CHB is likely that of a monoligated iridium (III/V) cycle operating with a 14 or 16 electron intermediates as shown in Scheme 43. With additional pyridine the catalyst can be di-ligated to form 3bh. However, loss of a pyridine is needed either before the C-H functionalization step or before coordination of the substrate to the metal center. The addition of excess pyridine can result in the catalyst being shut down 80 through a trispyridyl complex such as 3bk. All attempts to synthesize 3bk as of yet have been unsuccessful. The KIE data from the intramolecular and intermolecular experiments indicate that C-H bond cleavage is likely not the rate-determining step. As of yet the observation of a metal complex with and arene and a hydride on it has not been observed. Initial computational analysis performed by Milton R Smith III and HangYao Wang agrees that the C-H cleavage is likely not the rate-determining step. However, further computational studies, supported with experiments, are needed to help support this initial hypothesis and investigate the rate-determining step. The off-cycle reactions generating meta and para borylation can be limited with a reduction of the catalyst loading. This suggests that a possible aggregation or nanoparticle formation of iridium is leading to the side products and further increases in selectivity could be generated through isolating the catalyst on a solid support. 3.11 Pyridine Ligands for ortho CHB Conclusions A method for the ortho-borylation of C-H bonds on aryl esters, ketones and amides has been developed utilizing a variety of commercially available ligands. The tuneability of these ligands has been demonstrated based on electronic and steric factors. The reaction mechanism has been probed, however, further questions regarding the mechanism remain an area for future research. 81 Chapter 4. Experimental 4.1 General Considerations Tetrahydrofuran was distilled from sodium benzophenone ketyl. All other solvents were used as received unless specifically stated. All commercially available materials were used as received unless otherwise stated. All arenes and heteroarenes were purchased unless specifically stated. 1H and 13C NMR spectra were recorded on a Varian VXR-500 or Varian Unity-500-Plus spectrometers (499.74 and 125.67 MHz, respectively) and referenced to residual solvent signals. 11B spectra were recorded on Varian VXR-500 operating at 160.41 MHz. Crystal Structures were obtained on a Bruker APEX-II CCD x-ray diffractometer at 173 K during the acquisition. Olex2 was used to solve the structures using ShelXS for the structure solution program with direct methods used for the solution method. The refinement was done using least squares minimization method. GC-FID was taken on an Agilent 7890A GC. High resolution mass spectra (HRMS) was obtained at the Michigan State University Mass Spectroscopy Service Center. 82 4.2 Experimental Information for Chapter 2 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)piperidin-1-ium bromide(2b): 2-Bromo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (142 mg, 0.5 mmol), 5% Rh/C (25 mg), and a stir bar were loaded into a 300 mL pressure vessel. Ethanol (5 mL) was added and the reactor was sealed and pressurized with hydrogen gas (700 psi). After 16 hours the reactor was opened and filtered through Celite and washed with methanol (3 X 5 mL) the solvent was removed under vacuum to yield a white solid (143 mg, 98% yield) with a m.p. of 198-199°C. 1H NMR (500 MHz, D2O) δ 3.37 – 3.21 (m, 1H), 2.89 (td, J = 12.5, 3.2 Hz, 1H), 2.70 (dd, J = 12.6, 3.2 Hz, 1H), 1.91 (dtd, J = 17.4, 4.7, 4.2, 2.2 Hz, 1H), 1.88 – 1.70 (m, 2H), 1.70 – 1.56 (m, 2H), 1.56 – 1.37 (m, 1H), 1.17 (s, 12 H). 13C NMR (126 MHz, D2O) δ 75.55, 44.52, 24.28, 23.65, 22.53, 22.04. 11B NMR (160 MHz, D2O) δ 28.42. HRMS (ESI) m/z calcd. for C11H23B1N1O2 [M-Br]+ 212.1822 ound. 212.1819 There are 3 idenitfiable impurities that appear in the NMR spectrum. Ethanol had a quartet at 3.63 and a triplet at 1.15 which corresponds to 2.5% of the spectrum based on their integration. Piperdinium bromide has one distinguishable peak as a triplet at 2.9 that corresponds to 6.75% of the spectrum. Lastly, acetone has a singlet at 2.17 that corresponds to 1.1% of the spectrum. Three other impurity peaks are unidentified at 3.25 ppm (t), 2.29 ppm (t) as well as 1.28 ppm (s) which may be a pinacol boronate but is not confirmed. 83 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)piperidin-1-ium bromide(2c): 3-Bromo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (142 mg, 0.5 mmol), 5% Rh/C (25 mg), and a stir bar were loaded into a 300 mL pressure vessel. Ethanol (5 mL) was added and the reactor was sealed and pressurized with hydrogen gas (700 psi). After 16 hours the reactor was opened and filtered through Celite and washed with methanol (3 X 5 mL) the solvent was removed under vacuum to yield a white solid (134 mg, 94% yield) with a m.p. of 154-156°C. 1H NMR (500 MHz, D2O) δ 3.43 – 3.31 (m, 2H), 3.00 – 2.89 (m, 2H), 1.91 – 1.82 (m, 2H), 1.79 – 1.69 (m, 1H), 1.69 – 1.58 (m, 1H), 1.53 – 1.31 (m, 1H), 1.18 (s, 12H). 13C NMR (126 MHz, D2O) δ 75.55, 45.90, 44.43, 44.26, 23.63, 23.42, 22.79, 22.10, 21.37. 11B NMR (160 MHz, D2O) δ 30.84. HRMS (ESI) m/z calcd. for C11H23B1N1O2 [M-Br]+ 212.1822 Found, 212.1826. This compound was isolated as a mixture of the product 2c with the deborylated piperdinium bromide in a 4:1 ratio based on the integration of the most downfield peaks for the compounds. The distinguishable signal for the piperdinium bromide was a multiplet from 3.02 – 2.96 which correspond to the 4 hydrogens adjacent to the nitrogen. There was also a significant boronate singlet at 1.26 ppm that correlated to an 8:1 ratio of 2c pinacol vs boronate pinacol. 84 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine(2d′′′′)119: In a nitrogen filled glove box a Schlenk flask (25 mL) was loaded with bis(1,5- cyclooctadiene)di-μ-methoxydiiridium(I) (9.9 mg, 0.015 mmol), di-tert-butyl bipyridine (8 mg, 0.03 mmol) and pinacol borane (1.778g, 14 mmol). The flask was loaded with a stir bar and 2,6-dichloropyridine (1.47g, 10 mmol). The flask was capped with a septa, removed from the glove box and the solution was stirred for 14 hours at room temperature. After 14 hours the reaction was opened and the solvent removed by rotatory evaporation. Purification via a short silica plug (dichloromethane) and evaporation of solvent yielded a white solid (2.158g, 79% yield). All data matched reported literature spectra.119 1H NMR (500 MHz, CDCl3) δ 7.58 (s, 2H) 1.34 (s, 12H) 11B NMR (160 MHz, CDCl3) δ 29.45. A small water impurity peak was observed in the spectra at 1.56 ppm. 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)piperidin-1-ium chloride(2d): 2,6-Dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (137 mg, 0.5 mmol), 5% Rh/C (25 mg), and a stir bar were loaded into a 300 mL pressure vessel. Ethanol (5 mL) was added and the reactor was sealed and pressurized with hydrogen gas 85 (700 psi). After 16 hours the reactor was opened and filtered through Celite and washed with methanol (3 X 5 mL) the solvent was removed under vacuum to yield a white solid (94 mg, 76% yield) with a m.p. of 149-150.5°C. In water or deuterium oxide the pinacol would hydrolyze off leaving 4-boronopiperidin-1-ium chloride. Characterization based on the mixture of 2d and the hydrolyzed biproduct. 1H NMR (500 MHz, D2O) δ 3.19 (ddt, J = 24.0, 12.8, 3.7 Hz, 2H), 2.93 – 2.73 (m, 2H), 1.77 (dt, J = 14.9, 3.7 Hz, 2H), 1.52 (ddq, J = 15.0, 7.1, 3.9 Hz, 2H), 1.12 (s, 7H) 1.05(s, 6H) 13C NMR (126 MHz, D2O) δ 87.46, 46.99,, 26.10, 25.65. 11B NMR (160 MHz, D2O) δ 31.54. HRMS (ESI) m/z calcd. for C11H23B1N1O2 [M-Cl]+ 212.1822 Found. 212.1832. In water or deuterium oxide a slow conversion from one singlet peak at 1.05 converts to 1.12. This is a hydrolysis from the pinacol ester to the boronic acid. The impurity peak at 3.13 representing the deborylated piperdinium chloride remained unchanged at 5 % of the sample when the number of protons is taken into account. Shown below is a spectrum of pinacol taken in D2O that has 1 signal at 1.12 ppm. 86 Figure 20. 400 MHz 1H-NMR of pinacol in D2O 2-bromo-6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine2(2e′′′′): In a nitrogen filled glove box a Schlenk flask (25 mL) was loaded with Bis(1,5- cyclooctadiene)di-μ-methoxydiiridium(I) (36 mg, 0.055 mmol), di-tert-butyl bipyridine(32 mg, 0.12 mmol), pinacol borane (1.90 g, 15 mmol) an tetrahydrofuran (10 mL). The flask was loaded with a stir bar and 2-bromo-6-methylpyridine (1.70 g, 10 mmol). The flask was closed up, removed from the glove box, connected to a Schlenk line and placed in an oil bath. The reaction solution was stirred for 24 hours at 70 °C. 87 After 24 hours the reaction flask was opened and the solvent removed by rotary evaporation. Purification via a short silica plug (dichloromethane) and evaporation of solvent yielded a tan solid (2.55g, 86% yield) 1H NMR (500 MHz, CDCl3) δ 7.62 (s, 1H), 7.43 (s, 1H), 2.52 (s, 3H), 1.33 (s, 12H). 13C NMR (126 MHz, CDCl3) δ 159.41, 141.42, 129.93, 127.05, 84.76, 24.82, 23.96. 11B NMR (160 MHz, CDCl3) δ 29.76. Characterization data matched literature precedent.120 Cis-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)piperidin-1-ium bromide(2e): 2-Bromo-6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (85mg, 0.3 mmol), 5% Rh/Al2O3 (25 mg), and a stir bar were loaded into the pressure vessel. Ethanol (5 mL) was added and the reactor was sealed and pressurized with hydrogen gas (700 psi). After 16 hours the reactor was opened and filtered through Celite and washed with methanol (3 X 5 mL) the solvent was removed under vacuum to yield a tan solid (86 mg, 98% yield) with a m.p. of 209-211 °C. 1H NMR (500 MHz, D2O) δ 3.23 (ddd, J = 12.7, 4.2, 2.2 Hz, 1H), 2.99 (dqd, J = 12.9, 6.1, 2.7 Hz, 1H), 2.77 (td, J = 13.0, 3.3 Hz, 1H), 1.87 – 1.67 (m, 2H), 1.38 (dtd, J = 14.5, 13.2, 4.1 Hz, 1H), 1.26 – 1.15 (m, 1H), 1.10 (d, J = 2.1 Hz, 3H), 1.03 (s, 12H). 13C NMR (126 MHz, D2O) δ 75.54, 53.35, 45.09, 31.70, 23.64, 23.58, 23.15, 18.70. 11B NMR (160 MHz, D2O) δ 30.77. HRMS (ESI) m/z calcd. for C12H25B1N1O2 [M-Br]+ 226.1978; Found. 226.1986. A crystal structure was 88 obtained for this compound. Two impurities in the spectra were found and identified. Ethanol has a quartet at 3.65, and a triplet at 1.15 and integrates to 5% of the spctra. Acetone was found with a singlet at 2.20 which integrates to <1% in comparison to 2e. 2,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)piperidine(2f): 2,6-Dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (117 mg, 0.5 mmol), 5 % Rh/Al2O3 (50 mg), and a stir bar were loaded into the pressure vessel. Ethanol (5 mL) was added and the reactor was sealed and pressurized with hydrogen gas (700 psi). After 16 hours the reactor was opened and filtered through Celite and washed with methanol (3 X 5 mL) the solvent was removed under vacuum to yield yellow solid (100 mg, 85% yield). The compound was isolated as an incomplete hydrogenation of starting material. 1H NMR (500 MHz, CDCl3) δ 2.68 – 2.58 (m, 2H), 1.67 (d, J = 3.4 Hz, 2H), 1.35 (s, 1H), 1.23 (d, J = 6.2 Hz, 12H), 1.05 (d, J = 6.3 Hz, 6H), 0.96 (td, J = 12.9, 10.6 Hz, 2H). 11B NMR (160 MHz, CDCl3) δ 33.87. HRMS (ESI) m/z calcd. for C13H27B1N1O2 [M+H]+ 240.2135; Found. 240.2131. 2,6-Dimethyl-4-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)pyridine starting material peaks were found in the spectra at 7.30, 2.51, and 1.35 which integrate to 9.9 % of the isolated mixture. The Proton for the N-H peak was not observed. 89 tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrole-1-carboxylate (2g′′′′): In a nitrogen filled glove box a round bottom flask (50 mL) was loaded with bis(1,5- cyclooctadiene)di-μ-methoxydiiridium(I) (19.6 mg, 0.03 mmol, 0.5 mol %), di-tert-butyl bipyridine(15.8 mg, 0.058 mmol, 1 mol %), bis(pinacolato)diboron (1.58 g, 6.22 mmol), tetrahydrofuran (10 mL) and a stir bar. To this mixture was added N-Boc-pyrrole (1.67 mL, 10 mmol). The mixture was placed in an oil bath and the mixture was stirred for 16 hours at 55 °C. The reaction mixture was cooled, the THF was removed via rotary evaporation and the residue was passed through a silica plug (DCM) to yield a white solid (2.13g, 73% yield). 1H-NMR matched reported data.121 tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolidine-1-carboxylate (2g): tert-Butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrole-1- carboxylate (142 mg, 0.5 mmol), 10 % Pd/C (15 mg), and a stir bar were loaded into a 300 mL pressure vessel. Ethanol (5 mL) was added and the reactor was sealed and 90 pressurized with hydrogen gas (700 psi). After 16 hours the reactor was opened and the reaction mixture was filtered through Celite and washed with methanol (3 X 5 mL). The solvent was removed under vacuum to yield a clear oil (131 mg, 91% yield). 1H NMR (500 MHz, CDCl3, ppm) δ 3.49 (dt, J = 19.4, 9.7 Hz, 2H), 3.30 - 3.06 (m, 2H), 2.05 – 1.93 (m, 1H), 1.86 – 1.70 (m, 1H), 1.62 – 1.51 (m, 1H), 1.44 (s, 9H), 1.23 (d, J = 6.4 Hz, 12H) 13C NMR (126 MHz, CCDl3) δ 154.56, 83.44, 78.82, 47.96, 47.77, 46.82, 46.46, 28.57, 28.23, 27.51, 24.72.11B NMR (160 MHz, cdcl3) δ 33.62. δ HRMS (ESI) m/z calcd. for C15H28BNO4Na [M+Na]+ 320.2009; Found 320.2000 11 carbon resonances appear as the rotomomers show differing carbon resonances at room temperature for the pyrrolidine ring only. The carbon peaks were found to be 3 carbon reasonances for the boc group, 2 for the pinacol and 6 visible reasonances for the pyrrolidine. The carbon connected to the boron is not visible in the spectra. 4,4,5,5-tetramethyl-2-(5-methylfuran-2-yl)-1,3,2-dioxaborolane(2h′′′′): In a nitrogen filled glove box a round bottom flask (25 mL) was loaded with bis(1,5- cyclooctadiene)di-μ-methoxydiiridium(I) (9.9 mg, 0.015 mmol, 0.3 mol %), di-tert-butyl bipyridine(8.0 mg, 0.03 mmol, 0.6 mol %), bis(pinacolato)diboron(1.3 g, 5.1 mmol) and a stir bar. The RB was closed with a septa and removed from the glove box. 2- Methylfuran (5 mL) was added to the reaction mixture via syringe. The solution was stirred at room temperature for 3 hours. The reaction was opened up to air, and excess 2- methylfruan was removed in-vacuuo. The residual oil was passed through a silica column (EtoAc:Hexanes 5:95) to yield a white solid (1.5g, 72% yield). Spectra matched reported 91 data from literature.122 1H NMR (500 MHz, CDCl3) δ 6.98 (d, J = 3.2 Hz, 1H), 6.03 (dd, J = 3.2, 1.0 Hz, 1H), 2.86 (s, 3H), 1.33 (s, 12H). 4,4,5,5-tetramethyl-2-(5-methyltetrahydrofuran-2-yl)-1,3,2-dioxaborolane(2h): 4,4,5,5-Tetramethyl-2-(5-methylfuran-2-yl)-1,3,2-dioxaborolane (208 mg, 1 mmol), 10% Pd/C (25 mg), and a stir bar were loaded into the liner of a 300 mL pressure reactor. Ethanol (5 mL) was added and the reactor was sealed and pressurized with hydrogen gas (700 psi). After 16 hours the reactor was opened and the reaction mixture was filtered through Celite and washed with methanol (3 X 5 mL). The solvent was removed under vacuum to yield a clear oil (165 mg, 78% yield). 1H NMR (500 MHz, CDCl3) δ 3.83 (m, 1H) 3.48 (m, 1H) 2.06-1.92 (br m, 1H) 1.83-1.75 (m, 1H) 1.44-1.34(m, 1H) ,1.30-1.25 (br s, 13H) 1.25-1.20 (m, 3H) 11B NMR (160 MHz, CDCl3) δ 32.63. The compound is not very stable in CDCl3. Some boronate impurities are found in the boron NMR that was taken after the proton NMR. 4,4,5,5-tetramethyl-2-(tetrahydrofuran-2-yl)-1,3,2-dioxaborolane (2i): 2-(Furan-2-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (194 mg, 1 mmol), 10% Pd/C (25 mg), and a stir bar were loaded into a glass liner in a 300 mL pressure reactor. Ethanol (5 92 mL) was added and the reactor was sealed and pressurized with hydrogen gas (700 psi). After 16 hours the reaction mixture was filtered through Celite and washed with methanol (3 X 5 mL). The solvent was removed under vacuum to yield a clear oil (145 mg, 73% yield). 1H NMR (500 MHz, CDCl3) δ 3.81 (td, J = 7.8, 5.9 Hz, 1H), 3.60 – 3.41 (m, 2H), 1.91 – 1.72 (m, 2H), 1.63 – 1.52 (m, 1H), 1.46 (dqd, J = 11.9, 8.1, 5.9 Hz, 1H), 1.00 (d, J = 2.2 Hz, 12H). δ 11B NMR (160 MHz, C6D6) δ 32.6 All spectra matched previously reported literature data.123 Cis-4,4,5,5-tetramethyl-2-(-octahydrobenzofuran-2-yl)-1,3,2-dioxaborolane (2l): 2-(Benzofuran-2-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (122 mg, 0.5 mmol), 5% Rh/C (50 mg), and a stir bar were loaded into a glass liner in a 300 mL pressure reactor. Ethanol (10 mL) was added and the reactor was sealed and pressurized with hydrogen gas (700 psi). After 24 hours the reaction mixture was filtered through Celite and washed with ethanol (3 X 5 mL). The solvent was removed under vacuum to yield a clear oil (103 mg, 81% yield) 1H NMR (500 MHz, C6D6) δ 3.88 (dd, J = 11.1, 6.9 Hz, 1H) 3.67 (q, J = 3.8 Hz, 1H) 2.15-2.05 (m, 2H) 1.83-1.77 (m, 1H) 1.77-1.72 (m, 2H) 1.58-1.52 (m, 1H) 1.52-1.43 (m, 3H) 1.33-1.27 (m, 1H) 1.13-1.06 (m, 1H) 1.05 (s, 6H) 1.04 (s, 6H) 13C NMR (126 MHz, CD3OD) 83.7, 78.4, 38.0, 33.9, 27.8, 27.7 23.9, 23.6, 23.5 20.4 δ 11B NMR (160 MHz, C6D6) δ 32.4. The methyl NMR signals from the pinacol became inequivolent and different signals were seen in both the proton and the carbon spectra. The carbon bound to boron signal was not seen by 13C-NMR. 93 Assignment of stereochemistry By gCOSY the multiplet at 2.15-2.05 was 2 distinct protons that did not show correlation to eachother. The proton at 3.88 has a correlation with protons at 2.08 and 1.75. This indicates that 3.88 is Ha from Figure 20 as it only has a correlation to 2 other protons. As a result Hb is the other downfield proton at 3.67. Hb was found to correlate to protons at 2.12, 1.80 and 1.50. These are He, Hh and Hi. The proton at 2.12 did not have a correlation to 1.80. While 1.80 and 1.50 correlated to eachother. These correlations indicats that 2.12 is the proton assigned as He and protons at 1.80 and 1.50 are Hh and Hi. Based on the 1D-NOE data the excitation of Ha resulted in a NOE to protons at 3.67 (Hb), 2.12ppm(He) and 1.75 ppm(Hd or c). Interestingly enough there was an inverse correlation to the proton at 2.05 (Hd or c). This indicated that the protons Hb and He were all on the same face of the ring fused molecule. To further confirm this NOE date when Hb was excited showed NOE to 3.88 (Ha) as well as 2.12 94 Figure 21. gCOSY of compound 2l 95 Figure 22. NOE between protons on 2l showing cis stereochemistry 3.9ppm irradiated 96 Figure 23. NOE between protons on 2l showing cis stereochemistry 3.7ppm irradiated 2-cyclohexyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2o): 4,4,5,5-Tetramethyl-2-phenyl-1,3,2-dioxaborolane (2-4 mg, 1 mmol), 5% Rh/C (25 mg), and a stir bar were loaded into the pressure vessel. Ethanol (5 mL) was added and the reactor was sealed and pressurized with hydrogen gas (700 psi). After 16 hours the reactor was opened and the contents were filtered through Celite and washed with 97 methanol (3 X 5 mL). The solvent was removed under vacuum to yield a clear oil (208 mg, 99% yield). All spectral data matched literature data.124 1H NMR (500 MHz, CDCl3) δ 1.71 – 1.52 (m, 5H), 1.40 – 1.25 (m, 5H), 1.23 (s, 12H), 0.98 (tt, J = 10.1, 2.8 Hz, 1H). 13C NMR (126 MHz, CDCl3) δ 82.72, 27.95, 27.13, 26.75, 24.74. 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohexan-1-ol (2p) 3-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (110 mg, 0.5 mmol), 5 % Rh/C (25 mg), and a stir bar were loaded into the pressure vessel. Ethanol (5 mL) was added and the reactor was sealed and pressurized with hydrogen gas (700 psi). After 16 hours the reactor was opened and the contents were filtered through Celite and washed with methanol (3 X 5 mL). The solvent was removed under vacuum to yield a clear oil (90.4 mg, 80% yield). 1H NMR (500 MHz, CD3OD) δ 3.82 – 3.37 (m, 1H), 1.95 – 1.83 (m, 1H), 1.83 – 1.69 (m, 1H), 1.66 – 1.57 (m, 1H), 1.57 – 1.54 (m, 1H), 1.48 – 1.27 (m, 3H), 1.23 (d, J = 4.9 Hz, 12H), 1.13 – 0.99 (m, 1H), 0.97 – 0.85 (m, 1H). 13C NMR (126 MHz, CD3OD) δ 83.00 (d, J = 7.8 Hz) 82.72, 70.56, 67.70, 36.24, 35.30, 35.05, 34.19, 27.62, 26.87 – 26.22 (m), 25.58, 23.73 (dd, J = 5.0, 3.0 Hz), 22.66. 11B NMR (160 MHz, CD3OD) δ 33.86. HRMS (APCI-) m/z calcd. for C12H22BO3 [M-H]- 225.1662; Found. 225.1655. Isomer ratios determined by comparison of 2 separate signals at 3.6 and 3.4 98 respectively. These proton signals combine to form 1H and they are in a 5:4 ratio. It is assumed that the major product is the cis stereochemical projuct based on the history of hydrogenation chemistry. However, specific evidence was not gathered for this compound. 4,4,5,5-tetramethyl-2-(-3-(trifluoromethyl)cyclohexyl)-1,3,2-dioxaborolane (2q): 4,4,5,5-Tetramethyl-2-(3-(trifluoromethyl)phenyl)-1,3,2-dioxaborolane (136 mg, 0.5 mmol), 5% Rh/C (25 mg), and a stir bar were loaded into the pressure vessel. Ethanol (5 mL) was added and the reactor was sealed and pressurized with hydrogen gas (700 psi). After 16 hours the reactor was opened and the contents were filtered through Celite and washed with methanol (3 X 5 mL). The solvent was removed under vacuum to yield a clear oil (121 mg, 87 % yield). Both cis and trans diastereomers were seen via 19F-NMR in a 3:1 cis to trans ratio. 1H NMR (500 MHz, CDCl3) δ 2.06 – 1.70 (m, 6H), 1.47 – 1.32 (m, 1H), 1.32 – 1.07 (m, 22H), 0.91 (tt, J = 12.8, 3.1 Hz, 1H). 13C NMR (126 MHz, CDCl3) δ 127.9 (q, J = 280 Hz, CF3) 83.2, 83.1, 42.5 (q, J = 26.9 Hz), 40.1 (d, J = 26.1 Hz), 26.87, 26.77, 26.1 (q, J = 2.6 Hz), 25.8, 25.02(q, J = 2.2 Hz), 25.00 (q, J = 2.2 Hz), 24.77(d, J = 4.3 Hz), 24.7(d, J = 3.3 Hz), 23.86. 19F NMR (470 MHz, CDCl3) δ -73.63 (d, J = 8.6 Hz), -74.05 (d, J = 8.3 Hz). 11B NMR (160 MHz, CDCl3) δ 34.08. HRMS (AP-) m/z calcd. for C13H21B1O2F3 [M-H]- 277.1587; Found. 277.1583. Isomer ratios were 99 determined from 19F-NMR. 13C NMR peak at 40.1 is likely part of a quartet from the minor isomer that correlates to the quarter at 42.5 CF3 Ha Hb Bpin Hb Ha Figure 24. NOE between the major species of 2q showing cis stereochemistry ethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohexane-1-carboxylate (2r) 100 Ethyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (132 mg, 0.5 mmol), 5% Rh/C (25 mg), and a stir bar were loaded into the pressure vessel. Ethanol (5 mL) was added and the reactor was sealed and pressurized with hydrogen gas (700 psi). After 16 hours the reactor was opened and the contents were filtered through Celite and washed with methanol (3 X 5 mL). The solvent was removed under vacuum to yield a clear oil (129 mg, 96% yield). The reaction was isolated as a mixture of hydrogenated isomers in a 4.7:1 ratio as well as a small amount of starting material remaining. The determination of isomer ratio was found based on 2 quartets at 4.1 (minor) and 4.0 (major). 1H NMR (500 MHz, C6D6) δ 4.04 – 3.94 (m, 2H), 2.36 – 2.19 (m, 2H), 1.98 (dtq, J = 10.7, 3.7, 1.8 Hz, 1H), 1.94 – 1.84 (m, 1H), 1.74 – 1.61 (m, 2H), 1.58 – 1.45 (m, 2H), 1.44 (s, 1H), 1.28 (qd, J = 13.0, 3.5 Hz, 1H), 1.12 (d, J = 14.7 Hz, 2H), 1.06 (d, J = 7.7 Hz, 12H), 0.99 (td, J = 7.2, 4.9 Hz, 3H) 13C NMR (126 MHz, C6D6) δ 175.27, 82.65, 82.45, 82.38, 59.36, 50.53, 50.51, 44.07, 43.04, 42.46, 30.58, 29.73, 28.33, 27.16, 26.95, 26.81, 26.45, 26.22, 24.48, 24.44, 13.92. 11B NMR (160 MHz, C6D6) δ 34.15. HRMS (ES+) m/z calcd. for C15H27B1O4Na [M+Na] 305.1900; Found. 305.1893. All carbon peaks were reported for both isomers. Specific carbon reasonances for each isomer were not deteremined. An unknown aromatic compound with peaks at 8.88 (s), 8.18 (d, J = 8.2Hz) and 8.07 (d, J = 7.3Hz) in a 1:1:1 ratio was found to be at 4% of the sample when compared to the peak at 4.04-3.94 ppm. While this impurity matched the splitting pattern and coupling constant of the starting material, the location of the reasonances does not match. If this was the starting material the only peak that would potentially be visable in the carbon spectra would be the pinacol methyl protons which would make all 21 carbons show up from major isomer, minor and impurity compounds. An unknown impurity signal (potentially 101 water) was found at 0.2 that integrated to 1.9% when compared to the 1H at 4.04-3.94 ppm. A second boron signal was observed at 31.1 ppm that was attributed to the minor isomer. CO2Et Ha Hb Bpin Ha Hb Figure 25. NOE between the major species of 2r showing cis stereochemistry 102 4,4,5,5-tetramethyl-2-(3-methylcyclohexyl)-1,3,2-dioxaborolane (2s) 4,4,5,5-Tetramethyl-2-(m-tolyl)-1,3,2-dioxaborolane (116 mg, 0.5 mmol), 5% Rh/C (25 mg), and a stir bar were loaded into the pressure vessel. Ethanol (5 mL) was added and the reactor was sealed and pressurized with hydrogen gas (700 psi). After 16 hours the reactor was opened and the contents were filtered through Celite and washed with methanol (3 X 5 mL). The solvent was removed under vacuum to yield a clear oil (90 mg, 76% yield) NMR showed both cis and tans diastereomers were present in a 2:1 ratio based on the 2 different doublet signal at 0.91 ppm (minor isomer) compared to the signal at 0.84ppm (major isomer). Combined isomer peak shifts 1H NMR (500 MHz, C6D6) δ 2.16 – 2.07 (tm, 1H J = 13.7 Hz), 1.92 (tm, J = 11.9 Hz, 1H), 1.74 – 1.35 (m, 2H), 1.34 – 1.10 (m, 2H), 1.02 (d, J = 3.5 Hz, 12H), 0.98 – 0.76 (m, 4H). 13C NMR (126 MHz, C6D6) δ 82.45, 82.22, 36.75, 36.20, 35.43, 35.31, 33.50, 31.28, 27.65, 27.56, 27.48, 25.42, 24.55, 24.53, 24.50, 23.03, 22.68. 11B NMR (160 MHz, C6D6) δ 34.17. Assignable peaks for major isomer: 1H NMR (500 MHz, C6D6) δ 1.96 (tm, J = 11.5Hz), 0.88 (d, J = 6.5 Hz) Assignable peaks for minor isomer: 1H NMR (500 MHz, C6D6) δ 2.12 (tm, J = 13.7Hz), 0.96 (d, J = 6.5 Hz) “tm” - triplet of multiplets. HRMS (AP-) m/z calcd. for C14H28B1O3 [M+OMe]- 255.2132; Found. 255.2133. 103 Ha Hb Ha B O Hb O Figure 26. NOE between the major species of 2s showing cis stereochemistry 2-(-3-methoxycyclohexyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(2t) 2-(3-Methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (117 mg, 0.5 mmol), 5% Rh/C (25 mg), and a stir bar were loaded into the pressure vessel. Ethanol (5 mL) was added and the reactor was sealed and pressurized with hydrogen gas (700 psi). After 16 hours the reactor was opened and the contents were filtered through Celite and washed with methanol (3 X 5 mL). The solvent was removed under vacuum to yield a clear oil 104 (103 mg, 86% yield) 1H-NMR showed 2 diastereomers in a 4.5:1 ratio based on the integrations of the methoxy groups at 3.14. 1H NMR (500 MHz, C6D6) δ 3.14 (s, 3H), 2.96 (tt, J = 9.7, 3.9 Hz, 1H), 2.21 (d, J = 12.5 Hz, 1H), 1.92 – 1.85 (m, 1H), 1.85 – 1.67 (m, 2H), 1.62 (s, 2H), 1.54 – 1.41 (m, 1H), 1.41 – 1.23 (m, 2H), 1.15 (tddd, J = 13.0, 10.1, 6.0, 2.4 Hz, 1H), 1.02 (s, 12H). 13C NMR (126 MHz, CDCl3) δ 82.87, 82.66, 79.90, 55.49, 55.47, 32.75, 32.28, 27.90, 27.08, 27.04, 26.94, 26.70, 25.57, 24.74, 24.69, 24.64. 11B NMR (160 MHz, C6D6) δ 33.86. HRMS (ESI+) m/z calcd. for C13H25B1O3Na [M+Na]+ 263.1794; Found. 263.1806. The exact peaks were not possible to be separated in the 1H- NMR spectra due to overlapping signals. Signals in the carbon NMR were not determined to which isomer they corresponded. Major product found to be the cis isomer based on 1D-NOE spectra below. Difinitive major isomer distinguishable peaks were found at 3.14 (s) 2.96 (tt, J = 9.7, 3.9 Hz). Minor isomer signals were found at 3.30-3.24 (m) and 3.16 (s). 105 Hc Hc’ Ha Hb MeO Bpin Ha HC Hb Figure 27. NOE between the major species of 2t showing cis stereochemistry 2-(Trimethylsilyl)piperidin-1-ium (+)-camphorsulfonate (2u) 4,4,5,5-Tetramethyl-2-(m-tolyl)-1,3,2-dioxaborolane (1.51g, 10 mmol), 5% Rh/C (200 mg), (+) camphor sulfonic acid (2.32 g, 10 mmol), and a stir bar were loaded into the pressure vessel. Ethanol (20 mL) was added and the reactor was sealed and pressurized with hydrogen gas (700 psi). After 24 hours the reactor was opened and the contents were 106 filtered through Celite and washed with methanol (3 X 5 mL). The solvent was removed under vacuum to yield a clear oil (3.65 g, 95% yield) 1H NMR (500 MHz, CDCl3) δ 8.11 (m, 2H), 3.59 (t, J = 11.5 Hz, 1H), 3.28 (d, J = 14.7 Hz, 1H), 3.19 (q, J = 5.2 Hz, 1H), 3.10 – 2.92 (m, 1H), 2.78 (d, J = 14.7 Hz, 1H), 2.65 (ddd, J = 14.9, 11.6, 4.0 Hz, 1H), 2.58 – 2.45 (m, 1H), 2.32 (ddd, J = 18.2, 4.8, 3.2 Hz, 1H), 2.08 – 1.93 (m, 3H), 1.89 (s, 1H), 1.85 – 1.76 (m, 2H), 1.76 – 1.60 (m, 2H), 1.47 – 1.32 (m, 3H), 1.09 (s, 3H), 0.84 (s, 3H), 0.18 (d, J = 5.2 Hz, 9H).13C NMR (126 MHz, CDCl3) δ 216.72, 58.45, 48.10, 48.08, 47.87, 47.32, 47.13, 47.10, 44.69, 42.92, 42.67, 27.00, 26.89, 24.75, 24.70, 24.61, 23.80, 23.77, 22.52, 22.48, 20.01, 19.85, -3.46. HRMS (ESI+) m/z calcd. for C8H20N1Si1 [M- Camphorsulfonate]+ 158.1365; Found. 158.1366. Ion pairing with the (+)- camphorsulfonate resulted in seeing both R and S isomers of the 2- trimethylsilylpiperidine being distinct from eachother in the proton NMR. This differenciation in the carbon NMR results in seeing up to 12 reasonances from the piperdinium an 20 reasonances from the camphorsulfonate. However, the TMS group is distinctly 1 signal by carbon NMR which indicates that some or many carbon signals fall on top of echother in the spectra. There is a signal at 8.6 that is in the region of a separate NH peak which integrates to 0.45 to the NH2 of the piperdinium sulfonate of the product. At first it was thought that this signal was from de-silylated piperdinium camphorsulfonate, however the upfield reasonances that should correspond to this signal were not seen. As such it is unknown what that peak is. 107 2-(Trifluoromethyl)-5-(trimethylsilyl)piperidin-1-ium chloride(2v) 2-(Trifluoromethyl)-5-(trimethylsilyl)pyridine (110 mg, 0.5 mmol), 5% Rh/C (25 mg), and a stir bar were loaded into the pressure vessel. Ethanol (5 mL) was added and the reactor was sealed and pressurized with hydrogen gas (700 psi). After 16 hours the reactor was opened and the contents were filtered through Celite and washed with methanol (3 X 5 mL). The solvent was removed under vacuum to yield a white solid (111 mg, 99% yield). 1H NMR (500 MHz, D2O) δ 4.13 (qdd, J = 8.8, 6.1, 2.5 Hz, 1H), 3.89 (dqd, J = 13.3, 6.7, 3.2 Hz, 1H), 3.52 – 3.35 (m, 1H), 3.26 (dd, J = 13.3, 4.2 Hz, 1H), 2.98 (dtd, J = 22.5, 13.3, 2.3 Hz, 2H), 2.12 – 2.00 (m, 2H), 1.92 – 1.75 (m, 2H), 1.68 – 1.31 (m, 4H), 1.11 – 0.97 (m, 1H), -0.12 (s, 9H).13C NMR (126 MHz, D2O) δ 127.7 (q, J = 140 Hz), 58.95, 58.70, 53.86 (q, J = 30.4 Hz), 47.64, 46.14, 23.99, 23.98, 23.81, 23.60, 23.17, 22.65, 20.23, -2.37, -2.56. 19F NMR (470 MHz, D2O) δ Major: -68.50 (d, J = 8.8 Hz), -75.53 (d, J = 6.6 Hz), Minor: -75.47 (d, J = 6.7 Hz), -75.75 (d, J = 6.6 Hz). HRMS (ESI+) m/z calcd. for C9H19N1Si1F3 [M-Cl]+ 226.1239; Found. 226.1237. A small amount of ethanol was present in the spectra clearly visible in the proton and carbon spectra. The ratio between the trimethylsilane signal and the piperdinium C-H signals is not correct which indicates that either the de-silylated product is present in significant quantity or silicate clusters have formed. 3-(Benzofuran-2-yl)-1,1,1,3,5,5,5-heptamethyltrisiloxane (2w′′′′) 108 In a nitrogen filled glove box a Schlenk flask (100 mL) was filled with 2,3 benzofuran (1.18g, 10 mmol), bis(trimethylsiloxy)methylsilane (2.44g, 11 mmol) norborene (941mg, 10 mmol), [Ir(OMe)cod]2 (74 mg, 1.1 mol %), dtbpy (62 mg, 2.4 mol %), THF (10 mL), and a stir bar. The flask was closed with a septa and removed from the glove box. The reaction mixture was heated at 80°C for 24 hours. The reaction was stopped, and the solvent removed by rotary evaporation. The residue was purified by column chromatography (hexanes:ethyl acetate 95:5) to yield a clear colorless oil (2.41g, 71% yield). 1H NMR values matched literature precedent.125 1H NMR (500 MHz, CDCl3) δ 7.66 (dd, J = 8.0, 1.9 Hz, 1H), 7.62 – 7.55 (m, 1H), 7.36 (m, 1H), 7.27 (m, 1H), 7.09 (dt, J = 2.3, 1.0 Hz, 1H), 0.46 – 0.41 (m, 3H), 0.25 – 0.16 (m, 18H). 3-(2,3-Dihydrobenzofuran-2-yl)-1,1,1,3,5,5,5-heptamethyltrisiloxane(2w) 3-(Benzofuran-2-yl)-1,1,1,3,5,5,5-heptamethyltrisiloxane (169 mg, 0.5 mmol), 10% Pd/C (20 mg), and a stir bar were loaded into the pressure vessel. Ethanol (10 mL) was added and the reactor was sealed and pressurized with hydrogen gas (700 psi). After 16 hours the reactor was opened and the contents were filtered through Celite and washed with methanol (3 X 5 mL). The solvent was removed under vacuum to yield a clear oil (154 mg, 91% yield) 1H NMR (500 MHz, C6D6) δ 7.00 (dd, J = 7.3, 1.3 Hz, 1H), 6.97 – 6.89 109 (m, 1H), 6.86 – 6.78 (m, 1H), 6.73 (td, J = 7.3, 1.0 Hz, 1H), 4.10 (t, J = 11.1 Hz, 1H), 3.11 (ddt, J = 15.0, 11.4, 1.0 Hz, 1H), 2.99 (dd, J = 14.9, 10.8 Hz, 1H), 0.17 (d, J = 4.1 Hz, 3H), 0.11 (s, 9H), 0.05 (s, 9H). 13C NMR (126 MHz, C6D6) δ 161.23, 127.81, 127.55, 124.70, 119.98, 109.55, 74.95, 31.10, 1.49, 1.41, -2.91. HRMS (APCI+) m/z calcd. for C15H29O3Si3 [M+H]+ 341.1424; Found. 341.1428. The silane region of the spectra contains an unknown impurity peaks in approximately a 10% level base on protons in the silicon region. It is undetermined what these impurities are but it is likely that in ethanol siloxane polymers were made. There are many other impurities that are not determined. Cis-tert-butyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2- (trimethylsilyl)pyrrolidine-1-carboxylate(2x): tert-Butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trimethylsilyl)-1H-pyrrole- 1-carboxylate (167 mg, 0.5 mmol), 5% Rh/C (25 mg), and a stir bar were loaded into the pressure vessel. Ethanol (5 mL) was added and the reactor was sealed and pressurized with hydrogen gas (700 psi). After 16 hours the reactor was opened and the contents were filtered through Celite and washed with methanol (3 X 5 mL). The solvent was removed under vacuum to yield a white solid (116 mg, 70% yield) with a m.p. of 73.5-75 °C. 1H NMR (500 MHz, CDCl3) δ 3.75 (t, J = 9.5 Hz, 1H), 3.55-3.30 (m, 1H) 3.28-3.10 (m, 1H) 3.10 (q, J = 11.7, 9.7 Hz, 1H), 2.11 (m, 1H), 1.68 – 1.54 (m, 1H), 1.46 (m, 9H), 1.25 (s, 110 12H), 0.07 (s, 9H). 13C NMR (126 MHz, CDCl3) δ 154.4, 83.3, 50.05, 48.58, 31.68, 28.60, 26.89, 24.76, 24.72, -2.04. 11B NMR (160 MHz, C6D6) δ 33.61. Small impurities around 10% are due to tert-Butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H- pyrrole-1-carboxylate which comes from the desilylated compound. There is a peak in the carbon nmr at 78.3 that is impurity. Cyclohexyltriethoxysilane(2y) Triethoxy phenylsilane (123 mg, 0.5 mmol), 5% Rh/C (25 mg), and a stir bar were loaded into the pressure vessel. Hexanes (10 mL) were added and the reactor was sealed and pressurized with hydrogen gas (700 psi). After 16 hours the reactor was opened and the contents were filtered through Celite and washed with Hexanes (3 X 10 mL). The solvent was removed under vacuum to yield a clear oil (103 mg, 84% yield) 1H NMR (500 MHz, CDCl3) δ 3.81 (q, J = 7.0 Hz, 6H), 1.89 – 1.55 (m, 6H), 1.21 (t, J = 7.1 Hz, 16H), 0.79 (tt, J = 12.4, 3.0 Hz, 2H). 13C NMR (126 MHz, CDCl3) δ 58.40, 27.69, 27.66, 26.80, 26.77, 26.68, 22.84, 18.31. 29Si NMR (99 MHz, CDCl3) δ -48.51. 111 (S)-2-Methyl-1-((R)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)piperidin-1- yl)butan-1-one (2za): (S)-2-Methyl-1-((S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)piperidin-1- yl)butan-1-one (2zb) In a 2-dram vial 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)piperidin-1-ium bromide (435 mg, 1.5 mmol) was loaded along with a stir bar and ethyl acetate (10 mL). To this stirred suspension was added (S)-2-methylbutyric anhydride (0.3 mL, 1.5 mmol) followed by 1,8-diazabicyclo[5.4.0]undec-7-ene (0.45 mL, 3 mmol). The reaction mixture was stirred for 30 minutes. The solvent was removed by rotary evaporation. Silica column chromatography (MeOH:EtOAc:hexanes 1:10:89 to 2:20:78) was performed to yield 3 differing solutions across multiple fractions. Upon removal of solvent via rotary evaporation solution A (a clear solid 47.8 mg, 11% yield) contained compound 2za. Fraction B a clear crystalline solid contained a mixture of 2 different components. Fraction C (a white solid, 65.4 mg, 15% yield) contained 2zb. Suitable crystals for x-ray crystallography were obtained by slow evaporation of hexanes of 2za. (S)-2-methyl-1-((R)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)piperidin-1- yl)butan-1-one (2za): 112 1H NMR (500 MHz, C6D6) δ 2.87 (dd, J = 13.1, 4.5 Hz, 1H), 2.34 – 2.24 (m, 1H), 2.16 (td, J = 12.9, 3.2 Hz, 1H), 1.85 – 1.72 (m, 2H), 1.64 – 1.53 (m, 1H), 1.53 – 1.47 (m, 1H), 1.42 (d, J = 8.2 Hz, 12H), 1.11 – 0.93 (m, 3H), 0.90 – 0.77 (m, 1H), 0.76 (d, J = 6.8 Hz, 3H), 0.59 (t, J = 7.4 Hz, 3H). 13C NMR (126 MHz, C6D6) δ 176.32, 79.45, 44.25, 33.16, 27.53, 26.54, 25.98, 25.65, 25.56, 24.51, 16.03, 11.24. 11B NMR (160 MHz, C6D6) δ 13.65. HRMS (ESI+) m/z calcd. for C16H31B1N1O3 [M+H]+ 296.2397; Found. 296.2404. (S)-2-methyl-1-((S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)piperidin-1- yl)butan-1-one (2zb) 1H NMR (500 MHz, C6D6) δ 2.87 (dt, J = 13.0, 2.9 Hz, 1H), 2.30 (dd, J = 12.8, 3.7 Hz, 1H), 2.19 (td, J = 12.9, 3.2 Hz, 1H), 1.85 – 1.74 (m, 2H), 1.58 (dtd, J = 14.1, 12.8, 3.4 Hz, 1H), 1.53 – 1.43 (m, 2H), 1.41 (d, J = 7.1 Hz, 12H), 1.10 – 0.92 (m, 3H), 0.89 – 0.80 (m, 1H), 0.76 (d, J = 6.9 Hz, 3H), 0.60 (t, J = 7.5 Hz, 3H). 13C NMR (126 MHz, C6D6) δ 176.55, 79.51, 74.13, 44.36, 33.33, 27.35, 26.32, 26.08, 25.62, 25.40, 24.82, 24.50, 16.26, 11.23. 11B NMR (160 MHz, C6D6) δ 13.57. HRMS (ESI+) m/z calcd. for C16H31B1N1O3 [M+H]+ 296.2397; Found. 296.2406 Two singlets appear in the spectra of compound 2zb at 2.47 and 1.11 respectively. They are in a 1:6 ratio to eachother and are free pinacol in the sample. Relative to the bound pinacol the free pinacol makes up a 28.4% mol to mol ratio of the sample. 113 4.3 Experimental information for Chapter 3 General procedure for Table 9 In a nitrogen-filled glove box, a 3 mL Wheaton® conical vial was charged with [Ir(OMe)COD]2 (6.6 mg, 0.01 mmol), a monodentate pyridine (0.02 mmol), and bis(pinacolato)diboron (254 mg, 1 mmol). Tetrahydrofuran (2 mL) was added via syringe. A triangular stir bar was added followed by methyl benzoate (126 μL, 1.0 mmol). The conical vial was capped, removed from the glove box and heated to 70 oC for 14 hours. A GC/FID sample was made containing reaction solution (10 μL), 0.5 M naphthalene in ethyl acetate (100 μL) and ethyl acetate (890 μL). The results of the GC/FID were compared to a calibration curve of methyl 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)benzoate. Each ligand tested was run in duplicate. The ortho:(meta+para) ratio was estimated based on the GC/FID integrations. General procedure for Table 10 In a nitrogen filled glove box, a 3 mL Wheaton® conical vial was charged with [Ir(OMe)COD]2 (6.6 mg, 0.01 mmol), a monodentate pyridine (0.02 mmol), and bis(pinacolato)diboron (127 mg, 1 mmol). Tetrahydrofuran (1.5 mL) was added via syringe. A triangular stir bar was added followed by methyl benzoate (126 μL, 1.0 mmol). The conical vial was capped, removed from the glove box and heated to 70 oC for 14 hours. A GC/FID sample was made containing reaction solution (10 μL), 0.5 M naphthalene in ethyl acetate (100 μL) and ethyl acetate (890 μL). The results of the GC/FID were compared to a calibration curve of methyl 2-(4,4,5,5-tetramethyl-1,3,2- 114 dioxaborolan-2-yl)benzoate. Each ligand tested was run in duplicate. The ortho:(meta+para) ratio was estimated based on the GC/FID integrations. Methyl 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (3z)8 “Closed system” - In a nitrogen filled glove box a 3 mL Wheaton® conical vial was charged with [Ir(OMe)COD]2 (6.6 mg, 0.01 mmol), 2-methoxyisonicotinonitrile (2.6 mg, 0.02 mmol) and bis(pinacolato)diboron (305 mg, 1.2 mmol). Tetrahydrofuran (1.5 mL) was added via syringe. A triangular stir bar was added followed by addition of methyl benzoate (126 μL, 1.0 mmol). The conical vial was capped, removed from the glove box and heated to 70 oC for 16 hours. The solution was opened to air and concentrated using a rotary evaporator. Column chromatography (10:90 EtOAc : hexanes) on the residue yielded a clear colorless oil (135 mg, 55% yield). 1H NMR (500 MHz, CDCl3, ppm) δ 7.94 (d, 1H, J = 7.8 Hz) 7.55-7.48 (m, 2H) 7.45-7.40 (m, 1H) 3.92 (s, 3H) 1.43 (s, 12H). Data matched literature reference.126 “Open system” – In a nitrogen filled glove box a 10 mL Schlenk flask was charged with [Ir(OMe)COD]2 (6.6 mg, 0.01 mmol), 2-methoxyisonicotinonitrile (2.6 mg, 0.02 mmol), and bis(pinacolato)diboron (192 mg, 0.77 mmol). Tetrahydrofuran (1.5 mL) was added via syringe. A small stir bar was added to the Schlenk flask followed by addition of methyl benzoate (126 μL, 1.0 mmol) via a microliter syringe. A condenser fitted with 115 septa was attached to the Schlenk flask. The whole apparatus was removed from the glove box and connected to a nitrogen line through a needle inserted into the septa under positive nitrogen flow. An oil bath was used to heat the reaction to 70 oC for 4 hours. Column chromatography (5:95 EtOAc:hexanes) yielded a clear colorless oil (130 mg, 64% yield based on B2pin2, 50% yield based on arene). 1H NMR (500 MHz, CDCl3, ppm) δ 7.94 (d, 1H, J = 7.8 Hz) 7.55-7.48 (m, 2H) 7.45-7.40 (m, 1H) 3.92 (s, 3H) 1.43 (s, 12H). Data matched literature reference.126 Diborylated methyl benzoate (28% by GC/FID ratio) was observed in the crude reaction material for both open and closed systems by GC/FID but never recovered. Other mono borylated isomers were observed in trace amounts by GC/FID in the crude reaction but upon workup only ortho borylated product was observed in the 1H-NMR. N,N-Dimethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (3aa)9 In a nitrogen filled glove box a 3 mL Wheaton® conical vial was charged with [Ir(OMe)COD]2 (6.6 mg, 0.01 mmol), 2-methoxyisonicotinonitrile (2.6 mg, 0.02 mmol), N,N-dimethylbenzamide (149 mg, 1.0 mmol), and bis(pinacolato)diboron (305 mg, 1.2 mmol). Tetrahydrofuran (1.5 mL) was added via syringe. A triangular stir bar was added and the conical vial was capped. The reaction vial was removed from the glove box and heated to 70 oC for 16 hours. The solution was opened to air and concentrated using a rotary evaporator. Column chromatography (50:50 EtOAc:hexanes) on the residue 116 yielded a white solid (211 mg, 77% yield). 1H NMR (500 MHz, CDCl3, ppm) δ 7.82 (dd, 1H, J= 7.8, 0.9 Hz) 7.45 (td, 1H J = 7.8, 1.4 Hz) 7.37 (td, 1H, J = 7.3, 1.0 Hz) 7.30 (d, 1H, J= 7.1 Hz) 2.97 (br s, 6H) 1.32 (s, 12H). Data matched literature reference.127 There were 2 imputity peaks at 1.26 and 1.23 that integrated to 3% relative to the pinacol ester on compound 3aa. There was also an impurity at 2.02 that is likely acetone that integrated to less that 0.2% based on adjustment for number of protons. Methyl 3-fluoro-5-(trifluoromethyl)benzoate (3ab): A 50 mL round bottom flask was charged with 3-fluoro-5-(trifluoromethyl) benzoic acid (865 mg, 4.15 mmol), methanol (20 mL), and concentrated sulfuric acid (0.5 mL). The flask was fitted with a condenser, a stir bar was added and the reaction solution was refluxed for 3 hours. To the reaction mixture 20 mL of diethyl ether was added and the solution was washed with saturated potassium carbonate (3 x 50 mL), the organic layer was dried over magnesium sulfate and concentrated under vacuum to yield a clear colorless oil (712 mg, 77 %) 1H NMR (500 MHz, CDCl3, ppm) δ 8.11 (s, 1H) 7.92 (d, 1H, J= 9.0 Hz) 7.52 (d, 1H, J=8.3 Hz) 3.97 (s, 3H). 13C NMR (125 MHz, CDCl3, ppm) 164.6 (d, JCF = 2.7 Hz), 163.3, 161.3, 133.4 (d, JCF = 8.0 Hz), 122.9 (q, JCF = 274.9 Hz), 122.3 (t, JCF= 4.0 Hz), 120.0 (d, JCF = 22.9 Hz), 117.1 (dq, JCF = 24.6, 3.6 Hz), 52.8. 19F NMR (470 MHz, CDCl3, ppm) δ -63.02, -109.59 (J = 8.0 Hz). Anal. calcd. for C9H6F4O2 C 48.66 H 2.72; found C 48.83 H 3.33. 117 Methyl 3-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)- benzoate (3ab) In a nitrogen filled glove box a 3 mL Wheaton® conical vial was charged with [Ir(OMe)COD]2 (6.6 mg, 0.01 mmol), 2-methoxyisonicotinonitrile (2.6 mg, 0.02 mmol), and bis(pinacolato)diboron (305 mg, 1.2 mmol). Tetrahydrofuran (1.5 mL) was added via syringe followed by methyl 3-fluoro-5-(trifluoromethyl)benzoate (222 mg, 1.0 mmol). A triangular stir bar was added and the conical vial was capped. The reaction vial was removed from the glove box and heated to 70 oC for 16 hours. The vial was opened to air and concentrated using a rotary evaporator. Column chromatography (5:95 EtOAc:hexanes) on the residue yielded a light brown solid (237 mg, 84% yield) with a m.p. 73-74 oC. 1H NMR (500 MHz, CDCl3, ppm) δ 8.04 (d, 1H, J = 1.0 Hz) 7.46 (d, 1H, J = 7.8 Hz) 3.97 (s, 3H) 1.45 (s, 12H). 13C NMR (125 MHz, CDCl3, ppm) δ 166.1 (d, J = 2.6 Hz), 165.9, 164.0, 136.2 (d, JCF = 9.8 Hz), 133.7 (dq, J = 34.3, 8.8 Hz), 122.8 (dq, JCF = 274.8, 2.9 Hz), 121.5 (t, JCF= 3.9 Hz), 116.3 (dq, JCF = 27.8, 4.1 Hz), 85.0, 53.1, 24.8. 19F NMR (470 MHz, CDCl3, ppm) δ -63.02, -103.04 (J = 9.0 Hz). 11B NMR (160 MHz, CDCl3, ppm) 30.53. HRMS (ESI-) m/z calcd. for C14H14BO4F4 [M-CH3]- 333.0924; found 333.0935. Rgiochemistry was assigned based on size of the aromatic coupling constants. Having 1 aromatic proton with a coupling constant as low as 1 Hz indicates 118 that the proton is only influenced by long-range coupling. This means that only 1 proton in the aromatic region is on a carbon adjacent to a carbon-fluorine bond. tert-Butyl (2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl))benzoate (3ac) “Closed system” - In a nitrogen filled glove box a 3 mL Wheaton® conical vial was charged with [Ir(OMe)COD]2 (6.6 mg, 0.01 mmol), 2-methoxyisonicotinonitrile (2.6 mg, 0.02 mmol), and bis(pinacolato)diboron (305 mg, 1.2 mmol). Tetrahydrofuran (1.5 mL) was added via syringe. A triangular stir bar was added followed by addition of tert-butyl benzoate (126 μL, 1.0 mmol). The conical vial was capped, removed from the glove box and heated to 70 oC for 16 hours. The solution was opened to air and concentrated using a rotary evaporator. Column chromatography (10:90 EtOAc:hexanes) yielded a white solid (252 mg, 83% yield). 1H NMR (500 MHz, CDCl3, ppm) δ 7.82 (d, 1H, J = 7.8 Hz) 7.48- 7.44 (m, 2H) 7.37 (m, 1H) 1.59 (s, 9H) 1.42 (s, 12H). Data matched previously reported literature data.127 There existed small amounts of impurities between 1.4 and 1.2 it is believed that those come from boronates. They could also possibly come from a solvent mixture but this is unknown. The integrations of these impurities add up to 12% relative to that of the pinacol ester of the target compound. “Open system” - In a nitrogen filled glove box a 10 ml Schlenk flask was charged with [Ir(OMe)COD]2 (6.6 mg, 0.01 mmol), 2-methoxyisonicotinonitrile (2.6 mg, 0.02 mmol), 119 and bis(pinacolato)diboron (305 mg, 1.2 mmol) followed by addition of 1.5 mL of THF. tert-butyl benzoate (178 μL, 1.0 mmol) was added to the solution via microliter syringe. The flask was fitted with a condenser with septa on top of it and the whole apparatus was removed from the glove box. The apparatus was connected to a Schlenk line via a needle under positive nitrogen pressure. The solution was heated to 70 oC for 9 hours. After heating was done, the solvent was removed using a rotary evaporator and the oily residue was purified by column chromatography (5:95 EtOAc:hexanes) which yielded a white solid (226 mg, 74% yield). 1H NMR (500 MHz, CDCl3, ppm) δ 7.82 (d, 1H, J = 7.8 Hz) 7.48-7.44 (m, 2H) 7.38-7.34 (m, 1H) 1.59 (s, 9H) 1.42 (s, 12H). Data matched previously reported literature.127 Methyl 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trifluoromethyl)-benzoate (3ad) “Closed system” - In a nitrogen filled glove box a 3 mL Wheaton® conical vial was charged with [Ir(OMe)COD]2 (6.6 mg, 0.01 mmol), 2-methoxyisonicotinonitrile (2.6 mg, 0.02 mmol), and bis(pinacolato)diboron (305 mg, 1.2 mmol). Tetrahydrofuran (1.5 mL) was added via syringe. A triangular stir bar was added followed by addition of methyl 4- (trifluoromethyl)benzoate (160 μL, 1.0 mmol). The conical vial was capped, removed from the glove box and heated to 70 oC for 16 hours. The solution was opened to air and concentrated using a rotary evaporator. Column chromatography (5:95 EtOAc:hexanes) 120 on the residue yielded a clear colorless oil (215 mg, 65% yield). 1H-NMR (500 MHz, CDCl3, ppm) δ 8.04 (d, 1H, J= 7.6 Hz) 7.75 (s, 1H) 7.69 (d, 1H, J= 7.6 Hz) 3.95 (s, 3H) 1.44 (s, 12H). Data matched literature reference.127 A small amount of boronate impurities were on the spectra at 1.26 ppm with an integration of 5% relative to the pinacol ester peak from the target compound “Open system” – In a nitrogen filled glove box a 10 mL Schlenk flask was charged with [Ir(OMe)COD]2 (6.6 mg, 0.01 mmol), 2-methoxyisonicotinonitrile (2.6 mg, 0.02 mmol), and bis(pinacolato)diboron (192 mg, 0.77 mmol). Tetrahydrofuran (1.5 mL) was added via syringe. A small stir bar was added to the Schlenk flask followed by addition of methyl 4-(trifluoromethyl)benzoate (160 μL, 1.0 mmol) via a microliter syringe. A condenser fitted with a septa was attached to the Schlenk flask. The whole apparatus was removed from the glove box and connected to a nitrogen line through a needle inserted into the septa under positive nitrogen flow. An oil bath was used to heat the reaction at 70 oC for 4.5 hours. Column chromatography (5:95 EtOAc:hexanes) yielded a clear colorless oil (192 mg, 76% based on B2pin2, 58% based on arene) 1H NMR (500 MHz, CDCl3, ppm) δ 8.04 (d, 1H, J= 7.6 Hz) 7.75 (s, 1H) 7.69 (d, 1H, J= 7.6 Hz) 3.95 (s, 3H) 1.44 (s, 12H). Data matched literature reference.127 121 Methyl 3-bromo-5-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (3ae) Methyl 3-bromo-5-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (3af) In a nitrogen filled glove box a 10 mL Schlenk flask was charged with [Ir(OMe)COD]2 (6.6 mg, 0.01 mmol), 2-methoxyisonicotinonitrile (2.6 mg, 0.02 mmol), and bis(pinacolato)diboron (192 mg, 0.77 mmol). Tetrahydrofuran (1.5 mL) was added via syringe. A small stir bar was added to the Schlenk flask followed by addition of methyl 3-bromo-5-methyl benzoate (162 μL, 1 mmol) via a microliter syringe. A condenser fitted with a septa was attached to the Schlenk flask. The whole apparatus was removed from the glove box and connected to a nitrogen line through a needle inserted into the septa under positive nitrogen flow. An oil bath was used to heat the reaction flask to 70 oC for 48 hours. Column chromatography (4:96 EtOAc:hexanes) yielded compound 3ae as white solid (129.5 mg, 37% yield); m.p. 58-60 oC, and compound 3af as a white solid (73.3 mg, 21% yield); m.p. 97-98 oC. Starting material (66 mg, 29%) was also recovered. Structure assignments are based on likely positions relative to the size of the adjacent group. A methyl group is slightly larger than that of a bromine and as such the borylation occure adjacent to the bromine more readily. However, 2D experiments to confirm these assignment were not preformed. Methyl 3-bromo-5-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (3ae) 122 1H NMR (500 MHz, CDCl3, ppm) δ 7.93 (d, 1H, J= 1.7 Hz) 7.48 (d, 1H, J= 2.0 Hz) 3.91 (s, 3H) 2.43 (s, 3H) 1.45 (s, 12H). 13C NMR (125 MHz, CDCl3, ppm) δ 167.5, 143.5, 136.1, 135.0, 128.9, 122.7, 84.1, 52.6, 25.3, 21.3. 11B NMR (160 MHz, CDCl3, ppm) δ 30.8. HRMS (ESI) m/z calcd. for C15H20BBrNaO4 [M+Na]+ 377.0539, found 377.0547. Methyl 3-bromo-5-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (3af) 1H NMR (500 MHz, CDCl3, ppm) δ 7.74 (s, 1H) 7.52 (s, 1H) 3.91 (s, 3H) 2.35 (s, 3H) 1.48 (s, 12H). 13C NMR (125 MHz, CDCl3, ppm) δ 167.3, 140.6, 136.6, 135.0, 128.4, 126.7, 84.4, 52.5, 25.3, 20.9. 11B NMR (160 MHz, CDCl3, ppm) δ 30.2. Anal calcd. for C15H20BBrO4: C 50.75 H 5.68. Found C 50.99 H 5.58. tert-Butyl 2-fluorobenzoate (3ah′′′′) A round bottom flask (250 mL) was charged with toluene (40 mL), magnesium sulfate (5.2 g, 43.2 mmol), and a stir bar. Concentrated sulfuric acid (0.55 mL) was added to the vigorously stirred suspension. After 15 minutes 2-fluorobenzoic acid (1.48 g, 10.5 mmol) was added and the suspension was stirred for 15 minutes. The round bottom flask was fitted with a septa and tert-butanol (4.6 mL, 48.4 mmol) was added via syringe. The suspension was stirred at room temperature for 18 hours. Saturated potassium carbonate (3 x 75 mL) was used to wash the solution. The organic layer was separated and dried over magnesium sulfate. Upon concentration under vacuum, a clear colorless oil (1.51 g, 123 73% yield) was obtained. 1H NMR (500 MHz, CDCl3, ppm) δ 7.87 (td, 1H, J= 7.9, 1.9 Hz) 7.51-7.45 (m, 1H) 7.18 (t, 1H, J= 7.5 Hz) 7.11 (dd, 1H, J= 10.5, 8.6 Hz) 1.61 (s, 9H). 19F NMR (470 MHz, CDCl3, ppm) δ -110.3. Data matched literature reference.128 tert-Butyl 2-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (3ah) In a nitrogen filled glove box a 3 mL Wheaton® conical vial was charged with [Ir(OMe)COD]2 (6.6 mg, 0.01 mmol), 2-methoxyisonicotinonitrile (2.6 mg, 0.02 mmol), and bis(pinacolato)diboron (305 mg, 1.2 mmol). Tetrahydrofuran (1.5 mL) was added via syringe followed by tert-butyl 2-fluorobenzoate (196 mg, 1.0 mmol). A triangular stir bar was added and the conical vial was capped. The reaction vial was removed from the glove box and heated to 70 oC for 16 hours. The solution was opened to air and concentrated using a rotary evaporator. 19F-NMR of the crude reaction mixture showed 6 different products plus starting material (22%) with a majority of the mixture being ortho-borylation to the ester (57%). Column chromatography (10:90 Et2O:hexanes) on the residue afforded a white solid (148 mg, 46% yield) m.p.: 36-37 oC. 1H NMR (500 MHz, CDCl3, ppm) δ 7.43-7.35 (m, 2H) 7.12 (ddd, 1H, J= 10.2, 7.7, 1.6 Hz) 1.61 (s, 9H) 1.37 (s, 12H). 13C NMR (125 MHz, CDCl3, ppm) δ 165.8, 160.7, 158.7, 131.5 (d, JCF = 8.0 Hz), 129.2 (d, JCF = 3.7 Hz), 126.8 (d, JCF = 14.4 Hz), 84.2, 82.4, 28.2, 24.8. 19F NMR (470 MHz, CDCl3, ppm) δ -114.4 (dd, J= 10.1, 5.1 Hz). 11B NMR (160 MHz, CDCl3, ppm) δ 30.7. HRMS (ESI) m/z calcd. for C17H24BFNaO4 [M+Na]+ 345.1653; found 124 345.1663. Determination of regiochemistry was performed by comparing the spectra from literature of CHB of methyl 2-fluoro benzoate where ortho-borylation to both the ester129 and the fluorine130 are known. With borylation ortho to the fluorine there is a clear and defined triplet at 7.20 while with borylation ortho to the ester there is a clear and defined ddd at 7.16 on the methyl ester. The aromatic splitting pattern matched that of borylation ortho to the ester. Methyl 2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (3aj) In a nitrogen filled glove box a 3 mL Wheaton® conical vial was charged with [Ir(OMe)COD]2 (6.6 mg, 0.01 mmol), 2-methoxyisonicotinonitrile (2.6 mg, 0.02 mmol), and bis(pinacolato)diboron (305 mg, 1.2 mmol). Tetrahydrofuran (1.5 mL) was added via syringe. A triangular stir bar was added followed by addition of methyl o-toluate (140 μL, 1.0 mmol). The conical vial was capped, removed from the glove box and heated to 70 oC for 16 hours. The solution was opened to air and concentrated using a rotary evaporator. Column chromatography (5:95 EtOAc:hexanes) on the residue yielded a clear colorless oil (196 mg, 71% yield). 1H NMR (500 MHz, CDCl3, ppm) δ 7.55 (d, 1H, J = 7.6 Hz) 7.32 (t, 1H, J = 7.5 Hz) 7.27 (d, 1H, J= 7.5 Hz) 3.89 (s, 3H) 2.39 (s, 3H) 1.34 (s, 12H). Spectral data matched literature reference.129,131 Unknown methyl groups appear in the spectra around 2.5 there are 3 other methyl groups that would be from species off of an aromatic. This integrates to a 4:1 product to impurity ratio. 125 Methyl 6-fluoronicotinate (3ao′′′′) In a 100 mL round bottomed flask 6-fluoro-nicotinic acid (570 mg, 4.04 mmol) was dissolved in methanol (4 mL) and toluene (6 mL). The solution was slowly treated with trimethylsilyl diazomethane (2.2 mL, 2M in dichloromethane). After 2 hours of stirring the solution had a slightly yellow color. The solution was dried under vacuum to yield a white solid (509 mg, 81% yield) m.p. 52-53 oC. 1H NMR (500 MHz, CDCl3, ppm) δ 8.88 (d, 1H, J=2.0 Hz) 8.40 (td, 1H, J= 8.1, 2.4 Hz) 7.00 (dd, 1H, J= 8.6, 2.9 Hz) 3.95 (s, 3H). 13C NMR (125 MHz, CDCl3, ppm) δ 166.8, 164.8 (d, JCF= 17.3 Hz), 150.4 (d, JCF= 17.1 Hz), 142.6 (d, JCF= 8.6 Hz), 124.4 (d, JCF= 4.6 Hz), 109.5 (d, JCF= 37.3 Hz), 52.5. 19F NMR (470 MHz, CDCl3, ppm) δ -61.28 (d, 1F, J= 6.0 Hz). Data matched literature reference.132 Methyl 6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinate (3ao) In a nitrogen filled glove box a 3 mL Wheaton® conical vial was charged with [Ir(OMe)COD]2 (6.6 mg, 0.01 mmol), 2-methoxyisonicotinonitrile (2.6 mg, 0.02 mmol), methyl 6-fluoronicotinate (155 mg, 1.0 mmol), and bis(pinacolato)diboron (305 mg, 1.2 126 mmol). Tetrahydrofuran (1.5 mL) was added via syringe. A triangular stir bar was added and the conical vial was capped. The reaction vial was removed from the glove box and heated to 70 oC for 16 hours. The solution was opened to air and concentrated using a rotary evaporator. Column chromatography (5:95 EtOAc:hexanes) on the residue yielded a white solid (237 mg, 84% yield); m.p. 83-85 oC. 19F-NMR revealed about 3% of methyl 6-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinate131 that was unable to be separated. 1H NMR (500 MHz, CDCl3, ppm) δ 8.80 (s, 1H) 7.02 (d, 1H, J = 2.4 Hz) 3.96 (s, 3H) 1.42 (s, 12H). 13C NMR (125 MHz, CDCl3, ppm) δ 166.1 (d, JCF = 14.6 Hz), 164.1, 149.3 (d, JCF = 16.0), 127.0 (d, JCF =3.6 Hz), 112.7 (d, JCF = 36.3 Hz), 85.1, 52.7, 24.8. 19F NMR (470 MHz, CDCl3, ppm) δ -63.38. 11B NMR (160 MHz, CDCl3, ppm) δ 30.5. HRMS (ESI) m/z calc. for (C13H18NBO4F) [M+H]+ 282.1315; found 282.1312. Methyl 2-((2,3-dimethylphenyl)amino)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)benzoate (3az) In a glove box, a 15 mL pressure tube was charged with [Ir(OMe)COD]2 (3.3 mg, 0.005 mmol), 2-methoxyisonicotinonitrile (1.3 mg, 0.01 mmol), methyl 2-((2,3- dimethylphenyl)amino)benzoate (128 mg, 0.5 mmol), and bis(pinacolato)diboron (152 mg, 0.6 mmol). Tetrahydrofuran (2 mL) was added via syringe and a stir bar was added. The pressure tube was closed up, removed from the glove box and heated in an oil bath to 127 85 oC for 16 hours. The reaction was stopped and the volatiles were removed under vacuum. Column chromatography (5:95 EtOAc:Hexane) yielded an off white solid m.p. 96-98 oC (69.0 mg, 38% yield). 1H NMR (500 MHz, CDCl3, ppm) δ 8.80 (s, 1H), 7.21 (dd, 1H, J= 8.8, 6.6 Hz) 7.12-7.06 (m, 2H) 7.02-6.99 (m, 1H) 6.77(dd, 1H, J= 14.5, 0.8 Hz) 6.75 (dd, 1H, J= 16.2,, 1.4 Hz) 3.92 (s, 3H) 2.32 (s, 3H) 2.14 (s, 3H) 1.40 (s, 12H). 13C NMR (125 MHz, CDCl3, ppm) δ 169.4, 148.5, 138.9, 138.2, 133.1, 132.3, 126.6, 125.9, 122.9, 121.0, 115.2, 113.8, 83.7, 51.8, 25.0, 20.6, 13.9. 11B NMR (160 MHz, CDCl3, ppm) δ 30.8 (s, br). HRMS (ESI) m/z calcd. for C22H29BNO4 [M+H]+ 382.2190, found 382.2201. (2-((2,3-Dimethylphenyl)amino)phenyl)methanol (3az′′′′): Also isolated from this reaction by column chromatography was starting material (43.8 mg, 35%) and a yellow oil (2-((2,3-dimethylphenyl)amino)phenyl)methanol (20.4 mg, 18% yield). 1H NMR (500 MHz, CDCl3, ppm) δ 7.21-7.17 (m, 2H) 7.09 (t, 1H, J= 8.3 Hz) 7.05 (t, 1H, J= 7.6 Hz) 7.00 (d, 1H, J= 8.7 Hz) 7.89 (d, 1H, J= 7.7 Hz) 6.82 (t, 1H, J= 7.6 Hz) 4.76 (s, 2H) 2.33 (s, 3H) 2.15 (s, 3H). 13C NMR (125 MHz, CDCl3, ppm) δ 144.6, 140.7, 137.9, 129.4, 129.2, 128.0, 127.0, 125.9, 124.2, 119.2, 118.2, 115.8, 64.9, 20.7, 13.6. Spectral data matched litterature.133 128 (3ba) (3bb) Isopropyl 2-(4-(4-chloro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)benzoyl)phenoxy)-2-methylpropanoate (3ba) Isopropyl 2-(4-(4-chlorobenzoyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenoxy)-2-methylpropanoate (3bb): In a nitrogen filled glove box a 10 mL Schlenk flask was charged with [Ir(OMe)COD]2 (6.6 mg, 0.01 mmol), 2-methoxyisonicotinonitrile (2.6 mg, 0.02 mmol), isopropyl 2-(4- (4-chlorobenzoyl)phenoxy)-2-methylpropanoate (360 mg, 1.0 mmol), and bis(pinacolato)diboron (229 mg, 0.9 mmol). Tetrahydrofuran (2 mL) was added via syringe. A condenser fitted with a septa was attached to the Schlenk flask. The whole apparatus was removed from the glove box and connected to a nitrogen line through a needle inserted into the septa under positive nitrogen flow. An oil bath was used to heat the reaction mixture to 70 oC for 16 hours. Column chromatography (0:100-20:80 Et2O:hexanes) yielded a clear colorless oil (240 mg, 55% based on B2pin2) as a mixture of products in a 5:1 ratio determined by NMR spectroscopy. Chemical assignments were determined after a series of 2D NMR. The ipso carbon of the aromatic ether is expected to be around the 160 ppm range while the ipso carbon of the aromatic chloride is expected to be around 133 ppm.10 Using these known expected values the ipso carbon of the ether was correlated to the protons of the two compounds. The minor isomer had proton chemical shifts that were more distinctly visible. The minor component had a proton peak at 7.11 that is a doublet with a j coupling of 2.6 Hz. That is much too small of a coupling constant to be an ortho C-H coupling. As a result that was 129 labeled the proton adjacent to the boron. This proton, labeled A in the 2D spectra, had a 2D correlation to a carbon peak at 123 for the gHSQC and for gHMBCAD had signals to carbons at 134.8 and 117.7 ppm. The proton for the minor isomer should have shown a correlation to a more downfield carbon near 160 had it been adjacent to the ether. However that was not the case. Undetermined signals from the inseparable mixture: δ 7.70-7.65 (m, 3.6 H) 7.47-7.39 (m, 3.0 H) 7.10(d, 0.34H, J= 2.5 Hz) 6.82-6.79 (m, 2H) 6.77 (dd, 0.35H, J= 8.5, 2.8 Hz) 5.08 (sept, 1.3H, J= 6.0 Hz) 1.65-1.62 (m, 8.3H) 1.27 (s, 4.3H), 1.22 (s, 4.2H) 1.20 (s, 4.3H) 1.19 (s, 12.2H). 13C NMR (125 MHz, CDCl3, ppm) δ 195.9, 195.5, 173.2, 173.1, 159.7, 158.5, 142.2, 138.3, 136.7, 136.5, 134.8, 133.8, 131.8, 131.7, 131.2, 130.0, 129.7, 128.5, 123.2, 117.3, 84.3, 84.0, 79.3, 79.2, 69.3, 25.3, 24.7, 24.5, 21.5. 11B NMR (160 MHz, CDCl3, ppm) δ 30.2. HRMS (ESI) m/z calcd. for C26H33BClO6 [M+H]+ 487.2063; found 487.2066. Known peaks for Isopropyl 2-(4-(4-chloro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan- 2-yl)benzoyl)phenoxy)-2-methylpropanoate (3ba): 1H NMR (500 MHz, CDCl3, ppm) δ 5.08 (sept, 1H, J= 6.0 Hz) 1.19 (s, 12H). 13C NMR (125 MHz, CDCl3, ppm) δ 195.9, 173.1, 159.7, 84.3, 79.3, 69.3, 25.3, 24.5, 21.5. Known peaks for Isopropyl 2-(4-(4-chlorobenzoyl)-3-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)phenoxy)-2-methylpropanoate (3bb): 130 1H NMR (500 MHz, CDCl3, ppm) δ 7.47 (d, 1H, J= 8.4 Hz) 7.11 (d, 1H, J= 2.6 Hz) 6.78 (dd, 1H, J= 8.4, 2.6 Hz) 5.08 (sept, 1H, J= 6.0 Hz). 13C NMR (125 MHz, CDCl3, ppm) δ 195.5, 173.3, 158.5, 123.3, 84.8, 79.2, 69.3, 25.3, 24.7, 21.5. A O O B O A Cl O O O Figure 28. gHMQC for assignments of 3ba an 3bb. 131 Figure 29. gHMBCAD for assignments of 3ba an 3bb. 132 Figure 30. gCOSY for assignments of 3ba an 3bb. Procedure for Table 16 In a nitrogen filled glove box a stock solution of 2-methoxyisonicotinonitrile (26.1 mg, 0.2 mmol) in tetrahydrofuran (1 mL) was made. Various amounts of this stock solution (0 μL, 50 μL, 100 μL, 200 μL, and 400 μL) were added to 10 mL Schlenk flasks containing a stir bar, [Ir(OMe)COD]2 (6.6 mg, 0.01 mmol), bis(pinacolato)diboron (305 mg, 1.2 mmol), and tert-butyl benzoate (178 μL, 1.0 mmol). Tetrahydrofuran was added to the Schlenk flask to bring the total amount of tetrahydrofuran up to 1.5 mL (Stock solution plus solvent). The flask was fitted with a condenser with septa on top of it and the whole apparatus was removed from the glove box. The apparatus was connected to a Schlenk 133 line under positive nitrogen pressure and heated to 70 oC. GC/FID was used to monitor the reactions over time. Procedure for Scheme 40: In a nitrogen filled glove box, a 3 mL Wheaton® conical vial was charged with [Ir(OMe)COD]2 (6.6 mg, 0.01 mmol), 2-methoxyisonicotinonitrile (2.6 mg, 0.02 mmol), and bis(pinacolato)diboron (127 mg, 0.5 mmol). Tetrahydrofuran (1.5 mL) was added via syringe. A triangular stir bar was added followed by methyl benzoate (63 μL, 0.5 mmol) and cyclopropyl phenyl ketone (69.1 μL, 0.5 mmol). The conical vial was capped, removed from the glove box and heated to 70 oC for 3 hours. After 3 hours the solution was cooled and sample for GC/FID was taken. The following results were obtained: cyclopropyl phenyl ketone conversion was 62% and conversion of methyl benzoate was 10%. General procedure for catalyst concentration reactions Figure 16: In a nitrogen filled glove box, a well plate was set up with concurrent reactions. To each reaction was added from a stock solution bis(pinacolato)diboron (100 μL, 2M in THF), methyl benzoate (25 μL, 0.2 mmol) dodecane (10 μL) as an internal standard, and changing amounts of iridium and ligand solution such that the iridium to ligand ratio remained at 1:1. The reaction volume was brought up to 0.4 mL with extra THF. The well plate was capped, removed from the glove box and heated on a temperature controlled hot plate at 80 °C for 18h. The crude reaction conversions and selectivity ratios were determined by GC/FID and shown below. 134 Table 17. Underlying data for Figure 16 Entry [Ir]2 molarity o:m+p* 1 2 3 4 5 6 0.002461408 0.004922816 0.009845633 0.019691265 0.029536898 0.03938253 26.85 19.83 14.7 10.01 7.05 4.97 General procedure for catalyst concentration reactions Figure 17: In a nitrogen filled glove box, a well plate was set up with concurrent reactions. To each reaction was added from a stock solution bis(pinacolato)diboron (100 μL, 2M in THF), methyl benzoate (25 μL, 0.2 mmol) dodecane (10 μL) as an internal standard, and a changing amount of iridium from a 0.04M[Ir(OMe)cod]2 solution. The reaction volume was brought up to 0.4 mL with extra THF. The well plate was capped, removed from the glove box and heated on a temperature controlled hot plate at 80 °C for 18h. The crude reaction conversions and selectivity ratios were determined by GC/FID and shown below. 135 Table 18. Underlying data for Figure 17 Entry [Ir]2 (mols/L) Conversion (%) o:m+p 1 2 3 4 5 6 0.002461408 0.004922816 0.009845633 0.019691265 0.029536898 0.03938253 20.7 16.6 16.1 20.5 26.5 27.2 40 11 1.8 0.823 0.85 0.52 136 APPENDICES 137 APPENDIX A NMR Spectra 138 Figure A1. 500 MHz 1H NMR of 2b in D2O 139 Figure A2. 500 MHz 1H NMR of 2b in D2O from 3.9 to 1.0 ppm 140 Figure A3. 125 MHz 13C NMR of 2b in D2O 141 Figure A4. 125 MHz 13C NMR of 2b in D2O from 85 to 15 ppm 142 Figure A5. 500 MHz 1H NMR of 2c in D2O 143 Figure A6. 500 MHz 1H NMR of 2c in D2O from 3.6 to 0.6 ppm 144 Figure A7. 125 MHz 13C NMR of 2c in D2O 145 Figure A8. 125 MHz 13C NMR of 2c in D2O from 85 to 15 ppm 146 Figure A9. 160 MHz 11B NMR of 2c in D2O 147 Figure A10. 500 MHz 1H NMR of 2d′ in CDCl3 148 Figure A11. 160 MHz 11B NMR of 2d′′′′ in D2O 149 Figure A12. 500 MHz 1H NMR of 2d in D2O 150 Figure A13. 125 MHz 13C NMR of 2d in D2O 151 Figure A14. 125 MHz 13C NMR of 2d in D2O from 60 to 15 ppm 152 Figure A15. 160 MHz 11B NMR of 2d in D2O 153 Figure A16. 500 MHz 1H NMR of 2e′′′′ in CDCl3 154 Figure A17. 125 MHz 13C NMR of 2e′′′′ in CDCl3 155 Figure A18. 160 MHz 11B NMR of 2e′′′′ in CDCl3 156 Figure A19. 500 MHz 1H NMR of 2e in D2O 157 Figure A20. 500 MHz 1H NMR of 2e in D2O from 3.8 to 1.0 ppm 158 Figure A21. 125 MHz 13C NMR of 2e in D2O 159 Figure A22. 160 MHz 11B NMR of 2e in D2O 160 Figure A23. 500 MHz 1H NMR of 2f in CDCl3 161 Figure A24. 160 MHz 11B NMR of 2f in CDCl3 162 Figure A25. 500 MHz 1H NMR of 2g′ in CDCl3 163 Figure A26. 500 MHz 1H NMR of 2g in CDCl3 164 Figure A27. 500 MHz 1H NMR of 2g in CDCl3 from 4.0 to 0.9 ppm 165 Figure A28. 125 MHz 13C NMR of 2g in CDCl3 166 Figure A29. 125 MHz 13C NMR of 2g in CDCl3 from 85 to 15 ppm 167 Figure A30. 160 MHz 11B NMR of 2g in CDCl3 168 Figure A31. 500 MHz 1H NMR of 2h in CDCl3 169 Figure A32. 160 MHz 11B NMR of 2h in CDCl3 170 Figure A33. 500 MHz 1H NMR of 2l in C6D6 171 Figure A34. 500 MHz 1H NMR of 2l in C6D6 from 2.3ppm to 0.9ppm 172 Figure A35. 500 MHz 1H NMR of 2l in C6D6 from 4.1ppm to 3.5ppm 173 Figure A36. 125 MHz 13C NMR of 2l in C6D6 174 Figure A37. 125 MHz 13C NMR of 2l in C6D6 from 43ppm to 18 ppm 175 Figure A38. 160 MHz 11B NMR of 2l in C6D6 176 Figure A39. 500 MHz 1H NMR of 2o in CDCl3 177 Figure A40. 125 MHz 13C NMR of 2o in CDCl3 178 Figure A41. 160 MHz 11B NMR of 2o in CDCl3 179 Figure A42. 500 MHz 1H NMR of 2p in D2O 180 Figure A43. 160 MHz 11B NMR of 2p in D2O 181 Figure A44. 500 MHz 1H NMR of 2q in CDCl3 182 Figure A45. 500 MHz 1H NMR of 2q in CDCl3 183 Figure A46. 125 MHz 13C NMR of 2q in CDCl3 184 Figure A47. 125 MHz 13C NMR of 2q in CDCl3 from 44 to 22 ppm 185 Figure A48. 470 MHz 19F NMR of 2q in CDCl3 186 Figure A49. 500 MHz 1H NMR of 2r in C6D6 187 Figure A50. 125 MHz 13C NMR of 2r in C6D6 188 Figure A51. 160 MHz 11B NMR of 2r in C6D6 189 Figure A52. 500 MHz 1H NMR of 2s in C6D6 190 Figure A53. 500 MHz 1H NMR of 2s in C6D6 from 2.5 to 0.4 ppm 191 Figure A54. 125 MHz 13C NMR of 2s in C6D6 192 Figure A55. 160 MHz 11B NMR of 2s in C6D6 193 Figure A56. 500 MHz 1H NMR of 2t in C6D6 194 Figure A57. 500 MHz 1H NMR of 2t in C6D6 from 3.6 to 0.7 ppm 195 Figure A58. 500 MHz 1H NMR of 2t in C6D6 from 3.45 to 2.5 ppm 196 Figure A59. 125 MHz 13C NMR of 2t in CDCl3 197 Figure A60. 160 MHz 11B NMR of 2t in CDCl3 198 Figure A61. 500 MHz 1H NMR of 2u in CDCl3 199 Figure A62. 500 MHz 1H NMR of 2u in CDCl3 from 3.8 to 0.0 ppm 200 Figure A63. 125 MHz 13C NMR of 2u in CDCl3 201 Figure A64. 125 MHz 13C NMR of 2u in D2O from 60 to 18 ppm 202 Figure A65. 500 MHz 1H NMR of 2v in D2O 203 Figure A66. 500 MHz 1H NMR of 2v in D2O from 4.4 to -0.2ppm 204 Figure A67. 125 MHz 13C NMR of 2v in D2O 205 Figure A68. 470 MHz 19F NMR of 2v in D2O 206 Figure A69. 500 MHz 1H NMR of 2w in C6D6 207 Figure A70. 125 MHz 13C NMR of 2w in C6D6 208 Figure A71. 500 MHz 1H NMR of 2x in CDCl3 209 Figure A72. 125 MHz 13C NMR of 2x in CDCl3 210 Figure A73. 500 MHz 1H NMR of 2y in C6D6 211 Figure A74. 125 MHz 13C NMR of 2y in CDCl3 212 Figure A75. 99 MHz 29Si NMR of 2y in CDCl3 213 Figure A76. 500 MHz 1H NMR of 2za in C6D6 214 Figure A77. 500 MHz 1H NMR of 2za in C6D6 from 3.0 to 0.3 ppm 215 Figure A78. 125 MHz 13C NMR of 2za in C6D6 216 Figure A79. 125 MHz 13C NMR of 2za in C6D6 from 36 to 6 ppm 217 Figure A80. 160 MHz 11B NMR of 2za in C6D6 218 Figure A81. 500 MHz 1H NMR of 2zb in C6D6 219 Figure A82. 500 MHz 1H NMR of 2zb in C6D6 220 Figure A83. 125 MHz 13C NMR of 2zb in C6D6 221 Figure A84. 125 MHz 13C NMR of 2zb in C6D6 from 85 to 5 ppm 222 Figure A85. 160 MHz 11B NMR of 2zb in C6D6 223 Figure A86. 500 MHz 1H NMR of 3z in CDCl3 224 Figure A87. 500 MHz 1H NMR of 3z in CDCl3 from 9.0 to 6.5 ppm 225 Figure A88. 500 MHz 1H NMR of 3aa in CDCl3 226 Figure A89. 500 MHz 1H NMR of 3aa in CDCl3 from 9.0 to 6.5 ppm 227 Figure A90. 160 MHz 11B NMR of 3aa in CDCl3 228 Figure A91. 500 MHz 1H NMR of 3ab′ in CDCl3 229 Figure A92. 500 MHz 1H NMR of 3ab′ in CDCl3 from 9.0 to 6.5 ppm 230 Figure A93. 125 MHz 13C NMR of 3ab′ in CDCl3 231 Figure A94. 125 MHz 13C NMR of 3ab′ in CDCl3 from 150 to 110 ppm 232 Figure A95. 470 MHz 19F NMR of 3ab′ in CDCl3 233 Figure A96. 500 MHz 1H NMR of 3ab in CDCl3 234 Figure A97. 500 MHz 1H NMR of 3ab in CDCl3 from 8.4 to 7.0 ppm 235 Figure A98. 125 MHz 13C NMR of 3ab in CDCl3 236 Figure A99. 125 MHz 13C NMR of 3ab in CDCl3 from 168 to 108 ppm 237 Figure A100. 470 MHz 19F NMR of 3ab in CDCl3 238 Figure A101. 160 MHz 11B NMR of 3ab in CDCl3 239 Figure A102. 500 MHz 1H NMR of 3ac in CDCl3 240 Figure A103. 500 MHz 1H NMR of 3ac in CDCl3 from 7.9 to 7.2 ppm 241 Figure A104. 500 MHz 1H NMR of 3ad in CDCl3 242 Figure A105. 160 MHz 11B NMR of 3ad in CDCl3 243 Figure A106. 500 MHz 1H NMR of 3ae in CDCl3 244 Figure A107. 500 MHz 1H NMR of 3ae in CDCl3 from 8.0 to 7.35 ppm 245 Figure A108. 125 MHz 13C NMR of 3ae in CDCl3 246 Figure A109. 160 MHz 11B NMR of 3ae in CDCl3 247 Figure A110. 500 MHz 1H NMR of 3af in CDCl3 248 Figure A111. 500 MHz 1H NMR of 3af in CDCl3 from 7.85 to 7.40 ppm 249 Figure A112. 125 MHz 13C NMR of 3af in CDCl3 250 Figure A113. 160 MHz 11B NMR of 3af in CDCl3 251 Figure A114. 500 MHz 1H NMR of 3ah in CDCl3 252 Figure A115. 500 MHz 1H NMR of 3ah in CDCl3 from 7.50 to 7.00 ppm 253 Figure A116. 125 MHz 13C NMR of 3ah in CDCl3 254 Figure A117. 470 MHz 19F NMR of 3ah in CDCl3 255 Figure A118. 160 MHz 11B NMR of 3ah in CDCl3 256 Figure A119. 500 MHz 1H NMR of 3ai in CDCl3 257 Figure A120. 500 MHz 1H NMR of 3ao in CDCl3 258 Figure A121. 500 MHz 1H NMR of 3ao in CDCl3 from 9.0 to 6.8 ppm 259 Figure A122. 125 MHz 13C NMR of 3ao in CDCl3 260 Figure A123. 470 MHz 19F NMR of 3ao in CDCl3 261 Figure A124. 160 MHz 11B NMR of 3ao in CDCl3 262 pinB N H O O Figure A125. 500 MHz 1H NMR of 3az in CDCl3 263 pinB N H O O Figure A126. 500 MHz 1H NMR of 3az in CDCl3 from 9.0 to 6.5 ppm 264 pinB N H O O Figure A127. 125 MHz 13C NMR of 3az in CDCl3 265 Bpin O O Bpin Cl O O O Cl O O O major isomer minor isomer Figure A128. 500 MHz 1H NMR of 3ba and 3bb in CDCl3 266 Bpin O O Bpin Cl O O O Cl O O O major isomer minor isomer Figure A129. 500 MHz 1H NMR of 3ba and 3bb in CDCl3 between 2.0ppm and 1.0ppm 267 Bpin O O Bpin Cl O O O Cl O O O major isomer minor isomer Figure A130. 500 MHz 1H NMR of 3ba and 3bb in CDCl3 between 8.0ppm and 6.4ppm 268 Bpin O O Bpin Cl O O O Cl O O O major isomer minor isomer Figure A131. 125 MHz 13C NMR of 3ba and 3bb in CDCl3 269 APPENDIX B Crystal Structure Data 270 Table B1 Crystal data for compound 2e TMS691 C12H22BBrNO2 1.128 3.075 303.02 colourless needle 1.41×0.14×0.09 173(2) monoclinic P21/c 8.4980(17) 27.935(3) 7.5150(9) 90 90 90 1784.0(5) 4 1 1.541838 CuKα 3.164 71.638 5367 1647 1298 0.0349 97 1 0.432 -0.282 1.079 0.1594 0.1501 0.0646 0.0535 Compound Formula Dcalc./ g cm-3 µ/mm-1 Formula Weight Colour Shape Size/mm3 T/K Crystal System Space Group a/Å b/Å c/Å α/° β/° γ/° V/Å3 Z Z' Wavelength/Å Radiation type Θmin/° Θmax/° Measured Refl. Independent Refl. Reflections with I > 2(I) Rint Parameters Restraints Largest Peak Deepest Hole GooF wR2 (all data) wR2 R1 (all data) R1 271 Table B2 Crystal structure data for 2za MRS218A 1826283 C16H30BNO3 1.097 0.578 295.22 colourless chunk 0.30×0.29×0.28 173(2) orthorhombic -0.04(8) -0.04(7) P212121 11.80690(10) 14.68810(10) 30.9318(3) 90 90 90 5364.22(8) 12 3 1.541838 CuKα 4.007 72.061 32820 10453 9271 0.0451 586 0 0.423 -0.236 1.047 0.1593 0.1527 0.0645 0.0574 Compound CCDC Formula Dcalc./ g cm-3 µ/mm-1 Formula Weight Colour Shape Size/mm3 T/K Crystal System Flack Parameter Hooft Parameter Space Group a/Å b/Å c/Å α/° β/° γ/° V/Å3 Z Z' Wavelength/Å Radiation type Θmin/° Θmax/° Measured Refl. Independent Refl. Reflections Used Rint Parameters Restraints Largest Peak Deepest Hole GooF wR2 (all data) wR2 R1 (all data) R1 272 REFERENCES 273 REFERENCES (1) Brown, H. C.; Zweifel, G. J. Am. Chem. Soc. 1959, 81 (1), 247. (2) Brown, H. C.; Zweifel, G. J. Am. Chem. Soc. 1961, 83 (2), 486. 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