IRIDIUM CATALYZED C-H ACTIVATION BORYLATIONS OF FLUORINE BEARING ARENES AND RELATED STUDIES By Chathurika Ruwanthi Kumarihami Jayasundara A DISSERTATION Michigan State University in partial fulfillment of the requirements Submitted to for the degree of Chemistry – Doctor of Philosophy 2018 ABSTRACT IRIDIUM CATALYZED C-H ACTIVATION BORYLATIONS OF FLUORINE BEARING ARENES AND RELATED STUDIES By Chathurika Ruwanthi Kumarihami Jayasundara During the last two decades, iridium catalyzed aromatic borylation has emerged as one of the most convenient methodologies for functionalizing arenes and heteroarenes. The regioselectivity of Ir-catalyzed borylations are typically governed by sterics, therefore it complements the regioselectivity found in electrophilic aromatic substitution or directed ortho metalation. This unique regioselectivity and broad functional group tolerance (ester, amide, halogen, etc.) allows for synthesis of novel synthetic intermediates, many of which were previously either unknown or difficult to make. Since these reactions are mainly driven by sterics, it is possible to install boronic ester group (Bpin) next to small substituents like hydrogen, cyano, or fluorine. This feature is helpful but can also create challenges, specially in cases like borylation of fluoro arenes. These fluoro arenes tend give 1:1 mixture of steric (meta to fluorine) and electronic (ortho to fluorine) products. Therefore, to overcome this problem, we introduced a two-step Ir-catalyzed borylation/Pd-catalyzed dehalogenation sequence that allows one to synthesize fluoroarenes where the boronic ester is ortho to fluorine (electronic). Here, a halogen para to the fluorine is used as a sacrificial blocking group allowing the Ir-catalyzed borylation to favor the electronic product exclusively. Then the chemoselective Pd-catalyzed dehalogenation by KF activated polymethylhydrosiloxane (PMHS) is used to remove the halogen without compromising the Bpin group. Halosubstituted aryl boronates have the potential for orthogonal reactivity in cross-coupling reactions. We began exploring cross-coupling of triorganoindiums with these arylhalides bearing boronic esters in collaboration with Prof. P. Sestelo at University of da Coruña, Spain. We were able to synthesize borylated biaryls by merging Ir-catalyzed C–H borylations with Pd-catalyzed organoindium cross-couplings. As a part of the Dow–MSU-GOALI collaborations, we were able to synthesize a cobalt catalyst for C-H borylations of alkyl arenes and heteroarenes. This catalyst enables selective monoborylation of the benzylic position of alkyl arenes using pinacolborane (HBpin) as the boron source. In 2016, an internship opportunity led to the screening of ligands for C-H borylations at the Dow chemicals company in Midland, MI. From this internship opportunity, we discovered the first ligand controlled synthesis of 1,2-di and 1,2,3-tri borylated arenes. Also, I investigated a recyclable iridium heterogeneous catalyst for borylations during the internship. Finally, a bulky terphenyl incorporated bipyridine ligand is synthesized for selective iridium catalyzed para C–H borylations. iii To my beloved mother, Indra Kumarihami Bandara For her patience and her faith in me ACKNOWLEDGMENTS I am grateful to Prof. Robert Maleczka for taking me into his group and guiding me through the Ph.D. This work would not have been possible without all the assistance and encouragement I have received from him during my Ph.D. I am also very thankful to him for his patience and giving me time to recover after my car accident. I am thankful to Prof. Milton R Smith III for his valuable suggestions during boron group meetings. I would also like to thank Prof. Xuefei Huang, Prof. Babak Borhan and Prof. Gary Blanchard for serving on my guidance committee. During my time as a graduate student, I also had the opportunity to do an internship at The Dow Chemical Company in Midland. I am thankful to Rob, Mitch and Jossian for this amazing experience. I owe a great many thanks to Heidi Wardin for being there for me during my difficult times. It is always fun to talk to you about everything. I would also like to thank Dr. Staples for all the amazing work with crystal structures; specially the di- and tri- borylated compounds. I like to thank Dr. Holmes for all the help with NMR at MSU. My special thanks go to Dr. Sean Preshlock and Dr. Hao Li. I learned many great techniques from Dr. Li, which helped me to do well in my Ph.D. I am very thankful to all my group members; Rosario, Susan, Damith, Aaron, Fangyi, Jonathan, Pepe, Barry and Emmanuel. I am so grateful to Barry for being a good friend and a great lab partner. I would like to thank my apartment mate Dr. Daria Shamrova and also the Sri Lankans who helped me through the PhD. Special thanks go to Dilini, Punsisi, Gayanthi, Nalin, Thilani, Dhanushka and Viva. I would also like to thank my Starbucks matcha iv buddies Yuling and Oliva. Thank you for all the advice and guidance Yuling, I really appreciate it. Finally, I would like to thank the most important people in my life, My Family, for everything. A very special thank you goes to my mom for supporting all my decisions and being there for me every step of the way. v TABLE OF CONTENTS LIST OF TABLES ........................................................................................................... ix LIST OF FIGURES ....................................................................................................... xiii LIST OF SCHEMES ..................................................................................................... xix KEY TO ABBREVIATIONS ..................................................................................... xxiii Chapter 1. Introduction ................................................................................................... 1 1.1 Arylboronic Easters ............................................................................................................... 1 1.2 Methods of Synthesizing Arylboronic Easters ...................................................................... 2 1.3 Direct C–H activation borylations ......................................................................................... 2 1.4 Mechanism for direct C–H activation borylations ................................................................ 8 1.5 Regioselectivity in Ir-catalyzed CHBs ................................................................................ 11 REFERENCES .......................................................................................................................... 14 Chapter 2. A Catalytic Borylation / Dehalogenation Route to ortho-Fluoro Arylboronates .................................................................................................................. 18 2.1 Introduction ......................................................................................................................... 18 2.2 Alternate approach to o-fluoro arylboronates ...................................................................... 20 2.3 Borylation of fluoroarenes ................................................................................................... 20 2.4 Dehydrohalogenation of fluoroarenes ................................................................................. 21 2.5 One-pot borylation/dehalogenation ..................................................................................... 25 2.6 Recent advancements in selective o-fluoro arylboronic esters ............................................ 25 2.7 Conclusions ......................................................................................................................... 27 2.8 Experimental ........................................................................................................................ 27 REFERENCES .......................................................................................................................... 46 Chapter 3. Merging Iridium Catalyzed C-H Borylations with Organoindium Cross- Couplings ......................................................................................................................... 48 3.1 Introduction ......................................................................................................................... 48 3.2 Organoindium cross coupling .............................................................................................. 49 3.3 Investigations and optimizations ......................................................................................... 50 3.4 Cross-couplings of R3In with borylated haloarenes ............................................................. 52 3.5 One-pot borylations/cross-couplings of haloarenes ............................................................ 55 3.6 Experimental ........................................................................................................................ 56 REFERENCES .......................................................................................................................... 74 Chapter 4. Cobalt-Catalyzed C–H Borylations ............................................................ 78 4.1 C(sp3)–H borylations ........................................................................................................... 78 4.2 Cobalt catalyzed non-directed C(sp3)–H borylations .......................................................... 78 4.3 Synthesis of a new cobalt catalyst ....................................................................................... 79 4.4 Testing cobalt catalyst A reactivity ..................................................................................... 81 vi 4.5 C(sp2)–H of heteroarenes vs. C(sp2)–H and C(sp3)–H bonds of alkylated arenes .............. 88 4.6 Identifying the active catalyst species ................................................................................. 89 4.7 Conclusions ......................................................................................................................... 92 4.8 Experimental ........................................................................................................................ 93 REFERENCES ........................................................................................................................ 104 Chapter 5. First, Ligand Controlled Synthesis of 1,2-di and 1,2,3-tri Borylated Arenes via Iridium Catalyzed C-H Borylations ......................................................... 107 5.1 Introduction to aromatic di- and poly-boronic esters (PBEs) ............................................ 107 5.2 Data and Discussion .......................................................................................................... 108 5.3 Conclusions ....................................................................................................................... 126 5.4 Experimental ...................................................................................................................... 126 REFERENCES ........................................................................................................................ 135 Chapter 6: Ligand Screening for Ir–Catalyzed C–H Borylations ............................ 138 6.1 Introduction ....................................................................................................................... 138 6.2 Chelate-directed borylations .............................................................................................. 139 6.3 Relay-directed borylations ................................................................................................. 143 6.4 Outer sphere borylations .................................................................................................... 145 6.5 Monodentate Vs Bidentate ligands .................................................................................... 150 6.6 Results and Discussion ...................................................................................................... 152 6.7 Ligand synthesis ................................................................................................................ 180 6.8 Different metal catalyst for C-H borylations ..................................................................... 181 6.8 Conclusions ....................................................................................................................... 183 6.9 Experimental ...................................................................................................................... 183 REFERENCES ........................................................................................................................ 189 Chapter 7. Investigating Reactivity, Structure and Reusability of an Insoluble Iridium Catalyst for C-H Borylations ......................................................................... 192 7.1 Introduction ....................................................................................................................... 192 7.2 Heterogeneous catalyst ...................................................................................................... 194 7.3 Data and Discussion .......................................................................................................... 196 7.4 Conclusions ....................................................................................................................... 203 7.5 Experimental ...................................................................................................................... 203 REFERENCES ........................................................................................................................ 208 Chapter 8. Selective para-CH Activation Borylations ............................................... 210 8.1 Introduction ....................................................................................................................... 210 8.2 Sterically bulk ligand synthesis ......................................................................................... 211 8.3 Ligand synthesis for para selective C–H borylations ....................................................... 212 8.4 Synthesis of part A ............................................................................................................ 213 8.5 Synthesis of part B ............................................................................................................. 214 8.5 Synthesis of the bulky ligand ............................................................................................ 215 8.6 Iridium catalyzed selective para borylations ..................................................................... 216 8.7 Experimental ...................................................................................................................... 216 REFERENCES ........................................................................................................................ 225 vii APPENDICES ............................................................................................................... 229 APPENDIX A, crystal structures ............................................................................................ 230 APPENDIX B, nmr .................................................................... Error! Bookmark not defined. viii LIST OF TABLES Table 1. Hydrodehalogenation with Ammonium Formate .............................................. 44 Table 2. Solvent screening for L1 .................................................................................. 109 Table 3. Ir-catalyzed C-H borylation of 2, 6-CFA in THF. .......................................... 153 Table 4. Ir-catalyzed C-H borylation of 2, 6-CFA in Hexane. ....................................... 154 Table 5. Ir-catalyzed C-H borylation of 2, 6-CFA in CPME. ........................................ 155 Table 6. Ir-catalyzed C-H borylation of 2, 6-CFA in methyl cyclohexane. ................... 155 Table 7. Ir-catalyzed C-H borylation of 2, 6-CFA in Hunig’s base. .............................. 156 Table 8. Summary of Ir-catalyzed C-H borylation of 2, 6-CFA .................................... 157 Table 9. Ir-catalyzed C-H borylation of 2, 6-CFN in THF ............................................ 162 Table 10. Ir-catalyzed C-H borylation of 2, 6-CFN in hexane ...................................... 163 Table 11. Ir-catalyzed C-H borylation of 2, 6-CFN in CPME ....................................... 164 Table 12. Ir-catalyzed C-H borylation of 2, 6-CFN in methyl cyclohexane .................. 164 Table 13. Ir-catalyzed C-H borylation of 2, 6-CFN in Hunig’s base ............................. 165 Table 14. Summary of Ir-catalyzed C-H borylation of 2, 6-CFN .................................. 166 Table 15. Ir-catalyzed C-H borylation of Cl-OMePy in THF. ....................................... 169 Table 16. Ir-catalyzed C-H borylation of 4-OMe-Py in THF. ....................................... 172 Table 17. Ir-catalyzed C-H borylation of 4-OMe-Py in THF. ....................................... 173 Table 18. Ir-catalyzed C-H borylation of F-OMe-Py in THF with no stirring. ............. 174 Table 19. Ir-catalyzed C-H borylation of F-OMe-Py in hexane. ................................... 175 Table 20. Ir-catalyzed C-H borylation of 4-CN-2-OMe-Py in hexane. ......................... 178 Table 21. Ir-catalyzed C-H borylation of 4-CN-2-OMe-Py in hexane. ......................... 178 Table 22. Patinum catalyzed C-H borylation ................................................................. 183 Table 23. CHBs of benzene catalyzed by recyclable iridium catalyst ........................... 195 ix Table 30. Hydrogen Fractional Atomic Coordinates (×104) and Equivalent Isotropic Table 31. Fractional Atomic Coordinates (×104) and Equivalent Isotropic Displacement Table 35. Hydrogen Fractional Atomic Coordinates (×104) and Equivalent Isotropic Table 26. Fractional Atomic Coordinates (×104) and Equivalent Isotropic Displacement Table 24. NAA data for the black solid and the filtrate in hexane ................................. 198 Table 25. NAA data for the black solid and the filtrate in hexane ................................. 199 Parameters (Å2×103) for 67c. .......................................................................................... 232 Table 27. Anisotropic Displacement Parameters (×104) 67c. ........................................ 232 Table 28. Bond Lengths in Å for 67c. ............................................................................ 233 Table 29. Bond Angles in ° for 67c. ............................................................................... 234 Displacement Parameters (Å2×103) for 67c. ................................................................... 235 Parameters (Å2×103) for 68c. .......................................................................................... 237 Table 32. Anisotropic Displacement Parameters (×104) 68c. ........................................ 237 Table 33. Bond Lengths in Å for 68c. ............................................................................ 238 Table 34. Bond Angles in ° for 68c ................................................................................ 239 Displacement Parameters (Å2×103) for 68c. ................................................................... 240 Parameters (Å2×103) for 68*. .......................................................................................... 242 Table 37. Anisotropic Displacement Parameters (×104) 68*. ........................................ 243 Table 38. Bond Lengths in Å for 68*. ........................................................................... 244 Table 39. Bond Angles in ° for 68*. ............................................................................... 245 Displacement Parameters (Å2×103) for 68*. ................................................................... 246 Table 41. Atomic Occupancies for all atoms that are not fully occupied in 68*. .......... 248 Table 42. Fractional Atomic Coordinates (×104) and Equivalent Isotropic Displacement Parameters (Å2×103) for 69*. ............................................................... 250 Table 43. Anisotropic Displacement Parameters (×104) 69*. ................................... 251 Table 44. Bond Lengths in Å for 69*. ........................................................................... 252 Table 36. Fractional Atomic Coordinates (×104) and Equivalent Isotropic Displacement Table 40. Hydrogen Fractional Atomic Coordinates (×104) and Equivalent Isotropic x Table 48. Fractional Atomic Coordinates (×104) and Equivalent Isotropic Displacement Table 53. Fractional Atomic Coordinates (×104) and Equivalent Isotropic Displacement Table 45. Bond Angles in ° for 69*. .............................................................................. 253 Table 46. Hydrogen Fractional Atomic Coordinates (×104) and Equivalent Isotropic Displacement Parameters (Å2×103) for 69*. ............................................................... 254 Table 47. Atomic Occupancies for all atoms that are not fully occupied in 69*. ..... 256 Parameters (Å2×103) for 70c. .......................................................................................... 258 Table 49. Anisotropic Displacement Parameters (×104) 70c. ........................................ 258 Table 50. Bond Lengths in Å for 70c. ............................................................................ 259 Table 51. Bond Angles in ° for 70c. ............................................................................... 259 Displacement Parameters (Å2×103) for 70c. ................................................................... 260 Parameters (Å2×103) for 71cʹ. ......................................................................................... 263 Table 54. Anisotropic Displacement Parameters (×104) 71cʹ. ....................................... 263 Table 55. Bond Lengths in Å for 71cʹ. ........................................................................... 263 Table 56. Bond Angles in ° for 71cʹ. .............................................................................. 264 Displacement Parameters (Å2×103) for 71cʹ. .................................................................. 265 Parameters (Å2×103) for 72cʹ. ......................................................................................... 267 Table 59. Anisotropic Displacement Parameters (×104) 72cʹ. ....................................... 267 Table 60. Bond Lengths in Å for 72cʹ. ........................................................................... 268 Table 61. Bond Angles in ° for 72cʹ. .............................................................................. 268 Displacement Parameters (Å2×103) for 72cʹ. .................................................................. 270 Parameters (Å2×103) for 73cʹ. ......................................................................................... 272 Table 64. Anisotropic Displacement Parameters (×104) 73cʹ. ....................................... 272 Table 65. Bond Lengths in Å for 73cʹ. ........................................................................... 273 Table 62. Hydrogen Fractional Atomic Coordinates (×104) and Equivalent Isotropic Table 63. Fractional Atomic Coordinates (×104) and Equivalent Isotropic Displacement Table 52. Hydrogen Fractional Atomic Coordinates (×104) and Equivalent Isotropic Table 57. Hydrogen Fractional Atomic Coordinates (×104) and Equivalent Isotropic Table 58. Fractional Atomic Coordinates (×104) and Equivalent Isotropic Displacement xi Table 67. Hydrogen Fractional Atomic Coordinates (×104) and Equivalent Isotropic Table 66. Bond Angles in ° for 73cʹ. .............................................................................. 273 Displacement Parameters (Å2×103) for 73cʹ. .................................................................. 274 Table 68. Fractional Atomic Coordinates (×104) and Equivalent Isotropic Displacement Parameters (Å2×103) for 103. .............................................................. 277 Table 69. Anisotropic Displacement Parameters (×104) 103. .................................. 278 Table 70. Bond Lengths in Å for 103. .......................................................................... 279 Table 71. Bond Angles in ° for 103. .............................................................................. 280 Table 72. Hydrogen Fractional Atomic Coordinates (×104) and Equivalent Isotropic Displacement Parameters (Å2×103) for 103. .............................................................. 281 Table 73. Fractional Atomic Coordinates (×104) and Equivalent Isotropic Displacement Parameters (Å2×103) for L2*. ............................................................... 284 Table 74. Anisotropic Displacement Parameters (×104) L2*. ................................... 285 Table 75. Bond Lengths in Å for L2*. ........................................................................... 286 Table 76. Bond Angles in ° for L2*. ............................................................................... 288 Table 77. Hydrogen Fractional Atomic Coordinates (×104) and Equivalent Isotropic Displacement Parameters (Å2×103) for L2*. ............................................................... 290 xii LIST OF FIGURES Figure 10. Pd-catalyzed cross-couplings of various triorganoindium species with Figure 4. a) Structures of o-fluoroaryl motifs in pharmaceuticals and agrochemicals. b) o- Figure 1. Derivatization of the aryl boronic esters. ............................................................ 1 Figure 2. Transition state of proton transfer ..................................................................... 11 Figure 3. General regioselectivity in Ir-catalyzed CHBs .................................................. 12 fluoroaryl motifs as building block ................................................................................... 18 Figure 5. Borylation of fluoroarenesa ............................................................................... 21 Figure 6. Dehalogenation with PMHSa ............................................................................. 23 Figure 7. Different catalyst systems for selective ortho-fluoroarene borylation .............. 26 Figure 8. Borylation of halo arenes.a .............................................................................. 51 Figure 9. Pd-catalyzed cross-couplings of Ph3In with borylated haloarenesa ................... 53 borylated haloarenesa ........................................................................................................ 54 Figure 11. X-ray crystallography of complex A ............................................................ 81 Figure 12. Cobalt-Catalyzed CHBsa ................................................................................. 82 Figure 13. Cobalt-Catalyzed CHBs of Heterocyclesa ....................................................... 87 Figure 14. 1HNMR of complex A as HBpin concentration increases .............................. 90 ........................................................................................................................................... 91 Figure 15. 11BNMR of complex A as HBpin concentration increases ............................. 91 Figure 16. 11BNMR of complex A at coupled and decoupled .......................................... 92 Figure 17. Color difference after 18 h: (Right) with Hg, (Left) without Hg .................... 94 ........................................................................................................................................... 96 Figure 18. Spectra for Evans method calculations ............................................................ 96 Figure 19. 1H NMR of complex A in C6D6 ...................................................................... 96 Figure 20. Preparation of o-Benzenediboronic Acids ..................................................... 107 xiii Figure 21. Two possible regioisomers of di borylated arenes for 2,6-CFA ................... 110 Figure 22. X-ray crystallographic structure of 67c. ........................................................ 111 Figure 23. X-ray crystallographic structure of 68*. ........................................................ 112 Figure 24. Synthesis of 1,2-di and 1,2,3-tri borylated arenes/heteroarenes .................... 115 Figure 25. 19F NMR for CHBs of 74a in hexane (top) Vs. dioxane (bottom) ................ 118 Figure 26. 19F NMR for CHBs of 74a with 76 (top) Vs. 74a without 76 ....................... 121 Figure 27. ........................................................................................................................ 123 1) 1HNMR of 2,2ʹ-bipyrazine (L1) in C6D12 ............................................................... 123 1HNMR 2,2ʹ-bipyrazine (L1) + [Ir(OMe)COD]2 in C6D12 ..................................... 123 2) 3) 1HNMR 2,2ʹ-bipyrazine (L1) + B2Pin2 in C6D12 .................................................... 123 1HNMR 2,2ʹ-bipyrazine (L1) + [Ir(OMe)COD]2 + B2Pin2 in C6D12 ...................... 123 4) Figure 28. possible dearomatization structures for L1 .................................................... 124 Figure 29. CHBs with Ir-dtbpy system ........................................................................... 125 Figure 30. Possible transition state for Ir-bypyrazine system ......................................... 125 Figure 31. Substrate that did not give di or tri borylated compounds ............................. 133 Figure 32. Envisioned mechanism using hemi labile N, N-ligands. ............................... 141 Figure 33. Proposed catalytic cycle for silicon-directed ortho-borylations. ................... 143 Figure 34. Catalytic cycle for outer-sphere directed borylation ..................................... 145 Figure 35. Proposed transition states for ortho borylations of anilines .......................... 146 Figure 36. Hydrogen bond-directed meta borylation with an anionic ligand ................. 147 Figure 37. 14 Vs 16 electron intermediates .................................................................... 151 Figure 38. Scope of substrates ........................................................................................ 152 Figure 39. Scope of the ligands ....................................................................................... 152 Figure 40. 1HNMR of starting material 2,6-CFA ........................................................... 158 Figure 41. 19F-NMR of .................................................................................................. 160 xiv Figure 42. 1HNMR of crude reaction .............................................................................. 161 Figure 43. 1HNMR of starting material 2,6-CFN ........................................................... 167 Figure 44. 1HNMR of starting material 2,6-CFN ........................................................... 168 Figure 45. 1HNMR of starting material Cl-OMePy ........................................................ 170 Figure 46. 1H NMR of .................................................................................................... 171 Figure 47. Comparing Table 16 (entry 5) with Table 17 (entry 7). ................................ 174 Figure 48. 1HNMR of starting material F-OMe-Py ....................................................... 176 Figure 49. 1H NMR of .................................................................................................... 177 Figure 50. Solid state 13C NMR ..................................................................................... 202 Figure 51. Solid state 11B NMR ...................................................................................... 203 Figure 52. Discovery of selective para borylations ....................................................... 211 Figure 53. Selective iridium catalyzed C–H borylations ............................................... 212 Figure 54. Sterically bulky ligand ................................................................................... 212 Figure 55. Crude 1H NMR of the CHBs with 104 .......................................................... 223 Figure 56. 1H NMR of 23 ............................................................................................... 292 Figure 57. 13C NMR of 23 .............................................................................................. 293 Figure 58. 1H NMR of 24 ............................................................................................... 294 Figure 59. 13C NMR of 24 .............................................................................................. 295 Figure 60. 1H NMR of 25 ............................................................................................... 296 Figure 61. 13C NMR of 25 .............................................................................................. 297 Figure 62. 1H NMR of 26 ............................................................................................... 298 Figure 63. 13C NMR of 26 .............................................................................................. 299 Figure 64. 1H NMR of 27 ............................................................................................... 300 Figure 65. 13C NMR of 27 .............................................................................................. 301 Figure 66. 1H NMR of 28 ............................................................................................... 302 xv Figure 67. 13C NMR of 28 .............................................................................................. 303 Figure 68. 1H NMR of 29 ............................................................................................... 304 Figure 69. 13C NMR of 29 .............................................................................................. 305 Figure 70. 1H NMR of 31 ............................................................................................... 306 Figure 71. 13C NMR of 31 .............................................................................................. 307 Figure 72. 1H NMR of 32 ............................................................................................... 308 Figure 73. 13C NMR of 32 .............................................................................................. 309 Figure 74. 1H NMR of 35 ............................................................................................... 310 Figure 75. 13C NMR of 35 .............................................................................................. 311 Figure 76. 1H NMR of 36 ............................................................................................... 312 Figure 77. 13C NMR of 36 .............................................................................................. 313 Figure 78. 1H NMR of 38 ............................................................................................... 314 Figure 79. 13C NMR of 38 .............................................................................................. 315 Figure 80. 1H NMR of 41 ............................................................................................... 316 Figure 81. 13C NMR of 41 .............................................................................................. 317 Figure 82. 1H NMR of 42 ............................................................................................... 318 Figure 83. 13C NMR of 42 .............................................................................................. 319 Figure 84. 1H NMR of 43 ............................................................................................... 320 Figure 85. 13C NMR of 43 .............................................................................................. 321 Figure 86. 1H NMR of 47 ............................................................................................... 322 Figure 87. 13C NMR of 47 .............................................................................................. 323 Figure 88. 1H NMR of 52 ............................................................................................... 324 Figure 89. 13C NMR of 52 .............................................................................................. 325 Figure 90. 1H NMR of 67c .............................................................................................. 326 Figure 91. 13C NMR of 67c ............................................................................................. 327 xvi Figure 92. 1H NMR of 68c .............................................................................................. 328 Figure 93. 13C NMR of 68c ............................................................................................. 329 Figure 94. 1H NMR of 68* ............................................................................................. 330 Figure 95. 13C NMR of 68* ............................................................................................ 331 Figure 96. 1H NMR of 69c .............................................................................................. 332 Figure 97. 13C NMR of 69c ............................................................................................. 333 Figure 98. 1H NMR of 69* ............................................................................................. 334 Figure 99. 13C NMR of 69* ............................................................................................ 335 Figure 100. 1H NMR of 70c ............................................................................................ 336 Figure 101. 13C NMR of 70c ........................................................................................... 337 Figure 102. 1H NMR of 71cʹ ........................................................................................... 338 Figure 103. 13C NMR of 71cʹ .......................................................................................... 339 Figure 104. 1H NMR of 72cʹ ........................................................................................... 340 Figure 105. 13C NMR of 72cʹ .......................................................................................... 341 Figure 106. 1H NMR of 73cʹ ........................................................................................... 342 Figure 107. 13C NMR of 73cʹ .......................................................................................... 343 Figure 108. 1H NMR of 98 ............................................................................................. 344 Figure 109. 13C NMR of 98 ............................................................................................ 345 Figure 110. 1H NMR of 100 ........................................................................................... 346 Figure 111. 13C NMR of 100 .......................................................................................... 347 Figure 112. 1H NMR of 102 ........................................................................................... 348 Figure 113. 13C NMR of 102 .......................................................................................... 349 Figure 114. 1H NMR of 103 ........................................................................................... 350 Figure 115. 13C NMR of 103 .......................................................................................... 351 Figure 116. 1H NMR of L2 ............................................................................................. 352 xvii Figure 117. 13C NMR of L2 ............................................................................................ 353 xviii LIST OF SCHEMES Scheme 1. Common synthesis of aryl boronate esters ........................................................ 2 Scheme 2. Reactions of the CpFe(CO)2(Bcat) complex ..................................................... 3 Scheme 3. Reaction of the Cp*Ir(PMe3)(H)(Bpin) complex ............................................. 4 Scheme 4. CHBs with combination of (Ind)Ir(COD) and phosphine ligands ................... 5 Scheme 5. CHBs with combination of [Ir(COD)Cl]2 & 2,2’-bipyridine ligands ............... 6 Scheme 6. CHBs with combination of catalyst and ligand ................................................. 7 Scheme 7. Widely used catalyst and ligand combination for C–H borylations .................. 8 Scheme 8. Proposed Mechanism for the Ir-Phosphine system ........................................... 9 Scheme 9. Proposed Mechanism for the Ir-bpy system .................................................... 10 Scheme 10. Typical C–H borylation of 3-substituted fluorobenzenes ............................. 19 Scheme 11. Alternate approach to o-fluoro arylboronates ............................................... 20 Scheme 12. Patent example for dehalogenation with ammonium formate ...................... 22 Scheme 13. Dehalogenation with ammonium formate ..................................................... 22 Scheme 14. Protiodeborylation ......................................................................................... 24 Scheme 15. Selective debromonation ............................................................................... 24 Scheme 16. Hydrodehalogenation with Pd/C ................................................................... 24 Scheme 17. One-pot procedure ......................................................................................... 25 Scheme 18. Different type of cross-couplings for CC bond formation ............................ 48 Scheme 19. BF3K Suzuki cross-couplings with a Bpin group present ............................. 49 Scheme 20. Suzuki cross-couplings with an unreactive boronate group present ........ 49 Scheme 21. Organoindium cross-couplings ................................................................... 50 Scheme 22. Organoindium cross-couplings with a Bpin group present ........................... 50 Scheme 23. Synthesis of triorganoindiums ................................................................... 51 xix Scheme 24. Pd-catalyzed cross-couplings of Ph3In with borylated haloarene 23 ............ 52 Scheme 25. Pd-catalyzed cross-coupling side reactions ................................................... 53 Scheme 26. One pot borylation/cross-coupling reaction ................................................. 56 Scheme 27. Polyborylation with a) Cobalt catalyst b) Nickel catalyst ............................ 78 Scheme 28. Polyborylation with a) cobalt catalyst b) MOF ............................................. 79 Scheme 29. Synthesis of cobalt complex A ...................................................................... 80 Scheme 30. Chirik’s cobalt catalyst with ethylbenzene (58) ........................................ 84 Scheme 31. m-Fluorotoluene defluorinated in CHBs ....................................................... 86 Scheme 32. CHB of Toluene vs N-Methylpyrazole ......................................................... 89 Scheme 33. Hg test ........................................................................................................... 89 Scheme 34. Directed o-C−H Functionalization by –Bpza group ................................... 108 Scheme 35. Ligand screening for CHBs ......................................................................... 109 Scheme 36. CHBs of 67a ................................................................................................ 110 Scheme 37. C–H borylation of 68a ................................................................................. 111 Scheme 38. Multiple catalyst loading in CHBs .............................................................. 113 Scheme 39. CHBs of 67a and 68a .................................................................................. 113 Scheme 40. CHBs of 74a in hexane ................................................................................ 117 Scheme 41. CHBs of 23 in dioxane ................................................................................ 118 Scheme 42. CHBs of 75 in 1,4-dioxane .......................................................................... 119 Scheme 43. Equal molar CHBs of 74a and 75 ................................................................ 119 Scheme 44. a) CHBs of 76 b) Equal molar CHBs of 76 and 77 ..................................... 120 Scheme 45. CHBs of 74a with excess 76 ....................................................................... 121 Scheme 46. 1,4-Diboration of substituted pyrazines ...................................................... 124 Scheme 47. Analysis of regioselectivity in Ir-catalysed borylations. ............................. 138 Scheme 48. Oxygen-directed Ir-catalyzed borylations. .................................................. 140 xx Scheme 59. Lewis acid-base interaction for ortho-selective borylation of aryl sulfides. Scheme 49. Silica-SMAP- Ir-catalysed borylations. ..................................................... 140 Scheme 50. Selective borylation of 2-substituted indoles. ............................................. 141 Scheme 51. Directed borylation of aryl pyridines. ......................................................... 142 Scheme 52. Ir-catalysed C–H borylation of benzylic amines. ........................................ 142 Scheme 53. Silicon-directed ortho-borylations of arenes. .............................................. 144 Scheme 54. Silicon-directed borylations at the 7-position of indoles. ........................... 144 Scheme 55. Outer-sphere directed borylation of Boc-protected anilines. ...................... 145 Scheme 56. Outer-sphere directed borylation of free anilines. ....................................... 146 Scheme 57. Hydrogen bond-directed meta-selective borylation of aromatic amides. ... 147 Scheme 58. Aniline CHBs with B2eg2 ............................................................................ 148 ......................................................................................................................................... 149 Scheme 60. B–N bond-directed meta-selective borylation of aromatic aldehydes. ....... 149 directing group. ............................................................................................................... 150 Scheme 62. CHBs of 2,6-CFA (67) ................................................................................ 159 Scheme 63. Making boronic ester from boronic acid ..................................................... 159 Scheme 64. CHBs of borylated 2,6-CFA (67a) ............................................................. 161 Scheme 65. CHBS of 2,6-CFN ....................................................................................... 168 Scheme 66. Making boronic ester from boronic acid ..................................................... 170 Scheme 67. Making boronic ester from boronic acid ..................................................... 176 Scheme 68. CHBs of 2,6-CFA ........................................................................................ 179 Scheme 69. CHBs of 2,6-CFA with extra ligand ............................................................ 180 Scheme 70. Synthesis of DCE-bpy ligand ...................................................................... 180 Scheme 71. Synthesis of btf-DCA-bpy ligand ................................................................ 181 Scheme 72. Platinum catalyzed CHBs ............................................................................ 181 Scheme 61. ortho-selective borylation of unprotected phenols using Beg as traceless xxi Scheme 73. Platinum catalyzed CHBs of fluoroarenes .................................................. 182 Scheme 74. Synthesis of platinum catalyst ..................................................................... 182 Scheme 75. CHBs with Ir(0) nanopartcles ..................................................................... 192 Scheme 76. CHBs with 2,2′-bipyridine-4,4′-dicarboxylic acid ligand ........................... 193 Scheme 77. CHBs with silica-SMAP-Ir ......................................................................... 193 Scheme 78. CHBs with SBA-15-Ir(I) ............................................................................. 194 Scheme 79. CHBs of arenes and heteroarenes in an [IrCl(COD)]2 and 1 system .......... 194 Scheme 80. CHBs without pre-generated active catalyst ............................................... 196 Scheme 81.CHBs with pre-generated active catalyst ..................................................... 197 Scheme 82. Separation of the black solid ....................................................................... 198 Scheme 83. Synthesis of the black solid ......................................................................... 200 Scheme 84. Recycling of the black solid during CHBs .................................................. 200 Scheme 85. CHBs of the black solid Vs. dtbpy .............................................................. 201 Scheme 86. Synthesis of 5,5′-dibromo-2,2′-bipyridine .................................................. 213 Scheme 87.Miyaura coupling of 5,5′-dibromo-2,2′-bipyridine ...................................... 213 Scheme 88. Synthesis of terphenyl halides ..................................................................... 214 Scheme 89. Mechanism for synthesis of terphenyl halides ............................................ 215 Scheme 90. Synthesis of bulky ligand ........................................................................... 215 Scheme 91. C–H activation borylation ........................................................................... 216 xxii KEY TO ABBREVIATIONS 1,8-diaminonaphthalene Bis(pinacolato)diboron 4,4,5,5-Tetramethyl-1,3,2-dioxaborolane N-methyliminodiacetic propane-1,2-diol ethane-1,2-diol Benzyl tert-butyloxycarbonyl BDAN B2pin2 Bpin BMIDA Bpg Beg Bn Boc Bpy(CF3)2 4,4'-bis(trifluoromethyl)-2,2'-bipyridine bpy Cat CHBs Cp COD COE 2,6-CFA CPME CFN dmpe dppe dtbpy 2,2′-bipyridine Catecholate C–H activation borylations Cyclopentadienyl Cyclooctadiene Cyclooctene 2-Chloro-6-fluoroanisole Cyclopentylmethyl ether 1-Chloro-3-fluoro-2-methoxybenzonitrile Bis(dimethylphosphino)ethane 1,2-Bis(diphenylphosphino)ethane 4,4′-di-tert-butyl-2,2′-bipyridine xxiii DCA-bpy DCE-bpy 2,2′-Bipyridine-5,5′-dicarboxylic acid Dimethyl 2,2'-bipyridine-4,4'-dicarboxylate DoM EtOAc GC GCMS HBpin ICP In Ir ipcADI KF KOtBu L1 MOF Me MgSO4 NAA NMR NHC Pt Pd PMHS directed ortho metalation Ethyl acetate Gas chromatography Gas chromatography–mass spectrometry Pinacoleborane Induction Coupled Plasma Indium Iridium N,N´-di(-)isopinocampheyl)butane-2,3-diimine Potassium fluoride Potassium tert-butoxide 2,2’-Bipyrazine metal-organic framework Methyl Magnesium sulphate Neutron Atomic Absorption Nuclear magnetic resonance N-heterocyclic carbine Platinum Palladium Polymethylhydrosiloxane xxiv Pd(OAc)2 Pd(PPh3)2Cl2 Pd(dppf)Cl2 Palladium(II) acetate Bis(triphenylphosphine)palladium(II) dichloride [1,1'-Bis(diphenylphosphino)ferrocene]palladium(II) PBEs PBAs Pza THF tmp R3In XRD dichloride Poly-boronic esters Poly-boronic acids Pyrazolylaniline Tetrahydrofuran 3,4,7,8-tetramethylphenanthroline Triorganoindium X-ray powder diffraction xxv Chapter 1. Introduction 1.1 Arylboronic Easters Arylboronic esters are valuable synthetic intermediates in organic synthesis.1 Owing to their low toxicity, stability, ease of handling and their ultimate degradation into boric acid, boronic acids can be regarded as “green” compounds.2 Environmentally benign and user friendly characteristics make them more attractive than the other toxic, sensitive organometallic reagents. Also, versatile reactivity of arylboronic acid analogues makes derivatization easy (Figure 1).3,4 It has been well documented that these boronic esters/acids are mainly used in metal catalyzed cross–coupling reactions to form C–C bonds (e.g. Suzuki–Miyaura) or C-heteroatom bonds (e.g. Chan–Lam coupling). 5,6 R1 R2 BF3K R3 KHF2 B(OH)2 KIO4H+ R1 R2 R3 CuBr2 Br R1 R2 R3 OH R1 R2 R3 Aq. Oxone Acetone Bpin R3 Pd Ar-X Ar R3 R1 R2 R1 R2 R1 R2 R3 CuCl2 Zn(CN)2 Cu(NO3)2 Cu(OAc)2 HNRR’ Cl R1 R2 NRR’ R1 R2 R3 CN R3 Figure 1. Derivatization of the aryl boronic esters. 1 1.2 Methods of Synthesizing Arylboronic Easters Boron compounds are accessed mainly by two general methods starting from organic halides (Scheme 1). The first method involves making organometallic intermediates via metal–halogen exchange using arylmagnesium or aryllithium, followed by the reaction with trialkylboronates.7–9 Another widely used route for making boronate esters is Pd- or Cu-catalyzed borylations of aryl halides using a boron source such as bis(pinacolato)diboron (B2pin2) or pinacoleborane (HBpin).6,10 Also, Lewis acid catalyzed electrophilic borylations of electron-rich arenes,11–14 and Sandmeyer-type borylation of arylamines or diazonium salts with B2pin2,15–18 B2(OH)4 19 or R2N-BH2 20 are reported. However, most of these methods relies heavily on the availability of preceding organic halides R X x = Halide BuLi (or Mg) - 78 °C R MX B(OR')3 -MX(OR') R Pd(Cl)2dppf, KOAc, DMSO [B(OR')2]2 Miyaura Coupling OR' B OR' Scheme 1. Common synthesis of aryl boronate esters 1.3 Direct C–H activation borylations A long–standing challenge in synthetic chemistry is the direct, selective functionalization of various C–H bonds. Many research groups have made great progress towards functionalizing alkyl and aryl C–H bonds to C–C, C–O, C–N, C-X (X = F, Cl, Br and I) and etc. However, the direct conversion of C–H to C–B bonds is a more recent discovery and significant progress has been made by several research groups toward the development of this C–H bond functionalization in high yields and high 2 selectivity. Among these methods, iridium catalyzed C–H bond activation borylations (CHBs) is the most widely used route to synthesize oragnoboron compounds.2,21–23 This method reduces the number of steps and allows simple access to complementary regioselectivity. In 1993, Marder and co–workers reported the first synthesis of trisboryl iridium complexes and in supporting information GC/MS data indicated the formation of a small amount (<1%) of two isomers of toylboronate ester as side product arising form borylation of the toluene. However, the formation of this product was not discussed in the paper or further studies were done.24 In 1995, Hartwig and co–workers developed the first stoichiometric route to functionalized arenes and alkenes by irradiation of CpFe(CO)2(Bcat) (Cp = cyclopentadienyl, cat = 1,2-O2C6H4 =catecholate) (Scheme 2). In addition to the photochemical borylation of arenes by CpFe(CO)2(Bcat), similar borylations by Mn(CO)5(Bcat) and Re(CO)5(Bcat) were reported by the same group.25 Bcat PhH hv, 1 h 90% 10% Bcat Bcat + HBcat + [CpFe(CO)2]2 60% 56% hv, 1 h OC hv, 1 h H2 in pentane OMe Bcat + CO Fe CO Bcat OMe hv, 1 h + Bcat OMe OMe + Bcat Bcat 1.1 : 1.0, 70% 1.0 : 1.6 : 1.1, 52% Bcat Scheme 2. Reactions of the CpFe(CO)2(Bcat) complex 3 In 1999, Smith and co–workers developed the first thermal catalytic route to functionalized arenes using a Cp*Ir(PMe3)(H)(Bpin) catalyst (Scheme 3).21 Low turnover numbers were observed with 5 equiv of HBpin in deuterated benzene at 150 °C catalyzed by 17 mol % of Cp*Ir(PMe3)(H)(Bpin) to form C6D5Bpin in 53% yield (ca. 3 turnovers). Later the scope of the borylations of arenes was investigated by the same group.26 The borylation of mono substituted arenes provided a mixture of arylboronate esters, and the borylation of 1,3-disubstituted arenes exclusively gave the 3,5-disubstituted arylboronate esters. However, no studies on arenes containing amines, esters, amides, or of heteroarenes catalyzed by Cp*Ir(PMe3)(H)(Bpin) were reported. + H-Bpin Me3P Ir H Bpin 17 mol% 150 °C, 120h Bpin 53 % + H2 Scheme 3. Reaction of the Cp*Ir(PMe3)(H)(Bpin) complex Later studies reported that iridium systems containing phosphine- and nitrogen- based ligands could catalyze the borylation of arenes with faster rates and higher yields than those containing Cp* ligands. In 2002, Smith, Maleczka and co–workers tested the reactivity of (Ind)Ir(COD) and trimethylphosphine, 1,2-bis(dimethylphosphino)ethane (dmpe), or 1,2-bis(diphenylphosphino)ethane (dppe) as catalysts for the borylation of arenes with HBpin (Scheme 4).2 The highest yields of arylboronate esters was generated from a 2:1 ratio of PMe3 to (Ind)Ir(COD) or a 1:1 ratio of dmpe or dppe to (Ind)Ir(COD). Also, this system tolerated halogens, ethers, and esters. Borylations of pyridine was also reported. 4 R + H-Bpin Bpin L = dppe 95% Bpin 2 mol% (Ind)Ir(COD), 2 mol% L Bpin R + H2 150 °C Bpin F F F L = dmpe 63% Bpin Cl Cl L = dppe, 100°C 63% Bpin Bpin Cl N Cl Cl CO2Me L = dppe, 100°C 69% L = dppe, 100°C 95% OMe OMe L = dmpe 62% Scheme 4. CHBs with combination of (Ind)Ir(COD) and phosphine ligands Also in 2002, Ishiyama, Miyaura, Hartwig, and co-workers reported the borylation of arenes catalyzed by iridium complexes of bipyridine and di-tert- butylbipyridine. 27 They reported the borylation of arenes with B2pin2 in the presence of catalytic amounts of [Ir(COD)Cl]2 and 2,2′-bipyridine (bpy) or 4,4′-di-tert-butyl-2,2′- bipyridine (dtbpy) occurred at 80 °C. Moderate to good yields were observed for different arenes with B2pin2 catalyzed by 1.5 mol % [Ir(COD)Cl]2 and 3 mol % bpy (again regioselectivity was controlled by sterics). Monosubstituted arenes, such as anisole, and trifluoromethylbenzene gave an approximately statistical mixture of (2:1) products arising from meta- and para- borylation, with the product from ortho-borylation being observed (1%) only from the reaction of anisole (Scheme 5). 5 R + B2pin2 1.5 mol% [Ir(COD)Cl]2 3.0 mol% bpy 80 °C, 16h Bpin 2 R + H2 Bpin OMe 95% (1:74:25) (o: m: p) Bpin CF3 80% (0:70:30) (o: m: p) Bpin OMe 86% Bpin Cl 83% OMe Bpin 86% Bpin Cl Br OMe 73% Scheme 5. CHBs with combination of [Ir(COD)Cl]2 & 2,2’-bipyridine ligands The borylation of 1,3-disubstituted arenes formed 3,5-disubstituted arylboronate esters exclusively. Reactions catalyzed by the iridium catalyst containing the bipyridine derivative occur at room temperature to 80 °C, in many cases with turnover numbers between 500 and 1000. In contrast, the reactions catalyzed by the phosphine-ligated iridium complexes gave few turnover numbers. Ishiyama, Miyaura, Hartwig, and co-workers then developed similar catalyst systems that were more active at lower temperatures and that reacted with higher turnover numbers than the initial system. An induction period was observed with the borylation of benzene-d6 with B2pin2 in a combination of [Ir(COD)Cl]2 and bpy. During this induction period, the cyclooctadiene ligand was reduced to cyclooctene-d2. Therefore, [Ir(COE)2Cl]2 (COE = cyclooctene) was investigated as the iridium precursor, and dtbpy as the ligand. Borylation of benzene and yielded 80% PhBpin at room temperature with no observable induction period. This reaction was the first example of a metal-catalyzed borylation of an arene that occurred at room temperature. Furthermore, 6 they tested different Ir(I)-cyclooctadiene precursors such as [Ir(COD)Cl]2, [Ir(COD)2]BF4, [Ir(COD)(OH)]2, [Ir(COD)(OPh)]2, [Ir(COD)(OMe)]2, and [Ir(COD)(OAc)]2 for CHBs of benzene and found that [Ir(OMe)COD]2 is the most active catalyst for borylations.27 They also studied the borylation of arenes catalyzed by iridium complexes of a series of disubstituted 2,2′-bipyridines to investigate the importance of electronic and steric properties of the 2,2′-bipyridine ligand (Scheme 6). 1.5 mol% [Ir(X)Cl]2 3.0 mol% L Bpin 2 R + H2 2 R + B2pin2 X = OH, OPh, OMe rt L = R3 R2 R1 R1 R2 N N R4 R3 R4 R1, R2, R3, R4 = H, Me, NMe2, OMe, tBu, Cl, NO2 Scheme 6. CHBs with combination of catalyst and ligand Electronic properties: They studied borylations catalyzed by iridium complexes of a series of 4,4′-disubstituted-2,2′-bipyridine ligands and found that electron donating substituents, such as NMe2, OMe, or tBu, catalyzed the borylation benzene with B2pin2 with higher yields. However, bipyridine ligands containing electron-withdrawing groups, such as Cl and NO2, did not catalyze the borylations of benzene with B2pin2. Steric properties: 4,4′-Dimethyl-2,2′-bipyridine or 5,5′- dimethyl-2,2′-bipyridine ligands facilitated the reaction of benzene with B2pin2 to form PhBpin in good yields. However, the use of 3,3′-dimethyl- 2,2′-bipyridine as ligand yielded only 60% PhBpin, because of steric hindrance. However, the Ir-catalyzed reaction of benzene with B2pin2 catalyzed by 3,3′-dimethyl- 2,2′-bipyridine as the ligand gave only moderate yields of arylboronic esters. Methyl groups in the 3- and 3′-positions prevents the pyridine rings 7 from adopting a coplanar arrangement, and this structural change was proposed to be responsible for the lower yields. Also, 6,6′-dimethyl-2,2′-bipyridine was not an effective ligand in the reaction of benzene and B2pin2, due to proposed steric hindrance around the nitrogen atoms in 6,6′-dimethyl-2,2′-bipyridine preventing binding to the iridium complex. All these studies lead to discovery of the most reactive iridium catalyst and ligand system for C–H activation borylations (Scheme 7). 2 R + B2pin2 1.5 mol% [Ir(OMe)COD]2 3.0 mol% L tBu L = rt tBu N N Bpin 2 R + H2 Scheme 7. Widely used catalyst and ligand combination for C–H borylations 1.4 Mechanism for direct C–H activation borylations Smith and co-workers obtained data to distinguish between a catalytic cycle involving Ir(I) and Ir(III) intermediates and a cycle involving Ir(III) and Ir(V) intermediates. They prepared the Ir(I)-boryl complex Ir(Bpin)(PMe3)4 and the Ir(III)- boryl complex fac-Ir(Bpin)3(PMe3)3. Both Ir(Bpin)(PMe3)4 and fac- Ir(Bpin)3(PMe3)3 reacted with benzene to produce PhBpin.21 However, the reaction of Ir(Bpin)(PMe3)4 with iodobenzene did not produce the iodophenylboronic ester, whereas the reaction of Ir(III) complex with iodobenzene yielded a mixture of meta- and para-borylated iodo- benzene in 54% yield and PhBpin in 45% yield. The authors did not rule out a pathway involving Ir(I) and Ir(III) intermediates but favored a catalytic cycle involving Ir(III) and Ir(V) species (Scheme 8). 8 (PR3)nIrIII(Bpin)(E)2 PhH Bpin E Ph (PR3)nIrV H E E–E (PR3)nIrv(Bpin)(E)4 H2 HBpin or E–E (PR3)nIrIII(H)(E)2 E = H, Bpin n = 1, 2 PhBpin Scheme 8. Proposed Mechanism for the Ir-Phosphine system Further studies related to iridium catalyzed C–H borylations with bipyridine ligands were carried out by Hartwig and coworkers. In 2005, they reported some extensive mechanistic details about iridium catalyzed C–H borylations.28 Studies were based on the functionalization of arenes with the diboron reagent B2pin2 catalyzed by the combination of dtbpy and olefin-ligated iridium halide or olefin-ligated iridium alkoxide complexes. The catalyst resting state was identified as [Ir(dtbpy)(COE)(Bpin)3]. Comparing the kinetic isotope effects of the catalytic and stoichiometric reactions indicated that the reactive intermediate [Ir(dtbpy)(Bpin)3] cleaves the arene C-H bond. Synthesis of [Ir(dtbpy)(COE)(Bpin)3] was more facile with [Ir(COD)(OMe)]2, dtbpy, COE, and HBpin and less yield with B2pin2. 9 Hartwig and co–workers also proposed a catalytic cycle similar to that of Smith and co–workers that goes through a Ir(III)/Ir(v) cycle (Scheme 9). Also, kinetic studies showed that [Ir(dtbpy)(COE)(Bpin)3] complex reacts with arenes after reversible dissociation of COE. They also confirmed that an alternative mechanism in which the arene reacts with the Ir(I) complex [Ir(dtbpy)Bpin] after dissociation of COE and reductive elimination of B2pin2 does not occur to a measurable extent. HBpin B2pin2 N N N N H N N Ir Bpin Bpin Bpin Bpin Ir Bpin Bpin Ir Bpin Bpin N N oxidative addition Bpin Ph H Ir Bpin Bpin reductive elimination PhBpin Scheme 9. Proposed Mechanism for the Ir-bpy system The reaction of [Ir(dtbpy)(COE)(Bpin)3] with arenes and the catalytic reaction of B2pin2 with arenes catalyzed by the combination of [Ir(COD)(OMe)]2 and dtbpy occurs faster with electron-poor arenes than with electron-rich arenes. However, both the 10 stoichiometric and catalytic reactions also occur faster with the electron-rich heteroarenes thiophene and furan than with arenes, perhaps because η2-heteroarene complexes are more stable than the η2-arene complexes and the η2-heteroarene or arene complexes are intermediates that precede oxidative addition. The presence of electronic effects on relative reactivities of arenes in Ir-catalyzed CHBs has been noted from the earliest studies.26 Smith, Maleczka, Singleton and co- workers carried out experimental and computational investigation on the Ir-catalyzed CHBs arene and heteroarenes. Experiment and theory favor a model of C-H borylation where significant proton transfer character exists in the transition state (Figure 2).29 This explains the accelerated borylation rates in pyrrole, thiophenes, furan and the selective functionalization of C-H positions next to the heteroatoms in indole, benzofuran, benzothiophene, whose pKas’ are relatively low. B O O δ H δ Ir δ Figure 2. Transition state of proton transfer 1.5 Regioselectivity in Ir-catalyzed CHBs In electrophilic aromatic substitution (EAS) reactions, steric effects can influence the substitution, however electronic effects typically dominate. Substituents on aromatic rings fall into two classes: ortho, para directors and meta directors and EAS does not allways offer well-defined regiochemical outcomes. Ir-catalyzed CHBs are mainly governed by sterics. Figure 3 shows a summary of how CHBs work for arenes and heteroarenes. 11 S M/L M/L M/L M/L S meta:para = 2:1 X X = O,S S X X = O,S M/L N S N L S N L N X X = O,S N S N 2 3 1 Figure 3. General regioselectivity in Ir-catalyzed CHBs 12 REFERENCES 13 REFERENCES Boronic Acids Preparation and Applications in Organic Synthesis, Medicine and (1) Materials, 2., vollständig überarbeitete Auflage.; Hall, D. G., Ed.; Wiley-VCH: Weinheim, Bergstr, 2011. (2) Maleczka, R. E., Jr.; Smith, M. R., III. Remarkably Selective Iridium Catalysts for the Elaboration of Aromatic C–H Bonds. Science 2002, 295. (3) Mkhalid, I. A. I.; Barnard, J. H.; Marder, T. B.; Murphy, J. M.; Hartwig, J. F. C-H Activation for the Construction of C-B Bonds. Chem. Rev. 2010, 110, 890–931. (4) Hartwig, J. F. 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Commun. 2010, 46, 7724–7726. 17 Chapter 2. A Catalytic Borylation / Dehalogenation Route to ortho- Fluoro Arylboronates 2.1 Introduction Fluorinated arenes regularly emerge as lead candidates for pharmaceutical,1,2 agrochemical,3 and materials applications.4 Drug candidates with one or more fluorine atoms have become conventional. The special nature of fluorine shows a variety of properties to certain medicines, including enhanced binding interactions, metabolic stability, changes in physical properties, and selective reactivities (Figure 4a). a) Pharmaceuticals Agrochemicals Me HO O F F OO S N H N N N F OMe N Flurbiprofen (anti-inflammatory drug) Florasulam (herbicide) b) Fluoro Arylboronic Ester Building Blocks H2N F R B(OR)2 For a BtK inhibitor F pinB O N O R For an antibacterial agent Figure 4. a) Structures of o-fluoroaryl motifs in pharmaceuticals and agrochemicals. b) o-fluoroaryl motifs as building block Also, common to these fields is the use of arylboronic ester building blocks (Figure 4b).5,6 As such, preparations of arenes bearing both fluoro and boronate substituents are often sought after. Fluorobenzenes have been borylated via reactive intermediates generated by various methods including directed deprotonation and metal- halogen exchange.7 Such reactions typically demand the use of strong lithium bases 18 and/or cryogenic conditions. Activation of a properly positioned halogen by palladium8 represents a milder approach, but demands the regioselective installation of the halogen. Given the substrate dependence on aromatic halogenations, accessing suitable haloaromatic starting materials can be trivial or prohibitively difficult. Ir-catalyzed CHBs avoid the need for strong bases, cold temperatures, and/or halogen pre–functionalization. They tolerate numerous functional groups, including fluorine and have thus been used to generate many fluorobenzenes bearing a 4,4,5,5- tetramethyl-1,3,2-dioxaborolane (Bpin) group. Iridium catalyzed borylations are primarily driven by sterics, making it is relatively easy to install Bpin's ortho to hydrogen or fluorine vs. other aryl substituents.9 This feature can be very useful, but can also create challenges. Fluorine atom has been recognized as an unsuitable substituent for either steric or ortho-directing control of regioselectivity due to its small van der Waals radius and low coordination ability. Therefore, close competition between the sterics of the positions ortho (blue) to F vs. meta (red) to F has often made borylation via halogenated starting materials the preferred option for selective borylations of 3-substituted (or 2,3-disubstituted) fluorobenzenes. For example, under standard conditions, borylations of 3-substituted (or 2,3-disubstituted) fluorobenzenes typically afford ~1:1 mixtures of borylated arenes (Scheme 10). R 3 1 H F H cat. [Ir(OMe)COD]2 cat. dtbpy R 3 1 B2pin2, rt, THF Bpin F H R 3 1 F + (~1:1) H Bpin Scheme 10. Typical C–H borylation of 3-substituted fluorobenzenes For selective borylations ortho to the fluorine this requires the acquisition of 6- halo-3-substituted-fluorobenzenes. The availability of arenes with such a substitution 19 pattern is highly dependent on the nature of the substituent C-3 (and that at C-2). In fact, in certain instances the availability and/or costs of arenes with a bromo or iodo substituent positioned ortho to the fluorine make them unattractive starting materials, while analogous arenes with halogens para to the fluorine are more readily available. 2.2 Alternate approach to o-fluoro arylboronates We hypothesized that readily available 3-substituted fluoroarenes with a halo group para to the fluorine could serve as convenient starting materials for the generation of ortho borylated products. Specifically, in such cases the halogen would not serve as an activating group for metalation, but rather as a sacrificial blocking group in an Ir- catalyzed C–H borylation. In this way, borylation would only take place ortho to the fluorine and upon removal of the para positioned halogen the desired ortho borylated 3- substituted fluoroarene would be generated (Scheme 11). R X 3 1 H F H C–H borylation R X 3 1 F Bpin H dehalo- genation X = Br or Cl blocking group R 3 1 F Bpin H exclusive regioisomer Scheme 11. Alternate approach to o-fluoro arylboronates 2.3 Borylation of fluoroarenes To begin testing this hypothesis a variety of haloarenes were reacted with 1 mol % [Ir(OMe)(COD)]2, 2 mol % 4,4′-di-tert-butyl-2,2′-dipyridyl ligand (dtbpy) and 0.55 equiv of bis(pinacolato)diboron (B2Pin2) in THF at room temperature (Figure 5). Except where otherwise noted, all of these arenes selectively afforded the ortho borylated products in good yields. 20 Figure 5. Borylation of fluoroarenesa R2 X CF3 R1 F 1 mol % [Ir(OMe)COD]2 0.55 equiv B2pin2 2 mol % dtbpy, THF, rt, 24 h R2 X F H R1 F Bpin CO2Me F OMe F Br 1 (62%) Bpin Br F 2 (83%b) F Bpin Br NH2 3 (86%) F Bpin Br Bpin Br F MeO Bpin Br Br F3C Br 5 (86%d) 8 (71%) 6 (78%e) 9 (95%) Bpin Br F Bpin Me Br Me 4 (64%c) F Bpin N F Bpin F Bpin 7 (91%f) 10 (88%) aIsolated yields. bBorylation run at 60 °C for 36 h; product contains 3% of the meta Bpin isomer. cProduct contains 1% of the meta Bpin isomer. dProduct contains 4% of the meta Bpin isomer. eBorylation run with 0.5 mol % [Ir(OMe)COD]2, 1 mol % tmp, 3.0 equiv HBpin at 80 °C for 16 h. f Borylation run at 80 °C for 14 h after which 0.25 equiv HBpin was added and the reaction was allowed to continue at 80 °C for 10 h; product contains 9% of the meta Bpin isomer. 2.4 Dehydrohalogenation of fluoroarenes The key goal was to dehalogenate the borylated arenes without compromising the Bpin group. Radical based methods are not suitable for that task, but, despite the potential for unwanted Suzuki couplings, a few such Pd-mediated reductions have been reported. Among these, Pd/C mediated transfer hydrogenation using ammonium formate as an in- situ hydrogen donor was attractive owing to the mild and low cost nature of the reagents.10 Another example from the patent literature involved removing a chloride group in presence of a Bpin (Scheme 12). 21 O Bpin NH Cl 10 mol % Pd/C 10 equiv NH4+HCOO– MeOH, 60 °C 40 min O Bpin NH H Scheme 12. Patent example for dehalogenation with ammonium formate Unfortunately, in our hands, for fluoro aromatic systems except anisoles such reductions were almost always accompanied by 5-15% loss of the Bpin group as well as other unidentified impurities (Scheme 13).11 R1 R2 10 mol % Pd/C 10 equiv NH4+HCOO– R2 F R1 F MeOH, 60 °C Bpin X X = Br or Cl, R1 or R2 = CF3, Me, CO2Me, NH2 40 min H Bpin/H (5-15% H) Scheme 13. Dehalogenation with ammonium formate We next turned to our own experience with the hydrodehalogenation of 3-chloro- 5-methylphenylpinacolborane using fluoride activated polymethylhydrosiloxane (PMHS)12 in the presence of catalytic polysiloxane encapsulated Pd(0) nanoclusters.13 To see if we could build from this lone example, the borylated fluoroarenes were subjected to 4 equiv of PMHS, 2 equiv of aqueous KF, and 5 mol % Pd(OAc)2 in THF (Figure 6). Most substrates responded favorable to these reductions conditions, affording the desired products in 60–90% yield after 4-5 h reaction times and with no evidence of deborylation. Electron deficient arenes tended to undergo hydrodehalogenation slightly faster than electron rich arenes. The method was amenable to heterocycles as borylated 5-chloro-2-fluoropyridine underwent hydrodehalogenation in 1 h using only 2 equiv PHMS. 22 Figure 6. Dehalogenation with PMHSa R2 Br CF3 R1 F Bpin H (4 h, 79%) 11 F 5 mol % Pd(OAc)2 2 equiv KF, 4 equiv PMHS H2O, THF, rt, 4–5 h F Bpin R2 H CO2Me F (2.4/1) Bpin/H H (1 h, 37%b) 12 OMe F Bpin H (5 h, 91%) 13 NH2 R1 F Bpin Me F Bpin H (5 h, 89%c) 14 F F N F Bpin H (4 h, 63%d) 15 H F3C F MeO 16 (3 h, 69%) F Bpin H Bpin 17 (1 h, 98%e) Bpin H (4 h, 80%) 18 Bpin H (5 h, 89%) 19 Me F Bpin H (5 h, 80%c) 20 aIsolated yields of arylboronates. the 2.4/1 borylated/deborylated material was 60%. cVia chlorinated starting material 4; product contains 1% of the meta Bpin isomer per the starting material. dProduct contains 4% of the meta Bpin isomer per the starting material. eProduct included 9% of the meta Bpin isomer per the starting material, 1% of an unidentified fluorinated product and 2% starting material by 19F-NMR. bCombined yield of We were unable to completely eliminate protodeborylation as illustrated by the methylbenzoate example (compound 12). In an attempt to overcome this problem, 18- crown-6/KF in a water free reaction was explored.14 This met with limited success as hydrodehalogenation times increased due to low KF solubility and other unidentified products were observed by 19F-NMR. The dehalogenation shown in Scheme 14 indicates that the electronic influence of the fluorine is what heightens the propensity toward Protiodeborylation. Here the diborylated arene partially lost the Bpin group ortho to fluorine, while the meta Bpin remained completely intact. 23 pinB Me Cl F Bpin 5 mol % Pd(OAc)2 2 equiv KF 2 equiv PMHS H2O, THF, rt, 24 h Me pinB F (3/1) Bpin/H H 21 (85% combined Bpin/H products; 37% isolated diBpin 21) Scheme 14. Protiodeborylation Hydrodebromonations were generally more facile than hydrodechloronations. We were able to exploit this differential reactivity and selective remove a bromine in the presence of a chlorine by reducing the amount of PMHS to 2 equiv, which also resulted in increasing the reaction time (Scheme 15). Br F Bpin Cl 5 mol % Pd(OAc)2 2 equiv KF, 2 equiv PMHS H H2O, THF, rt, 28 h (85% by NMR) F Bpin Cl 22 Scheme 15. Selective debromonation We also screened Pd/C (10% wt) as a palladium source (Scheme 16). Employing 5 mol % Pd/C (with respect to Pd weight) gave the corresponding hydrodehalogenated product, but required 24 h to reach full conversion vs. 4 h with Pd(OAc)2. We attribute this time difference to the proficiency with which Pd(OAc)2 forms polysiloxane encapsulated Pd(0) nanoclusters.10 CF3 Br 1 5 mol % Pd/C 2 equiv KF, 4 equiv PMHS H2O, THF, rt, 24 h (83%) F Bpin CF3 H 11 F Bpin Scheme 16. Hydrodehalogenation with Pd/C 24 2.5 One-pot borylation/dehalogenation We investigated performing the Ir-catalyzed borylation and the Pd-catalyzed hydrodehalogenation in a single pot (Scheme 17). Again, longer reaction times were required to see full conversion during the dehalogenation step. This too is likely due to formation of the Pd(0) nanoparticles being slowed by the residuals from the borylation reaction. Nonetheless, the one-pot yields for the substrates tested, were comparable to the combined yields observed over two steps. R1 F H R2 Br 6 R1 = NH2, R2 = H 9 R1 = H, R2 = OMe 0.55 equiv B2pin2 1 mol % [Ir(OMe)COD]2 2 mol % dtbpy, THF, rt, 24 h then 5 mol % Pd(OAc)2 2 equiv KF, 4 equiv PMHS H2O, THF, rt. 24–40 h R1 F Bpin R2 H 16 (40 h, 62%) R1 = NH2, R2 = H 19 (24 h, 63%) R1 = H, R2 = OMe Scheme 17. One-pot procedure 2.6 Recent advancements in selective o-fluoro arylboronic esters To the best of our knowledge and as indicated by a SciFinder Scholar (2014) search, fluorinations of arylboronic esters are unknown. Recently there have been several reports of introducing Bpin group to fluoroaromatic rings using precious or base metals. Such examples include the use of phosphine.15 and POP supported rhodium catalysts,16 NHC17 and PSiN ligated platinum catalysts,18 as well as a pincer ligated cobalt catalyst,19 for the selective ortho-fluoroarene borylation (Figure 7). 25 a) Braun and Co-workers b) Esteruelas and Co-workers Et3P Bpin Rh PEt3 PEt3 – Limited substrate scope (arenes with multiple fluorines) – Excess material O PiPr2 Rh H PiPr2 – Limited substrate scope – Excess material – Elevated temperatures c) Chatani and Co-workers d) Iwasawa and Co-workers Cl N N Cl Pt Me2Si O Si Me2 – Broad substrate scope – Excess material – C–H borylations at the sterically encumbered position Me Si PCy2 Pt Cl NMe2 – Broad substrate scope – Excess material – Elevated temperatures – Electronically driven e) Chirik and Co-workers H N PiPr2 Co Bpin H PiPr2 – Broad substrate scope – Mild reaction conditions – Halogens are not tolerated (except fluorine) – No effect from directing groups (–NMe2 and –SiHMe2) Example: DG F PiPr2 Co Bpin H N H PiPr2 5 mol% Co catalyst 0.55 M in THF 1 equiv of B2pin2 50 °C, 24 h DG F Bpin Figure 7. Different catalyst systems for selective ortho-fluoroarene borylation These methods still suffer from excess use of substrate, limited functional group tolerance and expensive ligand synthesis. Selective borylation of fluoro arenes represent a new area that is still emerging and improved methods that can selectively generate either steric or electronic isomer exclusively without pre-functionalized arenes or without expensive ligand synthesis will be attractive. 26 2.7 Conclusions We have demonstrated a solution to the problem of selectively generating arylboronic esters ortho to fluorine via Ir-catalyzed C–H borylations when both the ortho and meta positions are sterically accessible. Furthermore, as para halogenated fluorobenzenes or often more available and/or less expensive than their ortho counterparts, this protocol can be competitive with Pd-catalyzed borylations. Finally, telescoping the borylation and hydrodehalogenation into a single reaction flask is viable. 2.8 Experimental Material and Methods All reactions were carried out in oven-dried glassware under an atmosphere of nitrogen, with magnetic stirring, and monitored by 1H-NMR and 19F-NMR. Tetrahydrofuran was freshly distilled from sodium/benzophenone under nitrogen. Palladium (II) acetate purchased from Strem, anhydrous A. C. S grade potassium fluoride, and polymethylhydrosiloxane (PMHS) purchased from Aldrich were used. Column chromatography was performed with silica gel (230-400 mesh) purchased from Silicycle. 1H, 13C, 11B, and 19F NMR spectra were recorded on an Agilent DirectDrive2 500 MHz NMR spectrometer equipped with an OneProbe operating at 499.7 MHz for 1H NMR, 125.7 MHz for 13C NMR, 470.1 MHz for 19F NMR and 160.3 MHz for 11B NMR. Elemental composition was determined by accurate mass analysis using a Waters GCT Premier gas chromatograph / time-of-flight mass spectrometer at the Michigan State University Mass Spectrometry Service Center; the products were ionized using an electron ionization source operated in the positive mode. Infrared spectroscopy was 27 obtained at Michigan State University using an FT-IR Mattson spectrometer. Melting points were measured on a Thomas-Hoover capillary melting point apparatus. General Procedure for Borylation: R1 R2 X 1 mol % [Ir(OMe)COD]2 0.55 equiv B2pin2 2 mol % dtbpy, THF, rt, 24 h R2 X F H R1 F Bpin In a nitrogen atmosphere glove box bis(pinacolato)boron (B2Pin2) (140 mg, 0.55 mmol) was weighed into a 20 mL vial containing a magnetic stir bar. [Ir(OMe)COD]2 (6.6 mg, 0.02 mmol) and 4,4’-di-tert-butyl-2,2’- dipyridyl ligand (5.4 mg, 0.02 mmol) were weighed into two test tubes separately, each being diluted with 2 mL of THF. The [Ir(OMe)COD]2 solution was transferred into the 20 mL vial containing B2Pin2. This mixture was stirred until a golden yellow clear solution was obtained (~ 1 min). Next the solution containing ligand was transferred into the vial and upon stirring the resulting solution turned a dark brown color. Finally, the substrate (1 mmol) was added to the vial, which was then sealed. The reaction mixture stirred for 24 h at room temperature, after which the vial was taken out of the glove box. The reaction mixture was passed through a short plug of silica eluting with a 10:1 hexane/ethyl acetate solution (2 x 20 mL). The volatiles were removed by rotary evaporation. Compound 1 CF3 F Br 1 Bpin 28 The general borylation procedure was carried out on 1.0 mmol of the starting arene. After workup 0.228 g of compound 1 were obtained as a white solid (mp 76–77 °C) in 62% yield. 1H NMR (500 MHz, CDCl3) ! 8.02 (dd, J = 2.5, 3.5 Hz, 1H), 7.78 (dd, J = 2.5, 6.5 Hz, 1H), 1.36 (s, 12H); 13C NMR (125 MHz, CDCl3) ! 162.9 (dd, J = 1.9, CDCl3) ! –61.9, –106.4; 11B NMR (160 MHz, CDCl3) ! 29.3 (brs). MS EI+ m/z 120.0 (qd, J = 33.1, 16.1 Hz), 116.3 (d, J = 3.5 Hz), 84.7, 24.8; 19F NMR (470 MHz, 259.7 Hz), 143.1 (d, J = 8.5 Hz), 132.8 (qd, J = 1.9, 4.7 Hz), 121.7 (q, J = 270.3 Hz), calculated for C13H14BBrF4O2 368.0206, found 368.0178. Compound 2 COOMe F Br Bpin 2 The general borylation procedure was carried out on 3.76 mmol of the starting arene. After workup 1.124 g of compound 2, containing ~3% of the meta Bpin isomer, were obtained as a white solid (mp 99–101 °C) in 83% isolated yield. 1H NMR (500 MHz, CDCl3) ! 8.13 (dd, J = 3.0, 3.0 Hz, 1H), 8.00 (dd, J = 2.5, 3.0 Hz, 1H), 3.92 (s, 3H), 1.37 (s, 12H); 13C NMR (125 MHz, CDCl3) ! 164.8 (d, J = 263.7 Hz), 163.9 (d, J = 4.6 Hz), 84.6, 52.6, 24.8; 19F NMR (470 MHz, CDCl3) ! –101.5; 11B NMR (160 MHz, CDCl3) ! 143.6 (d, J = 9.5 Hz), 137.7 (d, J = 1.9 Hz), 120.7 (d, J = 13.4 Hz), 116.3 (d, J = 3.7 Hz), 29.4 (brs). FT-IR: 2978.7, 2928.4, 2843.1, 1740.5, 1722.0, 1602.7, 1438.3, 1408.2, 1357.4, 1235.9, 1211.1, 1142.6, 980.0, 849.4, 787.6, 672.1 cm-1. MS EI+ m/z calculated for C14H17BBrFO4 358.0387, found 358.0422. 29 Compound 3 OCH3 F Br 3 Bpin The general borylation procedure was carried out on 1 mmol of the starting arene. After workup 0.283 g of compound 3 were obtained as a white solid (mp 79–80 °C) in 86% isolated yield. 1H NMR (500 MHz, CDCl3) ! 7.37 (dd, J = 2.5, 4.0 Hz, 1H), 7.14 (dd, J = 2.5, 7.5 Hz, 1H), 3.85 (s, 3H), 1.34 (s, 12H); 13C NMR (125 MHz, CDCl3) ! Hz), 116.0 (d, J = 3.7 Hz), 84.3, 56.6, 24.8; 19F NMR (470 MHz, CDCl3) ! –126.6; 11B NMR (160 MHz, CDCl3) ! 29.7 (brs). MS EI+ m/z calculated for C13H17BBrFO3 155.8 (d, J = 251.2 Hz), 148.3 (d, J = 13.2 Hz), 129.4 (d, J = 7.6 Hz), 119.6 (d, J = 2.9 330.0438, found 330.0467. Compound 4 CH3 Cl 4 F Bpin The general borylation procedure was carried out on 1 mmol of the starting arene. After workup 0.173 g of compound 4, containing ~1% of the meta Bpin isomer, were obtained as a white solid (mp 64–65 °C) in 64% isolated yield. 1H NMR (500 MHz, CDCl3) ! 7.49 (dd, J = 3.0, 6.5 Hz, 1H), 7.22 (dd, J = 2.0, 6.5 Hz, 1H), 2.23 (d, J = 2.0 Hz, 3H), 1.34 (s, 12H); 13C NMR (125 MHz, CDCl3) ! 163.9 (d, J = 247.5 Hz), 134.2 (d, 24.7, 14.5 (d, J = 3.9 Hz); 19F NMR (470 MHz, CDCl3) ! –109.9; 11B NMR (160 MHz, J = 5.7 Hz), 133.4 (d, J = 8.5 Hz), 128.4 (d, J = 2.9 Hz), 126.6 (d, J = 21.9 Hz), 84.1, 30 CDCl3) ! 29.8 (brs). MS EI+ m/z calculated for C13H17BClFO2 270.0994, found 270.0984. Compound 5 F 5 F Bpin Br The general borylation procedure was carried out on 1 mmol of the starting arene. After the workup 0.274 g of compound 5, containing ~4% of the meta Bpin isomer, were obtained as a white solid (mp 41–42 °C) in 86% isolated yield. 1H NMR (500 MHz, CDCl3) ! 7.57 (ddd, J = 2.0, 4.0, 5.0 Hz, 1H), 7.37 (ddd, J = 2.5, 7.0, 9.0 Hz, 1H), 1.34 (s, 12H); 13C NMR (125 MHz, CDCl3) ! 153.7 (dd, J = 11.4, 252.2 Hz), 150.3 (dd, J = 16.1, 84.6, 24.7; 19F NMR (470 MHz, CDCl3) ! -130.0, -134.9; 11B NMR (160 MHz, CDCl3) ! 253.2 Hz), 133.7 (dd, J = 4.0, 7.0 Hz), 123.4 (d, J = 20.0 Hz), 115.6 (dd, J = 4.0, 7.0 Hz), 29.3 (brs). MS EI+ m/z calculated for C12H14BBrF2O2 318.0238, found 318.0251. Compound 6 NH2 F Br 6 Bpin The borylation procedure1 was carried out on 1 mmol of the starting arene, using 0.5 mol % [Ir(OMe)COD]2, 1 mol % tmp (3,4,7,8-tetramethyl-1,10-phenanthroline) as the ligand, and 3.0 equiv of HBpin as the boron source at 80 °C for 16 h. The reaction mixture was stirred at 80 °C for 16 h. After the workup 0.246 g of compound 6 were obtained as a white solid (mp 99–100 °C) in 78% isolated yield. 1H NMR (500 MHz, 31 CDCl3) ! 7.17 (dd, J = 2.5, 4.0 Hz, 1H), 6.99 (dd, J = 2.5, 7.5 Hz, 1H), 3.82 (brs, 2H (NH2)), 1.36 (s, 12H); 13C NMR (125 MHz, CDCl3) ! 154.6 (d, J = 242.8 Hz), 135.9 (d, J 19F NMR (470 MHz, CDCl3) ! -127.7; 11B NMR (160 MHz, CDCl3) ! 29.7 (brs). FT-IR: = 16.1 Hz), 126.9 (d, J = 6.6 Hz), 121.9 (d, J = 3.7 Hz), 116.6 (d, J = 3.7 Hz), 84.2, 24.8; 3474.6, 3383.8, 2983.2, 2930.5, 1625.8, 1564.9, 1478.9, 1430.2, 1358.1, 1272.6, 1191.6, 1140.5, 972.9, 863.2, 846.0, 737.6, 675.0 cm-1. MS EI+ m/z calculated for C12H16BBrFNO2 315.0441, found 315.0465. Compound 7 N 7 F Bpin Cl The general borylation procedure was carried out on 4 mmol of the starting arene and the reaction mixture was heated for 80 ° C for 19 h. After 19 hr, 0.25 eqiv of HBpin was added and the mixture stirred for an additional 10 h at 80 °C. After the workup 0.9328 g of compound 7, containing ~9% of the meta Bpin isomer (isomer ratio = 89:11), were obtained as a white solid (mp 46–47 °C) in 91% isolated yield. For 7 1H NMR (500 MHz, CDCl3) ! 8.24 (d, J = 2.0 Hz, 1H), 8.12 (dd, J = 3.0, 7.0 Hz, 1H), 1.37 (s, 12H); 13C NMR (125 MHz, CDCl3) ! 165.1 (d, J = 243.8 Hz), 148.9 (d, J = 16.1 Hz), 147.5 (d, J = 8.5 Hz), 128.6, 84.8, 24.8; 19F NMR (470 MHz, CDCl3) ! -61.5; 11B NMR (160 MHz, CDCl3) ! 29.4 (brs). MS EI+ m/z calculated for C11H14BClFNO2 257.0790, found 257.0813. 32 Compound 8 F3C Br F 8 Bpin The general borylation procedure was carried out on 10 mmol of the starting arene. After workup 2.619 g of compound 8 were obtained as a white solid (mp 66–67 °C) in 71% isolated yield. 1H NMR (500 MHz, CDCl3) ! 8.03 (d, J = 5.5 Hz, 1H), 7.37 (d, J = 8.5 Hz, 1H), 1.37 (s, 12H); 13C NMR (125 MHz, CDCl3) ! 165.4 (d, J = 253.1 (m), 113.8, 84.8, 24.8; 19F NMR (470 MHz, CDCl3) ! –63.5, –102.9; 11B NMR (160 Hz), 142.8 (d, J = 8.5 Hz), 134.0 (qd, J = 8.5, 32.2 Hz), 121.9 (q, J = 272.2 Hz), 115.6 MHz, CDCl3) 29.5 (brs). MS EI+ m/z calculated for C13H14BBrF4O2 368.0206, found 368.0220. Compound 9 H3CO Br F 9 Bpin The general borylation procedure was carried out on 1 mmol of the starting arene. After workup 0.313 g of compound 9 were obtained as a white solid (mp 104–105 °C) in 95% isolated yield. 1H NMR (500 MHz, CDCl3) ! 7.89 (d, J = 6.5 Hz, 1H), 6.61 (d, J = 11.0 Hz, 1H), 3.72 (s, 3H), 1.35 (s, 12H); 13C NMR (125 MHz, CDCl3) ! 167.6 (d, J = (d, J = 2.9 Hz), 83.9, 56.4, 24.8; 19F NMR (470 MHz, CDCl3) ! –100.4; 11B NMR (160 MHz, CDCl3) ! 29.5 (brs). MS EI+ m/z calculated for C13H17BBrFO3 330.0438, found 251.2 Hz), 159.5 (d, J = 11.4 Hz), 140.2 (d, J = 10.4 Hz), 108.3 (d, J = 22.7 Hz), 105.9 330.0411. 33 Compound 10 H3C Cl F 10 Bpin The general borylation procedure was carried out on 10 mmol of the starting arene. After workup 2.38 g of compound 10 were obtained as a white solid (mp 48–49 °C) in 88% isolated yield. 1H NMR (500 MHz, CDCl3) ! 7.66 (d, J = 5.5 Hz, 1H), 6.91 (d, J = 9.5 Hz, 1H), 2.35 (s, 3H), 1.34 (s, 12H); 13C NMR (125 MHz, CDCl3) ! 165.4 (d, (d, J = 25.6 Hz), 84.1, 24.7, 20.4 (d, J = 1.9 Hz); 19F NMR (470 MHz, CDCl3) ! -106.5; 11B NMR (160 MHz, CDCl3) ! 29.8 (brs). MS EI+ m/z calculated for C13H17BClFO2 J = 249.4 Hz), 141.7 (d, J = 9.5 Hz), 136.5 (d, J = 8.5 Hz), 129.1 (d, J = 2.9 Hz), 117.7 270.0994, found 270.0997. General Procedure for the Hydrodehalogenation with PMHS: R1 R2 Br 5 mol % Pd(OAc)2 2 equiv KF, 4 equiv PMHS H2O, THF, rt, 4-5 h F Bpin R2 H R1 F Bpin A round bottom flask was charged with the borylated arene (1 mmol), Pd(OAc)2 (0.05 mmol, 0.011g), and 5 mL of freshly distilled THF. The round bottom flask was fitted with a septum and flushed with nitrogen. While being flushed, KF (0.116 g, 2 mmol) in 2 mL of degassed water was then introduced by syringe. The nitrogen inlet was removed and a balloon filled with nitrogen was attached to the flask. PMHS (0.24 mL, 4 mmol) was then slowly injected dropwise (Caution: Gas evolution and an exothermic reaction occure upon the addition of PMHS). The final reaction mixture was stirred until 1H (and 19F NMR) indicated the disappearance of starting material (~4 h unless otherwise noted). The reaction mixture 34 was then diluted with Et2O and the layers separated. The ether layer was filtered through a plug of Celite contained in a 60 mL syringe. The Celite was flushed with EtOAc. Finally, the volatiles were removed by rotary evaporation. The product was redisolved in hexane/EtOAc and passed through a small plug of silica gel eluting with 20 mL hexane, followed by 40 mL EtOAc. Compound 11 CF3 F H 11 Bpin The general hydrodehalogenation procedure with PMHS was applied to 1 mmol 1H), 7.70 (ddd, J = 1.5, 6.0, 7.5 Hz, 1H), 7.23 (dd, J = 6.5, 8.5 Hz, 1H), 1.37 (s, 12H); of borylated arene 1. After workup 0.229 g of compound 112 were obtained as as colorless oil in 79% yield. 1H NMR (500 MHz, CDCl3) ! 7.93 (ddd, J = 1.5, 5.5, 7.0 Hz, 13C NMR (125 MHz, CDCl3) ! 164.0 (dd, J = 1.9, 260.3 Hz), 140.7 (d, J = 9.5 Hz), 130.8 19F NMR (470 MHz, CDCl3) ! –61.6, –104.2; 11B NMR (160 MHz, CDCl3) ! 29.8 (brs). (qd, J = 2.5, 4.7 Hz), 123.5 (d, J = 4.1 Hz), 122.7 (q, J = 271.0Hz), 118.3 (m), 84.3, 24.8; MS EI+ m/z calculated for C13H15BF4O2 290.1101, found 290.1089. Compound 12 COOMe F H 12 Bpin The general hydrodehalogenation procedure with PMHS was applied to 1 mmol of borylated arene 2, with a reaction time of 1 h. After workup 0.286 g of a 2.4:1 ratio of 35 12 and methyl 2-fluorobenzoate containing was isolated in 60% combined yield. The mixture, which also contained a small amount of PMHS was subjected to column chromatography with hexane (50 mL) followed by hexane/ethyl acetate (4/1, 100 mL) to 8.03 (ddd, J = 2.0, 7.5, 7.5 Hz, 1H), 7.92 (ddd, J = 2.0, 5.5, 7.5 Hz, 1H), 7.21 (dd, J = 7.0, afford 0.1023 g of pure 12 as a white solid (mp 54–55 °C) in 37% isolated yield. (Note: Compounds were visualized using Alazarin TLC stain.) 1H NMR (500 MHz, CDCl3) ! 7.5 Hz, 1H), 3.92 (s. 3H), 1.37 (s, 12H); 13C NMR (125 MHz, CDCl3) ! 165.9 (d, J = 118.5 (d, J = 12.4 Hz), 84.2, 52.3, 24.8 (d, J = 4.75); 19F NMR (470 MHz, CDCl3) ! – 99.1; 11B NMR (160 MHz, CDCl3) ! 30.0 (brs). 263.7 Hz), 165.3 (d, J = 3.9 Hz), 141.4 (d, J = 9.5 Hz), 135.3, 123.6 (d, J = 3.7 Hz), Compound 13 OCH3 F H Bpin 13 The general hydrodehalogenation procedure with PMHS was applied to 1 mmol of borylated arene 3. The reaction ran for 5 h. After work up 0.228 g of 13 were obtained as a colorless oil in 91% isolated yield. 1H NMR (500 MHz, CDCl3) ! 7.27 (m, 1H), 7.06 (m, 2H), 3.87 (s, 3H), 1.36 (s, 12H); 13C NMR (125 MHz, CDCl3) ! 156.8 (d, J = 249.5 Hz), 83.9, 56.5, 24.8; 19F NMR (470 MHz, (CDCl3) ! –125.1; 11B NMR (160 MHz, CDCl3) ! 30.2 (brs). MS EI+ m/z calculated for C13H18BFO3 252.1333, found 252.1337. Hz), 147.5 (d, J = 12.3 Hz), 127.4 (d, J = 7.6 Hz), 123.8 (d, J = 3.7 Hz), 116.9 (d, J = 1.9 36 Compound 14 CH3 F H 14 Bpin The general hydrodehalogenation procedure with PMHS was applied to 1 mmol of borylated arene 4, which contained 1% of the meta Bpin isomer. The reaction ran for (ddd, J = 1.5, 5.0, 7.5 Hz, 1H), 7.29 (ddd, J = 1.0, 6.0, 7.0 Hz, 1H), 7.04 (dd, J = 7.5, 7.5 5 h. After work up 0.211 g of 14,2 which contained 1% of the meta Bpin isomer, were obtained as a colorless oil in 89% isolated yield. 1H NMR (500 MHz, CDCl3) ! 7.56 Hz, 1H), 2.28 (d, J = 2.5 Hz, 3H), 1.37 (s, 12H); 13C NMR (125 MHz, CDCl3) ! 165.6 (d, (d, J = 2.9 Hz), 83.8, 24.8, 14.6; 19F NMR (470 MHz, CDCl3) ! –106.9; 11B NMR (160 MHz, CDCl3) ! 30.4 (brs).1 MS EI+ m/z calculated for C13H18BFO2 236.1384, found J = 248.4Hz), 134.7 (d, J = 5.6 Hz), 134.1 (d, J = 8.6 Hz), 124.6 (d, J = 19.8 Hz), 123.4 236.1405. Compound 15 F 15 H F Bpin The general hydrodehalogenation procedure with PMHS was applied to 1 mmol of borylated arene 5, which contained 4% of the meta Bpin isomer. After work up 0.1512 g of 15, which contained 1% of the meta Bpin isomer, were obtained as a colorless oil in 63% isolated yield. 1H NMR (500 MHz, CDCl3) ! 7.45 (m, 1H), 7.23 (m, 1H), 7.06 (m, 1H), 1.36 (s, 12H); 13C NMR (125 MHz, CDCl3) ! 154.6 (dd, J = 11.5, 251.5 Hz), 150.5 (dd, J = 14.3, 247.6 Hz), 131.1 (dd, J = 3.7, 6.6 Hz), 124.1 (dd, J = 3.9, 37 5.7 Hz), 120.2 (d, J = 17.1 Hz), 84.2, 24.8; 19F NMR (470 MHz, CDCl3) ! –129.1, – 139.1; 11B NMR (160 MHz, CDCl3) ! 29.8 (brs). MS EI+ m/z calculated for C12H15BF2O2 240.1133, found 240.1142. Compound 16 NH2 F H 16 Bpin The general hydrodehalogenation procedure with PMHS was applied to 0.76 mmol of borylated arene 6. The reaction ran for 3 h. After work up 0.143 g of 16 were obtained as a white solid (mp 92–93 °C) in 69% isolated yield. 1H NMR (500 MHz, CDCl3) ! 7.09 (m, 1H), 6.95 (dd, J = 7.0, 8.0 Hz, 1H), 6.89 (ddd, J = 1.5, 6.5, 8.5 Hz, 1H), 3.72 (s, 2H), 1.37 (s, 12H); 13C NMR (125 MHz, CDCl3) ! 155.7 (d, J = 241.8 Hz), 83.8, 24.8; 19F NMR (470 MHz, CDCl3) ! –125.6; 11B NMR (160 MHz, CDCl3) ! 30.3 134.3 (d, J = 14.2 Hz), 125.3 (d, J = 7.6 Hz), 124.0 (d, J = 3.9 Hz), 119.9 (d, J = 3.7 Hz), (brs). MS EI+ m/z calculated for C12H17BFNO2 237.1336, found 237.1332. Compound 17 N F H 17 Bpin The general hydrodehalogenation procedure with PMHS was applied to 1 mmol of borylated arene 7, which contained 9% of the meta Bpin isomer, using 2 equiv of PMHS. The reaction ran for 1 h. After workup 19F NMR indicated an NMR yield of 88% 17, 9% of the meta Bpin isomer per the starting material, 2% starting material, and 38 (dd, J = 1.5, 4.5 Hz, 1H), 8.16 (ddd, J = 2.5, 7.0, 9.0 Hz, 1H), 7.17 (m, 1H) 1.35 (s, 12H); 1% of an unidentified fluorinated product. For 173 1H NMR (500 MHz, CDCl3) ! 8.28 13C NMR (125 MHz, CDCl3) ! 166.8 (d, J = 243.7 Hz), 150.6 (d, J = 14.2 Hz), 148.4 (d, J = 7.5 Hz), 120.9 (d, J = 4.75 Hz), 84.4, 24.7; 19F NMR (470 MHz, CDCl3) ! –57.8; 11B NMR (160 MHz, CDCl3) ! 29.7 (brs). MS EI+ m/z calculated for C11H15BFNO2 223.1180, found 223.1198. Compound 18 F3C H F 18 Bpin The general hydrodehalogenation procedure with PMHS was applied to 1 mmol of borylated arene 8. After workup 0.232 g of 18 were obtained as a colorless oil in 80% isolated yield. 1H NMR (500 MHz, CDCl3) ! 7.87 (dd, J = 6.5, 6.5 Hz, 1H), 7.40 (d, J = 8.0 Hz, 1H), 7.30 (d, J = 9.0 Hz, 1H), 1.38 (s, 12H); 13C NMR (125 MHz, CDCl3) ! (m), 112.3 (m), 84.8, 24.8; 19F NMR (470 MHz, CDCl3) ! –63.2, –100.6; 11B NMR (160 166.7 (d, J = 251.4 Hz), 137.6 (d, J = 8.5 Hz), 135.1 (m), 123.2 (q, J = 271.2 Hz), 120.3 MHz, CDCl3) 30.1 (brs). MS EI+ m/z calculated for C13H15BF4O2 290.1101, found 290.1102. Compound 19 H3CO H 19 F Bpin The general hydrodehalogenation procedure with PMHS was applied to 1 mmol of borylated arene 9. The reaction ran for 5 h. After workup 0.152 g of 19 were obtained 39 7.5 Hz, 1H), 6.70 (dd, J = 2.5, 8.0 Hz, 1H), 6.58 (dd, J = 2.5, 12.0 Hz, 1H), 3.83 (s, 3H), as a colorless oil in 61% isolated yield. 1H NMR (500 MHz, CDCl3) ! 7.66 (dd, J = 7.5, 1.36 (s, 12H); 13C NMR (125 MHz, CDCl3) ! 168.6 (d, J = 249.4 Hz), 163.9 (d, J = 11.2 24.8; 19F NMR (470MHz, CDCl3) ! -100.5; 11B NMR (160 MHz, CDCl3) ! 29.9 (brs). Hz), 137.7 (d, J = 10.5 Hz), 109.9 (d, J = 2.9 Hz), 101.1 (d, J = 27.5 Hz), 83.6, 55.4, MS EI+ m/z calculated for C13H18BFO3 252.1333, found 252.1329. Compound 20 H3C H F 20 Bpin The general hydrodehalogenation procedure with PMHS was applied to 1 mmol of borylated arene 10. The reaction ran for 5 h. After workup 0.189 g of 204 were obtained as a white solid (mp 58–60 °C) in 80% isolated yield. 1H NMR (500 MHz, CDCl3) ! 7.63 (dd, J = 7.0, 7.5 Hz, 1H), 6.96 (d, J = 7.5 Hz, 1H), 6.86 (d, J = 10.5 Hz, 1H), 2.37 (s. 3H), 1.37 (s, 12H); 13C NMR (125 MHz, CDCl3) ! 167.3 (d, J = 249.4 Hz), 83.7, 24.8, 21.5; 19F NMR (470 MHz, CDCl3) ! -103.8; 11B NMR (160 MHz, CDCl3) ! 144.4 (d, J = 8.5 Hz), 136.6 (d, J = 8.6 Hz), 124.5 (d, J = 2.9 Hz), 115.8 (d, J = 23.7 Hz), 30.3 (brs). MS EI+ m/z calculated for C13H18BFO2 236.1384, found 236.1391. Compound 21 pinB H Me 21 F Bpin 40 The general hydrodehalogenation procedure with PMHS was applied to 1 mmol of the starting borylated arene. The reaction ran for 24 h. After workup 0.324 g of a 3:1 ratio of 2,2'-(2-fluoro-3-methyl-1,4-phenylene)bis(4,4,5,5-tetramethyl-1,3,2- dioxaborolane) (21) and 2-(3-fluoro-2-methylphenyl)-4,4,5,5-tetramethyl-1,3,2- dioxaborolanein was isolated. The mixture was subjected to silica gel column chromatography eluting with hexane (100 mL) followed by hexane/ethyl acetate (9/1, 100 mL) to afford 0.135 g of 21 as a white solid (mp 163–165 °C) in 37% isolated yield. (Note: Compounds were visualized using Alazarin TLC stain.) 1H NMR (500 MHz, CDCl3) ! 7.50 (m, 2H), 2.45 (d, J = 3.0 Hz, 3H), 1.37 (s, 12H), 1.35 (s, 12H); 13C NMR (125 MHz, CDCl3) ! 165.4 (d, J = 247.6 Hz), 132.9 (d, J = 8.5 Hz), 130.8 (d, J = 17.1 CDCl3) ! –107.2; 11B NMR (160 MHz, CDCl3) ! 30.4 (brs). Anal. Calcd for Hz), 130.4 (d, J = 3.8 Hz), 83.8, 83.7, 24.87, 24.83, 13.30, 13.25; 19F NMR (470MHz, C19H29B2FO4: C, 63.0; H, 8.1. Found C, 61.6; H, 7.6. One Pot Borylation and Hydrodehalogenation R1 F H R2 Br 6 R1 = NH2, R2 = H 9 R1 = H, R2 = OMe 1 mol % [Ir(OMe)COD]2 2 mol % dtbpy, THF, rt, 24 h 0.55 equiv B2pin2 then 5 mol % Pd(OAc)2 2 equiv KF, 4 equiv PMHS H2O, THF, rt. time R1 F Bpin R2 H 16 (40 h, 62%) R1 = NH2, R2 = H 19 (24 h, 63%) R1 = H, R2 = OMe The general borylation procedure was carried out on 1 mmol of starting arene 9 and the reaction was complete after 24 h as judged by NMR. The reaction solution was transferred to an oven dried round bottom flask, which was sealed by a rubber septum 41 and brought out of the nitrogen atmosphere glove box. The general hydrodehalogenation procedure was followed for 24 h. The reaction mixture was then diluted with Et2O and the layers separated. The ether layer was filtered through a plug of silica gel. The silica gel was flushed with hexane (2 x 10 mL) and then with a 1:1 hexane/ethyl acetate mixture (10 mL). The eluted solution was concentrated by rotary evaporatoration. The product was dissolved in 10:1 hexane/ethyl acetate and filtered through another plug of silica gel to remove the final traces of boron and Pd byproducts. The plug was flushed with hexane (4 x 10 mL). The volatiles were removed by rotary evaporation to afford 0.1597 g of 19 as a light orange oil in 63% isolated yield. Hydrodehalogenation with NH4 +HCOO–: Borylated arenes, 1–4, 6, and 8–10, were dehalogenated via Pd/C mediated transfer hydrogenation using ammonium formate as an in situ hydrogen donor.5 Unfortunately, in our hands, aside from anisoles such reductions were almost always accompanied by 5-15% loss of the Bpin group as well as other unidentified impurities. See Table 1 for details. General Procedure for a One-pot Hydrodehalogenation with NH4 +HCOO–: The general borylation procedure was carried out on 1 mmol of starting arene and the reaction was complete after 24 h as judged by NMR. The reaction solution transferred to an oven dried Schlenk flask, which was sealed by a rubber septum and brought out of the nitrogen atmosphere glove box. Palladium on activated charcoal (10% 42 Pd by weight, 0.108 g) and ammonium formate (0.64 g, 10.0 mmol) in MeOH (30 mL) were introduced under a nitrogen atmosphere. The mixture was heated at 60 °C for 30– 40 min, cooled to RT and filtered through Celite®. The filter cake was rinsed with MeOH. The filtrate was concentrated and sent through a short silica plug using 1:1 hexane/ethyl acetate to remove boron waste and palladium residues. Then the filtrate ws concentrated to dryness and the residue partitioned between water (10 mL) and EtOAc (20 mL). The organic layer was washed with brine (20 mL), dried over anhydrous MgSO4 and concentrated to obtain the boronic ester. (Note: This protocol led to partial protodeborylation when performed on electron poor arenes.) 43 Table 1. Hydrodehalogenation with Ammonium Formate R1 10 mol % Pd/C 10 equiv NH4+HCOO– F MeOH, 60 °C 40 min Bpin Starting Arene R2 X Entry 1 2 3 4 5 6 7 8 CF3 F Bpin 1 CO2Me F Bpin F Bpin F Bpin F Bpin F Bpin F Bpin F Bpin 2 OMe 3 Me 4 NH2 6 81 93 104 Br Br Br Cl Br F3C Br MeO Br Me Cl R1 F Bpin R2 H Dehalogenation (rxn time, yielda) Product CF3 F Bpin/H 11 (40 min, 85:15) CO2Me F Bpin/H 12 (55 min, 87:13) OMe F Bpin 13 (40 min, 55%) Me F Bpin/H 14 (60 min, 96:4) NH2 F Bpin/H/Unk 16 (40 min, 93:6:1) F3C F Bpin/H 18 (40 min, 90:10) MeO F Bpin 19 (24 h, 78%)b Me F Bpin/H/Unk 20 (60 min, 87:7:6) aIsolated yields. bone pot reaction at room temperature. 44 REFERENCES 45 REFERENCES (a) Babudri, R.; Farinola, G. M.; Naso, F.; Ragni, R. Chem. Commun. 2007, Purser, S.; Moore, P. R.; Swallow, S.; Gouverneur, V. Chem. Soc. Rev. 2008, 37, (a) Jeschke, P. Chembiochem. 2004, 5, 570–589. (b) Jeschke, P. Pest Manag. Sci. (1) (a)Hagmann, W. K. J. Med. Chem. 2008, 51, 4359–4369. 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Chem. 2011, 76, 9602–9610. (8) (9) Science 2002, 295, 305-308. (b) Chotana, G. A.; Rak, M. A.; Smith, M. R. J. Am. Chem. Soc. 2005, 127, 10539–10544. (b) Mkhalid, I. A. I.; Barnard, J. H.; Marder, T. B.; Murphy, J. M.; Hartwig, J. F. Chem. Rev. 2010, 110, 890–931. Ishiyama, T.; Murata, M.; Miyaura, N. J. Org. Chem. 1995, 60, 7508–7510. (a) Cho, J. Y.; Tse, M. K.; Holmes, D.; Maleczka, R. E., Jr.; Smith, M. R., III, 46 Ghosh, B.; Maleczka, R. E., Jr. Tetrahedron Lett. 2011, 52, 5285–5287. A one-pot Ir-catalyzed borylation/dehalogenation sequence using ammonium For the versatile reducing ability of PMHS see: (a) Lawrence, N. J.; Drew, M. D.; (a) Maleczka, R. E., Jr.; Rahaim, R. J.; Teixeira, R. R. Tetrahedron Lett. 2002, 43, (10) (a) Yoakim, C.; Bailey, M. D.; Bilodeau, F.; Carson, R. J.; Fader, L.; Kawai, S.; Simoneau, S. L. B.; Surprenant, S.; Thibeault, C.; Tsantrizos, Y. S. Inhibitors of human immunodeficiency. virus replication U.S. Patent 8,338,441, December 25, 2012. (b) Rajagopal, S.; Spatola, A. F. J. Org. Chem. 1995, 60, 1347–1355. (c) Anwer, M. K.; Sherman, D. B.; Roney, J. G.; Spatola, A. F. J. Org. Chem. 1989, 54, 1284–1289. (11) Bushell, S. M. J. Chem. Soc., Perkin Trans 1. 1999, 3381–3391. (b) Lavis, J. M.; Maleczka, R. E., Jr. Polymethylhydrosiloxane (PMHS), In EROS-Electronic Encyclopedia of Reagents for Organic Synthesis; Paquette, L. A.; Crich, D.; Fuchs, P. L.; Wipf, P., Eds.; Wiley: New York, 2003, Online. (12) 7087–7090. (b) Rahaim, R. J.; Maleczka, R. E., Jr. Tetrahedron Lett. 2002, 43, 8823– 8826. (13) (14) formate was also effective, but only when the arene was electron rich. See experimental section for details. (15) Kalläne, S. I.; Teltewskoi, M.; Braun, T.; Braun, B. Organometallics 2015, 34, 1156–1169. (16) Esteruelas, M. A.; Olivan, M.; Vélez, A. Organometallics 2015, 34, 1911–19924. (17) Furukawa, T.; Tobisu, M.; Chatani, N. J. Am. Chem. Soc. 2015, 137, 1221112214. (18) Takaya, J.; Ito, S.; Nomoto, H.; Saito, N.; Kirai, N.; Iwasawa, N. Chem. Commun. 2015, 51, 17662–17665. (19) Obligacion, J. V.; Bezdek, M. J.; Chirik, P. J. J. Am. Chem. Soc. 2017, 139, 2825−2832. 47 Chapter 3. Merging Iridium Catalyzed C-H Borylations with Organoindium 3.1 Introduction Cross-Couplings Ir-catalyzed C-H borylation is a renowned method for making boronic esters of arene and heteroarenes.1 This method tolerates many functional groups including halogens.2 These halo boronic esters enables further orthogonal coupling reactions which leads to broad scope of diverse molecules. We and others have shown that halogen bearing arylboronic esters can undergo reactions to form C–C and C–N3 bonds leaving the boronic ester intact for future use. There are several reports for making C–C bonds, for example, some successes have also been realized for the Negishi,4–7 Stille,8 Kumada,9 and Hiyama10 couplings of Bpin substituted haloarenes (Scheme 18a–b) a) Negishi, Stille, or Kumada cross-couplings with a Bpin group present R3 R2 R1 Bpin + R3 R2 ZnX/SnR3/MgX Pd or Ni catalysis b) Hiyama cross-couplings with a Bpin or B(OH)2 group present R3 R1 Bpin + R2 Si(OAr)2 X X R1 Bpin R2 & R3 = 1° or 2° alkyl or aryl R2 R3 Ni photocatalysis R1 Bpin R2 & R3 = 1° or 2° alkyl Scheme 18. Different type of cross-couplings for CC bond formation Molander and co-workers have developed a complementary strategy whereby aryl-BF3K salts selectively couple with Bpin bearing haloarenes to in situ form Bpin substituted arenes that can be subjected to subsequent chemical events such as oxidation and Suzuki coupling reactions (Scheme 19).11 48 X R3 R1 Bpin + R2 BF3K R2 R3 Ir/Ni photo- catalysis R1 Bpin [O] or Suzuki products Scheme 19. BF3K Suzuki cross-couplings with a Bpin group present Cross coupling reactions of halo boronic esters occasionally suffer from unwanted polyphenyl formation or undergo hydrogen elimination which leads to other by-products. In cases where the borylation product bears a halide (e.g. Br) exposure to Suzuki conditions leads to the formation of hyperbranced polyphenyls.2 Therefore, to avoid these hyperbranching palladium mediated reactions of haloarenes bearing N- methyliminodiacetic12–16 acid and 1,8-diaminonaphthalene17,18 boronic esters (BMIDA and BDAN respectively) have been reported. Here unwanted polyphenylene formation is avoided as BMIDA and BDAN are unreactive under certain Suzuki conditions, (Scheme 20). The produced borylated biaryls have been used in iterative palladium catalyzed Suzuki-Miyaura cross-couplings popularized by Burke and others.19 X R BMIDA/BDAN + Ar Bpin Ar Pd catalysis R BMIDA/BDAN Bpin = B O O BMIDA = Me N B O O O BDAN = O H B H N N Scheme 20. Suzuki cross-couplings with an unreactive boronate group present 3.2 Organoindium cross coupling Seeking to build on our tandem Ir catalyzed borylations aminations, we sought cross– coupling conditions that would allow for C–C bond formation at the site of the halogen that would proceed without compromising the Bpin. The self-Suzuki reactions 49 are facilitated by the presence of aqueous base, and therefore should be minimized during base free Pd-catalyzed cross-coupling.3 Methodology that go close together with our need is Sarandeses–Sestelo couplings (Scheme 21). Here triorganoindium reagents possess the ability to transfer all three organic ligands; they are of low toxicity as compared to tin derivatives and they do not require the addition of base additives. R3 In + 3 R' X Pd catalyst THF R1 R2 R1 = OMe R2 = H R1= OCONEt2 R2 = Me 96% 99% Me R2 R1 N 78% 70% NO2 R2 R1 S 74% 88% 3 R' R Ph Ph 97% Ph Ph N 91% Ph Ph Ph S 84% Scheme 21. Organoindium cross-couplings Given these features, especially the ability to operate base-free and thereby minimize polyphenylene formation, we looked to merge Sarandeses–Sestelo cross- couplings with CHB’s and establish a method for the cross-coupling of triorganoindiums with CHB derived arylhalides bearing a Bpin substituent (Scheme 22).20–26 Br R1 Bpin + R2 via Ir-catalyzed CH borylation R3 Pd catalyst no base In 3 R2 R3 R1 Bpin R2 & R3 = 1° or 2° alkyl, vinyl, alkynyl, aryl, heteroaryl Scheme 22. Organoindium cross-couplings with a Bpin group present 3.3 Investigations and optimizations To begin, a variety of haloarenes were reacted with 0.05 mol % [Ir(OMe)(COD)]2, 0.10 mol % 4,4′-di-tert-butyl-2,2′-dipyridyl ligand (dtbpy) and 0.55 equiv of 50 bis(pinacolato)diboron (B2Pin2) in THF at room temperature to isolate borylated haloarenes 23–29 (Figure 8). Figure 8. Borylation of halo arenes.a X 0.05 mol % [Ir(OMe)COD]2 0.55 equiv B2pin2 0.10 mol % dtbpy X R 10 mmol Br THF, 24 h, 65 °C Br R 23–29 Bpin Br H3C Bpin NC Bpin Me2N 23, 79% 24, 78%[b][c] Br Br Br Bpin 25, 89%[b][d] Cl Bpin Cl Bpin F3C Bpin F3C Bpin H3C H3C 26, 71%[b] 27, 90%[b][c] 28, 95%[c] 29, 96%[b][c] [a] Yields are for isolated materials. [b] HBpin was the boron source. [c] run at room temperature for 48 h. See experimental section for details. [d] 72 h. With our CHB produced borylated haloarenes in hand, the plan was to react them with in situ generated triorganoindiums. Triorganoindiums are typically prepared by combining dry InCl3 with a organolithium or Gringnard species (Scheme 23). We chose to begin the cross-coupling studies with Ph3In prepares in this manner. 3 equiv RLi or RMgBr 1 equiv InCl3 THF, –78°C to rt R3In Scheme 23. Synthesis of triorganoindiums To begin testing the capacity of borylated haloarenes to undergo Pd-catalyzed cross-couplings with triorganoindium reagents, we first cannula transferred 0.4 equiv of Ph3In in THF to a THF solution of 5 mol % Pd(PPh3)2Cl2 and 1 mmol of 23 (Scheme 24 a). This reaction stalled after 16 h affording at that time a 70:30 mixture of cross-coupled product 31, unreacted 23, along with ~35% biphenyl. Despite additional experimentation 51 and the potential for all three phenyl groups to transfer, elimination of biphenyl as a byproduct was never realized. Nonetheless, increasing the stoichiometry of the Ph3In to 0.66 equiv and changing the catalyst to Pd(dppf)Cl2 resulted in the complete consumption of 23 after 16 h in refluxing THF (Scheme 24b). NMR and GC analyses of the crude reaction mixture indicated that aside from Ph–Ph formation, no other unwanted cross- couplings had occurred, nor was there loss of the Bpin group. a) b) H3C H3C Br 23 Br 23 5.0 mol % Pd(PPh3)2Cl2 0.4 equiv Ph3In Bpin THF, 16 h, 65 °C Ph H3C 70% conversion of 23 Bpin 31 (+ ~35% biphenyl) 5.0 mol % Pd(dppf)Cl2 0.6 equiv Ph3In Ph Bpin THF, 16 h, 65 °C H3C Bpin 31 100% conversion of 23 66% isolated yield (+ 21% isolated biphhenyl) Scheme 24. Pd-catalyzed cross-couplings of Ph3In with borylated haloarene 23 3.4 Cross-couplings of R3In with borylated haloarenes After these optimizations, we examined the reaction of Ph3In with various borylated haloarenes (Figure 9). Similar to 23, borylated 3-bromobenzonitrile (24) gave 32 in 72% isolated yield without any evidence of unreacted starting material, other cross- coupled products (aside from biphenyl), or deborylated materials in the crude product mixture. Likewise, aniline derivative 25 and 4-(Bpin)bromobenzene (30) coupled without incident affording 33 and 38 in 59% and 92% isolated yields respectively. NMR of the crude product mixture also indicated a clean reaction for 26, but 34 was isolated in only 37% yield, presumably due to losses during chromatographic purification. 52 Figure 9. Pd-catalyzed cross-couplings of Ph3In with borylated haloarenesa X R 24– 30 0.66 equiv InPh3 5 mol % Pd(dppf)Cl2 Bpin THF, 16 h, 65 °C R Ph Ph NC Bpin Me2N 32, 72% Ph Bpin 33, 59% Ph H3C H3C Ph Cl Bpin 35, 51%[b] F3C Bpin 36, 63% (X = Br)[b] 37, 0% (X = Cl) Ph 32–38 Ph Bpin Bpin 34, 37% Bpin 38, 92% [a] Yields are for isolated materials. [b] Minor amounts of byproducts were also observed. See experimetnal section for details. In contrast, while the cross-couplings of 35 and 36 gave desired products in 51% and 63% yields respectively, these reactions did show side products derived from the starting borylated haloarenes. Specifically, compounds stemming from ~10–20% deboronation of the cross-coupled products were observed for these substrates (Scheme 25). In addition, small amounts (1–4%) of over coupled products could also be seen in the crude reaction mixtures. Lastly, we were unable to affect the cross-coupling of chloroarene 29. Br R Bpin 27–28 5.0 mol% Pd(dppf)Cl2 0.6 equiv InPh3 THF, 16 h, 65 °C Ph Ph R + Ph R + R Ph + R + Ph Ph Bpin desired product Ph R byproducts Scheme 25. Pd-catalyzed cross-coupling side reactions 53 Figure 10. Pd-catalyzed cross-couplings of various triorganoindium species with borylated haloarenesa 0.66 equiv Rʹ3In 5 mol % Pd(dppf)Cl2 Bpin THF, 16–40 h, 65–80 °C R Rʹ Bpin 39–52 O N Bpin Br R 23–29 S 39, 64% (65 °C, 16 h) Ph H3C Bpin H3C Bpin H3C 40, 86% (65 °C, 16 h) 41, 55% (80 °C, 40 h) Ph TMS TMS H3C Bpin 42, 60% (80 °C, 48 h) Bpin 43, 81% (80 °C, 24 h) Me2N Bpin H3C Bpin 44, 58% (65 °C, 16 h) 45, 61% (65 °C, 16 h) H3C Bpin 46, 47% (65 °C, 16 h) Bpin 47, 81% (80 °C, 36 h) H3C Bpin 48, 74% (65 °C, 16 h) PhCH2 CH3 nBu nBu H3C Bpin H3C Bpin H3C Bpin 49, 71% (65 °C, 16 h) 50, 62% (65 °C, 16 h) 51, 56% (65 °C, 16 h) Bpin 52, 83% (65°C, 16 h) a Yields are for isolated materials. Other triorganoindium species were also tested (Figure 10). Triheteroarylindium reagents derived from 2-lithio forms of thiophene, furan, and pyridine afforded products 39, 40, and 41 in 64%, 86%, and 55% yields respectively. These results are notable since CHB of heteroarenes tend to be very facile.1 As such, CHB’s on 2-tolyl derivatives of thiophene, furan, or pyridines would borylate the heterocycle instead of generating 39– 41.27–29 54 Alkenes and alkynes are often problematic substituents in CHB’s owing to their ability to be hydroborated and/or otherwise compromise the effectiveness of the catalyst. This incompatibility creates the need for methods that can incorporate unsaturated groups post-CHB. With this want in mind, we were gratified to see that three different trialkynylindium reagents successfully coupled with three different borylated haloarenes, affording compounds 42–46 in good (81%) to modest (47%) isolated yields. Of similar utility, trivinylindium cross-coupled with 30 to give 43 in 81% isolated yield. The substrate scope was also extended to sp3 organoindium reagents. Tricyclopropylindium, Bn3In, and Me3In coupled with boronic ester 23 giving products 48, 49, and 50 in synthetically useful yields (74–62%). Notably, even the n-butyl groups of (n-Bu)3In were transferable, with 23 and 30 leading to products 51 and 52 in 56% and 83% isolated yields respectively. 3.5 One-pot borylations/cross-couplings of haloarenes Next, we investigated performing the CHB and a Sarandeses–Sestelo cross- coupling in a single pot (Scheme 26). Following their respective generation to crude solutions 24 and 27 was added a THF solution of Ph3In. For both substrates, the final products (32 and 35) were formed in yields comparable to the two-pot scheme. However, to achieve full conversion, longer reaction times and higher Pd loadings were required. We have observed the same phenomena in past efforts to telescope CHB’s and subsequent Pd-catalyzed transformations.30 We attribute this trend to residuals from the CHB causing a loss of catalytic activity. 55 Br 1.5 equiv HBpin 1 mol % [Ir(OMe)COD]2 2 mol % dtbpy THF, rt, 24 h; Ph Bpin R 24 R = CN 27 R = Cl then 0.66 equiv Ph3In 10 mol % Pd(dppf)Cl2 80 °C, 42 h R Bpin 32, 64% (R = CN) 35, 50% (R = Cl) Scheme 26. One pot borylation/cross-coupling reaction 3.6 Experimental General Borylation Procedure X 0.05 mol % [Ir(OMe)COD]2 0.55 equiv B2pin2 0.10 mol % dtbpy X R THF, 24 h, 65 °C R 23–29 Bpin In a nitrogen atmosphere glove box, bis(pinacolato)boron (B2Pin2) (1.40 g, 5.5 mmol, 0.55 equiv) was weighed into a 20 mL vial containing a magnetic stir bar. [Ir(OMe)COD]2 (3.3 mg, 0.005 mmol, 0.5 mol %) and 4,4’-di-tert-butyl-2,2’-dipyridyl ligand (2.7 mg, 0.010 mmol, 1.0 mol %) were weighed into two test tubes separately, each being diluted with 1 mL of THF. The [Ir(OMe)COD]2 solution was transferred into the 20 mL vial containing B2Pin2. This mixture was stirred until a golden yellow clear solution was obtained (~ 1 min). Next the solution containing ligand was transferred into the vial and upon stirring the resulting solution turned a dark brown color. Finally, the substrate (10.0 mmol) was added to the vial, which was then sealed and was taken out of the glove box. The reaction mixture was stirred for 24 h at 65 °C. Then, the reaction mixture was passed through a plug of silica (BD 60 mL Syringe/Luer-Lok Tip-silica up to 50 mL mark) eluting with a 10:1 hexane/ethyl acetate solution (2 x 200 mL). The volatiles were removed by rotary evaporation. 56 Compound 23 H3C Br Bpin 23 The general borylation procedure was carried out on the starting arene of 1-bromo-3- methylbenzene. After workup 2.356 g of compound 23 was obtained as a white solid (mp 74–76 °C, lit1a 74 – 76 °C) in 7% yield. 1H NMR (500 MHz, CDCl3) ! 7.74 (s, 1H), 7.54 (s, 1H), 7.43 (s, 1H), 2.33 (s, 3H), 1.35 (s, 12H); 13C NMR (125 MHz, CDCl3) ! 139.5, 134.7, 134.4, 133.8, 122.2, 84.3, 25.4, 20.6; 11B NMR (160 MHz, CDCl3) ! 30.5 (brs). MS EI+ m/z calculated for (M+H)+ C13H19BBrO2 297.0661, found 297.0640. Compound 24 Br NC Bpin 24 The general borylation procedure was carried out on 1.0 mmol of the starting arene at room temperature for 24h using HBpin (300 µL) as the boron source. After workup 0.238 g of compound 24 was obtained as a white solid (mp 87–88 °C, lit 83–86 °C) in 78% yield. 1H NMR (500 MHz, CDCl3) ! 8.14 (dd, J = 1.0, 2.0 Hz, 1H), 8.01 (dd, J = 1.0, 1.5 Hz,1H), 7.85 (dd, J = 1.5, 2.0 Hz, 1H), 1.36 (s, 12H); 13C NMR (125 MHz, CDCl3) ! 141.8, 136.8, 136.7, 122.6, 117.4, 113.8, 84.9, 24.8; 11B NMR (160 MHz, CDCl3) ! 29.5 (brs). MS EI+ m/z calculated for (M+H)+ C13H16BBrNO2 308.0457, found 308.0435. 57 Compound 25 Br Me2N Bpin 25 The general borylation procedure was carried out on 1.0 mmol of the starting arene at room temperature for 72 h using HBpin (300 µL) as the boron source. After workup 0.291 g of compound 25 was obtained as a white solid (mp 121–123 °C) in 89% yield. 1H NMR (500 MHz, Chloroform-d) δ 7.27 (s, 1H), 7.06 (dd, J = 2.6, 0.7 Hz, 1H), 6.93 (dd, J = 2.6, 1.8 Hz, 1H), 2.97 (s, 6H), 1.34 (s, 12H); 13C NMR (126 MHz, Chloroform-d) δ 151.2, 125.0, 123.3, 117.7, 116.9, 83.9, 40.5, 24.8.; 11B NMR (160 MHz, CDCl3) ! 29.9 (brs). MS EI+ m/z calculated for (M+H)+ C14H22BBrNO2 326.0927, found 326.0963. Compound 26 Br H3C H3C Bpin 26 The general borylation procedure was carried out on 1.0 mmol of the starting arene at room temperature for 24 h using HBpin (300 µL) as the boron source. After workup 0.220 g of compound 26 was obtained as a white solid (mp 103–105 °C) in 71% yield. 1H NMR (500 MHz, Chloroform-d) δ 7.84 (d, J = 1.1 Hz, 1H), 7.50 (d, J = 1.1 Hz, 1H), 2.39 (s, 3H), 2.34 (s, 3H), 1.34 (s, 12H); 13C NMR (126 MHz, Chloroform-d) δ 139.5, 137.9, 136.3, 134.9, 125.7, 83.9, 24.8, 21.0, 19.7; 11B NMR (160 MHz, CDCl3) ! 30.3 (brs). MS EI+ m/z calculated for (M+H)+ C14H21BBrO2 311.0818, found 311.0848. 58 Compound 27 Br Cl Bpin The general borylation procedure was carried out on 1.0 mmol of the starting arene at 27 room temperature for 48 h using HBpin (300 µL) as the boron source. After workup 0.287 g of compound 27 was obtained as a white solid (mp 51–53 °C) in 90% yield. 1H NMR (500 MHz, CDCl3) ! 7.80 (dd, J = 1.0, 1.0 Hz, 1H), 7.69 (dd, J = 0.5, 2.0 Hz,1H), 7.59 (dd, J = 2.0, 2.0 Hz, 1H), 1.35 (s, 12H); 13C NMR (125 MHz, CDCl3) ! 135.6, 134.8, 133.8, 133.1, 122.6, 84.5, 24.9; 11B NMR (160 MHz, CDCl3) ! 29.9 (brs). MS EI+ m/z calculated for (M+H)+ C12H16BBrClO2 317.0115, found 317.0147. Compound 28 Br F3C Bpin 28 The general borylation procedure was carried out on the starting arene at room temperature for 48h. After workup 3.312 g of compound 1f was obtained as a white solid (mp 51–52 °C) in 95% yield. 1H NMR (500 MHz, CDCl3) ! 8.10 (s, 1H), 7.98 (s,1H), 7.84 (s,1H), 1.36 (s, 12H); 13C NMR (125 MHz, CDCl3) ! 140.8, 131.9 (q, J = 32.3 Hz), 19F NMR (470 MHz, CDCl3) ! –62.7; 11B NMR (160 MHz, CDCl3) ! 29.8 (brs). MS EI+ 130.8 (q, J = 3.7 Hz), 129.8 (q, J = 3.3 Hz), 124.3 (q, J = 271.2 Hz), 122.5, 84.7, 24.8; m/z calculated for (M+H)+ C13H16BBrF3O2 351.0378, found 351.1444. 59 Compound 29 Cl F3C Bpin 29 The general borylation procedure was carried out on the starting arene at room temperature for 48h. After workup 2.7 g of compound 1g was obtained as a colorless oil in 96% yield. 1H NMR (500 MHz, CDCl3) δ 7.95 (dd, J = 2.2, 0.7 Hz, 1H), 7.93 (dd, J = 1.7, 0.8 Hz, 1H), 7.69 (dd, J = 2.4, 0.7 Hz, 1H), 1.36 (s, 12H). 13C NMR (126 MHz, CDCl3) δ 137.9, 134.5, 131.9(q, J = 32.3 Hz), 129.6 (q, J = 3.6 Hz), 127.9 (q, J = 3.9 Hz), 123.4 (q, J = 272.9 Hz), 84.6, 24.8. 11B NMR (160 MHz, CDCl3): δ 30.1(brs). General Procedure for Preparation of Indium Organometallics InCl3 was dried under high vacuum at 80 °C. A 25 mL round-bottomed flask with a stirrer bar was charged with dry InCl3 (0.6 mmol). A positive argon pressure was established and dry THF (3.0 mL) was added. The resulting solution was cooled to –78 °C, and a solution of RLi, or RMgBr (vinyl) (1.8 mmol) was slowly added (30-45 min). The mixture was stirred for 60 min, the cooling bath was removed, and the reaction mixture was warmed to room temperature. The resulting mixture was stirred at room temperature for 1-2 h. General Procedure for the Palladium-Catalyzed Cross Coupling Reactions A prepared solution of InR3 (0.6 mmol in dry THF) was added to mixture of the electrophile (1 mmol, 1 equiv) and Pd catalyst (0.05 mmol, 5.0 mol%) in dry THF (6 mL). The resulting mixture was refluxed under argon until the starting material had been consumed (NMR or GC). The reaction was then quenched by the addition of few drops of 60 MeOH. The crude mixture was passed through a plug of silica (BD 60 mL Syringe/Luer- Lok Tip-silica up to 50 mL mark). Elution with hexane to remove the biphenyl by product followed by elution with hexane/ethyl acetate solution. The volatiles were removed by rotary evaporation. The residue was further purified by silica chromatography to afford the cross-coupled product. Compound 31 Ph 31 Bpin H3C The general cross-coupling procedure was carried out on 1.0 mmol of 23 at 65 °C for 16 h. After purification by SiO2 chromatography (8:2 hexane/ethyl acetate) 0.193 g of compound 31 was isolated as a white solid (mp 93–95 °C, lit5 106–107 °C) in 66% yield. 1H NMR (500 MHz, CDCl3) δ 7.86 (dd, J = 1.9, 1.0 Hz, 1H), 7.65 – 7.61 (m, 3H), 7.52 (dd, J = 1.8, 0.9 Hz, 1H), 7.43 (dd, J = 7.7 Hz, 2H), 7.36 – 7.31 (m, 1H), 2.43 (s, 3H), 1.37 (s, 12H). 13C NMR (125 MHz, CDCl3) δ 141.2, 140.6, 137.6, 134.3, 130.9, 130.7, 128.6, 127.3, 127.1, 83.8, 24.9, 21.3. 11B NMR (160 MHz, CDCl3) ! 30.8 (brs). The spectral data were in accordance with those reported in the literature.5 HRMS (EI+) m/z 295.1867 [(M+H)+ calcd for C19H24BO2 295.1869]. Compound 32 Ph 32 NC Bpin 61 The general cross-coupling procedure was carried out on 1.0 mmol of 24 at 65 °C for 16 h. After purification by SiO2 chromatography (from 9:1 to 8:2 hexane/ethyl acetate) 0.221 g of compound 32 was isolated as a white solid (mp 98–99 °C) in 72 % yield. 1H NMR (500 MHz, CDCl3) δ 8.23 (dd, J = 2.0, 1.0 Hz, 1H), 8.07 (dd, J = 1.6, 1.0 Hz, 1H), 7.94 (t, J = 1.8 Hz, 1H), 7.64–7.59 (m, 2H), 7.52–7.45 (m, 2H), 7.44–7.39 (m, 1H), 1.38 (s, 12H). 13C NMR (126 MHz, CDCl3) δ 141.6, 138.9, 137.5, 136.9, 132.9, 129.0, 128.3, 127.2, 118.9, 109.9, 84.6, 24.9. 11B NMR (160 MHz, CDCl3) ! 30.0 (brs). HRMS EI+ m/z 306.1693 [(M+H)+ calcd for C19H21BNO2 306.1665]. Compound 33 Ph 33 Bpin Me2N The general cross-coupling procedure was carried out on 0.34 mmol of 25 at 65 °C for 16 h. After purification 0.065 g of compound 33 was isolated as a white solid (mp 125–129 ºC) in 59% yield. 1H NMR (300 MHz, CDCl3) δ 7.68.7.60 (m, 2H), 7.46–7.40 (m, 2H), 7.37–7.29 (m, 1H), 7.23–7.20 (m, 1H), 7.08–7.04 (m, 1H), 3.03 (s, 6H), 1.37 (s, 12H). 13C NMR (75 MHz, CDCl3) δ 150.7, 142.2, 141.8, 128.6, 127.6, 127.1, 122.5, 117.9, 114.8, 83.8, 41.0, 25.0. 11B NMR (128 MHz, CDCl3) δ 31.3 (brs). HRMS (ESI+) m/z 324.2137 [(M+H)+ calcd for C20H27BNO2 324.2129]. Compound 34 H3C H3C Ph Bpin 34 62 The general cross-coupling procedure was carried out on 0.34 mmol of 26 at 65 °C for 16 h. After purification 0.039 g of compound 34 was isolated as a white solid (mp 102–106 ºC) in 37% yield. 1H NMR (300 MHz, CDCl3) δ 7.62 (s, 1H), 7.56 (s, 1H), 7.43-7.28 (m, 5H), 2.36 (s, 3H), 2.19 (s, 3H), 1.35 (s, 12H). 13C NMR (75 MHz, CDCl3) δ 142.6, 142.0, 137.7, 136.7, 135.2, 134.3, 129.6, 128.0, 126.7, 83.8, 25.0, 20.6, 17.4. 11B NMR (128 MHz, CDCl3) δ 30.7 (brs). HRMS (ESI+) m/z 309.2020 [(M+H)+ calcd for C20H26BO2 309.2020]. Compound 35 5.0 mol% Pd(dppf)Cl2 0.6 equiv InPh3 Bpin THF, 16 h, 65 °C Cl Cl Br 27 Ph 35 Ph Ph + Bpin Cl + H Cl Ph Ph + Ph 35x 35y The general cross-coupling procedure was carried out on 1.0 mmol of 27 at 65 °C for 16 h. After 16 h a mixture of 35, 35x and 35y in ratio of 85:11:4 (NMR/GCMS) was obtained. After purification by SiO2 chromatography (hexane 100 mL then 9:1 hexane/ethyl acetate) 0.160 g of pure 35 was isolated as a white solid (mp 87–89 °C) in 51% yield. 1H NMR (500 MHz, Chloroform-d) δ 7.90 (dd, J = 1.8, 1.0 Hz, 1H), 7.75 (dd, J = 2.2, 0.9 Hz, 1H), 7.66 (dd, J = 1.9 Hz, 1H), 7.60 (dd, J = 8.2, 1.2 Hz, 2H), 7.43 (dd, J = 7.0, 6.0 Hz, 2H), 7.38–7.33 (m, 1H), 1.36 (s, 12H). 13C NMR (126 MHz, Chloroform- d) δ 142.5, 139.7, 134.4, 133.2, 131.5, 129.8, 128.8, 127.7, 127.2, 84.21, 24.86. 11B NMR (160 MHz, CDCl3) ! 30.1 (brs). HRMS EI+ m/z 315.1302 [(M+H)+ calcd for C18H21BClO2 315.1323]. 63 Compound 36 5.0 mol% Pd(dppf)Cl2 0.6 equiv InPh3 Bpin THF, 16 h, 65 °C F3C F3C Br 28 + F3C Bpin Ph 36 F3C Ph + H F3C 36x Ph + H Ph Ph 36z The general cross-coupling procedure was carried out on 1.0 mmol of 28 at 65 °C for 16 h. After 16 h a mixture of 36, 36x and 36z in ratio of 72:20:8 (NMR/GCMS) was obtained. After purification by SiO2 chromatography (Hexane 100 mL then from 9:1 to 8:2 hexane/ethyl acetate) 0.219 g of compound 36 was isolated as a white sticky solid as a mixture (36:36z = 90:1) in 63% yield. 1H NMR (500 MHz, CDCl3) 8.22 (s, 1H), 8.06 (s, 1H), 7.93 (d, J = 2.4 Hz, 1H), 7.65 (dd, J = 8.1, 2.2 Hz, 2H), 7.47 (dd, J = 8.3, 7.8 Hz, 2H), 7.43–7.36 (m, 1H), 1.39 (s, 12H). 13C NMR (126 MHz, CDCl3) δ 141.3, 139.7, 136.7, 130.6 (d, J = 31.8 Hz), 130.1 (d, J = 3.7 Hz), 128.9, 128.2 (q, J = 216.2 Hz),127.9, 127.3, 126.4 (d, J = 3.8 Hz), 84.4, 24.9. 19F NMR (470 MHz, CDCl3) ! –62.5. 11B NMR (160 MHz, CDCl3) ! 30.1 (brs). The spectral data were in accordance with those reported in the literature.6 HRMS EI+ m/z 349.1561 [(M+H)+ calcd for C19H21BF3O2 349.1587]. Compound 38 Ph 38 Bpin The general cross-coupling procedure was carried out on 1.0 mmol of 2-(4- bromophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (30) at 65 °C for 16 h. After purification by SiO2 chromatography (9:1 hexane/ethyl acetate) 0.257 g of compound 38 was isolated as a white solid (mp 100–101°C, lit7b 111–112 °C) in 92% yield. 1H NMR (500 MHz, Chloroform-d) δ 7.93 (d, J = 8.1 Hz, 2H), 7.67 – 7.64 (m, 4H), 7.48 (t, J = 7.6 64 Hz, 2H), 7.41–7.36 (m, 1H), 1.40 (s, 12H). 13C NMR (126 MHz, Chloroform-d) δ 143.9, 141.0, 135.3, 128.8, 127.6, 127.3, 126.5, 83.8, 24.9. 11B NMR (160 MHz, CDCl3) ! 30.7 (brs). The spectral data were in accordance with those reported in the literature.7 (EI+) m/z 281.1708 [(M+H)+ calcd for C18H22BO2 281.1713] Compound 39 S H3C Bpin 39 The general cross-coupling procedure was carried out on 0.34 mmol of 23 at 65 °C for 16 h. After purification 0.065 g of compound 39 was isolated as a white solid (mp 95–98 °C) in 64% yield. 1H NMR (300 MHz, CDCl3) δ 7.88 (s, 1H), 7.57 (s, 1H), 7.53 (s, 1H), 7.36 (dd, J = 3.6, 1.2 Hz, 1H), 7.26 (dd, J = 5.1, 1.2 Hz, 1H), 7.07 (dd, J = 5.1, 3.6 Hz, 1H), 2.40 (s, 3H), 1.37 (s, 12H). 13C NMR (75 MHz, CDCl3) δ 144.6, 137.9, 134.7, 134.0, 129.7, 129.5, 128.0, 124.7, 123.3, 84.0, 25.0, 21.4. 11B NMR (128 MHz, CDCl3) δ 31.0 (brs). HRMS (ESI+) m/z 301.1427 [(M+H)+ calcd for C17H22BO2S 301.1428]. Compound 40 O H3C Bpin 40 The general cross-coupling procedure was carried out on 0.34 mmol of 23 at 65 °C for 16 h. After purification 0.081 g of compound 40 was isolated as an orange oil in 86% yield. 1H NMR (300 MHz, CDCl3) δ 7.91 (s, 1H), 7.53 (s, 1H), 7.45 (s, 1H), 6.68 (d, J = 3.4 65 Hz, 1H), 6.49–6.43 (m, 1H), 2.39 (s, 3H), 1.36 (s, 12H); 13C NMR (75 MHz, CDCl3) δ 154.3, 142.0, 137.7, 134.6, 130.5, 127.6, 127.4, 111.7, 105.1, 84.0, 25.0, 21.4. 11B NMR (128 MHz, CDCl3) δ 30.1 (brs). HRMS (ESI+) m/z 285.1667 [(M+H)+ calcd for C17H22BO3 285.1656]. Compound 41 N H3C Bpin 41 The general cross-coupling procedure was carried out on 1.0 mmol of 23 at 80 °C for 40 h. After purification by SiO2 chromatography (from 9:1 to 7:3 hexane/ethyl acetate) 0.162 g of compound 41 was isolated as a white solid (mp 123–125 °C) in 55% yield. 1H NMR (500 MHz, CDCl3) δ 8.69 (d, J = 4.5 Hz, 1H), 8.15 (s, 1H), 7.99 (s, 1H), 7.80 (d, J = 7.9 Hz, 1H), 7.74 (dd, J = 7.5, 7.7 Hz, 1H), 7.69 (s, 1H), 7.22 (dd, J = 5.5, 6.2 Hz, 1H), 2.44 (s, 3H), 1.36 (s, 12H). 13C NMR (126 MHz, CDCl3) δ 157.6, 149.5, 138.7, 137.8, 136.6, 136.0, 130.6, 130.3, 121.9, 120.9, 83.8, 24.9, 21.3. 11B NMR (160 MHz, CDCl3) ! 30.4 (brs). (EI+) m/z 296.1839 [(M+H)+ calcd for C18H23BNO2 296.1822] Compound 42 Ph H3C Bpin 42 66 The general cross-coupling procedure was carried out on 1.0 mmol of 23 at 80 °C for 48 h. After purification by SiO2 chromatography (8:2 hexane/ethyl acetate) 0.192 g of compound 42 was isolated as a yellow oil in 60% yield. 1H NMR (500 MHz, CDCl3) δ 7.83 (d, J = 1.6 Hz, 1H), 7.60 (dd, J = 1.8, 1.0 Hz, 1H), 7.55–7.49 (m, 2H), 7.46 (dd, J = 1.8, 0.9 Hz, 1H), 7.39–7.31 (m, 3H), 2.36 (d, J = 0.8 Hz, 3H), 1.36 (s, 12H). 13C NMR (126 MHz, CDCl3) δ 137.3, 135.2, 135.2, 134.7, 131.5, 128.3, 128.1, 123.4, 122.7, 89.5, 89.1, 83.9, 24.9, 21.1. 11B NMR (160 MHz, CDCl3) ! 30.5 (brs). (EI+) m/z 319.1864 [(M+H)+ calcd for C21H24BO2 319.1869] Compound 43 Ph Bpin 43 The general cross-coupling procedure was carried out on 1.0 mmol of 2-(4- bromophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (30) at 80 °C for 24 h. After purification by SiO2 chromatography (9:1 hexane/ethyl acetate) 0.247 g of compound 43 was isolated as a brown solid (mp 88–89 °C, lit8 93–95 °C) in 81% yield. 1H NMR (500 MHz, CDCl3) δ 7.80 (d, J = 8.1 Hz, 2H), 7.57–7.52 (m, 4H), 7.38–7.34 (m, 3H), 1.36 (s, 12H). 13C NMR (126 MHz, CDCl3) δ 136.3, 134.6, 131.6, 130.8, 128.4, 125.9, 123.1, 90.7, 89.5, 83.9, 24.9. 11B NMR (160 MHz, CDCl3) ! 30.6 (brs). (EI+) m/z 305.1710 [(M+H)+ calcd for C20H22BO2 305.1713]. Spectral data were consistent with literature8 reported values except the 13C peak reported at 137.13 was not observed.8 Presumably this peak is that of the carbon bearing boron. Such carbons are often difficult to observe. 67 Compound 44 TMS Me2N Bpin 44 The general cross-coupling procedure was carried out on 0.34 mmol of 25 at 65 °C for 16 h. After purification 0.068 g of compound 44 was isolated as a yellow oil in 58% yield. 1H NMR (300 MHz, CDCl3) δ 7.31 (s, 1H), 7.14–7.10 (m, 1H), 6.93–6.89 (m, 1H), 2.95 (s, 6H), 1.33 (s, 12H), 0.23 (s, 9H). 13C NMR (75 MHz, CDCl3) δ 149.9, 127.1, 123.2, 119.1, 118.4, 106.3, 92.8, 83.9, 40.8, 25.0, 0.2. 11B NMR (128 MHz, CDCl3) δ 31.0 (brs). HRMS (ESI+) m/z 344.2226 [(M+H)+ calcd for C19H31BNO2Si 344.2211]. Compound 45 TMS H3C Bpin 45 The general cross-coupling procedure was carried out on 0.34 mmol of 23 at 65 °C for 16 h. After purification 0.065 g of compound 45 was isolated as a white solid (mp 77–79 ºC) in 61% yield. 1H NMR (300 MHz, CDCl3) δ 7.74 (s, 1H), 7.56 (s, 1H), 7.38 (s, 1H), 2.31 (s, 3H), 1.34 (s, 12H), 0.23 (s, 9H). 13C NMR (75 MHz, CDCl3) δ 137.3, 135.7, 135.5, 135.2, 122.7, 105.4, 93.8, 84.1, 25.0, 21.1, 0.2. 11B NMR (128 MHz, CDCl3) δ 30.6 (brs). HRMS (ESI+) m/z 315.1935 [(M+H)+ calcd for C18H28BO2Si 315.1946]. 68 Compound 46 H3C Bpin 46 The general cross-coupling procedure was carried out on 0.34 mmol of 23 at 65 °C for 16 h. After purification 0.045 g of compound 46 was isolated as a yellow solid (mp 68–70 ºC) in 47% yield. 1H NMR (300 MHz, CDCl3) δ 7.65 (s, 1H), 7.50 (s, 1H), 7.29 (s, 1H), 2.30 (s, 3H), 1.48–1.37 (m, 1H), 1.33 (s, 12H), 0.87–0.73 (m, 4H). 13C NMR (75 MHz, CDCl3) δ 137.2, 135.4, 134.9, 134.5, 123.5, 93.2, 84.0, 75.9, 25.0, 21.1, 8.7, 0.3. 11B NMR (128 MHz, CDCl3) δ 31.1 (brs). HRMS (ESI+) m/z 305.1672 [(M+Na)+ calcd for C18H23BO2Na 305.1683]. Compound 47 Bpin 47 The general cross-coupling procedure was carried out on 1.0 mmol of 2-(4- bromophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (30) at 80 °C for 36 h. After purification by SiO2 chromatography (9:1 hexane/ethyl acetate) 0.187 g of compound 47 was isolated as a colorless oil in 81% yield. 1H NMR (500 MHz, CDCl3) δ 7.78 (d, J = 8.0 Hz, 2H), 7.42 (d, J = 8.5 Hz, 2H), 6.74 (dd, J = 17.6, 10.9 Hz, 1H), 5.83 (dd, J = 17.6, 0.9 Hz, 1H), 5.30 (dd, J = 10.9, 1.0 Hz, 1H), 1.36 (s, 12H). 13C NMR (126 MHz, CDCl3) δ 140.2, 136.9, 135.0, 125.5, 114.9, 83.8, 24.9. 11B NMR (160 MHz, CDCl3) ! 30.6 (brs). 69 The spectral data were in accordance with literature.9 HRMS (EI+) m/z 231.1546 [(M+H)+ calcd for C14H20BO2 231.1556]. Compound 48 H3C Bpin 48 The general cross-coupling procedure was carried out on 0.34 mmol of 23 at 65 °C for 16 h. After purification 0.065 g of compound 48 was isolated as a yellow solid (mp 76–78 ºC) in 74% yield. 1H NMR (300 MHz, CDCl3) δ 7.44 (s, 1H), 7.36 (s, 1H), 6.99 (s, 1H), 2.33 (s, 3H), 1.97–1.84 (m, 1H), 1.35 (s, 12H), 0.98–0.88 (m, 2H), 0.77–0.68 (m, 2H). 13C NMR (75 MHz, CDCl3) δ 143.3, 137.2, 132.7, 129.6, 129,4, 83.8, 25.0, 21.3, 15.3, 9.0. 11B NMR (128 MHz, CDCl3) δ 30.7 (brs). HRMS (ESI+) m/z 281.1678 [(M+Na)+ calcd for C16H23BO2Na 281.1683]. Compound 49 PhCH2 H3C Bpin 49 The general cross-coupling procedure was carried out on 0.34 mmol of 23 at 65 °C for 16 h. After purification 0.074 g of compound 49 was isolated as a white solid (mp 116–119 ºC) in 71% yield. 1H NMR (300 MHz, CDCl3) δ 7.53–7.46 (m, 2H), 7.31–7.23 (m, 2H), 7.21–7.14 (m, 3H), 7.08 (s, 1H), 3.95 (s, 2H), 2.30 (s, 3H), 1.34 (s, 12H). 13C NMR (75 MHz, CDCl3) δ 141.6, 140.5, 137.6, 133.5, 133.0, 132.6, 129.0, 128.5, 126.1, 83.9, 42.0, 70 25.0, 21.3. 11B NMR (128 MHz, CDCl3) δ 30.7 (brs). HRMS (ESI+) m/z 309.2035 [(M+H)+ calcd for C20H26BO2 309.2020]. Compound 50 CH3 H3C Bpin 50 The general cross-coupling procedure was carried out on 0.34 mmol of 23 at 65 °C for 16 h. After purification 0.048 g of compound 50 was isolated as a white solid (mp 91–93 ºC, lit10 90–91 ºC) in 62 % yield. 1H NMR (300 MHz, CDCl3) δ 7.46 (s, 2H), 7.12 (s, 1H), 2.34 (s, 6H), 1.36 (s, 12H). 13C NMR (75 MHz, CDCl3) δ 137.3, 133.1, 132.5, 83.8, 25.0, 21.3. 11B NMR (128 MHz, CDCl3) δ 31.1 (brs). The spectral data were in accordance with those reported in the literature.10 HRMS (ESI+) m/z 233.1715 [(M+H)+ calcd for C14H22BO2 233.1707]. Compound 51 nBu H3C Bpin 51 The general cross-coupling procedure was carried out on 0.34 mmol of 23 at 65 °C for 16 h. After purification 0.052 g of compound 51 was isolated as a yellow oil in 56% yield. 1H NMR (300 MHz, CDCl3) δ7.46 (s,1H), 7.44 (s, 1H), 7.10 (s, 1H), 2.62–2.54 (m, 2H), 2.33 (s, 3H), 1.66–1.53 (m, 2H), 1.43–1.36 (m, 2H), 1.35 (s, 12H), 0.92 (t, J = 7.3 Hz, 3H). 13C NMR (75 MHz, CDCl3) δ 142.4, 137.2, 132.9, 132.5, 132.0, 83.8, 35.7, 34.0, 71 25.0, 22.7, 21.3, 14.1. 11B NMR (128 MHz, CDCl3) δ 31.0 (brs). HRMS (ESI+) m/z 275.2168 [(M+H)+ calcd for C17H28BO2 275.2176]. Compound 52 nBu Bpin 52 The general cross-coupling procedure was carried out on 1.0 mmol of 2-(4- bromophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (30) at 65 °C for 16 h. After purification by SiO2 chromatography (9:1 hexane/ethyl acetate) 0.215 g of compound 52 was isolated as a colorless oil in 83% yield. 1H NMR (500 MHz, CDCl3) δ 7.75 (d, J = 7.9 Hz, 2H), 7.21 (d, J = 7.8 Hz, 2H), 2.64 (t, J = 8.0 Hz, 2H), 1.67–1.55 (m, 2H), 1.37 (m, 2H), 1.35 (s, 12H), 0.93 (t, J = 7.4 Hz, 3H). 13C NMR (126 MHz, CDCl3) δ 146.4, 134.8, 127.9, 83.6, 35.9, 33.5, 24.9, 22.4, 13.9. 11B NMR (160 MHz, CDCl3) ! 30.8 (brs). The spectral data were in accordance with those reported in the literature.11 HRMS (EI+) m/z 261.1986 [(M+H)+ calcd for C16H26BO2 261.2025]. 72 REFERENCES 73 REFERENCES (1) Mkhalid, I. A. I.; Barnard, J. H.; Marder, T. B.; Murphy, J. M.; Hartwig, J. F. C-H Activation for the Construction of C-B Bonds. Chem. Rev. 2010, 110, 890–931. (2) Maleczka, R. E., Jr.; Smith, M. R., III. Remarkably Selective Iridium Catalysts for the Elaboration of Aromatic C–H Bonds. Science 2002, 295. (3) Holmes, D.; Chotana, G. A.; Maleczka, R. E., Jr; Smith, M. R., 3rd. 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Cobalt-Catalyzed C–H Borylations 4.1 C(sp3)(cid:1)H borylations Aryl/alkyl boronic acids and their derivatives find widespread utility as intermediates in organic synthesis. However, while borylations of C(sp2)–H has been well documented, whereas C–H borylations of unactivated C(sp3)–H bonds are still emerging. Pioneering work by the Hartwig group has shown that metal-boryl catalysts based on Re,1 Rh,2–4 and Ru5 complexes allow the preparation of primary alkylboronates from alkanes through activation of terminal primary C−H bonds. Recently, a number of research groups have reported C–H borylations of C(sp3)–H bonds in arene systems using precious metals. However, these type of C–H borylations usually require directing groups,6–9 highly active substrates,10,11 and/or high temperatures.5,12 A handful of non– directed methods have been reported for selectively functionalize benzylic C–H bonds.13– 15 4.2 Cobalt catalyzed non-directed C(sp3)–H borylations Me Me a) b) Me Me N N Co Cy Cy RCO2 O2CR R = 3-heptyl 5–20 mol % 2.0 equiv B2pin2 0.2 equiv HBpin CPME, 100 °C 16–120 h Me Me Ni N N R R PivO OPiv 15–20 mol % 4.0 equiv B2pin2 CPME, 80 °C 48 h Bpin Bpin Bpin + SiO2, Et3N Bpin Bpin Bpin Scheme 27. Polyborylation with a) Cobalt catalyst b) Nickel catalyst 78 Chirik and co-workers have recently synthesized geminal diboronates and polyboronate compounds, via CHBs of both benzylic and unactivated C(sp3)–H bonds using 5–20 mol % of an air-stable α-diimine cobalt bis(carboxylate) catalyst (Scheme 27 a).16 They subsequently showed that an α-diimine nickel compounds can catalyze chemoselective triborylation of benzylic C(sp3)–H bonds by B2pin2 (Scheme 27b).17 Huang and co-workers have reported that 1,1,1-tris(boronates) substituted at homobenzylic carbons can be efficiently and selectively prepared from styrenes and B2pin2 with Co(I) precatalysts (Scheme 28a).18 These reactions proceed via Co-catalyzed double dehydrogenative borylation of vinylarenes, and subsequent hydroboration of 1,1- diborylalkene intermediates, with in situ generated HBpin. Benzylic CHBs have also been described by Lin and co-workers using a metal-organic framework (MOF) with catalytically active cobalt nodes (Scheme 28b).19 a) b) Ar R2 2.0 mol % [Co]-cat. 4.0 mol % NaBEt3H 2.0 equiv B2pin2 pentane, 25 °C 12–72 h Bpin Ar R1 cat. UIO-Co, cat NaBEt3H (1:5) 0.5 equiv B2pin2 103 °C, 48–144 h R2 Bpin Bpin N N Cl Co Cl tBu2P [Co]-precatalyst Bpin R1 R1= H, Me R2 = H, Me, OMe, tBu, Cl Scheme 28. Polyborylation with a) cobalt catalyst b) MOF 4.3 Synthesis of a new cobalt catalyst The cobalt catalyzed processes are interesting but it is not widely used method due to lack of functional group tolerance (e.g. Cl, Br, I). Therefore, we decided to build a catalyst system that can overcome these limitations. Choice of Co complex A to explore 79 catalytic CHBs was motivated by Herrmann’s Rh and Ir N-heterocyclic carbene complexes that facilitate CHBs of arene C(sp2)–H bonds.20 They synthesized bridged and unbridged N-heterocyclic carbene (NHC) ligands that are metalated with [Ir/Rh(COD)2Cl]2 to give rhodium(I/III) and iridium(I) mono- and biscarbene substituted complexes. Given this precedent we wondered if NHC complexes of Co, the lightest Group 9 element, would behave like Herrmann’s catalysts. Cobalt complex A was synthesized by reacting CoCl2 with potassium t-butoxide and 1,3-diisopropyl-1H- imidazol-3-ium chloride in THF (Scheme 29). CoCl2 + N N iPr Cl iPr KOtBu THF, rt, 1 h iPr N iPr N Co N iPr N iPr OtBu OtBu A Scheme 29. Synthesis of cobalt complex A Recrystallization from pentane afforded single crystals suitable for X-ray diffraction studies (Figure 11). There are three broad resonances (41.70, 39.00, 8.76, 2.31 ppm) in the 1H NMR spectrum (C6D6) of A. Assignments for the O-t-Bu and NHC ligand’s methyl protons can be made based on integrations. The lowest intensity resonances (41.70 and 39.00) are due to the NHC ligand’s isopropyl methine and imidazolyl ring protons. Application of the Evans method yields an eff = 4.20 B for A. Although A is air-sensitive, it has remained active for more than one year when stored at -35 °C. 80 Figure 11. X-ray crystallography of complex A The structure of A, shown in Figure 6, reveals a distorted tetrahedral geometry with rotational disorder of the methyl group about the O1–C19 vector in one O-t-Bu ligand. The bond angles with Co at the vertex range from 102.6° for ÐO1-Co1-C10 and ÐO2-Co1-C1 to 123.4° for ÐO2-Co1-O1. There are close contacts between the O-t-Bu O atoms and the methine H atoms of the NHC isopropyl groups as represented by H13–O2 and H7–O2 distances of 2.698 and 2.112 Å, respectively. The latter O–H distance is typical for structures with O…H hydrogen bonding. However, the short O…H distances in A could simply be geometric consequences of the sterically most favored orientation of bulky i-Pr and t-Bu groups. 4.4 Testing cobalt catalyst A reactivity With Co complex A in hand, we explored its proclivity for CHBs (Figure 12). A sealed tube reaction of toluene with 2 mol % Co precatalyst A, 2.6 equiv HBpin in THF at 80 °C for 48 h gave a 63% conversion (GC) of the starting material to a 2:3 mixture of mono (53a) and di (53b) benzylic CHB products. When activated with 0.05 equiv HBpin, B2pin2 could be used as the boron source, but the conversion was nearly identical to that obtained with HBpin. B2pin2 was less practical for isolating diborylated products since 81 chromatographic separation with silica gel of unreacted B2pin2 promotes the protodeboronation of PhCH(Bpin)2.16 Figure 12. Cobalt-Catalyzed CHBsa 3 mol% [Co] catalyst A R 5.3 equiv HBpin 80 °C, 48 h Bpin R Entry Starting material Products Ratio/isolated yield 1 2 3 4 5 6 7 MeO 53 54 55 56 57 58 59 Bpin Bpin Bpin 53a:53b = 1:9 53a+53b = 80% 53a 53b Bpin Bpin 54a Bpin Bpin 54a:54b = 1:1.9 54a+54b = 78% 54b (38%) Bpin Bpin 55a:55b = 1:1 55a+55b = 33% 55a 55b Bpin Bpin 56a H 56b Bpin Bpin Bpin Bpin 53b 58a 59a Bpin 56a:56b = 1:1 56a+56b = 21% (36%b) 57b = 30% 58a = 49% (74%b) 59a = 35% aIsolated yields. bBorylation with 20 mol % of A. Since HBpin is a liquid, we explored CHBs in neat HBpin (2.6 equiv). This gave a modest improvement in conversion (70%). Increasing the reaction temperature to 150 °C decreased conversion (52% at 4 h), with no further conversion at longer reaction times. 82 As depicted in entry 1 of Figure 12, an excellent isolated yield with high selectivity for the PhCH(Bpin)2 was obtained at 80 °C with 5.3 equiv of HBpin and 3 mol % A (97% conversion, mono:di = 1:9). These optimized conditions established an efficiency for Co precatalyst A that was on par with Chirik’s best conditions for the diborylation of toluene.16 CHBs of m-xylene, p-xylene, and cymene were examined in neat HBpin (5.3 equiv per arene) with 2 mol % A. All three compounds were selectively borylated at their benzylic positions. Nonetheless, there were differences between substrates. m-Xylene afforded a 1:1 mixture of the mono (54a) and geminally diborylated (54b) products (74% conversion). Increasing the HBpin stoichiometry to 6.7 equiv improved conversion and selectivity for 54b (81% conversion, 54a:54b = 1:2). The borylated products were isolated as a mixture in 78% yield after workup, and the diborylated (54b) material could be separated by column chromatography with recovery of only 38% of 54b that was present in mixture, presumably due to protodeboronation. Surprisingly, CHB of p-xylene with 6.7 equiv of HBpin ceased after 40% conversion, giving 33% isolated yield of a 1:1 mixture of mono (55a) to geminally substituted diborylation (55b) products. Cymene was the least reactive substrate giving only 33% conversion and 21% isolated yield of the mono (56a) and geminally substituted diborylation (56b) products in a 1:1 ratio. Despite m-xylene being more reactive than p-xylene, the Co precatalyst system appears to be very sensitive to sterics at the benzylic position as indicated by the borylation of methyl vs. isopropyl substituents on cymene. The inert nature of the isopropyl group was studied further through the attempted borylations of isopropylbenzene, as well as 1,3-di- and 1,3,4-triisopropylbenzene. All three compounds 83 failed to borylate at any position, including the benzylic and C(sp2)–H bonds. Chirik and co-workers showed that the isopropyl methyl groups of cymene (56) can be borylated, albeit more slowly than the aryl methyl site.16 Empirically, the more reactive the substrate, the more likely it undergoes di-borylation. We tested CHBs of ethylbenzene and isopentylbenzene (entries 6 and 7). Under our standard conditions using 2 mol % A, ethylbenzene gave the monoborylated benzyl- Bpin product (58a) as the exclusive product, but with a modest 42% conversion. Interestingly, reducing HBpin to 2.6 equiv gave 51% conversion and 58a was isolated in 49% yield. Increasing the loading of A to 20 mol % and HBpin to 3.3 equiv improved the yield of 58a to 74% (77% conversion). CHB of isopentylbenzene using 2 mol % A, and 5.3 equiv of HBin gave 59a exclusively (35% isolated yield, 44% conversion). The ability of solutions of HBpin and A to catalyze the selective production of monoborylated 58a from ethylbenzene stands in contrast to the use of Chirik’s Co catalyst and conditions, which in our hands afforded a mixture of polyborylated products (Scheme 30). Cy N Cy N Co(O2CR)2 R = 3-heptyl 20 mol % [Co] 20 mol % HBpin 2 equiv B2pin2 CPME, 100 °C, 120 h Bpin Bpin Bpin + Bpin Bpin + Bpin Bpin Bpin Scheme 30. Chirik’s cobalt catalyst with ethylbenzene (58) Furthermore, Lin’s Co-MOF catalysts gave a 4:1 mixture of benzylic and aryl borylation products. While Ni(cod)2/Icy-catalyzed (Icy=1,3-bis(cyclohexyl) imidazolium- 84 2-ylidene) CHBs of arenes (arene:HBpin=9-7.5:1) can generate monoborylated products at primary and secondary benzylic positions, functionalization of C(sp2)–H sites is favored. Monoborylations of toluene and meta-xylene have been reported using the UiO- Co MOF catalysts in Scheme 28b. For these substrates the selectivity for C(sp3)–H borylation is high, but the use of excess arene ([substrate]:[B2pin2] ≥ 90) potentially biases selectivities for monoborylation as compared to our chemistry where the arene is the limiting reagent. For substrates with secondary and tertiary C–H bonds, the selectivity for C(sp3)–H vs. C(sp2)–H borylation drops to 4:1 with the UiO-Co MOF catalysts. Entries 6 and 7 of Figure 12 indicate that selective monoborylation for substrates that exhibit poor selectivity with other catalysts is achievable with precatalyst A. We subjected 1-methoxy-3-methylbenzene (entry 5) to the CHB conditions in Figure 12. Unfortunately, the OMe substituent was cleaved giving diborylated toluene 53b in 30% isolated yield. Chirik saw minor amounts (13%) of C–OMe cleavage with his cobalt catalyst,16 but methoxy substituents were tolerated in his benzylic borylations catalyzed by (ipcADI)Ni(OPiv)2 (ipcADI = N,N´-di(-)isopinocampheyl)butane-2,3- diimine).17 Chatani did observe PhBpin as a byproduct of C–OMe cleavage in Ni(cod)2/Icy-catalyzed borylations of anisole, where C(sp2)–H borylation predominated to produce a mixture of monoborylated anisoles.21 m-Fluorotoluene defluorinated in CHBs with precatalyst A, as judged from 19F- NMR and 11B-NMR. The NMR data pointed to trace amounts of unidentified species where C–B or B–F bond formation had occurred. When 1-methyl-4- (trifluoromethyl)benzene (60) was subjected to our standard CHB conditions, only 6% conversion of 60 was observed. GCMS indicated the formation of compound 60a, 85 defluorinated 60a´ (60a:60a´ = 5:1), and two additional unidentified compounds both with m/z = 277 (Scheme 31). The reduction of C(sp2)–F and C(sp3)–F bonds by precatalyst A, contrasts C(sp2)–F compatibility for 5-fluoro-N-methylindole5a and C(sp3)–F compatibility for triflouromethylbenzene5b in Ni-catalyzed CHBs. It should be noted that C–F bonds were problematic when CHBs of arenes containing C(sp2)–F bonds or CF3 groups were attempted using Ni(cod)2/Icy catalysts.21 The UiO-Co MOF catalysts tolerate Cl and OMe groups, in contrast to CHBs catalyzed by precatalyst A.19 CF3 CH3 60 2 mol% [Co] catalyst A 2.6 equiv HBpin 80 °C, 18 h CF3 CH3 Bpin 60a Bpin 60a´ Scheme 31. m-Fluorotoluene defluorinated in CHBs The reaction scope for Co precatalyst A can be extended to certain heteroarenes (Figure 13). N-Methylpyrrole was exceptionally reactive and formed the 2-borylated product 61a and its 2,5-diborylated counterpart, 61b. Although 61a is prone to protodeboronation during purification, we managed to obtain a crystal structure of the product, which confirmed the assigned regiochemistry (see experimental section). With HBpin as the limiting reagent, good yields of 61a have been reported with the Ni(cod)2/Icy CHB catalyst.21 Both N-methylpyrazole and N-methylindole also borylate primarily at the position alpha to the formally sp3 N, affording 62a and 63a, respectively. N- Methylpyrazole is efficiently borylated under these conditions giving 5-borylated pyrazole (62a) in 90% yield, representing the first CHB of N-methylpyrazole catalyzed by a 3d metal.22 For N-methylindole, minor amounts of diborylated indole and N-methyl- 86 4,5,6,7-tetrahydro-1H-indole were also detected in addition to 63a. It is noteworthy that 6-methyl-1H-indole (64) itself undergoes C2–C3 hydrogenation under these conditions to give 6-methlylindoline (64c) as the major product (54% conversion). Quantitative yields of 63a have been reported for CHBs mediated by the Ni(OAc)2/Icy precatalyst/ligand combination with N-methylindole being the limiting reagent.21 Figure 13. Cobalt-Catalyzed CHBs of Heterocyclesa R N Z Z = C, N 3 mol% [Co] catalyst A 5.3 equiv HBpin 80 °C, 48 h R Z N Bpin Z = C, N Entry Starting material Products Ratio/isolated yield 8 9 10 11 12 13 N 61 N N 62 N H N Ph N 63 64 N 65 66 N N 62a N 63a H N 64c pinB Ph Bpin N 65b N Bpin 66a pinB Bpin N 61a N 61b 61a:61b = 2:1 61a+61b = 88% Bpin Bpin 62a = 90% Bpin 63a = 53%b 64c = 54%c 65b = 51%d 66a = 6% aIsolated yields. b88% isolated material with the monoborylated, diborylated, and hydrogenated products present in ac 5:2:1 ratio. The monoborylated product was isolated in 53% yield. cBased on NMR yield. dAfter 48 h another 3 mol % of A and 0.4 equiv of HBpin were added and the mixture was heated at 80 °C for 24 h. 87 To compare C(sp3)–H vs. C(sp2)–H CHB selectivity between arenes and heteroarenes, we examined CHB of N-benzylpyrrole (65) with precatalyst A. Exclusive C(sp2)–H CHB occurred at the 2-position. The general borylation conditions with 6.7 equiv of HBpin gave 95% conversion, affording a mixture of mono and diborylated products (mono:di = 1.3:1). After 48 h, more precatalyst A (3 mol %) and HBpin (2.7 equiv) were added to the reaction mixture, which was heated at 80 °C for an additional 24 h. Compound 65b was isolated as a white solid in 51% yield (X-ray crystal structure CCDC 1576846). To test whether alkyl groups attached to heteroarenes are similarly disposed towards C(sp3)–H CHBs with precatalyst A like arenes are, we subjected indole 66 to identical borylation conditions using precatalyst A. Since the 2-position of indole preferentially borylates with Ir and other Co CHB catalysts, we selected a 2-methyl substrate to favor C(sp3)–H CHB. Only 9% of 66 was converted (based on NMR) with borylation exclusively at the 3-position affording 66a. As with arenes, Co precatalyst A appears to be narrowly tuned to certain classes of heterocycles. Thiophenes, pyridines and their benzo-fused derivatives were not borylated under these conditions. When borylation of equimolar amounts of m-xylene and 2-methylthiophene was attempted under standard conditions no reaction proceeded presumably due to poisoning of the Co precatalyst by thiophenes. 4.5 C(sp2)–H of heteroarenes vs. C(sp2)–H and C(sp3)–H bonds of alkylated arenes To investigate how fast CHB of C(sp2)–H of heteroarenes vs. C(sp2)–H and C(sp3)–H bonds of alkylated arenes, the CHB of a toluene/N-methylpyrazole mixture was performed (Scheme 32). The preference for C(sp2)–H CHB at C5 of N-methylpyrazole 88 further validates that CHBs of heterocycle C(sp2)–H bonds with precatalyst A are favored over C (sp3)–H CHBs of alkyl groups in substituted arenes and heteroarenes. N N + 53 62 3 mol% [Co] precatalyst A 6.7 equiv HBpin 80 °C, 24 h Bpin Bpin Bpin + + N N Bpin 62a 53b 53a 15% 100% (53a:53b = 1:2) Scheme 32. CHB of Toluene vs N-Methylpyrazole 4.6 Identifying the active catalyst species The identity of the catalytically active species is presently unknown. The addition of one drop of mercury to a borylation reaction completely inhibited the reaction (Scheme 33). This likely indicates that the true catalysts generated from A are heterogeneous.23 Notably, similar mercury poisoning has been reported for CHBs catalyzed by species generated from combinations of N-heterocyclic carbene ligands and Ni precatalysts.21 + Hg 3 mol% [Co] catalyst A 5.3 equiv HBpin 80 °C, 18 h 3 mol% [Co] catalyst A 5.3 equiv HBpin 80 °C, 18 h No C-H activation borylation Bpin Bpin Bpin conversion 60% Scheme 33. Hg test When HBpin is added to solutions of A, the chemical shifts for the paramagnetically shifted proton resonances assigned to A remain constant, but the intensities for decrease and vanish when [HBpin]0 ~ 3 [A]0 (Figure 14). 89 1H NMR (C6D6) 500 MHz [A]0 = 0.03 M + [HBpin] = 0.27 M [A]0 = 0.03 M + [HBpin] = 0.09 M [A]0 = 0.03 M Figure 14. 1HNMR of complex A as HBpin concentration increases The 11B NMR spectra initially show one sharp resonance at δ 22.5. The chemical shift and line width are virtually identical to those reported for t-BuOBpin. When [HBpin]0 > 3 [A]0, a broader resonance appears at δ29.5, which is close to the chemical shift for HBpin (11B{1H} NMR, C6D6. d 28.5 ,1JH–B = 179 Hz). In the 11B NMR spectrum when [A]0 = 0.03 M and [HBpin]0 = 0.27 M, the full width at half maximum (FWHM) is 450 Hz for the resonance at δ29.5 (Figure 15). 90 11B NMR (C6D6) 165 MHz [A]0 (0.03 M) + [HBpin] 0 (0.27 M) [A]0 (0.03 M) + [HBpin] 0 (0.09 M) 2 1 90 80 70 60 50 40 30 20 10 0 f1 (ppm) -10 -20 -30 -40 -50 -60 -70 -80 -90 Figure 15. 11BNMR of complex A as HBpin concentration increases The broadening and 1.1 ppm upfield shift for the HBpin 11B resonances is due to interaction of HBpin with unidentified paramagnetic or diamagnetic species. For [A]0 = 0.03 M, [HBpin]0 = 0.27 M, resonances for precatalyst A are undetected in 1H NMR spectra, and no other 11B resonances are observed, aside from those noted above. Thus, A is converted to unidentified species before catalysis ensues. Coupled: Line width at half maximum for 29.5 ppm is 449.77 Hz and for 22.5 ppm is 91.84 Hz (Figure 16) Decoupled: Line width at half maximum for 29.5 ppm is 297.71 Hz and for 22.5 ppm is 92.26 H (Figure 16) 91 11B NMR (C6D6) 165 MHz 45 40 35 30 Coupled Decoupled 25 20 15 10 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0 -0.5 Figure 16. 11BNMR of complex A at coupled and decoupled f1 (ppm) 4.7 Conclusions Co compound A is the first 3d transition metal precatalyst that can monoborylate primary and secondary benzylic C–H bonds with high selectivity. Compound A is also the first Co precatalyst capable of borylating both C(sp3)–H bonds of alkyl benzenes and C(sp2)–H bonds in heterocycles. For diborylations, Co precatalyst A is generally more selective for the geminally diborylated products than previously described Co catalysts. Like Ni(cod)2/Icy-catalyzed CHBs, catalysis with compound A is completely inhibited by adding elemental Hg. 92 4.8 Experimental General Procedures In a nitrogen-filled glovebox, a 5 mL vial was charged with cobalt complex A (15.3 mg, 0.03 mmol, 3 mol %) followed by addition of HBpin (0.8 mL, 5.3 mmol). The reaction mixture was stirred at room temperature until its color changed from purple to brown ((cid:1)5 min). Next, the substrate (1 mmol) was then introduced by syringe. The vial was capped, taken out of the glovebox, and placed in an oil bath that was preheated to 80 °C. The reaction was allowed to proceed at this temperature for 48 h. At that time, the mixture was cooled to room temperature and analyzed by GC and NMR. The crude mixture was transferred into a 20 mL vial, and any excess HBpin was removed by rotary evaporation. A black-blue residue was obtained. To that residue was added deionized water, and the resultant mixture was stirred until the black-blue color had disappeared. The aqueous layer was extracted with dichloromethane (2 × 5 mL). The combined organics were dried over MgSO4, concentrated, and passed through a short silica plug with hexane or hexane/EtOAc (9/1) as eluent. This plug step removed boronate byproducts from the reaction mixture. Hg Test In a nitrogen-filled glovebox, a 5 mL vial was charged with cobalt complex A (15.3 mg, 0.03 mmol, 3 mol %) followed by addition of HBpin (0.8 mL, 5.3 mmol). The reaction mixture was stirred at room temperature until its color changed from purple to brown ((cid:1)5 min). Next, toluene (1 mmol) was introduced. Finally, 1 drop of Hg was placed in the vial (dark brown reaction mixture) (Scheme 33). The vial was capped, taken 93 out of the glovebox, and placed in an oil bath that was preheated to 80 °C. The reaction was allowed to proceed at this temperature for 18 h. A transparent (green in color) reaction mixture was observed after 18 h. 1H NMR confirmed no CHB (Figure 17). Figure 17. Color difference after 18 h: (Right) with Hg, (Left) without Hg Preparation of Precatalyst A Inside a nitrogen-filled glovebox, an oven-dried flask was charged with CoCl2 (344 mg, 2.65 mmol) and 1,3-diisopropyl-1H-imidazol-3-ium chloride (1.010 g, 5.3 mmol). THF (16 mL) was added followed by addition of KOtBu (1.19 g, 10.6 mmol) in one portion. The resulting mixture was stirred inside the glovebox for 1 h. Then, solvent was removed under vacuum. The residue was suspended in toluene and filtered through a pad of Celite. The filtrate was collected, and solvent was removed under vacuum, providing a dark purple crystalline material that was dried under vacuum. Recrystallization from pentane at −35 °C afforded 1.140 g (84%) of crystalline complex A (mp 165 °C dec). Single crystals suitable for X-ray diffraction studies were selected from the recrystallization, and such analysis confirmed the structure. 1H NMR (500 MHz, C6D6, ppm): δ 41.70 (s, 4 H), 39.00 (br s, 4 H), 8.76 (br s, 18 H), 2.31 (br s, 24 H). Complex A is stable on storage in the glovebox at −35 °C but quickly decomposes on exposure to ambient atmospheric conditions. 94 Calculating magnetic moment A 2% (0.0094M) standard solution of hexamethyldisiloxane in benzene-d6 was prepared. This solution was added into a capillary and the capillary was sealed. Inside a glove box, pre-catalyst A (15.3 mg, 0.03 mmol) was dissolved in 1.00 mL of the standard solution and then transferred to an NMR tube. The sealed capillary was then inserted into the tube containing the sample solution and the 1H NMR spectrum was acquired. The difference between the two hexamethyldisiloxane signals was measured (in Hz). The experimental Dn value was 453.5 Hz. Using this value, the magnetic susceptibility (Cm) was determined using equation 1, where n is the proton frequency for the spectrometer (500 MHz) and [C] is the concentration of the precatalyst in the standard solution (0.03 M). The effective magnetic moment (µeff) was then determined using equation 2, at T = 294.2 K. This yielded an experimental magnetic moment of 4.20 µB., which is slightly higher than the theoretical spin-only magnetic moment of 3.88 µB for a pseudotetrahedral d7, high-spin configuration.24 The effective magnetic moment for precatalyst A calculated by the Evans method is 4.29 µB. 4*(+ −"-./= 3000 453.5 "#=3000Δ( 4*500 0.03 −(−268.7 8 10:;) =7483.4 8 10:;=:> ?@AA=2.828 "#B= 2.828 7214.7 8 10:;=:>(294.2)=4.20 ?D 95 1H NMR (C6D6) 500 MHz S Figure 18. Spectra for Evans method calculations Figure 19. 1H NMR of complex A in C6D6 96 Compound 53a & 53b Bpin 53a 53b Bpin Bpin The general borylation procedure was carried out on toluene to afford 0.265 g of the products as a white solid (53a:53b = 1:9) in 80% yield. For 53b: 1H NMR (500 MHz, CDCl3, ppm) δ 7.27 (d, J = 6.5 Hz, 2 H), 7.22 (t, J = 7.5 Hz, 2 H), 7.08 (t, J = 7.0 Hz, 1 H), 2.30 (s, 1 H), 1.23 (s, 12 H), 1.21 (s, 12 H). 13C NMR (125 MHz, CDCl3, ppm) δ 139.49, 129.13, 127.92, 124.15, 83.34, 24.68, 24.59. 11B NMR (160 MHz, CDCl3, ppm) δ 33.3.16 Compound 54a & 54b Bpin 54a 54b Bpin Bpin The general borylation procedure was carried out on m-xylene using 1.0 mL HBpin (6.7 equiv). This modified procedure afforded 0.248 g of the products (54a:54b = 1:1.9) in 78% yield. SiO2 column chromatography, eluting with hexane/EtOAc (5:1) afforded 0.136 g of the diborylated product (54b) as a white sticky solid in 38% yield. 1H NMR (500 MHz, CDCl3, ppm) δ 7.13–7.09 (m, 2 H),7.05 (s, 1 H), 6.89 (d, J= 6.5 Hz, 1 H), 2.29 (s, 3 H), 2.26 (s, 1 H), 1.23 (s, 12 H), 1.22 (s, 12 H). 13C NMR (125 MHz, CDCl3, ppm) δ 139.26, 137.26, 129.94, 127.78, 126.23, 125.01, 83.30, 24.69, 24.60. 11B NMR (160 MHz, CDCl3, ppm) δ 32.9. For 54a: 1H NMR (500 MHz, CDCl3, ppm) δ 7.13 (t, J= 7.5 Hz, 1 H), 7.00 (s, 1 H), 6.98 (s, 1 H), 6.94 (d, J = 7.5 Hz, 1 H), 2.31 (s, 3 H), 97 2.26 (s, 2 H), 1.24 (s, 12 H). 13C NMR (125 MHz, CDCl3, ppm) δ 138.46, 137.72, 129.86, 128.13, 125.96, 125.60, 83.37, 24.72, 21.52. 11B NMR (160 MHz, CDCl3, ppm) δ 33.1. Compound 55a & 55b Bpin 55a 55b Bpin Bpin The general borylation procedure was carried out on p-xylene using 1.0 mL HBpin (6.7 equiv). This modified procedure afforded 0.098 g of the products as an oil (55a:55b = 1:1) in 33% yield. Diborylated product (55b): 1H NMR (500 MHz, CDCl3, ppm) δ 7.15 (d, J= 7.5 Hz, 2 H), 7.02 (d, J= 7.5 Hz, 2 H), 2.28 (s, 3 H), 2.25 (s, 1 H), 1.23–1.22 (overlapping peaks, 24 H).11B NMR (160 MHz, CDCl3, ppm) δ 33.0. Monoborylated product (55a):1H NMR (500 MHz, CDCl3, ppm) δ 7.07 (m, 4 H), 2.29 (s, 3 H), 2.25 (s, 2 H), 1.21 (s, 12 H). 7.07 (m, 4 H), 2.29 (s, 3 H), 2.25 (s, 2 H), 1.21 (s, 12 H). Compound 56a & 56b Bpin 56a 56b Bpin Bpin The general borylation procedure was carried out on cymene and afforded 0.091 g of the products as an oil mixture (56a:56b = 1:1) in 21% yield. Monoborylated product (56a): 1H NMR (500 MHz, CDCl3, ppm) δ 7.11 (s, 4 H), 2.85 (m, 1 H), 2.27 (s, 2 H), 1.21 (s, 12 H). Diborylated product (56b): 1H NMR (500 MHz, CDCl3, ppm) δ 7.19 (d, J 98 = 8.5 Hz, 2 H), 7.07 (d, J = 8.5 Hz, 2 H), 2.85 (m, 1 H), 2.29 (s, 1 H), 1.24 (s, 12 H), 1.23 (s, 12 H). Compound 58a Bpin 58a The general borylation procedure was carried out on ethylbenzene with 2 mol % Co precatalyst (10.2 mg, 0.02 mmol) and HBpin (0.4 mL, 2.6 mmol). This modified procedure afforded 0.106 g of the product was isolated as colorless oil in 49% yield. 1H NMR (500 MHz, CDCl3, ppm) δ 7.27–7.21 (m, 4 H), 7.14–7.12 (m, 1 H), 2.43 (q, J = 7.5 Hz, 1 H), 1.33 (d, J = 7.5 Hz, 3 H), 1.21 (s, 6 H), 1.20 (s, 6 H). 13C NMR (125 MHz, CDCl3, ppm) δ 144.95, 128.29, 127.78, 125.08, 83.27, 24.62, 24.58, 17.06. 11B NMR (160 MHz, CDCl3, ppm) δ 33.3. Compound 59a Bpin 59a The general borylation procedure was carried out on isopentylbenzene with 2 mol % Co precatalyst (10.2 mg, 0.02 mmol). After workup 0.097 g of the product were isolated as a colorless oil in 35% yield. 1H NMR (500 MHz, CDCl3, ppm) δ 7.27–7.21 (m, 4 H), 7.14–7.12 (m, 1 H), 2.43 (t, J = 8.0 Hz, 1 H), 1.72–1.58 (m, 2 H), 1.52–1.45 (m, 1 H), 1.20 (s, 6 H), 1.18 (s, 6 H), 0.90 (d, J = 7.0 Hz, 3 H), 0.88 (d, J = 6.5 Hz, 3 H). 13C 99 NMR (125 MHz, CDCl3, ppm) δ 143.45, 128.34, 128.23, 125.02, 83.19, 41.46, 29.72 (C– B), 26.87, 24.57, 22.99, 22.17. 11B NMR (160 MHz, CDCl3, ppm) δ 33.2. Compound 61a & 61b pinB Bpin N 61a N 61b Bpin The general borylation procedure was carried out on N-methylpyrrole with 2 mol % Co precatalyst (10.2 mg, 0.02 mmol). This modified procedure afforded 0.211 g of the products as a solid mixture (61a:61b = 2:1) in 88% yield. 2-Borylated N-methylpyrrole is not stable and deboronates back to starting material. Monoborylated product (61a): 1H NMR (500 MHz, CDCl3, ppm) δ 6.81–6.80 (m, 2 H), 6.15 (dd, J = 2.5, 3.5 Hz, 1 H), 3.85 (s, 3 H), 1.27 (s, 12 H). 13C NMR (125 MHz, CDCl3, ppm) δ 128.2, 121.8, 108.3, 83.0, 36.6, 24.8. 11B NMR (160 MHz, CDCl3, ppm) δ 28.9. Diborylated product (61b): 1H NMR (500 MHz, CDCl3, ppm) δ 6.77 (s, 2 H), 4.01 (s, 3 H), 1.30 (s, 24 H). 13C NMR (125 MHz, CDCl3, ppm) δ 121.6, 108.1, 83.1, 24.5. 11B NMR (160 MHz, CDCl3, ppm) δ 28.9. Compound 62a N N 62a Bpin The general borylation procedure was carried out on N-methylpyrazole with 2 mol % Co precatalyst (10.2 mg, 0.02 mmol). This modified procedure afforded 0.185 g of 62a as white solid (mp = 59–60 °C; lit. 74–75 °C) in 90% yield. 1H NMR (500 MHz, CDCl3, 100 ppm) δ 7.49 (d, J = 2.0 Hz, 1 H), 6.71 (d, J = 2.0 Hz, 1 H), 4.09 (s, 3 H), 1.34 (s, 12 H). 13C NMR (125 MHz, CDCl3, ppm) δ 138.3, 115.8, 84.1, 39.3, 24.8. 11B NMR (160 MHz, CDCl3, ppm) δ 27.7. HRMS (EI+) m/z 209.1452 [(M+H+) calcd for C10H18BN2O2 209.1461]. Compound 63a N 63a Bpin The general borylation procedure was carried out on N-methylindole and afforded 0.227 g of a mixture of products. SiO2 column chromatography, eluting with hexane/CH2Cl2 (3:1) afforded 0.133 g of the 2-borylated product was isolated as a white solid (mp = 82–84 °C) in 53% yield. Over time in a refrigerator 63a developed a brownish color. 1H NMR (500 MHz, CDCl3, ppm) δ 7.65 (d, J = 8.0 Hz, 1 H), 7.35 (d, J = 8.0 Hz, 1 H), 7.28–7.25 (m, 1 H), 7.13 (s, 1 H), 7.09 (t, J = 7.5 Hz, 1 H), 3.98 (s, 3 H), 1.37 (s, 12 H). 13C NMR (125 MHz, CDCl3, ppm) δ 140.1,127.8, 123.2, 121.6, 119.3, 114.2, 109.7, 83.7, 32.2, 24.8. 11B NMR (160 MHz, CDCl3, ppm) δ 28.4. HRMS (EI+) m/z 258.1662 [(M+H+) calcd for C15H21BNO2 258.1665]. Compound 65b pinB Ph Bpin N 65b The general borylation procedure was carried out on 1-benzyl-1H-pyrrole and after 48 h another 3 mol % Co precatalyst and HBpin (0.4 mL) was added and heated at 80 °C for 101 another 48 h. This modified procedure afforded 0.207 g of the product as white solid (mp = 107–108 °C) in 51 % yield. 1H NMR (500 MHz, CDCl3, ppm) δ 7.23–7.16 (m, 2H), 7.16–7.11 (m, 1H), 7.04–6.99 (m, 2H), 6.85 (s, 2H), 5.73 (s, 2H), 1.22 (s, 24H). 13C NMR (126 MHz, CDCl3, ppm) δ 141.2, 127.8, 126.5, 126.3, 121.9, 83.3, 51.7, 24.6. 11B NMR (160 MHz, CDCl3, ppm) δ 27.8. HRMS (EI+) m/z 410.2708 [(M+H+) calcd for C23H34B2NO4 410.2674]. Compound 66a N Bpin 66a The general borylation procedure was carried out on 1,2-dimethylindole and afforded 0.016 g of product as a sticky white solid in 6% yield. 1H NMR (500 MHz, CDCl3) δ 8.03–7.97 (m, 1H), 7.25 (dt, J = 8.0, 0.9 Hz, 1H), 7.18–7.04 (m, 2H), 3.67 (s, 3H), 2.64 (s, 3H), 1.36 (s, 12H). 13C NMR (126 MHz, Chloroform-d) δ 147.5, 137.9, 132.4, 121.8, 120.8, 120.1, 108.5, 82.3, 24.9. 102 REFERENCES 103 REFERENCES (1) Chen, H.; Hartwig, J. F. Catalytic, Regiospecific End-Functionalization of Alkanes: Rhenium-Catalyzed Borylation under Photochemical Conditions. 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Educ. 1971, 48, 328–386. 106 Chapter 5. First, Ligand Controlled Synthesis of 1,2-di and 1,2,3-tri Borylated Arenes via Iridium Catalyzed C-H Borylations 5.1 Introduction to aromatic di- and poly-boronic esters (PBEs) Aromatic di and polyboronic acids(PBAs)/esters (PBEs) are valuable synthetic intermediates in organic synthesis1,2 for formation of transition metal catalyzed C-C and carbon-heteroatom bond formation.3–5 However, installing two or three boryl groups in the aromatic ring is challenging. Traditionally, installing two boryl groups (E) on aromatic ring relied on pre-functionalized mono or 1,2-dihalobenzene (A) compounds (Figure 20). These undergo metal-halogen6–9 (Mg or Li) exchange or Pd-catalyzed Miyaura coupling10–12 to give o-benzenediboronic acids. Recently, Pt- and Cu-catalyzed 1,2-diborylation of in situ generated arynes has attracted attention as a convenient method to form o- benzenediboronic acids.13–15 Other methods include high yielding 1,2-selective dual C−H/C−X borylation starting with mono halobenzene (B).16,17 X Y R A X H R B R E H H R D non-directed C-H borylation B(OR)2 B(OR)2 directed borylation R B(OR)2 H C Figure 20. Preparation of o-Benzenediboronic Acids Given the substrate dependence on aromatic halogenations, accessing suitable haloaromatic starting materials can be trivial or prohibitively difficult. Installing, two or 107 three boryl groups on an aromatic ring starting from unfunctionalized arenes would be attractive. Recently, Yoshida and co-workers reported formation of o-benzenediboronic acid via Ir catalyzed ortho C-H borylation directed by pyrazolylaniline modified boronyl group (C).18 This is the first report achieving o-C−H borylation directed by a boronyl group using Ir as the catalyst. First, non-functionalized arenes are borylated using non-directed C-H activation borylation using Ir catalyst. Then the boronyl group is modified by pyrazolylaniline, which leads to the formation of the Bpza group. This PZA-modified boronyl group behave as a temporary directing group in Ir-catalyzed o-C−H borylations yeilding 1,2–benzenediboronic acid derivatives (Scheme 34). H H R nondirected C–H borylation Bpza H R directed C–H borylation Bpza Bpin R HN B N N Bpza Scheme 34. Directed o-C−H Functionalization by –Bpza group It would be an attractive method if we could achieve 1,2–benzenediboronic acid derivatives without any directing groups. Up to date there have been no report of non- directed iridium catalyzed C-H borylation to give 1,2-diborylated arenes without using any prefunctionalized starting arenes (D). 5.2 Data and Discussion In 2014, we reported selectively generating arylboronic esters ortho to fluorine via Ir-catalyzed C–H borylations followed by hydrodehalogenations (Chapter 2).19 However, a more attractive method would be the selective Ir-catalyzed C-H borylations ortho to 108 fluorine via ligand control. Therefore, our group continued studies on selective Ir- catalyzed C–H borylations with various ligand systems. These ligands were reacted with 1 mol % [Ir(OMe)(COD)]2, 2 mol % ligand and 1.00 equiv of B2Pin2 in hexane at 60 °C (more in detail about ligand screening in Chapter 6) (Scheme 35). R2 R1 F 1 mol % [Ir(OMe)COD]2 1.00 equiv B2pin2 R1 R2 2 mol % Ligand, hexane 60 °C, 24 h R1 F + Bpin Electronic R2 F + di Bpin Steric Scheme 35. Ligand screening for CHBs We were interested in any ligand system that favored exclusively one of the isomers (steric or electronics) over the other one. However, among these ligands 2,2’- bipyrazine (L1) stood out for resulting in significant amounts of diborylated arenes when screening against 1-chloro-3-fluoro-2-methoxybenzene (2,6-CFA). Diborylation was enhanced when reactions were run in non-polar solvents such as hexane and methyl- cyclohexane (Table 2). Table 2. Solvent screening for L1 N N N N L1 OMe F Cl 67 1 mol % [Ir(OMe)COD]2 1.00 equiv B2pin2 2 mol % L1, hexane 60 °C, 24 h OMe Cl Cl F + Bpin 67a OMe F + di Bpin 67b Entry Solvent THF Hexane CPME Me–cyclohexane Hunig's Base 1,4–dioxane 1 2 3 4 5 6 Conversion(GC) 67a/67b/Di 49% 77% 77% 82% 84% 34% 44/52/4 35/40/25 39/49/12 35/44/21 41/43/16 54/31/15 109 The two possibilities for the diborylations of 2,6–CFA are 1,2 (67c) and 1,3 (67c´) di- substituted borylated arenes (Figure 21). The regiochemical course of these Ir- catalyzed borylation reactions are primarily driven by sterics,20,21 making it relatively easy to install two Bpin groups 1,3 (67c´) over 1,2 (67c). OMe F Cl Cl or Bpin pinB Bpin 67c OMe F Bpin 67c´ Figure 21. Two possible regioisomers of di borylated arenes for 2,6-CFA For ease of isolation and characterization of 67c or 67c´, we carried out CHBs of 67a under the same reaction conditions as in Table 2. It was crucial that we confirm the diborylated product formed in Scheme 36 was the same as which appeared in Table 2 entry 2 (by comparing 1H NMRof the crude product, chemical shift at δ 7.60 in the aromatic region and the δ -121.69 chemical shift by 19F NMR). After confirming the diborylated product was the same product formed from both reactions, we proceed to isolation. N N N N L1 OMe F Cl Cl 67 OMe 67a F Bpin Scheme 36. CHBs of 67a 110 1 mol % [Ir(OMe)COD]2 1.00 equiv B2pin2 2 mol % L1, hexane 60 °C, 24 h OMe Cl Cl F + Bpin 1 mol % [Ir(OMe)COD]2 1.00 equiv B2pin2 2 mol % L1, hexane 60 °C, 24 h Cl 67a OMe Bpin 67c OMe Bpin 67b F + Cl OMe F Cl or Bpin pinB Bpin 67c F Bpin OMe 67cʹ F Bpin Cl or pinB F Bpin OMe 67cʹ CHBs of 67a was carried out and after 48 h 65% of the diborylated product was formed. We thought the best way to identify the correct regioisomer of the diborylated product was through X-ray crystallography. Indeed, after isolation, and X-ray crystallography confirmed that the correct structure was that of 67c. (Figure 22). Figure 22. X-ray crystallographic structure of 67c. This is the first Ir catalyzed non-directed CHBs that forms 1,2- diborylated arenes. Intrigued by this unusual reactivity of ligand L1, we set out to see if we could synthesize more 1,2 diborylated arenes. We started with mono borylated arenes and performed Ir- catalyzed borylations to obtain diborylated arenes. 1 mol % [Ir(OMe)COD]2 0.55 equiv B2pin2 2 mol % L1, hexane 60 °C, 48 h CF3 Bpin 68a + pinB Bpin CF3 Bpin 68c CF3 Bpin 68* Bpin Scheme 37. C–H borylation of 68a One such example is the borylation of 4,4,5,5-tetramethyl-2-(4- (trifluoromethyl)phenyl)-1,3,2-dioxaborolane (68a) (Scheme 37). After 48 h, an off white fine powder crashed out of the crude reaction mixture. This fine powder was separated from the reaction mixture by simple gravity filtration. 1H NMR of this fine white powder 111 suggested the presence of 12xCH3 groups {δ 1.48 (12H), 1.33 (24H)}. Astonished by this result, we were determined to get an X-ray crystal structure. After growing crystals and subjecting them to X-ray, we finally confirmed that it is triborylated arene (68*) (Figure 23). In 2017, Suginome and co–workers reported isolation of 1,2,3-benzenetriboronic acid pinacol ester (5%) using the PZA directing group. Up to date no one had ever directly installed three Bpin group next to each other in an arene system. We and others have showed that it is possible to directly install several Bpin groups in Sp3 carbons22,23 but not in Sp2 arene system.24 Therefore, this is the first report, where direct iridium catalyzed CHBs were able to install multiple boryl groups next to each other without any directing groups. Figure 23. X-ray crystallographic structure of 68*. However, this catalyst system is not reactive as the most commonly used [Ir(OMe)COD]2 and dtbpy system. After 48 h only 45% conversion was observed. Therefore, to have a better conversion to polyborylated compounds, we increased the catalyst loading to 3 mol % of [Ir(OMe)COD]2, 6 mol % of 1 and 1.00 equiv of B2pin2 in hexane 60 °C for 48 h. However, this did not help to improve product formation. Next, we tried introducing a new catalyst loading after every 48 h (1–2 times) after the first addition. This helped to consume all the starting material (Scheme 38). 112 Bpin R Het 1 mol % [Ir(OMe)COD]2 0.75 equiv B2pin2 2 mol % L1, hexane 60 °C, 48 h Bpin R Het Bpin Bpin + R Het partial conversion Bpin Bpin 1 mol % [Ir(OMe)COD]2 0.55 equiv B2pin2 2 mol % L1, hexane 60 °C, 48 h X(1-2) Bpin R Het Bpin Bpin + R Het full conversion Bpin Bpin Scheme 38. Multiple catalyst loading in CHBs With this new finding in hand we set out to investigate our previously described substrates (67a and 68a) as well as new substrates for making 1,2-di or 1,2,3-tri borylated compounds (Scheme 39). CHBs of 67a with only two catalyst loadings, was able to afford full conversion to 67c, which was isolated in 81% yield. In this case, no tri borylation was observed. On the other hand, 68a used up 3 loadings and was able to isolate 68c (61%) and 68* (6%). 1) 1 mol % [Ir(OMe)COD]2 0.75 equiv B2pin2, 60 °C, 2 mol % L1 48 h, hexane 2) 1 mol % [Ir(OMe)COD]2 0.55 equiv B2pin2, 60 °C, 2 mol % L1 48 h, hexane x1 1) 1 mol % [Ir(OMe)COD]2 0.75 equiv B2pin2, 60 °C, 2 mol % L1 48 h, hexane 2) 1 mol % [Ir(OMe)COD]2 0.55 equiv B2pin2, 60 °C, 2 mol % L1 48 h, hexane x2 OMe Cl F Bpin 67a CF3 Bpin 68a Cl OMe Bpin F Bpin 67c, 81% CF3 CF3 + pinB Bpin Bpin 68c, 61% Bpin 68*, 6% Bpin Scheme 39. CHBs of 67a and 68a 113 Intrigued by these data, we started screening C-H borylations of mono borylated compounds. Our main goal was to make sterically demanding 1,2–di and 1,2,3–tri borylated compounds (Figure 24). Thus, we purchased commercially available boronic acids and converted them to corresponding boronic esters or unless otherwise noted. CHBs of 4,4,5,5-tetramethyl-2-(4-(trifluoromethoxy)phenyl)-1,3,2-dioxaborolane (69a) resulted in a similar borylation pattern like (68a). After three catalyst loadings, 1,2- di (69c)was formed in 46 % and 1,2,3-tri (69*) in 10% yields. Next, we tried the CHB of 2-(3-chloro-5-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (70). This substrate was synthesized in our lab, as part of an on–going project. After reacting with three catalyst loadings (cid:2)92% product formation was observed. (70c: tri = 97:3). The 1,2- diborylated (70c) was isolated in 46% yield, however, we were unable to isolate the tri borylated product (Figure 24). Next, we investigated CHB of pentafluorosulfanylbenzene (71). After the first catalyst loading, two mono borylated products meta borylated 71a, para borylated 71aʹ and a single diborylated product (71cʹ) were generated in a ratio of 63: 31: 6. Introduction of the second catalyst loading, formation of 71cʹ was enhanced. During the course of the reaction diborylated compound 71cʹ crashes out from the reaction mixture and 32% was isolated after a simple filtration. Surprisingly, pentafluorosulfanylbenzene gave 1,3- diborylated product 17cʹ and not the 1,2-di borylated product aas before. compound 71aʹ was unreactive for further CHBs. 114 Figure 24. Synthesis of 1,2-di and 1,2,3-tri borylated arenes/heteroarenes R1 H R2 Bpin R3 H 1) 1 mol % [Ir(OMe)COD]2 0.75 equiv B2pin2, 60 °C, 2 mol % L1 48 h, hexane 2) 1 mol % [Ir(OMe)COD]2 0.55 equiv B2pin2, 60 °C, 2 mol % L1 48 h, hexane x2 R1 H R2 Bpin R3 R1 + Bpin pinB R2 Bpin R3 Bpin Entry Starting material Products OMe Cl Cl F Bpin 67a CF3 Bpin 68a OCF3 Bpin 69 Cl F Cl OMe Bpin F Bpin 67c, 81% CF3 Bpin Bpin 68c, 61% OCF3 CF3 pinB Bpin Bpin 68*, 6% OCF3 Bpin pinB Bpin 69c, 46% F Bpin Bpin 70c, 52% SF5 Bpin Bpin 69*, 10% SF5 Bpin 71a SF5 Bpin 71aʹ 1 2 3 4 5 6 7 Bpin 70a SF5 71 O 72a N N 73 pinB Bpin 71cʹ, 34% Bpin pinB O Bpin 72cʹ, 69% N N Bpin 73cʹ, 36% pinB 115 We also investigated CHBs of mono borylated 1,4 substitution of bromo, toluene, isopropyl, chloro and cyano. Surprisingly, these compounds did not show any CHBs. We also tried CHBs of 1,3-dicyanobenzene and 2-bromothiphene. 1,3-Dicyanobenzne showed no CHBs, but 2-bromothiphene progressed half way through to the 5-mono borylated species. However, borylation of the species didn’t progress any further even after adding a second loading of catalyst and a black film was formed around the wall of the vial. Nevertheless, this was a promising result for catalytic activity of this ligand system and motivated us to investigate more into heteroarenes. C-H borylation of 2-methyl furan resulted in a mixture of 5-mono and diborylated compounds. For the ease of isolation and characterization of the diborylated product, a CHB was carried out with compound 72a. Two diborylated regioisomers {1,3-di (72cʹ) and 1,2-di (72c)} and one tri borylated isomer were observed in a ratio of 78: 17: 5 (confirmed by GCMS and 1HNMR). The favored regioisomer was 1,3-diborylated methyl furan (72cʹ) which was isolated in 69% yield. C-H borylation next to the methyl group was favored over the Bpin group in 72a. We also investigated CHB of N-methyl pyrazole (73). We were able to isolate 1,3-diborylated N-methylpyrazole (73cʹ) in 36% yield. Surprisingly, only one regioisomer was observed with borylation next to nitrogen favored. CHBs of N-methylindole gave a mixture of 2- and 3- mono borylated products, where 2- borylated N-methylindole is the more favored regioisomer for mono borylation and also several di- borylated isomers (GCMS). Even though this ligand system gives unprecedented chemistry, it is reactive towards limited substrate scope. This system shows an intriguing bias towards fluoro containing arenes. However, the fluorine need not be directly attached to the arene. To 116 understand more about how this system work in CHBs we carried out further investigations. As we know from chapter 2, fluoro arenes often gives a mixture of products (steric and electronic). A hydrogen next to fluorine is more susceptible for CHBs due to its acidity. Therefore, CHBs of 2-(4-fluorophenyl)-4,4,5,5-tetramethyl- 1,3,2-dioxaborolane (74a) should favor C–H activation next to fluorine (Scheme 40). 1 mol % [Ir(OMe)COD]2 2 mol % L1 0.75 equiv B2pin2, 60 °C, 48 h, hexane F Bpin 74a F Bpin 74c conversion 57 % 3:1 + Bpin F Bpin Bpin 74cʹ Scheme 40. CHBs of 74a in hexane Surprisingly, CHBs of 74a favors borylation next to Bpin group. This CHB activation catalyst system going against fundamentals of iridium catalyzed CHBs, which is borylation is sterically driven. Several regioisomers of di and tri borylated products were observed by 19F NMR and GCMS. Intrigued by the results in Scheme 41, we wanted to investigate the outcome if we used different type of boron derivatives, such as, propane-1,2-diol (Bpg), ethane-1,2-diol (Beg), N-methyliminodiacetic acid (BMIDA) and 1,8-diaminonaphthalene (BDAN) boronic esters. These different boron derivatives vary with sterics and electronic properties. Unfortunately, synthesis of the Bpg derivative starting from (4- fluorophenyl)boronic acid was unsuccessful. Nevertheless, we were able to buy the BMIDA of fluorobenzene (75). 117 BMIDA compounds are not soluble in hexane, which led us to change the solvent for the CHBs. Initial solvent screening suggested that this catalyst system gives lower conversions to the diborylated product in relatively polar solvents, such as THF and 1,4- dioxane (Figure 23). As BMIDA arenes readily dissolve in 1,4-dioxane at elevated temperatures, we repeated the reaction in Scheme 41 in 1,4-dioxane to see if the same selectivity observed in hexane repeated (Scheme 41). 1 mol % [Ir(OMe)COD]2 2 mol % L1 0.75 equiv B2pin2, 60 °C, 48 h, dioxane F Bpin 74a F Bpin 74c conversion 50 % 6:1 + Bpin F Bpin Bpin 74cʹ Scheme 41. CHBs of 23 in dioxane Remarkably, in dioxane a significant bias towards 1,2-diborylation (74c) was observed. In hexane only a 3:1 ratio was observed for 74c:74cʹ, but with dioxane as the solvent the selectivity raised to 6:1. This shows that not only the substrate electronics, but also the solvent electronics influence selectivity (Figure 25). Figure 25. 19F NMR for CHBs of 74a in hexane (top) Vs. dioxane (bottom) 118 We proceed to investigate to this remarkable catalyst system further. CHB of 75 in 1,4-dioxane was attempted (Scheme 42), unfortunately no C–H borylation was observed and only starting material was present in the crude reaction mixture. F BMIDA 75 1 mol % [Ir(OMe)COD]2 2 mol % L1 0.75 equiv B2pin2, 60 °C, 48 h, dioxane no reaction BMIDA = Me N B O O O O Scheme 42. CHBs of 75 in 1,4-dioxane We hypothesized that we did not see CHBs due to several possible reasons: 1. BMIDA is more sterically hindered compared to Bpin group 2. Boron has an empty p-orbital in a Bpin group but not in a BMIDA group 3. BMIDA ability to coordinate to the catalyst and shut down the CHB To test these hypothesis, we set up a CHB with equal molar amount of 74a and 75 in 1,4-dioxane (Scheme 43). After 48 h, only 22% product formation (74c and 74cʹ) was observed compared to the 50% (Scheme 41) resulted in absence of 75. Selectivity decreased to 4:1 from 6:1. This shows that, changing Bpin group has an effect, but we cannot clearly indicate that this is a “boron directed” CHBs without additional evidence. F F + BMIDA 75 Bpin 74a 1 mol % [Ir(OMe)COD]2 2 mol % L1 0.75 equiv B2pin2, 60 °C, 48 h, dioxane F Bpin 74c + Bpin F Bpin Bpin 74cʹ conversion 22 % 4:1 Scheme 43. Equal molar CHBs of 74a and 75 119 Another unanswered question is what is the role of fluorine? To answer that question, we investigated CHBs of borylated benzene (76) (Scheme 44 a). Even though, there are many available hydrogens, no CHBs were observed. Next, we added hexafluorobenzene (77) as an external fluorine source to see whether it will promote any CHBs of 76 (Scheme 44 b). Unfortunately, no evidence for any kind of CHBs were observed. a) b) Bpin 76 1 mol % [Ir(OMe)COD]2 2 mol % L1 0.75 equiv B2pin2, 60 °C, 48 h, hexane No reaction + F F Bpin 76 F F 77 F F 1 mol % [Ir(OMe)COD]2 2 mol % L1 0.75 equiv B2pin2, 60 °C, 48 h, hexane No reaction Scheme 44. a) CHBs of 76 b) Equal molar CHBs of 76 and 77 We also investigated CHBs of 76 (1 mmol) with 74a (0.5 mmol). The outcome of this reaction was astonishing (Scheme 45). In presence of excess 76, after 48 h only 15% product formation was observed for 74a and no CHBs were observed from 76. This shows that conversion has significantly decreased in presence of an excess external Bpin- arene. We also know that catalyst activity diminishes as the reaction progress and when we use B2pin2 as the boron source. Maybe there is some kind of deactivation is coming from boron source itself. NMR studies will help to get more information regarding this deactivation by monitoring catalyst behavior as reaction progresses. 120 Bpin F + 76 1 mmol Bpin 74a 0.5 mmol 1 mol % [Ir(OMe)COD]2 2 mol % L1 0.75 equiv B2pin2, 60 °C, 48 h, hexane F Bpin 74c + Bpin F Bpin Bpin 74cʹ conversion 0% conversion 15 % Scheme 45. CHBs of 74a with excess 76 Furthermore, only one regioisomer 74cʹ was observed in contrast to Scheme 41, (Figure 26). This suggest that an excess external Bpin source changes the selectivity for CHBs. Figure 26. 19F NMR for CHBs of 74a with 76 (top) Vs. 74a without 76 NMR Experiments All reactions were run in C6D12 at 900 MHz. 1) (0.02 mmol) 2,2ʹ-bipyrazine (L1) in (1.0 mL) C6D12 Ligand L1 is sparingly soluble in C6D12 at room temperature. By proton NMR three major peaks were observed in the aromatic region of the spectrum. 1H NMR 121 (900 MHz, C6D12) δ 9.61 (s, 1H), 8.48 (d, J = 2.1 Hz, 1H), 8.44 (d, J = 2.2 Hz, 1H) (Figure 27.1). 2) (0.02 mmol) 2,2ʹ-bipyrazine (L1) + (0.01 mmol) [Ir(OMe)COD]2 in (1.0 mL) C6D12 No significant color change or changes to the ligand proton signals and the catalyst proton signals were observed. Therefore, at room temperature there is not a rapid reaction between the ligand and the Ir pre–catalyst (Figure 27.2). 1H NMR (900 MHz, C6D12) δ 9.61 (s, 1H), 8.48 (d, J = 2.1 Hz, 1H), 8.44 (d, J = 2.2 Hz, 1H), 3.45 (d, J = 4.1 Hz, 8H), 3.17 (s, 6H), 2.23 – 2.12 (m, 8H), 1.33 (d, J = 7.8 Hz, 8H). 3) (0.02 mmol) 2,2ʹ-bipyrazine (L1) + (0.04 mmol) B2Pin2 in (1.0 mL) C6D12 Next, the ligand was combined with B2pin2. It is noteworthy that B2pin2 is only sparingly soluble in C6D12. As soon as the ligand is combined with B2pin2 the solution turned green. Bipyrazine proton peaks in the aromatic region did not completely disappear, however new three up field shifted peaks were observed {δ 7.13 (s, 1H), 6.83 (d, J = 5.3 Hz, 1H), 6.35 (d, J = 5.4 Hz, 1H)}. Also 1H-NMR spectrum became messier with this combination. Therefore, there is a rapid reaction between the ligand and B2pin2 (Figure 27.3). 4) (0.02 mmol) 2,2ʹ-bipyrazine (L1) +(0.01 mmol) [Ir(OMe)COD]2 + (0.12 mmol) B2Pin2 in (1.0 mL) C6D12 122 After combining the ligand, Ir-precatalyst and B2pin2, a green solution was observed and in the 1H NMR spectrum, the bipyrazine proton peaks in the aromatic region completely disappeared. We did not observe a messy proton NMR spectrum like in the previous case. However, we did observe the three up- field shifted peaks {δ 7.92 (s, 1H), 6.81 (s, 1H), 6.33 (s, 1H)} with slightly different chemical shifts than in the previous case (Figure 19.4). When all three species are combined together an immediate degradation of the ligand is not observed. However, after 24 h the proton NMR spectrum of this mixture is messy and we were unable to detect the three up field shifted proton signals. 1H NMR (C6H12) 900 MHz 1H NMR (C6H12) 900 MHz 1H NMR (C6H12) 900 MHz 1H NMR (C6H12) 900 MHz 12.0 11.5 11.0 10.5 10.0 9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 f1 (ppm) 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0 -0.5 Figure 27. 4 3 2 1 1) 1HNMR of 2,2ʹ-bipyrazine (L1) in C6D12 2) 1HNMR 2,2ʹ-bipyrazine (L1) + [Ir(OMe)COD]2 in C6D12 3) 1HNMR 2,2ʹ-bipyrazine (L1) + B2Pin2 in C6D12 4) 1HNMR 2,2ʹ-bipyrazine (L1) + [Ir(OMe)COD]2 + B2Pin2 in C6D12 123 Usually CHBs with this catalyst system are run at 60 °C, therefore future investigations of NMR studies should be run at that temperature. This will help to avoid any unambiguous data due to solubility issues. Moreover, investigating changes in the 11BNMR spectra may also be important for a clearer understanding of the chemical reactions between the ligand, Ir pre-catalyst and B2pin2. In 2012, Suginome and co-workers reported an efficient dearomatizing of pyrazines to 1,4-dihydropyrazines and 1,2,3,4-tetrahydropyrazine via transition-metal- free addition of boron reagents (Scheme 46).25 Dearomatization is facile with B-B, B-Si, and B-H boron reagents. The authors suggest that high reactivities of pyrazines in the dearomatizing addition reactions may due to the formation of B–N bonds. R1 R2 N N 1.0 equiv B2pin2, rt, 2 h, pentane R1 Bpin N N Bpin R2 Scheme 46. 1,4-Diboration of substituted pyrazines Up-field shifted proton signals in the presence of B2pin2 may suggest there is some kind of dearomatization taking place via the addition of B2pin2 to the 2,2ʹ- bipyrazine ligand (L1). This may lead to rapid degradation or polymerization of (L1) {messy proton NMR}. Possible dearomatized structures of L1 are shown in Figure 28. Bpin N N Bpin Bpin N N Bpin A N N Bpin N N Bpin B Figure 28. possible dearomatization structures for L1 124 The most commonly used iridium catalyst system for CHBs is [Ir(OMe)COD]2, dtbpy and B2pin2 and these CHBs are sterically driven (Figure 29). From previous reports, we know the active catalyst of the Ir-dtbpy system is a 16e– trisBpin Ir complex. Bpin Ir Bpin Bpin + N N DG 16-electron intermediates L L Bpin Ir H Bpin Bpin DG L L Bpin Bpin Bpin Ir H DG Figure 29. CHBs with Ir-dtbpy system Clearly, we do not have a solid explanation for these results and more work has to be done to understand how this system works during CHBs. As for future work, repeating the CHBs in Scheme 45b with pentafluorobezene or 1,3,5-trifluorobenzene would be worth exploring.This system (Ir-bypyrazine) is favoring CHBs next to a Bpin group, giving rise to sterically demanding 1,2-di and 1,2,3-tri borylated compounds. Therefore, we can hypothesis several scenarios; 1) 2,2ʹ-Bipyrazine behaves as a hemi labile ligand and a14e– system might be involved. 2) A nitrogen of one of the bypyrazine rings coordinates to a Bpin group of the substrate and directs CHBs next to that Bpin group (Figure 30). N Bpin Ir N H N N BO O Bpin Bpin R2 R1 Figure 30. Possible transition state for Ir-bypyrazine system 125 5.3 Conclusions This is the first ligand controlled synthesis of 1,2-di and 1,2,3-triborylated arenes via direct Ir-catalyzed borylation. Also, unprecedented, synthesis of 1,2,3-triborylated arenes via non-directed Ir-catalyzed borylation. This system shows an intriguing bias towards fluoro containing arenes. However, the fluorine need not be directly attached to the arene. Works with heteroarenes to give 1,3-diboryalted heteroarenes. 5.4 Experimental All commercially available chemicals were used as received unless otherwise indicated. Solvents were degassed. All experiments were assembled in a glovebox under a nitrogen atmosphere. Analytical Methods. 1H NMR spectra were recorded on a Varian VXR-500 or Varian Unity-500-Plus spectrometer (499.74 MHz) and referenced to residual solvent signals. 11B NMR spectra were recorded on a Varian VXR-500 spectrometer operating at 160.41 MHz, 125.7 MHz for13C NMR and 470.1 MHz for 19F NMR. All coupling constants are apparent J values measured at the indicated field strengths. Melting points were measured on a MEL-TEMP or Thomas-Hoover capillary melting apparatus and are uncorrected. Elemental composition was determined by high resolution/accurate mass spectrometry analysis using a Thermo Scientific LTQ-Orbitrap Velos mass spectrometer at the Molecular Metabolism and Disease Collaborative Mass Spectrometry Core facility at Michigan State University. Samples were introduced to the mass spectrometer by direct infusion electrospray ionization in positive ionization mode, and data was acquired 126 at a resolution of 100,000 defined at m/z 400. Melting points were measured on Stuart Scientific capillary melting point apparatus. General Procedure for Borylation In a nitrogen atmosphere glove box bis(pinacolato)boron (B2Pin2) (0.192 g, 0.75 mmol) was weighed into a 20 mL vial containing a magnetic stir bar. [Ir(OMe)COD]2 (6.6 mg, 0.01 mmol) and 2,2’-bipyrazine ligand (3.3 mg, 0.02 mmol) were weighed into two test tubes separately, each being diluted with 0.5 mL of hexane. The [Ir(OMe)COD]2 solution was transferred into the 20 mL vial containing B2Pin2. This mixture was stirred until a golden yellow solution was obtained (~ 1 min). Next the solution containing ligand was transferred into the vial and upon stirring the resulting solution turned a dark green color. Finally, the substrate (1.0 mmol) was added to the vial. 0.5 mL of hexane was used to rinse the test tubes and transfer any remaining catalyst/ligand/substrate. Then sealed the vial and mixture was stirred for 48 h at 60 °C. After, 48 h GC and NMR data were collected. If reaction is not completed added another loading of catalyst {Ir (0.01 mmol), ligand (0.02 mmol), B2Pin2 (0.55 mmol) and 1.5 mL hexane}. Work up procedure A: Part 1 The reaction mixture was passed through a plug of silica (BD 60 mL Syringe/Luer-Lok Tip-silica up to 50 mL mark) eluting with a 4:1 hexane/ethyl acetate solution (2 x 200 mL) and fractions were collected. The volatiles were removed by rotary evaporation (from this step, most of the excess B2pin2 was removed). The collected fractions were re- 127 dissolved in a minimum amount of hexane and kept inside the refrigerator for crystal formation. After crystals were formed, these fractions were washed with cold hexane (1 mL*2) to remove any residual B2pin2. The left-over crystals were collected and dried. Part 2 If the crystallization did not work, the material was purified using a SiO2 column chromatography. eluting with hexane (B2pin2 will elute with hexane) and then with hexane/ethyl acetate (4:1). Work up procedure B: Tri-broylated compounds usually crash out from the crude reaction mixture. In these cases, the solid is filter using a disposable filter cone. CH2Cl2 is then added and collect the solution. Volatiles are removed by rotary evaporation and pure tri borylated product is obtained as solid. Compound 67c OMe Cl Bpin 67c F Bpin The general borylation procedure was carried out on the starting arene of 2-(4-chloro-2- fluoro-3-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane. After work up procedure A, 0.412 g of compound 67c was obtained as a white solid (mp > 200°C) in 86% yield. 1H NMR (500 MHz, Chloroform-d) δ 7.60 (d, J = 1.1 Hz, 1H), 3.97 (d, J = 1.8 Hz, 3H), 1.42 (s, 12H), 1.33 (s, 12H). 13C NMR (126 MHz, Chloroform-d) δ 158.1 (d, J = 245.0 Hz), 145.7 (d, J = 15.3 Hz), 132.5 (d, J = 2.8 Hz), 128.5, 84.6, 84.5, 61.4 (d, J 128 = 5.3 Hz), 24.9, 24.8. 19F NMR (470 MHz, Chloroform-d) δ -121.69. 11B NMR (160 MHz, Chloroform-d) δ 30.2. MS EI+ m/z calculated for (M+H)+ C19H29B2ClFO5 413.1874, found 413.1887. Compound 68c CF3 Bpin 68c Bpin The general borylation procedure was carried out on the starting arene of 4,4,5,5- tetramethyl-2-(4-(trifluoromethyl)phenyl)-1,3,2-dioxaborolane with 3 loading of catalyst. After work up procedure A, 0.244 g of compound 68c was obtained as a waxy solid in 61% yield. 1H NMR (500 MHz, Chloroform-d) δ 7.90 (dd, J = 1.9, 1.0 Hz, 1H), 7.73 (dd, J = 8.0, 1.9, 1H), 7.61 (ddd, J = 7.8, 1.0 Hz, 1H), 1.38 (s, 12H), 1.38 (s, 12H). 13C NMR (126 MHz, Chloroform-d) δ 133.5, 130.9 (q, J = 32.0 Hz), 129.9 (q, J = 3.7 Hz), 125.6 (q, J = 3.8 Hz), 124.3 (d, J = 272.4 Hz), 84.3, 84.3, 24.9.19F NMR (470 MHz, Chloroform-d) δ -62.95. 11B NMR (160 MHz, Chloroform-d) δ 30.9. MS EI+ m/z calculated for (M+H)+ C19H28B2F3O4 399.2126, found 399.2133. Compound 68* pinB CF3 Bpin 68* Bpin The general borylation procedure was carried out on the starting arene of 4,4,5,5- tetramethyl-2-(4-(trifluoromethyl)phenyl)-1,3,2-dioxaborolane with 3 loading of catalyst. 129 After work up procedure B, 0.0310 g of compound 68* was obtained as a white solid in 6% yield. 1H NMR (500 MHz, Chloroform-d) δ 8.17 (q, J = 0.7 Hz, 2H), 1.50 (s, 12H), 1.35 (s, 24H). C NMR (126 MHz, Chloroform-d) δ 133.85 (q, J = 3.7 Hz), 129.06 (q, J = 32.2 Hz), 124.43 (d, J = 272.7 Hz), 84.44, 84.31, 25.82, 24.75.19F NMR (470 MHz, Chloroform-d) δ -62.78. 11B NMR (160 MHz, Chloroform-d) δ 30.4. MS EI+ m/z calculated for (M+H)+ C25H39B3F3O6 525.2977, found 399.2136. (decomposing during ESI to give similar products as 399-di) Compound 69c OCF3 Bpin Bpin 69c The general borylation procedure was carried out on the starting arene of 4,4,5,5- tetramethyl-2-(4-(trifluoromethoxy)phenyl)-1,3,2-dioxaborolane. After work up procedure A, 0.190 g of compound 69c was obtained as an oil in 46% yield. 1H NMR (500 MHz, Chloroform-d) δ 7.69 (d, J = 8.2 Hz, 1H), 7.45 (s, 1H), 7.21 (dd, J = 8.2, 2.6 Hz, 1H), 1.37 (s, 12H), 1.36 (s, 12H). 13C NMR (126 MHz, Chloroform-d) δ 150.2 (d, J = 1.7 Hz), 135.5, 125.4, 121.24, 120.4 (d, J = 257.1 Hz), 84.3, 84.2, 24.9.19F NMR (470 MHz, Chloroform-d) δ -57.47. 11B NMR (160 MHz, Chloroform-d) δ 30.9. Compound 69* OCF3 pinB Bpin Bpin 69* 130 The general borylation procedure was carried out on the starting arene of 4,4,5,5- tetramethyl-2-(4-(trifluoromethoxy)phenyl)-1,3,2-dioxaborolane. After work up procedure B, 0.056 g of compound 69* was obtained as a white solid (mp > 200°C) in 10% yield. 1H NMR (500 MHz, Chloroform-d) δ 7.75 (d, J = 1.0 Hz, 2H), 1.48 (s, 12H), 1.33 (s, 24H). 13C NMR (900 MHz, Chloroform-d) δ 148.95, 142.87(C-B), 135.10(C-B), 129.86, 120.66 (q, J = 256.7 Hz), 84.43 (d, J = 9.5 Hz), 25.97, 24.90.19F NMR (470 MHz, Chloroform-d) δ -57.35. 11B NMR (160 MHz, Chloroform-d) δ 30.9. MS EI+ m/z calculated for (M+H)+ C25H39B3F3O7 541.2927, found 541.2940. Compound 70c Cl F Bpin Bpin 70c The general borylation procedure was carried out on the starting arene of 2-(3-chloro-5- fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane. After work up procedure A, 0.198 g of compound 70c was obtained as a white solid in 52% yield. 1H NMR (500 MHz, Chloroform-d) δ 7.55 (d, J = 1.9 Hz, 1H), 7.09 (dd, J = 8.6, 1.9 Hz, 1H), 1.41 (s, 12H), 1.33 (s, 12H). 13C NMR (126 MHz, Chloroform-d) δ 135.8 (d, J = 9.6 Hz), 130.6 (d, J = 2.9 Hz), 117.8, 117.6, 84.5 (d, J = 7.7 Hz), 24.94, 24.82. 19F NMR (470 MHz, Chloroform-d) δ -103.99 (d, J = 8.9 Hz). 11B NMR (160 MHz, Chloroform-d) δ 30.0. MS EI+ m/z calculated for (M+H)+ C18H27B2ClFO4 383.1768, found 383.1782. 131 Compound 71cʹ SF5 pinB 71cʹ Bpin The general borylation procedure was carried out on the starting arene of pentafluoro(phenyl)-λ6-sulfane. Final crude mixture contained mixture of products in ratio of 38: 34: 28 for di: 4-mono: 3-mono. After work up procedure B, 0.1532 g of compound 71cʹ was obtained as a white solid in 34% yield. 1H NMR (500 MHz, Chloroform-d) δ 8.36 (s, 1H), 8.23 (d, J = 1.1 Hz, 2H), 1.36 (s, 24H). 13C NMR (126 MHz, Chloroform-d) δ 153.6, 143.9, 134.3 (m), 84.4, 24.9. 19F NMR (470 MHz, Chloroform-d) δ 84.75 (p, J = 150.5 Hz), 62.80 (d, J = 150.0 Hz). 11B NMR (160 MHz, Chloroform-d) δ 29.7. MS EI+ m/z calculated for (M+H)+ C17H28B2F5O4S 457.1814, found 457.1902. Compound 72cʹ pinB O Bpin 72cʹ The general borylation procedure was carried out on the starting arene of 4,4,5,5- tetramethyl-2-(5-methylfuran-2-yl)-1,3,2-dioxaborolane. Final crude mixture contained mixture of products in ratio of 78: 17: 5 for 2,4di: 2,3di: tri. 2,4-diborylated compound was isolated by passing the concentrated crude reaction mixture through a celite/silica (3:1) plug and collecting fractions using hexane. After further purification using another Celite/silica (2:1) plug with hexane, 0.2314 g of compound 72cʹ was obtained as a sticky white solid in 69% yield (mp: 96–98 °C). 1H NMR (500 MHz, Chloroform-d) δ 7.22 (s, 132 1H), 2.51 (s, 3H), 1.32 (s, 12H), 1.29 (s, 12H). 13C NMR (126 MHz, Chloroform-d) δ 167.2, 129.4, 83.9, 83.1, 24.8, 24.7, 14.4. 11B NMR (160 MHz, Chloroform-d) δ 29.6, 27.1. MS EI+ m/z calculated for (M+H)+ C17H29B2O5 335.2201, found 335.2264. Compound 73cʹ N N 73cʹ pinB Bpin The general borylation procedure was carried out on the starting arene of 1-methyl-1H- pyrazole. After work procedure A 0.120 g of compound 73cʹ white solid in 36% yield. 1H NMR (500 MHz, Chloroform-d) δ 7.15 (d, J = 0.8 Hz, 1H), 4.12 (s, 3H), 1.32 (s, 12H), 1.30 (s, 12H). 13C NMR (126 MHz, Chloroform-d) δ 124.4, 84.0, 83.8, 24.79, 24.77. 11B NMR (160 MHz, CDCl3) δ 28.2. MS EI+ m/z calculated for (M+H)+ C14H29B2N2O4 335.2313, found 335.2369. 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Commun. 2012, 48, 8571. 137 Chapter 6: Ligand Screening for Ir–Catalyzed C–H Borylations 6.1 Introduction The regioselectivity in most of the catalysts developed for the borylation of alkanes and arenes is mainly governed by steric factors. Complementary regioselectivity is obtained by directed ortho metalation (DoM) methodologies using aryl/alkyl metals and cryogenic temperatures. The development of site-selective directed borylations provides a very attractive alternative to the directed ortho metalation (DoM) methodologies, not only because of their higher versatility in cross-coupling applications, but also because of the specific transformations developed for organoboranes, including oxidation, halogenation, amination, etherification (known as the Chan–Lam–Evans), etc. Bpin Ir Bpin Bpin + L L DG 16-electron intermediates A L L L L Bpin Ir DG Bpin Bpin H B Bpin Ir H Bpin Bpin DG products L L Bpin Bpin Bpin Ir H DG C Sterically controlled products Scheme 47. Analysis of regioselectivity in Ir-catalysed borylations. The direct borylation catalyzed by the 1:2 [Ir(OMe)(COD)]2/dtbpy system takes place through a [Ir(dtbpy)(Bpin)3] 16e–catalytically active species (A) (Scheme 47).1,2 In sensitivity of this process towards any directing effects is due to the lack of an additional vacant coordination sites in complex B formed upon coordination of directing 138 functionalities. Therefore, the reaction can only proceed via intermediate (C) and thus the regioselectivity is driven by sterics. Recently, in order to enable directing group effects in these reactions, different strategies based on catalyst or substrate modification have been developed. These afford attractive site-selective borylation methodologies for the synthesis of ortho-substituted arylboronic esters. Three types of approaches have been designed: 1. Chelate-directed borylations 2. Relay-directed borylations 3. Outer sphere H-bond-directed borylations. 6.2 Chelate-directed borylations The first strategy consists of modification of the ligand to the Ir catalyst so as to enable an additional vacant coordination site in the catalyst–substrate complex. Ishiyama, Miyaura et al. developed a catalytic system based on the use of [Ir(OMe)(COD)]2, and an electron-poor phosphine such as P[3,5-(CF3)2C6H3]3 3 as the ligand. This enabled the site- selective borylation of several substrates containing oxygen-based directing groups (Scheme 48). The method was first applied to the ortho-regioselective borylation of benzoates using B2pin2 in octane at 80 °C for 16 h. However, excess of arene (5 equiv.) was needed to avoid partial ortho, orthoʹ-diborylations. Later, by using AsPh3 instead of phosphine ligand increased the catalyst activity (Scheme 48). These reactions take place at 120 °C for 16 h, with a broad family of ketones containing different functional groups.4 139 R OR1 O H [Ir(OMe)COD]2 (1.5 mol %) P[3,5-(CF3)2C6H3]3 (3.0 mol %) B2Pin2 (1.0 equiv) octane, 80 °C R1 = Me, Et, iPr, tBu R OR1 O H [Ir(OMe)COD]2 (1.5 mol %) AsPh3 (3.0 mol %) B2Pin2 (1.0 equiv) octane, 120 °C R1 = Me, Et, iPr, tBu R R OR1 O Bpin 57–99% OR1 O Bpin 80–154% Scheme 48. Oxygen-directed Ir-catalyzed borylations. Sawamura et al reported a different approach using a solid-supported monophosphine–Ir system(Silica-SMAP–Ir) for the directed ortho-borylation of functionalized arenes in a very efficient manner (Scheme 49).5 This reaction is successful with different oxygenated directing groups. It is noteworthy that the chlorine atom of aryl chlorides can behave as a directing group. Presumably, the supported catalyst assists the formation of 14-electron intermediates for the successive coordination/CH activation. Unfortunately, this heterogeneous catalyst cannot be recovered for recycling. Later, the method was extended to phenol derivatives bearing oxygenated protecting/directing groups and also to heteroarenes bearing 2-methoxycarbonyl as the directing group.6,7 R DG H X = COOR, CONMe2, Cl, etc or H CO2Me X X = O, S, NH, NMe, NCOOR Silica-SMAP-Ir (0.25 – 0.5 mol %) B2pin2 ( 0.5 – 1.0 equiv) 25 – 100 °C R DG Bpin 50 – 108% or Bpin CO2Me X 56 – 99% Scheme 49. Silica-SMAP- Ir-catalyzed borylations. Maleczka, Smith and co-workers reported selective borylation at the 7-position of 2-substituted indoles (Scheme 50).8 Control experiments and labelling studies performed 140 support a mechanism where N-chelation to the iridium center (or the boron atom of a boryl ligand) directs the borylation. R1 N H R2 [Ir(OMe)COD]2 (1.5 mol %) dtbpy (3.0 mol %) HBpin ( 1.5 equiv) hexane, 60 °C R H R1 N H R2 R Bpin 45 – 92% Scheme 50. Selective borylation of 2-substituted indoles. Lassalate and co-workers introduced a more general nitrogen directed Ir-catalyzed arene ortho-borylations.9 Here, they replaced the dtbpy ligand with a hemi labile N,N ligand that facilitates the temporary generation of a coordinatively unsaturated intermediate C from the established catalytic species A via complex B (Figure 32). Complex C is pre-organized for the intramolecular activation of C(ortho)–H bonds (D), from which reductive elimination (E) and re-coordination of the hemi labile ligand (F) lead to the product and regenerates catalyst A after reaction with B2pin2. HBpin DG B2pin2 Bpin Bpin Bpin N N Ir A N N Bpin Bpin Ir DG F Bpin Bpin N N Bpin Bpin Ir DG Bpin H E N N Ph Bpin Bpin Bpin Ir DG B Bpin Bpin N N H Bpin Ir DG C N N H Bpin Ir DG D Bpin Bpin Figure 32. Envisioned mechanism using hemi labile N, N-ligands. 141 [Ir(OMe)(COD)]2 combined with picolinaldehyde N, N-dibenzylhydrazone (L) used for the borylation of 2-arylpyridines under mild conditions (Scheme 51). Depending on the steric hindrance around the biaryl axis, two types of products were observed. Hindered products revealed no internal N–B interactions, and the (hetero)aromatic rings arrange in a perpendicular fashion. However, less hindered products present intramolecular N–B bonds in planar structures. R R1 N H 1.0 equiv B2pin2 1 mol % L 0.5 mol % [Ir(OMe)COD]2 5.0 mol % HBpin THF, 50–80 °C L = N N NBn2 R R1 N or Bpin R R1 N Bpin 62–88 % 64–85 % Scheme 51. Directed borylation of aryl pyridines. Clark and co–workers reported a similar idea where nitrogen-directed ortho-C–H borylation of benzylic amines using the picolylamine ligand with [Ir(OMe)(COD)]2 as the catalyst (Scheme 52).10 The origin of the ortho-regioselectivity seems to lie in the hemilability of the ligand, instead of a hydrogen bonding directing effect as it was originally proposed. NMe2 3.0 mol % L 1.5 mol % [Ir(OMe)COD]2 R1 1.2 equiv B2pin2 Me-cyclohexane, 70 °C R1 L = NH2 N NMe2 Bpin 37–82% Scheme 52. Ir-catalysed C–H borylation of benzylic amines. 142 6.3 Relay-directed borylations Hartwig and co-workers developed a strategy for the site-selective Ir(III) catalyzed borylation of arenes based on the use of silanes as traceless directing groups.11 Benzyl dimethylsilanes substrates, undergoes Si–H/Ir–B E-bond metathesis between the catalytically active species A to form a silyl bis boryl Ir complex B (Figure 33). With complex B, the intramolecular activation of the ortho CH bonds takes place preferentially to afford intermediate C, which after reductive elimination to give D and then reaction with B2pin2 releases the product and regenerates the catalyst. SiHR2 X Bpin B2pin2 N N D Bpin Ir H SiR2 X Bpin Bpin Ir Bpin Bpin N N A Bpin H Ir N N Bpin SiR2 X C SiHR2 X H HBpin Bpin Ir N N H Bpin SiR2 X B Figure 33. Proposed catalytic cycle for silicon-directed ortho-borylations. This approach affords the corresponding ortho-borylated products in good to excellent yields. Formation of small amounts of ortho, orthoʹ- diborylated arylboronic esters is observed in some cases. The methodology has been applied to interesting 143 substrates, such as silyl ethers and silyl amines, formed in situ by iridium-catalyzed silylation of the corresponding phenols and anilines (Scheme 53). SiHMe2 0.5 mol % dtbpy 0.25 mol % [Ir(Cl)COD]2 R H R1 ZH R1 H Z = O, NMe 1.0 equiv B2pin2 5.0 mol % HBpin THF, 80 °C 1) Et2SiH2 0.5 mol % [Ir(Cl)COD]2 2) 2.0 mol % dtbpy 1.0 mol % [Ir(Cl)COD]2 1.0 equiv B2pin2 5.0 mol % HBpin THF, 80 °C 3) KHF2 R1 R1 R SiHMe2 Bpin 60–82% ZH BF3K 79–100% Scheme 53. Silicon-directed ortho-borylations of arenes. This method has been extended for the regioselective borylation at the 7-position of indoles (Scheme 54).12 Usually indoles are borylated at the most reactive 2-position by direct borylation. This procedure tolerates the use of unsubstituted substrates, in contrast, to the previously mentioned methods based on chelating effects.7,8 The Ru-catalyzed N- silylation followed by Ir-catalyzed borylation affords the corresponding 7-borylated indoles with complete regioselectivity in moderate yields. R H N + Et2SiH2 1) 1 mol %[Ru] toluene, rt 2) solvent removal 45 – 66% H SiHEt2 N R Bpin H N R 1) [Ir], B2pin2 THF, 80 °C 2) NaOAc (3M, aq) [Ru] = [RuCl2(p-cymene)]2 [Ir] = dtbpy[IrCl(OMe)]2 Scheme 54. Silicon-directed borylations at the 7-position of indoles. 144 6.4 Outer sphere borylations H-bond-directed: Outer sphere director refers to the recognition of a functionality in the substrate by a ligand on the catalyst. Smith, Maleczka, Singleton et al.13 studied the directing effect of acidic NH groups in monoprotected anilines, finding out that Boc protecting groups provide significant ortho selectivity in the borylations performed with B2pin2 as the reagent and [Ir(OMe)(COD)]2/dtbpy catalytic system (Scheme 55). R R1 NHBoc 4.0 mol % dtbpy 2.0 mol % [Ir(Cl)COD]2 H 1.0 equiv B2pin2 0.2 equiv HBpin MTBE, 50 °C R R1 NHBoc Bpin 40–95% Scheme 55. Outer-sphere directed borylation of Boc-protected anilines. Control experiments and computational studies support an outer sphere mechanism initiated by the formation of a (Boc)NH–O hydrogen bond between the NH group of the substrate and the basic oxygen atom of one of the catalyst boryl groups (Figure 34). HBpin B2pin2 Bpin Ir Bpin H N N C Bpin Ir Bpin Bpin N N A NHBoc H N N Bpin Ir H Bpin O B O H N Boc B Figure 34. Catalytic cycle for outer-sphere directed borylation NHBoc Bpin 145 We also reported that Bpin can be used as a traceless directing group for the ortho borylation of a variety of anilines (Scheme 56).14 Here, 3,4,7,8-tetramethyl-1,10- phenanthroline (tmphen) serves as the ligand and HBpin (2–3 equiv.) as the protecting group as well as the borylating reagent. The NBpin directing group can be installed and removed in situ. The products were isolated in better yields compared with those observed by using the NBoc protecting group. However, the scope of the method is again limited to para-substituted substrates. R R1 NH2 1.0–5.0 mol % tmphen 0.25–2.5 mol % [Ir(OMe)COD]2 H 3.0 equiv HBpin THF, 80 °C R R1 NH2 Bpin 26–93% Scheme 56. Outer-sphere directed borylation of free anilines. The previously reported traceless CHBs of primary anilines consistent with an outer-sphere mechanism involving N−H··· O hydrogen bonding between the aniline substrate (NH–Boc or NH–Bpin) and a Ir− Bpin ligand (Figure 35).13,14 These required C4 substituents larger than H to achieve high ortho selectivity. Furthermore, substitution at C-2 position is not allowed. Poor regioselectivity N N Bpin Ir H Bpin O B O H N R1 R R2 R1 = Boc, Bpin, R2 = H Figure 35. Proposed transition states for ortho borylations of anilines 146 Kanai, Kuninobu and co-workers reported an elegant use of H-bonding interaction for remote C–H borylations (Scheme 57).15 A pendant urea moiety covalently linked to bipyridine core unit shows secondary H-bonding interaction with an H-bond acceptor group present on aromatic amides, aryl phosphonates, phosphonic diamides and phosphine oxides. This secondary interaction facilitates high selectivity for meta-C–H activation borylations. O NR2 1.5 mol % [Ir(OMe)COD]2 3.0 mol % L O NR2 via R1 p-xylene, 25 °C, 16 h L = N N HN HN O R1 Bpin i n k e r l N N Ir H N H O O X N H R2 Scheme 57. Hydrogen bond-directed meta-selective borylation of aromatic amides. In 2017, Phipps and co-workers introduced a single anionic bipyridine ligand containing a remote sulfonate unit that allows meta-selective borylation of a range of aromatic trifluoroamide substrates. They proposed that meta selectivity is due to hydrogen-bonding interaction between the substrate and the anionic ligand present in the catalyst (Figure 36).16,17 via OO S O COCCF3 H N Ir H R N N Figure 36. Hydrogen bond-directed meta borylation with an anionic ligand 147 Very recently, Smith, Maleczka, Chattopadhyay and co-workers reported high ortho selectivity for CHBs of aniline using B2eg2 (eg = ethylene glycolate) as the boron source.18 Here, they reported that by changing the boron reagent from HBpin or B2pin2 to bis(ethylene glycolato)diboron (B2eg2), ortho CHBs can be accomplished with a wide variety of anilines including anilines with no substituents at the 4-position and 2- substituted anilines (Scheme 58). Computational results show that Beg outperforms Bpin because the N(H)Beg substituent and Beg ligands can adopt optimal hydrogen-bonding configurations with minimal steric interference. R R1 NH2 H 1. 0.5 mol % [Ir(OMe)COD]2 0.5 equiv B2eg2 THF, 80 °C, 10 min 2. 2.5 mol % [Ir(OMe)COD]2 5.0 mol % dtbpy, 2.0 equiv Et3N, 2.0 equiv B2eg2 THF, 80 °C, 12 h R R1 NHBeg Beg 3.0 equiv pinacol CHCl3, rt, 1 h R R1 NH2 Bpin >99% ortho 20 - 97% Scheme 58. Aniline CHBs with B2eg2 Lewis acid-base controlled: Kuninobu, Kanai and co-workers recently reported a novel Lewis acid-base controlled ortho-selective CHBs of aryl sulfides.19 The noncovalent interaction in the form of a Lewis acid-base interaction between the S-atom of the substrate and boryl group of ligands facilitate the ortho-borylation of aryl sulfides (Scheme 59). Here electronic properties of boryl ligand affects the ortho-selectivity. Therefore, the boryl ligand is made electron-deficient by introducing a trifluoromethyl group on the ligand, which increases the selectivity (ortho/others) up to 30/1. However, this method is limited to only methyl substituted for aryl sulfides. 148 SR2 R1 6.0 mol % L 3.0 mol % [Ir(OMe)COD]2 0.5 equiv B2pin2 p-xylene, 55 °C, 24 h R1 SR2 Bpin via L = N N BO O CF3 O B O N Ir SMe N CF3 Lewis acid-base interaction Scheme 59. Lewis acid-base interaction for ortho-selective borylation of aryl sulfides. They extended the same strategy for the ortho-selective borylation of phenols and anilines by introducing an electron-withdrawing group at the bipyridine ligand system.20 The authors expect a similar mechanism as their previous report is operative, where an outer-sphere directed Lewis acid-base interaction exists between a boryl ligand of the iridium metal center and a sulfur atom of the substrate. In 2016, Chattopadhyay and co-workers reported an efficient method for the meta-selective borylation of aromatic aldehydes using an electrostatic interaction and boron-nitrogen non-covalent interaction (Scheme 60).21 In-situ generated imines from the corresponding aromatic aldehydes are utilized for a B–N noncovalent interaction, which results in high meta selectivity. Imines together with the electron-rich 3,4,7,8- tetramethylphenanthroline (TMP) as ligand exhibited very high selectivity for the meta- position. CHO R1 via N N CHO R1 Bpin i) 4.0-10.0 equiv R-NH2, DCM, rt, 4 h evaporated under reduced pressure ii) 3.0 mol % TMP 1.5 mol % [Ir(OMe)COD]2 0.7 equiv B2pin2 5.0 mol % HBpin THF, 90 °C, 12 h Bpin Ir H Bpin O B O N R Scheme 60. B–N bond-directed meta-selective borylation of aromatic aldehydes. 149 Electrostatic interactions: In 2018, Malezcka, Singleton, Smith and co-workers reported a novel approach for ortho CHBs of phenols based on the electrostatic interaction between the partial negatively charged OBpin group and partial positively charged bipyridine ring of the ligand (Scheme 61).22 Like previous aniline borylations, 4-substituents larger than H were necessary to achieve high ortho selectivity. This indicates that the OBpin directing effect is not strong enough to override the steric control. Computational studies predicted that the ortho CHB transition state could be significantly stabilized if the Bpin groups on Ir and the phenol boronate ester were replaced with Beg (eg = ethylene glycolate). This lead to exquisite ortho selectivities for Ir-catalyzed CHBs of phenols with B2eg2 as the diboron reagent. OH R1 i) 1.5 mol % [Ir(OMe)COD]2 3.0 mol % dtbpy 1.5 equiv B2eg2 1.5 equiv Et3N PhMe, 80 °C, 2–3 h ii) solvent removed, CHCl3, 3.0 equiv pinacol, rt, 40 min OH R1 Bpin via Beg Ir H Beg Beg R1 N N O δ+ δ- BO O Scheme 61. ortho-selective borylation of unprotected phenols using Beg as traceless directing group. 6.5 Monodentate Vs Bidentate ligands From previous reported work, it is obvious that bipyridine borylation catalysts are more reactive than their chelating phosphine counterparts. Furthermore, monophosphine ligated catalysts can be effective for ortho borylations.23 It is surprising that pyridines have not gained much attention as monodentate ligands for borylations. 150 Therefore, in collaboration with Dow Chemical Company, we began screening iridium catalyst systems with different substrates, ligands and solvent in order to understand how electronics affect the C-H activation-borylation of different functionalized arenes and heterocycles. Importantly, we decided to look at bidentate ligands that are not commonly used and also monodentate pyridines as potential ligands in borylation for directing group containing substrates. During non-directed borylation, the metal center is coordinated by a bidentate pyridine ligand, thus leaving one open coordination site for the substrate to bind and undergo the C-H activation step. However, with monodentate pyridines as ligands, an additional free coordination site on the metal center may be open. We hypothesized that appropriate monopyridine ligands might favor a 14 electron intermediate 1 over 16 electron intermediate 2 and allow for directed borylation (Figure 37). In particular, pyridines that are electron-poor or sterically hindered were considered to be likely candidates. 14 – electron intermediate 1 Bpin Ir L Bpin Bpin 16 – electron intermediate 2 Bpin Ir Bpin Bpin L L L DG DG Bpin DG Bpin + Bpin DG DG Figure 37. 14 Vs 16 electron intermediates 151 First, we selected a set of substrates that included fluoro arenes as well as pyridine substrates (Figure 38). We anticipate that some of the pyridine substrates would also behave as the ligand. OMe CN F Cl F Cl F F COOMe F Cl F N Cl CN OMe F3C CF3 Cl N OMe F N OMe N F N OMe N N Cl CF3 N OMe Cl N COOH F N Cl N OMe F N Figure 38. Scope of substrates COOMe Then we selected several bidentate and monodentate ligands for screening (Figure 39). Each substrate (1mmol) was screened with 1 mol % [Ir(OMe)COD]2 as the the pre- catalyst, 2 mol % of ligand, 1 equiv of B2pin2 as the boron source and different solvent at 60°C for 24h. Figure 39. Scope of the ligands 6.6 Results and Discussion 1) Iridium catalyzed C-H borylation of 1-chloro-3-fluoro-2-methoxybenzene (2,6- CFA) 152 Iridium catalyzed C-H borylation for CFA with different solvent, ligands and boron sources were screened. a) Tetrahydrofuran (THF) OMe F Cl 1 mol % [Ir(OMe)COD]2 2 mol % Ligand Cl OMe 1 equiv B2pin2 THF 60 °C, 24 h 67 Bpin steric OMe F Cl + + Di F Bpin electronic Table 3. Ir-catalyzed C-H borylation of 2, 6-CFA in THF. 1 2 3 4 5 6 7 8 Ligand Bpy(CF3)2 4-CN-2-MeO-Py 4-Cl-2-MeO-Py 4-CF3-2-MeO-Py 2-MeO-Py DCE-bpy DCA-bpy Bipyrazine Stirring time Reaction time Conversion Pre-catalyst (%) 100% 85% 82% 71% 83% 100% 100% 49% 16 h 24 h 24 h 24 h 24 h 24 h 15 h 24 h No stirring St/Ele/di 39/58/3 20/57/23 20/70/10 19/73/8 25/67/8 47/46/7 44/50/6 44/52/4 Bidentate ligands showed the highest reactivity and the least selectivity. These ligands gave 1:1 mixture of the steric and the electronic products. However, monodentate ligands showed more selectivity towards the electronic product (>4:1). These monodentate ligands were less reactive than bidentate ligands. High temperature and longer reaction time could help the reaction to progress. b) Hexane OMe F Cl 1 mol % [Ir(OMe)COD]2 2 mol % Ligand Cl OMe 1 equiv B2pin2 hexane 60 °C, 24 h 67 Bpin steric 153 OMe F Cl + + Di F Bpin electronic Table 4. Ir-catalyzed C-H borylation of 2, 6-CFA in Hexane. ligand loading Pre-catalyst Stirring time Reaction time Conversion (%) Entry 1 2 3 4 5 6 7 8 9 10 Ligand Bpy(CF3)2 4-CN-2-MeO-Py 4-Cl-2-MeO-Py 4-CF3-2-MeO-Py 2-MeO-Py DCE-bpy DCA-bpy Bipyrazine 4-CN-2-MeO-Py 5 mol% 4-Cl-2-MeO-Py 2 mol% No stirring 24 h 24 h 24 h 24 h 24 h 24 h 15 h 24 h 24 h 24 h 92% 93% 77% 51% 78% 100% 100% 77% 0% 8% St/Ele/di 36/54/10 21/60/19 18/77/5 18/79/3 24/69/7 46/48/6 39/58/3 35/40/25 34/66 Entry 2, showed the best result that is close to our target. Conversion > 90% and selectivity > 4:1 favoring the electronic product. Bipyrazine ligand in hexane gave better conversion than THF and significant amount of diborylation product was observed. Entry 9, 10 indicated that excess amount of monodentate ligands may shut down the catalyst system. c) Cyclopentylmethyl ether (CPME-50 ppm BHT as the inhibitor) OMe F Cl + + Di F Bpin electronic OMe F Cl 1 mol % [Ir(OMe)COD]2 2 mol % Ligand Cl OMe 1 equiv B2pin2 CPME 60 °C, 24 h 67 Bpin steric 154 Table 5. Ir-catalyzed C-H borylation of 2, 6-CFA in CPME. Ligand Bpy(CF3)2 4-CN-2-MeO-Py 4-Cl-2-MeO-Py 4-CF3-2-MeO-Py 2-MeO-Py DCE-bpy DCA-bpy Bipyrazine Entry 1 2 3 4 5 6 7 8 Pre-catalyst Stirring time Reaction time No stirring 24 h 24 h 24 h 24 h 24 h 6 h 22 h 24 h Conversion (%) 98% 61% 54% 41% 73% 100% 100% 77% St/Ele/di 37/59/4 25/65/10 20/77/3 19/77/4 24/70/6 46/46/8 43/54/3 39/49/12 Monodentate ligands gave better selectivity favoring the electronic product than the bidentate ligands. However, these monodentate ligands were less reactivity than bidentate ligands. d) Methyl Cyclohexane OMe F Cl 1 mol % [Ir(OMe)COD]2 2 mol % Ligand Cl OMe 1 equiv B2pin2 Me-cyclohexane 60 °C, 24 h 67 Bpin steric OMe F Cl + + Di F Bpin electronic Table 6. Ir-catalyzed C-H borylation of 2, 6-CFA in methyl cyclohexane. Ligand Bpy(CF3)2 4-CN-2-MeO-Py 4-Cl-2-MeO-Py 4-CF3-2-MeO-Py 2-MeO-Py DCE-bpy DCA-bpy Bipyrazine Stirring time Reaction Pre-catalyst time 24 h 24 h 24 h 24 h 24 h 24 h 7 h 24 h No stirring Conversion (%) 93% 85% 59% 42% 54% 100% 100% 82% St/Ele/di 35/55/10 22/64/14 18/79/3 18/82/0 25/70/5 43/46/11 38/60/2 35/44/21 Entry 1 2 3 4 5 6 7 8 155 In entry 2, no borylated products were observed after 7 h. However, after 24 h 83% product formation was observed. This indicates a possibility of an induction period. e) Hunig’s base OMe F Cl 1 mol % [Ir(OMe)COD]2 2 mol % Ligand Cl OMe 1 equiv B2pin2 Hunig’s base 60 °C, 24 h 67 Bpin steric OMe F Cl + + Di F Bpin electronic Table 7. Ir-catalyzed C-H borylation of 2, 6-CFA in Hunig’s base. Entry 1 2 3 4 5 6 7 8 Ligand Bpy(CF3)2 4-CN-2-MeO-Py 4-Cl-2-MeO-Py 4-CF3-2-MeO-Py 2-MeO-Py DCE-bpy DCA-bpy Bipyrazine Pre-catalyst Stirring time Reaction time Conversion (%) 80% 36% 3% 0% 34% 100% 100% 84% 24 h 24 h 24 h 24 h 24 h 24 h 24 h 24 h No stirring St/Ele 37/58/5 34/66/0 29/71/0 44/53/3 37/58/5 41/43/16 Pyridine ligands showed less reactivity in Hunig’s base as the solvent. One possibility is due to the coordinating ability of the solvent itself to the catalyst system. However bidentate ligands showed good reactivity in Hunig’s base. Moreover, electron deficient bidentate ligands in Hunig’s base favored the electronic borylated product. f) Summary of 2, 6-CFA C-H borylation OMe F Cl 1 mol % [Ir(OMe)COD]2 2 mol % Ligand Cl OMe 67 1 equiv B2pin2 Solvent 60 °C, 24 h Bpin steric 156 OMe F Cl + + Di F Bpin electronic Table 8. Summary of Ir-catalyzed C-H borylation of 2, 6-CFA Ligand 4-CN-2-MeO- 4-Cl-2-MeO- 4-CF3-2-MeO- THF Hexane Py Py Py Conv (%) St/Ele/di Conv (%) St/Ele/di Conv (%) CPME St/Ele/di Conv Hunig's Base Me-cyclohexane St/Ele/di (%) St/Ele/di Conv (%) Bpy(CF3)2 100% 39/58/3 92% 36/54/10 98% 37/59/4 80% 37/58/5 93% 35/55/10 85% 20/57/23 93% 21/60/19 61% 25/65/10 36% 34/66/0 85% 22/64/14 59% 18/79/3 82% 20/70/10 77% 18/77/5 54% 20/77/3 3% 71% 19/73/8 51% 18/79/3 41% 19/77/4 0% 42% 18/82/0 2-MeO-Py 83% 25/67/8 78% 24/69/7 73% 24/70/6 34% 29/71/0 54% 25/70/5 DCE-bpy 100% 47/46/7 100% 46/48/6 100% 46/46/8 100% 44/53/3 100% 43/46/11 DCA-bpy 100% 44/50/6 100% 39/58/3 100% 43/54/3 100% 37/58/5 100% 38/60/2 Bipyrazine 49% 44/52/4 77% 35/40/25 77% 39/49/12 84% 41/43/16 82% 35/44/21 Several different monodentate and bidentate ligands were screened. Best results obtain did not meet the target of >90% yield and >6:1 favoring electronic product. Fastest reactivity in all the solvents for 2,6-CFA was observed with DCAbpy and DCEbpy bidentate ligands. Moreover, best selectivity for the electronic product was observed with 4-Cl-2-OMepy and 4-CN-2-OMepy monodentate ligands. Pyridine ligands, more electron deficient the ligand is favor the electronic product in non- polar solvent but less conversion. g) Discussion From the above data we see that bidentate ligands are very reactive compared to monodentate ligands. Bpy(CF3)2 gave the best selectivity towards electronic product where as other bidentate ligands gave a 1:1 mixture of steric and electronic products. In contrast, monodentate pyridine ligands favored the electronic product, but was less reactive than bipyridine ligands. 157 Bipyrazine showed different reactivity and selectivity compared to mono- and bidentate ligands. Significant amounts of diborylations were observed, especially in nonpolar solvents. To understand the reactivity and selectivity, we fully characterize the starting material by NMR. Furthermore, we prepared authentic materials from alternative routes and compared spectral data with the crude reaction mixture. 2,6-CFA has three different protons. In 1HNMR the most down field peak corresponds to the proton close to chlorine (H1) (Figure 40). Sterically favored hydrogen (H2) and the hydrogen close to fluorine (H3) are over lapping with each other and up field in the spectrum. F Cl H1 OMe H2 F H3 H1 H2&H3 Figure 40. 1HNMR of starting material 2,6-CFA 158 C-H borylations of 2,6-CFA gives three products, including two mono (electronic and steric) and one diborylated product (Scheme 62). From previous studies, we know that it is easier to borylate next to fluorine (Chapter 2) than a chlorine. OMe F Cl 1 mol % [Ir(OMe)COD]2 2 mol % Ligand Cl OMe OMe F Cl + + Di F Bpin electronic 67 1 equiv B2pin2 Solvent 60 °C, 24 h Bpin steric Scheme 62. CHBs of 2,6-CFA (67) However, to prove borylation is favored at H3 over H1, and also to get NMR data on the electronic product we synthesized the boronic ester from the previously made (4- chloro-2-fluoro-3-methoxyphenyl) boronic acid (67aʹ) (Scheme 63). OMe F Cl 1 equiv pinacole 4 equiv anhy MgSO4 rt, 24 h B(OH)2 67a’ OMe Cl F Bpin 67a Scheme 63. Making boronic ester from boronic acid We compared the 19F-NMR of starting material 2,6-CFA (67), 67a and the crude reaction mixture from the C-H borylation of 2,6-CFA to get a picture of the products formed during the C-H borylation (Figure 41). 159 SM SM OMe F Cl Bpin 67b Diborylation I II III OMe Cl F Bpin 67a Figure 41. 19F-NMR of I) C–H borylation crude reaction of CFA in THF II) C–H borylation crude reaction of CFA in hexane III) Pure compound (67a) Spectrum (III) correlates with spectra I and II, confirming that the borylation take place ortho to fluorine (67a) over chlorine. Significant amount of diborylations of CFA were observed with the bipyrazine ligand in hexane as the solvent. 19F-NMR of crude reaction mixture shows a broad single peak (small coupling) for the diborylations product. This suggest that it is a 1,2-diborylation product (67c) vs the 1,3-diborylation product (67cʹ). However, forming (67c) would be considered unfavored under iridium catalyzed C-H activation borylation. In order to confirm the structure of the CFA diborylations product, C-H activation borylation of compound (67a) was carried out (Scheme 64). 160 OMe Cl F Bpin 67a 1 mol % [Ir(OMe)COD]2 2 mol % Bipyrazine OMe Cl 1 equiv B2pin2 hexane 60 °C, 72 h Bpin 67c F Cl or Bpin pinB Conversion 45% Add another catalyst loading(24 h) Conversion 64% F Bpin OMe 67cʹ Scheme 64. CHBs of borylated 2,6-CFA (67a) 1H NMR of the crude reaction mixture showed a single peak for the newly formed diborylated species. This had a coupling constant of J=1.2 Hz (Figure 42). This suggests that 67c is the diborylated species and not 67cʹ (for 67cʹ proton we expect a larger coupling constant with fluorine since it is meta to fluorine). Further studies and results are discussed in Chapter 5. Figure 42. 1HNMR of crude reaction 161 2) Iridium catalyzed C-H borylation of 1-chloro-3-fluoro-2-methoxybenzonitrile (78, CFN) Iridium catalyzed C-H borylation for CFN with different solvent, ligands and boron sources were screened. a) Tetrahydrofuran (THF) CN F Cl 1 mol % [Ir(OMe)COD]2 2 mol % Ligand Cl CN 1 equiv B2pin2 THF 60 °C, 24 h Bpin steric 78 CN F Cl + + Di F Bpin electronic Table 9. Ir-catalyzed C-H borylation of 2, 6-CFN in THF Reaction Ligand Entry ligand loading 2 mol% Stirring time 1 2 3 4 5 6 7 8 9 12 Bpy(CF3)2 4-CN-2-MeO- Py 4-Cl-2-MeO- Py 4-CN-2-MeO- Py 4-Cl-2-MeO- Py 4-CF3-2- MeO-Py 2-MeO-Py DME-bpy DCA-bpy Bipyrazine time 24 h 24 h 5 mol% 2 mol% No stirring 24 h 24 h 24 h 24 h 24 h 7 h 24 h 24 h Conversion (%) 100% St/Ele/di 42/52/6 0% 8% 0% - 70/30/0 - 24% 74/26/0 23% 22% 100% 100% 100% 76/24/0 72/28/0 49/31/20 47/36/17 66/31/3 Excess monodentate ligands showed no CHBs with CFN. In general, pyridine ligands indicated less reactivity with CFN. The steric product was the most favored borylated product with majority of the ligand systems (except entry 1) for CFN. 162 b) Hexane CN F Cl 1 mol % [Ir(OMe)COD]2 2 mol % Ligand Cl CN 1 equiv B2pin2 hexane 60 °C, 24 h Bpin steric 78 CN F Cl + + Di F Bpin electronic Table 10. Ir-catalyzed C-H borylation of 2, 6-CFN in hexane Entry Ligand Conversion (%) St/Ele/di Reaction Time/h loading Stirring time ligand before adding substrate Bpy(CF3)2 1 2 mol% 4-CN-2-MeO-Py 5 mol% 2 4-Cl-2-MeO-Py 3 4-CN-2-MeO-Py 4 4-Cl-2-MeO-Py 5 6 4-CF3-2-MeO-Py DME-bpy 7 8 2-OMepy DCA-bpy 9 Bipyrazine 10 11 2-OMepy DCAbpy 12 No stirring No stirring 2 mol% 60 min 22 h 24 h 24 h 24 h 24 h 24 h 7 h 24 h 5 h 17 h 24 h 5 h 100% 0% 8% 5% 23% 23% 100% 29% 100% 100% 15% 100% 36/58/6 70/30/0 one isomer 68/32/0 67/33/0 49/43/8 68/32/0 44/49/7 60/34/6 68/32/0 45/50/5 Pre-generating the active catalyst before introducing the substrate slightly enhanced the reactivity of the monodentate ligands. However, there were no significant change for bidentate ligands. These ligands showed high reactivity with or without pre- generating the active catalyst. Overall, monodentate ligands were less reactive for CFN and less amount of diborylated products were formed with these ligands. 163 c) Cyclopentylmethyl ether (CPME-50 ppm BHT as the inhibitor) CN F Cl 1 mol % [Ir(OMe)COD]2 2 mol % Ligand Cl CN 1 equiv B2pin2 CPME 60 °C, 24 h 78 CN F Cl + + Di F Bpin electronic Bpin steric Table 11. Ir-catalyzed C-H borylation of 2, 6-CFN in CPME Entry Ligand Reaction time Conversion (%) St/Ele/di Stirring time before adding substrate 60 min 1 2 3 4 5 6 Bpy(CF3)2 4-CN-2-MeO-Py 4-Cl-2-MeO-Py DCE-bpy DCA-bpy Bipyrazine 20 h 24 h 24 h 1.5 h 1.5 h 20 h 100% 15% 18% 100% 100% 100% 37/58/5 63/37/0 68/32/0 48/46/6 50/44/6 64/30/6 Similar trend of reactivity was observed for CFN as previous cases. Bpy(CF3)2 was the only ligand, that favored the electronic product. d) Methyl cyclohexane CN F Cl 1 mol % [Ir(OMe)COD]2 2 mol % Ligand Cl CN 1 equiv B2pin2 Me-cyclohexane 60 °C, 24 h Bpin steric 78 CN F Cl + + Di F Bpin electronic Table 12. Ir-catalyzed C-H borylation of 2, 6-CFN in methyl cyclohexane Entry 1 2 3 Ligand Bpy(CF3)2 4-CN-2-MeO-Py 4-Cl-2-MeO-Py Stirring time Reaction time 19 h 24 h 24 h 164 Conversion (%) 100% (19h) 17% 25% St/Ele/di 39/58/3 66/34/0 64/36/0 4-CF3-2-MeO-Py Table 12 (cont’d) 4 5 6 7 8 9 2-MeO-Py DCE-bpy DCA-bpy Bipyrazine 2-CN-4-Ome-Py 60 min 24 h 24 h 2 h 2 h 15 h 24 h 28% 30% 100% 100% 100% 65% 66/34/0 66/34/0 47/43/10 44/52/4 60/35/5 73/27/0 There were no significant deviations observed in Me-cyclohexane for CFN. Similar trend was observed as previous solvent systems. e) Hunig’s base CN F Cl 1 mol % [Ir(OMe)COD]2 2 mol % Ligand Cl CN 1 equiv B2pin2 Hunig’s base 60 °C, 24 h 78 CN F Cl + + Di F Bpin electronic Bpin steric Table 13. Ir-catalyzed C-H borylation of 2, 6-CFN in Hunig’s base Conversion (%) Stirring time Reaction time Entry 1 2 3 4 5 6 7 8 Ligand Bpy(CF3)2 4-CN-2-MeO-Py 4-Cl-2-MeO-Py 4-CF3-2-MeO-Py 2-MeO-Py DCE-bpy DCA-bpy Bipyrazine 60 min 24 h 24 h 24 h 24 h 24 h 24 h 24 h 17 h 98% 7% 8% 10% 8% 98% 98% 100% St/Ele/di 36/60/4 70/30/0 71/29/0 55/45/0 69/31/0 37/61/2 36/61/3 63/33/4 In previous solvent systems only Bpy(CF3)2 ligand favored the electronic product formation for CFN. However, in Hunig’s base except bipyrazine, all the other bidentate ligands (DCAbpy, DCEbpy and Bpy(CF3)2 favored the electronic product over the steric product 165 Monodentate pyridine ligands showed less/or no reactivity in Hunig’s base. If monodentate pyridine ligands go through a 14 electron intermediate, then there are several vacant coordination sites at the metal center and theses ligands are less sterically hindered that bidentate ligands. As stated earlier Hunig’s base solvent itself has the ability to coordinate to the catalyst system. This could be a reason for deactivation of the catalyst system. f) Summary of 2, 6-CFN C-H borylation CN F Cl 1 mol % [Ir(OMe)COD]2 2 mol % Ligand Cl CN 1 equiv B2pin2 Solvent 60 °C, 24 h Bpin steric 78 CN F Cl + + Di F Bpin electronic Table 14. Summary of Ir-catalyzed C-H borylation of 2, 6-CFN Bpy(CF3)2 ligand favored the electronic product of CFN in all the solvents. Generating the active catalyst before introducing the substrate was only important for the reactivity of the monodentate pyridine ligands. These ligands were less reactive in CHBs 166 THF Hexane Conv (%) St/Ele/di Conv (%) St/Ele/di Conv (%) St/Ele/di Conv 100% 42/52/6 100% 36/58/6 98% Hunig’s base CPME Me-Cyclohexane (%) St/Ele/di Conv (%) St/Ele/di 36/60/4 100% 39/58/3 100% 37/58/5 - 5% one isomer 74/26/0 23% 68/32/0 7% 8% 70/30/0 17% 66/34/0 15% 63/37/0 71/29/0 25% 64/36/0 18% 68/32/0 76/24/0 23% 72/28/0 100% 49/43/8 67/33/0 10% 23% 8% 22% 100% 49/31/20 29% 68/32/0 98% 100% 47/36/17 100% 44/49/7 98% 55/45/0 28% 66/34/0 69/31/0 30% 66/34/0 37/61/2 100% 47/43/10 100% 48/46/6 36/61/3 100% 44/52/4 100% 50/44/6 66/31/3 100% 60/34/6 100% 63/33/4 100% 60/35/5 100% 64/30/6 65% 73/27/0 Ligand Bpy(CF3)2 0% 24% 4-CF3-2-OMe- 4-CN-2-OMe- 4-Cl-2-OMe- Py Py Py 2-OMe-Py DCE-bpy DCA-bpy Bipyrazine 100% 2-CN-4-OMe for benzonitrile. All the monodentate ligands favored the steric product. However, Hunig’s base was an ideal solvent for favoring the electronic product with electron deficient ligands. g) Discussion In 2,6-CFN (Figure 43) the most down field hydrogen (H2) is para to the cyano group and it is the most sterically and electronically favored hydrogen in this case. We assume that this is the reason for C-H borylation of 2, 6-CFN substrate favoring compound 74b as the major product with a majority of ligands. Hydrogen (H1) is close to chlorine and more deshielded than the hydrogen close to fluorine (H3). Cl H CN H F H H H H Figure 43. 1HNMR of starting material 2,6-CFN 167 C–H activation borylation of 2,6 CFN with DCE-bpy as the ligand in THF gave significant amounts of diborylation. Therefore, to identify the diborylated species we did a thorough investigation on the 1H-NMR of the crude reaction mixture (Figure 44). CN Cl F Bpin 78a CN F Cl Bpin 78b Cl pinB F Bpin CN 78cʹ Figure 44. 1HNMR of starting material 2,6-CFN There are two possibilities, either 1,2–diborylated product (78c) or 1,3– diborylated product (78cʹ) (Scheme 65). Based on coupling constants 1,3–diborylation (78cʹ) is the diborylated product and not 78c. Substrate (78a) already known in literature. CN Cl 1 mol % [Ir(OMe)COD]2 2 mol % DCE-bpy Cl F CN Cl F + Bpin F Cl + CN Bpin 78b F + Cl Bpin pinB CN Bpin 78c CN F Bpin 78cʹ 78 1 equiv B2pin2 THF 60 °C, 24 h 78a Scheme 65. CHBS of 2,6-CFN 168 3) Iridium catalyzed C–H borylation of 2-chloro-6-methoxypyridine (Cl-OMepy) Iridium catalyzed C-H borylation for Cl-OMepy with different solvent, ligands and boron sources were screened. Three mono borylated regioisomers are possible with this substrate. a) Tetrahydrofuran (THF) Cl N OMe 1 mol % [Ir(OMe)COD]2 2 mol % Ligand Cl N 1 equiv B2pin2 THF 60 °C, 24 h 79 Bpin 79a OMe + Cl N OMe + Cl N OMe + Di Bpin pinB 79b 79bʹ Table 15. Ir-catalyzed C-H borylation of Cl-OMePy in THF. Stirring time Reaction time Conversion (%) (79a)/(79b)/(79c)/di Entry 1 2 3 4 5 6 7 Ligand Bpy(CF3)2 4-CN-2-MeO-Py 4-Cl-2-MeO-Py 4-CF3-2-MeO-Py 2-MeO-Py DCE-bpy DCA-bpy No stirring 8 h 24 h 24 h 24 h 24 h 3 h 2 h 100% 55% 58% 58% 77% 100% 100% 82/14/0/4 75/13/12/0 75/18/7/0 72/20/8/0 79/17/4/0 90/10/0/0 88/10/0/2 Bipyridine ligands showed high reactivity (Entry 1,6,7) in CHBs of Cl-OMepy when compared to monodentate ligands. Bidentate ligands gave two mono and one diborylated products. However, monodentate pyridine ligands gave three mono borylated products but no diborylated products. DCAbpy and DCEbpy ligands showed high reactivity in CHBs of Cl-OMepy. These two ligands gave full conversion to the desired borylated product within 2-3 h. 169 b) Discussion Starting material of Cl-OMepyridine (Figure 45) has three different protons. The most down field hydrogen (H2) is para to the nitrogen group and it is the most sterically and electronically favored hydrogen in this case. Therefore, this is the main reason for obtaining 79a as the major isomer with all ligands. (H1) and (H3) assignments are inconclusive. Cl H N OMe H H 79 H2 H3 H1 Figure 45. 1HNMR of starting material Cl-OMePy To confirm which isomer is major between 79b and 79bʹ, we purchased the boronic acid (79b0) and converted it into the boronic ester (Scheme 66). Cl N OMe 1 equiv pinacole 4 equiv anhy MgSO4 rt, 24 h B(OH)2 79b0 Cl N OMe Bpin 79b 69 % Scheme 66. Making boronic ester from boronic acid 170 Now by comparing 1H-NMR of the crude reaction mixture for C-H borylation of Cl-OMe-pyridine with the 1H-NMR of synthesized authentic sample 79b, gives a clear indication about which isomer is made as the electronic product. Borylation ortho to methoxy group (79b) is favored over borylation ortho to chlorine (79bʹ) (Figure 46). Cl N OMe Bpin Cl N OMe Bpin 1 2 Figure 46. 1H NMR of 1) Crude C-H borylation reaction mixture 2) Pure compound 79b Interestingly, this is a very good example to show how selectivity changes in different substrates. We expect C-H borylation to favor ortho to chlorine compared to a methoxy group due to sterics. However, the major electronic product here is borylation ortho to methoxy (79b). Not enough evidence exists to prove which diborylated product is made during this C-H borylation. 171 4) Iridium catalyzed C-H borylation of 4-methoxypyridine (4-OMe-pyridine) a) Tetrahydrofuran (THF) – No active catalyst pregenerate 4-OMe pyridine was screened with several monodentate and bidentate ligands in THF as the solvent. Here the active catalyst was not formed prior to introducing the substrate. N OMe 80 1 mol % [Ir(OMe)COD]2 2 mol % Ligand N 1 equiv B2pin2 THF 60 °C, 24 h OMe 80a Bpin Table 16. Ir-catalyzed C-H borylation of 4-OMe-Py in THF. Entry 1 2 3 4 5 Ligand Bpy(CF3)2 4-CN-2-MeO-Py 4-Cl-2-MeO-Py DCE-bpy DCA-bpy Stirring time Reaction time Conversion (%) No stirring 24 h 24 h 24 h 24 h 24 h 0% 0% 0% 17% 0% Monodentate or bidentate ligands did not show C-H borylations for 4-OMepy (except for entry 4). This is may be due to the strong coordinating ability of the substrate. We hypothesized that 4-OMepy coordinates to the metal center and deactivate the catalyst system. Therefore, by generating the active catalyst before introducing the substrate might help to carry out CHBs. With DCAbpy ligand a black solid was observed, however in this case no black solid was formed. This again confirmed that the active catalyst was not formed. 172 b) Tetrahydrofuran (THF) – pre–generate active catalyst 2) N 1) 1 mol % [Ir(OMe)COD]2 2 mol % Ligand 1 equiv B2pin2 THF 1.0 mL 60 °C, 1 h OMe THF 0.5 mL 60 °C, 24 h N OMe 80a Bpin Table 17. Ir-catalyzed C-H borylation of 4-OMe-Py in THF. Entry 1 2 3 4 5 6 7 8 9 Ligand Bpy(CF3)2 4-CN-2-MeO-Py 4-Cl-2-MeO-Py 4-CF3-2-MeO-Py 2-MeO-Py DCE-bpy DCA-bpy Dtbpy Dtbpy Stirring Time/min Conversion (%) Reaction time 24h 30 30 24h 30 24h 24h 60 60 24h 60 24h 5h 60 20 24h 60 24h 0% 0% 0% 0% 0% 12% 100% 15% 15% Generating the active catalyst first before introducing the substrate did not help with CHBs of 4-OMepy with most of the ligands except DCAbpy ligand. All monodentate ligands and Bpy(CF3)2 completely failed in CHB. DCA-bpy ligand showed remarkable reactivity in CHBs throughout the ligand screening process. This is an example that shows the exceptional reactivity of DCAbpy compared to the most commonly used dtbpy ligand. In depth discussion about the reactivity of DCAbpy is discussed in Chapter 7. 173 In Table 16, entry 5 a black solid was not observed, however, in Table 17 for DCAbpy (entry 7) a black solid was observed (Figure 47) and complete conversion to the desire borylated product was observed in 5 h. Figure 47. Comparing Table 16 (entry 5) with Table 17 (entry 7). 5) Iridium catalyzed C–H borylation of 2-Fluoro-6-methoxypyridine (F-OMe-py) 1) Tetrahydrofuran (THF) F N OMe 1 mol % [Ir(OMe)COD]2 2 mol % Ligand F N 1 equiv B2pin2 THF 60 °C, 24 h Bpin 81a 81 OMe + F N OMe F N OMe + + Di pinB Bpin 81b 81bʹ Table 18. Ir-catalyzed C-H borylation of F-OMe-Py in THF with no stirring. Entry Ligand Substrate Source Conversion (%) Ste(81a) 7.55 Ele1(81b) Ele2(81c) 7.69 7.30 Di1 9.92 Di2 9.97 N/A 25 N/A 3 3 36 40 10 N/A 18 14(9.3) 8 33 6 1 DCA-bpy Matrix Scientific Batch #041031 Combi-Block Batch #L30987 2# DCA-bpy 3# Bpy(CF3)2 4# Bipyrazine 5* No ligand *No PCl3 issue #PCl3 issue 100% 100% 99% 60% 64% 50 53 38 30 13 25 33 39 11 8 174 CHBs of F-OMepy gave several mono and di borylated products. CHB without any ligands progressed up to 64% and showed different selectivity. Since there was a PCl3 contamination inside the box most of the the CHBs results of F-OMe-pyridine were inconclusive. 2) Hexane F N OMe 1 mol % [Ir(OMe)COD]2 2 mol % Ligand F N OMe + F N OMe F N OMe + + Di Bpin 81bʹ 1 equiv B2pin2 hexane 60 °C, 24 h Bpin 81a pinB 81b 81 Table 19. Ir-catalyzed C-H borylation of F-OMe-Py in hexane. Entry Ligand Substrate Source Matrix Scientific Stirring time Conversion Reaction (%) time 7.69 7.55 Ste(81a) Ele1(81b) Ele2 7.30 Di1 9.92 Di2 9.97 Batch #041031 No stirring Combi- Block Batch #L30987 24 h 24 h 24 h 24 h 100% 94% 96% 45% 47 33 59 26 33 46 14 17 1 5 2 17 6 10 6 19 2(11.5) 44 6 7 1# DCA-bpy 2# dtfbpy 3# Bipyrazine No 4* ligands *No PCl3 issue # PCl3 issue 3) Discussion Starting material of F-OMe-pyridine has three different protons (Figure 48). The most down field hydrogen (H2) is para to nitrogen group and it is the most sterically and electronically favored hydrogen. Therefore, the major isomer in C–H borylation is 81a (steric product). (H1) and (H3) assignments are inconclusive. 175 F H N OMe H H 81 H Figure 48. 1HNMR of starting material F-OMe-Py 2-Fluoro pyridine substrates usually have unusual coupling patterns. In Figure 40, we don’t see H-F coupling patterns in the starting material. This is a characteristic feature of 2-fluoropyridines. In Cl-OMe-pyridine, borylation ortho to methoxy (79b) was preferred over borylation ortho to chlorine. To confirm unambiguously the major electronic product for F-OMe-pyridine is compound (81b), we made an authentic sample starting from its boronic acid derivative (81b0) (Scheme 67). 1 equiv pinacole 4 equiv anhy MgSO4 rt, 24 h F N OMe (OH)2B 81b0 F N OMe pinB 81b 61% Scheme 67. Making boronic ester from boronic acid Next, we compared the 1HNMR of the crude reaction for C–H borylations of compound 81 with the authentic sample. This clearly shows that that major electronic 176 isomer is 81b, that is borylation ortho to fluorine group (81b) is favored over borylation to ortho to methoxy group (Figure 49). This is favored sterically as well as electronically. F N OMe pinB Bpin 81c F N OMe pinB 81b F N OMe Bpin 81a 1 2 Figure 49. 1H NMR of 1) Crude C-H borylation reaction mixture Table 18 (entry1) 2) Pure compound 81b Note that meta H-F coupling in 2-fluoropyridine is close to 8.7 Hz. It is unusually a large coupling constant. From this, we can confirm the structure of diborylation is to be 1, 3- diborylation (81c). 6) Iridium catalyzed C–H borylation of 2methoxy-isonicotinonitrile (4-CN-2-OMe- pyridine) Next, we invested reactivity of ligands. Can the ligand itself be the substrate as well as the ligand for itself? To address this, we carried out following screenings. N OMe 1 mol % [Ir(OMe)COD]2 2 mol % Ligand 1 equiv B2pin2 THF 60 °C, 24 h CN 82 pinB OMe + N CN 82a N OMe Bpin CN 82b 177 Table 20. Ir-catalyzed C-H borylation of 4-CN-2-OMe-Py in hexane. Entry 1 2 Ligand Conversion (%) No ligand dtbpy 0% 65% - 55/40/5 (82a)/(82b)/unknown Reaction time 24h 24h • We have already encountered excess ligand of 4-CN-2-OMe-pyridine shuts down the Iridium catalyst system. There for entry 1 outcome is not surprising. • Entry 2 with the most reactive ligand gave only 65% conversion. GC-MS confirms 3 monoborylated products (mass of 260). However, major isomer is 82a as confirmed by NMR. 5) Iridium catalyzed C–H borylation of 4-methoxypicolinonitrile (2-CN-4-OMe- pyridine) N CN 2) 1) 1 mol % [Ir(OMe)COD]2 2 mol % Ligand 1 equiv B2pin2 Solvent 1.0 mL 60 °C, 1 h OMe 83 Solvent 0.5 mL 60 °C, 24 h pinB N CN + N CN Bpin OMe OMe Table 21. Ir-catalyzed C-H borylation of 4-CN-2-OMe-Py in hexane. 83b 83a solvent THF Hexane Ligand Bpy(CF3)2 DCA-bpy Bipyrazine 4-Cl-2-OMepy Hexane + THF Bipyrazine 4-CN-2-OMepy No ligand dtbpy THF Entry 1 2 3 4 5 6 7 8 Conversion 58% 100% 0% 0% 0% 0% 0% 100% (83a)/(83b) 88/12 98/2 - - - - - 90/10 Reaction time 24h 24h 24h 24h 24h 24h 24h 5h Bidentate ligands showed high reactivity for CHBs in THF. Starting material was not soluble in hexane. 178 7) Investigating deactivating nature of 4-methoxypicolinonitrile (2-CN-4-OMe- pyridine) Table 21 (entry 7) 2-CN-4-OMe-pyridine substrate could not act as the ligand or as the substrate. We hypothesis that, these 4-OMe pyridine ligands have a strong coordinating ability that will deactivate the catalyst system. In order to investigate further, we set up the f reaction (Scheme 68) where CFA is borylated using Ir catalyst with the 4- CN-2-OMe pyridine as the ligand. After 24 h a mixture of products ste: elec: di in a ratio of 20:57:23 were observed (85% product formation). Surprisingly, this mono dentate ligand favors electronic product (elec). This indicated the 4-CN-2-OMepy is an excellent ligand for borylations and it favors electronic product in fluoro arenes. OMe 1 mol % [Ir(OMe)COD]2 2 mol % 4–CN–2–OMepy Cl F Cl OMe F Cl + OMe + Di F Bpin Electronic 1 equiv B2pin2 THF 60 °C, 24 h Bpin Steric 85 % (ste:elec:di = 20/57/23) Scheme 68. CHBs of 2,6-CFA 67 Next, we set up the same reaction and after 10 h, a mixture of products ste: elec: di in a ratio of 32:58:10 were observed (35% product formation). At 10 h mark we introduced another loading of the 4-CN-2-OMepy ligand. Extra ligand diminishes the catalyst activity. After 24 h only 55% product formation was observed. This shows that in the presence of excess pyridine ligands the Iridium catalyst system slowly shuts down. However, more experiments are need to make a solid conclusion about any coordination ability. 179 OMe 1 mol % [Ir(OMe)COD]2 2 mol % 4–CN–2–OMepy Cl F Cl F Cl + OMe Bpin ste + Di F Bpin OMe elec 35% (ste:elec:di = 32/58/10) 67 1 equiv B2pin2 THF 60 °C, 10 h 2 mol % 4–CN–2–OMepy F Cl + Cl OMe Bpin ste + Di F Bpin OMe elec 55% (ste:ele:di = 34/57/9) Scheme 69. CHBs of 2,6-CFA with extra ligand 6.7 Ligand synthesis 1) Synthesis of dimethyl [2,2'-bipyridine]-4,4'-dicarboxylate ligand (DME-bpy) O HO N N OH 84 O H2SO4 MeOH 65 °C, 24 h O MeO N N OMe 85 97 % O Scheme 70. Synthesis of DCE-bpy ligand As a part of the Dow-MSU collaboration we envisioned that new ligand systems may result new regioselectivity in C–H borylations. Since the DCA-bpy ligand was extremely reactive, we were intrigued about the reactivity of ester version of this dicarboxylic ligand. Therefore, we esterified the dicarboxylic bipyridine ligand as follows (Scheme 71) 180 2) Synthesis of 5,5'-bis(trifluoromethyl)-[2,2'-bipyridine]-4,4'-dicarboxylic acid (Btf-DCA-bpy) DCA-bpy (84) and DCE-bpy (85) ligands showed excellent reactivity in C-H activation borylation. Therefore, we challenged ourself with making more electron deficient dicarboxylic bipyridine ligands (Scheme 71). HOOC F3C Cl N 86 1 equiv Zn 1 equiv NiCl2.6H2O 2 equiv PPh3 DMF, 80°C, 48 h HOOC F3C COOH CF3 . N N 87 Scheme 71. Synthesis of btf-DCA-bpy ligand Even though, these reaction conditions worked for synthesis of 4,4',5,5'- tetrakis(trifluoromethyl)-2,2'-bipyridine (dtfbpy), in our hands for synthesizing ligand (87) did not work. Major product of Scheme 71 was de-halogenated product of compound (86). 6.8 Different metal catalyst for C-H borylations Iridium catalyzed borylation, the state-of-the-art method for the functionalization of simple arenes, is not capable of functionalizing the more hindered C(sp2)−H bonds found in 1,3,5-triethylbenzene. In 2015, Chatani and co-workers reported the first platinum catalyzed C-H borylation on sterically demanding substrates such as 1,3,5- triethylbenzene (Scheme 72).24 2 mol % Pt catalyst 0.30 M B2pin2 140 °C, 20 h Excess Bpin 68% Scheme 72. Platinum catalyzed CHBs 181 The platinum/NHC catalyst system allowed the facile synthesis of ortho- fluorophenylboronic ester derivatives from fluoroarenes (Scheme 73). Inspired by this work, we tried using platinum chemistry to obtain the electronic product or borylation ortho to fluorine as the major product in our systems. We were also intrigued by the possibility of this catalyst to give diborylation products. Cy N N Cy Pt 90 Si Si O 2 mol % Pt catalyst 2.0 M B2pin2 80 °C, 20 h F F 5 equiv Bpin 4 3 F F 42% (3:4 = 99:1) Scheme 73. Platinum catalyzed CHBs of fluoroarenes Synthesis of platinum catalyst Pt2(dvms)3 ICy.HCl KtOBu rt Cy N N Cy Pt Si Si O 89 Scheme 74. Synthesis of platinum catalyst 90 Pt2(dvms)3 precursor came in poly(dimethylsiloxane) vinyl terminated thick solution. Therefore the final catalyst (white solid) was contaminated with PDMS. This siloxane is insoluble in water and ethanol, but soluble in other organic solvents like the compound itself. Therefore, it was difficult to obtain this catalyst in pure form. However, we went ahead and screened some substrates for C-H borylation. In the future, when 182 making this catalyst, it will be crucial to avoid siloxanes (one can buy Pt2(dvms)3 in xylene or synthesize 90 from H2PtCl6) Cy N N Cy Pt 90 Si Si O Arene B2pin2 60–80 °C, 24 h Borylated arene Table 22. Patinum catalyzed C-H borylation loading solvent Entry Substrate Substrate 2,6-CFA 2 mmol 1 2-CN-4- OMepy 1 mmol loading B2pin2 0.3 equiv neat 0.5 equiv THF 2 1.4 mol% 80 C 2.2 mol% 60 C Catalyst loading Tempe Reaction time Conversion St/elec/di 24h 24h 50% 24/70/6 0% - Platinum catalyst favored the electronic product in CHBs of 2,6-CFA. However, Pt-catalyst did not show any borylation product for 2-CN-4-OMepy. 6.8 Conclusions DCA-bpy and DCE-bpy are the most reactive ligands for CHBs. Bidentate ligands more reactive than mono dentate ligands. Furthermore, electron deficient bidentate ligand (Bpy(CF3)2) and mono dentate pyridine ligands favor electronic product of fluoro arenes. We also found that excess mono dentate ligands shut down the catalyst system and finally platinum catalyst also favor the electronic product of fluoro arenes. 6.9 Experimental Material and Methods All reactions were performed at the Dow chemical company at Midland, MI. 183 General procedure for Iridium catalyzed C-H borylation In a nitrogen atmosphere glove box, bis(pinacolato)boron (B2Pin2) (256 mg, 1.0 mmol, 1.0 equiv) was weighed into a 16 mL vial containing a magnetic stir bar. [Ir(OMe)COD]2 (6.6 mg, 0.01 mmol, 1.0 mol %) and the ligand (0.02 mmol, 2.0 mol %) were weighed into two test tubes separately, each being diluted with 0.5 mL of solvent. The [Ir(OMe)COD]2 solution was transferred into the 16 mL vial containing B2Pin2. This mixture was stirred until a golden yellow clear solution was obtained (~ 1 min). Next the solution containing ligand was transferred into the vial and upon stirring the resulting solution turned a dark brown color. Finally, the substrate (1.0 mmol) was added to the vial with the remaining solvent (0.5 mL). The reaction mixture was stirred for 24 h at 60 °C. General procedure for Iridium catalyzed C-H borylation with pre-generated catalyst In a nitrogen atmosphere glove box, bis(pinacolato)boron (B2Pin2) (256 mg, 1.0 mmol, 1.0 equiv) was weighed into a 16 mL vial containing a magnetic stir bar. [Ir(OMe)COD]2 (6.6 mg, 0.01 mmol, 1.0 mol %) and the ligand (0.02 mmol, 2.0 mol %) were weighed into two test tubes separately, each being diluted with 0.5 mL of solvent. The [Ir(OMe)COD]2 solution was transferred into the 16 mL vial containing B2Pin2. This mixture was stirred until a golden yellow clear solution was obtained (~ 1 min). Next the solution containing ligand was transferred into the vial and upon stirring the resulting solution turned a dark brown color. The reaction mixture was stirred for 1 h at 60 °C. 184 Finally, the substrate (1.0 mmol) was added to the vial with the remaining solvent (0.5 mL). Next the vial was closed and stirred for 24 h at 60 °C Compound 67a OMe F Cl 67a Bpin A mixture of boronic acid (9.8 mmol, 2.0g), pinacol (9.8 mmol) and anhydrous MgSO4 (40.0 mmol) in MTBE (120 ml) was stirred at room temperature for 16 h (monitored using 1H-NMR) . The solution was filtered and the filtrate was extracted with water (2 × 50 ml). Then, dried over MgSO4, filtered, and concentrated in vacuo with no further purification to give the desired boronic ester in white solid of 2.30 g (82%). 1H NMR (400 MHz, Chloroform-d) δ 7.35 (dd, J = 8.1, 5.6 Hz, 1H), 7.14 (dd, J = 8.1, 1.4 Hz, 1H), 3.96 (d, J = 1.4 Hz, 3H), 1.36 (s, 13H). 13C NMR (101 MHz, Chloroform-d) δ 160.35 (d, J = 254.5 Hz), 144.23 (d, J = 15.4 Hz), 131.76 (d, J = 4.0 Hz), 130.44 (d, J = 8.9 Hz), 125.17 (d, J = 3.6 Hz), 84.14, 61.45 (d, J = 5.0 Hz), 24.80. 19F NMR (376 MHz, Chloroform-d) δ -118.10 (d, J = 5.8 Hz). Compound 79b Cl N OMe Bpin 79b A mixture of boronic acid (2.67 mmol, 0.5g), pinacol (2.67 mmol) and anhydrous MgSO4 (10.0 mmol) in MTBE (40 ml) was stirred at room temperature for 16 h (monitored using 1H-NMR) . The solution was filtered and the filtrate was extracted with water (2 × 50 185 ml). Then, dried over MgSO4, filtered, and concentrated in vacuo with no further purification to give the desired boronic ester in white solid of 0.50 g (69%). 1H NMR (400 MHz, Chloroform-d) δ 7.91 (d, J = 7.5 Hz, 1H), 6.88 (d, J = 7.5 Hz, 1H), 3.97 (s, 3H), 1.34 (s, 12H). 13C NMR (101 MHz, Chloroform-d) δ 167.17, 151.41, 148.48, 115.96, 83.98, 54.44, 24.79. Compound 81b MeO N F Bpin 81b A mixture of boronic acid (2.93 mmol, 0.5g), pinacol (2.93 mmol) and anhydrous MgSO4 (11.7 mmol) in MTBE (40 ml) was stirred at room temperature for 16 h (monitored using 1H-NMR). The solution was filtered and the filtrate was extracted with water (2 × 50 ml). Then, dried over MgSO4, filtered, and concentrated in vacuo with no further purification to give the desired boronic ester in white solid of 0.45 g (61%). 1H NMR (400 MHz, Chloroform-d) δ 8.00 (dd, J = 8.8, 8.0 Hz, 1H), 6.59 (dd, J = 8.0, 2.1 Hz, 1H), 3.94 (s, 3H), 1.34 (s, 12H). 19F NMR (376 MHz, Chloroform-d) δ -58.92 (d, J = 9.1 Hz). 13C NMR (101 MHz, Chloroform-d) δ 167.75, 165.86 (d, J = 14.7 Hz), 165.30, 149.41 (d, J = 7.8 Hz), 106.93 (d, J = 4.9 Hz), 83.85, 53.96, 24.73. 19F NMR (376 MHz, Chloroform-d) δ -58.92 (d, J = 9.1 Hz). Dimethyl [2,2'-bipyridine]-4,4'-dicarboxylate ligand O N MeO OMe N O 85 186 To a suspension of 4,4'-dicarboxy-2,2'-bipyridine (5.0 g, 20.47 mmol) in absolute methanol (200 mL) was added concentrated sulfuric acid (5 ml). The mixture was refluxed (65 ºC) for 24 h to obtain a clear pink solution and then cooled to room temperature. Water was added (white slurry was formed) and the pH was adjusted to neutral with K2CO3 solution. Then the excess methanol was removed under vacuum. The resulting precipitate was extracted with ethyl acetate. The precipitate did not dissolve in EtOAc, therefore filter the white precipitate and wash with water. Finally dried under vacuum at 55 ºC to remove excess water. 1H NMR (400 MHz, Chloroform-d) δ 8.97 (dd, J = 1.6, 0.9 Hz, 1H), 8.87 (dd, J = 4.9, 0.9 Hz, 1H), 7.91 (dd, J = 5.0, 1.6 Hz, 1H), 4.00 (s, 3H). 13C NMR (101 MHz, Chloroform-d) δ 165.62, 156.51, 150.13, 138.60, 123.22, 120.56, 52.73. Platinum catalyst synthesis To a suspension of ICy.HCl and Pt catalyst in toluene under nitrogen was added tBuOK. The reaction mixture was stirred at room temperature for 3 h. The resulting mixture was filtered through a silica/celite (1:1) pad and it was washed with hexane/Et2O (8:2). The filtrate was concentrated in vacuo to obtain a pale yellow solid. 187 REFERENCES 188 REFERENCES (1) Ishiyama, T.; Takagi, J.; Ishida, K.; Miyaura, N.; Anastasi, N. R.; Hartwig, J. F. Mild Iridium-Catalyzed Borylation of Arenes. High Turnover Numbers, Room Temperature Reactions, and Isolation of a Potential Intermediate. J. Am. Chem. Soc. 2002, 124, 390– 391. (2) Boller, T. M.; Murphy, J. M.; Hapke, M.; Ishiyama, T.; Miyaura, N.; Hartwig, J. F. Mechanism of the Mild Functionalization of Arenes by Diboron Reagents Catalyzed by Iridium Complexes. Intermediacy and Chemistry of Bipyridine-Ligated Iridium Trisboryl Complexes. J. Am. Chem. Soc. 2005, 127, 14263–14278. (3) Ishiyama, T.; Isou, H.; Kikuchi, T.; Miyaura, N. Ortho-C–H Borylation of Benzoate Esters with Bis(pinacolato)diboron Catalyzed by Iridium–phosphine Complexes. Chem. Commun. 2010, 46, 159–161. (4) Sasaki, I.; Taguchi, J.; Doi, H.; Ito, H.; Ishiyama, T. Iridium(I)-Catalyzed C-H Borylation of α,β-Unsaturated Esters with Bis(pinacolato)diboron. Chem. Asian J. 2016, 11, 1400– 1405. (5) Kawamorita, S.; Ohmiya, H.; Hara, K.; Fukuoka, A.; Sawamura, M. Directed Ortho Borylation of Functionalized Arenes Catalyzed by a Silica-Supported Compact Phosphine-Iridium System. J. Am. Chem. Soc. 2009, 131, 5058–5059. (6) Yamazaki, K.; Kawamorita, S.; Ohmiya, H.; Sawamura, M. Directed Ortho Borylation of Phenol Derivatives Catalyzed by a Silica-Supported Iridium Complex. Org. Lett. 2010, 12, 3978–3981. (7) Kawamorita, S.; Ohmiya, H.; Sawamura, M. Ester-Directed Regioselective Borylation of Heteroarenes Catalyzed by a Silica-Supported Iridium Complex. J. Org. Chem. 2010, 75, 3855–3858. (8) Paul, S.; Chotana, G. A.; Holmes, D.; Reichle, R. C.; Maleczka, R. E., Jr; Smith, M. R., 3rd. Ir-Catalyzed Functionalization of 2-Substituted Indoles at the 7-Position: Nitrogen- Directed Aromatic Borylation. J. Am. Chem. Soc. 2006, 128, 15552–15553. (9) Ros, A.; Estepa, B.; López-Rodríguez, R.; Álvarez, E.; Fernández, R.; Lassaletta, J. M. Use of Hemilabile N,N Ligands in Nitrogen-Directed Iridium-Catalyzed Borylations of 189 Arenes. Angew. Chem. Int. Ed Engl. 2011, 50, 11724–11728. (10) Roering, A. J.; Hale, L. V. A.; Squier, P. A.; Ringgold, M. A.; Wiederspan, E. R.; Clark, T. B. Iridium-Catalyzed, Substrate-Directed C-H Borylation Reactions of Benzylic Amines. Org. Lett. 2012, 14, 3558–3561. (11) Boebel, T. A.; Hartwig, J. F. Silyl-Directed, Iridium-Catalyzed Ortho-Borylation of Arenes. A One-Pot Ortho-Borylation of Phenols, Arylamines, and Alkylarenes. J. Am. Chem. Soc. 2008, 130, 7534–7535. (12) Robbins, D. W.; Boebel, T. A.; Hartwig, J. F. Iridium-Catalyzed, Silyl-Directed Borylation of Nitrogen-Containing Heterocycles. J. Am. Chem. Soc. 2010, 132, 4068– 4069. (13) Roosen, P. C.; Kallepalli, V. A.; Chattopadhyay, B.; Singleton, D. A.; Maleczka, R. E., Jr; Smith, M. R., 3rd. Outer-Sphere Direction in Iridium C-H Borylation. J. Am. Chem. Soc. 2012, 134, 11350–11353. (14) Preshlock, S. M.; Plattner, D. L.; Maligres, P. E.; Krska, S. W.; Maleczka, R. E., Jr.; Smith, M. R., III. A Traceless Directing Group for C–H Borylation. Angew. Chem. Int. Ed. 2013, 52, 12915–12919. (15) Kuninobu, Y.; Ida, H.; Nishi, M.; Kanai, M. A meta-Selective C-H Borylation Directed by a Secondary Interaction between Ligand and Substrate. Nat. Chem. 2015, 7, 712–717. (16) Davis, H. J.; Genov, G. R.; Phipps, R. J. Meta -Selective C−H Borylation of Benzylamine-, Phenethylamine-, and Phenylpropylamine-Derived Amides Enabled by a Single Anionic Ligand. Angew. Chem. Int. Ed. 2017, 56, 13351–13355. (17) Davis, H. J.; Mihai, M. T.; Phipps, R. J. Ion Pair-Directed Regiocontrol in Transition- Metal Catalysis: A Meta-Selective C-H Borylation of Aromatic Quaternary Ammonium Salts. J. Am. Chem. Soc. 2016, 138, 12759–12762. (18) Smith, M. R.; Bisht, R.; Haldar, C.; Pandey, G.; Dannatt, J. E.; Ghaffari, B.; Maleczka, R. E.; Chattopadhyay, B. Achieving High Ortho Selectivity in Aniline C–H Borylations by Modifying Boron Substituents. ACS Catal. 2018, 6216–6223. 190 (19) Li, H. L.; Kuninobu, Y.; Kanai, M. Lewis Acid-Base Interaction-Controlled Ortho - Selective C−H Borylation of Aryl Sulfides. Angew. Chem. Int. Ed. 2017, 56, 1495–1499. (20) Li, H.-L.; Kanai, M.; Kuninobu, Y. Iridium/Bipyridine-Catalyzed Ortho-Selective C-H Borylation of Phenol and Aniline Derivatives. Org. Lett. 2017, 19, 5944–5947. (21) Bisht, R.; Chattopadhyay, B. Formal Ir-Catalyzed Ligand-Enabled Ortho and Meta Borylation of Aromatic Aldehydes via in Situ-Generated Imines. J. Am. Chem. Soc. 2016, 138, 84–87. (22) Chattopadhyay, B.; Dannatt, J. E.; Andujar-De Sanctis, I. L.; Gore, K. A.; Maleczka, R. E., Jr; Singleton, D. A.; Smith, M. R., 3rd. Ir-Catalyzed Ortho-Borylation of Phenols Directed by Substrate-Ligand Electrostatic Interactions: A Combined Experimental/in Silico Strategy for Optimizing Weak Interactions. J. Am. Chem. Soc. 2017, 139, 7864– 7871. (23) Ghaffari, B.; Preshlock, S. M.; Plattner, D. L.; Staples, R. J.; Maligres, P. E.; Krska, S. W.; Maleczka, R. E., Jr; Smith, M. R., 3rd. Silyl Phosphorus and Nitrogen Donor Chelates for Homogeneous Ortho Borylation Catalysis. J. Am. Chem. Soc. 2014, 136, 14345–14348. (24) Furukawa, T.; Tobisu, M.; Chatani, N. C-H Functionalization at Sterically Congested Positions by the Platinum-Catalyzed Borylation of Arenes. J. Am. Chem. Soc. 2015, 137, 12211–12214. 191 Chapter 7. Investigating Reactivity, Structure and Reusability of an Insoluble Iridium Catalyst for C-H Borylations 7.1 Introduction Since the first catalysts for the direct borylation of arenes based on Cp*Ir complexes were reported by Smith and co-workers,1 various iridium systems containing phosphine- and nitrogen-based ligands have been studied. However, C−H borylation is usually catalyzed by homogeneous iridium complexes, which shares common drawbacks, that is, catalyst recovery and recycling is difficult. It is highly desirable to develop a new catalyst system that is stable, easy to recover and reuse. In 2007, Zhu et al. synthesized ionic liquid-stabilized iridium (0) nanoparticles for the C−H borylation of arenes by pinacolborane (HBpin) (Scheme 75).2,3 This system could be reused at least six times. However, the catalyst was difficult to recover because the products had to be separated from the reaction mixture by distillation. H-Bpin + H FG (1) Nano-Ir (0), additive (2) HCl (aq) (FG = H, Me, MeO, CF3 ) B(OH)2 FG (meta-, para-) Scheme 75. CHBs with Ir(0) nanopartcles In 2009, Nishida and co-workers obtained an insoluble iridium complex by filtration from the reaction mixtures of 2,2′-bipyridine-4,4′-dicarboxylic acid, [IrCl(COD)]2 and B2pin2 (Scheme 76).4,5 This system could be reused 10 times over 1 week in C−H borylation reactions. However, the structure of this iridium complex was unknown due to its instability in air and insolubility in organic media. 192 1.2 mmol [Ir[(COD)Cl]2 Bpin (240 mmol) (8.0 mmol) HOOC COOH + B2Pin2 2.4 mmol DCAbpy 80 °C, 4h N N DCAbpy (1) Scheme 76. CHBs with 2,2′-bipyridine-4,4′-dicarboxylic acid ligand In the same year, Sawamura and co-workers reported a supported catalyst for aryl borylations.6 Their studies showed that reaction of Bpin with methylbenzoates catalyzed by the combination of [Ir(COD)(OMe)]2 and a silica-supported phosphine ligand resulted in ortho-directed aromatic borylation in excellent yields (Scheme 77).6,7 However, the proposed Ir(I) complex formed during the reaction was not actually isolated because it is not air stable and is moisture sensitive. + B2Pin2 (30 mmol) (0.5 mmol) 0.5 mol % Silica-SMAP-Ir Bpin 80 °C, 3h Ir OMe P Si O Si O O O Silica-SMAP-Ir Scheme 77. CHBs with silica-SMAP-Ir In 2014, Jones and co-workers a developed an immobilized bipyridine-iridium system prepared from a silica-supported bipyridine ligand for C–H borylation (Scheme 78).8 They synthesized a mesoporous silica (SBA-15)-supported bipyridine iridium complex by grafting bipyridine onto the silica support, followed by complexation of an iridium(I) precursor in the presence of HBpin and cyclooctene. This heterogeneous catalyst system is highly air stable and can be reused several times without significantly affecting the structure or the texture of the catalyst. 193 0.0035 mmol Ir cat 0.25 mmol B2pin2 Hexane FG Bpin FG 1.0 mmol SBA-15 with Ir(I) N N Bpin Bpin Ir Bpin O SiMe3 O Si OMe O O SiMe3 Scheme 78. CHBs with SBA-15-Ir(I) 7.2 Heterogeneous catalyst Nishida and co-workers4 investigated CHBs of different substrates with 0.75 mol % [Ir(COD)Cl]2 1.5 mol% of 84 and 0.6 equiv of B2pin2 (Scheme 79). Surprisingly, in the reaction of anisole, the borylated product was obtained in low yield. The assumption was that the methoxy group may coordinate with the iridium catalyst because 10 ppm iridium was detected in the filtrate. However, reactions using other substrates proceeded smoothly and tolerated functionalities such as Cl, CO2Me, and CF3. R 2.0 mmol + B2pin2 1.2 mmol 0.75 mol % [Ir(COD)Cl]2 1.5 mol % DCAbpy Methylcyclohexane 80 °C, 12h Bpin R OMe Bpin 20% o:m:p = 6:76:18 10 ppm Ir in filtrate Cl Cl Bpin 83% COOMe Bpin 76% m:p = 50:50 CF3 Bpin CF3 F3C Bpin 95% 64% m:p = 58:42 13% 3,5-diborylated product S Bpin Cl N Cl O Bpin 86% 78% 84% Scheme 79. CHBs of arenes and heteroarenes in an [IrCl(COD)]2 and 1 system 194 They also showed that this heterogeneous iridium complex (“black solid”) can easily filtered under nitrogen and could be reused more than 10 times for one week. No iridium was leached into the filtrates (Table 23). + B2pin2 1.0 mmol 60 mmol 1.5 mol % [Ir(COD)Cl]2 3.0 mol % DCAbpy 80 °C, 12h Bpin Table 23. CHBs of benzene catalyzed by recyclable iridium catalyst Iridium Complex (reusable) Cycle 1-10 ICP Ir leaching (ppm) <0.1 Conversion % 96-99 Unfortunately, few structural information about this reusable black solid was obtained because of its instability in air and its insolubility in organic solvents. However, ICP analysis of the complex showed that it contained both iridium and boron atoms in a molar ratio of 1:2.3-2.5. Therefore, they hypothesized that this complex may have a structure similar to that of the tris(boryl)iridium complex reported by Miyaura and co– workers.9 Also, not much information was offered about the regioselectivity of this heterogeneous catalyst with their limited substrate scope. Even though, this is a very promising system for recycling iridium in CHBs, there are many questions to be answered. During ligand screening at the Dow Chemical Company (Chapter 6) we saw exceptional reactivity for CHBs with a 2,2′-bipyridine-4,4′- dicarboxylic (84) acid ligand. Inspired by previous work and our own curiosity as to how this heterogeneous system worked we began investigation into 2,2′-bipyridine-4,4′- dicarboxylic acid (84, DCAbpy) ligand. Our main objectives of this project were as follows: 195 o Ligand reactivity with [Ir(OMe)COD]2 o Regioselectivity during CHBs with their heterogeneous catalyst system o Comparison with the dtbpy ligand system o In depth structural analysis of the black solid 7.3 Data and Discussion Reactivity To begin investigating CHBs we chose [Ir(OMe) COD]2 as the pre-catalyst since this is the most active and widely used pre-catalyst for CHBs. We were intrigued by the results obtained during the ligand screening in Chapter 6. We saw contrasting reactivity and regioselectivity between dtbpy and DCAbpy ligands with the same pre-catalyst in CHBs of arenes. One such example is the borylation of 4-methoxy pyridine (80). OMe N 80 1 mol %[Ir(OMe)COD]2 2 mol % Ligand B2Pin2 , THF, 60 °C, 24 h Bpin OMe N 80a dtbpy = 0% DCAbpy = 0% Scheme 80. CHBs without pre-generated active catalyst Both ligands dtbpy and DCAbpy showed no C–H activation of 80 when the reaction was run without pre-generated active catalyst (Scheme 80). However, when CHBs of 80 was carried out with pre-generated active catalyst, the two ligands showed different reactivity (Scheme 81). First, 1.0 mol % of Ir catalyst, 2.0 mol % of ligand and 1.0 equiv of B2pin2 were combined in THF and heated at 60 °C for 30 min. After 60 min, the substrate (80) was introduced and the reaction mixture heated at 60 °C for 24 h. The 196 reaction mixture was monitored by NMR. After 5 h, full product (80a) formation was seen with the DCAbpy ligand, but only 15% product formation was observed with widely used ligand dtbpy even after 24 h. Scheme 82 is an example where dtbpy fails in CHBs. As we discovered in Chapter 6, DCAbpy shows exceptional reactivity with wide range of substrates than dtbpy. However, it is noteworthy that pre-generating the catalyst is not necessary for non-coordinating substrates. 1 mol %[Ir(OMe)COD]2 2 mol % Ligand B2Pin2 , THF, 60 °C, 60 min Ir Active Catalyst OMe N 60 °C, 24h OMe Bpin N 80a dtbpy = 15% (24 h) DCAbpy = 100% (5 h) Scheme 81.CHBs with pre-generated active catalyst Nishida and co-workers mentioned that CHBs of anisole resulted in lower yield and 10 ppm of Ir was observed due to coordination of the OMe group to Ir. To test this, we chose 2-chloro-6-methoxypyridine (79) for borylations. In a nitrogen filled glove box 10 mmol of 79 reacted with 1.0 mol% Ir catalyst (purchased from Johnson Matthey), 2.0 mol % ligand and 1.0 equiv of B2pin2 at 60°C for 24 h. After 24 h, all starting material was consumed and two mono borylated products (79a and 79b) and a black solid (Scheme 82) were generated. 197 O N Cl 10 mmol 79 1 mol %[Ir(OMe)COD]2 2 mol % DCABpy B2pin2 , Hexane, 60 °C, 24 h O N Cl + O N Cl black solid + pinB Bpin 79b 79a 100 % conversion (7:1) hot filteration Filtrate (products + hexane + Ir ?) Black solid 0.132 g Scheme 82. Separation of the black solid In the glove box the black solid was separated by filtration. Next, small samples in plastic containers were prepared from the filtrate and the black solid for NAA (Neutron Atomic Absorption) studies. This gives an idea about how much Ir is incorporated in the black solid as well as the filtrate (Table 24). Table 24. NAA data for the black solid and the filtrate in hexane Material-hexane Black solid Filtrate NAA study Ir (wt%) 21.0 % 0.069 % In contrast to Nishida’s catalyst system, the amount of Ir leaking out (0.069%) was negligible even in the presence of an anisole group. We also observed that the best solvents for recovering the black solid are non–polar solvents such as hexane. When we repeated the same reaction in THF we had difficulties filtering the material out and the amount of Ir incorporated in black solid was less than what we observed where hexane was the solvent (Table 25). 198 Table 25. NAA data for the black solid and the filtrate in hexane Material-THF Black solid Filtrate NAA study Ir (wt%) 9.8 % 0.058 % Recycling of the Black Solid Our next goal was to investigate recycling the black solid. In a nitrogen filled glove box 10 mmol of 79 was reacted with 1.0 mol% Ir catalyst (made at MSU), 2.0 mol % ligand and 1.0 equiv of B2pin2 at 60°C for 24 h (Scheme 83). After 24 h, the black solid was separated by filtration. A portion of the black solid was used for solid state NMR/XRD (X-ray powder diffraction) and the other portion stored inside the glove box for 5 months. The filtrate was taken out of the glove box and was used to isolate mono borylated mixture (79a and 79b) in 90%. NAA and ICP (Inductively Coupled Plasma) data suggested that incorporation of Ir in the black solid is about 10-11%. It is noteworthy that amount of Ir incorporation depends on the brand, batch of [Ir(OMe)COD]2 used. This is not a surprising fact because, in our previous reports we have observed this phenomenon. 199 O N Cl 10 mmol 79 1 mol %[Ir(OMe)COD]2 2 mol % DCABpy B2Pin2 , Hexane, 60 °C, 24 h solid state NMR XRD O N Cl + O N Cl black solid + pinB Bpin filter O N Cl + O N Cl Bpin 79a pinB 90 % 79b Black solid 0.160 g NAA = 11.4 % ICP = 10.8 % Stored in glove box for 5 months Scheme 83. Synthesis of the black solid The black solid stored in the glove box under nitrogen for five months was used to run CHBs of 2,6-CFA (67) (Scheme 84). Compound 67 (1 mmol) was combined with 0.55 equiv of B2pin2 and 0.0375 g (0.0041 g of Ir) of the black solid in hexane at 60 °C for 24 h. After 24 h, the starting material was fully consumed and we separated out the black solid to reuse it in another CHBs cycle. From the filtrate mixture of mono borylates; electronic (67a) and steric (67b) products were isolated in 85% yield as a mixture (2:1 = 67a:67b). For the second cycle, the same reaction conditions were used and after 24 h 92% of product formation was observed. This indicates that the black solid can be reuse even in small quantities to obtain high reactivity. OMe F Cl 67, 1 mmol 0.0375 g Black solid (0.0041 g of Ir) 0.55 equiv B2Pin2 , Hexane, 60 °C, 24 h OMe Cl Cl + F Bpin 67a OMe F Bpin 67b 67a : 67b = 2:1 Cycle 1 2 Conversion 100% (86%) 92% Scheme 84. Recycling of the black solid during CHBs 200 It is noteworthy that borylation of 2,6-CFA with the black solid favors regioselectivity next to fluorine (67a, electronic). We investigate CHBs using the black solid with several other fluorine containing compounds and compared the regioselectivity with dtbpy (Scheme 85). All three fluoro arenes showed full consumption of starting arene in 12 h. CHBs of 1,3-bis(trifluoromethyl)benzene gave the only one regioisomer, borylation at the C5 position (91) in 94% isolated yield. R1 R2 1 mmol 1.7 mol% Ir 0.55 equiv B2pin2 Hexane 60 °C, 12 h R1 R2 F3C CF3 Cl Bpin 91 F Bpin 93 F Cl + Bpin 92 1:1 dtbpy = 2:1 Bpin H3C F Bpin 95 F H3C + Bpin 94 1:2 dtbpy = 1:1 1.7 mol % Ir = 94 % (100 %) 1.7 mol % Ir = 70 % (100 %) 1.7 mol % Ir = 63 % (100 %) Scheme 85. CHBs of the black solid Vs. dtbpy CHBs of 1-chloro-3-fluorobenzene with the black solid gave a 1:1 mixture of 92 (steric) and 93 (electronic) mono borylated products in 70% yield. However, CHBs of 1- Chloro-3-fluorobenzene with dtbpy ligand gave a 2:1 ratio of 92 and 93 favoring the steric product. CHBs of 1-fluoro-3-methylbenzene with the black solid gave a mixture of 95 and 96 favoring the electronic product (2:1). In contrast, dtbpy ligand gave a 1:1 mixture of 95 and 96. All these data indicate that CHBs with the black solid give a different region chemical outcome than does dtbpy and in fluoro arenes the electronic product is more favored over the sterics with the black solid catalyst. However, more in depth substrate screening is required to make a solid conclusion about regioselectivity of CHBs with this black solid catalyst. 201 Characterization of the Black Solid The black solid catalyst was confirmed as an amorphous solid from X-ray powder diffraction. Also, since the solid is not soluable in any organic solvents, we carried out solid state NMR. 13C solid state NMR indicated presence of C-O (84.5 ppm) and CH3 (26.5 ppm) carbon bonds (Figure 50). 11B solid state NMR shows a peak at 17 ppm (Figure 51). This is in contrast to the value we see in iridum trisbpin complex, which is 35 ppm (Ir–B). Furthermore, IR spectra indicated presence of a C=O (peak at 1710 cm- 1) bond. Black solid{[Ir(COD)Cl]2 + DCAbpy} was reported as an ignitable by Nishida and co-workers, however in our hands the black solid from [Ir(OMe)COD]2 and DCAbpy was not ignitable. However, we observed a color change from black to brown when the solid was exposed to the air. Figure 50. Solid state 13C NMR 202 Figure 51. Solid state 11B NMR 7.4 Conclusions Nishida’s black solid is a remarkable reusable heterogeneous catalyst for CHBs. It is easier to separate from the crude reaction mixture and can be reused several times without any Ir leaking or decrease in the reactivity. DCAbpy is an affordable ligand and also it is easy to use. Furthermore, DCAbpy showed exceptionally high reactivity than dtbpy and different region chemical preference than dtbpy. 7.5 Experimental All reactions were run inside a nitrogen filled glove box at Dow Chemical company in Midland. General procedure for Iridium catalyzed C-H borylation In a nitrogen atmosphere glove box, bis(pinacolato)boron (B2Pin2) (256 mg, 1.0 mmol, 1.0 equiv) was weighed into a 16 mL vial containing a magnetic stir bar. [Ir(OMe)COD]2 (6.6 mg, 0.01 mmol, 1.0 mol %) and DCAbpy ligand (4.8 mg, 0.02 203 mmol, 2.0 mol %) were weighed into two test tubes separately, each being diluted with 0.5 mL of solvent. The [Ir(OMe)COD]2 solution was transferred into the 16 mL vial containing B2Pin2. This mixture was stirred until a golden yellow clear solution was obtained (~ 1 min). Next the solution containing ligand was transferred into the vial and upon stirring the resulting solution turned a dark brown color. Finally, the substrate (1.0 mmol) was added to the vial with the remaining solvent (0.5 mL). The reaction mixture was stirred for 24 h at 60 °C. General procedure for Iridium catalyzed C-H borylation with pre-generated catalyst In a nitrogen atmosphere glove box, bis(pinacolato)boron (B2Pin2) (256 mg, 1.0 mmol, 1.0 equiv) was weighed into a 16 mL vial containing a magnetic stir bar. [Ir(OMe)COD]2 (6.6 mg, 0.01 mmol, 1.0 mol %) and DCAbpy ligand (4.8 mg, 0.02 mmol, 2.0 mol %) were weighed into two test tubes separately, each being diluted with 0.5 mL of solvent. The [Ir(OMe)COD]2 solution was transferred into the 16 mL vial containing B2Pin2. This mixture was stirred until a golden yellow clear solution was obtained (~ 1 min). Next the solution containing ligand was transferred into the vial and upon stirring the resulting solution turned a dark brown color. The reaction mixture was stirred for 1 h at 60 °C. Finally, the substrate (1.0 mmol) was added to the vial with the remaining solvent (0.5 mL). Next the vial was closed and stirred for 24 h at 60 °C 204 Synthesis of the black solid In a nitrogen atmosphere glove box, bis(pinacolato)boron (B2Pin2) (2.56 g, 1.0 mmol, 1.0 equiv) was weighed into a 50 mL vial containing a magnetic stir bar. [Ir(OMe)COD]2 (66 mg, 0.1 mmol, 1.0 mol %) and DCAbpy ligand (48 mg, 0.2 mmol, 2.0 mol %) were weighed into two test tubes separately, each being diluted with 5.0 mL of solvent. The [Ir(OMe)COD]2 solution was transferred into the 50 mL vial containing B2Pin2. This mixture was stirred until a golden yellow clear solution was obtained (~ 3 min). Next the solution containing ligand was transferred into the vial and upon stirring the resulting solution turned a dark brown color. Finally, the substrate (10.0 mmol) was added to the vial with the remaining solvent (5.0 mL). The reaction mixture was stirred for 24 h at 60 °C. After 24 h, the reaction mixture was filtered through a plastic disposable filter cone inside the glove-box and the black solid obtained was washed twice with 10 mL solvent. The black solid was dried under over nitrogen atmosphere. General procedure for Iridium catalyzed C-H borylation with the black solid In a nitrogen atmosphere glove box, the black solid (0.0375 g) was weighed into a 16 mL vial containing a magnetic stir bar. Bis(pinacolato)boron (B2Pin2) (150 mg, 0.55 mmol, 0.5 equiv) and the substrate (1 mmol) were weighed into two test tubes separately, each being diluted with 0.5 mL of solvent. The B2Pin2 solution was transferred into the 16 mL vial containing the black solid. Next the solution containing the substrate was transferred into the vial. The reaction mixture was stirred for 24 h at 60 °C. Finally, the 205 substrate (1.0 mmol) was added to the vial with the remaining solvent (0.5 mL). Next the vial was closed and stirred for 24 h at 60 °C After 24 h, the reaction mixture was filtered through a plastic disposable filter cone inside the glove-box and the black solid obtained was washed twice with 10 mL hexane. The solid obtained from this filtration was used for the next cycle of CHBs. The filtrate was take out from the glove box and excess solvent was removed using the rotary evaporator. The oncentrated sample was passed through a plug of silica (BD 60 mL Syringe/Luer-Lok Tip-silica up to 50 mL mark) eluting with a 10:1 hexane/ethyl acetate solution (200 mL). The volatiles were removed by rotary evaporation to give the borylated product. 206 REFERENCES 207 REFERENCES (1) Cho, J.-Y.; Iverson, C. N.; Smith, M. R. Steric and Chelate Directing Effects in Aromatic Borylation. J. Am. Chem. Soc. 2000, 122, 12868–12869. (2) Yinghuai, Z.; Chenyan, K.; Peng, A. T.; Emi, A.; Monalisa, W.; Kui-Jin Louis, L.; Hosmane, N. S.; Maguire, J. A. Catalytic Phenylborylation Reaction by iridium(0) Nanoparticles Produced from Hydridoiridium Carborane. Inorg. Chem. 2008, 47, 5756– 5761. (3) Yinghuai, Z.; Yan, K. C.; Jizhong, L.; Hwei, C. S.; Hon, Y. C.; Emi, A.; Zhenshun, S.; Winata, M.; Hosmane, N. S.; Maguire, J. A. Iridium(I)-Salicylaldiminato-Cyclooctadiene Complexes Used as Catalysts for Phenylborylation. J. Organomet. Chem. 2007, 692, 4244–4250. (4) Tagata, T.; Nishida, M.; Nishida, A. Development of Recyclable Iridium Catalyst for C– (5) Tagata, T.; Nishida, M.; Nishida, A. Continuous-Flow C–H Borylation of Arene H Borylation. Tetrahedron Lett. 2009, 50 (45), 6176–6179. Derivatives. Adv. Synth. Catal. 2010, 352, 1662–1666. (6) Kawamorita, S.; Ohmiya, H.; Hara, K.; Fukuoka, A.; Sawamura, M. Directed Ortho Borylation of Functionalized Arenes Catalyzed by a Silica-Supported Compact Phosphine-Iridium System. J. Am. Chem. Soc. 2009, 131, 5058–5059. (7) Kawamorita, S.; Ohmiya, H.; Sawamura, M. Ester-Directed Regioselective Borylation of Heteroarenes Catalyzed by a Silica-Supported Iridium Complex. J. Org. Chem. 2010, 75, 3855–3858. (8) Wu, F.; Feng, Y.; Jones, C. W. Recyclable Silica-Supported Iridium Bipyridine Catalyst for Aromatic C–H Borylation. ACS Catal. 2014, 4 (5), 1365–1375. (9) Ishiyama, T.; Takagi, J.; Ishida, K.; Miyaura, N.; Anastasi, N. R.; Hartwig, J. F. Mild Iridium-Catalyzed Borylation of Arenes. High Turnover Numbers, Room Temperature Reactions, and Isolation of a Potential Intermediate. J. Am. Chem. Soc. 2002, 124 (3), 208 390–391. (10) Preshlock, S. M.; Ghaffari, B.; Maligres, P. E.; Krska, S. W.; Maleczka, R. E., Jr; Smith, M. R., 3rd. High-Throughput Optimization of Ir-Catalyzed C-H Borylation: A Tutorial for Practical Applications. J. Am. Chem. Soc. 2013, 135 (20), 7572–7582. 209 Chapter 8. Selective para-CH Activation Borylations 8.1 Introduction Numerous C–H bond borylation and silylation methods are currently available. Although many methods have been developed for the ortho-borylation1–6 of arenes, remote C−H bond (meta and para) borylation remains difficult. Smith, Maleczka, Hartwig and co–workers reported exclusive meta-borylations/silylations from 1,3- disubstituted arenes and this regiochemistry results essentially from sterics.7–9 Recently, meta-selective borylation have been developed using the concept of noncovalent interaction10–12 between the substrate and ligand.13,14 However, there was no general method for the para selective borylation until 2015, when Itami and Segawa reported selective para-borylation by use of a bulky diphosphine ligand.15,16 The basis behind this para borylation is the use of a bulky ligand that sterically blocks the ortho and meta positions resulting, a para selectivity. Very Recently, Nakao and co–workers reported a novel concept for para-borylation of benzamides and pyridines via a cooperative Ir/Al catalysis.17 The para-selectivity was controlled by a bulky aluminum-based Lewis acid catalyst. Also, in 2017 Chattopadhyay and co–workers introduced a L-shaped ligand for para selective borylations of aromatic esters.18 A noncovalent interaction between the substrate and a L-shaped ligand facilitate the Ir-catalyzed para C−H borylation of aromatic esters (Figure 52). 210 Sterically controlled Cooperative Al/Ir catalysis Non-covalent interaction Me Me Me MeO MeO P P Ir H Me Me R Me Me Me Segawa & Itami 2015 Me tBu tBu O tBu O Me Al tBu N Me Ir Nakao 2017 Me Bpin Ir Bpin N pinB N N EtO O [M] O Chattopadhyay 2017 Figure 52. Discovery of selective para borylations 8.2 Sterically bulk ligand synthesis Similar to Itami and Segawa’s bulky diphosphine ligand, we envisioned that a ligand-controlled, para-selective C−H borylation could be achieved by iridium catalysis with sterically hindered ligands. Generally, in C−H borylations,19,20 arenes approach from the top side of square pyramidal iridium triboryl complex (Figure 53, left). In theory, bulky substituents on bipyridine ligands would restrict the upper hemisphere around the iridium center so that the para-C−H bond reacts preferentially over those in meta- positions (Figure 53, right). Because the boryl group can be easily converted into various functional groups,21,22 para-selective C−H borylation would be an extremely powerful method in organic synthesis. 211 Conventional C–H borylation Bulky ligand blocking meta approach meta para meta para H H N N Bpin Bpin Ir Bpin H H N N Bpin Bpin Ir Bpin Figure 53. Selective iridium catalyzed C–H borylations 8.3 Ligand synthesis for para selective C–H borylations In 2014, we designed a bulky ligand (L2) that was a modified bipyridine. The sysnthsis ligand (L2) consists of two parts (Part-A and Part-B) (Figure 54). Part-A is a borylated bipyridine unit and Part-B is a terphenyl moiety. We hypothesized that this bulky ligand (L2) would be suitable for the para C−H activation due to the following two considerations. First, in the presence of [Ir(COD)(OMe)]2 and B2pin2, L2 would form the standard tris(boryl)iridium complex, which would facilitate the C−H borylation. Second, the terphenyl moiety will disfavor meta C-H activation due to steric hindrance. The designed ligand (L2) was synthesized using Suzuki cross coupling of part A and part B. pinB N N Bpin part A I Ar Ar part B Ar Ar Ar Ar N N L2 Figure 54. Sterically bulky ligand 212 8.4 Synthesis of part A In 2012, Woltering and co–workers reported a scalable, inexpensive synthetic route for versatile building block 5,5′-dibromo-2,2′-bipyridine (98)23 that was based off the study by Romero and Ziesse.24 Synthesis of 5,5′-dibromo-2,2′-bipyridine begins with reacting 48% (wt/wt) aqueous HBr with 2,2′-bipyridine (96) in methanol at 0 °C to obtain 2,2′-bipyridine dihydrobromide (97) (Scheme 86). Next, 2,2′-bipyridine dihydrobromide (97) is reacted with bromine under pressure to yield a mixture of 5,5′- dibromo-2,2′-bipyridine (98) and 5-bromo-2,2′-bipyridine (99). After column chromatography 5,5′-dibromo-2,2′-bipyridine (98) was isolated. 1) 3.00 equiv, 48% (wt/wt) HBr(aq) MeOH 2) 2.50 equiv, acetyl bromide MeOH - 2Br NH NH 2.06 equiv Br2 185 °C, 72 h stainless steel bomb Br Br + N N N N Scheme 86. Synthesis of 5,5′-dibromo-2,2′-bipyridine 97 Br 98 99 N N 96 Pure 5,5′-dibromo-2,2′-bipyridine (98) was subjected for Miyaura coupling conditions to give the desired diborylated bipyridine 5,5'-bis(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-2,2'-bipyridine (100) in 18–34% yield (Scheme 87). 5 mol % Pd(dppf)Cl2 2.4 equiv B2Pin2 3.0 equiv KOAc dioxane, 105 °C, 17 h Br Br N N 98 3 mmol pinB N N 100 18–34 % part A Bpin Scheme 87.Miyaura coupling of 5,5′-dibromo-2,2′-bipyridine 213 8.5 Synthesis of part B Power and co-workers did pioneering work on synthesis of sterically encumbered aryl groups.25 We were interested in a terphenyl moiety featuring two phenyls, or substituted phenyl, rings at the ortho positions of a central aryl ring. The most common synthetic route to these compounds begins with terphenyl halides, which are typically made from aniline derivatives. It has been shown that it is possible to synthesize iodo compounds like 2,6- diphenyl-4-methyliodobenzene (103) through a five-step route commencing with commercially available 2,6-dibromo-4-methylaniline (101) (Scheme 88).26 NH2 Br Step 1 Br NaNO2, HCl, H2O Br I Br KI,H2O 101 102 57% Step 2 1) C8H9MgBr THF, rt, 4h 2) I2 I Ar Ar 103 41% Scheme 88. Synthesis of terphenyl halides 1,3-Dibromo-2-iodo-5-methylbenzene (102) was synthesized via diazotization and treatment with potassium iodide of commercially available 2,6-dibromo-4- methylaniline (101) (Step 1) (Scheme 88). Terphenyl was synthesized by a one pot reaction of a 1,2,3-trihalobenzene (102) with excess of a arylGrignard reagent. The mechanism involves Grignard exchange at the central halogen, followed by two cycles of magnesium halide loss and regioselective capture of the resulting aryne by the aryl- Grignard reagent (Scheme 89).27 Finally, quenching by I2 gives the desired 2,6- diphenyl- 4-methyliodobenzene (103) in 41% yield. 214 I Br Br ArMgBr Br MgBr Br –MgBr2 Br ArMgBr Br MgBr Ar 102 I Ar Ar I2 MgBr Ar Ar ArMgBr 103 part B –MgBr2 Ar Scheme 89. Mechanism for synthesis of terphenyl halides 8.5 Synthesis of the bulky ligand Finally, by combining part A and part B through a Suzuki reaction would afford the desired bulky ligand (L2) (Scheme 90). The challenge was to successfully couple the sterically encumber terphenyl with the 5,5′-diBpin-2,2′-bipyridine. Since synthesizing parts A and B are time consuming and low yielding, we avoided extensive screening of Suzuki conditions. Instead, we chose the most frequently used Suzuki conditions (Scheme 90). I Ar Ar Br + Part B 2.1 equiv N N Part A 0.4 mmol 10 mol %Pd(PPh3)4 20 equiv K2CO3 dioxane/H2O 102 °C, 48 h N N L2 Scheme 90. Synthesis of bulky ligand Br LCMS indicated the major Suzuki product to be the mono coupled product, with the product minor beign L2. After column chromatography, the sterically hindered ligand 215 (L2) was isolated in 15%. With only few milligrams in hand, we moved to the next step, that is iridium catalyzed C–H borylation. 8.6 Iridium catalyzed selective para borylations tert-Butylbenzene was chosen as the substrate to test ligand (L2). C–H borylation was carried out on this substrate with 1 mol % [Ir(OMe)COD]2, 2 mol % ligand and 1.6 equiv of HBpin in THF at 80 °C for 24 h (Scheme 91). This resulted in borylations at the para, meta and di–meta positions in a ratio of 74: 25: 1. 1 mol % [Ir(OMe)COD]2 2 mol % ligand 1.6 equiv HBpin THF 80 ° C, 24 h + + Bpin 105 106 Bpin pinB Bpin 107 L2 ligand 105: 106: 107 = 74: 25: 1 dtbpy 105: 106: 107 = 23: 59: 18 Scheme 91. C–H activation borylation 104 CHBs of 104 with dtbpy ligand favors the meta (106) regioisomer over para (05) and considerable amount of di–borylation (107) is also formed. Therefore, this indicates a promising result for selective para C-H borylations using terphenyl moieties with bipyridine ligands, but more work is needed in modifying new sterically hindered ligand systems. 8.7 Experimental Unless indicated otherwise all reactions were carried out in oven-dried glassware under an atmosphere of argon, with magnetic stirring, and monitored by GC-MS or 1H- NMR. Tetrahydrofuran was freshly distilled from sodium/benzophenone under nitrogen. 216 Standard Schlenk techniques on a double manifold vacuum line were used in the manipulation of air and moisture sensitive compounds. Compound 98 Br N N 98 Br Carry out Steps 1–14 of the described reaction in a well-vented fume hood and keep the sash down during the entire course of the reaction. Have a Na2S2O3 solution at hand in case of bromine spillages. Wipe all equipment and the fume hood surface thoroughly using Na2S2O3 solution. 1) Charge a mortar with 12.0 g of 2,2′-bipyridine dihydrobromide 97 (1.00 equiv.). Take up 4.00 ml of bromine (2.06 equiv.) in a 5-ml disposable plastic syringe with a long needle. Slowly add the bromine, making sure that the tip of the needle is digging into 97. From time to time, mix and grind the solids using the pestle. Caution Slowly inject the bromine to minimize evaporation. This ensures reproducibility and prevents the release of bromine vapor. 2) Grind the mixture until a homogenous non fuming orange powder is obtained. (cid:0) Critical step Grinding until a fine powder is obtained is crucial to ensure reproducibility. 3) Transfer the reaction mixture into a 15-ml sample vial using a plastic funnel and compress it using a spatula. 217 4) Transfer the sample vial into the stainless steel bomb using tweezers and seal the steel bomb in the fume hood using adjustable wrenches. 5) Place the stainless steel bomb in an insulated oil bath with a thermocouple temperature sensor. Cover the apparatus with a blast shield and heat the oil bath to 185 °C for 72 h. 6) Switch off the heating and allow the apparatus to cool to room temperature. Remove the blast shield and open the stainless steel bomb in the fume hood using adjustable wrenches. 7) Place the sample vial into a mortar and carefully smash the vial using the pestle; remove pieces of glass with the tweezers. Pestle the reaction cake until a fine powder is obtained. 8) Transfer the crude product into a large conical ask with a teflon-coated magnetic stirrer bar and add 200 ml of 2 M NaOH solution. 9) Add 10 g of EDTA tetrasodium salt,10 g of Na2SO3 and 200 ml of CH2Cl2. Cover the conical ask with a watch glass and stir the mixture at 1,250 r.p.m. for 2 h at room temperature. 10) Separate the organic phase and extract the aqueous phase five times with 200 ml of CH2Cl2 using a separatory funnel. 11) Combine the organic phases in a conical ask, add 120 g of anhydrous Na2SO4 and stir for 15 min; next, filter the mixture and transfer it to a round-bottom ask. 12) Add silica (20 g for 1 g of crude) and remove the solvents using a rotary evaporator. 13) Purify the crude product by flash chromatography on silica gel using CH2Cl2. 218 14) Collect the product containing fractions in a round-bottom ask and remove the solvents using a rotary evaporator. Order of elution: 5,5′-dibromo-2,2′-bipyridine 98→ 5-bromo-2,2′-bipyridine 99 →2,2′-bipyridine 96. 2.680 g of a colorless crystalline powder was obtained. 1H NMR (500 MHz, CDCl3) δ 8.71 (d, J = 2.3 Hz, 2H), 8.40 – 8.16 (m, 2H), 7.94 (dd, J = 8.5, 2.3 Hz, 2H). 13C NMR (126 MHz, CDCl3) δ 153.6, 150.3, 139.6, 122.2, 121.4. The spectral data were in accordance with those reported in the literature.23 MS EI+ m/z calculated for (M+H)+ C10H7Br2N2 312.8976, found 312.9032. Compound 100 pinB N N 100 Bpin Pd(dppf)Cl2 (0.122 g, 0.15 mmol, 5.0 mol%), KOAc (0.883 g, 9.0 mmol, 3.0 equiv), and bis(pinacolato)diboron (1.82 g, 7.16 mmol, 2.4 equiv) were added to a flask equipped with a magnetic stirring bar, a septum inlet, and a condenser. The flask was flushed with argon and then charged with degassed dioxane (10 mL) and 5,5′-dibromo-2,2′-bipyridine (0.942 g, 3.0 mmol). The mixture was then stirred at 105 °C for 17 h. Then, excess dioxane was pumped off and purify the crude product by flash chromatography on silica gel using EtOAc/CH2Cl2. After purification 0.298–0.414 g of 100 was isolated as a light pink solid in 18–34% yield. 1H NMR (500 MHz, CDCl3) δ 9.01 (d, J = 1.5 Hz, 2H), 8.42 (d, J = 7.9 Hz, 2H), 8.19 (d, J = 7.8 Hz, 2H), 1.37 (s, 24H). 11B NMR (160 MHz, CDCl3) ! 30.0 (brs). 13C NMR (126 MHz, CDCl3) δ 157.9, 155.1, 143.3, 120.6, 84.2, 24.9. MS EI+ m/z calculated for (M+H)+ C22H31B2N2O4 409.2469, found 409.2542. 219 Compound 102 28 I Br Br A solution of 2,6-dibromo-4-methylaniline (7.0 g, 26.4 mmol) in CH3COOH (80 mL) 102 was added dropwise into a solution of NaNO2 (2.0 g, 28.8 mmol) in conc. H2SO4 (16 mL) keeping the temperature of the solution below 20 °C using an ice bath. The mixture was stirred for 4 h at rt. After addition of a solution of KI (31.8 g, 192 mmol) and I2 (6.6 g, 26 mmol) in H2O (60 mL), the resulting mixture was stirred for 12 h at rt. 15% NaOH aq (1200 mL) was added. The resulting material was extracted with EtOAc (150 mL x 3). The combined organic phase was washed with H2O (150 mL x 2) and brine (150 mL) and dried over Na2SO4. The solvents were evaporated and recrystallization/sublimation gave 5.620 g of 102 as a white solid (mp 66–67 °C, lit 52–54 °C29) in 57% yield.1H NMR (500 MHz, CDCl3) δ 7.39 (d, J = 0.7 Hz, 2H), 2.26 (d, J = 0.8 Hz, 3H). 13C NMR (126 MHz, CDCl3) δ 141.0, 131.9, 130.8, 104.9, 20.4. The spectral data were in accordance with those reported in the literature.28 MS EI+ m/z calculated for (M+NH4)+ C7H9NBr2I 391.8146, found 391.8290. Compound 103 26 I 103 CCDC 1850721 220 To a suspension of 2.00 g (5.30 mmol) of 2,6-dibromo-4-methyliodobenzene 12 ml of THF (purge 1 hr with Ar), 32 ml (15.9 mmol, 3.0 equiv) of 0.5 M (3,5- dimethylphenyl)magnesium bromide (Aldrich) was added drop-wise and stirred for 4 h at room temperature. Iodine (2.600 g, 10.60 mmol) was added to the reaction mixture and stirred overnight. A solution of ca. 30 ml of 1 N Na2SO3 was added to the reaction mixture and the slurry was extracted with ether. The organic layer was sequentially washed with water and aqueous saturated NaCl and dried over anhydrous MgSO4. After purification by column chromatography 0.922 g of 103 was isolated as a white solid (mp 111–113 °C) in 41% yield. 1H NMR (500 MHz, CDCl3) δ 7.06 (dd, J = 0.7, 0.7 Hz, 2H), 7.04 – 7.01 (m, 2H), 6.98 (dd, J = 1.4, 0.8 Hz, 4H), 2.37 (s, 12H), 2.34 (s, 3H). 13C NMR (126 MHz, CDCl3) δ 147.9, 145.6, 137.3, 137.2, 129.4, 128.9, 127.2, 99.5, 21.4, 20.7. MS EI+ m/z calculated for (M+H)+ C23H24I 427.0923, found 427.0996. Compound L2 N N L2 100 (0.163 g, 0.4 mmol) and 103 (0.366 g, 0.86 mmol, 2.1 equiv) were added to a schlenk flask equipped with a magnetic stirring bar, a septum inlet, and a condenser. The flask was under vacuum for 1 h. Then K2CO3 (2.378 g, 17.2 mmol), 20 mL of dioxane and water (460 µL) were added and performed freeze-pump thaw for 2 times. Finally, introduced Pd(PPh3)4 (0.086 mmol, 10.0 mol%) under argon and 3 more freeze-pump 221 thaws were performed. Reaction mixture was reflux at 102 °C for 48 h. Then, excess dioxane was pumped off and purify the crude product by flash chromatography on silica gel using EtOAc/CH2Cl2. After purification 0.019 g of L2 was isolated as a off-white solid in 6% yield. 1H NMR (500 MHz, CDCl3) δ 8.05 (s, 2H), 7.88 (d, J = 8.3 Hz, 2H), 7.25 (d, J = 0.8 Hz, 4H), 7.23 – 7.19 (m, 2H), 6.77 (s, 4H), 6.67 (s, 8H), 2.46 (s, 6H), 2.13 (s, 24H). 13C NMR (126 MHz, CDCl3) δ 151.3, 149.0, 142.4, 141.2, 137.6, 137.2, 130.3, 128.2, 127.9, 123.4, 120.9, 119.4, 34.7, 21.2, 21.2. MS EI+ m/z calculated for (M+H)+ C56H53N2 753.4209, found 753.4357. CHBs of tert-butylbenzene (104) 104 1 mol % [Ir(OMe)COD]2 2 mol % ligand 1.6 equiv HBpin THF 80 ° C, 24 h + + Bpin 105 106 Bpin pinB Bpin 107 In a nitrogen atmosphere glove box, [Ir(OMe)COD]2 (6.6 mg, 0.001 mmol, 1.0 mol %) was weighed into a 10 mL pressure tube containing a magnetic stir bar. Add HBpin (250 µL) and 0.5 mL of THF and stir until clear orange/yellow color solution was observed. Next, L2 ligand (15 mg, 0.020 mmol, 2.0 mol %) was weighed into a test tube. Transfer the ligand into the tube and use 0.5 mL THF to wash and transfer remaining ligand in the test tube. Finally, the substrate (1.0 mmol) was added to the tube with 1 mL of THF, which was then sealed and was taken out of the glove box. The reaction mixture was stirred for 24 h at 80 °C. After 24 h crude reaction was sampled using NMR. 222 Bpin 105 Figure 55. Crude 1H NMR of the CHBs with 104 223 REFERENCES 224 REFERENCES (1) Boebel, T. A.; Hartwig, J. F. Silyl-Directed, Iridium-Catalyzed Ortho-Borylation of Arenes. 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Chem. 2006, 691, 2546– 2553. 228 APPENDICES 229 APPENDIX A Crystal Structures 230 Compound 67c 67c (CCDC Compound 1851790) C19H28B2ClFO5 Formula 1.258 Dcalc./ g cm-3 1.849 µ/mm-1 412.48 Formula Weight colourless Colour chunk Shape 0.26×0.20×0.17 Size/mm3 173(2) T/K monoclinic Crystal System P21/c Space Group 12.39890(10) a/Å 10.69680(10) b/Å 17.1694(2) c/Å 90 a/° 106.9840(10) b/° 90 g/° 2177.84(4) V/Å3 4 Z 1 Z' 1.541838 Wavelength/Å Radiation type CuKa 3.727 Qmin/° 72.029 Qmax/° 24237 Measured Refl. Independent Refl. 4268 Reflections Used 3577 Rint 0.0412 Parameters 262 0 Restraints Largest Peak 0.325 Deepest Hole -0.255 GooF 1.043 0.1085 wR2 (all data) wR2 0.1029 R1 (all data) 0.0495 R1 0.0400 231 Ueq 44.35(15) 39.1(3) 39.2(3) 36.4(3) 36.3(3) 30.3(3) 34.3(3) 29.2(3) 27.8(3) 26.5(3) 24.5(3) 25.7(3) 29.0(3) 65.6(7) 33.5(4) 37.0(4) 54.1(6) 60.1(6) 73.1(8) 72.0(8) 29.6(4) 31.7(4) 36.4(4) 46.8(5) 38.3(4) 48.1(5) 26.2(4) 27.8(4) y 7340.9(4) 3830.8(10) 5881.8(12) 2592.8(10) 1453.9(10) 3000.1(10) 4655.0(11) 6004.9(14) 5458.6(14) 4382.8(14) 3842.2(13) 4436.3(14) 5507.5(15) 6719(3) 1303.7(15) 534.8(15) 1013(2) 1258(2) 83(2) -532(2) 3099.8(15) 3897.4(15) 1796.1(16) 3756(2) 3129.5(18) 4766.3(18) 2599.2(16) 4006.2(16) x 9069.6(4) 6250.1(9) 7267.4(11) 5644.2(10) 7160.2(10) 8095.6(10) 9313.3(11) 8398.6(14) 7555.4(14) 7059.7(13) 7337.0(13) 8191.7(13) 8711.0(14) 6369(2) 5392.6(14) 6280.4(15) 4177.1(16) 5543(2) 5856(2) 6799(2) 8459.5(14) 9554.4(15) 8631.7(15) 7514.7(17) 10600.3(15) 9782(2) 6711.2(15) 8546.4(16) Table 26. Fractional Atomic Coordinates (×104) and Equivalent Isotropic Displacement Parameters (Å2×103) for 67c. Atom z Cl1 5235.5(3) F1 4875.5(6) O1 5679.2(7) O2 3056.9(8) O3 3774.9(8) O4 2475.1(7) O5 2678.8(7) C1 4751(1) C2 5014.3(9) C3 4602.5(9) C4 3960.5(9) C5 3703.9(9) C6 4108(1) C7 5513.3(15) C8 2769.7(11) C9 3419.7(11) C10 2719.3(16) C11 1927.8(13) C12 4116.6(15) C13 3071.8(19) C14 1736.2(9) C15 2036.9(10) C16 1451.1(11) C17 1101.3(12) C18 2446.8(11) C19 1402.9(13) B1 3575.7(11) B2 2945.0(11) Table 27. Anisotropic Displacement Parameters (×104) 67c. Atom Cl1 F1 O1 O2 O3 O4 O5 C1 C2 C3 C4 C5 C6 C7 C8 C9 C10 C11 C12 U23 -16.51(18) -3.5(4) -6.1(5) -5.9(5) -0.9(5) -7.2(4) -8.9(5) -3.6(6) -0.7(6) 2.8(6) 0.8(5) -1.1(6) -1.9(6) -4.1(12) -9.0(7) -3.6(7) -16.7(10) -12.1(10) 12.8(11) U13 15.5(2) 19.7(5) 14.6(6) -3.0(5) -2.6(5) 10.4(5) 22.7(6) 4.2(7) 6.2(6) 6.8(6) 1.7(6) 5.9(6) 9.7(7) 32.1(12) 3.8(7) 1.2(8) 5.1(10) 9.0(11) 0.9(13) U12 -16.29(19) -10.7(4) 3.7(6) -2.9(4) -5.0(5) -5.3(5) -8.0(5) -3.2(6) 3.3(6) -0.8(6) 0.3(6) -0.7(6) -6.5(6) 25.3(13) -5.9(6) -7.8(7) -9.4(8) -20.3(12) -46.5(14) U11 59.0(3) 39.9(6) 53.4(8) 30.9(6) 31.1(6) 35.4(6) 48.5(7) 36.6(9) 34.5(8) 26.8(8) 26.8(7) 29.4(8) 33.9(8) 68.4(15) 32.5(9) 35.9(9) 31.8(10) 79.3(16) 91.2(19) U22 30.4(2) 40.5(6) 37.7(7) 22.3(6) 21.3(5) 27.4(6) 24.3(6) 20.1(7) 24.5(7) 25.7(7) 19.9(7) 21.5(7) 24.2(8) 80.9(17) 23.5(8) 21.8(8) 37.9(10) 56.1(13) 64.1(15) U33 44.0(3) 41.9(6) 28.2(6) 46.8(7) 47.6(7) 28.8(6) 36.7(6) 27.6(8) 22.9(7) 26.5(8) 23.2(7) 25.0(7) 29.2(8) 56.5(14) 40.2(9) 46.4(10) 85.0(16) 39.6(11) 51.2(13) 232 U23 -26.0(12) -2.3(6) -3.3(6) -12.1(7) -0.8(8) -7.0(8) 3.9(8) -1.4(7) U13 -5.3(13) 8.8(7) 16.5(7) 7.7(8) 4.8(8) 9.6(8) 34.2(11) 7.0(7) U12 8.3(9) 5.5(7) -0.2(7) 1.5(7) 19.9(9) -3.2(7) 0.5(9) -2.8(7) Table 27 (cont’d) Atom C13 C14 C15 C16 C17 C18 C19 B1 U11 50.9(13) 35.9(9) 44.2(10) 38.3(9) 48.1(11) 34.5(9) 73.8(14) 27.2(9) U22 34.8(11) 29.0(8) 24.0(8) 32.2(9) 52.9(12) 40.1(10) 34.4(10) 24.1(8) U33 112(2) 24.0(8) 30.5(8) 36.6(9) 34.7(10) 39.7(10) 46.8(11) 26.8(8) Table 28. Bond Lengths in Å for 67c. Length/Å Atom 1.7384(15) Cl1 1.3604(18) F1 O1 1.3690(19) 1.392(3) O1 1.4669(18) O2 1.362(2) O2 O3 1.4628(19) 1.348(2) O3 1.469(2) O4 1.363(2) O4 1.4674(19) O5 O5 1.360(2) 1.384(2) C1 1.379(2) C1 1.396(2) C2 C3 1.374(2) 1.412(2) C4 1.583(2) C4 1.396(2) C5 C5 1.561(2) 1.554(2) C8 1.516(3) C8 1.511(3) C8 1.520(3) C9 C9 1.516(3) 1.558(2) C14 1.514(2) C14 1.519(2) C14 C15 1.523(2) 1.519(2) C15 Atom C1 C3 C2 C7 C8 B1 C9 B1 C14 B2 C15 B2 C2 C6 C3 C4 C5 B1 C6 B2 C9 C10 C11 C12 C13 C15 C16 C17 C18 C19 233 Table 29. Bond Angles in ° for 67c. Atom C2 B1 B1 B2 B2 C2 C6 C6 O1 O1 C1 F1 F1 C4 C3 C3 C5 C4 C6 C6 C1 O2 O2 O2 C10 C11 C11 O3 O3 O3 C12 C13 C13 O4 O4 O4 C16 C16 C17 O5 O5 O5 C18 C19 C19 O2 O3 O3 O4 O5 O5 Atom O1 O2 O3 O4 O5 C1 C1 C1 C2 C2 C2 C3 C3 C3 C4 C4 C4 C5 C5 C5 C6 C8 C8 C8 C8 C8 C8 C9 C9 C9 C9 C9 C9 C14 C14 C14 C14 C14 C14 C15 C15 C15 C15 C15 C15 B1 B1 B1 B2 B2 B2 Atom C7 C8 C9 C14 C15 Cl1 Cl1 C2 C1 C3 C3 C2 C4 C2 C5 B1 B1 B2 C4 B2 C5 C9 C10 C11 C9 C9 C10 C8 C12 C13 C8 C8 C12 C15 C16 C17 C15 C17 C15 C14 C18 C19 C14 C14 C18 C4 O2 C4 C5 O4 C5 Angle/° 115.48(15) 107.16(12) 107.62(13) 106.11(13) 106.65(12) 119.50(12) 119.55(13) 120.95(14) 122.60(14) 120.76(15) 116.47(14) 116.33(14) 118.44(13) 125.22(15) 116.57(14) 118.75(14) 124.66(14) 123.22(14) 119.58(14) 117.08(14) 121.20(15) 102.69(12) 108.81(14) 106.16(15) 114.58(16) 114.23(17) 109.68(17) 103.24(12) 105.84(15) 108.66(16) 113.45(18) 114.11(17) 110.8(2) 102.19(12) 108.68(14) 106.63(14) 114.85(14) 110.21(14) 113.56(15) 101.67(13) 106.47(13) 108.75(13) 113.56(14) 115.06(15) 110.50(16) 122.76(14) 114.31(14) 122.80(14) 124.05(15) 114.21(15) 121.69(14) 234 Table 30. Hydrogen Fractional Atomic Coordinates (×104) and Equivalent Isotropic Displacement Parameters (Å2×103) for 67c. Atom H6 H7A H7B H7C H10A H10B H10C H11A H11B H11C H12A H12B H12C H13A H13B H13C H16A H16B H16C H17A H17B H17C H18A H18B H18C H19A H19B H19C x 9290 5731 6600 6143 4043 4029 3673 5035 5366 6325 6491 5301 5503 7208 6202 7323 9199 8889 7918 6809 7696 7429 11206 10845 10423 9142 9883 10467 Ueq 35 98 98 98 81 81 81 90 90 90 110 110 110 108 108 108 55 55 55 70 70 70 57 57 57 72 72 72 y 5901 6374 7515 6856 1213 123 1514 1864 417 1465 -238 -584 781 -197 -1095 -995 1358 1850 1336 3295 3786 4608 3687 2677 2530 5336 4272 5251 z 3937 5086 5329 6008 3240 2599 2286 1575 1701 1961 4556 3922 4321 2708 2765 3517 1883 964 1321 1028 583 1284 2749 2032 2824 1201 949 1650 235 Compound 68c 68c (CCDC 1838224) Compound C19H27B2F3O4 Formula 1.245 Dcalc./ g cm-3 0.851 µ/mm-1 398.02 Formula Weight colourless Colour chunk Shape 0.18×0.14×0.07 Size/mm3 173(2) T/K orthorhombic Crystal System -1.3(5) Flack Parameter -0.9(4) Hooft Parameter P212121 Space Group 10.5055(7) a/Å 11.7536(8) b/Å 17.1954(11) c/Å 90 a/° 90 b/° 90 g/° 2123.2(2) V/Å3 4 Z 1 Z' 1.541838 Wavelength/Å Radiation type CuKa 4.557 Qmin/° 71.472 Qmax/° 8302 Measured Refl. Independent Refl. 3858 Reflections Used 2108 Rint 0.0979 Parameters 261 0 Restraints Largest Peak 0.425 Deepest Hole -0.265 GooF 0.973 0.2515 wR2 (all data) wR2 0.2107 R1 (all data) 0.1427 R1 0.0880 236 Table 31. Fractional Atomic Coordinates (×104) and Equivalent Isotropic Displacement Parameters (Å2×103) for 68c. Atom F1 F2 F3 O1 O2 O3 O4 C1 C2 C3 C4 C5 C6 C7 C8 C9 C10 C11 C12 C13 C14 C15 C16 C17 C18 C19 B1 B2 x 2838(7) 2605(6) 3707(6) 4187(5) 6235(5) 8408(5) 8878(5) 4596(8) 4456(8) 5508(7) 6729(8) 6842(8) 5808(8) 3470(9) 4335(9) 5770(9) 3714(11) 3639(15) 6314(10) 6330(14) 9779(7) 9917(7) 10089(11) 10449(10) 9675(9) 11160(8) 5305(8) 7991(9) y 4246(6) 3404(7) 2681(5) 6834(5) 7410(5) 5533(5) 6400(5) 4224(6) 5080(6) 5659(6) 5352(6) 4511(7) 3944(7) 3630(7) 7912(7) 8085(8) 8819(9) 7854(11) 9224(9) 7510(11) 5791(8) 6682(8) 6163(10) 4663(8) 7898(7) 6637(9) 6641(7) 5813(7) Ueq 104(3) 104(3) 93(2) 48.9(14) 48.0(14) 49.7(14) 48.7(14) 42.4(19) 39.4(17) 39.1(17) 41.0(18) 45.9(19) 45.4(19) 51(2) 54(2) 61(3) 91(4) 114(6) 84(4) 94(4) 52(2) 48(2) 72(3) 69(3) 58(2) 61(3) 37.9(19) 42(2) z 5874(5) 4814(4) 5726(5) 3218(4) 3425(4) 3373(3) 4534(3) 5040(5) 4484(5) 4187(5) 4454(5) 5023(5) 5317(5) 5353(5) 2795(6) 2784(6) 3351(8) 2069(8) 2813(8) 2050(6) 3343(6) 3987(5) 2540(6) 3546(7) 3714(6) 4429(6) 3597(5) 4097(6) Table 32. Anisotropic Displacement Parameters (×104) 68c. Atom F1 F2 F3 O1 O2 O3 O4 C1 C2 C3 C4 C5 C6 C7 C8 C9 C10 C11 U11 104(5) 89(4) 82(4) 51(3) 43(3) 54(3) 47(3) 55(5) 45(4) 49(4) 51(4) 46(4) 53(5) 57(5) 61(5) 60(5) 93(8) 152(13) U33 119(6) 81(5) 132(6) 54(3) 55(4) 44(3) 49(3) 45(4) 42(4) 40(4) 39(4) 49(5) 43(5) 49(5) 54(5) 61(6) 118(11) 105(10) U22 91(5) 141(7) 65(4) 41(3) 46(3) 51(3) 50(3) 28(3) 32(3) 28(3) 33(4) 43(4) 40(4) 47(5) 47(5) 63(5) 62(6) 85(8) U23 -23(5) 25(5) 50(4) 13(3) 16(3) -10(3) -12(3) 2(3) -6(3) -2(3) -1(3) 2(4) 10(4) 9(4) 21(4) 31(5) 15(7) 59(8) 237 U13 71(5) -15(4) 17(4) -10(3) 0(3) 10(3) 7(3) 18(4) 5(4) 4(4) 3(4) 8(4) 8(4) 5(4) -12(5) -9(5) 34(8) -79(10) U12 -17(4) -67(5) -8(3) -16(2) -8(2) -9(3) 1(3) -2(3) -3(3) -7(3) 3(3) 4(4) 6(3) -9(4) -14(4) -17(4) 21(6) -59(8) U23 46(7) 26(6) -13(4) -2(4) -9(5) -10(6) 1(5) -9(5) -2(4) 3(4) U13 -27(7) 25(8) 16(4) 13(4) 27(5) 10(6) 6(5) -1(5) -6(4) 5(4) U12 -25(5) 22(8) -9(4) -4(4) -23(6) 9(5) -2(4) -3(4) -3(3) 6(4) Table 32 (cont’d) Atom C12 C13 C14 C15 C16 C17 C18 C19 B1 B2 U11 67(6) 146(12) 43(4) 39(4) 83(7) 63(6) 61(5) 47(5) 41(4) 49(5) U22 61(6) 83(8) 56(5) 52(5) 82(7) 62(6) 45(5) 71(6) 33(4) 31(4) U33 125(11) 52(6) 58(5) 52(5) 51(6) 83(8) 68(6) 66(6) 39(5) 45(5) Table 33. Bond Lengths in Å for 68c. Length/Å Atom 1.330(10) F1 F2 1.325(10) 1.310(10) F3 1.468(9) O1 1.362(10) O1 O2 1.443(10) 1.363(10) O2 1.473(9) O3 1.359(11) O3 O4 1.478(10) 1.382(11) O4 1.395(11) C1 1.399(11) C1 1.476(11) C1 C2 1.395(10) 1.410(11) C3 1.552(11) C3 1.396(11) C4 C4 1.559(12) 1.371(11) C5 1.522(13) C8 1.573(15) C8 C8 1.448(13) 1.456(13) C9 1.549(15) C9 1.532(12) C14 1.485(13) C14 C14 1.541(13) 1.525(12) C15 C15 1.512(12) Atom C7 C7 C7 C8 B1 C9 B1 C14 B2 C15 B2 C2 C6 C7 C3 C4 B1 C5 B2 C6 C9 C10 C11 C12 C13 C15 C16 C17 C18 C19 238 Table 34. Bond Angles in ° for 68c Atom O1 O2 O3 O4 C1 C1 C1 C2 C3 C3 C3 C4 C4 C4 C5 C6 C7 C7 C7 C7 C7 C7 C8 C8 C8 C8 C8 C8 C9 C9 C9 C9 C9 C9 C14 C14 C14 C14 C14 C14 C15 C15 C15 C15 C15 C15 B1 B1 B1 B2 B2 B2 Atom C8 C9 C14 C15 C6 C7 C7 C1 C4 B1 B1 B2 C3 B2 C4 C1 C1 F1 C1 F1 F2 C1 C9 C10 C10 O1 C9 C10 C8 C12 C13 C13 C8 C13 C15 C16 C17 C17 C15 C17 C14 C18 C19 C14 C14 C18 O2 C3 C3 O4 C4 C4 Angle/° 106.8(6) 106.7(6) 107.3(7) 105.3(6) 119.9(7) 120.5(8) 119.6(7) 121.3(8) 118.5(7) 119.6(7) 121.9(7) 123.8(7) 119.2(7) 116.7(7) 122.3(8) 118.8(7) 112.8(7) 103.7(8) 112.9(8) 103.3(8) 107.6(8) 115.4(8) 103.1(7) 103.9(7) 109.2(9) 109.4(7) 119.7(10) 110.3(10) 104.6(7) 110.3(8) 104.7(8) 109.2(9) 120.7(9) 106.2(10) 102.0(6) 107.9(8) 105.2(7) 112.5(8) 116.7(8) 111.3(9) 103.7(6) 106.5(7) 108.1(7) 113.7(8) 114.9(7) 109.4(8) 113.8(7) 123.7(7) 122.4(7) 113.7(7) 123.5(8) 122.2(8) Atom B1 B1 B2 B2 C2 C2 C6 C3 C2 C2 C4 C3 C5 C5 C6 C5 F1 F2 F2 F3 F3 F3 O1 O1 C9 C11 C11 C11 O2 O2 O2 C8 C12 C12 O3 O3 O3 C15 C16 C16 O4 O4 O4 C18 C19 C19 O1 O1 O2 O3 O3 O4 239 Table 35. Hydrogen Fractional Atomic Coordinates (×104) and Equivalent Isotropic Displacement Parameters (Å2×103) for 68c. Atom H2 H5 H6 H10A H10B H10C H11A H11B H11C H12A H12B H12C H13A H13B H13C H16A H16B H16C H17A H17B H17C H18A H18B H18C H19A H19B H19C x 3628 7665 5913 2909 3550 4294 3921 3801 2726 6014 6049 7245 7257 6121 5967 9901 10995 9577 10225 11373 10175 8908 10406 9555 11144 11865 11278 Ueq 47 55 55 137 137 137 171 171 171 127 127 127 141 141 141 108 108 108 104 104 104 87 87 87 92 92 92 y 5272 4324 3373 8521 9521 8980 7187 8544 7790 9615 9652 9171 7452 7966 6746 5546 6357 6832 4438 4763 4070 7917 8165 8394 7197 6811 5874 z 4305 5213 5702 3556 3061 3783 1773 1765 2178 3282 2352 2825 2102 1590 1993 2175 2509 2407 4078 3508 3182 3389 3410 4166 4851 4074 4647 240 Compound 68* Compound 68*(CCDC 1838225) 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 a/° b/° g/° V/Å3 Z Z' Wavelength/Å Radiation type Qmin/° Qmax/° Measured Refl. Independent Refl. Reflections Used Rint Parameters Restraints Largest Peak Deepest Hole GooF wR2 (all data) wR2 R1 (all data) R1 C25H38B3F3O6 1.214 0.798 523.98 colourless block 0.45×0.35×0.18 173(2) orthorhombic 0.1(4) 0.13(5) P212121 11.6356(2) 12.0322(3) 20.4719(4) 90 90 90 2866.10(10) 4 1 1.541838 CuKa 4.262 72.173 18600 5516 5174 0.0305 376 0 0.834 -0.577 1.064 0.2069 0.2026 0.0879 0.0834 241 Table 36. Fractional Atomic Coordinates (×104) and Equivalent Isotropic Displacement Parameters (Å2×103) for 68*. Atom F1 F2 F3 O1 O2 O3 O4 O5 O5A O6 O6A C1 C2 C3 C4 C5 C6 C7 C8 C9 C10 C11 C12 C13 C14 C15 C16 C17 C18 C19 C20 C20A C21 C21A C22 C22A C23 C23A C24 C24A C25 C25A B1 B2 B3 y 6410(6) 7481(4) 7365(5) 4297(5) 3361(5) 2079(3) 3303(3) 3117(7) 3482(10) 4886(7) 4715(9) 5860(4) 5355(4) 4506(4) 4115(3) 4618(4) 5493(4) 6773(6) 3557(8) 3358(7) 4192(6) 2427(6) 4431(6) 2272(5) 1384(4) 2256(4) 625(5) 693(5) 2336(8) 2167(8) 3059(10) 3533(12) 4239(12) 4000(10) 2412(12) 2099(11) 2736(17) 4517(14) 4173(14) 3130(11) 4720(30) 4657(17) 4039(4) 3136(4) 4225(5) x 8733(8) 8572(6) 7296(6) 9454(4) 7999(4) 6166(4) 5163(4) 4338(8) 4012(8) 3820(8) 4207(9) 7477(5) 8080(4) 7602(4) 6487(4) 5879(4) 6382(5) 8025(7) 9922(7) 8911(6) 10921(6) 10313(6) 8756(8) 8834(5) 5495(4) 4882(4) 6315(5) 4694(6) 5339(7) 3586(6) 3285(10) 2880(10) 2805(9) 3197(10) 2350(12) 2552(15) 3718(18) 2067(16) 2167(16) 3646(15) 2120(20) 2329(12) 8347(4) 5924(4) 4655(5) z 4807(4) 5596(2) 4898(3) 7132(3) 7530(2) 6639(2) 7215(2) 5597(5) 5858(5) 5365(5) 5020(5) 5624(2) 6124(2) 6495(2) 6338(2) 5822(2) 5477(2) 5247(3) 7637(4) 8034(4) 7950(4) 7320(3) 8517(3) 8404(3) 7084(3) 7532(3) 7436(5) 6667(3) 8218(3) 7550(5) 5191(6) 5531(6) 5254(7) 4880(6) 5544(11) 5413(8) 4530(8) 5849(9) 5955(9) 4371(8) 4718(9) 4508(6) 7072(3) 6746(2) 5589(3) Ueq 196(4) 140(3) 133(3) 103(2) 79.7(16) 78.7(16) 68.6(13) 49(2) 55(2) 52(2) 60(2) 45.3(12) 40.1(11) 33.1(9) 30.1(9) 34.9(9) 44.4(11) 73(2) 97(3) 85(3) 78(2) 67.5(15) 80(2) 61.2(16) 46.4(12) 44.3(12) 81(2) 66.5(15) 83(2) 89(2) 50.4(18) 54(3) 51(3) 50.4(18) 81(2) 66.5(15) 83(2) 67.5(15) 67.5(15) 66.5(15) 83(2) 65(5) 34.6(10) 29.9(9) 39.8(12) 242 Table 37. Anisotropic Displacement Parameters (×104) 68*. Atom F1 F2 F3 O1 O2 O3 O4 O5 O5A O6 O6A C1 C2 C3 C4 C5 C6 C7 C8 C9 C10 C11 C12 C13 C14 C15 C16 C17 C18 C19 C20 C20A C21 C21A C22 C22A C23 C23A C24 C24A C25 C25A B1 B2 B3 U22 123(5) 118(4) 113(4) 127(5) 103(4) 27.3(17) 30.7(18) 40(5) 77(7) 37(4) 66(6) 42(3) 43(3) 31(2) 30(2) 31(2) 41(2) 80(4) 111(6) 103(5) 89(5) 69(4) 90(5) 72(4) 28(2) 35(2) 44(3) 51(3) 103(5) 106(6) 58(5) 68(8) 65(8) 58(5) 44(3) 51(3) 103(5) 69(4) 69(4) 51(3) 103(5) 85(10) 35(2) 29(2) 38(3) U11 262(10) 201(6) 161(5) 59(3) 56(2) 98(3) 96(3) 45(5) 41(5) 51(5) 57(6) 62(3) 45(3) 36(2) 30(2) 38(2) 56(3) 97(5) 71(5) 70(4) 57(4) 53(3) 108(6) 50(3) 36(2) 43(3) 43(3) 72(4) 89(4) 47(4) 44(4) 38(6) 34(5) 44(4) 43(3) 72(4) 89(4) 53(3) 53(3) 72(4) 89(4) 51(8) 34(2) 23(2) 43(3) U33 203(7) 102(3) 126(4) 123(4) 80(3) 111(4) 79(3) 62(6) 48(5) 68(6) 56(5) 32(2) 33(2) 32(2) 31(2) 36(2) 36(2) 43(3) 109(6) 83(5) 89(5) 81(4) 43(3) 61(3) 75(3) 55(3) 155(7) 77(4) 57(3) 114(6) 49(5) 55(7) 55(7) 49(5) 155(7) 77(4) 57(3) 81(4) 81(4) 77(4) 57(3) 59(9) 35(2) 38(2) 38(3) U23 48(5) 65(3) 84(4) 86(4) 56(3) -2.7(19) 10.6(18) 3(4) 20(5) -2(4) 17(5) 2.2(19) -0.8(19) -3.9(17) -6.6(16) -4.6(17) 5(2) 27(3) 62(5) 47(4) 26(4) -11(3) -2(3) 27(3) 7(2) 14(2) 4(4) -2(3) -8(3) 14(5) -8(4) 3(7) -21(6) -8(4) 4(4) -2(3) -8(3) -11(3) -11(3) -2(3) -8(3) 16(9) -2(2) -0.1(19) -3(2) U13 163(7) -81(4) -79(4) -51(3) -35(2) 72(3) 53(3) -18(4) -9(4) -21(4) -23(4) -7(2) -6.3(19) -0.8(17) 2.1(16) -4.5(18) -14(2) -23(3) -45(5) -38(4) -39(4) -6(3) -2(3) -21(3) 15(2) 12(2) -23(4) -11(3) 6(3) 29(4) -19(4) -8(5) -18(5) -19(4) -23(4) -11(3) 6(3) -6(3) -6(3) -11(3) 6(3) -40(7) 3(2) -0.2(19) -8(2) U12 -30(6) -122(4) -75(4) -53(3) -39(2) -2(2) 7(2) -12(4) -22(5) -1(3) -27(5) -22(2) -17(2) -7.2(18) -1.2(17) -2.8(18) -14(2) -48(4) -47(5) -32(4) -22(4) 16(3) 40(5) -8(3) -2.3(19) -3(2) -1(2) -12(3) -12(4) 14(4) -9(4) -16(5) 1(5) -9(4) -1(2) -12(3) -12(4) 16(3) 16(3) -12(3) -12(4) -14(8) -5(2) -2.5(18) -2(2) 243 Table 38. Bond Lengths in Å for 68*. Length/Å 1.297(10) 1.282(7) 1.318(9) 1.469(8) 1.331(7) 1.479(7) 1.307(6) 1.462(6) 1.320(6) 1.454(6) 1.322(6) 1.482(13) 1.384(11) 1.479(15) 1.290(11) 1.433(14) 1.336(10) 1.484(13) 1.406(10) 1.382(7) 1.382(7) 1.486(7) 1.389(6) 1.417(6) 1.570(7) 1.408(6) 1.586(6) 1.396(7) 1.575(7) 1.449(12) 1.531(9) 1.575(13) 1.636(12) 1.514(9) 1.565(7) 1.504(8) 1.513(8) 1.505(9) 1.512(8) 1.531(18) 1.52(2) 1.50(2) 1.494(18) 1.784(19) 1.65(2) 1.62(2) 1.47(3) 1.57(2) 1.490(19) Atom C7 C7 C7 C8 B1 C9 B1 C14 B2 C15 B2 C20 B3 C20A B3 C21 B3 C21A B3 C2 C6 C7 C3 C4 B1 C5 B2 C6 B3 C9 C10 C11 C12 C13 C15 C16 C17 C18 C19 C21 C22 C23 C21A C22A C23A C24 C25 C24A C25A Atom F1 F2 F3 O1 O1 O2 O2 O3 O3 O4 O4 O5 O5 O5A O5A O6 O6 O6A O6A C1 C1 C1 C2 C3 C3 C4 C4 C5 C5 C8 C8 C8 C9 C9 C14 C14 C14 C15 C15 C20 C20 C20 C20A C20A C20A C21 C21 C21A C21A 244 Table 39. Bond Angles in ° for 68*. Atom O1 O2 O3 O4 O5 O5A O6 O6A C1 C1 C1 C2 C3 C3 C3 C4 C4 C4 C5 C5 C5 C6 C7 C7 C7 C7 C7 C7 C8 C8 C8 C8 C8 C8 C9 C9 C9 C9 C9 C9 C14 C14 C14 C14 C14 C14 C15 C15 C15 C15 C15 C15 Atom C8 C9 C14 C15 C20 C20A C21 C21A C7 C2 C7 C3 C4 B1 B1 B2 C3 B2 B3 C4 B3 C5 F3 C1 F1 F3 C1 C1 C10 C11 O1 C10 C11 C11 C12 C13 O2 C12 C13 C12 C15 C16 C17 C15 C17 C15 C14 C18 C19 C14 C19 C14 Angle/° 106.4(5) 106.2(4) 109.5(4) 110.0(4) 105.0(8) 107.1(8) 109.3(8) 102.2(8) 119.5(5) 119.3(4) 121.2(5) 121.6(4) 119.1(4) 117.0(4) 123.9(4) 120.4(4) 119.2(4) 120.5(4) 123.5(4) 119.6(4) 116.9(4) 121.1(4) 102.4(7) 112.6(7) 107.2(8) 105.3(7) 114.5(5) 113.9(6) 105.9(6) 109.9(7) 101.2(6) 117.7(8) 108.8(7) 112.6(7) 109.9(6) 108.0(5) 101.1(6) 107.3(7) 118.1(8) 111.9(6) 102.9(4) 107.9(5) 107.0(5) 114.6(6) 109.1(5) 114.8(5) 102.6(4) 106.3(5) 107.2(5) 115.4(5) 109.5(6) 114.9(5) Atom B1 B1 B2 B2 B3 B3 B3 B3 C2 C6 C6 C1 C2 C2 C4 C3 C5 C5 C4 C6 C6 C1 F1 F1 F2 F2 F2 F3 O1 O1 C9 C9 C9 C10 O2 O2 C8 C8 C8 C13 O3 O3 O3 C16 C16 C17 O4 O4 O4 C18 C18 C19 245 Table 39 (cont’d) Atom O5 O5 O5 C22 C23 C23 O5A O5A O5A C21A C21A C23A O6 O6 O6 C20 C25 C25 O6A O6A O6A C20A C25A C25A O1 O2 O2 O3 O3 O4 O5 O5A O5A O6 O6 O6A Atom C20 C20 C20 C20 C20 C20 C20A C20A C20A C20A C20A C20A C21 C21 C21 C21 C21 C21 C21A C21A C21A C21A C21A C21A B1 B1 B1 B2 B2 B2 B3 B3 B3 B3 B3 B3 Atom C21 C22 C23 C21 C21 C22 C21A C22A C23A C22A C23A C22A C20 C24 C25 C24 C20 C24 C20A C24A C25A C24A C20A C24A C3 O1 C3 O4 C4 C4 C5 O6A C5 O5 C5 C5 Angle/° 102.2(8) 110.5(11) 104.0(12) 100.0(11) 116.1(13) 122.5(13) 101.5(9) 102.2(11) 111.2(11) 107.2(11) 103.0(12) 128.7(12) 102.5(8) 105.4(11) 110.6(16) 101.3(12) 119.8(14) 115.6(12) 103.9(9) 104.6(11) 109.1(11) 115.1(11) 119.2(12) 104.0(11) 121.4(4) 112.3(5) 126.3(4) 114.2(4) 122.7(4) 123.1(4) 121.8(6) 115.5(7) 127.1(6) 112.6(7) 125.7(6) 117.4(5) Table 40. Hydrogen Fractional Atomic Coordinates (×104) and Equivalent Isotropic Displacement Parameters (Å2×103) for 68*. Atom H2 H6 H10A H10B H10C H11A H11B H11C H12A H12B x 8842 5964 11545 11200 10657 9634 10801 10746 8879 9318 Ueq 48 53 117 117 117 101 101 101 120 120 y 5593 5841 4271 3782 4930 1978 2020 2578 5116 4388 z 6216 5135 7632 8332 8086 7216 7628 6919 8268 8872 246 y 4432 2208 2253 1651 186 125 1070 1185 237 208 1672 2998 2390 2836 1512 2097 1688 2303 2829 1750 1728 2030 2196 3397 2403 4487 5244 4403 3891 3671 4916 2494 3475 2877 5274 4126 5069 4261 4756 5386 Table 40 (cont’d) x 7978 8074 9427 8950 6747 5882 6849 4214 4203 5147 5114 5022 6179 3264 3363 3290 2651 1695 2099 2398 3207 1873 4343 4003 3091 1300 2414 2004 2705 1505 1904 3980 4234 3006 1587 1679 2632 1593 2592 2232 Atom H12C H13A H13B H13C H16A H16B H16C H17A H17B H17C H18A H18B H18C H19A H19B H19C H22A H22B H22C H22D H22E H22F H23A H23B H23C H23D H23E H23F H24A H24B H24C H24D H24E H24F H25A H25B H25C H25D H25E H25F Ueq 120 92 92 92 121 121 121 100 100 100 124 124 124 134 134 134 121 121 121 100 100 100 124 124 124 101 101 101 101 101 101 100 100 100 124 124 124 98 98 98 z 8700 8607 8743 8101 7117 7723 7698 6401 6949 6381 8464 8431 8206 7753 7804 7103 5679 5249 5929 5837 5205 5133 4577 4303 4278 5652 5763 6322 6284 5924 6082 4602 4095 4098 4894 4503 4400 4509 4057 4714 247 Table 41. Atomic Occupancies for all atoms that are not fully occupied in 68*. Occupancy 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 Atom O5 O5A O6 O6A C20 C20A C21 C21A C22 H22A H22B H22C C22A H22D H22E H22F C23 H23A H23B H23C C23A H23D H23E H23F C24 H24A H24B H24C C24A H24D H24E H24F C25 H25A H25B H25C C25A H25D H25E H25F 248 Compound 69* 69* (CCDC Compound 1819547) C25H38B3F3O7 Formula 1.236 Dcalc./ g cm-3 0.829 µ/mm-1 539.98 Formula Weight colourless Colour chunk Shape 0.21×0.20×0.19 Size/mm3 173(2) T/K orthorhombic Crystal System 0.0(2) Flack Parameter -0.13(12) Hooft Parameter P212121 Space Group 11.5779(3) a/Å 11.9042(3) b/Å 21.0598(6) c/Å 90 a/° 90 b/° 90 g/° 2902.58(13) V/Å3 4 Z 1 Z' 1.541838 Wavelength/Å Radiation type CuKa 4.198 Qmin/° 72.355 Qmax/° 21149 Measured Refl. Independent Refl. 5615 4195 Reflections Used Rint 0.0604 389 Parameters Restraints 0 Largest Peak 0.808 -0.372 Deepest Hole GooF 1.271 wR2 (all data) 0.3245 wR2 0.2936 0.1244 R1 (all data) R1 0.1021 249 Table 42. Fractional Atomic Coordinates (×104) and Equivalent Isotropic Displacement Parameters (Å2×103) for 69*. Atom x F1 8491(9) 9706(7) F2 F3 9034(8) O1 4244(6) O2 4027(5) 5987(6) O3 O4 5236(5) O5 7873(10) O5A 8095(16) O6 9458(8) 9176(11) O6A O7 7963(6) C1 7490(6) C2 6429(6) 5914(5) C3 C4 6465(4) C5 7561(5) C6 8059(6) 3217(8) C7 C8 2881(7) C9 2354(10) C10 3630(11) 2146(8) C11 C12 2362(9) C13 5432(6) C14 4808(5) C15 4622(9) 6361(7) C16 C17 3517(7) C18 5134(9) C19 8774(13) 9141(13) C19A C20 9866(11) C20A 9537(11) C21 8430(20) 8790(19) C21A C22 8710(30) C22A 10290(20) C23 10780(30) 8872(14) C23A C24 10050(20) C24A 10890(18) C25 8771(9) B1 4696(6) 5894(5) B2 B3 8267(6) y 5983(8) 6203(11) 7626(6) 4673(6) 3432(5) 2029(4) 3238(4) 3462(12) 3063(12) 4178(10) 4653(11) 6843(5) 5861(6) 5480(6) 4570(5) 4091(4) 4507(4) 5413(6) 4033(10) 3533(9) 4750(13) 3083(15) 4324(10) 2344(11) 1307(5) 2165(5) 542(6) 603(6) 2207(9) 2065(11) 3360(15) 2910(15) 3481(13) 4078(13) 4200(20) 2340(20) 1990(30) 2430(40) 4030(40) 4580(16) 2320(30) 4240(30) 6712(11) 4184(6) 3084(5) 4049(6) Ueq 139(4) 154(4) 113(3) 76.8(18) 72.0(18) 73.3(19) 63.3(16) 47(3) 60(4) 44(2) 56(3) 78.8(19) 54.1(16) 47.8(14) 38.0(12) 32.0(11) 36.0(12) 51.6(16) 77(3) 75(3) 102(4) 125(6) 84(2) 106(5) 49.1(16) 44.4(14) 69(2) 82(3) 80(3) 88(3) 57(3) 57(3) 49(2) 49(2) 84(2) 61(4) 87(7) 84(2) 87(7) 57(4) 84(2) 61(4) 86(3) 39.3(13) 34.4(12) 39.5(14) z 5452(4) 4795(5) 5301(4) 4971(3) 4178(3) 3457(3) 2763(3) 2398(7) 2586(9) 2879(5) 2650(6) 4610(4) 4298(4) 4506(3) 4184(3) 3650(3) 3459(3) 3801(4) 5134(5) 4489(5) 5426(6) 5595(6) 4098(6) 4499(7) 2984(4) 2539(3) 3350(5) 2676(7) 2592(6) 1844(5) 1912(8) 2194(8) 2346(7) 2053(7) 1445(13) 1579(14) 1696(19) 2670(20) 1945(18) 1498(8) 2630(20) 2074(13) 5004(4) 4433(3) 3268(3) 2886(4) 250 Table 43. Anisotropic Displacement Parameters (×104) 69*. U23 Atom F1 37(5) F2 -85(8) F3 -33(4) -11(3) O1 O2 -24(3) O3 -1(3) -1(2) O4 O5 -23(6) O5A -14(6) O6 1(5) -14(6) O6A O7 -12(3) C1 -13(3) C2 -9(3) 6(2) C3 C4 6(2) C5 0(2) C6 -10(3) -1(5) C7 C8 6(5) C9 -9(7) C10 90(10) 14(4) C11 C12 -22(8) C13 -1(3) C14 -8(3) 7(4) C15 C16 -6(5) C17 9(6) C18 -7(5) -15(5) C19 C19A -15(5) C20 -6(4) -6(4) C20A C21 14(4) C21A -33(6) C22 -54(9) 14(4) C22A C23 -54(9) C23A -2(7) C24 14(4) -33(6) C24A C25 -31(5) B1 6(3) B2 4(2) B3 2(3) U22 156(7) 251(12) 83(4) 92(4) 84(4) 33(2) 34(2) 60(9) 40(7) 49(5) 60(7) 63(3) 52(3) 55(3) 40(3) 33(2) 38(3) 59(4) 112(7) 103(7) 147(11) 205(16) 110(6) 121(9) 31(3) 37(3) 42(4) 43(4) 98(7) 130(9) 80(8) 80(8) 59(6) 59(6) 110(6) 75(11) 97(16) 110(6) 97(16) 84(10) 110(6) 75(11) 134(9) 52(3) 36(3) 42(3) U11 179(8) 80(4) 146(6) 64(3) 54(3) 87(4) 91(4) 25(4) 72(10) 37(5) 53(6) 90(4) 56(4) 46(3) 36(3) 30(2) 31(2) 43(3) 57(5) 47(4) 72(6) 83(7) 58(4) 70(6) 48(3) 43(3) 90(6) 54(4) 47(4) 81(6) 40(6) 40(6) 38(5) 38(5) 58(4) 43(6) 76(11) 58(4) 76(11) 41(7) 58(4) 43(6) 71(5) 34(3) 26(2) 33(3) U33 82(5) 133(7) 109(5) 75(4) 78(4) 100(5) 64(3) 56(8) 69(11) 45(6) 55(7) 84(5) 54(4) 43(3) 38(3) 32(3) 39(3) 53(4) 62(5) 77(6) 86(8) 86(8) 84(5) 127(11) 69(4) 53(4) 75(5) 148(10) 96(7) 53(5) 50(7) 50(7) 52(6) 52(6) 84(5) 65(9) 89(14) 84(5) 89(14) 44(7) 84(5) 65(9) 52(4) 32(3) 41(3) 43(4) U13 -38(5) -23(5) -43(5) 22(3) 28(3) -56(4) -44(3) 5(5) 37(8) 1(4) 21(6) -24(4) -10(3) 4(3) -2(2) 0(2) -3(2) -3(3) 21(4) 14(4) 35(6) -5(6) 1(4) 47(7) -14(3) -9(3) 9(5) 25(5) -23(5) -15(5) 9(5) 9(5) 13(4) 13(4) 1(4) 24(5) 34(8) 1(4) 34(8) -11(6) 1(4) 24(5) 4(4) 4(3) 1(2) 1(3) U12 -69(7) 8(6) -43(4) -18(3) -27(3) -4(2) -4(2) -8(5) -15(6) -6(4) -27(5) -15(3) -13(3) -5(3) -5(2) -4.9(19) -11(2) -21(3) -13(5) -18(4) -3(7) -22(8) 18(4) -48(6) -6(2) -7(2) -9(4) -2(3) -1(4) -19(6) 4(5) 4(5) -10(4) -10(4) 18(4) -28(6) -43(10) 18(4) -43(10) 1(7) 18(4) -28(6) -51(6) 1(2) -1(2) -8(2) 251 Table 44. Bond Lengths in Å for 69*. Length/Å Atom F1 1.322(13) F2 1.317(15) F3 1.291(11) 1.454(10) O1 O1 1.376(10) O2 1.485(9) O2 1.301(9) 1.464(8) O3 O3 1.321(8) O4 1.449(7) O4 1.321(8) O5 1.47(2) 1.323(16) O5 O5A 1.48(2) O5A 1.348(18) O6 1.473(18) 1.388(12) O6 O6A 1.491(17) O6A 1.368(12) O7 1.448(8) 1.261(13) O7 C1 1.380(10) C1 1.347(11) C2 1.411(9) 1.412(8) C3 C3 1.574(8) C4 1.419(7) C4 1.589(8) C5 1.419(8) 1.557(9) C5 C7 1.533(14) C7 1.452(15) C7 1.565(16) 1.513(14) C8 C8 1.537(15) C13 1.564(9) C13 1.517(11) 1.509(11) C13 C14 1.499(10) C14 1.516(13) C19 1.57(2) 1.46(3) C19 C19 1.69(3) C19A 1.49(2) C19A 1.52(3) C19A 1.76(3) 1.51(4) C20 C20 1.52(4) C20A 1.52(2) C20A 1.58(2) Atom C25 C25 C25 C7 B1 C8 B1 C13 B2 C14 B2 C19 B3 C19A B3 C20 B3 C20A B3 C1 C25 C2 C6 C3 C4 B1 C5 B2 C6 B3 C8 C9 C10 C11 C12 C14 C15 C16 C17 C18 C20 C21 C22 C20A C21A C22A C23 C24 C23A C24A 252 Table 45. Bond Angles in ° for 69*. Atom Atom B1 C7 B1 C8 B2 C13 C14 B2 B3 C19 B3 C19A B3 C20 C20A B3 C25 C1 C2 O7 C6 O7 C6 C2 C3 C1 C2 C4 C2 B1 C4 B1 C5 C3 C3 B2 C5 B2 C4 B3 C4 C6 C6 B3 C1 C5 O1 C8 C10 O1 C8 C10 C9 O1 C9 C8 C9 C10 C7 O2 O2 C11 O2 C12 C7 C12 C7 C11 C11 C12 O3 C14 O3 C15 C16 O3 C15 C14 C16 C14 C16 C15 C13 O4 O4 C17 O4 C18 C17 C13 C17 C18 C13 C18 O5 C20 O5 C22 C20 C22 O5 C21 C21 C20 Atom O1 O2 O3 O4 O5 O5A O6 O6A O7 C1 C1 C1 C2 C3 C3 C3 C4 C4 C4 C5 C5 C5 C6 C7 C7 C7 C7 C7 C7 C8 C8 C8 C8 C8 C8 C13 C13 C13 C13 C13 C13 C14 C14 C14 C14 C14 C14 C19 C19 C19 C19 C19 Angle/° 106.5(7) 107.1(6) 108.6(5) 109.7(5) 109.9(11) 104.3(13) 105.3(9) 106.3(9) 118.7(8) 117.2(7) 119.2(7) 123.5(6) 118.4(6) 120.1(5) 116.2(6) 123.6(5) 119.3(5) 121.3(4) 119.4(5) 124.6(5) 118.9(6) 116.5(5) 119.8(6) 101.7(7) 106.0(8) 110.3(11) 110.8(10) 115.4(10) 111.8(10) 101.2(7) 108.2(8) 106.4(8) 116.4(10) 112.5(10) 111.2(10) 103.1(5) 106.2(7) 107.8(7) 114.3(6) 115.8(8) 109.0(6) 102.9(5) 106.7(7) 107.4(7) 115.9(7) 108.8(8) 114.4(7) 99.1(12) 103.5(14) 106.4(18) 102.7(15) 123.4(17) 253 Table 45 (cont’d) Angle/° 118(2) 104.4(12) 108.2(14) 109.8(18) 109.2(15) 100.5(17) 123(2) 103.8(11) 114.0(14) 105(2) 106.3(18) 121(2) 105.0(16) 100.0(11) 109.0(13) 101.5(13) 111.3(13) 114.4(17) 118.3(17) 98.0(13) 105.4(8) 110.9(9) 111.6(8) 116.5(8) 112.9(12) 119.5(6) 113.9(6) 126.6(6) 114.9(5) 122.1(5) 122.9(5) 113.1(9) 127.3(8) 113.7(9) 126.2(8) 119.5(7) 120.2(7) Atom Atom C22 C21 C20A O5A C21A O5A C22A O5A C21A C20A C22A C20A C22A C21A C19 O6 C23 O6 C24 O6 C19 C23 C24 C23 C19 C24 C19A O6A C23A O6A C24A O6A C23A C19A C24A C19A C24A C23A F1 F2 F1 F3 F2 F3 F1 O7 F2 O7 F3 O7 C3 O1 O1 O2 C3 O2 O4 O3 C4 O3 C4 O4 O6 O5 C5 O5 O6A O5A C5 O5A C5 O6 C5 O6A Table 46. Hydrogen Fractional Atomic Coordinates (×104) and Equivalent Isotropic Displacement Parameters (Å2×103) for 69*. y Atom H2 5823 H6 5701 5080 H9A H9B 4303 H9C 5351 H10A 2569 2667 H10B H10C 3419 H11A 5101 Atom C19 C19A C19A C19A C19A C19A C19A C20 C20 C20 C20 C20 C20 C20A C20A C20A C20A C20A C20A C25 C25 C25 C25 C25 C25 B1 B1 B1 B2 B2 B2 B3 B3 B3 B3 B3 B3 x 6056 8791 2670 1668 2140 4145 2958 4044 2300 z 4858 3680 5816 5530 5131 5368 5753 5954 4228 Ueq 57 62 153 153 153 187 187 187 126 254 Table 46 (cont’d) x 1328 2335 2224 1629 2900 5074 4159 4110 6992 6037 6657 3301 3196 3212 4757 4882 5973 7690 9020 8349 8580 9437 8126 8990 9189 7906 10350 11011 10141 10424 11170 11349 8077 9247 8866 10552 10420 9307 11082 11256 11173 Atom H11B H11C H12A H12B H12C H15A H15B H15C H16A H16B H16C H17A H17B H17C H18A H18B H18C H21A H21B H21C H21D H21E H21F H22A H22B H22C H22D H22E H22F H23A H23B H23C H23D H23E H23F H24A H24B H24C H24D H24E H24F y 4151 4234 2091 2355 1829 34 101 997 1090 203 57 2425 1465 2759 2666 1334 2131 3985 4253 4933 1557 2359 2733 1521 1870 1791 2910 2468 1655 4593 3462 4399 4298 4365 5400 2373 1831 1995 5014 3719 4089 Ueq 126 126 159 159 159 104 104 104 123 123 123 120 120 120 132 132 132 126 126 126 91 91 91 131 131 131 126 126 126 131 131 131 85 85 85 126 126 126 91 91 91 z 4165 3647 4063 4733 4709 3618 3050 3616 2534 2311 2985 3024 2496 2290 1602 1681 1799 1255 1113 1655 1666 1280 1395 2045 1320 1599 3051 2432 2803 1668 1686 2222 1502 1099 1536 3002 2310 2751 1955 1775 2504 255 Table 47. Atomic Occupancies for all atoms that are not fully occupied in 69*. Atom Occupancy O5 O5A O6 O6A C19 C19A C20 C20A C21 H21A H21B H21C C21A H21D H21E H21F C22 H22A H22B H22C C22A H22D H22E H22F C23 H23A H23B H23C C23A H23D H23E H23F C24 H24A H24B H24C C24A H24D H24E H24F 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 256 Compound 70c 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 a/° b/° g/° V/Å3 Z Z' Wavelength/Å Radiation type Qmin/° Qmax/° Measured Refl. Independent Refl. Reflections Used Rint Parameters Restraints Largest Peak Deepest Hole GooF wR2 (all data) wR2 R1 (all data) R1 70c (CCDC 1851809) C18H26B2ClFO4 1.269 1.933 382.46 colourless chunk 0.24×0.18×0.15 173(2) monoclinic P21/n 10.5496(2) 11.5620(2) 16.4588(2) 90 94.4870(10) 90 2001.40(6) 4 1 1.541838 CuKa 4.678 71.956 16503 3891 3282 0.0459 243 0 0.606 -0.346 1.180 0.1833 0.1783 0.0739 0.0641 257 Ueq 45.0(3) 47.6(6) 31.5(5) 29.9(5) 37.7(6) 38.7(6) 28.7(7) 31.5(7) 30.4(7) 25.4(7) 23.9(6) 25.6(6) 30.6(7) 29.0(7) 42.6(9) 44.6(9) 39.0(8) 40.1(9) 35.4(8) 32.3(7) 66.6(15) 73.2(17) 65.1(14) 71.3(16) 26.6(7) 26.1(7) y 8861.0(9) 8619(2) 7279(2) 6119(2) 5210(2) 5494(2) 8243(3) 8691(3) 8177(3) 7255(3) 6832(3) 7328(3) 6975(3) 5905(3) 6733(4) 8021(4) 4773(3) 5788(4) 4439(3) 4500(3) 3267(4) 4971(5) 3481(4) 4704(5) 6841(3) 5817(3) x 9082.4(9) 4355(2) 3964(2) 3481(2) 6120(2) 8253(2) 7746(3) 6558(3) 5529(3) 5599(3) 6831(3) 7890(3) 2618(3) 2496(3) 2356(4) 1873(4) 2851(4) 1222(3) 6692(4) 8148(3) 6102(5) 6350(6) 8641(5) 9001(5) 4339(4) 7065(4) z 4481.6(6) 4712.5(14) 6555.8(14) 5447.5(13) 6653.3(15) 6626.2(16) 4853.1(19) 4608(2) 4939(2) 5478.1(18) 5713.4(18) 5392.5(18) 6581(2) 6012(2) 7460(2) 6252(3) 6440(2) 5523(2) 7278(2) 7158(2) 7181(4) 8082(3) 6707(4) 7924(3) 5841(2) 6340(2) Table 48. Fractional Atomic Coordinates (×104) and Equivalent Isotropic Displacement Parameters (Å2×103) for 70c. Atom Cl1 F1 O1 O2 O3 O4 C1 C2 C3 C4 C5 C6 C7 C8 C9 C10 C11 C12 C13 C14 C15 C16 C17 C18 B1 B2 Table 49. Anisotropic Displacement Parameters (×104) 70c. Atom Cl1 F1 O1 O2 O3 O4 C1 C2 C3 C4 C5 C6 C7 C8 C9 C10 C11 C12 C13 C14 U23 17.1(4) 20.9(11) -4.6(10) -6.3(10) 21.0(11) 22.2(12) 1.3(13) 6.3(13) 5.2(13) -0.1(12) -1.0(12) -0.7(12) -3.4(14) -4.0(14) -7.6(16) -3.6(18) 0.3(16) -11.1(17) 12.1(14) 10.3(14) U13 3.6(4) 0.2(10) 3.4(9) 4.5(9) 6.3(10) 1.9(10) 4.0(13) 1.0(14) 0.8(13) 1.3(12) 0.8(12) -1.2(12) 6.6(13) 3.2(12) 12.0(16) 6.6(17) 8.2(16) -0.1(14) 9.0(15) 1.5(14) U11 38.9(5) 35.2(12) 28.3(12) 25.0(12) 29.8(13) 28.9(13) 30.6(17) 37.2(19) 28.9(17) 27.6(16) 25.7(16) 26.1(16) 27.6(17) 23.3(16) 47(2) 37(2) 38(2) 23.7(17) 42(2) 36.7(19) U22 51.8(6) 53.1(14) 36.3(13) 38.5(13) 42.2(14) 40.3(14) 29.6(17) 29.2(17) 32.5(17) 25.1(15) 23.3(15) 25.4(15) 34.1(18) 34.5(18) 50(2) 43(2) 33.7(19) 57(2) 29.0(17) 26.4(16) U33 44.2(5) 54.1(13) 30.0(11) 26.6(11) 41.7(13) 46.7(14) 26.1(15) 28.0(16) 29.4(16) 23.5(14) 22.6(14) 24.8(15) 30.9(17) 29.3(16) 32.1(18) 54(2) 46(2) 39.1(19) 36.1(18) 33.6(17) 258 U12 -17.3(4) 10.8(10) -5.3(10) -3.1(10) 1.6(11) 0.8(11) -7.4(14) -2.7(14) 6.4(14) 0.0(13) -1.3(12) -3.2(13) -2.7(14) -1.2(14) -3.6(19) 10.8(18) -2.6(16) -5.7(16) 6.4(16) 1.8(15) U23 18(3) 14(3) 3(3) 21(3) 3.2(14) -0.7(14) U13 5(3) 32(3) 38(3) -23(2) -0.1(14) 4.1(14) U12 -7(2) 34(3) 10(2) -19(3) 3.3(15) -0.6(14) Table 49 (cont’d) Atom C15 C16 C17 C18 B1 B2 U11 49(3) 91(4) 61(3) 73(3) 24.2(18) 28.1(19) U22 40(2) 90(4) 45(2) 85(4) 28.3(18) 25.1(17) U33 110(4) 43(2) 95(4) 52(3) 27.1(17) 25.3(17) Table 50. Bond Lengths in Å for 70c. Atom Cl1 F1 O1 O1 O2 O2 O3 O3 O4 O4 C1 C1 C2 C3 C4 C4 C5 C5 C7 C7 C7 C8 C8 C13 C13 C13 C14 C14 Atom C1 C3 C7 B1 C8 B1 C13 B2 C14 B2 C2 C6 C3 C4 C5 B1 C6 B2 C8 C9 C10 C11 C12 C14 C15 C16 C17 C18 Length/Å 1.734(3) 1.365(4) 1.466(4) 1.368(4) 1.468(4) 1.358(4) 1.455(4) 1.354(4) 1.455(4) 1.357(4) 1.386(5) 1.382(5) 1.386(5) 1.385(4) 1.415(4) 1.573(5) 1.396(4) 1.569(5) 1.550(5) 1.520(5) 1.519(5) 1.519(5) 1.518(5) 1.565(5) 1.494(6) 1.529(6) 1.507(6) 1.509(6) Table 51. Bond Angles in ° for 70c. Atom O1 O2 O3 O4 C1 C1 C1 C2 Atom C7 C8 C13 C14 Cl1 Cl1 C2 C1 Angle/° 106.3(3) 106.3(2) 108.0(3) 108.3(3) 119.0(3) 119.3(3) 121.6(3) 116.4(3) Atom B1 B1 B2 B2 C2 C6 C6 C3 259 Table 51 (cont’d) Atom C3 C3 C3 C4 C4 C4 C5 C5 C5 C6 C7 C7 C7 C7 C7 C7 C8 C8 C8 C8 C8 C8 C13 C13 C13 C13 C13 C13 C14 C14 C14 C14 C14 C14 B1 B1 B1 B2 B2 B2 Atom C2 C4 C2 C5 B1 B1 B2 C4 B2 C5 C8 C9 C10 C8 C8 C9 C7 C11 C12 C7 C7 C11 C14 C15 C16 C14 C16 C14 C13 C17 C18 C13 C18 C13 C4 O1 C4 O4 C5 C5 Atom F1 F1 C4 C3 C3 C5 C4 C6 C6 C1 O1 O1 O1 C9 C10 C10 O2 O2 O2 C11 C12 C12 O3 O3 O3 C15 C15 C16 O4 O4 O4 C17 C17 C18 O1 O2 O2 O3 O3 O4 Angle/° 117.0(3) 117.7(3) 125.3(3) 116.3(3) 118.3(3) 125.2(3) 122.2(3) 120.0(3) 117.8(3) 120.4(3) 102.1(2) 108.6(3) 105.9(3) 114.5(3) 113.8(3) 111.0(3) 102.6(3) 106.1(3) 108.7(3) 113.7(3) 114.8(3) 110.2(3) 103.9(3) 109.5(4) 104.6(3) 115.6(3) 109.5(4) 113.0(4) 103.5(3) 106.0(3) 108.1(3) 114.0(3) 109.1(4) 115.4(4) 121.6(3) 114.2(3) 123.9(3) 114.4(3) 123.8(3) 121.8(3) Table 52. Hydrogen Fractional Atomic Coordinates (×104) and Equivalent Isotropic Displacement Parameters (Å2×103) for 70c. Atom H2 H6 H9A H9B H9C H10A y 9316 7035 6144 6454 7446 8706 x 6456 8716 2950 1482 2467 2140 z 4234 5546 7687 7479 7780 6572 Ueq 38 31 64 64 64 67 260 Table 52 (cont’d) Atom H10B H10C H11A H11B H11C H12A H12B H12C H15A H15B H15C H16A H16B H16C H17A H17B H17C H18A H18B H18C x 963 2037 2914 2196 3671 1048 550 1244 5196 6522 6203 6695 6712 5423 8078 8667 9499 9890 8868 8797 y 7888 8145 4161 4568 4860 6491 5677 5120 3317 2737 2978 5757 4499 4999 3331 2797 3651 4701 4088 5453 Ueq 67 67 58 58 58 60 60 60 100 100 100 110 110 110 98 98 98 107 107 107 z 6292 5681 6033 6806 6757 5200 5894 5157 7267 7581 6630 8131 8537 8094 6216 7060 6552 7792 8318 8159 261 Compound 71cʹ 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 a/° b/° g/° V/Å3 Z Z' Wavelength/Å Radiation type Qmin/° Qmax/° Measured Refl. Independent Refl. Reflections Used Rint Parameters Restraints Largest Peak Deepest Hole GooF wR2 (all data) wR2 R1 (all data) R1 71cʹ (CCDC 1818920) C18H27B2F5O4S 1.398 1.919 456.07 colourless plate 0.35×0.31×0.16 173(2) orthorhombic Pbcn 14.6808(2) 13.28800(10) 11.10730(10) 90 90 90 2166.80(4) 4 0.5 1.541838 CuKa 6.004 70.063 12825 2059 1888 0.0298 143 0 0.464 -0.426 1.045 0.0956 0.0933 0.0365 0.0338 262 Table 53. Fractional Atomic Coordinates (×104) and Equivalent Isotropic Displacement Parameters (Å2×103) for 71cʹ. Atom S1 F1 F2 F3 O1 O2 C1 C2 C3 C4 C5 C6 C7 C8 C9 C10 B1 x 5000 5000 5043.1(6) 6081.4(6) 6600.7(6) 6150.2(8) 5000 5517.7(8) 5523.3(8) 5000 7133.5(9) 6601.5(11) 7170.2(11) 8086.2(11) 5842.8(16) 7191.5(19) 6103.1(10) y 5576.7(3) 6770.1(10) 5630.2(7) 5624.3(7) 2525.0(7) 1047.6(8) 4215.9(15) 3705.2(11) 2657.5(11) 2146.3(15) 1740.1(11) 766.0(12) 1985.4(14) 1788.6(15) 530.4(19) -145.0(15) 2066.7(12) z 7500 7500 8922.2(8) 7440.5(8) 4823.6(9) 5680.7(9) 7500 6649.7(11) 6641.9(11) 7500 4221.9(12) 4552.9(14) 2889.6(14) 4752.0(15) 3664.8(19) 4802(2) 5693.3(13) Ueq 21.48(17) 36.0(3) 34.1(3) 34.6(3) 25.0(3) 30.5(3) 17.7(4) 18.9(3) 19.0(3) 19.3(4) 22.9(3) 32.8(4) 35.5(4) 39.9(4) 65.6(8) 69.6(8) 20.4(3) U13 -0.41(15) 0.9(6) -1.7(3) 1.1(4) 11.4(4) 17.7(4) -3.0(6) 0.6(5) 0.0(5) -0.7(6) 6.6(5) 18.8(7) 10.8(6) 1.8(7) 22.3(10) 52.5(14) 0.3(5) U12 0 0 -4.5(4) -8.1(3) 4.4(4) -1.0(4) 0 -0.6(5) 0.8(5) 0 4.1(5) -2.6(6) 7.1(7) 6.8(7) -42.9(12) 21.7(11) 0.9(6) Table 54. Anisotropic Displacement Parameters (×104) 71cʹ. Atom S1 F1 F2 F3 O1 O2 C1 C2 C3 C4 C5 C6 C7 C8 C9 C10 B1 U11 25.3(3) 50.4(8) 54.9(6) 26.7(5) 27.7(5) 42.5(6) 18.1(9) 15.4(6) 16.0(6) 18.7(9) 23.1(7) 42.4(9) 36.5(8) 26.7(8) 62.8(13) 105(2) 18.8(7) U22 19.8(3) 18.4(7) 27.5(5) 28.5(5) 22.3(5) 22.3(6) 18.4(9) 25.5(7) 24.4(8) 20.1(10) 24.3(8) 26.3(8) 46.1(10) 55.5(11) 85.8(18) 28.6(11) 23.6(8) U33 19.4(3) 39.4(7) 20.0(5) 48.8(6) 25.1(5) 26.8(5) 16.6(8) 15.7(6) 16.5(6) 19.2(9) 21.3(6) 29.8(8) 24.0(8) 37.3(9) 48.3(12) 75.5(15) 18.7(7) U23 0 0 -5.5(3) 2.4(4) 1.0(4) -1.5(4) 0 2.4(5) -0.6(5) 0 -2.4(5) -7.8(6) 3.8(7) -11.6(8) -39.4(11) 7.2(10) -0.4(6) Table 55. Bond Lengths in Å for 71cʹ. Atom F1 F21 F2 F31 Length/Å 1.5857(14) 1.5826(9) 1.5826(9) 1.5902(10) Atom S1 S1 S1 S1 263 Table 55 (cont’d) Atom F3 C1 C5 B1 C6 B1 C2 C21 C3 C4 B1 C31 C6 C7 C8 C9 C10 Length/Å 1.5902(10) 1.808(2) 1.4651(16) 1.3556(17) 1.4657(16) 1.3560(19) 1.3894(16) 1.3894(16) 1.392(2) 1.3999(16) 1.5657(19) 1.3999(16) 1.556(2) 1.5162(19) 1.519(2) 1.520(3) 1.514(3) Atom S1 S1 O1 O1 O2 O2 C1 C1 C2 C3 C3 C4 C5 C5 C5 C6 C6 Table 56. Bond Angles in ° for 71cʹ. Atom S1 S1 S1 S1 S1 S1 S1 S1 S1 S1 S1 S1 S1 S1 S1 O1 O2 C1 C1 C1 C2 C3 C3 C3 C4 C5 C5 C5 C5 C5 C5 Atom F3 F31 C1 F1 F1 F2 F31 F3 F31 F3 C1 C1 F3 C1 C1 C5 C6 S1 S1 C21 C3 C4 B1 B1 C3 C6 C7 C8 C6 C8 C6 Angle/° 87.72(4) 87.72(4) 180.0 87.42(4) 87.42(4) 174.85(7) 89.99(5) 89.81(5) 89.81(5) 89.99(5) 92.58(4) 92.58(4) 175.44(7) 92.28(4) 92.28(4) 107.03(11) 106.66(11) 119.24(9) 119.24(9) 121.52(19) 119.73(12) 118.54(12) 120.58(11) 120.88(14) 121.96(18) 102.50(10) 108.13(11) 106.53(11) 115.30(13) 109.66(13) 113.95(13) Atom F1 F1 F1 F2 F21 F21 F21 F21 F2 F2 F21 F2 F31 F31 F3 B1 B1 C2 C21 C2 C1 C2 C2 C4 C31 O1 O1 O1 C7 C7 C8 264 Table 56 (cont’d) Atom Atom C5 C6 C9 C6 C6 C10 C5 C6 C5 C6 C9 C6 O2 B1 B1 C3 C3 B1 Atom O2 O2 O2 C9 C10 C10 O1 O1 O2 Angle/° 102.51(11) 106.02(13) 107.86(14) 112.69(15) 114.90(15) 111.90(19) 114.45(12) 123.18(13) 122.37(12) Table 57. Hydrogen Fractional Atomic Coordinates (×104) and Equivalent Isotropic Displacement Parameters (Å2×103) for 71cʹ. Atom H2 H4 H7A H7B H7C H8A H8B H8C H9A H9B H9C H10A H10B H10C x 5867 5000 6549 7483 7502 8332 8480 8061 5466 6108 5465 7615 7537 6805 y 4069 1431 2056 1442 2618 2469 1305 1624 -18 327 1131 8 -318 -714 z 6076 7500 2577 2460 2771 4649 4337 5611 3982 2893 3547 5459 4076 5032 Ueq 23 23 53 53 53 60 60 60 98 98 98 104 104 104 265 Compound 72cʹ 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 a/° b/° g/° V/Å3 Z Z' Wavelength/Å Radiation type Qmin/° Qmax/° Measured Refl. Independent Refl. Reflections Used Rint Parameters Restraints Largest Peak Deepest Hole GooF wR2 (all data) wR2 R1 (all data) R1 72cʹ (CCDC 1843466) C8.5H14BO2.5 1.100 0.625 167.01 colourless needle 0.31×0.14×0.05 173(2) monoclinic P21/c 13.567(2) 12.3554(18) 12.677(2) 90 108.348(12) 90 2017.0(6) 8 2 1.541838 CuKa 3.432 72.426 16929 3701 2206 0.0606 232 0 0.436 -0.345 1.052 0.2775 0.2365 0.1364 0.0878 266 Table 58. Fractional Atomic Coordinates (×104) and Equivalent Isotropic Displacement Parameters (Å2×103) for 72cʹ. Atom O1 O5 O4 C4 C1 C2 C3 C13 C16 C12 B2 B1 C6A C5 C17 C15 C8A C14 O3B O3A C7 C9A C10A C11A O2A O2B y 5170.8(19) 8221(2) 7846(2) 6068(3) 5083(3) 5896(3) 6538(3) 8927(4) 9983(4) 8901(4) 7555(3) 4181(3) 2864(4) 6307(4) 8353(5) 9045(6) 3539(6) 9778(5) 4191(7) 3963(7) 3048(5) 1768(4) 3042(7) 2077(6) 3380(11) 3521(12) x 8377(2) 6564(2) 5876(2) 7894(3) 8046(3) 7367(3) 7257(3) 5661(4) 5848(4) 5460(4) 6561(3) 8493(3) 9491(5) 8174(4) 4732(4) 4409(5) 10447(5) 6221(7) 8328(8) 8040(8) 8619(6) 9864(5) 8683(7) 7792(6) 9111(12) 9311(13) z 8762(2) 8834(2) 7000(2) 9016(3) 7618(3) 7186(4) 8075(3) 8404(4) 8999(4) 7180(4) 7981(4) 7053(4) 6719(5) 10235(4) 8673(6) 6407(5) 6486(7) 6901(7) 5835(9) 6060(9) 5736(5) 7100(5) 4607(6) 5870(9) 7460(11) 7694(11) Ueq 56.2(7) 59.2(8) 76.0(10) 53.0(9) 52.1(9) 55.7(10) 48.9(9) 67.8(12) 77.0(14) 77.6(15) 49.5(10) 53.8(11) 95.3(19) 83.1(15) 114(2) 145(3) 142(3) 159(4) 65.1(18) 61.2(16) 122(3) 110(2) 161(4) 177(5) 61.2(16) 65.1(18) Table 59. Anisotropic Displacement Parameters (×104) 72cʹ. Atom O1 O5 O4 C4 C1 C2 C3 C13 C16 C12 B2 B1 C6A C5 C17 C15 C8A C14 O3B O3A U11 56.1(16) 59.7(16) 76(2) 50(2) 40.9(19) 40.9(19) 38.4(18) 71(3) 80(3) 83(3) 42(2) 42(2) 124(5) 113(4) 86(4) 127(5) 103(5) 222(9) 81(6) 70(5) U22 44.1(14) 55.1(15) 75(2) 48(2) 42.5(19) 47(2) 38.0(17) 60(2) 60(3) 74(3) 43(2) 42(2) 82(4) 76(3) 84(4) 164(7) 136(6) 89(4) 63(4) 62(4) U33 76.0(19) 60.7(16) 65.7(19) 71(3) 73(3) 73(3) 73(2) 70(3) 83(3) 68(3) 67(3) 75(3) 88(4) 72(3) 204(8) 100(5) 227(9) 238(10) 50(4) 57(4) U23 3.3(12) -10.9(12) -24.9(15) -6.2(18) -9.7(17) -19.3(18) -10.9(16) -10(2) -23(2) -16(2) -12.4(19) -8(2) 4(3) 8(2) 8(4) -51(4) -61(6) 66(5) -6(2) -2(2) 267 U13 31.5(13) 15.8(13) 7.7(15) 32.5(19) 18.4(17) 9.0(17) 20.4(17) 19(2) 15(2) 12(2) 23(2) 16(2) 45(3) 48(3) 92(5) -28(4) 109(6) 177(8) 18(2) 27(2) U12 7.1(11) 17.7(12) 31.2(16) -3.9(16) -1.7(14) 5.5(15) -2.5(14) 24(2) 18(2) 37(2) -1.7(16) 5.0(17) 58(3) 23(3) 15(3) 92(5) -22(4) 67(5) 31(4) 26(3) Table 59 (cont’d) Atom C7 C9A C10A C11A O2A O2B U11 137(5) 130(5) 220(9) 117(6) 70(5) 81(6) U22 111(5) 75(3) 162(7) 108(5) 62(4) 63(4) Table 60. Bond Lengths in Å for 72cʹ. U33 97(4) 137(5) 89(5) 323(13) 57(4) 50(4) U23 -48(4) 9(3) -24(5) -134(7) -2(2) -6(2) U13 5(4) 59(4) 30(5) 93(7) 27(2) 18(2) U12 70(4) 59(3) 107(7) -43(4) 26(3) 31(4) Atom O1 O1 O5 O5 O4 O4 C4 C4 C1 C1 C2 C3 C13 C13 C13 C12 C12 B1 B1 B1 B1 C6A C6A C6A C6A C6A O3B O3A C7 C7 Atom C4 C1 C13 B2 C12 B2 C3 C5 C2 B1 C3 B2 C16 C12 C17 C15 C14 O3B O3A O2A O2B C8A C7 C9A O2A O2B C7 C7 C10A C11A Length/Å 1.377(4) 1.381(5) 1.463(5) 1.358(5) 1.467(5) 1.346(5) 1.362(5) 1.500(6) 1.356(5) 1.549(5) 1.424(5) 1.554(5) 1.488(6) 1.489(6) 1.574(7) 1.463(7) 1.610(9) 1.488(11) 1.244(13) 1.295(11) 1.411(10) 1.644(9) 1.441(8) 1.473(6) 1.364(15) 1.560(14) 1.481(9) 1.506(8) 1.462(9) 1.687(10) Table 61. Bond Angles in ° for 72cʹ. Atom O1 O5 O4 C4 C4 C4 Atom C1 C13 C12 C5 O1 C5 Angle/° 106.7(3) 105.8(3) 106.4(3) 114.5(4) 110.8(3) 134.7(4) Atom C4 B2 B2 O1 C3 C3 268 Table 61 (cont’d) Atom C1 C1 C1 C2 C3 C3 C3 C13 C13 C13 C13 C13 C13 C12 C12 C12 C12 C12 C12 B2 B2 B2 B1 B1 B1 B1 B1 B1 C6A C6A C6A C6A C6A C6A C6A C6A C6A O3B O3A C7 C7 C7 C7 C7 C7 C7 C7 C7 O2A O2B Atom B1 O1 B1 C3 C2 B2 B2 C16 C12 C17 C12 C17 C17 C13 C14 C14 O4 C13 C14 C3 O5 C3 C1 C1 O2A C1 C1 O3B C8A C9A O2B C8A O2B C8A C7 C9A C8A B1 C7 O3B O3A C10A C11A C11A C11A O3B O3A C11A C6A C6A Angle/° 119.8(3) 108.8(3) 131.4(4) 108.6(4) 105.1(3) 127.9(4) 127.0(4) 110.2(4) 103.4(3) 106.5(4) 119.6(4) 107.8(4) 108.6(5) 103.2(4) 105.0(4) 107.1(5) 110.2(4) 121.0(5) 109.1(6) 125.4(4) 113.7(3) 120.9(3) 121.4(4) 118.9(4) 106.9(6) 131.6(7) 120.1(6) 115.9(9) 104.1(6) 122.2(6) 108.2(5) 108.4(5) 110.0(7) 112.2(10) 97.8(5) 111.6(8) 102.0(10) 97.1(5) 107.7(7) 104.2(6) 103.9(6) 124.0(7) 101.1(6) 117.8(6) 95.0(6) 100.8(6) 117.9(6) 110.0(7) 114.8(12) 97.8(7) Atom O1 C2 C2 C1 C4 C4 C2 O5 O5 O5 C16 C16 C12 O4 O4 C13 C15 C15 C15 O5 O4 O4 O3B O3A O3A O2A O2B O2B C7 C7 C7 C9A C9A O2A O2A O2A O2B C7 B1 C6A C6A C6A C6A O3B O3A C10A C10A C10A B1 B1 269 Table 62. Hydrogen Fractional Atomic Coordinates (×104) and Equivalent Isotropic Displacement Parameters (Å2×103) for 72cʹ. Atom H2 H16A H16B H16C H5A H5B H5C H17A H17B H17C H15A H15B H15C H8AA H8AB H8AC H14A H14B H14C H9AA H9AB H9AC H10A H10B H10C H11A H11B H11C y 6017 9874 10486 10284 5712 6981 6385 8067 7758 8877 8516 8938 9779 3153 3602 4263 9816 10489 9562 1369 1387 1818 3655 3101 2364 1372 2231 2063 x 7022 5871 5286 6512 7939 7837 8929 4973 4472 4174 3942 4417 4166 10680 11025 10204 6870 5884 6370 9996 9335 10507 9105 7984 9004 8024 7094 7779 z 6418 9772 8634 8983 10607 10343 10550 9432 8148 8606 6576 5644 6485 5933 7180 6208 7521 6790 6224 6491 7337 7727 4512 4072 4479 5682 5367 6638 Ueq 67 115 115 115 125 125 125 171 171 171 218 218 218 213 213 213 238 238 238 165 165 165 242 242 242 266 266 266 270 Compound 73cʹ 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 a/° b/° g/° V/Å3 Z Z' Wavelength/Å Radiation type Qmin/° Qmax/° Measured Refl. Independent Refl. Reflections Used Rint Parameters Restraints Largest Peak Deepest Hole GooF wR2 (all data) wR2 R1 (all data) R1 73cʹ (CCDC 1840217) C16H28B2N2O4 1.110 0.621 334.02 colourless chunk 0.32×0.24×0.14 213(2) monoclinic P21/c 13.5810(3) 12.1863(2) 12.7568(3) 90 108.8070(10) 90 1998.56(7) 4 1 1.541838 CuKa 3.438 72.168 18729 3904 2909 0.0366 230 0 0.539 -0.362 1.085 0.2799 0.2575 0.1107 0.0904 271 Table 63. Fractional Atomic Coordinates (×104) and Equivalent Isotropic Displacement Parameters (Å2×103) for 73cʹ. Atom O1 O2 O3 O4 N1 N2 C1 C2 C3 C4 C5 C6 C7 C8 C9 C10 C11 C12 C13 C14 C15 C16 B1 B2 x 3427.3(18) 4076(2) 804(2) 1837(3) 2099(2) 1609(2) 2733(2) 2623(2) 1920(2) 1887(4) 4323(3) 4484(3) 4126(3) 5280(4) 3682(7) 5523(5) 567(4) 1429(5) -429(5) 235(5) 1361(7) 2264(5) 3411(3) 1507(2) y 1821.8(18) 2150(2) 6653(2) 5970(2) 3992(2) 4882(2) 3506(2) 4137(2) 4979(2) 3646(3) 1088(3) 1085(4) 44(3) 1661(5) 178(5) 903(6) 7252(4) 6999(5) 6617(7) 8367(5) 6982(6) 7979(5) 2469(3) 5889(3) z 1140.5(18) 2967(2) 2385(2) 3970(2) 966(2) 1172(2) 1909(3) 2757(3) 2274(3) -180(3) 1575(3) 2783(3) 951(3) 1374(7) 2974(8) 3587(5) 3259(4) 4231(4) 3435(7) 2910(5) 5343(5) 4126(8) 1987(3) 2876(3) Ueq 67.9(7) 89.8(9) 89.7(9) 106.5(12) 58.0(6) 60.3(7) 52.5(7) 56.6(7) 53.9(7) 86.1(12) 77.5(10) 91.9(14) 86.3(12) 146(3) 191(4) 167(4) 101.7(16) 131(2) 171(4) 141(2) 174(4) 186(4) 53.7(8) 55.1(8) Table 64. Anisotropic Displacement Parameters (×104) 73cʹ. Atom O1 O2 O3 O4 N1 N2 C1 C2 C3 C4 C5 C6 C7 C8 C9 C10 C11 C12 C13 C14 C15 C16 U11 77.4(14) 94.7(18) 115(2) 126(2) 66.1(15) 65.1(15) 43.5(13) 43.8(14) 45.5(14) 127(3) 81(2) 98(3) 95(3) 117(4) 261(9) 157(5) 137(4) 143(4) 100(4) 169(6) 266(9) 127(5) U22 62.4(13) 91.4(19) 84.1(17) 93(2) 47.6(13) 46.7(13) 45.2(14) 49.9(15) 43.5(14) 75(2) 71(2) 93(3) 72(2) 91(3) 102(4) 193(7) 91(3) 124(4) 228(8) 105(4) 163(6) 125(5) U33 63.5(13) 68.8(15) 83.2(17) 76.2(17) 70.1(15) 78.6(17) 70.6(17) 72.3(19) 77.2(19) 69(2) 79(2) 74(2) 85(2) 283(9) 311(11) 99(4) 91(3) 102(3) 223(8) 157(5) 85(3) 325(11) U23 -8.6(10) -29.1(13) 11.6(13) -25.6(14) -0.1(11) 3.5(11) -9.4(12) -16.9(14) -9.2(13) 5.1(18) -12.0(17) -17(2) -22.1(19) 13(4) 87(5) -50(4) 2(2) -49(3) -113(6) 4(4) -20(4) -138(6) 272 U13 21.9(11) 6.4(13) 49.9(16) -0.2(15) 35.7(13) 36.5(13) 21.0(12) 13.2(13) 25.9(13) 49(2) 23.1(18) 12(2) 20(2) 137(5) 230(9) -29(3) 55(3) 6(3) 104(5) 62(5) 46(4) 100(6) U12 22.2(11) 40.7(15) 50.2(16) 61.2(18) 0.6(11) 4.9(11) -3.6(11) 2.0(11) -3.5(11) 18(2) 25.2(18) 51(2) 23(2) 18(3) 71(5) 109(5) 59(3) 73(4) -34(4) 81(4) 110(6) -50(4) U23 -11.3(14) -5.7(15) U13 22.0(15) 21.8(15) U12 -2.3(13) 2.1(13) Table 64 (cont’d) Atom B1 B2 U11 48.7(16) 44.6(15) U22 48.9(17) 45.8(16) U33 65.9(19) 77(2) Table 65. Bond Lengths in Å for 73cʹ. Atom O1 O1 O2 O2 O3 O3 O4 O4 N1 N1 N1 N2 C1 C1 C2 C3 C5 C5 C5 C6 C6 C11 C11 C11 C12 C12 Atom C5 B1 C6 B1 C11 B2 C12 B2 N2 C1 C4 C3 C2 B1 C3 B2 C6 C7 C8 C9 C10 C12 C13 C14 C15 C16 Length/Å 1.467(4) 1.344(4) 1.460(4) 1.342(4) 1.452(4) 1.337(4) 1.453(5) 1.324(5) 1.342(3) 1.368(4) 1.459(4) 1.337(4) 1.374(4) 1.548(4) 1.402(4) 1.552(4) 1.485(5) 1.479(5) 1.567(6) 1.625(8) 1.469(6) 1.438(7) 1.636(8) 1.456(6) 1.450(8) 1.682(9) Table 66. Bond Angles in ° for 73cʹ. Atom O1 O2 O3 O4 N1 N1 N1 N2 C1 C1 C1 C2 C3 Atom C5 C6 C11 C12 C1 C4 C4 N1 C2 B1 B1 C3 C2 Angle/° 106.3(3) 106.5(3) 107.0(3) 106.4(3) 112.9(2) 118.7(3) 128.4(3) 105.6(2) 104.6(2) 127.1(3) 128.3(3) 107.2(3) 109.7(2) Atom B1 B1 B2 B2 N2 N2 C1 C3 N1 N1 C2 C1 N2 273 Table 66 (cont’d) Atom N2 C2 O1 O1 O1 C6 C7 C7 O2 O2 O2 C5 C10 C10 O3 O3 C12 C12 C12 C14 O4 O4 C11 C11 C11 C15 O1 O2 O2 O3 O4 O4 Atom C3 C3 C5 C5 C5 C5 C5 C5 C6 C6 C6 C6 C6 C6 C11 C11 C11 C11 C11 C11 C12 C12 C12 C12 C12 C12 B1 B1 B1 B2 B2 B2 Atom B2 B2 C6 C7 C8 C8 C6 C8 C5 C9 C10 C9 C5 C9 C13 C14 O3 C13 C14 C13 C15 C16 O4 C15 C16 C16 C1 O1 C1 C3 O3 C3 Angle/° 122.8(3) 127.5(3) 102.7(3) 109.7(3) 107.3(3) 108.5(4) 119.8(4) 108.2(4) 103.2(3) 105.8(4) 110.5(4) 106.0(5) 120.8(4) 109.4(5) 105.4(4) 111.0(4) 103.5(3) 105.0(5) 123.4(5) 107.2(5) 111.2(5) 106.2(4) 104.6(3) 123.8(6) 99.3(6) 110.1(6) 126.2(3) 113.5(3) 120.3(3) 125.7(3) 112.9(3) 121.4(3) Table 67. Hydrogen Fractional Atomic Coordinates (×104) and Equivalent Isotropic Displacement Parameters (Å2×103) for 73cʹ. Atom H2 H4A H4B H4C H7A H7B H7C H8A H8B H8C H9A H9B H9C H10A H10B H10C H13A y 4000(30) 3742 2878 4086 -273 -462 182 2063 1109 2164 345 -545 194 1426 163 1001 7106 x 2920(30) 1153 2071 2296 3479 4693 4075 5050 5783 5599 3534 3993 3041 6009 5750 5494 -785 z 3520(30) -584 -198 -521 978 1280 187 682 1339 1978 3652 3032 2354 3455 3506 4332 3793 Ueq 71(10) 129 129 129 130 130 130 220 220 220 287 287 287 250 250 250 257 274 Table 67 (cont’d) Atom H13B H13C H14A H14B H14C H15A H15B H15C H16A H16B H16C x -188 -904 793 64 -373 956 1028 2055 2933 1995 2344 y 5974 6392 8754 8744 8346 6352 7649 6933 7863 8694 7946 Ueq 257 257 212 212 212 260 260 260 278 278 278 z 3896 2722 2748 3498 2251 5424 5471 5876 4689 4232 3399 275 Compound 103 1850721) 103 (CCDC Compound C23H23I Formula 1.446 Dcalc./ g cm-3 12.821 µ/mm-1 426.31 Formula Weight colourless Colour chunk Shape 0.41×0.18×0.05 Size/mm3 173(2) T/K monoclinic Crystal System P21/c Space Group 24.3583(9) a/Å 10.6108(3) b/Å 15.9920(6) c/Å 90 a/° 108.596(2) b/° 90 g/° 3917.5(2) V/Å3 8 Z 2 Z' 1.541838 Wavelength/Å Radiation type CuKa 4.586 Qmin/° 72.506 Qmax/° 6301 Measured Refl. Independent Refl. 6301 Reflections with I > 4823 2(I) . Rint Parameters 444 Restraints 0 Largest Peak 1.954 -1.796 Deepest Hole GooF 1.041 wR2 (all data) 0.2410 wR2 0.2192 0.1075 R1 (all data) R1 0.0845 276 x 4277.7(5) 3516(5) 3358(6) 2840(5) 2498(6) 2681(6) 3207(6) 3691(5) 3754(6) 4038(6) 4240(6) 4194(6) 3920(5) 4073(7) 4437(6) 1943(6) 3351(6) 2929(7) 3051(7) 3588(7) 3973(8) 3853(7) 2608(10) 4570(7) 601.4(4) 1408(5) 1598(6) 2150(6) 2480(6) 2260(6) 1730(7) 1295(5) 1246(7) 1020(6) 858(6) 911(7) 1123(5) 951(8) 725(7) 3048(6) 1550(6) 1033(6) 897(7) 1274(7) 1805(6) 1942(6) 310(7) 2248(8) Ueq 44.7(3) 27(3) 31(3) 28(3) 32(3) 32(3) 31(3) 33(3) 39(3) 34(3) 41(4) 34(3) 29(3) 48(4) 45(4) 39(3) 32(3) 39(3) 41(4) 46(4) 47(4) 41(3) 63(6) 57(4) 34.2(3) 24(2) 32(3) 33(3) 32(3) 30(3) 34(3) 26(3) 39(3) 35(3) 32(3) 35(3) 27(3) 55(5) 47(4) 45(4) 29(3) 37(3) 37(3) 41(4) 33(3) 31(3) 53(4) 45(4) Table 68. Fractional Atomic Coordinates (×104) and Equivalent Isotropic Displacement Parameters (Å2×103) for 103. Atom I1 C1 C2 C3 C4 C5 C6 C7 C8 C9 C10 C11 C12 C13 C14 C15 C16 C17 C18 C19 C20 C21 C22 C23 I1A C1A C2A C3A C4A C5A C6A C7A C8A C9A C10A C11A C12A C13A C14A C15A C16A C17A C18A C19A C20A C21A C22A C23A z 1162.3(7) 278(10) 433(9) -134(10) -860(9) -1018(10) -426(9) 1182(10) 2070(11) 2735(10) 2509(11) 1647(10) 984(9) 3653(12) 1407(12) -1445(10) -675(10) -783(10) -1034(11) -1188(11) -1085(11) -853(11) -1104(14) -1228(14) 1828.9(6) 1746(8) 2068(9) 2027(9) 1650(9) 1317(10) 1351(10) 2504(9) 3330(10) 3804(10) 3379(10) 2556(11) 2117(10) 4668(11) 2149(12) 1602(12) 947(9) 295(10) -100(11) 179(11) 811(10) 1218(10) -827(11) 1107(12) y 237.1(9) -574(11) -1763(14) -2267(11) -1586(13) -381(12) 145(12) -2609(14) -2278(14) -3138(12) -4245(14) -4568(13) -3734(11) -2857(16) -5762(16) -2147(14) 1424(12) 2410(14) 3624(11) 3771(14) 2879(14) 1666(13) 4615(14) 3129(18) 5228.0(8) 4607(11) 3415(12) 3003(12) 3702(12) 4901(12) 5374(11) 2530(11) 2784(13) 1915(13) 753(12) 445(11) 1339(10) 2167(17) -849(13) 3236(14) 6631(11) 6841(13) 8004(13) 8981(11) 8828(12) 7638(12) 8230(16) 9918(14) 277 Table 69. Anisotropic Displacement Parameters (×104) 103. U23 Atom I1 5.1(4) C1 8(5) 2(6) C2 C3 2(5) C4 8(5) C5 -2(5) 1(5) C6 C7 1(6) C8 2(7) 2(6) C9 C10 7(7) C11 14(6) C12 1(5) -3(8) C13 C14 -16(8) C15 15(6) C16 3(5) -3(5) C17 C18 -7(5) C19 1(6) C20 6(6) 3(6) C21 C22 -17(7) C23 17(9) I1A 3.6(3) -8(5) C1A C2A 5(5) C3A 2(5) C4A -8(5) 8(5) C5A C6A 4(5) C7A 0(5) 8(6) C8A C9A 10(6) C10A 9(6) C11A 2(5) 1(5) C12A C13A 5(7) C14A -10(7) C15A 6(7) -3(5) C16A C17A -3(6) C18A 12(6) C19A 1(6) -2(5) C20A C21A -2(5) U11 40.8(6) 18(6) 20(6) 21(6) 27(7) 16(7) 38(8) 18(6) 27(7) 34(7) 26(7) 19(7) 29(7) 47(9) 28(8) 35(8) 37(7) 55(10) 43(9) 55(10) 66(11) 50(9) 89(15) 48(10) 30.5(5) 20(6) 31(7) 43(8) 27(7) 28(7) 49(9) 19(6) 58(10) 35(7) 25(6) 37(8) 24(6) 81(13) 56(10) 30(8) 34(7) 32(8) 37(8) 65(10) 41(8) 29(7) U22 34.3(6) 22(6) 42(8) 22(6) 33(7) 28(7) 31(7) 33(7) 33(8) 28(7) 29(7) 30(7) 22(6) 50(9) 40(9) 35(8) 18(6) 30(7) 7(6) 23(7) 28(8) 25(7) 24(8) 59(11) 27.3(5) 29(6) 20(6) 22(6) 27(6) 23(6) 14(6) 18(6) 31(7) 34(7) 24(6) 9(5) 15(6) 51(10) 18(7) 35(8) 14(5) 37(8) 32(7) 9(6) 21(6) 19(6) U33 47.6(6) 39(7) 31(7) 42(8) 33(8) 43(8) 27(7) 37(8) 58(11) 37(8) 63(11) 54(9) 32(7) 44(10) 57(10) 47(9) 41(8) 28(8) 59(10) 52(10) 45(10) 51(10) 65(12) 65(12) 46.4(6) 23(6) 32(7) 31(7) 34(7) 43(8) 44(8) 35(8) 30(8) 39(8) 49(8) 56(9) 45(8) 34(10) 76(12) 72(12) 42(8) 43(9) 49(9) 67(11) 50(9) 40(9) 278 U13 -2.0(4) 7(5) 7(5) 11(6) 4(5) -2(5) 14(5) -7(5) 14(7) 6(6) 7(7) 15(6) 3(5) 10(7) -2(6) 16(6) 11(6) 7(6) -3(7) 7(7) 16(8) 22(7) 9(10) 19(9) 14.5(4) 7(5) -7(5) 7(6) -4(5) 14(6) 23(7) 2(5) 18(7) 15(6) 14(6) 9(6) 14(5) 18(8) 34(8) 18(7) 17(6) 16(6) 25(7) 47(9) 30(7) 4(6) U12 -9.8(4) 7(5) 0(6) 5(5) 5(6) 6(5) 3(6) -11(5) -2(6) 5(6) -1(6) 4(5) 8(5) -1(7) -3(6) 2(6) 4(6) 0(7) -4(6) -14(7) -10(8) 0(6) 11(8) -6(9) 1.5(3) 4(5) -9(5) -3(6) -9(6) -3(5) -14(6) -1(5) -3(7) -1(6) 2(6) -2(5) 0(5) -24(9) -7(6) 0(7) -9(5) -9(6) 7(7) 8(6) 4(6) -10(5) U33 44(9) 49(9) U23 28(8) -2(6) U13 0(7) 17(7) U12 -1(8) -3(7) Table 69 (cont’d) U22 Atom 50(9) C22A 34(7) C23A Table 70. Bond Lengths in Å for 103. Length/Å Atom I1 2.123(13) C1 1.365(19) C1 1.370(19) 1.404(18) C2 C2 1.509(19) C3 1.397(18) C4 1.404(19) 1.50(2) C4 C5 1.44(2) C6 1.487(19) C7 1.42(2) 1.40(2) C7 C8 1.40(2) C9 1.37(2) C9 1.47(2) C10 1.39(2) 1.379(18) C11 C11 1.50(2) C16 1.44(2) C16 1.37(2) 1.41(2) C17 C18 1.41(2) C18 1.49(2) C19 1.31(2) 1.40(2) C20 C20 1.56(2) I1A 2.117(12) C1A 1.388(18) C1A 1.411(18) 1.44(2) C2A C2A 1.497(18) C3A 1.37(2) C4A 1.418(18) 1.49(2) C4A C5A 1.40(2) C6A 1.487(18) C7A 1.39(2) 1.410(17) C7A C8A 1.412(19) C9A 1.40(2) C9A 1.47(2) 1.40(2) C10A C11A 1.373(19) C11A 1.526(18) U11 54(10) 52(10) Atom C1 C2 C6 C3 C7 C4 C5 C15 C6 C16 C8 C12 C9 C10 C13 C11 C12 C14 C17 C21 C18 C19 C22 C20 C21 C23 C1A C2A C6A C3A C7A C4A C5A C15A C6A C16A C8A C12A C9A C10A C13A C11A C12A C14A 279 Table 70 (cont’d) Length/Å Atom 1.37(2) C16A 1.406(17) C16A 1.38(2) C17A 1.36(2) C18A 1.55(2) C18A 1.37(2) C19A 1.411(19) C20A 1.55(2) C20A Table 71. Bond Angles in ° for 103. Angle/° Atom Atom C2 I1 119.4(10) C2 C6 123.4(13) C6 I1 117.2(9) 118.9(13) C3 C1 C1 C7 125.6(12) C3 C7 115.5(12) C4 C2 121.0(12) 118.8(12) C5 C3 C3 C15 119.6(12) C5 C15 121.7(12) C4 C6 120.1(12) C1 C5 117.7(12) 127.8(13) C16 C1 C5 C16 114.4(13) C8 C2 120.3(13) C12 C2 118.8(13) 120.8(13) C8 C12 C9 C7 117.8(14) C8 C13 118.8(14) C10 C8 119.4(15) 121.7(14) C13 C10 C9 C11 123.5(14) C10 C14 123.3(14) C12 C10 118.1(13) 118.6(15) C14 C12 C11 C7 120.4(14) C17 C6 118.5(13) C21 C6 122.1(12) C21 C17 119.4(13) 119.5(15) C16 C18 C17 C19 116.2(14) C17 C22 117.0(16) C19 C22 126.8(15) 124.4(14) C18 C20 C19 C21 119.9(17) C19 C23 121.5(14) C21 C23 118.6(15) 120.4(15) C20 C16 C2A I1A 117.8(10) C2A C6A 121.7(12) Atom C17A C21A C18A C19A C22A C20A C21A C23A Atom C1 C1 C1 C2 C2 C2 C3 C4 C4 C4 C5 C6 C6 C6 C7 C7 C7 C8 C9 C9 C9 C10 C11 C11 C11 C12 C16 C16 C16 C17 C18 C18 C18 C19 C20 C20 C20 C21 C1A C1A 280 Table 71 (cont’d) Angle/° Atom Atom 120.5(9) I1A C6A 117.7(12) C3A C1A 126.2(13) C7A C1A 116.0(11) C7A C3A 123.2(12) C2A C4A 116.5(13) C5A C3A 121.8(12) C15A C3A 121.6(13) C15A C5A 123.4(12) C4A C6A 125.7(13) C16A C1A 117.4(11) C1A C5A 116.9(11) C16A C5A 121.7(12) C2A C8A 119.1(12) C12A C8A 118.7(12) C2A C12A 123.3(13) C9A C7A 124.5(14) C13A C8A 114.4(14) C8A C10A 121.2(13) C13A C10A 124.3(12) C11A C9A 120.4(13) C14A C10A 118.8(12) C10A C12A 120.9(14) C14A C12A 120.1(14) C7A C11A 123.3(12) C6A C17A 118.6(12) C21A C17A 118.0(12) C6A C21A 121.5(13) C18A C16A 120.9(14) C22A C17A 119.5(15) C17A C19A 119.6(13) C22A C19A 122.0(13) C20A C18A 118.2(12) C21A C19A 122.5(13) C23A C19A 119.2(14) C23A C21A 120.1(13) C20A C16A Table 72. Hydrogen Fractional Atomic Coordinates (×104) and Equivalent Isotropic Displacement Parameters (Å2×103) for 103. Atom y -3085.05 H3 H5 89.17 H8 -1501.63 H10 -4825.63 H12 -3926.05 -2299.89 H13A H13B -3643.46 H13C -2440.44 H14A -6364.76 -6123.65 H14B H14C -5577.45 Atom C1A C2A C2A C2A C3A C4A C4A C4A C5A C6A C6A C6A C7A C7A C7A C8A C9A C9A C9A C10A C11A C11A C11A C12A C16A C16A C16A C17A C18A C18A C18A C19A C20A C20A C20A C21A x 2721.01 2457.84 3609.41 4421.45 3887.31 4403.66 4123.37 3715.45 4122.53 4717.39 4630.77 34 38 47 50 35 72 72 72 68 68 68 Ueq z -21.7 -1516.17 2208.03 2966.16 390.23 3919.66 3990.8 3660.44 1159.16 1936.32 969.89 281 Table 72 (cont’d) x 2025.25 1757.17 1682.55 2570.79 3674.33 4122.31 2617.95 2223.77 2690.8 4526.69 4854.8 4700.88 2293.37 2481.88 1369.93 701.73 1153.34 609.8 902.02 1296.43 320.98 760.94 972.79 3023.84 3140.99 3351.6 763.12 1165.84 2298.75 152.02 367.22 38.12 2504.31 2041.46 2479.51 Atom H15A H15B H15C H17 H19 H21 H22A H22B H22C H23A H23B H23C H3A H5A H8A H10A H12A H13D H13E H13F H14D H14E H14F H15D H15E H15F H17A H19A H21A H22D H22E H22F H23D H23E H23F Ueq 58 58 58 47 55 49 95 95 95 86 86 86 40 36 47 38 33 83 83 83 71 71 71 68 68 68 44 49 37 79 79 79 67 67 67 y -2941.65 -1559 -2308.32 2244.88 4572.88 1004.98 4874.77 4281.05 5343.96 3043.48 2517.1 3984.02 2207.34 5410.1 3583.91 133.41 1154.41 1719.61 3074.95 1876.25 -811.86 -1466.78 -1100.51 3124.97 2427.08 3850.17 6169.98 9792.32 7517.19 7422.49 8788.4 8621.15 9757.76 10714.04 9972.52 z -1694.01 -1924.34 -1098.83 -686.23 -1378.97 -819.36 -510.89 -1425.13 -1420.72 -1855.39 -886.65 -1030.01 2273.12 1056.22 3588.15 3668.18 1552.43 4712.1 4732.51 5135.36 1765.91 2619.28 1800.86 983.39 1911.15 1881.51 112.81 -70.22 1675.36 -1095.23 -1279.74 -565.87 1708.53 1093.37 706.62 282 Compound L2* L2* (CCDC Compound 1851547) C29H22N2 Formula 1.203 Dcalc./ g cm-3 0.540 µ/mm-1 398.48 Formula Weight colourless Colour plate Shape 0.28×0.28×0.09 Size/mm3 173(2) T/K monoclinic Crystal System P21/n Space Group 9.92670(10) a/Å 10.3265(2) b/Å 42.9795(5) c/Å 90 a/° 93.1340(10) b/° 90 g/° 4399.16(11) V/Å3 8 Z 2 Z' 1.541838 Wavelength/Å Radiation type CuKa 2.059 Qmin/° 73.064 Qmax/° 25709 Measured Refl. Independent Refl. 8557 Reflections with I > 6629 2(I) Rint 0.0390 Parameters 561 0 Restraints Largest Peak 0.218 Deepest Hole -0.213 GooF 1.021 0.1276 wR2 (all data) wR2 0.1153 R1 (all data) 0.0625 R1 0.0461 283 Table 73. Fractional Atomic Coordinates (×104) and Equivalent Isotropic Displacement Parameters (Å2×103) for L2*. Atom N1 N2 C1 C2 C3 C4 C5 C6 C7 C8 C9 C10 C11 C12 C13 C14 C15 C16 C17 C18 C19 C20 C21 C22 C23 C24 C25 C26 C27 C28 C29 N1A N2A C1A C2A C3A C4A C5A C6A C7A C8A C9A C10A C11A C12A C13A C14A C15A C16A C17A C18A y 5968.8(15) 3741(2) 7345.2(15) 6629.9(15) 7240.1(16) 8539.1(16) 9221.5(16) 8661.0(16) 6681.8(15) 6657.1(17) 5972.4(17) 5269.6(17) 5264.3(16) 4464.6(17) 4453(2) 3673(2) 2926(2) 2989(3) 5208.2(15) 4355.4(17) 3042.1(18) 2569.3(17) 3404.0(17) 4712.8(17) 9166.2(19) 9519.4(16) 10235.9(18) 11103(2) 11277(2) 10564(2) 9691(2) 6067.4(14) 3314.2(16) 6975.1(15) 6366.5(15) 7084.9(15) 8391.0(15) 8975.6(15) 8292.2(15) 6240.0(15) 6663.2(16) 5131.2(16) 4506.9(16) 4996.2(15) 4335.6(16) 4753(2) 4106(2) 3080(2) 2718(2) 4969.6(15) 4417.6(17) x 10598.3(15) 8337.5(19) 9829.4(15) 9651.8(15) 9778.6(16) 10136.2(16) 10355.0(16) 10189.9(15) 9643.8(16) 10659.7(18) 8479.1(17) 8401.0(17) 9479.7(17) 9444.7(18) 10512(2) 10443(3) 9321(2) 8301(3) 9369.8(16) 10216.9(18) 9915(2) 8774(2) 7950.7(19) 8247.9(17) 10305.5(19) 10376.2(18) 11560(2) 11720(3) 10704(3) 9532(3) 9367(2) 3460.8(14) 5273.6(18) 3637.4(15) 3096.9(16) 2910.0(16) 3244.5(16) 3784.7(16) 3990.0(15) 3849.2(15) 3283.3(16) 4633.7(17) 4836.9(16) 4241.3(16) 4435.8(17) 3771(2) 3981(3) 4834(2) 5465(2) 2721.7(16) 1841.8(18) z 7132.5(3) 7490.5(4) 6331.0(4) 6052.1(4) 5765.8(4) 5746.8(4) 6022.8(4) 6314.6(4) 6633.5(4) 6868.7(4) 6686.6(4) 6954.9(4) 7171.7(4) 7458.5(4) 7676.4(4) 7936.0(5) 7971.6(5) 7744.3(5) 6054.2(3) 6222.4(4) 6230.6(4) 6071.0(4) 5897.6(4) 5886.9(4) 5435.6(4) 6592.5(4) 6638.2(5) 6883.3(6) 7084.6(6) 7044.7(5) 6801.3(4) 6365.1(3) 6702.6(4) 5518.2(3) 5244.8(3) 4971.8(4) 4956.3(4) 5225.7(4) 5505.0(4) 5816.5(3) 6088.1(3) 5840.4(4) 6121.3(4) 6379.6(4) 6687.2(4) 6939.4(4) 7220.9(5) 7240.3(4) 6979.0(5) 5232.9(3) 5435.7(4) Ueq 41.7(3) 62.7(5) 32.1(3) 32.3(3) 34.6(3) 35.7(3) 36.6(4) 34.1(3) 33.9(3) 39.8(4) 38.2(4) 38.8(4) 36.7(4) 39.8(4) 50.7(5) 63.1(6) 63.7(6) 72.8(7) 32.1(3) 39.1(4) 45.0(4) 45.7(4) 44.7(4) 39.2(4) 46.5(4) 39.7(4) 50.8(5) 67.8(7) 75.0(8) 69.1(7) 51.8(5) 36.2(3) 50.2(4) 29.7(3) 31.5(3) 33.6(3) 33.0(3) 32.3(3) 30.7(3) 30.9(3) 33.3(3) 35.0(3) 35.1(3) 32.4(3) 35.8(4) 53.2(5) 64.8(6) 56.6(5) 57.3(5) 32.0(3) 39.5(4) 284 Table 73 (cont’d) Atom z 5414.7(4) C19A 5192.3(4) C20A 4989.2(4) C21A 5008.2(4) C22A 4656.0(4) C23A 5777.5(4) C24A 5882.9(4) C25A 6128.7(4) C26A 6270.1(4) C27A 6164.9(4) C28A 5922.4(4) C29A Table 74. Anisotropic Displacement Parameters (×104) L2*. Atom U23 -3.4(6) N1 N2 19.3(9) C1 -2.1(6) C2 -1.4(6) -1.7(7) C3 C4 4.5(7) C5 2.0(7) C6 -3.1(7) -4.8(6) C7 C8 -1.9(7) C9 -3.9(7) C10 -3.9(7) -5.8(7) C11 C12 -4.8(7) C13 3.6(9) C14 10.8(10) 17.2(10) C15 C16 28.9(13) C17 -2.4(6) C18 -2.9(7) C19 3.0(7) -3.7(8) C20 C21 -10.1(8) C22 -3.5(7) C23 12.0(8) -2.9(7) C24 C25 3.7(9) C26 -0.7(11) C27 -23.6(11) -25.7(11) C28 C29 -17.3(9) N1A 0.1(6) N2A 6.7(7) 0.1(6) C1A C2A -1.2(6) C3A -3.3(6) x y 1510(2) 3118.5(18) 2069(2) 2343.5(17) 2944(2) 2877.0(18) 3261.0(18) 4177.2(16) 3037.6(19) 9134.6(16) 4634.3(16) 8996.1(16) 4070.8(18) 10138.7(17) 4689(2) 10826.0(19) 5889(2) 10383(2) 6463(2) 9260(2) 5842.7(17) 8564.9(18) U11 U22 U33 36.5(7) 40.1(8) 48.4(8) 59.9(11) 76.1(13) 52.5(10) 30.2(7) 30.4(8) 36.0(8) 31.9(8) 29.5(8) 35.9(8) 33.8(8) 34.3(9) 36.1(8) 32.0(8) 34.3(8) 41.2(9) 33.2(8) 26.3(8) 50.7(10) 30.4(8) 30.5(8) 41.4(9) 32.6(8) 29.6(8) 40.1(8) 43.6(9) 37.3(9) 38.8(9) 37.2(8) 42.0(9) 36.1(8) 38.6(9) 41.7(10) 37.0(8) 33.9(8) 34.3(9) 42.8(9) 48.6(10) 36.7(9) 35.1(8) 57.2(12) 49.1(11) 45.7(10) 72.4(15) 63.0(14) 53.0(12) 49.4(12) 65.5(14) 77.2(15) 69.6(15) 88.1(18) 61.0(13) 37.7(8) 28.7(8) 30.5(7) 43.2(9) 35.8(9) 38.4(9) 57.0(11) 33.5(9) 45.0(10) 52.6(11) 26.6(8) 59.3(11) 46.7(10) 36.9(10) 50.6(10) 42.9(9) 35.7(9) 38.9(9) 47.2(10) 43.2(10) 49.6(10) 46.1(9) 28.5(8) 43.6(9) 54.8(11) 37.9(10) 57.9(11) 83.5(17) 40.0(11) 75.3(15) 107(2) 48.1(13) 66.1(15) 56.1(13) 70.4(15) 79.4(16) 50.3(11) 54.7(12) 49.6(11) 41.1(7) 36.8(7) 31.2(7) 67.0(10) 42.8(9) 40.3(8) 30.8(7) 26.8(7) 32.2(7) 35.2(8) 28.8(8) 31.2(7) 41.1(9) 29.3(8) 30.6(8) 285 Ueq 46.6(4) 48.1(4) 46.3(4) 38.0(4) 40.5(4) 33.2(3) 40.0(4) 49.1(5) 54.0(5) 51.3(5) 40.4(4) U13 2.6(6) 5.7(8) 4.6(6) 4.6(6) 4.7(6) 5.8(6) 4.4(7) 2.8(6) 6.9(6) 3.9(7) 7.6(6) 11.2(7) 10.0(6) 10.7(7) 2.0(8) -5.4(10) 11.4(10) 6.8(11) 8.3(6) 3.3(7) 6.4(8) 15.6(8) 4.4(8) 0.8(7) 5.8(8) -6.6(7) -14.6(9) -37.5(13) -32.7(15) -9.6(11) -3.6(8) 4.8(5) -0.6(7) 6.5(6) 7.3(6) 3.7(6) U12 -2.9(6) -17.6(9) 1.3(6) 0.3(6) 1.0(6) 3.6(6) -0.1(6) 1.3(6) 2.6(6) -3.8(7) -0.3(7) -4.0(7) -0.4(7) -1.3(7) -8.9(9) -2.1(11) -3.5(12) -23.8(13) -1.5(6) -0.1(7) 5.6(8) -6.6(8) -7.5(8) 0.8(7) -1.0(8) 4.0(7) -5.3(8) -13.2(11) 12.9(13) 21.4(13) 8.1(9) -0.3(6) 7.8(8) 1.8(6) -0.6(6) -3.3(6) U33 32.0(8) 36.2(8) 33.0(8) 31.3(8) 32.7(8) 30.8(8) 36.1(8) 31.6(8) 34.1(8) 40.3(10) 38.9(10) 35.9(10) 45.4(11) 30.1(7) 39.5(9) 47.3(10) 50.9(11) 42.3(10) 32.7(8) 35.5(9) 32.2(8) 42.6(9) 48.4(10) 42.5(10) 45.9(10) 40.5(9) U23 2.3(6) 0.3(6) 0.2(6) 0.5(6) -1.7(6) 0.0(6) 3.2(6) 1.0(6) 2.1(7) 6.8(9) 4.3(10) 11.4(9) 11.9(9) -0.1(6) -2.8(7) 3.9(8) -1.0(8) -8.6(7) -0.6(7) 4.3(7) 0.7(6) -5.3(7) -15.0(8) -12.9(9) 1.9(9) 1.0(7) U13 4.6(6) 4.4(6) 3.8(6) 3.4(6) 4.2(6) 10.0(6) 6.9(6) 2.4(6) -1.7(6) 11.6(8) 12.3(10) -7.7(9) -5.3(10) 3.1(6) 12.9(7) 14.5(8) 5.4(9) 12.6(8) 11.1(7) -1.9(7) 5.3(6) 5.0(7) 13.7(8) 2.3(8) -6.4(8) 1.4(7) U12 0.4(6) -1.2(6) -0.5(6) -4.4(6) 0.7(6) 2.3(7) 4.1(6) -4.1(6) -5.6(7) 11.2(10) 3.6(13) -8.0(11) 9.0(10) -1.4(6) -3.5(7) -11.9(8) -9.4(8) -1.7(8) -4.5(7) -4.6(7) -6.6(6) -3.8(7) -12.5(9) -23.1(10) -11.2(9) -3.0(7) Table 74 (cont’d) U22 Atom 30.6(8) C4A 23.6(7) C5A 27.2(8) C6A 28.0(8) C7A 32.4(8) C8A 31.8(8) C9A 29.3(8) C10A 31.1(8) C11A 33.5(8) C12A 55.7(12) C13A 68.7(15) C14A 53.9(12) C15A 46.6(11) C16A 27.8(8) C17A 34.5(9) C18A 39.4(10) C19A 26.6(9) C20A 34.0(9) C21A 33.6(9) C22A 30.3(8) C23A 29.9(8) C24A 34.2(9) C25A 40.1(10) C26A 61.3(13) C27A 62.5(13) C28A 39.2(9) C29A Table 75. Bond Lengths in Å for L2*. Atom Length/Å N1 1.343(2) 1.346(2) N1 N2 1.342(2) N2 1.341(3) C1 1.411(2) 1.408(2) C1 C1 1.490(2) C2 1.394(2) C2 1.495(2) C3 1.391(2) 1.387(2) C4 C4 1.504(2) C5 1.399(2) C6 1.491(2) 1.389(2) C7 C7 1.398(2) C9 1.368(2) C10 1.381(2) 1.486(2) C11 C12 1.375(3) C13 1.381(3) U11 36.7(8) 37.2(8) 32.1(7) 33.7(8) 34.9(8) 43.2(9) 40.3(9) 34.4(8) 39.3(9) 64.5(12) 87.8(17) 78.7(14) 79.1(14) 38.3(8) 45.8(9) 54.5(11) 67.1(12) 63.5(12) 48.8(9) 55.2(10) 37.9(8) 43.6(9) 60.0(12) 58.0(12) 44.6(10) 41.5(9) Atom C8 C11 C12 C16 C2 C6 C7 C3 C17 C4 C5 C23 C6 C24 C8 C9 C10 C11 C12 C13 C14 286 Table 75 (cont’d) Atom C15 C16 C18 C22 C19 C20 C21 C22 C25 C29 C26 C27 C28 C29 C8A C11A C12A C16A C2A C6A C7A C3A C17A C4A C5A C23A C6A C24A C8A C9A C10A C11A C12A C13A C14A C15A C16A C18A C22A C19A C20A C21A C22A C25A C29A C26A C27A C28A C29A Atom C14 C15 C17 C17 C18 C19 C20 C21 C24 C24 C25 C26 C27 C28 N1A N1A N2A N2A C1A C1A C1A C2A C2A C3A C4A C4A C5A C6A C7A C7A C9A C10A C11A C12A C13A C14A C15A C17A C17A C18A C19A C20A C21A C24A C24A C25A C26A C27A C28A Length/Å 1.371(3) 1.370(3) 1.392(2) 1.390(2) 1.390(2) 1.381(3) 1.378(3) 1.385(2) 1.393(3) 1.392(3) 1.385(3) 1.376(4) 1.380(4) 1.384(3) 1.343(2) 1.350(2) 1.343(2) 1.342(2) 1.412(2) 1.406(2) 1.495(2) 1.392(2) 1.490(2) 1.392(2) 1.387(2) 1.506(2) 1.398(2) 1.492(2) 1.393(2) 1.385(2) 1.374(2) 1.382(2) 1.491(2) 1.369(3) 1.388(3) 1.355(3) 1.368(3) 1.389(2) 1.395(2) 1.383(2) 1.386(3) 1.380(3) 1.380(2) 1.392(2) 1.394(2) 1.388(2) 1.385(3) 1.379(3) 1.382(2) 287 Table 76. Bond Angles in ° for L2*. Atom Atom C8 C11 C16 C12 C7 C2 C6 C2 C6 C7 C1 C17 C1 C3 C3 C17 C4 C2 C3 C23 C5 C3 C23 C5 C4 C6 C1 C24 C5 C1 C24 C5 C8 C1 C8 C9 C9 C1 C7 N1 C10 C7 C9 C11 N1 C10 C12 N1 C10 C12 N2 C11 N2 C13 C13 C11 C14 C12 C15 C13 C16 C14 N2 C15 C2 C18 C22 C2 C22 C18 C19 C17 C18 C20 C21 C19 C20 C22 C21 C17 C6 C25 C29 C6 C29 C25 C26 C24 C27 C25 C28 C26 C27 C29 C28 C24 C8A C11A C12A C16A C2A C7A Atom N1 N2 C1 C1 C1 C2 C2 C2 C3 C4 C4 C4 C5 C6 C6 C6 C7 C7 C7 C8 C9 C10 C11 C11 C11 C12 C12 C12 C13 C14 C15 C16 C17 C17 C17 C18 C19 C20 C21 C22 C24 C24 C24 C25 C26 C27 C28 C29 N1A N2A C1A Angle/° 117.89(15) 117.67(19) 119.01(14) 118.87(14) 122.11(14) 121.58(14) 120.01(15) 118.39(14) 121.55(15) 120.59(15) 117.92(15) 121.49(16) 122.42(15) 123.67(15) 119.14(15) 117.17(15) 121.61(15) 116.47(15) 121.76(15) 124.04(16) 120.07(16) 119.56(16) 121.89(16) 117.46(15) 120.65(15) 116.81(16) 122.00(17) 121.18(16) 119.02(19) 119.7(2) 117.8(2) 123.8(2) 121.10(15) 120.22(15) 118.68(15) 120.37(17) 120.29(17) 119.56(17) 120.49(17) 120.54(16) 119.70(17) 122.02(16) 118.18(18) 120.7(2) 120.4(2) 119.6(2) 120.4(2) 120.7(2) 117.62(14) 117.46(17) 121.12(14) 288 Table 76 (cont’d) Atom C1A C1A C2A C2A C2A C3A C4A C4A C4A C5A C6A C6A C6A C7A C7A C7A C8A C9A C10A C11A C11A C11A C12A C12A C12A C13A C14A C15A C16A C17A C17A C17A C18A C19A C20A C21A C22A C24A C24A C24A C25A C26A C27A C28A C29A Atom C2A C7A C17A C1A C17A C2A C23A C3A C23A C6A C24A C1A C24A C1A C1A C8A C7A C7A C11A C10A C12A C12A C11A C13A C11A C14A C13A C16A C15A C2A C22A C2A C17A C20A C19A C22A C17A C6A C29A C6A C24A C25A C26A C29A C24A Atom C6A C6A C1A C3A C3A C4A C3A C5A C5A C4A C1A C5A C5A C8A C9A C9A N1A C10A C9A N1A N1A C10A N2A N2A C13A C12A C15A C14A N2A C18A C18A C22A C19A C18A C21A C20A C21A C25A C25A C29A C26A C27A C28A C27A C28A Angle/° 118.75(14) 120.13(13) 122.83(14) 119.42(14) 117.75(14) 122.41(14) 120.90(14) 117.65(14) 121.45(14) 121.91(14) 122.45(14) 119.86(14) 117.65(14) 121.00(14) 122.37(14) 116.61(14) 124.03(15) 120.52(15) 119.06(15) 122.16(14) 117.53(14) 120.31(15) 116.94(15) 122.17(16) 120.88(16) 118.9(2) 119.6(2) 118.39(18) 123.5(2) 122.70(14) 118.16(15) 119.14(14) 120.84(16) 120.15(16) 119.71(16) 120.02(17) 121.12(16) 120.38(15) 118.45(15) 121.10(15) 120.82(17) 119.96(18) 119.64(17) 120.59(18) 120.53(18) 289 Table 77. Hydrogen Fractional Atomic Coordinates (×104) and Equivalent Isotropic Displacement Parameters (Å2×103) for L2*. Atom H3 H5 H8 H9 H10 H13 H14 H15 H16 H18 H19 H20 H21 H22 H23A H23B H23C H25 H26 H27 H28 H29 H3A H5A H8A H9A H10A H13A H14A H15A H16A H18A H19A H20A H21A H22A H23D H23E H23F H25A H26A H27A H28A H29A y 6767.54 10083.47 7147.75 5978.21 4798.55 4963.26 3654.11 2392.81 2482.38 4666.35 2479.14 1693.37 3085.84 5264.98 8885.23 10090.39 8923.36 10131 11569.27 11872.11 10670 9213.74 6677.01 9847.47 7403.85 4806.97 3765.45 5458.86 4373.95 2633.79 2021.68 4928.07 2764.38 1467.61 2360.47 4530.81 10046.45 8903.24 8927.93 10445.18 11583.35 10840.99 8968.02 7803.33 x 9620.5 10621.24 11430.34 7756.65 7626.36 11268.53 11155.26 9253.89 7538.44 10988.91 10484.17 8561.79 7190.16 7692.24 11138.83 10318.15 9567.62 12250.36 12518.16 10806.85 8848.66 8574.14 2548.36 4017.06 2749.85 5025.93 5367.94 3189.6 3539.51 4986.01 6058.7 1471.32 910.4 1854.82 3321.07 3843.77 3050.23 2183.39 3747.2 3269.83 4298.28 6305.69 7274.85 6234.53 z 5583.23 6013.62 6841.8 6539.46 6990.94 7649.3 8085.84 8144.57 7767.4 6329.81 6344.09 6080.44 5786.89 5766.7 5354.45 5459.74 5293.87 6502.59 6912.06 7246.6 7182.18 6776.95 4793.32 5220.27 6076.93 5664.89 6137.44 6922.43 7395.07 7426.85 6993.58 5587.48 5550.19 5179.94 4839.47 4868.81 4699.52 4555.78 4521.28 5787.5 6198.47 6435.07 6257.91 5855.45 Ueq 42 44 48 46 47 61 76 76 87 47 54 55 54 47 70 70 70 61 81 90 83 62 40 39 40 42 42 64 78 68 69 47 56 58 56 46 61 61 61 48 59 65 62 48 290 APPENDIX B NMR 291 1H NMR in CDCl3 (500 MHz) H3C Br 23 Bpin Figure 56. 1H NMR of 23 292 13C NMR in CDCl3 (125 MHz) Br 23 H3C Bpin Figure 57. 13C NMR of 23 293 1H NMR in CDCl3 (500 MHz) Br NC Bpin 24 Figure 58. 1H NMR of 24 294 13C NMR in CDCl3 (125 MHz) Br 24 NC Bpin Figure 59. 13C NMR of 24 295 1H NMR in CDCl3 (500 MHz) Me2N Br 25 Bpin Figure 60. 1H NMR of 25 296 13C NMR in CDCl3 (125 MHz) Br 25 Bpin Me2N Figure 61. 13C NMR of 25 297 1H NMR in CDCl3 (500 MHz) H3C H3C Br 26 Bpin Figure 62. 1H NMR of 26 298 13C NMR in CDCl3 (125 MHz) H3C H3C Br 26 Bpin Figure 63. 13C NMR of 26 299 1H NMR in CDCl3 (500 MHz) Br 27 Cl Bpin Figure 64. 1H NMR of 27 300 13C NMR in CDCl3 (125 MHz) Br 27 Cl Bpin Figure 65. 13C NMR of 27 301 1H NMR in CDCl3 (500 MHz) Br 28 F3C Bpin Figure 66. 1H NMR of 28 302 13C NMR in CDCl3 (125 MHz) Br 28 F3C Bpin Figure 67. 13C NMR of 28 303 1H NMR in CDCl3 (500 MHz) Cl 29 F3C Bpin Figure 68. 1H NMR of 29 304 13C NMR in CDCl3 (125 MHz) Cl 29 F3C Bpin Figure 69. 13C NMR of 29 305 1H NMR (CDCl3) 500 MHz Ph 31 Bpin H3C 5 8 7 . 1 6 7 . 1 5 7 . 2 4 7 . 2 3 7 . 0 0 . 1 0 0 3 . 0 0 . 1 7 1 . 2 1 1 . 1 2 4 2 . 6 3 . 1 1 5 3 . 7 9 3 1 . 14 13 12 11 10 9 8 7 6 f1 (ppm) 5 4 3 2 1 0 -1 -2 Figure 70. 1H NMR of 31 306 18000 17000 16000 15000 14000 13000 12000 11000 10000 9000 8000 7000 6000 5000 4000 3000 2000 1000 0 -1000 13C NMR (CDCl3) 125 MHz Ph 31 Bpin H3C 0 2 . 1 4 1 . 2 6 0 4 1 . 3 6 7 3 1 . 8 2 4 3 1 . 7 8 0 3 1 . 6 6 0 3 1 . 6 5 8 2 1 . 6 2 7 2 1 . 6 0 7 2 1 . 1 8 3 8 . 7 8 4 2 3 3 . 1 2 65 60 55 50 45 40 35 30 25 20 15 10 5 0 -5 230 220 210 200 190 180 170 160 150 140 130 120 110 f1 (ppm) 100 90 80 70 60 50 40 30 20 10 0 -10 Figure 71. 13C NMR of 31 307 1H NMR (CDCl3) 500 MHz Ph 32 NC Bpin 2 2 8 . 6 0 8 . 3 9 7 . 0 6 7 . 7 4 7 . 1 4 7 . 0 0 . 1 8 9 0 . 7 9 0 . 9 0 2 . 0 1 . 2 0 1 . 1 7 3 . 1 0 0 3 1 . 14 13 12 11 10 9 8 7 6 f1 (ppm) 5 4 3 2 1 0 -1 -2 Figure 72. 1H NMR of 32 308 8000 7500 7000 6500 6000 5500 5000 4500 4000 3500 3000 2500 2000 1500 1000 500 0 -500 13C NMR (CDCl3) 125 MHz Ph 32 NC Bpin 3 6 . 1 4 1 . 6 8 8 3 1 6 1 . 7 2 1 . 0 5 7 3 1 . 2 9 6 3 1 . 7 8 2 3 1 . 0 0 9 2 1 . 5 2 8 2 1 . 6 8 8 1 1 . 7 5 2 1 1 . 5 5 4 8 . 7 8 4 2 60 55 50 45 40 35 30 25 20 15 10 5 0 -5 200 190 180 170 160 150 140 130 120 110 100 f1 (ppm) 90 80 70 60 50 40 30 20 10 0 -10 Figure 73. 13C NMR of 32 309 1H NMR (CDCl3) 500 MHz Ph Cl Bpin 35 1 9 7 . 7 7 7 . 7 6 7 . 1 6 7 . 5 4 7 . 7 3 7 . 0 0 . 1 1 9 0 . 3 0 . 1 4 1 . 2 2 3 2 . 8 1 . 1 7 3 . 1 . 1 0 4 1 14 13 12 11 10 9 8 7 6 f1 (ppm) 5 4 3 2 1 0 -1 -2 Figure 74. 1H NMR of 35 310 7000 6500 6000 5500 5000 4500 4000 3500 3000 2500 2000 1500 1000 500 0 -500 . 7 4 2 4 1 . 1 7 9 3 1 . 2 4 4 3 1 . 7 7 8 2 1 . 5 7 7 2 1 9 1 . 7 2 1 8 1 . 3 3 1 9 4 . 1 3 1 . 3 8 9 2 1 . 1 2 4 8 6 8 4 2 . 13C NMR (CDCl3) 125 MHz Ph Cl Bpin 35 230 220 210 200 190 180 170 160 150 140 130 120 110 f1 (ppm) 100 90 80 70 60 50 40 30 20 10 0 -10 Figure 75. 13C NMR of 35 311 40 35 30 25 20 15 10 5 0 2 2 8 . 6 0 8 . 3 9 7 . 5 6 7 . 8 4 7 . 0 4 7 . 1H NMR (CDCl3) 500 MHz Ph F3C Bpin 36 0 0 . 1 2 0 . 1 6 3 2 . 5 0 . 1 9 9 0 . 0 1 . 2 9 3 . 1 6 8 2 1 . 12.5 12.0 11.5 11.0 10.5 10.0 9.5 9.0 8.5 8.0 7.5 7.0 6.5 5.5 6.0 f1 (ppm) 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0 -0.5 -1.0 Figure 76. 1H NMR of 36 312 8000 7500 7000 6500 6000 5500 5000 4500 4000 3500 3000 2500 2000 1500 1000 500 0 -500 6 2 . 1 4 1 . 0 7 9 3 1 . 0 7 6 3 1 . 4 7 0 3 1 . 8 4 0 3 1 . 5 0 0 3 1 . 8 8 8 2 1 . 2 9 7 2 1 . 8 2 7 2 1 . 7 4 6 2 1 . 7 3 5 2 1 . 0 2 3 2 1 . 6 3 4 8 8 8 4 2 . 13C NMR (CDCl3) 125 MHz Ph F3C Bpin 36 220 210 200 190 180 170 160 150 140 130 120 100 110 f1 (ppm) 90 80 70 60 50 40 30 20 10 0 Figure 77. 13C NMR of 36 313 120 110 100 90 80 70 60 50 40 30 20 10 0 -10 1H NMR (CDCl3) 500 MHz Ph Bpin 38 9 8 7 . 2 6 7 . 5 4 7 . 6 3 7 . 0 0 2 . 6 1 . 4 7 1 . 2 8 0 . 1 6 3 . 1 4 5 3 1 . 14 13 12 11 10 9 8 7 6 f1 (ppm) 5 4 3 2 1 0 -1 -2 Figure 78. 1H NMR of 38 314 7000 6500 6000 5500 5000 4500 4000 3500 3000 2500 2000 1500 1000 500 0 -500 13C NMR (CDCl3) 125 MHz Ph Bpin 38 . 6 8 3 4 1 . 9 9 0 4 1 . 3 2 5 3 1 . 5 4 6 2 1 . 5 7 8 2 1 . 4 5 7 2 1 . 2 2 7 2 1 . 1 8 3 8 8 8 4 2 . 230 220 210 200 190 180 170 160 150 140 130 120 110 f1 (ppm) 100 90 80 70 60 50 40 30 20 10 0 -10 Figure 79. 13C NMR of 38 315 50 45 40 35 30 25 20 15 10 5 0 -5 5 1 . 8 9 9 7 . 9 7 7 . 4 7 7 . 9 6 7 . 3 2 7 . 4 4 2 . 6 3 . 1 1H NMR (CDCl3) 500 MHz 0 7 8 . N H3C Bpin 41 14 13 12 11 10 9 8 7 6 f1 (ppm) 5 4 3 2 1 0 -1 -2 Figure 80. 1H NMR of 41 316 1900 1800 1700 1600 1500 1400 1300 1200 1100 1000 900 800 700 600 500 400 300 200 100 0 -100 1H NMR (CDCl3) 500 MHz . 8 5 7 5 1 . 9 4 9 4 1 N H3C Bpin 41 . 4 7 8 3 1 . 3 8 7 3 1 . 4 6 6 3 1 . 3 0 6 3 1 . 5 6 0 3 1 6 9 . 1 2 1 . 6 8 0 2 1 4 8 3 8 . 9 8 4 2 . 0 3 . 1 2 230 220 210 200 190 180 170 160 150 140 130 120 110 f1 (ppm) 100 90 80 70 60 50 40 30 20 10 0 -10 Figure 81. 13C NMR of 41 317 85 80 75 70 65 60 55 50 45 40 35 30 25 20 15 10 5 0 -5 3 8 7 . 0 6 7 . 1 5 7 . 6 4 7 . 4 3 7 . 1H NMR (CDCl3) 500 MHz Ph H3C Bpin 42 6 2 . 1 8 2 . 1 8 8 . 1 3 1 . 1 6 5 3 . 7 3 2 . 6 3 . 1 4 4 3 . 0 0 2 1 . 13 12 11 10 9 8 7 6 f1 (ppm) 5 4 3 2 1 0 -1 -2 Figure 82. 1H NMR of 42 318 7000 6500 6000 5500 5000 4500 4000 3500 3000 2500 2000 1500 1000 500 0 -500 . 2 3 7 3 1 . 3 2 5 3 1 8 1 . 5 3 1 . 2 7 4 3 1 5 5 . 1 3 1 . 0 3 8 2 1 . 8 0 8 2 1 . 5 4 3 2 1 . 0 7 2 2 1 9 4 9 8 . 8 0 9 8 . 6 9 3 8 . 8 8 4 2 . 6 0 . 1 2 13C NMR (CDCl3) 125 MHz Ph H3C Bpin 42 190 180 170 160 150 140 130 120 110 100 f1 (ppm) 90 80 70 60 50 40 30 20 10 Figure 83. 13C NMR of 42 319 55 50 45 40 35 30 25 20 15 10 5 0 -5 IH NMR (CDCl3) 500 MHz Ph Bpin 43 9 7 7 . 5 5 7 . 5 3 7 . 0 0 2 . 0 2 4 . 8 1 . 3 6 3 . 1 7 7 5 1 . 14 13 12 11 10 9 8 7 6 f1 (ppm) 5 4 3 2 1 0 -1 -2 Figure 84. 1H NMR of 43 320 6500 6000 5500 5000 4500 4000 3500 3000 2500 2000 1500 1000 500 0 -500 . 9 2 6 3 1 . 8 5 4 3 1 5 6 . 1 3 1 . 6 7 0 3 1 . 5 3 8 2 1 . 4 9 5 2 1 4 1 . 3 2 1 13C NMR (CDCl3) 125 MHz Ph Bpin 43 220 210 200 190 180 170 160 150 140 130 120 110 100 f1 (ppm) 9 6 0 9 . 3 5 9 8 . 6 9 3 8 . 9 8 4 2 . 90 80 70 60 50 40 30 20 10 0 Figure 85. 13C NMR of 43 321 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 -10 1H NMR (CDCl3) 500 MHz 8 7 7 . 3 4 7 . 4 7 6 . 3 8 5 . 0 3 5 . 6 3 . 1 Bpin 47 13 12 11 10 9 8 0 0 2 . 6 1 . 2 7 1 . 1 7 3 2 . 1 0 4 . 1 6 f1 (ppm) 5 4 3 2 1 0 -1 8 0 4 1 . Figure 86. 1H NMR of 47 322 11000 10000 9000 8000 7000 6000 5000 4000 3000 2000 1000 0 -1000 13C NMR (CDCl3) 125 MHz Bpin 47 7 1 . 0 4 1 . 9 9 4 3 1 . 4 8 6 3 1 . 9 4 5 2 1 . 5 8 4 1 1 . 6 7 3 8 6 8 4 2 . 230 220 210 200 190 180 170 160 150 140 130 120 110 f1 (ppm) 100 90 80 70 60 50 40 30 20 10 0 -10 Figure 87. 13C NMR of 47 323 32 30 28 26 24 22 20 18 16 14 12 10 8 6 4 2 0 -2 13C NMR (CDCl3) 125 MHz 5 7 7 . 2 2 7 . 5 6 2 . nBu Bpin 52 0 0 2 . 9 1 . 2 8 3 2 . 1 6 . 1 6 3 . 1 5 3 . 1 3 9 0 . 9 5 2 . 8 4 . 1 7 4 3 1 . 6 9 3 . 14 13 12 11 10 9 8 7 6 f1 (ppm) 5 4 3 2 1 0 -1 -2 Figure 88. 1H NMR of 52 324 13000 12000 11000 10000 9000 8000 7000 6000 5000 4000 3000 2000 1000 0 -1000 13C NMR (CDCl3) 125 MHz nBu Bpin 52 . 0 4 6 4 1 . 0 8 4 3 1 . 1 9 7 2 1 0 6 3 8 . 9 8 5 3 . 0 5 3 3 . 6 8 4 2 . 7 3 2 2 . 6 9 3 1 . 230 220 210 200 190 180 170 160 150 140 130 120 110 f1 (ppm) 100 90 80 70 60 50 40 30 20 10 0 -10 Figure 89. 13C NMR of 52 325 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 -10 1H NMR (CDCl3) 500 MHz OMe Cl Bpin 67c F Bpin 0 6 7 . 0 6 7 . 7 9 3 . 7 9 3 . 2 4 . 1 3 3 . 1 14 13 12 11 10 9 8 7 0 0 . 1 6 9 2 . 4 6 f1 (ppm) 5 Figure 90. 1H NMR of 67c 326 3 2 1 0 -1 -2 12000 11000 10000 9000 8000 7000 6000 5000 4000 3000 2000 1000 0 -1000 3 1 . 2 1 3 2 2 1 . . 5 0 9 5 1 0 1 . 7 5 1 . 4 6 5 4 1 . 5 4 2 3 1 . 2 5 8 2 1 0 6 4 8 . 3 4 . 1 6 . 7 9 4 2 13C NMR (CDCl3) 125 MHz OMe Cl Bpin 67c F Bpin 230 220 210 200 190 180 170 160 150 140 130 120 110 f1 (ppm) 100 90 80 70 60 50 40 30 20 10 0 -10 Figure 91. 13C NMR of 67c 327 110 100 90 80 70 60 50 40 30 20 10 0 -10 1H NMR (CDCl3) 500 MHz CF3 Bpin 68c Bpin 0 9 7 . 2 7 7 . 0 6 7 . 0 0 . 1 3 1 . 1 9 1 . 1 8 3 . 1 . 1 7 4 2 14 13 12 11 10 9 8 7 6 f1 (ppm) 5 4 3 2 1 0 -1 -2 Figure 92. 1H NMR of 68c 328 8500 8000 7500 7000 6500 6000 5500 5000 4500 4000 3500 3000 2500 2000 1500 1000 500 0 -500 . 8 4 3 3 1 1 0 . 1 3 1 . 6 7 0 3 1 . 4 9 9 2 1 . 9 6 5 2 1 . 3 3 5 2 1 6 1 . 3 2 1 . 7 3 4 8 9 8 4 2 . 13C NMR (CDCl3) 125 MHz CF3 Bpin 68c Bpin 200 190 180 170 160 150 140 130 120 110 100 f1 (ppm) 90 80 70 60 50 40 30 20 10 0 -10 Figure 93. 13C NMR of 68c 329 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 -10 1H NMR (CDCl3) 500 MHz 7 1 . 8 0 5 . 1 5 3 . 1 CF3 Bpin 68* Bpin pinB 14 13 12 11 10 9 0 0 2 . 8 7 6 f1 (ppm) 5 4 3 2 1 0 -1 -2 8 1 . 2 1 7 1 . 4 2 Figure 94. 1H NMR of 68* 330 12000 11000 10000 9000 8000 7000 6000 5000 4000 3000 2000 1000 0 -1000 5 9 . 8 4 1 0 1 . 5 3 1 6 8 . 9 2 1 6 3 . 2 2 1 2 2 . 1 2 1 8 0 . 0 2 1 5 9 . 8 1 1 4 4 . 4 8 6 9 . 5 2 0 9 . 4 2 13 C NMR (CDCl3) 125 MHz CF3 Bpin 68* Bpin pinB 220 210 200 190 180 170 160 150 140 130 120 110 80 70 60 50 40 30 20 10 0 -10 100 90 f1 (ppm) Figure 95. 13C NMR of 68* 331 1400 1300 1200 1100 1000 900 800 700 600 500 400 300 200 100 0 -100 1H NMR (CDCl3) 500 MHz OCF3 Bpin Bpin 69c 0 7 7 . 6 4 7 . 2 2 7 . 0 0 . 1 1 0 . 1 1 1 . 1 8 3 . 1 7 3 . 1 3 5 0 1 . 3 6 2 1 . 14 13 12 11 10 9 8 7 6 f1 (ppm) 5 4 3 2 1 0 -1 -2 Figure 96. 1H NMR of 69c 332 4500 4000 3500 3000 2500 2000 1500 1000 500 0 . 2 2 0 5 1 . 1 2 0 5 1 . 5 4 5 3 1 13 C NMR (CDCl3) 125 MHz OCF3 Bpin Bpin 69c . 3 4 5 2 1 5 4 . 1 2 1 4 2 . 1 2 1 . 0 4 9 1 1 . 0 4 9 1 1 . 5 3 7 1 1 . 9 2 4 8 6 1 . 4 8 6 8 4 2 . 230 220 210 200 190 180 170 160 150 140 130 120 110 f1 (ppm) 100 90 80 70 60 50 40 30 20 10 0 -10 Figure 97. 13C NMR of 69c 333 60 55 50 45 40 35 30 25 20 15 10 5 0 -5 1H NMR (CDCl3) 500 MHz 5 7 7 . 8 4 . 1 3 3 . 1 OCF3 pinB Bpin Bpin 69* 14 13 12 11 10 9 0 0 2 . 8 7 6 f1 (ppm) 5 4 3 2 1 0 -1 -2 0 8 2 1 . 9 1 . 5 2 Figure 98. 1H NMR of 69* 334 17000 16000 15000 14000 13000 12000 11000 10000 9000 8000 7000 6000 5000 4000 3000 2000 1000 0 -1000 13C NMR (CDCl3) 900 MHz 9 2 . 5 3 1 2 7 . 0 3 1 8 5 . 0 3 1 4 4 . 0 3 1 0 3 . 0 3 1 7 4 . 6 2 1 7 2 . 5 2 1 8 8 . 5 8 5 7 . 5 8 6 2 . 7 2 0 2 . 6 2 OCF3 pinB Bpin Bpin 69* 190 180 170 160 150 140 130 120 110 100 f1 (ppm) 90 80 70 60 50 40 30 20 10 Figure 99. 13C NMR of 69* 335 1300 1200 1100 1000 900 800 700 600 500 400 300 200 100 0 -100 1H NMR (CDCl3) 500 MHz 5 7 7 . 8 4 . 1 3 3 . 1 Cl F Bpin Bpin 70c 17000 16000 15000 14000 13000 12000 11000 10000 9000 8000 7000 6000 5000 4000 3000 2000 1000 0 -1000 14 13 12 11 10 9 0 0 2 . 8 7 6 f1 (ppm) 5 4 3 2 1 0 -1 -2 Figure 100. 1H NMR of 70c 336 0 8 2 1 . 9 1 . 5 2 . 6 2 6 6 1 . 1 3 4 6 1 13 C NMR (CDCl3) 125 MHz Cl F Bpin Bpin 70c . 8 7 5 3 1 . 2 6 0 3 1 . 2 8 7 1 1 . 1 5 4 8 4 9 4 2 . 2 8 4 2 . 70 65 60 55 50 45 40 35 30 25 20 15 10 5 0 -5 230 220 210 200 190 180 170 160 150 140 130 120 110 f1 (ppm) 100 90 80 70 60 50 40 30 20 10 0 -10 Figure 101. 13C NMR of 70c 337 1H NMR (CDCl3) 500 MHz SF5 pinB Bpin 71cʹ 6 3 8 . 3 2 8 . 0 0 . 1 4 1 . 2 6 3 . 1 8 6 6 2 . 14 13 12 11 10 9 8 7 6 f1 (ppm) 5 4 3 2 1 0 -1 -2 Figure 102. 1H NMR of 71cʹ 338 17000 16000 15000 14000 13000 12000 11000 10000 9000 8000 7000 6000 5000 4000 3000 2000 1000 0 -1000 13C NMR (CDCl3) 125 MHz . 4 4 3 5 1 . 6 9 3 4 1 SF5 pinB Bpin 71cʹ . 2 3 4 3 1 . 5 2 4 3 1 . 8 2 4 3 1 . 9 3 4 8 6 2 7 7 . 6 8 4 2 . 250 200 150 100 50 0 230 220 210 200 190 180 170 160 150 140 130 120 110 f1 (ppm) 100 90 80 70 60 50 40 30 20 10 0 -10 Figure 103. 13C NMR of 71cʹ 339 1H NMR (CDCl3) 500 MHz O Bpin 72cʹ pinB 2 2 7 . 1 5 2 . 2 3 . 1 9 2 . 1 14 13 12 11 10 9 8 0 0 . 1 7 6 f1 (ppm) 9 7 3 . 8 4 5 1 . 7 4 5 1 . 5 4 3 2 1 0 -1 -2 340 Figure 104. 1H NMR of 72cʹ 4500 4000 3500 3000 2500 2000 1500 1000 500 0 13C NMR (CDCl3) 125 MHz . 0 2 7 6 1 . 2 4 9 2 1 O Bpin 72cʹ pinB 3 9 3 8 . 9 0 3 8 . . 0 7 4 2 9 3 4 1 . 120 110 100 90 80 70 60 50 40 30 20 10 0 -10 230 220 210 200 190 180 170 160 150 140 130 120 110 f1 (ppm) 100 90 80 70 60 50 40 30 20 10 0 -10 Figure 105. 13C NMR of 72cʹ 341 1H NMR (CDCl3) 500 MHz 6 1 . 7 3 1 . 4 3 3 . 1 2 3 . 1 Bpin N N 73cʹ pinB 4500 4000 3500 3000 2500 2000 1500 1000 500 0 13 12 11 10 9 8 0 0 . 1 7 6 f1 (ppm) 5 2 3 3 . 4 Figure 106. 1H NMR of 73cʹ 342 3 9 . 1 1 5 2 2 1 . 3 2 1 0 -1 13CNMR (CDCl3) 125 MHz Bpin N N 73cʹ pinB . 7 3 4 2 1 . 3 0 4 8 3 4 4 7 . . 9 7 4 2 24 22 20 18 16 14 12 10 8 6 4 2 0 -2 220 210 200 190 180 170 160 150 140 130 120 100 110 f1 (ppm) 90 80 70 60 50 40 30 20 10 0 Figure 107. 13C NMR of 73cʹ 343 1H NMR (CDCl3) 500 MHz Br Br N N 98 1 7 8 . 0 7 8 . 0 7 8 . l 3 c d c 6 2 7 . 9 6 8 . 9 2 8 . 8 2 8 . 8 2 8 . 5 9 7 . 5 9 7 . 4 9 7 . 3 9 7 . 3 9 7 . O D H 5 5 . 1 14 13 12 11 10 9 8 7 6 f1 (ppm) 5 4 3 2 1 0 -1 -2 Figure 108. 1H NMR of 98 344 1000 900 800 700 600 500 400 300 200 100 0 13C NMR (CDCl3) 125 MHz Br Br N N 98 . 5 6 3 5 1 . 8 2 0 5 1 . 1 6 9 3 1 . 1 2 2 2 1 5 4 . 1 2 1 230 220 210 200 190 180 170 160 150 140 130 120 110 f1 (ppm) 100 90 80 70 60 50 40 30 20 10 0 -10 Figure 109. 13C NMR of 98 345 30 28 26 24 22 20 18 16 14 12 10 8 6 4 2 0 -2 1H NMR (CDCl3) 500 MHz pinB Bpin N N 100 1 0 9 . 1 0 9 . 3 4 8 . 2 4 8 . 0 2 8 . 9 1 . 8 14 13 12 11 10 0 0 . 1 9 0 2 . 1 3 2 . 1 8 7 6 f1 (ppm) 7 3 . 1 3 0 4 1 . 5 4 3 2 1 0 -1 -2 346 Figure 110. 1H NMR of 100 2800 2600 2400 2200 2000 1800 1600 1400 1200 1000 800 600 400 200 0 -200 13C NMR (CDCl3) 125 MHz pinB Bpin N N 100 . 8 9 7 5 1 . 8 0 5 5 1 . 5 2 3 4 1 . 2 6 0 2 1 . 1 2 4 8 . 4 7 6 7 . 7 8 4 2 25 20 15 10 5 0 230 220 210 200 190 180 170 160 150 140 130 120 110 f1 (ppm) 100 90 80 70 60 50 40 30 20 10 0 -10 Figure 111. 13C NMR of 100 347 1H NMR (CDCl3) 500 MHz 9 3 7 . 5 2 2 . I Br Br 102 14 13 12 11 10 9 8 7 6 f1 (ppm) 5 4 3 2 1 0 -1 -2 0 0 2 . 8 6 3 . Figure 112. 1H NMR of 102 348 2500 2000 1500 1000 500 0 13C NMR (CDCl3) 125 MHz I Br Br 102 5 0 . 1 4 1 7 9 . 1 3 1 . 7 7 0 3 1 . 6 8 4 0 1 2 4 0 2 . 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 0 -1 -2 230 220 210 200 190 180 170 160 150 140 130 120 110 f1 (ppm) 100 90 80 70 60 50 40 30 20 10 0 -10 Figure 113. 13C NMR of 102 349 1H NMR (CDCl3) 500 MHz I 103 5 0 7 . 2 0 7 . 7 9 6 . 5 9 . 1 0 0 2 . 0 8 3 . 7 3 2 . 3 3 2 . 8 0 3 1 . 9 1 . 3 11.5 11.0 10.5 10.0 9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 f1 (ppm) 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0 -0.5 Figure 114. 1H NMR of 103 350 9000 8000 7000 6000 5000 4000 3000 2000 1000 0 13C NMR (CDCl3) 125 MHz 5 0 . 1 4 1 I 103 7 9 . 1 3 1 . 7 7 0 3 1 . 6 8 4 0 1 2 4 0 2 . 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 0 -1 -2 230 220 210 200 190 180 170 160 150 140 130 120 110 f1 (ppm) 100 90 80 70 60 50 40 30 20 10 0 -10 Figure 115. 13C NMR of 103 351 5 0 8 . 7 8 7 . 5 2 7 . 2 2 7 . 7 7 6 . 7 6 6 . 1H NMR (CDCl3) 500 MHz N N L2 0 0 2 . 5 1 . 2 4 5 3 . 4 6 . 1 2 0 4 . 7 0 7 . 6 4 2 . 3 1 . 2 6 5 8 . 9 3 3 2 . 12.5 12.0 11.5 11.0 10.5 10.0 9.5 9.0 8.5 8.0 7.5 7.0 6.5 5.5 6.0 f1 (ppm) 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0 -0.5 -1.0 Figure 116. 1H NMR of L2 352 16000 15000 14000 13000 12000 11000 10000 9000 8000 7000 6000 5000 4000 3000 2000 1000 0 -1000 . 0 4 2 4 1 7 1 . 1 4 1 . 0 2 7 3 1 4 3 . 1 5 1 . 3 0 9 4 1 13C NMR (CDCl3) 125 MHz N N L2 . 3 3 0 3 1 . 0 2 8 2 1 . 9 3 3 2 1 . 5 9 0 2 1 . 7 3 9 1 1 4 2 . 1 2 5 1 . 1 2 28 26 24 22 20 18 16 14 12 10 8 6 4 2 0 -2 200 190 180 170 160 150 140 130 120 110 100 f1 (ppm) 90 80 70 60 50 40 30 20 10 0 Figure 117. 13C NMR of L2 353