iv To My family, friends, professors, and colleagues v TABLE OF CONTENTS LIST OF TABLES .......................................................................................................... vii LIST OF FIGURES ....................................................................................................... viii Chapter 1 Synthesis And Suzuki Coupling Of B/Sn Bismetallic Arenes ......................1 1.1 Introduction ................................................................................................................1 1.2 Proposed pathways to bismetallic arenes ...................................................................5 1.3 Selective suzuki coupling of the b/sn bismetallic arenes ...........................................9 1.4 Experimental section ................................................................................................12 1.5 Summary ..................................................................................................................21 Chapter 2 Electronics Driven Regioselective Ir-Catalyzted C-H Activation/Borylation Of Fluorinated Benzenes .................................................................. 22 2.1 Introduction ..............................................................................................................22 2.2 Screening borylation conditions ..............................................................................31 2.3 Ligand effects hypothesis ........................................................................................33 2.4 Searching for new ligands ........................................................................................34 2.5 Results and discussions ............................................................................................37 2.6 Tandem borylation-Suzuki coupling ........................................................................41 2.7 Kinetics study of the borylations with electron deficient ligands ............................42 2.7.1 Preparation of stock solutions ...........................................................................43 2.7.2 Preparation of stock solutions ...........................................................................44 2.7.3 Preparation of stock solutions ...........................................................................46 2.7.4 Preparation of stock solutions ...........................................................................49 2.7.5 Preparation of stock solutions ...........................................................................51 2.7.6 Preparation of stock solutions ...........................................................................53 2.7.7 Preparation of stock solutions ...........................................................................55 2.8 Probing the ligand decomposition ...........................................................................57 2.9 Degradation of ttfbpy during borylation ..................................................................60 2.10 Borylation under a H2 atmosphere .........................................................................61 2.11 Temperature effect or borylation reagent effect ....................................................65 2.12 Summary ................................................................................................................66 2.13 Experimental ..........................................................................................................67 Chapter 3 Desymmetrization Of Diboryl Aromatics .......................................................... 86 3.1 Introduction ..............................................................................................................86 3.2 Synthesis of the (PinB)Ar(BF3)Cs salts. ..................................................................90 3.2.1 Desymmetrizing 2,2'-(5-bromo-2-fluoro-1,3-phenylene)bis(BPin) .................90 3.2.2 Desymmetrizing 2,2'-(5-methoxy-2-fluoro-1,3-phenylene)bis(BPin) ..............91 vi 3.3 Synthesis of the (PinB)Ar(BMida). .........................................................................92 3.4 Summary ................................................................................................................102 APPENDIX .....................................................................................................................104 REFERENCES ...............................................................................................................224 vii LIST OF TABLES Table 1. Attempts of borylation of arylstannanes ................................................................6 Table 2. Stannylation of bromophenyl boronic esters .........................................................8 Table 3. Base screening for selective Suzuki couplings of B/Sn bismetallic arenes .........10 Table 4. Selective Suzuki coupling of 2a-f with 8 .............................................................11 Table 5. Borylation screening ............................................................................................32 Table 6. Borylation screening with bpy(CF3)x ligands ......................................................38 Table 7. Borylation of 12a by HBPin ................................................................................41 Table 8. Tandem borylation-Suzuki coupling ...................................................................42 Table 9. Summary of kinectic studies at high concentration .............................................49 Table 10. First order kinetic behavior of borylation of 12a ...............................................53 Table 11. Results of kinetic studies of the borylation of 12c .............................................56 Table 12. Desymmetrizing 2,2'-(5-methoxy-2-fluoro-1,3-phenylene)bis(BPin) ...............91 viii LIST OF FIGURES Figure 1. Different types of bifunctional cross coupling partners .......................................1 -coupling cascade synthesis of mepanipyrim .............................2 Figure 3. One pot C-N/C-C bond formations sequence .......................................................2 Figure 4. Syntheis and Stille coupling of 1,4-B/Sn diene compound ..................................3 Figure 5. Synthesis and Stille coupling of a 1,4-B/Sn benzene ...........................................3 ....4 -type borylation-reduction-stannylation sequence on nitro- ..................................................................................4 Figure 8. Chmeoselective Suzuki coupling of B/Sn bismetalic diene .................................5 Figure 9. Proposed routes to m-B/Sn bismetallic arenes .....................................................6 Figure 10. Synthesis of B/Sn bismetallic arenes via Pd catalyzed stannylation ..................7 Figure 11. Synthesis of 2a via Zn mediated stannylation ....................................................7 Figure 12. Attempts of stannylation on bromoheteroaryl boronic esters .............................9 Figure 13. Suzuki couplings of 1f and 2f with various electrophiles ................................12 Figure 14. Structure of fludrocortisone ..............................................................................22 molecules ...........................................................................................................................23 Figure 16. Borylation of fluorobenzenes or fluorination of aromatic boronic acids and/or esters ..................................................................................................................................24 Figure 17. General Scheme of Balz-Shiemann reaction ....................................................24 Figure 18. Fluorination with DAST ...................................................................................25 Figure 19. An example of asymmetric electrophilic fluorination ......................................25 ix Figure 20. Palladium catalyzed electrophilic C-H fluorinations .......................................25 Figure 21. Lithiation/borylation at cryogentic condition and its possible risk ..................26 Figure 22. General scheme of a Suzuki-Miyaura coupling reaction .................................27 aromatic borylation ....................................................27 Figure 24. Sandmeyer type borylation of ortho fluoroanilines ..........................................28 Figure 25. Pt-catalyzed C-H activation/borylation on fluorobenzene ...............................28 Figure 26. Borylation ortho to F on a 1,4-substituted benzene ..........................................28 Figure 27. Possible synthetic routes for regioselective borylation on 1-fluoro-3-chloro-benzene derivatives ............................................................................................................29 Figure 28. Regiochemical outcomes in borylation of 1,3-disubstituted benzenes ............30 Figure 29. Ligands used for screening ...............................................................................31 Figure 30. Literature synthesis of bis- and tetra- CF3 substituted bipyridines ...................34 Figure 31. Improving the synthesis of 4,4-bistrifluoromethyl bipyridine (btfbpy) ...........35 Figure 32. Proton NMR of the mixture of reduction products, aliphatic part ...................36 Figure 33. Proton NMR of the mixture of reduction products, aromatic part ...................36 Figure 34. 19F NMR of the mixture of reduction products ................................................37 Figure 35. Improving the synthesis of 4,4',5,5'-tetratrifluoromethyl bipyridine (ttfbpy) ..38 Figure 36. Resurrecting the borylation ..............................................................................39 Figure 37. Borylation by HBPin ........................................................................................40 Figure 38. Synthesis of pre-assembled catalyst .................................................................43 Figure 39. Kinetic study of the borylation of 12a ..............................................................43 Figure 40. First order fitting for the reaction described in 2.7.1 ........................................44 Figure 41. 19F NMR of the CF3 region, from bottom to top: 0.0, 1.0, 2.3, 3.5, 4.8, 6.0 hours after substrate (12a) was added. .........................................................................................45 x Figure 42. Kinetic study of the borylation of 12a ..............................................................45 Figure 43. 1st order fitting for the reaction described in 2.7.2 ..........................................46 Figure 44. 19F NMR of the CF3 region, from bottom to top: 0.0, 1.0, 2.3, 3.5, 4.8, 6.0 hours after substrate (12a) was added. .........................................................................................47 Figure 45. Kinetic study of the borylation of 12a ..............................................................47 Figure 46. 1st order fitting for the reaction described in 2.7.3 ...........................................48 Figure 47. 19F NMR of the CF3 region, from bottom to top: 0.0, 1.0, 2.3, 3.5, 4.8, 6.0 hours after substrate (12a) was added ..........................................................................................48 Figure 48. Kinetic study of the borylation of 12a ..............................................................49 Figure 49. First order fitting for the reaction described in 2.7.4 ........................................50 Figure 50. 19F NMR of the CF3 region, from bottom to top: 0.0, 1.0, 2.3, 3.5, 4.8, 6.0 hours after substrate (12a) was added ..........................................................................................51 Figure 51. Kinetic study of the borylation of 12a ..............................................................51 Figure 52. First order fitting for the reaction described in 2.7.5 ........................................51 Figure 53. 19F NMR of the CF3 region, from bottom to top: 0.0, 1.0, 2.3, 3.5, 4.8, 6.0 hours after substrate (12a) was added ..........................................................................................53 Figure 54. Kinetic study of the borylation of 12c ..............................................................54 Figure 55. First order fitting for the reaction described in 2.7.6 ........................................54 Figure 56. Kinetic study of borylation of 12c ....................................................................55 Figure 57. First order fitting for the reaction described in 2.7.7 ........................................56 Figure 58. 1H NMR of the preassembled catalyst (15) treated by B2Pin2 and HBPin in THF-d8, top: Compound 15, mid: Compound 15 and 5 equiv B2Pin2 after 4 h at 298 K, bottom: Additional 5 equiv HBPin added, then after 4 h at 298 K .................................................57 Figure 59. 11B NMR of the preassembled catalyst (15) treated by B2Pin2 and HBPin in THF-d8, top: Compound 15, mid: Compound 15 and 5 equiv B2Pin2 after 4 h at 298 K, bottom: Additional 5 equiv HBPin added, then after 4 h at 298 K ....................................58 xi Figure 60. 19F NMR of the preassembled catalyst (15) treated by B2Pin2 and HBPin in THF-d8, top: Compound 15, mid: Compound 15 and 5 equiv B2Pin2 after 4 h at 298 K, bottom: Additional 5 equiv HBPin added, then after 4 h at 298 K ....................................59 Figure 61. Borylation of 12a by stoichiometric 15 ............................................................59 Figure 62. Borylation of 12c by stoichiometric Ir and ttfbpy ............................................60 Figure 63. Borylation of 12c with stoichiometric Ir and ttfbpy, top: Before heating, mid: 4.5 h Heating, bottom: 9 h Heating ....................................................................................61 Figure 64. H2 influence on borylation................................................................................62 Figure 65. Conversions of the borylation of 12a with HBPin affected by H2 ...................62 Figure 66. Regioselectivity of the borylation of 12a with HBPin affected by H2 .............63 Figure 67. H2 influence on borylation................................................................................63 Figure 68. Borylation of 12a by HBPin affected by H2 .....................................................64 Figure 69. Borylation of 12a by HBPin affected by H2 .....................................................64 Figure 70. Borylation of 12a by HBPin with btfbpy at high temperature .........................65 Figure 71. Borylation of 12a by HBPin at high temperature .............................................66 Figure 72. Borylation with B2Pin2 at higher temperature. .................................................67 Figure 73. Borylation of substrate 12d ..............................................................................73 ..............................................................86 3M salts ........................................................86 boron ...................................................87 Figure 77. Two approaches toward unsymmetric diborates ..............................................88 Figure 78. Desymmetrizing Ar(BPin)2 by H2Mida............................................................88 Figure 79. Desymmetrizing Ar(BPin)2 via Ar(BPin)BF3M salt ........................................89 Figure 80. Desymmetrizing 2,2'-(5-bromo-2-fluoro-1,3-phenylene)bis(BPin) .................89 xii Figure 81. Desymmetrizing 2,2'-(5-methoxy-2-fluoro-1,3-phenylene)bis(BPin) in water ...................................................................................................................................91 Figure 82. 1H NMR of PhBF3Cs in CD3CN ......................................................................92 Figure 83. 11B NMR of PhBF3Cs in CD3CN .....................................................................93 Figure 84. 19F NMR of PhBF3Cs in CD3CN......................................................................94 Figure 85. 11B NMR after adding 1 equiv TMSCl.............................................................94 Figure 86. 19F NMR after adding 1 equiv TMSCl .............................................................95 Figure 87. 11B NMR after adding 2 equiv TMSCl.............................................................95 Figure 88. Activation of PhBF3Cs by TMSCl ...................................................................95 Figure 89. Formation of PhBF3- after adding Na2Mida .....................................................96 Figure 90. Protection of PhBF2 by Mida ligand in DMSO ................................................96 Figure 91. 19F NMR after adding 2 equiv TMSCl .............................................................96 Figure 92. 1H NMR of the crude product of Figure 90 in DMSO-d6 ...............................97 Figure 93. 11B NMR of the crude product of Figure 90 in DMSO-d6 ..............................98 Figure 94. Optimization of the reaction conditions ...........................................................99 Figure 95. Attempted transformation of 17a ...................................................................100 Figure 96. Stepwise transformation of 17a and 17b ........................................................100 Figure 97 119Sn NMR of compound 2a ............................................................................105 Figure 98 11B NMR of compound 2a ..............................................................................106 Figure 99 13C NMR of compound 2a ..............................................................................107 Figure 100 1H NMR of compound 2a..............................................................................108 Figure 101 119Sn NMR of compound 2b .........................................................................109 Figure 102 11B NMR of compound 2b ............................................................................110 Figure 103 13C NMR of compound 2b ............................................................................111 xiii Figure 104 19F NMR of compound 2b .............................................................................112 Figure 105 1H NMR of compound 2b .............................................................................113 Figure 106 119Sn NMR of compound 2c ..........................................................................114 Figure 107 11B NMR of compound 2c .............................................................................115 Figure 108 13C NMR of compound 2c .............................................................................116 Figure 109 1H NMR of compound 2c ..............................................................................117 Figure 110 119Sn NMR of compound 2d .........................................................................118 Figure 111 11B NMR of compound 2d ............................................................................119 Figure 112 13C NMR of compound 2d ............................................................................120 Figure 113 1H NMR of compound 2d .............................................................................121 Figure 114 119Sn NMR of compound 2e ..........................................................................122 Figure 115 11B NMR of compound 2e .............................................................................123 Figure 116 13C NMR of compound 2e .............................................................................124 Figure 117 1H NMR of compound 2e ..............................................................................125 Figure 118 119Sn NMR of compound 2f ..........................................................................126 Figure 119 11B NMR of compound 2f .............................................................................127 Figure 120 13C NMR of compound 2f .............................................................................128 Figure 121 19F NMR of compound 2f..............................................................................130 Figure 122 1H NMR of compound 2f ..............................................................................130 Figure 123 119Sn NMR of compound 4a..........................................................................131 Figure 124 13C NMR of compound 4a ............................................................................132 Figure 125 1H NMR of compound 4a..............................................................................133 Figure 126 119Sn NMR of compound 4b .........................................................................134 xiv Figure 127 13C NMR of compound 4b ............................................................................135 Figure 128 19F NMR of compound 4b .............................................................................136 Figure 129 1H NMR of compound 4b .............................................................................137 Figure 130 119Sn NMR of compound 4c ..........................................................................138 Figure 131 13C NMR of compound 4c .............................................................................139 Figure 132 1H NMR of compound 4c ..............................................................................140 Figure 133 119Sn NMR of compound 4d .........................................................................141 Figure 134 13C NMR of compound 4d ............................................................................142 Figure 135 1H NMR of compound 4d .............................................................................143 Figure 136 119Sn NMR of compound 4e ..........................................................................144 Figure 137 13C NMR of compound 4e .............................................................................145 Figure 138 1H NMR of compound 4e ..............................................................................146 Figure 139 119Sn NMR of compound 4f ..........................................................................147 Figure 140 13C NMR of compound 4f .............................................................................148 Figure 141 19F NMR of compound 4f..............................................................................149 Figure 142 1H NMR of compound 4f ..............................................................................150 Figure 143 119Sn NMR of compound 5............................................................................151 Figure 144 13C NMR of compound 5 ..............................................................................152 Figure 145 1H NMR of compound 5................................................................................153 Figure 146 119Sn NMR of compound 7............................................................................154 Figure 147 13C NMR of compound 7 .............................................................................155 Figure 148 1H NMR of compound 7................................................................................156 Figure 149 13C NMR of compound 11 ............................................................................157 xv Figure 150 19F NMR of compound 11 .............................................................................158 Figure 151 1H NMR of compound 11..............................................................................159 Figure 152 1H NMR of mixture of compounds 13d and .........................................160 Figure 153 11B NMR of mixture of compounds 13d ........................................161 Figure 154 13C NMR of mixture of compounds 13d and ........................................162 Figure 155 19F NMR of mixture of compounds 13d and ........................................163 Figure 156 1H NMR of mixture of compounds 13e and ..........................................164 Figure 157 11B NMR of mixture of compounds 13e and ........................................165 Figure 158 13C NMR of mixture of compounds 13e and ........................................166 Figure 159 19F NMR of mixture of compounds 13e and .........................................167 Figure 160 1H NMR of mixture of compounds 13f and ..........................................168 Figure 161 11B NMR of mixture of compounds 13f and .........................................169 Figure 162 13C NMR of mixture of compounds 13f and .........................................170 Figure 163 19F NMR of mixture of compounds 13f and ..........................................171 Figure 164 1H NMR of mixture of compounds 13a and .........................................172 Figure 165 11B NMR of mixture of compounds 13a and ........................................173 Figure 166 13C NMR of mixture of compounds 13a and ........................................174 Figure 167 19F NMR of mixture of compounds 13a and ........................................175 Figure 168 1H NMR of mixture of compounds 13c and ..........................................176 Figure 169 11B NMR of mixture of compounds 13c and ........................................177 Figure 170 13C NMR of mixture of compounds 13c and ........................................178 Figure 171 19F NMR of mixture of compounds 13c and .........................................179 Figure 172 1H NMR of mixture of compounds 13b and .........................................180 xvi Figure 173 11B NMR of mixture of compounds 13b and ........................................181 Figure 174 13C NMR of mixture of compounds 13b and ........................................182 Figure 175 19F NMR of mixture of compounds 13b and ........................................183 Figure 176 1H NMR of compound 14a............................................................................184 Figure 177 13C NMR of compound 14a ..........................................................................185 Figure 178 19F NMR of compound 14a ...........................................................................186 Figure 179 1H NMR of compound ..........................................................................187 Figure 180 13C NMR of compound .........................................................................188 Figure 181 19F NMR of compound ..........................................................................189 Figure 182 1H NMR of mixture of compounds 14b and .........................................190 Figure 183 19F NMR of mixture of compounds 14b and ........................................191 Figure 184 1H NMR of compound ..........................................................................192 Figure 185 13C NMR of compound .........................................................................193 Figure 186 19F NMR of compound .........................................................................194 Figure 187 1H NMR of compound 14c ............................................................................195 Figure 188 13C NMR of compound 14c ...........................................................................196 Figure 189 19F NMR of compound 14c ...........................................................................197 Figure 190 1H NMR of compound ..........................................................................198 Figure 191 13C NMR of compound .........................................................................199 Figure 192 19F NMR of compound ..........................................................................200 Figure 193 1H NMR of compound 14d ...........................................................................201 Figure 194 13C NMR of compound 14d ..........................................................................202 Figure 195 19F NMR of compound 14d ...........................................................................203 xvii Figure 196 1H NMR of compound ..........................................................................204 Figure 197 13C NMR of compound .........................................................................205 Figure 198 19F NMR of compound .........................................................................206 Figure 199 1H NMR of mixture of compounds 14e and ..........................................207 Figure 200 13C NMR of mixture of compounds 14e and ........................................208 Figure 201 19F NMR of mixture of compounds 14e and .........................................209 Figure 202 1H NMR of mixture of compounds 14f and ..........................................210 Figure 203 1H NMR of mixture of compounds 14f and ..........................................211 Figure 204 19F NMR of mixture of compounds 14f and ..........................................212 Figure 205 1H NMR of mixture of compounds 17a and 18a ..........................................213 Figure 206 11B NMR of mixture of compounds 17a and 18a .........................................214 Figure 207 19F NMR of mixture of compounds 17a and 18a ..........................................215 Figure 208 1H NMR of compound 17b ...........................................................................216 Figure 209 13C NMR of compound 17b ..........................................................................217 Figure 210 1H NMR of compound 19a............................................................................218 Figure 211 13C NMR of compound 19a ..........................................................................219 Figure 212 1H NMR of compound 19b ...........................................................................220 Figure 213 11B NMR of compound 19b ..........................................................................221 Figure 214 13C NMR of compound 19b ..........................................................................222 Figure 215 19F NMR of compound 19b ...........................................................................223 tEnptµJpJJJJJJJJJJ JJJJJnJJnJJJJJJJJJnJJJJJJJJJJnJJ JJJJJnJJJnJJJJJJnJJJJJJJJJJJJJnJJJJJJJJJJJJJJJJJ onovice versain situin situ NMR sampleNMR sample NMR sample:NMR sampleNMR sampleNMR sampleNMR sampled8d8d8JJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJJ JJJJJJJJJJJJJJ.JJJJJJJJ J J J J J J J JJJJJJJJJJJJJJJJJJJJJJJJJ J J J J J J J J J J J J J J J J J JJJJJJJ J J J J J d6JJJJJJJ J J J J J J JJJJJJ J J J J J d6JJJJJJ J J J J J J JJJJJJJJJJJJJJJJJJJJJJN,NN,NN,NJJJJJJ J J J J J J J J J J J J J J JdJ J J dJ J dJ J dJ J J JJd6d6J J J J J JJ J J J J J J J 105 NMR spectra 106 107 108 109 110 111 112 113 114 115 116 117 118 119 120 121 122 123 124 125 126 127 128 129 130 131 132 133 134 135 136 137 138 139 140 141 142 143 144 145 146 147 148 149 150 151 152 153 154 155 156 157 158 159 160 161 162 163 164 165 166 167 168 169 170 171 172 173 174 175 176 177 178 179 180 181 182 183 184 185 186 187 188 189 190 191 192 193 194 195 196 197 198 199 200 201 202 203 204 205 206 207 208 209 210 211 212 213 214 215 216 217 218 219 220 221 222 223 J Am Chem Soc121Science 295J. Am. Chem. Soc. 124Chem. Rev.110Chem Commun46Chem Sci3J Am Chem Soc127J Am Chem Soc125Angew Chem Int Edit50Boronic Acids: Preparation and Applications in Organic Synthesis, Medicine and Materials, 2nd edAngew Chem Int Edit25Chem Rev95Liebigs Ann-ReclAngew Chem Int Edit49J Am Chem Soc121Org Lett6Chem-Eur J15Org Lett14Synlett Org. Lett. 7Angew. Chem. Int. Ed. 42J. Am. Chem. Soc. 130J. Org. Chem. 54Arch. Pharm. 329Org Lett14Org Lett15J Org Chem79Angew Chem Int Edit52J. Am. Chem. Soc. 130J. Am. Chem. Soc. 127J. Org. Chem. 71J. Am. Chem. Soc. 129Chem. Comm. J. Am. Chem. Soc. 127J. Am. Chem. Soc. 133Chemistry of TinOrganotin ChemistryScience 295J. Am. Chem. Soc. 124Chem. Rev.110J Org Chem77J Am Chem Soc127J. Am. Chem. Soc. 125Org. Biomol. Chem. 3Adv. Synth. Catal. 346Synthesis Synthesis Chem. Soc. Rev. 35Adv. Synth. Catal. 349Angew. Chem. Int. Ed. 47Chem. Rev. 111Org Lett14J Am Chem Soc75J Am Chem Soc76Chem Soc Rev37Chem Rev114Science334J Med Chem51J Fluorine Chem107Angew Chem Int Edit44Accounts Chem Res38Accounts Chem Res37Chem Rev96Chem Rev104Chem Rev110J Am Chem Soc131J Am Chem Soc128Org Process Res Dev18Org Lett10J Am Chem Soc130Chem Commun51Chem-Eur J20J Am Chem Soc137J Am Chem Soc121Science 295J. Am. Chem. Soc. 124Chem. Rev.110J Am Chem Soc131Chem Commun46J Am Chem Soc134Angew Chem Int Edit52Chem Commun46Chem Sci3J Am Chem Soc135Synthetic Communications23B Chem Soc Jpn63Inorg Chem31J Am Chem Soc127Tetrahedron Lett57Org Process Res Dev18Tetrahedron64Angew Chem Int Edit48Angew Chem Int Edit48Org Lett11J Am Chem Soc129Org Lett10J Am Chem Soc130J Am Chem Soc129J Am Chem Soc130J Am Chem Soc130J. Am. Chem. Soc.130Org. Lett.4