5-fluoro-1-hydroxy-3H-2,1-benzoxaborole

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: This compound was made from 18m in the same manner as compound 19b: 1H NMR (300 MHz, DMSO-d6) δ (ppm) 4.95 (s, 2H), 7.29 (td, J=9.0, 2.7 Hz, 1H), 7.41-7.46 (m, 2H), 9.29 (s, 1H); ESI-MS m/z 151 (M−H)−; HPLC purity 100%; Anal (C7H6BFO2) C, H.

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: This compound was made from 18h in the same manner as compound 19b: mp 124-128° C.; 1H NMR (300 MHz, DMSO-d6) δ (ppm) 4.53 (d, 2H), 4.94 (s, 2H), 5.24 (t, 1H), 7.26 (d, 1H), 7.33 (s, 1H), 7.64 (d, 1H), 9.08 (s, 1H); ESI-MS m/z 163 (M−H)−; HPLC purity 100%.

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: This compound was made from 18g in the same manner as compound 19b: mp 102-104° C.; 1H NMR (300 MHz, DMSO-d6) δ (ppm) 3.77 (s,3H), 4.91 (s, 2H), 6.88 (d, J=8.1 Hz, 1H), 6.94 (s, 1H), 7.60 (d, J=8.1 Hz, 1H), 8.95 (s, 1H); ESI-MS m/z 163 (M−H)−; HPLC purity 100%; Anal (C8HgBO3) C, H.

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: This compound was made from 18e in the same manner as compound 19b: mp 124-128° C.; 1H NMR (300 MHz, DMSO-d6) δ (ppm) 2.33 (s, 3H), 4.91 (s, 2H), 7.13 (d, J=7.2 Hz, 1H), 7.18 (s, 1H), 7.58 (d, J=7.2 Hz, 1H), 9.05 (s, 1H); ESI-MS m/z 147 (M−H)−; HPLC purity 99.0%; Anal (C8HgBO2) C, H.

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: This compound was made from 18d in the same manner as compound 19b: mp 142-144° C. 1H NMR (300 MHz, DMSO-d6) δ (ppm) 4.96 (s, 2H), 7.38 (d, J=7.8 Hz, 1H), 7.49 (s, 1H), 7.71 (d, J=7.8 Hz, 1H), 9.30 (s, 1H); ESI-MS m/z 167 (M−H)−; HPLC purity 99.0%; Anal (C7H6ClO2.0.1H2O)C, H.

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 5b (73.2 g, 293 mmol) in dry THF (400 mL) was added n-butyllithium (1.6 M in hexanes; 200 mL) over 45 min at −78° C. under nitrogen atmosphere. Anion precipitated. After 5 min, (i-PrO)3B (76.0 mL, 330 mmol) was added over 10 min, and the mixture was allowed to warm to room temperature over 1.5 h. Water and 6 N HCl (55 mL) were added, and the solvent was removed under reduced pressure to about a half volume. The mixture was poured into ethyl acetate and water. The organic layer was washed with brine and dried over anhydrous Na2SO4. The solvent was removed under reduced pressure. To a solution of the residue in tetrahydrofuran (360 mL) was added 6 N HCl (90 mL), and the mixture was stirred at 30° C. overnight. The solvent was removed under reduced pressure to about a half volume. The mixture was poured into ethyl acetate and water. The organic layer was washed with brine and dried over anhydrous Na2SO4. The solvent was removed under reduced pressure, and the residue was treated with i-Pr2O/hexane to give 19b (26.9 g, 60%) as a white powder: mp 118-120° C.; 1H NMR (300 MHz, DMSO-d6) δ (ppm) 4.95 (s, 2H), 7.15 (m, 1H), 7.24 (dd, J=9.7, 1.8 Hz, 1H), 7.74 (dd, J=8.2, 6.2 Hz, 1H), 9.22 (s, 1H); ESI-MS m/z 151 (M−H)−; HPLC purity 97.8%; Anal (C7H6BFO2) C, H. Anion precipitated the solvent was removed under reduced pressure to about a half volume The mixture was poured into ethyl acetate and water The organic layer was washed with brine dried over anhydrous Na2SO4 The solvent was removed under reduced pressure To a solution of the residue in tetrahydrofuran (360 mL) was added 6 N HCl (90 mL) The solvent was removed under reduced pressure to about a half volume The mixture was poured into ethyl acetate and water The organic layer was washed with brine dried over anhydrous Na2SO4 The solvent was removed under reduced pressure the residue was treated with i-Pr2O/hexane

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Charge a 100 mL round bottom flask with trifluoro-methanesulfonic acid 6-methanesulfonyloxy-1-[4-(2-piperidin-1-yl-ethoxy)-benzoyl]-naphthalen-2-yl ester (2.3 g, 3.8 mmol), 5-fluoro-3H-benzo[c][1,2]oxaborol-1-ol (1.16 g, 7.6 mmol) and Pd(PPh3)4 (220 mg, 0.19 mmol) and purge with nitrogen. Add degassed DME (36 mL) and 2M Na2CO3 (4 mL) to the flask and plunge into a 75° C. oil bath and stir overnight. Pour the reaction into saturated aqueous sodium bicarbonate and extract with methylene chloride. Wash the organic layer with water and dry with sodium sulfate. Filter and concentrate to an amber foam. Purify the crude material on silica gel (1% to 6% methanol in methylene chloride) to yield 1.6 g (73%) of the title compound as a tan foam. 1H NMR (CDCl3) δ7.98 (d, J=8.4 Hz, 1H), 7.90 (d, J=2.5 Hz, 1H), 7.60 (bs, 3H), 7.43 (d, J=8.4 Hz, 1H), 7.35 (d, J=8.6 Hz, 1H), 7.23 (bs, 11), 6.90-6.70 (m, 4H), 4.40-4.25 (m, 2H), 4.12 (m, 2H), 3.23 (s, 3H), 2.76 (t, J=5.4 Hz, 2H), 2.49 (bs, 4H), 1.59 (m, 5H), 1.45 (m, 1H). purge with nitrogen Add degassed DME (36 mL) and 2M Na2CO3 (4 mL) to the flask and plunge into a 75° C. oil bath Pour the reaction into saturated aqueous sodium bicarbonate extract with methylene chloride Wash the organic layer with water dry with sodium sulfate Filter concentrate to an amber foam Purify the crude material on silica gel (1% to 6% methanol in methylene chloride)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Charge a 100 mL round bottom flask with trifluoro-methanesulfonic acid 6-methanesulfonyloxy-1-[4-(2-piperidin-1-yl-ethoxy)-benzoyl]-naphthalen-2-yl ester (2.3 g, 3.8 mmol), 5-fluoro-3H-benzo[c][1,2]oxaborol-1-ol (1.16 g, 7.6 mmol) and Pd(PPh3)4 (220 mg, 0.19 mmol) and purge with nitrogen. Add degassed DME (36 mL) and 2M Na2CO3 (4 mL) to the flask and plunge into a 75° C. oil bath and stir overnight. Pour the reaction into saturated aqueous sodium bicarbonate and extract with methylene chloride. Wash the organic layer with water and dry with sodium sulfate. Filter and concentrate to an amber foam. Purify the crude material on silica gel (1% to 6% methanol in methylene chloride) to yield 1.6 g (73%) of the title compound as a tan foam. 1H NMR (CDCl3) δ7.98 (d, J=8.4 Hz, 1H), 7.90 (d, J=2.5 Hz, 1H), 7.60 (bs, 3H), 7.43 (d, J=8.4 Hz, 1H), 7.35 (d, J=8.6 Hz, 1H), 7.23 (bs, 11), 6.90-6.70 (m, 4H), 4.40-4.25 (m, 2H), 4.12 (m, 2H), 3.23 (s, 3H), 2.76 (t, J=5.4 Hz, 2H), 2.49 (bs, 4H), 1.59 (m, 5H), 1.45 (m, 1H). purge with nitrogen Add degassed DME (36 mL) and 2M Na2CO3 (4 mL) to the flask and plunge into a 75° C. oil bath Pour the reaction into saturated aqueous sodium bicarbonate extract with methylene chloride Wash the organic layer with water dry with sodium sulfate Filter concentrate to an amber foam Purify the crude material on silica gel (1% to 6% methanol in methylene chloride)

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Dissolve 1-bromo-2-(1-ethoxy-ethoxymethyl)-4-fluoro-benzene(5.4 g, 19.5 mmol) in dry THF (100 mL) and cool to −78° C. under nitrogen. Add butyl lithium (2.5M in Hexanes, 10.2 mL, 25.4 mmol) dropwise at −78° C. Upon complete addition, stir the reaction at −78° C. for 10 minutes and then add trimethyl borate (4.4 mL, 39 mmol) and warm the reaction to room temperature. Pour the reaction into 1N HCl (100 mL) and stir for 1 hour. Extract the biphasic mixture with ether three times. Dry the combined organic layers with sodium sulfate, filter and concentrate in vacuo. Triturate the oily residue with cold hexanes to yield 2.1 g (70%) of the title compound as a white solid. 1H NMR (d6-DMSO) 9.18 (s, 1H), 7.70 (dd, J=8.2, 5.8 Hz, 1H), 7.20 (dd, J=9.5, 2.7 Hz, 1H), 7.11 (m, 1H), 4.92 (s, 1H). dropwise at −78° C Upon complete addition the reaction at −78° C. for 10 minutes the reaction to room temperature Pour stir for 1 hour Extract the biphasic mixture with ether three times Dry the combined organic layers with sodium sulfate filter concentrate in vacuo Triturate the oily residue with cold hexanes

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Dissolve 1-bromo-2-(1-ethoxy-ethoxymethyl)-4-fluoro-benzene(5.4 g, 19.5 mmol) in dry THF (100 mL) and cool to −78° C. under nitrogen. Add butyl lithium (2.5M in Hexanes, 10.2 mL, 25.4 mmol) dropwise at −78° C. Upon complete addition, stir the reaction at −78° C. for 10 minutes and then add trimethyl borate (4.4 mL, 39 mmol) and warm the reaction to room temperature. Pour the reaction into 1N HCl (100 mL) and stir for 1 hour. Extract the biphasic mixture with ether three times. Dry the combined organic layers with sodium sulfate, filter and concentrate in vacuo. Triturate the oily residue with cold hexanes to yield 2.1 g (70%) of the title compound as a white solid. 1H NMR (d6-DMSO) 9.18 (s, 1H), 7.70 (dd, J=8.2, 5.8 Hz, 1H), 7.20 (dd, J=9.5, 2.7 Hz, 1H), 7.11 (m, 1H), 4.92 (s, 1H). dropwise at −78° C Upon complete addition the reaction at −78° C. for 10 minutes the reaction to room temperature Pour stir for 1 hour Extract the biphasic mixture with ether three times Dry the combined organic layers with sodium sulfate filter concentrate in vacuo Triturate the oily residue with cold hexanes

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: This compound was made from 18m in the same manner as compound 19b: 1H NMR (300 MHz, DMSO-d6) δ (ppm) 4.95 (s, 2H), 7.29 (td, J=9.0, 2.7 Hz, 1H), 7.41-7.46 (m, 2H), 9.29 (s, 1H); ESI-MS m/z 151 (M−H)−; HPLC purity 100%; Anal (C7H6BFO2) C, H.