(2-Bromophenoxy)(tert-butyl)dimethylsilane

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

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

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

Procedure: A solution of bromo-2-[(tert-butyl)dimethylsiloxy]benzene (2.1 g, 7.4 mmol) in Et2O (35 mL) was cooled to −78° C. and treated with 1.7 M tert-butyllithium in hexanes (8.6 mL, 15 mmol). The reaction was stirred for 30 min and a solution of (R)-tert-butyl 3-(N-methoxy-N-methylcarbamoyl)piperidine-1-carboxylate (1.0 g, 3.7 mmol) in Et2O was added slowly. The reaction was allowed to stir and warm to rt over a two hour period. Sat'd aq ammonium chloride was added to quench the reaction. The aq phase was extracted with Et2O three times. The combined organic layers were washed with brine and dried over MgSO4. The solvent was removed by evaporation and the crude product was purified by flash chromatography on silica gel eluting with EtOAc/hexanes to give a mixture of (2-tert-butyldimethylsiloxyphenyl)((R)—N-Boc-piperidin-3-yl)methanone and (2-hydroxyphenyl)((R)—N-Boc-piperidin-3-yl)methanone. A −20° C. solution of the crude mixture in tetrahydrofuran was treated with 1.3 M 4-methoxybutylmagensium chloride in THF (14.9 mL, 19.4 mmol). The reaction was stirred and allowed to warm to rt over a two hour period. The reaction was quenched with ammonium chloride. The aq layer was extracted with Et2O. The combined organic layers were dried over MgSO4 and filtered. The solvent was evaporated and the crude product was purified by flash chromatography on silica gel eluting with EtOAc/hexanes to afford 2-((S)-1-hydroxy-5-methoxy-1-((R)—N-Boc-piperidin-3-yl)pentyl)[tert-butyldimethylsiloxy]benzene (874 mg, 47%) and 2-((S)-1-hydroxy-5-methoxy-1-((R)—N-Boc-piperidin-3-yl)pentyl)phenol (650 mg, 45%). to stir to quench the reaction The aq phase was extracted with Et2O three times The combined organic layers were washed with brine dried over MgSO4 The solvent was removed by evaporation the crude product was purified by flash chromatography on silica gel eluting with EtOAc/hexanes to give The reaction was stirred to warm to rt over a two hour period The reaction was quenched with ammonium chloride The aq layer was extracted with Et2O The combined organic layers were dried over MgSO4 filtered The solvent was evaporated the crude product was purified by flash chromatography on silica gel eluting with EtOAc/hexanes

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

Procedure: A solution of bromo-2-[(tert-butyl)dimethylsiloxy]benzene (2.1 g, 7.4 mmol) in Et2O (35 mL) was cooled to −78° C. and treated with 1.7 M tert-butyllithium in hexanes (8.6 mL, 15 mmol). The reaction was stirred for 30 min and a solution of (R)-tert-butyl 3-(N-methoxy-N-methylcarbamoyl)piperidine-1-carboxylate (1.0 g, 3.7 mmol) in Et2O was added slowly. The reaction was allowed to stir and warm to rt over a two hour period. Sat'd aq ammonium chloride was added to quench the reaction. The aq phase was extracted with Et2O three times. The combined organic layers were washed with brine and dried over MgSO4. The solvent was removed by evaporation and the crude product was purified by flash chromatography on silica gel eluting with EtOAc/hexanes to give a mixture of (2-tert-butyldimethylsiloxyphenyl)((R)—N-Boc-piperidin-3-yl)methanone and (2-hydroxyphenyl)((R)—N-Boc-piperidin-3-yl)methanone. A −20° C. solution of the crude mixture in tetrahydrofuran was treated with 1.3 M 4-methoxybutylmagensium chloride in THF (14.9 mL, 19.4 mmol). The reaction was stirred and allowed to warm to rt over a two hour period. The reaction was quenched with ammonium chloride. The aq layer was extracted with Et2O. The combined organic layers were dried over MgSO4 and filtered. The solvent was evaporated and the crude product was purified by flash chromatography on silica gel eluting with EtOAc/hexanes to afford 2-((S)-1-hydroxy-5-methoxy-1-((R)—N-Boc-piperidin-3-yl)pentyl)[tert-butyldimethylsiloxy]benzene (874 mg, 47%) and 2-((S)-1-hydroxy-5-methoxy-1-((R)—N-Boc-piperidin-3-yl)pentyl)phenol (650 mg, 45%). to stir to quench the reaction The aq phase was extracted with Et2O three times The combined organic layers were washed with brine dried over MgSO4 The solvent was removed by evaporation the crude product was purified by flash chromatography on silica gel eluting with EtOAc/hexanes to give The reaction was stirred to warm to rt over a two hour period The reaction was quenched with ammonium chloride The aq layer was extracted with Et2O The combined organic layers were dried over MgSO4 filtered The solvent was evaporated the crude product was purified by flash chromatography on silica gel eluting with EtOAc/hexanes

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

Procedure: A solution of 2-bromophenol (5 mL, 47 mmol), imidazole (8 g, 118 mmol) and tert-butyldimethylsilyl chloride (8.6 g, 57 mmol) in DMF (50 mL) was stirred at rt overnight. The reaction was treated with water (150 mL) and extracted with Et2O (4×25 mL). The organic phase was washed with 50% aq lithium chloride solution twice, dried over MgSO4 and filtered. The solvent was evaporated and the crude product was purified by filtration through silica gel, washing with 1:1 EtOAc/hexanes to afford bromo-2-[(tert-butyl)dimethylsiloxy]benzene (13.4 g, 99%). extracted with Et2O (4×25 mL) The organic phase was washed with 50% aq lithium chloride solution twice dried over MgSO4 filtered The solvent was evaporated the crude product was purified by filtration through silica gel washing with 1:1 EtOAc/hexanes

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

Procedure: A solution of bromo-2-[(tert-butyl)dimethylsiloxy]benzene (2.1 g, 7.4 mmol) in Et2O (35 mL) was cooled to −78° C. and treated with 1.7 M tert-butyllithium in hexanes (8.6 mL, 15 mmol). The reaction was stirred for 30 min and a solution of (R)-tert-butyl 3-(N-methoxy-N-methylcarbamoyl)piperidine-1-carboxylate (1.0 g, 3.7 mmol) in Et2O was added slowly. The reaction was allowed to stir and warm to rt over a two-hour period. Saturated aq ammonium chloride was added to quench the reaction. The aq phase was extracted with Et2O three times. The combined organic layers were washed with brine and dried over MgSO4. The solvent was removed by evaporation and the crude product was purified by flash chromatography on silica gel eluting with EtOAc/hexanes to give a mixture of (2-tert-butyldimethylsiloxyphenyl)((R)—N-Boc-piperidin-3-yl)methanone and (2-hydroxyphenyl)((R)—N-Boc-piperidin-3-yl)methanone. A −20° C. solution of the crude mixture in tetrahydrofuran was treated with 1.3 M 4-methoxybutylmagnesium chloride in THF (14.9 mL, 19.4 mmol). The reaction was stirred and allowed to warm to rt over a two hour period. The reaction was quenched with ammonium chloride. The aq layer was extracted with Et2O. The combined organic layers were dried over MgSO4 and filtered. The solvent was evaporated and the crude product was purified by flash chromatography on silica gel eluting with EtOAc/hexanes to afford 2-((S)-1-hydroxy-5-methoxy-1-((R)—N-Boc-piperidin-3-yl)pentyl)[tertbutyldimethylsiloxy]benzene (874 mg, 47%) and 2-((S)-1-hydroxy-5-methoxy-1-((R)—N-Boc-piperidin-3-yl)pentyl)phenol (650 mg, 45%). to stir to quench the reaction The aq phase was extracted with Et2O three times The combined organic layers were washed with brine dried over MgSO4 The solvent was removed by evaporation the crude product was purified by flash chromatography on silica gel eluting with EtOAc/hexanes to give The reaction was stirred to warm to rt over a two hour period The reaction was quenched with ammonium chloride The aq layer was extracted with Et2O The combined organic layers were dried over MgSO4 filtered The solvent was evaporated the crude product was purified by flash chromatography on silica gel eluting with EtOAc/hexanes

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

Procedure: A solution of bromo-2-[(tert-butyl)dimethylsiloxy]benzene (2.1 g, 7.4 mmol) in Et2O (35 mL) was cooled to −78° C. and treated with 1.7 M tert-butyllithium in hexanes (8.6 mL, 15 mmol). The reaction was stirred for 30 min and a solution of (R)-tert-butyl 3-(N-methoxy-N-methylcarbamoyl)piperidine-1-carboxylate (1.0 g, 3.7 mmol) in Et2O was added slowly. The reaction was allowed to stir and warm to rt over a two-hour period. Saturated aq ammonium chloride was added to quench the reaction. The aq phase was extracted with Et2O three times. The combined organic layers were washed with brine and dried over MgSO4. The solvent was removed by evaporation and the crude product was purified by flash chromatography on silica gel eluting with EtOAc/hexanes to give a mixture of (2-tert-butyldimethylsiloxyphenyl)((R)—N-Boc-piperidin-3-yl)methanone and (2-hydroxyphenyl)((R)—N-Boc-piperidin-3-yl)methanone. A −20° C. solution of the crude mixture in tetrahydrofuran was treated with 1.3 M 4-methoxybutylmagnesium chloride in THF (14.9 mL, 19.4 mmol). The reaction was stirred and allowed to warm to rt over a two hour period. The reaction was quenched with ammonium chloride. The aq layer was extracted with Et2O. The combined organic layers were dried over MgSO4 and filtered. The solvent was evaporated and the crude product was purified by flash chromatography on silica gel eluting with EtOAc/hexanes to afford 2-((S)-1-hydroxy-5-methoxy-1-((R)—N-Boc-piperidin-3-yl)pentyl)[tertbutyldimethylsiloxy]benzene (874 mg, 47%) and 2-((S)-1-hydroxy-5-methoxy-1-((R)—N-Boc-piperidin-3-yl)pentyl)phenol (650 mg, 45%). to stir to quench the reaction The aq phase was extracted with Et2O three times The combined organic layers were washed with brine dried over MgSO4 The solvent was removed by evaporation the crude product was purified by flash chromatography on silica gel eluting with EtOAc/hexanes to give The reaction was stirred to warm to rt over a two hour period The reaction was quenched with ammonium chloride The aq layer was extracted with Et2O The combined organic layers were dried over MgSO4 filtered The solvent was evaporated the crude product was purified by flash chromatography on silica gel eluting with EtOAc/hexanes

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

Procedure: A solution of bromo-2-[(tert-butyl)dimethylsiloxy]benzene (2.1 g, 7.4 mmol) in Et2O (35 mL) was cooled to −78° C. and treated with 1.7 M tert-butyllithium in hexanes (8.6 mL, 15 mmol). The reaction was stirred for 30 min and a solution of (R)-tert-butyl 3-(N-methoxy-N-methylcarbamoyl)piperidine-1-carboxylate (1.0 g, 3.7 mmol) in Et2O was added slowly. The reaction was allowed to stir and warm to rt over a two-hour period. Saturated aq ammonium chloride was added to quench the reaction. The aq phase was extracted with Et2O three times. The combined organic layers were washed with brine and dried over MgSO4. The solvent was removed by evaporation and the crude product was purified by flash chromatography on silica gel eluting with EtOAc/hexanes to give a mixture of (2-tert-butyldimethylsiloxyphenyl)((R)—N-Boc-piperidin-3-yl)methanone and (2-hydroxyphenyl)((R)—N-Boc-piperidin-3-yl)methanone. A −20° C. solution of the crude mixture in tetrahydrofuran was treated with 1.3 M 4-methoxybutylmagnesium chloride in THF (14.9 mL, 19.4 mmol). The reaction was stirred and allowed to warm to rt over a two hour period. The reaction was quenched with ammonium chloride. The aq layer was extracted with Et2O. The combined organic layers were dried over MgSO4 and filtered. The solvent was evaporated and the crude product was purified by flash chromatography on silica gel eluting with EtOAc/hexanes to afford 2-((S)-1-hydroxy-5-methoxy-1-((R)—N-Boc-piperidin-3-yl)pentyl)[tertbutyldimethylsiloxy]benzene (874 mg, 47%) and 2-((S)-1-hydroxy-5-methoxy-1-((R)—N-Boc-piperidin-3-yl)pentyl)phenol (650 mg, 45%). to stir to quench the reaction The aq phase was extracted with Et2O three times The combined organic layers were washed with brine dried over MgSO4 The solvent was removed by evaporation the crude product was purified by flash chromatography on silica gel eluting with EtOAc/hexanes to give The reaction was stirred to warm to rt over a two hour period The reaction was quenched with ammonium chloride The aq layer was extracted with Et2O The combined organic layers were dried over MgSO4 filtered The solvent was evaporated the crude product was purified by flash chromatography on silica gel eluting with EtOAc/hexanes

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

Procedure: Magnesium turnings (0.53 g, 22 mmol) and 20 mL of THF were placed into a two-necked flask. Next, tert-butyldimethylsilyloxyphenyl bromide (5.64 g, 19.6 mmol) was added and the mixture was heated under reflux for 2 h before it was cooled to room temperature. The brown mixture was added to a solution of trimethyl borate (2.43 g, 24 mmol) in 5 mL of THF through a dropping funnel at −78° C. and allowed to warm to room temperature overnight. After hydrolysis with 90 mL of ca. 0.1 M hydrochloric acid followed by standard work-up with methyl tert-butyl ether, the brown residue was washed with 20 mL of cold hexane, and the resulting white product (3.86 g, 78%) was dried in vacuo. Mp: 175° C. (1H NMR (300 MHZ, CDCl3): δ0.25 (s, 6H); 1.01 (s, 9H); 6.95 (d, J=8.5 Hz, 2H); 8.11 (d, J 8.5 Hz, 2H). 13C NMR (75 MHZ, CDCl3): δ−4.3; 18.1; 25.7; 119.8; 137.5; 159.8. Reference: Bolm, C.; Derrien, N.; Seger, A. Synlett 1996, 387. the mixture was heated under reflux for 2 h before it to warm to room temperature overnight the brown residue was washed with 20 mL of cold hexane the resulting white product (3.86 g, 78%) was dried in vacuo

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

Procedure: A solution of bromo-2-[(tert-butyl)dimethylsiloxy]benzene (2.1 g, 7.4 mmol) in Et2O (35 mL) was cooled to −78° C. and treated with 1.7 M tert-butyllithium in hexanes (8.6 mL, 15 mmol). The reaction was stirred for 30 min and a solution of (R)-tert-butyl 3-(N-methoxy-N-methylcarbamoyl)piperidine-1-carboxylate (1.0 g, 3.7 mmol) in Et2O was added slowly. The reaction was allowed to stir and warm to rt over a two hour period. Sat'd aq ammonium chloride was added to quench the reaction. The aq phase was extracted with Et2O three times. The combined organic layers were washed with brine and dried over MgSO4. The solvent was removed by evaporation and the crude product was purified by flash chromatography on silica gel eluting with EtOAc/hexanes to give a mixture of (2-tert-butyldimethylsiloxyphenyl)((R)-N-Boc-piperidin-3-yl)methanone and (2-hydroxyphenyl)((R)-N-Boc-piperidin-3-yl)methanone. A −20° C. solution of the crude mixture in tetrahydrofuran was treated with 1.3 M 4-methoxybutylmagensium chloride in THF (14.9 mL, 19.4 mmol). The reaction was stirred and allowed to warm to rt over a two hour period. The reaction was quenched with ammonium chloride. The aq layer was extracted with Et2O. The combined organic layers were dried over MgSO4 and filtered. The solvent was evaporated and the crude product was purified by flash chromatography on silica gel eluting with EtOAc/hexanes to afford 2-((S)-1-hydroxy-5-methoxy-1-((R)-N-Boc-piperidin-3-yl)pentyl)[tert-butyldimethylsiloxy]benzene (874 mg, 47%) and 2-((S)-1-hydroxy-5-methoxy-1-((R)-N-Boc-piperidin-3-yl)pentyl)phenol (650 mg, 45%). to stir to quench the reaction The aq phase was extracted with Et2O three times The combined organic layers were washed with brine dried over MgSO4 The solvent was removed by evaporation the crude product was purified by flash chromatography on silica gel eluting with EtOAc/hexanes to give The reaction was stirred to warm to rt over a two hour period The reaction was quenched with ammonium chloride The aq layer was extracted with Et2O The combined organic layers were dried over MgSO4 filtered The solvent was evaporated the crude product was purified by flash chromatography on silica gel eluting with EtOAc/hexanes

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

Procedure: A solution of 2-bromophenol (5 mL, 47 mmol), imidazole (8 g, 118 mmol) and tert-butyldimethylsilyl chloride (8.6 g, 57 mmol) in DMF (50 mL) was stirred at rt overnight. The reaction was treated with water (150 mL) and extracted with Et2O (4×25 mL). The organic phase was washed with 50% aq lithium chloride solution twice, dried over MgSO4 and filtered. The solvent was evaporated and the crude product was purified by filtration through silica gel, washing with 1:1 EtOAc/hexanes to afford bromo-2-[(tert-butyl)dimethylsiloxy]benzene (13.4 g, 99%). extracted with Et2O (4×25 mL) The organic phase was washed with 50% aq lithium chloride solution twice dried over MgSO4 filtered The solvent was evaporated the crude product was purified by filtration through silica gel washing with 1:1 EtOAc/hexanes