2-(2-bromophenyl)propan-2-ol

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

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

Procedure: To a stirred solution of 2-(2-bromophenyl)propan-2-ol (step 1, 6.91 g, 32.1 mmol) in tetrahydrofuran (32 mL) was added dropwise a 1.59 M solution of butyllithium in tetrahydrofuran (46.5 mL, 73.9 mmol) at −78° C. for 20 min and the mixture was stirred for 1 h at the same temperature. To the mixture was added dropwise a solution of 1-methylpiperidin-4-one (5.09 g, 45.0 mmol) in tetrahydrofuran (18 mL) at −78° C. for 10 min. This resulting mixture was slowly warmed up to room temperature and stirred for 18 h at the same temperature. The reaction mixture was quenched by the addition of water, and concentrated to give an orange residue. The crude material was partitioned between diethyl ether and water, and then the organic layer washed with brine, dried over sodium sulfate, and evaporated. The residue was purified by column chromatography on silica gel (150 g) eluting with hexane/ethyl acetate (5/1), dichloromethane/methanol (10/1), then dichloromethane/methanol/triethylamine (10/1/1) to afford 4.62 g (58%) of the title compound as a slight yellow syrup: stirred for 18 h at the same temperature The reaction mixture was quenched by the addition of water concentrated to give an orange residue The crude material was partitioned between diethyl ether and water the organic layer washed with brine dried over sodium sulfate evaporated The residue was purified by column chromatography on silica gel (150 g) eluting with hexane/ethyl acetate (5/1), dichloromethane/methanol (10/1)

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

Procedure: To a solution of methyl 2-bromobenzoate (20.76 g, 96 mmol) in 120 mL of anhydrous ether under Argon at 0° C. was slowly added methylmagnesium bromide (77 mL, 3.26 M) at a rate that the internal temperature of the mixture was below 20° C. A white suspension resulted, and the mixture was stirred at room temperature for 2 h. The mixture was cooled in an ice-water bath. To the reaction mixture was very slowly added hydrochloric acid (400 mL, 0.5 M). The pH of the final mixture was adjusted to less than about 6 with few drops of 2M hydrochloric acid. The layers were separated, and the aqueous layer was extracted twice with ether. The organic layers were combined and dried over magnesium sulfate. The organic fraction was filtered, and the filtrate was concentrated to yield the title compound as a pale yellow liquid, which was distilled under vacuum to afford the title Compound 10d as a colorless liquid (16.9 g, 82%, b.p. about 65-70° C./0.3 mmHg). 1H NMR (400 MHz, CDCl3) δ (ppm): 7.67 (dd, 1H, J=1.7, 7.9 Hz), 7.58 (dd, 1H, J=1.3, 7.9 Hz), 7.30 (ddd, 1H, J=1.4, 7.4, 7.9 Hz), 7.10 (ddd, 1H, J=1.7, 7.4, 7.8 Hz), 2.77 (br s, 1H), 1.76 (s, 6H). at 0° C. was below 20° C A white suspension resulted The mixture was cooled in an ice-water bath The layers were separated the aqueous layer was extracted twice with ether dried over magnesium sulfate The organic fraction was filtered the filtrate was concentrated

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

Procedure: To a solution of methyl 2-bromobenzoate (20.76 g, 96 mmol) in 120 mL of anhydrous ether under Argon at 0° C. was slowly added methylmagnesium bromide (77 mL, 3.26 M) at a rate that the internal temperature of the mixture was below 20° C. A white suspension resulted, and the mixture was stirred at room temperature for 2 h. The mixture was cooled in an ice-water bath. To the reaction mixture was very slowly added hydrochloric acid (400 mL, 0.5 M). The pH of the final mixture was adjusted to less than about 6 with few drops of 2M hydrochloric acid. The layers were separated, and the aqueous layer was extracted twice with ether. The organic layers were combined and dried over magnesium sulfate. The organic fraction was filtered, and the filtrate was concentrated to yield the title compound as a pale yellow liquid, which was distilled under vacuum to afford the title Compound 10d as a colorless liquid (16.9 g, 82%, b.p. about 65-70° C./0.3 mmHg). 1H NMR (400 MHz, CDCl3) δ (ppm): 7.67 (dd, 1H, J=1.7, 7.9 Hz), 7.58 (dd, 1H, J=1.3, 7.9 Hz), 7.30 (ddd, 1H, J=1.4, 7.4, 7.9 Hz), 7.10 (ddd, 1H, J=1.7, 7.4, 7.8 Hz), 2.77 (br s, 1H), 1.76 (s, 6H). at 0° C. was below 20° C A white suspension resulted The mixture was cooled in an ice-water bath The layers were separated the aqueous layer was extracted twice with ether dried over magnesium sulfate The organic fraction was filtered the filtrate was concentrated

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

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

Procedure: In a nitrogen atmosphere, 49.5 mL of 3.0 M methylmagnesium bromide-diethyl ether solution was dropwise added to tetrahydrofuran (200 mL) solution of 10.7 g of methyl 2-bromobenzoate with cooling with ice. This was stirred at that temperature for 15 minutes, and then stirred at room temperature for 6 days. Aqueous saturated ammonium chloride solution was added to the reaction liquid, and extracted with diethyl ether. The diethyl ether layer was washed with saturated saline water, and then dried with anhydrous magnesium sulfate. The solvent was evaporated off under reduced pressure, and the residue was separated and purified through silica gel column chromatography (hexane/ethyl acetate=9/1) to obtain 7.4 g of the entitled compound. with cooling with ice stirred at room temperature for 6 days extracted with diethyl ether The diethyl ether layer was washed with saturated saline water dried with anhydrous magnesium sulfate The solvent was evaporated off under reduced pressure the residue was separated purified through silica gel column chromatography (hexane/ethyl acetate=9/1)

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

Procedure: In a nitrogen atmosphere, 49.5 mL of 3.0 M methylmagnesium bromide-diethyl ether solution was dropwise added to tetrahydrofuran (200 mL) solution of 10.7 g of methyl 2-bromobenzoate with cooling with ice. This was stirred at that temperature for 15 minutes, and then stirred at room temperature for 6 days. Aqueous saturated ammonium chloride solution was added to the reaction liquid, and extracted with diethyl ether. The diethyl ether layer was washed with saturated saline water, and then dried with anhydrous magnesium sulfate. The solvent was evaporated off under reduced pressure, and the residue was separated and purified through silica gel column chromatography (hexane/ethyl acetate=9/1) to obtain 7.4 g of the entitled compound. with cooling with ice stirred at room temperature for 6 days extracted with diethyl ether The diethyl ether layer was washed with saturated saline water dried with anhydrous magnesium sulfate The solvent was evaporated off under reduced pressure the residue was separated purified through silica gel column chromatography (hexane/ethyl acetate=9/1)

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

Procedure: To a solution of 2-(2-bromo-phenyl)-propan-2-ol (4.0 g, 18.6 mmol, prepared as described in Egan, W. et al. J. Am. Chem. Soc., 1971, 93, 6205) in 60 mL of anhydrous THF under argon at −78° C. was slowly added n-butyl lithium (15 mL, 2.5 M). The mixture was stirred at −78° C. for 2 h, and then triisopropylborate (5.5 mL, 24.2 mmol) was added to the mixture. The mixture was allowed to warm to room temperature and stirred at room temperature for 12 h. The mixture was then cooled to 0° C. and hydrochloric acid (10 mL, 1N) was added to the mixture until pH was <5. The mixture was then stirred at room temperature for 1 h. The two layers were separated. The aqueous layer was extracted twice with ethyl acetate. The organic layers were combined, dried with anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to afford a yellow oil. The oil was purified by chromatography (silica, EtOAc: hexanes,1:3) to afford a white solid (1.16 g, 40%). 1H NMR (400 MHz, CDCl3) δ (ppm): 7.53 (m, 1H), 7.36 (m, 2H), 7.28 (m, 1H), 1.62 (s, 3H), 1.61 (s, 3H). at −78° C. to warm to room temperature stirred at room temperature for 12 h The mixture was then cooled to 0° C. The mixture was then stirred at room temperature for 1 h The two layers were separated The aqueous layer was extracted twice with ethyl acetate dried with anhydrous sodium sulfate filtered The filtrate was concentrated under reduced pressure to afford a yellow oil The oil was purified by chromatography (silica, EtOAc: hexanes,1:3)

Conditions: temp:-75.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of n-BuLi (21.2 ml, 0.053 mol) in anhydrous THF (160 mL) at −78° C. under argon was slowly added a solution of 2-(2-bromophenyl)propan-2-ol (XCV) (0.0212 mol, 4.55 g) in anhydrous THF (50 mL) while maintaining the temperature below −65° C. After addition was complete, the reaction mixture was stirred at −75° C. for 30 min. To this mixture was added in portions trimethyl borate (0.032 mol, 3.3 g), and the reaction mixture was stirred at −78° C. for 30 min and then at room temperature overnight. The mixture was cooled to 0° C., carefully quenched with 1M aqueous HCl, and stirred at room temperature for 15 min. The mixture was acidified to pH 3 with 2M HCl and stirring was continued for 1 hour. The two phases were separated and the aqueous layer was extracted with EtOAc. The combined organic phases were dried over MgSO4. The crude product was purified by silica gel chromatography using DCM followed by DCM/MeOH 300/1 to give 3,3-dimethylbenzo[c][1,2]oxaborol-1(3H)-ol (XCVI) as a light yellow oil (1.37 g; 8.5 mmol, 40% yield). 1H NMR (CDCl3) δ ppm 1.54 (s, 6H), 7.25-7.29 (m, 1H), 7.33 (d, J=7 Hz, 1H), 7.45 (td, J=7 Hz, J=1 Hz, 1H), 7.68 (d, J=7 Hz, 1H). while maintaining the temperature below −65° C After addition the reaction mixture was stirred at −78° C. for 30 min at room temperature overnight The mixture was cooled to 0° C. carefully quenched with 1M aqueous HCl stirred at room temperature for 15 min stirring was continued for 1 hour The two phases were separated the aqueous layer was extracted with EtOAc The combined organic phases were dried over MgSO4 The crude product was purified by silica gel chromatography

Conditions: temp:-2.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirring solution of methyl 2-bromobenzoate (XCIV) (5 g, 0.0233 mol) in THF (30 mL) under argon at 0° C. was added dropwise MeMgBr (19.4 mL, 0.058 mol), maintaining the temperature in the range of −5 to 0° C. The reaction mixture was stirred at 0° C. for 1 hour and then at room temperature overnight. The mixture was cooled to 0° C. and 1M aqueous HCl (35 mL) was added, maintaining the temperature below 5° C., after which it was allowed to reach room temperature and was stirred for 30 minutes. To this mixture EtOAc (35 mL) was added and after stirring for 5 minutes a white precipitate was removed by filtration through a Celite pad. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic fractions were concentrated, washed with brine and dried over MgSO4. Crude XCV was purified by silica gel chromatography using DCM then DCM/MeOH 300/1 to give 2-(2-bromophenyl)propan-2-ol (XCV) as a light yellow oil (4.55 g; 21.2 mmol, 91% yield). 1H NMR (CDCl3) δ ppm 1.75 (s, 6H), 2.85 (brs, 1H), 7.09 (td, J=7 Hz, J=2 Hz, 1H), 7.29 (td, J=7 Hz, J=1 Hz, 1H), 7.58 (dd, J=7, J=1, 1H), 7.67 (dd J=7, J=2, 1H). at room temperature overnight The mixture was cooled to 0° C. maintaining the temperature below 5° C. to reach room temperature was stirred for 30 minutes after stirring for 5 minutes a white precipitate was removed by filtration through a Celite pad The layers were separated the aqueous layer was extracted with EtOAc The combined organic fractions were concentrated washed with brine dried over MgSO4 Crude XCV was purified by silica gel chromatography

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

Procedure: To a stirred solution of 2-(2-bromophenyl)propan-2-ol (step 1, 6.91 g, 32.1 mmol) in tetrahydrofuran (32 mL) was added dropwise a 1.59 M solution of butyllithium in tetrahydrofuran (46.5 mL, 73.9 mmol) at −78° C. for 20 min and the mixture was stirred for 1 h at the same temperature. To the mixture was added dropwise a solution of 1-methylpiperidin-4-one (5.09 g, 45.0 mmol) in tetrahydrofuran (18 mL) at −78° C. for 10 min. This resulting mixture was slowly warmed up to room temperature and stirred for 18 h at the same temperature. The reaction mixture was quenched by the addition of water, and concentrated to give an orange residue. The crude material was partitioned between diethyl ether and water, and then the organic layer was washed with brine, dried over sodium sulfate, and evaporated. The residue was purified by column chromatography on silica gel (150 g) eluting with hexane/ethyl acetate (5/1), dichloromethane/methanol (10/1), then dichloromethane/methanol/triethylamine (10/1/1) to afford 4.62 g (58%) of the title compound as a slight yellow syrup: stirred for 18 h at the same temperature The reaction mixture was quenched by the addition of water concentrated to give an orange residue The crude material was partitioned between diethyl ether and water the organic layer was washed with brine dried over sodium sulfate evaporated The residue was purified by column chromatography on silica gel (150 g) eluting with hexane/ethyl acetate (5/1), dichloromethane/methanol (10/1)

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

Procedure: To a stirred solution of 2-(2-bromophenyl)propan-2-ol (step 1, 6.91 g, 32.1 mmol) in tetrahydrofuran (32 mL) was added dropwise a 1.59 M solution of butyllithium in tetrahydrofuran (46.5 mL, 73.9 mmol) at −78° C. for 20 min and the mixture was stirred for 1 h at the same temperature. To the mixture was added dropwise a solution of 1-methylpiperidin-4-one (5.09 g, 45.0 mmol) in tetrahydrofuran (18 mL) at −78° C. for 10 min. This resulting mixture was slowly warmed up to room temperature and stirred for 18 h at the same temperature. The reaction mixture was quenched by the addition of water, and concentrated to give an orange residue. The crude material was partitioned between diethyl ether and water, and then the organic layer washed with brine, dried over sodium sulfate, and evaporated. The residue was purified by column chromatography on silica gel (150 g) eluting with hexane/ethyl acetate (5/1), dichloromethane/methanol (10/1), then dichloromethane/methanol/triethylamine (10/1/1) to afford 4.62 g (58%) of the title compound as a slight yellow syrup: stirred for 18 h at the same temperature The reaction mixture was quenched by the addition of water concentrated to give an orange residue The crude material was partitioned between diethyl ether and water the organic layer washed with brine dried over sodium sulfate evaporated The residue was purified by column chromatography on silica gel (150 g) eluting with hexane/ethyl acetate (5/1), dichloromethane/methanol (10/1)