tert-butyl 4-bromo-3-chlorobenzoate

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

Procedure: To a cold (−40° C.) solution of 2-adamantanone (1.50 g, 10.00 mmol) and tert-butyl 4-bromo-3-chlorobenzoate (2.45 g, 10.00 mmol) in anhydrous tetrahydrofuran (120 mL) was added isopropylmagnesium chloride lithium chloride complex (1.3 M solution in tetrahydrofuran, 10 mL, 13 mmol). The reaction mixture was warm to ambient temperature over 2 hours and heated to reflux for 1 hour. After cooling to ambient temperature, the mixture was quenched with saturated aqueous ammonium chloride (10 mL), diluted with ethyl acetate (200 mL), washed with saturated aqueous ammonium chloride heated to reflux for 1 hour After cooling to ambient temperature the mixture was quenched with saturated aqueous ammonium chloride (10 mL) diluted with ethyl acetate (200 mL) washed with saturated aqueous ammonium chloride

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

Procedure: To a mixture of tert-butyl 4-bromo-3-chlorobenzoate (4.00 g, 13.70 mmol) in anhydrous tetrahydrofuran (40 mL) was added isopropylmagnesium chloride (1.3 M solution in tetrahydrofuran, 13.8 mL, 17.9 mmol) at −40° C. The reaction mixture was warmed to ambient temperature and stirred for 1 hour. To this mixture was then added a solution of copper(I) cyanide (1.35 g, 15.10 mmol) and lithium chloride (1.28 g, 30.20 mmol) in anhydrous tetrahydrofuran (5 mL) at 0° C. The reaction mixture was stirred for 10 minutes at 0° C., then 2-cyclohexen-lone (1.32 mL, 13.70 mmol) and trimethylsilyl chloride (1.74 mL, 13.80 mmol) were added to the reaction mixture. The reaction mixture was stirred for 16 hours at ambient temperature. After addition of 1 N hydrochloric acid (10 mL), the reaction mixture was stirred for 1 hour and then diluted with ethyl acetate (150 mL). The organic phase was washed with 1 N hydrochloric acid (10 mL), brine (10 mL), and dried over anhydrous sodium sulfate. Filtration and concentration of the filtrate gave tert-butyl 3-chloro-4-(3-oxocyclohexyl)benzoate as an oil (4.20 g, quant.), which was used without further purification. The reaction mixture was stirred for 10 minutes at 0° C. The reaction mixture was stirred for 16 hours at ambient temperature the reaction mixture was stirred for 1 hour The organic phase was washed with 1 N hydrochloric acid (10 mL), brine (10 mL) dried over anhydrous sodium sulfate Filtration and concentration of the filtrate

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

Procedure: To a solution of tert-butyl 4-bromo-3-chlorobenzoate (0.875 g, 3.00 mmol) in tetrahydrofuran (5 mL) was added isopropylmagnesium chloride lithium chloride complex (1.3 M solution in anhydrous tetrahydrofuran, 2.78 mL, 3.61 mmol) at −40° C. The reaction was allowed to warm to ambient temperature and stirred for 1 hour (solution A). In a separate flask, a solution of spiro(adamantane-2,2′-oxirane) (0.492 g, 3.00 mmol) in anhydrous tetrahydrofuran (5 mL) was treated with boron trifluoride diethyl etherate (0.38 mL, 3.0 mmol) at 0° C. for 30 minutes (solution B). Solution A was then transferred via cannula to solution B at 0° C. The reaction mixture was allowed to warm to ambient temperature and stirred for 16 hours. After quenched with saturated ammonium chloride solution (5 mL), the mixture was extracted with ethyl acetate (3×10 mL). The combined organic phase was dried over anhydrous sodium sulfate, and filtered. Concentration of the filtrate in vacuo gave a residue which was purified by silica gel column chromatography using 0-100% ethyl acetate in hexanes as eluent to afford the title compound as a colorless solid (0.32 g, 33%): 1H NMR (300 MHz, DMSO-d6) δ 7.84 (dd, J=8.1, 1.4 Hz, 1H), 7.80 (d, J=1.5 Hz, 1H), 7.64 (d, J=8.1 Hz, 1H), 5.44 (br s, 1H), 5.18 (d, J=10.3 Hz, 1H), 2.36-2.29 (m, 1H), 2.06-1.34 (m, 22H), 1.08-1.01 (m, 1H); MS (ES+) m/z 359.2, 361.2 (M−17). to warm to ambient temperature After quenched with saturated ammonium chloride solution (5 mL) the mixture was extracted with ethyl acetate (3×10 mL) The combined organic phase was dried over anhydrous sodium sulfate filtered Concentration of the filtrate in vacuo gave a residue which was purified by silica gel column chromatography