p-Bromochlorobenzene → 3-(4-Chlorophenyl)-8-methyl-8-azabicyclo[3.2.1]octan-3-ol

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Reaction Steps

2.5 M n-butyl lithium (17.96 mL, 40.90 mmol) was added to -70 ° C diethyl ether (35 mL) and 4-bromochlorobenzene (9.03 g, 47.15 mmol) in diethyl ether (20mL) was added dropwise over 20 minutes. The mixture was stirred in the cold for 20 minutes then 8-Methyl-8-aza-bicyclo[3.2.1]octan-3-one (5 g, 35.92 mmol) in diethyl ether (12 mL) was added dropwise over 5 minutes. Cooling bath was removed and when internal temperature of −20° C. was reached the solution was quenched with 1N hydrochloric acid (200 mL). The aqueous layer was raised to pH=10 with ammonium hydroxide and extracted with diethyl ether (three times, 200 mL each). The combined organic layers were washed with brine (100 mL), dried with magnesium sulfate and concentrated to yield racemic3-(4-Chloro-phenyl)-8-methyl-8-aza-bicyclo[3.2.1]octan-3-ol (6.87 g, contains 9% 8-Methyl-8-aza-bicyclo[3.2.1]octan-3-one) as a white solid. Solid was used without further purification.

Provenance & Evidence