3-((Benzyloxy)methyl)cyclobutanone → 3-Benzyloxymethyl-1-(4-pyrrolidin-1-ylmethyl-phenyl)-cyclobutanol

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Reaction Steps

To a stirring solution of 1-(4-bromo-benzyl)-pyrrolidine (1.9 g, 7.9 mmol) in 13 mL of tetrahydrofuran at −78 C (iPrOH/dry ice) was added slowly down the side of the flask a solution of n-butyl lithium (3.2 mL, 7.9 mmol, 2.5 M in THF). After 30 minutes a precooled −78 C (iPrOH/CO2 ice) solution of 3-benzyloxymethyl-cyclobutanone (1.0 g, 5.3 mmol, in 1 mL of THF) was added via cannula down the side of the flask (wash 1 mL). The resulting solution was stirred at −78 C for 30 minutes, then quenched with a saturated solution of aqueous NH4OH and diluted with EtOAc. The layers were separated and the organic layer was dried over magnesium sulfate, filtered through a fritted funnel and then concentrated under reduced pressure. Purification of this material was accomplished by flash column chromatography using a Biotage column, eluting with a gradient of 2% MeOH/CH2Cl2 w/0.1% NH4OH through 30% MeOH/CH2Cl2 w/0.1% NH4OH. The product containing fractions were collected and concentrated under reduced pressure to yield the title compound (1.3 g, 71% yield) as a colorless oil and a 3:1 mixture of cis:trans isomers.

Provenance & Evidence