An efficient synthesis of 3,3-difluoro-pyrrolidine hydrochloride starting with 2-chloro-2,2-difluoroacetic acid

A facile and fluorination-free synthesis of 3,3-difluoropyrrolidine hydrochloride (3), an important synthon in the synthesis of biologically active compounds, is reported. The seven-step synthesis starts from the commercially available 2-chloro-2,2-difluoroacetic acid (1) in a three-step telescoped process that produces crystalline N,N-diethyl-2,2-difluoro-3-hydroxy-4-nitrobutanamide (2). A convenient and high-yielding reductive nitromethylation of 2 followed by a catalytic hydrogenation/cyclization sequence and borane reduction affords 3 in good yield and purity.