Regioselective C2-lithiation of N-Boc-3-bromopyrroles: a novel approach towards the synthesis and scale-up of 3-(2-formyl-4-methyl-1-H-pyrrol-3-yl)propanoic acid

Abstract

ortho-Lithiation of N-Boc-3-bromopyrroles (7b, 7d) with LDA in THF at −75°C, followed by reactions with ethyl formate gave exclusive C2-formylpyrroles (9b, 9c, 9d, 9e) in good yields. This methodology was applied to the synthesis of 3-(2-formyl-4-methyl-1-H-pyrrol-3-yl)propanoic acid (4a), a penultimate precursor to SU5402. The process for making 4a has also been optimized which involves a non-chromatography eight-step synthesis with an overall 18% yield.