Direct synthesis of benzylic amines by palladium-catalyzed carbonylative aminohomologation of aryl halides

Abstract

Benzylic amines are valuable compounds with important applications in areas including pharmaceuticals and agrochemicals. The known procedures for their synthesis are limited by difficulties in functionalizing the parent aminomethyl groups. On the other hand, carbonylation reactions offer a potent method to introduce carbonyl groups and homologate carbon chains. However, carbonylative aminohomologation of aryl halides is challenging due to competing reactions and the need to balance multiple sequential steps. Here we report a palladium-catalyzed carbonylative aminohomologation reaction for the direct aminomethylation of aryl halides. The reaction proceeds via a tandem palladium-catalyzed formylation, followed by imine formation and formic acid-mediated reduction. Useful functional groups including chloride, bromide, ester, ketone, nitro, and cyano are compatible with this reaction. Both aryl iodides and bromides are suitable substrates and a wide range of synthetically useful amines are efficiently obtained in moderate to excellent yields.

Palladium can catalyse both the reductive carbonylation of aryl halides to aldehydes, and the reductive amination of benzaldehydes with amines. Here the authors describe a tandem reductive carbonylation/reductive amination using carbon monoxide as the carbonyl source, constituting aminomethylation of aryl halides