Zinc-Promoted Aminomethylation of Organic Halides

Significance

This work presents an extremely simple and surprisingly general synthetic method for aminomethylation of organic halides, i.e. formation of tertiary amines with one ‘additional’ CH₂ group. The described method is an ingenious one-pot combination of a Barbier-type reaction and acid-catalyzed imine formation. The mechanism differs from the usual formation of organozinc species followed by a nucleophilic attack. Copper iodide was found to catalyze the process, whereas a radical quencher such as BHT is an inhibitor. The reaction starts with the formation of a radical derived from the alkyl halide, which reacts immediately with a highly electrophilic immonium cation. Probably, the copper salts participate in this step. This is leading to a cation-radical, which is reduced by Zn to form the final amine. The radical pathway was proved by using the ‘radical clock’ 6-iodo-1-hexene, which gave mostly the cyclization product.