Direct alkylation of N,N-dialkyl benzamides with methyl sulfides under transition metal-free conditions

Direct conversion of amides to ketones typically requires the use of transition metal catalysts or reactive organometallic reagents. Here the direct alkylation of benzamides with methyl sulfides using LDA as base provides access to thioalkoxyketones. Amides are a fundamental and widespread functional group, and are usually considered as poor electrophiles owing to resonance stabilization of the amide bond. Various approaches have been developed to address challenges in amide transformations. Nonetheless, most methods use activated amides, organometallic reagents or transition metal catalysts. Here, we report the direct alkylation of N,N-dialkyl benzamides with methyl sulfides promoted by the readily available base LDA (lithium diisopropylamide). This approach successfully achieves an efficient and selective synthesis of alpha-sulfenylated ketones without using transition-metal catalysts or organometallic reagents. Preliminary mechanism studies reveal that the deprotonative aroylation of methyl sulfides is promoted by the directed ortho-lithiation of the tertiary benzamide with LDA.