A Fast and General Route to Ketones from Amides and Organolithium Compounds under Aerobic Conditions: Synthetic and Mechanistic Aspects

We report that the nucleophilic acyl substitution reaction of aliphatic and (hetero)aromatic amides by organolithium reagents proceeds quickly (20 s reaction time), efficiently, and chemoselectively with a broad substrate scope in the environmentally responsible cyclopentyl methyl ether, at ambient temperature and under air, to provide ketones in up to 93 % yield with an effective suppression of the notorious over-addition reaction. Detailed DFT calculations and NMR investigations support the experimental results. The described methodology was proven to be amenable to scale-up and recyclability protocols. Contrasting classical procedures carried out under inert atmospheres, this work lays the foundation for a profound paradigm shift of the reactivity of carboxylic acid amides with organolithiums, with ketones being straightforwardly obtained by simply combining the reagents under aerobic conditions and with no need of using previously modified or pre-activated amides, as recommended.

Automated summary

The nucleophilic acyl substitution reaction of aliphatic and (hetero)aromatic amides with organolithium reagents in cyclopentyl methyl ether proceeds efficiently, providing ketones with up to 93% yield while effectively suppressing over-addition reactions. The methodology allows for straightforward synthesis of ketones under aerobic conditions without the need for pre-activated amides. The study demonstrates a paradigm shift in the reactivity of carboxylic acid amides with organolithiums.