Flipping the Metalation of 4-Dimethylaminopyridine: Steric Repulsion versus London Dispersion Attraction

It has been shown that azomethines, hydrazones, and oximes derived from 2(7)-carbonyl derivatives of 1,8-bis(dimethylamino)naphthalene can undergo acid-catalyzed heterocyclization leading to a nucleophilic displacement of the 1-NMe2 group. The process is believed to be directly connected with the proton sponge nature of the substrates, in which 1-NMe2, being a poor leaving group, is preliminary activated via the formation of a chelated protonated form. A number of difficult to access derivatives of benzo[g]indazole, benzo[g]quinazoline, naphtho[2,1-d]isoxazole, and 8-dimethylamino-1-naphthol have been prepared in moderate to high yields.

Chem. Eur. J. 2025, 31, e202403422