We have developed a direct alkynylation of aldehydes catalyzed by an N-heterocyclic carbene (NHC), employing alkynyl(aryl)iodonium salts as alkynyl transfer reagents. The reaction proceeds under mild, metal-free conditions and provides an entry to a range of heteroaryl-propargyl ketones, containing various groups in good to excellent yields. In particular, the method allows for the preparation of arylpropargyl ketone products with pharmaceutically-relevant five- and six-membered heterocyclic moieties (e.g., pyrazole, thiazole, pyridine, and quinoxaline) as well as these having fluorinated substituents. The mechanism of the reaction was subject to experimental and computational mechanistic investigations. The 13C-labbeling and DFT calculations have shown that the alkynyl group transfer proceeds via a direct substitution of iodine by the Breslow intermediate occurring at α-acetylenic carbon. Additionally, the kinetic studies, corroborated by the computed free energy profile, have identified the formation of Breslow intermediate to be the turnover-limiting step of the catalytic cycle.

N-Heterocyclic carbene-catalyzed synthesis of ynones via C–H alkynylation of aldehydes with alkynyliodonium salts

ACS Spring 2022

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