Skeletal Editing of Indoles and Pyrroles by LiHMDS Nitrogen Insertion Reaction

Key words

indoles - pyrroles - quinazolines - pyrimidines - atom insertion - skeletal editing

Significance

Skeletal editing is attractive for late-stage diversification of bioactive molecules to modulate physicochemical and/or pharmacokinetic properties. Indoles are abundant and pharmaceutically relevant heterocycles; carbon atom and nitrogen atom insertion methods are known. Nitrogen atom insertion to pyrroles, generating pyrimidines, is challenging (carbon atom insertions are known). Reported here is a new method for nitrogen atom insertion reactions of 1H-indoles and 1H-pyrroles. This transformation is made possible by the discovery of lithium bis(trimethylsilyl)amide (LiHMDS) as a competent nitrogen atom source.

Comment

The present method is applicable to unprotected substrates, which is convenient for high-throughput and late-stage structural diversification of indole and pyrrole libraries. However, yields for 1H-indoles are lower than for TBS-protected indoles (complementary protocol from the same group; Science 2022, 377, 1104—1109). The ability to access pyrroles using the current approach with LiHMDS is a considerable achievement; pyrroles are not viable substrates using the complementary protocol. The identification of LiHMDS as an atom transfer reagent for nitrogen insertion reactions is noteworthy and should be explored.

Publication History

Article published online:
16 January 2024