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.

 

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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.

 

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Publication History

Article published online:
16 January 2024