Ring-opening decarbonylative C(sp3)–C(sp3) cross-electrophile coupling of cyclic imides with unactivated alkyl chlorides

TL;DR

A new nickel-mediated method enables efficient cross-electrophile coupling of cyclic imides with alkyl chlorides to build complex amides.

Contribution

A novel decarbonylative C(sp3)–C(sp3) cross-electrophile coupling using cyclic imides and unactivated alkyl chlorides is introduced.

Findings

Selective endocyclic N–C(O) activation enables ring-opening coupling with alkyl chlorides.

The method allows rapid synthesis of structurally diverse α- and β-substituted amides.

Catalytic turnover is demonstrated under modified conditions.

Abstract

Herein we report a nickel-mediated decarbonylative cross-electrophile coupling of N-Boc succinimides and glutarimides with unactivated alkyl chlorides. The transformation proceeds via selective endocyclic N–C(O) activation, which opens a new entry point into C(sp3)–C(sp3) cross-electrophile coupling and, through incorporation of the ring-opened imide scaffold, establishes a highly modular platform to rapidly build molecular complexity. In situ halide exchange enables the use of abundant alkyl chlorides, while broad functional group tolerance grants access to structurally diverse α- and β-substituted amides. As a result, the method provides a new retrosynthetic disconnection to aliphatic amides, exemplified by the synthesis of densely substituted carbocyclic amides and novel capsaicin precursors. The transformation further exhibits catalytic turnover under modified conditions, demonstrating the catalytic potential of this underexplored activation mode.

Selective nickel-mediated endocyclic N–C(O) activation establishes cyclic imides as competent electrophiles in decarbonylative C(sp3)–C(sp3) cross-electrophile coupling with unactivated alkyl chlorides.

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