Organophotocatalytic N-O Bond Cleavage of Weinreb Amides: Mechanism-Guided Evolution of a PET to ConPET Platform

A mild, organophotocatalytic N-O bond cleavage of Weinreb amides is disclosed, thereby expanding the chemistry of this venerable motif beyond acylation. This redox neutral process begins to reconcile the ubiquity of N-O bonds in contemporary synthesis with the disproportionately harsh, stoichiometric conditions that are often required for bond cleavage. The strategy is compatible with the parent alkyl derivatives (N-OMe, N-OAlkyl), thereby complementing tailored O-substituent approaches that require N-OAr groups (Ar = electron-deficient). A broad range of acyclic and cyclic derivatives are disclosed (>40 examples, up to 95%), and the synthetic utility of the method is demonstrated in a range of applications. In the case of cyclic Weinreb amide derivatives, this platform enables ambiphilic amide aldehydes, of varying chain lengths, to be generated in a single transformation. Inspired by Emil Fischer's seminal 1908 synthesis of aminoacetaldehyde using sodium amalgam, this method provides a milder route to access this important class of materials. Mechanistically guided reaction development demonstrates the involvement of a photoinduced electron transfer (PET) mechanism, and this has been further advanced to a consecutive photoinduced electron transfer (ConPET) manifold: this has significantly expanded the scope of compatible substrates.

Automated summary

This study presents a mild organophotocatalytic N-O bond cleavage method that allows for the cleavage of bonds without harsh conditions. The method demonstrates synthetic utility for a broad range of compounds and enables the synthesis of ambiphilic amide aldehydes with varying chain lengths.