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.