Proton-Coupled Electron Transfer in Organic Synthesis: Activation of Amides Towards Challenging Bond Homolyses

Abstract

Amidyl radicals are classical intermediates that are well-known to achieve olefin-addition reactions as well as C-H abstractions via hydrogen-atom transfer. Despite their synthetically useful reactivity, methods to generate these radicals with mild and catalytic conditions from the native N-H bonds of amides are not documented. This dissertation describes the development of catalytic protocols in the activation of N-H bonds of amides to perform carboamination, hydroamidation, and C-H abstractions via amidyl radicals.

First, through use of the excited state of an iridium photocatalyst and a phosphate base, proton-coupled electron transfer activation of the N-H bond of N-aryl amides was effected. This process generates amidyl radicals, representing a net formal homolysis. These reactive amidyl intermediates could continue by adding into pendant olefins. With an appropriate olefin acceptor or a H-atom donor, carboamination and hydroamidation reaction protocols were developed. These reactions demonstrate broad scopes and functional group compatibility. Furthermore, evidence from luminescence quenching experiments strongly suggest a concerted proton-coupled electron transfer mechanism for these types of activations.

This method was extended to N-alkyl amides, which exhibit stronger N-H bond strengths. By developing novel conditions for PCET activation of these much stronger bonds mainly by use of a more oxidizing iridium photocatalyst in its excited state, we could effect distal C-H alkylation reactions along with intermolecular variants. Again, the mechanistic data gathered from these experiments favor the probability of a concerted proton-coupled electron transfer as the mechanism of activation. Finally, by appending the phosphate base to the amide, more efficient yields of intermolecular C-H alkylation product could be obtained. This approach may potentially lend itself further to unique selectivities virtually inaccessible by other means.