Evidence for a Radical Mechanism in Cu(II)-Promoted SnAP Reactions

Abstract

Saturated nitrogen heterocycles can be found with increasing abundance in bioactive molecules despite a limited number of methods to access these scaffolds. However, the coupling of recently introduced SnAP [tin (Sn) amine protocol] reagents with a wide range of aldehydes and ketones has proven to be a reliable, practical, and versatile one-step approach to saturated N-heterocycles. While effective, the lack of mechanistic understanding limits efforts to develop new catalytic and enantioselective variants. To distinguish between a polar or radical mechanism, we assessed Lewis and Brønsted acids, radical trapping experiments, and radical clock SnAP reagents reinforcing the current understanding of the SnAP protocol as a radical cyclization.

Ketones as strategic building blocks for the synthesis of natural product-inspired compounds

“…Insights into the reaction mechanism can be drawn from related studies using aldehyde starting materials. 130 Cu II -Mediated oxidation of the ketone-derived alkyl stannane 91 would give the corresponding α-heteroatom-stabilised alkyl radical 92 by SET. Subsequent 6- endo-trig cyclisation of the radical to the pendent imine forms the nitrogen-centred radical cation 93 , which is reduced by the transiently-generated Cu I .…”