Radical 1,4-acylcyanoalkylation of alkenes for the synthesis of ζ-ketonitriles

Abstract

Two-component alkene coupling reactions serve as an efficient platform for the synthesis of complex molecular architectures. Leveraging the differences in activation energy barriers among carbon radical precursors and the polarity matching between radicals, this work reports the first example of radical 1,4-acylcyanoalkylation to synthesize challenging-to-access ζ-ketonitriles using two identical alkenes. In the metal-free system, 2-(tert-butylperoxy)-2-methylpropane (DTBP) respectively activates α-C–H bonds of aldehydes and alkyl nitriles to generate acyl and cyanoalkyl radicals. The reaction sequence involves selective radical addition of the acyl radical to two identical alkenes, followed by radical–radical coupling with the cyanoalkyl radical, thereby constructing three C–C bonds under simple conditions. Remarkably, when tertiary alkyl aldehydes are employed, decarbonylation preferentially occurs to form alkyl radicals, enabling 1,4-alkylcyanoalkylation of alkenes. Mechanistic studies and density functional theory (DFT) calculations reveal that the success of this 1,4-acylcyanoalkylation process is governed by both the preferential addition of acyl radicals to alkenes and the thermodynamic stability associated with the two-component alkene addition cascade.