Nucleophilicity versus Bronsted Basicity Controlled Chemoselectivity: Mechanistic Insight into Silver- or Scandium-Catalyzed Diazo Functionalization

Diazo compounds are popular carbenoid precursors that can react with various transition metals to afford carbene species for further transformations. In this study, density functional theory calculations were used to reveal the mechanisms of silver- and scandium-catalyzed alkylation of diazo compounds to construct compounds with tertiary or quaternary carbon centers. The results show that, with a silver(I) salt as the catalyst, the reaction starts with carbenation of silver(I) to afford a Fisher-type silver carbene. Nucleophilic addition of silver carbene complex yields an enolate intermediate, which is followed by annulation/retro-aldol reaction to give a dialkylation product. Meanwhile, scandium(III) salt behaves as Lewis acid to generate free carbene, which is followed by conjugate addition of free carbene to produce an enolate intermediate. Subsequent 1,4-proton transfer to a synthesized monoalkylation product is more favorable than nucleophilic addition process. Computational studies show that formation of mono- or dialkylation products from enolate intermediates results from competition between the nucleophilicity and Bronsted basicity of the alpha-carbon in the enolate intermediate, which is mainly controlled by the transition-metal catalyst. The global nucleophilicity and Laplacian of the electron density were evaluated to reveal factors affecting the nucleophilicity and Bronsted basicity.