Mechanistic insights into the C(sp3)-H heteroarylation of amides and Fukui function analysis of regioselectivity

Abstract

• The underlying mechanism of visible-light-enabled C(sp 3 )-H heteroarylation of amides. • Protonated heteroarenes promoting coupling reaction. • Fukui functions predicting the reactive sites of the protonated heteroarenes in heteroarylation of amides. A computational study is carried out to understand the mechanism and excellent regioselectivity in metal-free heteroarylation of amides reported by Zhu’s group. The heteroarylation reaction started with the initial generation of key nitrogen-centered radicals via ligand exchange between reactant 1a and initiator PIFA under visible-light irradiation. Following, this reaction undergoes four-stages: 1,5-hydrogen atom transfer, C C coupling, single electron transfer and proton transfer. The C C coupling step is identified as the selectivity-determining step in which the carbon-centered radical ( C ) selectively only attacks the carbon atom adjacent to nitrogen of lepidine ( 2a ). And the radical C more easily attacks the protonated 2a , compared with unprotonated 2a , due to significantly lowered SOMO/LUMO energy difference between them to promote this nucleophilic radical addition. From the calculated result, we can see that the positive effect of the acidity of the reaction substrates on the nucleophilic addition to heteroarenes. Fukui functions of different types of heteroarene substrates are calculated to predict the favorable nucleophilic sites. The calculated most favorable reactive sites of heteroarene substrates are well consistent with the experimental observed ones. This theoretical research provides deeper understandings for the underlying mechanism and the origin of exclusive regioselectivity of the heteroarylation of amides.