Unified Mechanistic Concept of the Copper-Catalyzed and Amide-Oxazoline-Directed C(sp2)–H Bond Functionalization

Density functional theory calculations have been performed to provide the unified mechanism of Cu(II)-catalyzed and amide-oxazoline (Oxa)-directed C(sp2)–H functionalization reactions. The common steps of the studied seven reactions (such as C–H bond vinylation, phenylation, trifluoromethylation, amination, alkynylation, and hydroxylation) are complexation, N–H and C–H bond deprotonation, and Cu(II)/Cu(II) → Cu(I)/Cu(III) disproportionation, leading to the Cu(III) intermediate. The mechanism of the studied C–H functionalization reactions, initiated from the Cu(III) intermediate, depends on the nature of coupling partners. With vinyl- or phenyl-Bpin, which bear no acidic proton (called as a Type-I reaction), the coupling partners are the in situ generated (by addition of anions) anionic borates, which coordinate to the Cu(III) intermediate and undergo concerted transmetalation and reductive elimination to form a new C–C bond. In contrast, with imidazole, aromatic amines, terminal alkyne, and water (called as a Type-II reaction), which bear an acidic proton, the real coupling partners are their in situ generated deprotonated derivatives, which coordinate to copper and lead to a final product with the C–Y bond (Y = C, N, and O) via the reductive elimination pathway. The C(sp2)–H bond trifluoromethylation with TMSCF3 is identified as a special case, positioned between the Type-I and Type-II reaction types. The real coupling partner of this reaction is the in situ generated (via the CF3–-to-OH– ligand exchange) CF3– anion that binds to the Cu(III) intermediate and undergoes the C–CF3 reductive elimination. Our calculations, consistent with the experimental KIE study, have established C–H bond activation as a rate-limiting step for all reactions.