Two-Stage Catalysis in the Pd-Catalyzed Formation of 2,2,2-Trifluoroethyl-Substituted Acrylamides: Oxidative Alkylation of PdII by an IIII Reagent and Roles for Acetate, Triflate, and Triflic Acid

In the synthesis of 2,2,2-trifluoroethyl-substituted acrylamides, two-stage palladium-catalysis is indicated experimen-tally, including oxidative alkylation of Pd-II to Pd-IV by [I(III)Mes-(CH2CF3)](+) (Besset et al., Chem. Commun., 2021, 57, 6241). For N-(quinolin-8-yl)-2-(phenyl)acrylamide [LH2 = H2C=C(Ph)-C(O)-NH-,N], studied by density functional theory herein, the first stage involves palladium acetate-promoted NH-deprotonation and concerted metalation-deprotonation CH-activation for Pd-(OAc)(2)(LH2), followed by the transfer of [CH2CF3](+) from I-III to give a Pd-IV intermediate that undergoes reductive elimination to form the acrylamide-CH2CF3 linkage. The second stage employs [Pd(LH)(NCMe)](+) as the catalyst, with steps including outer-sphere CH-activation by triflate and crucial roles for Pd-IV, acetonitrile solvent, and N-protonation of the product by triflic acid to form [LH2(CH2CF3)](+). In an apparently unique process, the first stage is faster than the second and produces the catalyst, but the second stage is catalytic to provide high yields of the product.

Automated summary

This study reveals the two-stage palladium-catalyzed reaction mechanism for the synthesis of 2,2,2-trifluoroethyl-substituted acrylamides. In the first stage, palladium acetate promotes NH-deprotonation and CH-activation, leading to the formation of Pd-IV intermediate. In the second stage, [Pd(LH)(NCMe)](+) is used as the catalyst, and outer-sphere CH-activation and N-protonation reactions result in the formation of the product.