Theoretical Investigations of Palladium‐Catalyzed [3+2] Annulation via Benzylic and meta C−H Bond Activation

Abstract

The Palladium‐catalyzed reaction of aromatic amides with maleimides results in the formation of a double C−H bond activation product, which occurs at both the benzylic and meta positions. Computational chemistry studies suggest that the first C−H bond activation unfolds via a six‐membered palladacycle, maleimide insertion, protonation of the Pd−N bond, and then activation of the meta C−H bond. The process concludes with reductive elimination, producing an annulation product. The energy decomposition analysis (EDA) showed that the deformation energy favors the ortho C‐H bond activation process. However, this route is non‐productive. The interaction energy controls the site where the maleimide is inserted into the Pd−C(sp3) bond, which determines its site selectivity. The energetic span model indicates that the meta C−H bond activation step is the one that determines the turnover frequency. Regarding the directing group, it has been concluded that the strong Pd‐S bonding and the destabilizing effect of the deformation energy allow the 2‐thiomethylphenyl to function effectively as a directing group.

DFT Study on the Mechanism of the Palladium-Catalyzed [3 + 2] Annulation of Aromatic Amides with Maleimides via Benzylic and meta-C–H Bond Activation: Role of the External Ligand Ac-Gly-OH

“…Based on the mechanistic studies by Jeganmohan and co-workers and literatures, ,− ,− we proposed a more detailed mechanism for the palladium-catalyzed [3 + 2] annulation using Ac-Gly-OH as an external ligand, as shown in Scheme . First, the coordination of the external ligand Ac-Gly-OH and the deprotonation of Ac-Gly-OH by the acetates in Pd­(OAc) 2 generate the Pd­(II) chelate B .…”

“…In 2023, the density functional theory (DFT) mechanism study of the palladium-catalyzed [3 + 2] annulation of aromatic amides with maleimides using N,S-bidentate chelating groups was reported by Mori and group . To the best of our knowledge, although Jeganmohan and co-workers proposed a plausible reaction pathway, no DFT mechanism study of the palladium-catalyzed [3 + 2] annulation of aromatic amides with maleimides using Ac-Gly-OH as an external ligand has been reported.…”

Palladium Catalysis: Dependence of the Efficiency of C−C Bond Formation on Carboxylate Ligand and Alkali Metal Carboxylate or Carboxylic Acid Additive. Part A: the C(sp2)−C(sp2), C(sp2)−C(sp3) and C(sp3)−C(sp3) Bonds

“…A domino reaction leading to five membered cycle 33a2 may occur. The reaction starts by coordination and C( sp 3 )−H activation of the substrate to Pd(OCOt−Bu) 2 giving 33bA which inserts into the C=C bond of N ‐methylmaleimide leading to six‐membered palladacycle 33bB (Scheme 33b) [168a,b] . Protonation of the Pd−N bond of 33bB with t ‐BuCO 2 H provides either 33a1 and the starting catalyst (path a ) or intermediate 33bC which undergoes insertion into the C3( sp 2 )−H bond giving palladacycle 33bD (path b ).…”

Transition-Metal-Catalyzed Dehydrogenative (3 + 2) Annulation of Aromatic Compounds: Synthesis of Indenes and Indanes via Dual Functionalization of Benzylic and ortho C–H Bonds

“…Reductive elimination, involving regeneration of the palladium catalyst facilitated by copper pivalate oxidation, leads to the formation of the annulation product ( 27a ). Computational chemistry studies give an in-depth understanding of the site selectivity of the reaction and indicate that the second C–H bond activation step is the rate-determining step of the reaction …”

“…Computational chemistry studies give an in-depth understanding of the site selectivity of the reaction and indicate that the second C−H bond activation step is the rate-determining step of the reaction. 21 Despite the success in achieving selective benzylic followed by meta-C−H bond activation with robust chelating groups, it is worth noting that these sophisticated directing templates often necessitate additional steps for installation and conversion postannulation. Consequently, the exploration of uncharted territory involving neutral weak-chelating directing groups takes on paramount significance.…”