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

Abstract

The mechanism of the Ac-Gly-OH-assisted palladium-catalyzed [3 + 2] annulation of aromatic amides with maleimides is investigated using density functional theory calculations. The results show that the reaction undergoes the sequential steps of N−H bond deprotonation, first benzylic C−H bond activation, maleimide insertion, second meta-C−H bond activation, reductive elimination, and oxidation. The external ligand Ac-Gly-OH acts as the internal base for hydrogen abstraction in the first benzylic C−H bond activation. The maleimide insertion step is found to be the rate-determining step. Based on the nearly same energetic span of the two pathways to generate the enantio products, the computational results are consistent with the experimental observation that the terminal [3 + 2] annulation products are racemic when using an achiral ligand. These calculation results disclose the detailed reaction mechanism and shed light on some experimental ambiguities.

Distinguishing the Internal/External Base-Assisted Deprotonation Mechanisms in Aromatic C–H Activation with the Pd(II)/LA Catalyst

“…In both DFT calculations and experimental tests, two categories of base-assisted deprotonation pathways for C–H activation have been proposed, including internal ,− and external − base-assisted deprotonations (Scheme ). Typically, the AMLA mechanism is characteristic of internal base-assisted deprotonation, while the CMD mechanism is characteristic of either internal or external base-assisted deprotonation .…”

Cascade [4 + 1] Annulation through Activation of the C(sp2)–H Bond Enabling Benzothiadiazinoisoindolcarboxylate, Benzothiadiazinoisoindole, and Benzothiadiazinoisoindolepyrrolidinedione as Hybrid Spiro-Heterocyclic Frameworks

“…In this regard, to materialize the previously mentioned spiro heterocycles we have chosen metal-catalyzed C–H bond activation protocol as the conveying tool. From the literature, it is evident that the transition metal-catalyzed ortho -C–H bond activation technique becomes a prevailing tool in the organic synthetic domain appropriating hustle-free operative tactics by judicious choice of transition metal to fabricate new C–C and C-heteroatom bonds from the convenient starting materials . In particular, metal-catalyzed ortho -C–H bond activation of benzothiadiazine dioxides or dihydrobenzothiadiazine dioxides are not explored immensely and needs to be unveiled vastly within the domain of metal-catalyzed organic synthesis.…”