Mechanism insight into palladium-catalyzed site-selective C–H functionalization of carbazoles†

Carbazole alkaloids have great potential for applications in biomedicine and materials science. Direct C–H functionalization to construct carbazole derivatives, however, has been a great challenge. Herein, we theoretically investigated a palladium-catalyzed site-selective direct C–H functionalization (alkylation and acylation) strategy for free NH-carbazoles by density functional theory (DFT) methods. Calculations show that C–H activation is the rate determining step for the conversion, with a potential barrier of 23.4 kcal mol⁻¹. Meanwhile, the six-membered ring C–H activation intermediate formed at the C1-position is the most stable and kinetically favorable under the synergistic effect of norbornene (NBE) and palladium(ii) catalysts. In contrast, the large tension prevents the formation of activation intermediates at the C2, C3, or C4-positions, leading to excellent site-selectivity for the transformation. We also investigated the mechanism of the key acylation step, oxidative addition, under the same conditions. In agreement with experiments, benzoic anhydride was theoretically rationalized to act as an acylating agent in this conversion with an oxidative addition potential barrier of 13.3 kcal mol⁻¹. Further calculations also indicate the possible great potential of acyl halides as acylating agents following the protocol, with an oxidative addition barrier of only 2.6 kcal mol⁻¹.