Exploring the necessity of an acidic additive for Pd(ii)-catalyzed exclusive C4-fluoroalkylation of 3-acetylindole: a detailed DFT study on the mechanism and regioselectivity

The reaction mechanisms of Pd(II)-catalyzed exclusive C4-fluoroalkylation of indole, with an acetyl group as the directing group at the C3 site, were explored via density functional theory calculations (DFT). Our results reveal that the regioselectivity of the C4 site over the C2 site is mainly achieved in the step of C-H activation. Compared to original Pd(OAc)(2), Pd(TFA)(2) formed via the addition of acidic TFA (Trifluoroacetic Acid) has important advantages. At first, it reduces the energy barrier of the C-H activation step for both the C4 site and C2 site. Furthermore, it leads to a larger degree of lowering of the energy barrier of C4-H activation when compared to that of C2-H activation. These advantages could give rise to the experimental observation of an exclusive C4 product with good yield under mild reaction conditions. Thus the necessity of an acidic additive of TFA should arise from its capability of leading to the formation of Pd(TFA)(2). Detailed analysis indicates that, in the C-H activation step, electron density is donated from the indole substrate to the Pd-catalyst as the acceptor. Compared to Pd(OAc)(2), the ability of Pd(TFA)(2) as the electron acceptor is enhanced due to more electron-withdrawing ligands of CF3COO-. This enhanced accepting ability could lead to a larger amount of donated electron density which will give rise to a lower energy barrier and thus to a higher degree of feasibility of the reaction. Furthermore, this enhanced accepting ability will also lead to a higher degree of preference to the C4 site since its donating ability is verified to be stronger than that of the C2 site. Based on this analysis, other acidic additives, capable of introducing a strong electron-withdrawing ligand into the Pd-catalyst, could also realize the exclusive C4 functionalization under mild reaction conditions. This prediction was theoretically verified in the case of HOTf, whose acidity is stronger than that of TFA. Thus we hope that our theoretical results would promote related experimental exploration in the near future.