Concerted vs Nonconcerted Metalation-Deprotonation in Orthogonal Direct C-H Arylation of Heterocycles with Halides: A Computational Study.

A computational study on the base-assisted orthogonal C-H arylation of azoles with halides is reported. Although concerted metalation-deprotonation (CMD) is favored under acetate assistance at the C5 site that displays the best balance of nucleophilic and acidic character, the most acidic C2 site may be selectively targeted under carbonate assistance by taking advantage of a carbanionic-type (or non-concerted) metalation-deprotonation mechanism (nCMD). For the latter, several experimental probes including base, ligand, and solvent effects have been collected in favor of an outer-sphere deprotonation process after the formation of a [(Ln)(N1-heteroaryl)PdArX] complex. However, no computational analysis of this fundamental elementary step has been so far provided. We have carried out a series of density functional theory (DFT) calculations that delineate the structural and energetic aspects of the nCMD pathway. Starting with the oxa(thia)zole-4-carboxylates selected in our group to engineer the competitive C2 vs C5 arylation in azoles, we show that the energy barrier of the C2 anion generation is lying unexpectedly lower than the prior heterocycle coordination to Pd that is eventually identified as the rate-determining step. These calculations provide satisfactory explanations for the experimental observations of the divergence between nCMD and CMD reactivity, and notably a lower barrier at the C2 site for the nCMD process. On the other hand, the nCMD process is ineffective at the C5 site. Evaluation of various azoles reveals that the nCMD mechanism at C2 is viable from the most acidic (benzo)oxazoles to moderately acidic (benzo)thiazoles, as well as weakly acidic imidazoles. In all cases, in accordance with previously reported experimental data in orthogonal direct C-H arylation of azoles, the nCMD route is found energetically competitive to the CMD one at C5 for all azoles, except for imidazole which needs stronger basic conditions than simple carbonate assistance. Additionally, the acetate ligand, which is the base of choice for CMD, was found inefficient for nCMD and the comparative performance of acetate vs carbonate to assist CMD in the azole series reveals also considerable changes from electronically close but environmentally divergent C5-H vs C2-H bonds.