Mechanism of Direct C–H Arylation of Pyridine via a Transient Activator Strategy: A Combined Computational and Experimental Study

Abstract

Recently, we realized the highly selective one-pot synthesis of 2,6-diarylpyridines by using a Pd-catalyzed direct C-H arylation approach via a transient activator strategy. Although methylation reagent as a transient activator and Cu(I) salt or oxide were found to be prerequisites, details regarding the mechanism remained unclear. In this paper, DFT calculations combined with experimental investigations were carried out to elucidate the principle features of this transformation. The results reveal (1) the origin of the exquisite diarylating selectivity of the pyridine under the transient strategy; (2) the possible demethylating reagent as the counteranion of the pyridinium salt; (3) the reason why CuO is a better Cu(I) resource than others.

Mechanism of Ir-Mediated Selective Pyridine o-C–H Activation: The Role of Lewis Acidic Boryl Group

“…Direct C–H activation and functionalization catalyzed by transition metals (TMs) has gained intense attention as a powerful methodology in organic synthesis due to bypassing the preactivation of substrates. − This advanced strategy opens the door to introduce valuable structural motifs to benzene derivatives. − However, similar transformations for pyridine are challenging due to its π-electron-deficient character and catalytic deactivation arising from the affinity of the nitrogen site for transition metals. Therefore, selective direct C–H activation and functionalization of pyridine derivatives using transition metals have attracted significant attention. , Several different strategies, such as preactivation, − transient mediators, , directing groups, − steric control, and temporary dearomatization, have been employed to achieve this goal.…”

“…Therefore, selective direct C−H activation and functionalization of pyridine derivatives using transition metals have attracted significant attention. 13,19 Several different strategies, such as preactivation, 20−25 transient mediators, 26,27 directing groups, 28−30 steric control, 31 and temporary dearomatization, 32 have been employed to achieve this goal.…”

Regioselective Direct C–H Trifluoromethylation of Pyridine

“…Nonetheless these systems suffered from the low reactivity and regioselectivity, particularly for pyridine compounds. In recent years, our group has developed a new activation strategy for pyridine C–H functionalization by using pyridinium salts as the pyridine surrogate. , The formation of pyridinium salts greatly increases the acidity of C–H bond ortho to the pyridine nitrogen and, hence, improves the reaction reactivity and site selectivity . We envision that an efficient and regioselective pyridine trifluoromethylation would be achievable by using the same strategy.…”

“…Then the decarboxylation occurs on I under high temperature (150 °C) to form a solvent cage stabilized intermediate ( II ) . Subsequently the CF 3 anion nucleophilically attacks the pyridinium salt in a regioselective manner to produce the dearomatizated intermediate ( III ), which is then oxidized , by silver salt to afford the trifluoromethylated N -methylpyridinium salts ( IV ), and then the methyl group might be removed by the nucleophilic attack with the anion in the system , to give the final product (Scheme )…”

“…13,14 The formation of pyridinium salts greatly increases the acidity of C−H bond ortho to the pyridine nitrogen and, hence, improves the reaction reactivity and site selectivity. 15 We envision that an efficient and regioselective pyridine trifluoromethylation would be achievable by using the same strategy. Herein, we report a regioselective trifluoromethylation of pyridines by using N-methylpyridinium iodide salts in combination with trifluoroacetic acid.…”