Cross-Dehydrogenative Coupling of Azoles with α-C(sp³)–H of Ethers and Thioethers under Metal-Free Conditions: Functionalization of H–N Azoles via C–H Activation

Abstract

A metal-free cross-dehydrogenative coupling method for the synthesis of N-substituted azoles has been developed. The TBAI/TBHP system catalyzed the coupling of azoles with ethers and thioethers via α-C(sp(3))-H activation. Under the optimized conditions, a diverse range of un/substituted azoles such as 1H-benzimidazole, 9H-purine, 1H-benzotriazole, 1H-1,2,3-triazole, 1H-1,2,4-triazole, and 1H-pyrazole were successfully employed for coupling with various ethers and thioethers such as tetrahydrofuran, tetrahydropyran, 1,4-dioxane, diethyl ether, tetrahydrothiophene, and 1,3-dithiolane.

Ruthenium-Catalyzed C–H Bond Activation Approach to Azolyl Aminals and Hemiaminal Ethers, Mechanistic Evaluations, and Isomer Interconversion

“…1,2,4-Triazole reacted very cleanly resulting in only the N 1 product (as evidenced by two aryl proton resonances in the 1 H NMR spectrum). This regiochemical outcome is comparable to those observed in reactions mediated by n -Bu 4 N + I − / t -BuOOH 18 and FeCl 3 / t -BuOOH. 19 In the reaction of 1,2,3-triazole, the N 1 product predominated, although HRMS data indicated that another chromatographically isolated fraction may contain a trace of the N 2 isomer.…”

“…18 Although a mechanistic assessment of the FeCl 3 -catalyzed reactions of benzotriazole is not available, and neither are exactly comparable data in the other cases, KIE values have been reported for hemiaminal ether formation from imidazole and carbazole. 19,20 These data along with reaction conditions are shown in Table 3 and the results implicate a slow hydrogen atom abstraction step.…”

“…Notably, these previous reports 16–18 only describe reactions of BtH. As reactions can depend upon the structure of the benzotriazole, 5,6-DMBtH has also been evaluated in this work so as to offer a comparison to reactions of BtH.…”

“…As reactions can depend upon the structure of the benzotriazole, 5,6-DMBtH has also been evaluated in this work so as to offer a comparison to reactions of BtH. 22 In FeCl 3 -catalyzed reactions of BtH with THF and 1,4-dioxane, 16 as well as in a n -Bu 4 N + I − -catalyzed reaction of BtH with THP, 18 no N 2 isomers were reported. Because formation of both isomers is reported for other ethers, and has been observed herein, we wonder whether these prior reactions led to only a single isomer, or whether the N 2 isomers were formed in low amounts, or were lost during isolation procedures, or rearranged (see below).…”

“…Because formation of both isomers is reported for other ethers, and has been observed herein, we wonder whether these prior reactions led to only a single isomer, or whether the N 2 isomers were formed in low amounts, or were lost during isolation procedures, or rearranged (see below). Also interesting to note is that even with an identical reagent combination but under different conditions, 17,18 variability in the N 1/ N 2 ratios seems possible (see reactions of THF using n -Bu 4 N + I − / t -BuOOH in Table 4). …”