Taming Ambident Triazole Anions: Regioselective Ion Pairing Catalyzes Direct N-Alkylation with Atypical Regioselectivity

Controlling the regioselectivity of ambident nucleophiles towards alkylating agents is a fundamental problem in het- erocyclic chemistry. Unsubstituted triazoles are particularly challenging, often requiring inefficient stepwise protection-deprotection strategies and pre-functionalization protocols. Herein we report on the alkylation of archetypal ambident 1,2,4-triazole, 1,2,3-triazole and their anions, analyzed by in situ 1H/19F NMR, kinetic modelling, diffusion-ordered NMR spectroscopy, X-ray crystallography, highly correlated coupled-cluster computations [CCSD(T)-F12, DF-LCCSD(T)-F12, DLPNO-CCSD(T)] and Marcus theory. The resulting mechanistic insights allow design of an organocatalytic methodology for ambident control in the direct N-alkylation of unsubstituted triazole anions. Amidinium and guanidinium receptors are shown to act as strongly-coordinating phase-transfer organo- catalysts, shuttling triazolate anions into solution. The intimate ion-pairs formed in solution retain the reactivity of libe...