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

• Published in: Journal of the American Chemical Society 2019-05, Vol.141 (17), p.7181-7193
• Main Authors: Dale, Harvey J. A, Hodges, George R, Lloyd-Jones, Guy C
• Format: Article
• Language: English
• ISSN: 0002-7863; 1520-5126
• DOI: 10.1021/jacs.9b02786

Controlling the regioselectivity of ambident nucleophiles toward alkylating agents is a fundamental problem in heterocyclic chemistry. Unsubstituted triazoles are particularly challenging, often requiring inefficient stepwise protection–deprotection strategies and prefunctionalization 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 modeling, 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 organocatalysts, shuttling triazolate anions into solution. The intimate ion pairs formed in solution retain the reactivity of liberated triazole anions but, by virtue of highly regioselective ion pairing, exhibit alkylation selectivities that are completely inverted (1,2,4-triazole) or substantially enhanced (1,2,3-triazole) compared to the parent anions. The methodology allows direct access to 4-alkyl-1,2,4-triazoles (rr up to 94:6) and 1-alkyl-1,2,3-triazoles (rr up to 99:1) in one step. Regioselective ion pairing acts in effect as a noncovalent in situ protection mechanism, a concept that may have broader application in the control of ambident systems.