Copper-Catalyzed Synthesis of 1,2,4-Triazoles

Significance

Reported is the efficient copper-catalyzed synthesis of 1,2,4-triazoles 3 and 5 from amidines 1 or 2-aminopyridines 4 and nitriles 2. Both alkyl (1˚, 2˚, and 3˚) and aryl amidines are tolerated in this reaction with equal efficiency. One example of a 5-amino-1,2,4-triazole was also prepared from a guanidine precursor. A wide range of starting nitriles bearing EDG, EWG, and heterocycles may be used although, in general, electron-deficient nitriles gave higher yields than the electron-rich substrates. A mechanism involving the copper-promoted addition of the amine into the nitrile followed by oxidative cyclization is presented by analogy to related processes.

Comment

The 1,2,4-triazole nucleus is found in many biologically active substances (see Book below). Important examples include the antifungal agent fluconazole and the antiviral nucleoside ­ribavirin. 1,2,4-Triazoles are usually constructed using intramolecular condensation reactions (E. Huntsman, J. Balsells Eur. J. Org. Chem. 2005, 3761). The current method provides a rapid, catalytic method for the preparation of 1,2,4-triazole derivatives from simple and readily available starting materials in one pot.

Book: A. D. M. Curtis, In Science of Synthesis, Vol. 13; R. C. Storr, T. L. Gilchrist, Eds.; Georg ­Thieme Verlag: Stuttgart, 2003, 603-640.