pubs.acs.org/joc
achieve, especially when attempting to elaborate preformed
Practical Synthesis of Functionalized
1,5-Disubstituted 1,2,4-Triazole Derivatives
1,2,4-triazole rings.10 In support of drug development pro-
grams at Merck, we were specifically interested in the prepara-
tion of 1,5-disubstituted-1,2,4-triazoles with carboxamide11 or
carboxylate12 functionalities in the 5-position. In this Note, we
report a practical synthetic method to efficiently access 1,2,4-
triazoles with protected 5-carboxamide or 5-carboxylate func-
tionality. The proposed strategy is shown in Figure 1, where
Yingju Xu,* Mark McLaughlin, Emily N. Bolton, and
Robert A. Reamer
Department of Process Research, Merck Reseaerch
Laboratories, Merck & Co., Inc., Rahway, New Jersey 07065,
United States
(5) Selected examples of the synthesis of 1,2,4-triazole rings: (a) Bekircan,
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J. H. Synthesis 1997, 12, 1461–1466. (c) Al-Masoudi, N. A.; Al-soud, Y. A.;
Ali, I. A. I. Nucleosides, Nucleotides Nucleic Acids 2007, 26, 37–43. (d) Carter,
K. R.; Miller, R. D.; Hedrick, J. L. Macromolecules 1993, 26, 2209–2215. (e)
Received September 7, 2010
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A general approach for the synthesis of 1,5-disubstituted-1,2,4-
triazole compounds is described. A series of new oxamide-
derived amidine reagents can be accessed in excellent yield
with minimal purification necessary. Typically, these amidine
reagents are stable crystalline solids and in certain cases were
found to exist in a cyclic form as determined by NMR spec-
troscopy. Under optimized conditions, the direct reaction of
these prepared reagents with various hydrazine hydrochloride
salts efficiently generates the target triazoles. Both aromatic
and aliphatic hydrazines react readily with the amidine re-
agents under very mild reaction conditions, delivering desired
1,5-disubstituted-1,2,4-triazole derivatives in good yields.
(6) For review for the synthesis of 3,4,5-trisubstituted-1,2,4-triazol, see:
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Katritzky, A. R.; Qi, M.; Feng, D.; Zhang, G.; Griffith, M. C.; Watson, K.
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chemical control of the substitution pattern can be difficult to
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8666 J. Org. Chem. 2010, 75, 8666–8669
Published on Web 11/16/2010
DOI: 10.1021/jo1017603
r
2010 American Chemical Society