DOI: 10.1002/chem.201302997
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Synthetic Methods
Facile One-Pot Synthesis of [1,2,3]Triazolo[1,5-a]Pyridines from 2-
Acylpyridines by Copper(II)-Catalyzed Oxidative NÀN Bond
Formation
Tasuku Hirayama, Satoshi Ueda, Takahiro Okada, Norihiko Tsurue, Kensuke Okuda, and
Hideko Nagasawa*[a]
Abstract: An efficient and simple method for the synthesis
of various [1,2,3]triazolo[1,5-a]pyridines has been estab-
lished. The method involves a copper(II)-catalyzed oxidative
NÀN bond formation that uses atmospheric oxygen as the
terminal oxidant following hydrazonation in one pot. The
use of ethyl acetate as the solvent dramatically promotes
the oxidative NÀN bond-formation reaction and enables the
application of oxidative cyclization in the efficient one-pot
reaction. A mechanism for the reaction was proposed on the
basis of the results of a spectroscopic study.
CÀN bond formation by using catalytic copper salts.[11] In addi-
tion to these successes, we have also reported a facile method
for the preparation of 3-substituted [1,2,4]triazolo[1,5-a]pyri-
dines through a copper-catalyzed tandem addition–oxidative
cyclization.[12] During further development of simple and versa-
tile catalytic methods for the synthesis of heteroaromatic scaf-
folds for drug discovery applications, we discovered an effi-
cient one-pot synthesis of [1,2,3]triazolo[1,5-a]pyridines by
means of copper(II)-catalyzed NÀN bond formation. Although
there have been a number of reports on NÀN bond-formation
reactions,[13] there are very few catalytic synthetic methods for
NÀN bond formation[14] compared with those for CÀC bond
formation[15] and CÀO or CÀN bond-formation reactions.[16] Pre-
viously, Mori et al. reported that a strong fluorescent com-
pound was formed in the flow injection–fluorometric detection
system of amino acids by the use of aerial oxidation of 2-pyrid-
yl ketone hydrazone, or 2,2’-dipyridyl ketone hydrazone, cata-
lyzed by copper(II) species. The fluorescent product was found
to have the structure of a derivative of [1,2,3]triazolo[1,5-
a]pyridine.[17] Although only a few 2-pyridyl ketone hydrazones
were examined for the oxidative cyclization, we consider that
the reaction can be established as a practical and versatile syn-
thetic method for a wide range of [1,2,3]triazolo[1,5-a]pyridine
derivatives.
Introduction
Triazolopyridine structures are fundamental building blocks for
numerous pharmaceutical and functional materials. As an im-
portant class of triazolopyridines, [1,2,3]triazolo[1,5-a]pyridines
have been studied by Jones et al.[1] and Abarca et al.[2] since
the early 1980 s. Although pharmacological studies of these
compounds are rare,[2d] their coordination chemistry and distin-
guishing fluorescent properties have been widely investigated
and applied to material science.[3] Because of the versatility of
the triazolopyridines, considerable attention has been paid to
the development of efficient methods for their synthesis. Tradi-
tionally, [1,2,3]triazolo[1,5-a]pyridines have been synthesized
by the oxidative cyclization of 2-pyridyl ketone hydrazones by
using at least a stoichiometric, if not an excess, amount of oxi-
dants such as Pb(OAc)2,[4] copper salts,[3g,5] MnO2,[3f,6] hyperva-
lent iodine,[7] Ag2O,[8] and Ni peroxide.[9]
To develop economic and environmentally benign catalytic
oxidative reactions, the use of a copper salt as a catalytic oxi-
dant is highly attractive, owing to the low cost and low toxicity
of the compounds. Dçring et al. previously reported copper-
catalyzed oxidative cyclization of 2-iminopyridine derivatives
for the synthesis of imidazo[1,5-a]pyridines by using atmos-
pheric oxygen as the terminal oxidant.[10] Recently, Buchwald
and co-workers have raised the possibility of preparing various
N-heterocycles by means of CÀH bond functionalization and
Therefore, we herein describe an efficient method for the
preparation of [1,2,3]triazolo[1,5-a]pyridines by means of cop-
per(II)-catalyzed oxidative NÀN bond formation. In the present
reaction, only a catalytic amount of Cu(OAc)2 is required, and
atmospheric oxygen serves as the terminal oxidant. Also, a con-
venient one-pot method for the synthesis of various
[1,2,3]triazolo[1,5-a]pyridines from the corresponding 2-acyl-
pyridines was developed on the basis of the oxidative cycliza-
tion reaction. In addition, a reaction mechanism is proposed
on the basis of a spectroscopic study. Throughout the entire
one-pot reaction, only a catalytic amount of copper(II) salt is
[a] Dr. T. Hirayama, Dr. S. Ueda, T. Okada, N. Tsurue, Prof. K. Okuda,
Prof. H. Nagasawa
Laboratory of Medicinal and Pharmaceutical Chemistry
Gifu Pharmaceutical University
1-25-4, Daigaku-nishi, Gifu 501-1196 (Japan)
Fax: (+81)58-230-8112
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201302997.
Chem. Eur. J. 2014, 20, 4156 – 4162
4156
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