An efficient one-pot three-component reaction to produce 1,4-disubstituted-1,2,3-triazoles catalyzed by a dicopper-substituted silicotungstate

Article abstract of DOI:10.1246/cl.2008.1258

The dicopper-substituted γ-Keggin silicotungstate with bis-μ-1,1-azido ligands TBA₄H₂ [γ-SiW ₁₀O₃₆Ou₂ (μ-1, 1-N₃)₂] (TBA = tetrabutylammonium) could act as an effective homogeneous precatalyst for the one-pot synthesis of various kinds of 1,4-disubstituted-l, 2,3-triazole derivatives from organic halides, NaN₃, and alkynes. Copyright

Full text of DOI:10.1246/cl.2008.1258

1258
Chemistry Letters Vol.37, No.12 (2008)
An Efficient One-pot Three-component Reaction to Produce 1,4-Disubstituted-1,2,3-triazoles
Catalyzed by a Dicopper-substituted Silicotungstate
Kazuya Yamaguchi, Miyuki Kotani, Keigo Kamata, and Noritaka Mizunoꢀ
Department of Applied Chemistry, School of Engineering, The University of Tokyo,
7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8656
(Received September 25, 2008; CL-080923; E-mail: tmizuno@mail.ecc.u-tokyo.ac.jp)
The dicopper-substituted ꢀ-Keggin silicotungstate with
bis-ꢁ-1,1-azido ligands TBA4H2[ꢀ-SiW10O36Cu2(ꢁ-1,1-N3)2]
(TBA = tetrabutylammonium) could act as an effective homo-
geneous precatalyst for the one-pot synthesis of various kinds
of 1,4-disubstituted-1,2,3-triazole derivatives from organic hal-
ides, NaN3, and alkynes.
of 1,4-disubstituted-1,2,3-triazole derivatives (Table S1). The
reaction smoothly proceeded in polar organic solvents such as
acetonitrile, methanol, and N,N-dimethylformamide. After the
reaction was completed, the pure organic azides were obtained
in >90% isolated yields by Kugelrohr distillation.
Using the benzyl azide obtained, the I-mediated 1,3-dipolar
cycloaddition of benzyl azide to phenylacetylene was next car-
ried out in order to optimize the reaction conditions (Table S2).
Among the solvents tested, polar organic solvents such as aceto-
nitrile, methanol, and N,N-dimethylformamide gave the corre-
sponding 1,4-disubstituted-1,2,3-triazole of 1-benzyl-4-phenyl-
1H-1,2,3-triazole in high yields, while non-polar toluene, hep-
tane, and 1,2-dichloroethane were poor solvents. In polar organic
solvents, the reactions efficiently proceeded without any addi-
tives such as reducing agents and nitrogen bases. It is noted that
no precautions to exclude oxygen were necessary in all I-medi-
ated reactions. Under the optimized conditions, various combi-
nations of organic azides and alkynes were efficiently converted
into the corresponding 1,4-disubstituted-1,2,3-triazole deriva-
tives in excellent yields (14 examples, Table S3).
Triazole derivatives are very important five-membered ni-
trogen heterocycles and have a wide range of applications in-
cluding biochemicals, agrochemicals, dyes, photostabilizers,
and corrosion inhibitors.1 The Huisgen 1,3-dipolar cycloaddition
of organic azides to alkynes is one of the most powerful synthet-
ic routes to triazole derivatives and shows high chemoselectivity
because many functional groups do not react with organic azides
or alkynes.2 However, this transformation is not regioselective
and gives a ca. 1:1 mixture of 1,4- and 1,5-regioisomers.2 The
groups of Sharpless et al.3a and Meldal et al.3b have independent-
ly reported that copper salts dramatically accelerate the reaction
and make it totally regioselective to the 1,4-regioisomers. Now,
the copper-mediated regioselective 1,3-dipolar cycloaddition
has been used for the tailor-made syntheses of triazole deriva-
tives with various functional groups because of the exclusive
1,4-regioselectivity and wide synthetic scope.3 Recently, the
one-pot synthesis of 1,4-disubstituted-1,2,3-triazole derivatives
from organic halides, NaN3, and alkynes has received much
attention.4
The interests in the catalysis of partially metal-substituted
polyoxometalates, which are synthesized by the substitution of
metal cations into the vacant site(s) of lacunary polyoxometa-
lates as structural motifs, have been growing because of the rich
diversity of lacunary polyoxometalates.5 To date, various kinds
of metal-substituted polyoxometalates have been synthesized
and used as catalysts for various functional group transforma-
tions.5 Very recently, we have reported that dicopper-substituted
ꢀ-Keggin silicotungstate with bis-ꢁ-1,1-azido ligands TBA4H2-
[ꢀ-SiW10O36Cu2(ꢁ-1,1-N3)2] (denoted as I, Figure S1) showed
high catalytic activity for the oxidative alkyne–alkyne homocou-
pling6a,6b and 1,3-dipolar cycloaddition of organic azides to al-
kynes.6c In this paper, the application of I to the one-pot three-
component reaction of organic halides, NaN3, and alkynes to
produce 1,4-disubstituted-1,2,3-triazole derivatives is described
(eq 1).
Under the conditions described in Table S2, the 1,3-dipolar
cycloaddition did not proceed at all in the absence of the catalyst
or in the presence of copper(I) and copper(II) salts such as
.
[Cu(OTf)]2 C6H6, [Cu(CH3CN)4]PF6, [Cu(CH3CN)4]ClO4,
.
.
Cu(ClO4)2 6H2O, CuCl2, and CuSO4 5H2O. The monocopper-
substituted silicotungstate TBA4[ꢂ-H2SiW11CuO39], the non-
copper-substituted silicotungstate TBA4[ꢀ-SiW12O40], and a
mixture of TBA4[ꢀ-SiW10O34(H2O)2] and CuCl2 were almost
inactive. Therefore, the diazido-bridged dicopper core {Cu2(ꢁ-
1,1-N3)2} in I plays an important role in the present 1,3-dipolar
cycloaddition. We have very recently proposed that the I-
promoted alkyne–alkyne homocoupling proceeds via the dicop-
per(II) alkynyl intermediate of {Cu2(ꢁ-CꢁCR)2} followed by
the elimination of the corresponding 1,3-diyne with the forma-
tion of reduced dicopper(I) species.6a,6b Under the present trans-
formations, the corresponding 1,3-diynes could be detected as
by-products albeit in small amounts in most substrates tested
(<1% yield), suggesting the formation of the dicopper(I) spe-
cies. Thus, it is likely that the copper(I) acetylide species would
be formed by the reaction of the dicopper(I) species in I with an
alkyne followed by the reaction with an azide to form the corre-
sponding triazole.
Finally, we turn our attention to the one-pot three compo-
nent synthesis of 1,4-disubstituted-1,2,3-triazole derivatives
from the corresponding organic halides, NaN3, and alkynes
(12 examples, Table 1).4,7,8 The overall conversion of organic
halides to 1,4-disubstituted-1,2,3-triazole derivatives was ac-
complished as a one-pot procedure by simply adding alkynes
to the reaction solution after the SN2 displacement of organic
N
R
I
N
N
ð1Þ
R
X
R'
+ NaN +
3
NaX
R'
First, we examined the reactivity of organic halides with
NaN3 prior to the development of a one-pot sequential synthesis
Copyright Ó 2008 The Chemical Society of Japan

Chemistry Letters Vol.37, No.12 (2008)
1259
ꢃ
Table 1. One-pot syntheses of 1,4-disubstituted-1,2,3-triazole
derivatives from organic halides, NaN3, and alkynes catalyzed
by Ia
to the direct addition of N3 to alkynes was observed in any
case.
In summary, the efficient one-pot synthesis of 1,4-disubsti-
tuted-1,2,3-triazole derivatives from organic halides, NaN3,
and alkynes was realized in the presence of I.
N
R
N
N
i) NaN3
ii) R'
R
X
R'
Timeb
/h
Yieldc
/%
We are grateful to Dr. S. Yamaguchi (The Univ. of Tokyo)
for his help in experiments. This work was supported in part by a
Grant-in-Aid for Scientific Research from the Ministry of Edu-
cation, Culture, Sports, Science and Technology of Japan.
Entry Halide
Alkyne
Cl
1
31
48
48
31
31
31
72
72
50
81
(2a)
(2b)
(2c)
(2b)
(1a)
2
3
4
5
6
7
8
9
1a
1a
1a
1a
1a
1a
1a
89
References and Notes
1
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90
MeO
94
88d
91d
94d
71
F
(2b)
(2f)
2
3
Cl
(2g)
(2h)
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aReaction conditions: (i) I (2 mol % with respect to halides), hal-
ide (0.5 mmol), NaN3 (0.525 mmol), CH3CN/CH3OH (2 mL,
1/1 v/v), 60 ꢂC under an air atmosphere for 7 h, (ii) followed
by addition of an alkyne (1 mmol), 60 ꢂC, under an air atmo-
b
c
d
sphere. Total reaction time. Isolated yields. GC yields.
halides with NaN3 was completed. The procedures are as fol-
lows: Into a glass vial were successively placed I (2 mol %),
an organic halide (0.5 mmol), NaN3 (0.525 mmol, 1.05 equiv
with respect to halides), and acetonitrile/methanol (2 mL, 1/1
v/v). The reaction mixture was stirred at 60 ꢂC. After 7 h, an al-
kyne (1 mmol, 2 equiv with respect to halides) was added to the
mixture and the reaction was carried out at 60 ꢂC for an appro-
priate time. Although it took longer reaction times to attain high
yields of the corresponding 1,4-disubstituted-1,2,3-triazoles, the
amounts of alkynes could be reduced: The reaction of 1a with an
equimolar amount of 2a under the conditions in Table 1 gave the
corresponding triazole in 74% yield for 53 h, for example. Iso-
lation and purification of 1,4-disubstituted-1,2,3-triazoles were
carried out by column chromatography on silica gel using a
mixed solvent of hexane and diethyl ether as an eluent (5/1 v/v).
Benzyl halides as well as alkyl halides were successfully
used and the reactions efficiently proceeded to give the corre-
sponding 1,4-disubstituted-1,2,3-triazoles in excellent yields.
For alkynes, electron-rich and -poor phenylacetylenes as well
as aliphatic terminal alkynes worked well as reaction partners
of organic halides. It was confirmed by X-ray crystallographic
analyses and/or NOE experiments that the 1,4-disubstituted-
1,2,3-triazole derivatives were formed in a completely regiose-
lective manner without formation of 1,5-regioisomers in all cas-
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The reaction rate for the cycloaddition of an azide to an alkyne de-
creased in the presence of NaN3 and NaCl (Table S3), which is
likely due to the competitive coordination of N3 or Clꢃ to the
active copper site. Although the present one-pot procedure needs
longer time than the step-by-step synthesis, it completely avoids
the isolation of an explosive organic azide. This is a very important
advantage of the present one-pot procedure.
Supporting Information is also available electronically on the CSJ-
Journal Web site, http://www.csj.jp/journals/chem-lett/index.html.
4
5
6
7
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Published on the web (Advance View) November 15, 2008; doi:10.1246/cl.2008.1258