A convenient synthesis of 1-substituted 1,2,3-triazoles via CuI/Et 3N catalyzed 'click chemistry' from azides and acetylene gas

Article abstract of DOI:10.1055/s-0029-1216745

Copper(I)-catalyzed 'click chemistry' using acetylene gas was successfully explored under mild conditions. 1-Substituted-1,2,3-triazoles were conveniently synthesized from the corresponding aromatic and aliphatic azides. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0029-1216745

LETTER
1453
A Convenient Synthesis of 1-Substituted 1,2,3-Triazoles via CuI/Et3N
Catalyzed ‘Click Chemistry’ from Azides and Acetylene Gas
S
ynthesis of 1-S
u
ubstituted 1
-
Y
zoles ong Wu,a Yong-Xin Xie,a Zi-Sheng Chen,a Yan-Ning Niu,a Yong-Min Liang*a,b
a
State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou 730000, P. R. of China
State Key Laboratory of Solid Lubrication, Lanzhou Institute of Chemical Physics, Chinese Academy of Science, Lanzhou 730000,
b
P. R. of China
Fax +86(931)8912582; E-mail: liangym@lzu.edu.cn
Received 5 January 2009
usage of acetylene gas under mild conditions. Herein, we
wish to report our results in this paper.
Abstract: Copper(I)-catalyzed ‘click chemistry’ using acetylene
gas was successfully explored under mild conditions. 1-Substituted-
1,2,3-triazoles were conveniently synthesized from the correspond-
ing aromatic and aliphatic azides.
In preliminary experiments, benzyl azide (1a) was chosen
for the template reaction with acetylene gas. The results
Key words: azides, copper(I) catalysis, click chemistry, acetylene are summarized in Table 1. Initially, acetone was chosen
gas, 1,2,3-triazoles
as the solvent. No product was isolated when the reaction
was conducted at room temperature even for 24 hours in
the presence of 10 mol% CuI (entry 1, Table 1). It was re-
ported that organic bases could help the formation of the
active copper acetylide complex, and promoted the ‘click’
reaction.2b,4e,9 Therefore, we tried adding 40 mol% Et3N
into the reaction system. To our delight, the reaction gave
the corresponding compound 2a in 38% yield (entry 2,
Table 1). Encouraged by this positive result, other polar
solvents were also investigated (entries 3–9, Table 1).
Clearly, the reaction was dramatically affected by sol-
vent.10 Dimethyl sulfoxide was found to be one of the best
solvents to give good yields. It should be pointed out that
MeCN and DMSO–H2O both gave excellent results in the
model reaction (entries 6 and 9, Table 1), but only medi-
um yields were obtained when other azides were exploited
as the reactant.11 Thus, DMSO was chosen as the typical
solvent in subsequent experiments. Other Cu(I) catalysts
were investigated, which showed lower activity (entries
10–12, Table 1). Decreasing the reaction time from 24
hours to 14 hours gave rise to a reduction of the yield (en-
try 13, Table 1). The loading of Et3N was also examined
(entries 14 and 15, Table 1). When 20 mol% Et3N were
used, the yield of the product was reduced to 69%. Adding
1.0 equivalent Et3N to the reaction system did not signifi-
cantly improve the result. Other organic bases were also
introduced into the reaction mixture and gave slightly
lower yields (entries 16–18, Table 1). In comparison with
the base-free conditions, inorganic base (K2CO3) did not
improve the result (entries 19 and 20, Table 1). Reducing
the amount of catalyst CuI to 5 mol% again led to a drop
of product yield to 72% (entry 21, Table 1). The reaction
did not proceed without the presence of catalyst (entry 22,
Table 1).
1,2,3-Triazole derivatives have displayed an ample range
of application in pharmaceutical, agrochemical, and mate-
rial sciences.1 Since Fokin and Sharpless developed
Cu(I)-catalyzed 1,3-dipolar Huisgen cycloaddition reac-
tion of azides with alkynes,2 ‘click chemistry’ has re-
ceived growing interest in the regioselective synthesis of
1,4-disubstituted 1,2,3-triazoles.3 The formation of tria-
zoles in ‘click chemistry’ has represented definitive ad-
vances: reliable, effective, benign in reaction conditions,
and high tolerance to many functional groups. Through
this reaction, a wide variety of compounds with an inert
triazole heterocycle could be prepared that are of interest
in medicinal chemistry and material science.4
Due to the contributions from Sharpless group and others,
most reports were focused on the preparations of 1,4-di-
substituted 1,2,3-triazoles.3,5 To our best knowledge, syn-
thesis of 1-substituted-1,2,3-triazole received little
attention.6 One of the most convenient entries is the 1,3-
dipolar Huisgen cycloaddition reaction of azides with
acetylene gas.7 However, the typical Huisgen cycloaddi-
tion processes required elevated temperature, high pres-
sure, and special reaction vessel. Reviewing the
mechanism of the ‘click chemistry’, 1-substituted-1,2,3-
triazole compounds would be similarly produced when
acetylene gas was used as substrate. It was recently report-
ed that 1-substituted-1,2,3-triazoles were successfully
synthesized under the ‘click’ conditions from trimethyl-
silylacetylene and azides.6a However, deprotection of tri-
methylsilylacetylene made this process less atom
economic. Motivated by our interesting in the ‘click
chemistry’,8 we examined the feasibility to synthesize 1-
substituted-1,2,3-triazole via ‘click’ approach by direct
With the optimal conditions in hand, a variety of azides
were explored in this ‘click’ process. Generally, as shown
in Table 2, the reactions were highly influenced by steric
and electronic effects. Both electron-rich and electron-
deficient aromatic azides, bearing substituents at meta-
and para-position, afforded the product in excellent
yields. It should be noted that the reaction of electron-rich
azide (4-methoxy-phenyl azide) was slower than other
SYNLETT 2009, No. 9, pp 1453–1456
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x.
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x.
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Advanced online publication: 04.05.2009
DOI: 10.1055/s-0029-1216745; Art ID: W00709ST
© Georg Thieme Verlag Stuttgart · New York

1454
L.-Y. Wu et al.
LETTER
Table 1 Optimization of the Reaction Conditionsa
Table 2 Reaction of Acetylene Gas with Different Azidesa
N
CuI (10 mol%)
Et3N (40 mol%)
N
Cu(I), base
N3
N
R
N
N
N
+
RN3
+
solvent
DMSO, r.t., 1 atm
1
2
1a
2a
Entry Azide
1
Time (h) Triazole12,13 Yield (%)b
Entry Solvent
Cu(I)
(10 mol%)
Base (mol%)
Yield
(%)b
N3
24
24
2a
2b
85
92
1
2
acetone
acetone
THF
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
–
0
38
23
31
44
89
85
17
85
78
76
31
80
69
83
80
78
77
54
59
72
0
N3
Et3N (40)
Et3N (40)
Et3N (40)
Et3N (40)
Et3N (40)
Et3N (40)
Et3N (40)
Et3N (40)
Et3N (40)
Et3N (40)
2
3
N3
4
MeOH
DMF
3
24
24
2c
93
93
5
Me
Me
N3
6
MeCN
DMSO
dioxane
4
2d
7
Me
8
N3
5
48
2e
45
9
DMSO/H2Oc CuI
CuBr
CuCl
10
11
12
13e
14
15
16
17
18
19
20
21f
22
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
N3
6
48
24
24
2f
90
92
93
MeO
CuSO4/Vcd Et3N (40)
N3
N3
7
2g
2h
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
–
Et3N (40)
Et3N (20)
Et3N (40)
2,6-lutidine (40)
pyridine (40)
i-Pr2NEt (40)
K2CO3 (40)
–
Cl
Cl
8
Cl
N3
9
24
2i
54
N3
N3
10
24
24
24
2j
2k
2l
89
86
90
Br
Br
11
Et3N (40)
–
N3
12
a Unless otherwise noted, all reactions were performed with 0.4 mmol
Et3N, 1.0 mmol of azide, 1.5 mL of solvent, and 0.1 mmol catalyst un-
der a balloon pressure of acetylene atmosphere at r.t.
b Isolated yield.
EtO2C
N3
13
24
24
2m
2n
91
92
c VDMSO/VH2O = 4:1.
d Vc = sodium ascorbate.
O2N
e 14 h.
O2N
N3
f The amount of 5 mol% CuI was used.
14
4-substitued phenyl ones; the yield of 90% was isolated
by prolonging the reaction time to 48 hours (entry 6, 15
Table 2).
24
24
2o
2p
76
97
N3
ortho-Substituted aromatic azides, 2-methylphenyl azide
16
n-C8H17 N3
and 2-chlorophenyl azide, provided moderate yields in
45% and 54%, respectively (entries 5 and 9, Table 2).
Compared with benzyl azide, the reaction of methyl ben-
a All reactions were performed with 0.4 mmol Et3N, 1.0 mmol of
azides, 1.5 mL of DMSO, and 0.1 mmol CuI under a balloon pressure
of acetylene atmosphere at r.t., unless otherwise noted.
b Isolated yield.
zyl azide gave a lower yield (76%, entry 15, Table 2),
Synlett 2009, No. 9, 1453–1456 © Thieme Stuttgart · New York

LETTER
Synthesis of 1-Substituted 1,2,3-Triazoles
1455
(5) (a) Krasinski, A.; Fokin, V. V.; Sharpless, K. B. Org. Lett.
2004, 6, 1237. (b) Rasmussen, L. K.; Boren, B. C.; Fokin,
V. V. Org. Lett. 2007, 9, 5337. (c) Zhang, L.; Chen, X.;
Xue, P.; Sun, H. H. Y.; Williams, I. D.; Sharpless, K. B.;
Fokin, V. V.; Jia, G. J. Am. Chem. Soc. 2005, 127, 15998.
(d) Ackermann, L.; Potukuchi, H. K.; Landsberg, D.;
Vicente, R. Org. Lett. 2008, 10, 3081. (e) Boren, B. C.;
Narayan, S.; Rasmussen, L. K.; Shang, L.; Zhao, H.; Lin, Z.;
Jia, G.; Fokin, V. V. J. Am. Chem. Soc. 2008, 130, 8923.
(f) Chuprakov, S.; Chernyak, N.; Dudnik, A. S.; Gevorgyan,
V. Org. Lett. 2007, 9, 2333.
which was due to higher steric hindrance. In the case of
aliphatic azide (n-octanyl azide) the reaction worked well
to give the triazole in 97% yield (entry 16, Table 2).
In summary, CuI and Et3N in DMSO proved to be an ef-
fective and convenient catalytic system for ‘click chemis-
try’ with acetylene gas. The reaction produced a series of
1-substituted-1,2,3-triazoles in moderate to excellent
yields from both aliphatic and aromatic azides.
(6) (a) Fletcher, J. T.; Walz, S. E.; Keeney, M. E. Tetrahedron
Lett. 2008, 49, 7030. (b) Song, R.-J.; Deng, C.-L.; Xie,
Y.-X.; Li, J.-H. Tetrahedron Lett. 2007, 48, 7845.
(c) Taillefer, M.; Xia, N.; Ouali, A. Angew. Chem. Int. Ed.
2007, 46, 934. (d) Cristau, H. J.; Cellier, P. P.; Spindler,
J.-F.; Taillefer, M. Chem. Eur. J. 2004, 10, 5607.
(e) Taillefer, M.; Cristau, H.-J.; Cellier, P. P.; Spindler, J.-F.
FR 2833947, 2001. (f) Taillefer, M.; Cristau, H.-J.; Cellier,
P. P.; Spindler, J.-F. WO 0353225, 2001; Pr. Nb. Fr 2001
16547. (g) Taillefer, M.; Cristau, H.-J.; Cellier, P. P.;
Spindler, J.-F.; Ouali, A. FR 2840303, 2002. (h) Taillefer,
M.; Cristau, H.-J.; Cellier, P. P.; Spindler, J.-F.; Ouali, A.
WO 03101966, 2002; Pr. Nb. Fr 200206717.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
Acknowledgment
The authors thank the NSF-20621091 and the ‘Hundred Scientist’
from the Chinese Academy of Sciences for the financial support of
this work. Thank Dr. Ze-Yi Yan of Lanzhou University for his help
in preparation of manuscript.
References and Notes
(7) (a) Fan, H.; Xu, G.; Chen, Y.; Jiang, Z.; Zhang, S.; Yang, Y.;
Ji, R. Eur. J. Med. Chem. 2007, 42, 1137. (b) Kauer, J. C.;
Carboni, R. A. J. Am. Chem. Soc. 1967, 89, 2633.
(8) (a) Yan, Z.-Y.; Zhao, Y.-B.; Fan, M.-J.; Liu, W.-M.; Liang,
Y.-M. Tetrahedron 2005, 61, 9331. (b) Zhao, Y.-B.; Yan,
Z.-Y.; Liang, Y.-M. Tetrahedron Lett. 2006, 47, 1545.
(c) Yan, Z.-Y.; Niu, Y.-N.; Wei, H.-L.; Wu, L.-Y.; Zhao,
Y.-B.; Liang, Y.-M. Tetrahedron: Asymmetry 2006, 17,
3288. (d) Wu, L.-Y.; Yan, Z.-Y.; Xie, Y.-X.; Niu, Y.-N.;
Liang, Y.-M. Tetrahedron: Asymmetry 2007, 18, 2086.
(e) Niu, Y.-N.; Yan, Z.-Y.; Li, G.-Q.; Wei, H.-L.; Gao,
G.-L.; Wu, L.-Y.; Liang, Y.-M. Tetrahedron: Asymmetry
2008, 19, 912.
(9) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett.
1975, 16, 4467.
(10) The present reaction exhibited strong solvent effect, which is
greatly different from the typical ‘click chemistry’. The
discrepancy was presumed to cause by the acetylene gas. In
the reactions, abundant reddish-brown precipitate was
formed.
(1) Reviews on 1,2,3-triazoles, see: (a) Fan, W.-Q.; Katritzky,
A. R. In Comprehensive Heterocyclic Chemistry II, Vol. 4;
Katritzky, A. R.; Rees, C. W.; Scriven, E. F. V., Eds.;
Elsevier: Oxford, UK, 1996, 1–126. (b) Dehne, H. In
Methoden der Organischen Chemie (Houben-Weyl), Vol.
E8d; Schumann, E., Ed.; Thieme: Stuttgart, 1994, 305.
(2) (a) Kolb, H. C.; Finn, M. G.; Sharpless, K. B. Angew. Chem.
Int. Ed. 2001, 40, 2004. (b) Rostovtsev, V. V.; Green, L. G.;
Fokin, V. V.; Sharpless, K. B. Angew. Chem. Int. Ed. 2002,
41, 2596. (c) Tornøe, C. W.; Christensen, C.; Meldal, M.
J. Org. Chem. 2002, 67, 3057.
(3) For recent reviews, see: (a) Bock, V. D.; Hiemstra, H.; van
Maarseveen, J. H. Eur. J. Org. Chem. 2006, 51.
(b) Fournier, D.; Hoogenboom, R.; Schubert, U. S. Chem.
Soc. Rev. 2007, 36, 1369. (c) Moses, J. E.; Moorhouse, A.
D. Chem. Soc. Rev. 2007, 36, 1249. (d) Wu, P.; Fokin, V. V.
Aldrichimica Acta 2007, 40, 7. (e) Tron, G. C.; Pirali, T.;
Billington, R. A.; Canonico, P. L.; Sorba, G.; Genazzani,
A. A. Med. Res. Rev. 2008, 28, 278. (f) Gil, M. V.; Arévalo,
M. J.; López, Synthesis 2007, 1589. (g) Meldal, M.;
Tornøe, C. W. Chem. Rev. 2008, 108, 2952.
(11) Acetonitrile and DMSO–H2O both gave excellent results in
the template reaction. But when other azides used, the yields
decreased significantly. In MeCN, 2b and 2c were obtained,
respectively, in 52% and 63% after 24 h. In DMSO–H2O
(4:1), 4-methylphenyl azide was tried, but the yield was only
poor 40%. Therefore, we chose DMSO as typical solvent in
subsequent experiments. The reason of the discrepancy is
unknown.
(4) For examples, see: (a) Whiting, M.; Muldoon, J.; Lin, Y.-C.;
Silverman, S. M.; Lindstrom, W.; Olson, A. J.; Kolb, H. C.;
Finn, M. G.; Sharpless, K. B.; Elder, J. H.; Fokin, V. V.
Angew. Chem. Int. Ed. 2006, 45, 1435. (b) Kolb, H. C.;
Sharpless, K. B. Drug Discov. Today 2003, 8, 1128. (c) Ye,
C. F.; Gard, G. L.; Winter, R. W.; Syvret, R. G.; Twamley,
B.; Shreeve, J. M. Org. Lett. 2007, 9, 3841. (d) Angelos, S.;
Yang, Y. W.; Patel, K.; Stoddart, J. F.; Zink, J. I. Angew.
Chem. Int. Ed. 2008, 47, 2222. (e) Fazio, F.; Bryan, M. C.;
Blixt, O.; Paulson, J. C.; Wong, C.-H. J. Am. Chem. Soc.
2002, 124, 14397. (f) Lutz, J.-F. Angew. Chem. Int. Ed.
2007, 46, 1018.
(12) Typical Procedure for Compound 2.
To a 5 mL flask with Et3N (0.4 mmol), azides 1 (1.0 mmol),
and solvent (1.5 mL), CuI (0.1 mmol) was added into the
mixture under N2 atmosphere. The flask was purged with
acetylene for several times. Then the mixture was stirred
under a balloon pressure of acetylene at r.t. After the
designed time, the mixture was diluted with 25 mL EtOAc,
and washed by 10 mL H2O for four times then by brine. The
organic phase dried over anhyd Na2SO4. After removal of
the solvent under reduced pressure, the residue was purified
on SiO2 with PE–EtOAc (4:1 to 1:2). Caution: Azides are
potentially explosive compounds and should be handled
with great care.
Synlett 2009, No. 9, 1453–1456 © Thieme Stuttgart · New York

1456
L.-Y. Wu et al.
LETTER
(13) Analytical Data of Selected Products
134.2, 129.34, 129.33, 121.7, 121.1, 117.5, 21.2 ppm.
Compound 2a: white solid, mp 51–53 °C. 1H NMR (400
MHz, CDCl3): d = 7.71 (s, 1 H), 7.48 (s, 1 H), 7.37 (m, 3 H),
7.27 (m, 2 H), 5.57 (s, 2 H) ppm. 13C NMR (100 MHz,
CDCl3): d = 134.6, 134.0, 128.9, 128.5, 127.8, 123.3, 53.7
ppm. MS (EI): m/z = 159 [M+], 130, 104, 91, 77.
MS (EI): m/z = 159 [M+].
Compound 2f: white solid, mp 78–80 °C. 1H NMR (400
MHz, CDCl3): d = 7.94 (s, 1 H), 7.85 (s, 1 H), 7.65 (dd,
J1 = 6.9 Hz, J2 = 2.1 Hz, 2 H), 7.03 (dd, J1 = 6.9 Hz, J2 = 2.1
Hz, 2 H), 3.88 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3):
d = 160.1, 135.7, 131.1, 123.0, 122.6, 115.1, 55.9 ppm.
MS (EI): m/z = 175 [M+].
Compound 2b: pale yellow solid, mp 52–53 °C. 1H NMR
(400 MHz, CDCl3): d = 8.04 (s, 1 H), 7.88 (s, 1 H), 7.77 (m,
2 H), 7.56 (m, 2 H), 7.47 (m, 1 H). 13C NMR (100 MHz,
CDCl3): d = 137.5, 135.7, 130.0, 129.0, 122.8, 121.0 ppm.
MS (EI): m/z = 145 [M+].
Compound 2g: pale yellow solid, mp 111–113 °C. 1H NMR
(400 MHz, CDCl3): d = 8.01 (s, 1 H), 7.85 (s, 1 H), 7.70 (d,
J = 8.8 Hz, 2 H), 7.50 (d, J = 8.8 Hz, 2 H) ppm. 13C NMR
(100 MHz, CDCl3): d = 138.6, 134.5, 134.0, 130.0, 121.6,
120.2, 20.8 ppm. MS (EI): m/z = 179 [M+].
Compound 2c: 1H NMR (400 MHz, CDCl3): d = 7.99 (s, 1
H), 7.80 (s, 1 H), 7.59 (d, J = 6.8 Hz, 2 H), 7.28 (d, J = 6.8
Hz, 2 H), 2.39 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3):
d = 138.6, 134.5, 134.0, 130.0, 121.6, 120.2, 20.8 ppm.
MS (EI): m/z = 159 [M+].
Compound 2h: pale yellow solid, mp 91–93 °C. 1H NMR
(400 MHz, CDCl3): d = 8.05 (s, 1 H), 7.85 (s, 1 H), 7.79 (s,
1 H), 7.65 (d, J = 7.6 Hz, 1 H), 7.46 (d, J = 8.0 Hz, 1 H), 7.41
(d, J = 8.0 Hz, 1 H) ppm. 13C NMR (100 MHz, CDCl3): d =
137.7, 135.4, 134.6, 130.8, 128.7, 121.7, 120.7, 118.5 ppm.
MS (EI): m/z = 179 [M+].
Compound 2d: yellow oil. 1H NMR (400 MHz, CDCl3): d =
7.98 (s, 1 H), 7.79 (s, 1 H), 7.54 (s, 1 H), 7.47 (d, J = 8.0 Hz,
1 H), 7.35 (d, J = 7.6 Hz, 1 H), 7.20 (d, J = 7.2 Hz, 1 H), 2.40
(s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): d = 139.8, 136.8,
Synlett 2009, No. 9, 1453–1456 © Thieme Stuttgart · New York

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