The use of calcium carbide in the synthesis of 1-monosubstituted aryl 1,2,3-triazole via click chemistry

Article abstract of DOI:10.1055/s-0029-1218346

The synthesis of 1-monosubstituted aryl 1,2,3-triazoles was achieved using calcium, carbide as a source of acetylene. The copper-catalyzed 1,3-dipolar cycloaddition reactions were carried out without nitrogen protection and in a MeCN - H₂O mixt

Full text of DOI:10.1055/s-0029-1218346

LETTER
3163
The Use of Calcium Carbide in the Synthesis of 1-Monosubstituted Aryl
1,2,3-Triazole via Click Chemistry
C
u-Catayzed1,3-D
u
ipolar
C
yclo
b
addition of
C
o
alcium
C
arbide an
J
d
A
zidesiang,a Chunxiang Kuang,*a Qing Yangb
a
Department of Chemistry, Tongji University, Siping Road 1239, Shanghai 200092, P. R. of China
Fax +86(21)65983191; E-mail: kuangcx@tongji.edu.cn
b
Department of Biochemistry, School of Life Sciences, Fudan University, Handan Road 220, Shanghai 200433, P. R. of China
Received 28 August 2009
amount of CuI in different solvents. Product 2a was final-
ly obtained when 1-azido-4-methylbenzene (1a) and cal-
cium carbide were reacted in the presence of 0.05
equivalents of CuI and sodium ascorbate in a solvent mix-
Abstract: The synthesis of 1-monosubstituted aryl 1,2,3-triazoles
was achieved using calcium carbide as a source of acetylene. The
copper-catalyzed 1,3-dipolar cycloaddition reactions were carried
out without nitrogen protection and in a MeCN–H2O mixture. The
yields ranged from moderate to excellent. The reaction conditions ture of THF–H2O (20:1), although the initial yield was un-
were found to be successful for aryl azide reactants, including ana-
satisfactory (Table 1, entry 1).
logues with various functionalities.
Various conditions were then examined to optimize the
Key words: calcium carbide, 1-monosubstitued 1,2,3-triazole, cop-
yield and functionality of 1-monosubstitued 1,2,3-triaz-
per-catalyzed, click chemistry
oles (Table 1). The presence of CuI was obvious, and its
absence resulted in no product formation (Table 1, entry
19). An increase of the water content in the solvent result-
The click synthesis of 1,2,3-triazoles has received much
ed in an increase in the yield of the target 1,2,3-triazoles
attention because of their wide range of applications in the
(Table 1, entry 2). Moderate amount of water was needed
fields of pharmaceuticals, materials science, and molecule
to react with CaC2 to form acetylene which was then cap-
structure design.1 1,4-Disubstituted-1,2,3-triazoles can be
tured by the Cu catalyst and fed into the click reaction cy-
synthesized efficiently when employing the robust Cu-
cle. When dry MeCN was used as solvent, no product was
catalyzed Huisgen 1,3-dipolar cycloaddition.2 The Cu-
observed (Table 1, entry 20). Interestingly, an overabun-
catalyzed azide–alkyne 1,3-dipolar cycloaddition has
dance of water was unfavorable to this system. The reason
been established as one of the most reliable means for the
may be that it will decrease the solubility of acetylene in
covalent assembly of complex molecules. However, there
this reaction system. It was found eventually that the reac-
are few reports in the literature concerning the synthesis
tion proceeded more efficiently when conducted in the
of 1-monosubstituted 1,2,3-triazoles via this useful click
presence of CuI/sodium ascorbate (0.3 equiv) in MeCN–
reaction. 1-Monosubstitued 1,2,3-triazoles were mainly
H2O (2:1) at room temperature (Table 1, entries 12–14),
prepared by cycloaddition of azides with acetylene3 and
and 1.3 equivalents of calcium carbide was required to
its derivatives, such as acetylides (trimethylsilylacetylene
give a good yield of the cycloaddition product. Hence,
product 2a was isolated with 88% yield using these opti-
and ethynyltributyltin),4 vinyl compounds (vinyl acetate,
vinyl ethers, vinyl amines, and vinyl sulfoxides),5 and
mum reaction conditions (Table 1, entry 14).
propiolic acid.6 Herein we report a mild, convenient and
A series of aryl azides prepared according to literature
inexpensive method for the preparation of 1-monosubsti-
tuted aryl 1,2,3-triazoles (2), in which calcium carbide
was reacted directly aryl azides (1) via the copper-cata-
procedures7 were subjected to the reaction with CaC2 un-
der optimized reaction conditions. The reactions finished
in different time period and afforded 1-monosubstitued
lyzed 1,3-dipolar cycloaddition reaction (Scheme 1). It is
1,2,3-triazoles in moderate to excellent yields as shown in
the first report that calcium carbide instead of alkyne is
Table 2. The reaction of aryl azides carrying electron-
used in a click reaction.
withdrawing group such as nitro or fluoro substituents
proceeded in higher yields (Table 2, entries 6, 8) as com-
pared to those azides carrying electron-donating groups
such as methyl and (E)-bromovinyl (Table 2, entries 4,
An initial study to screen the reaction conditions was con-
ducted with 1-azido-4-methylbenzene (1a) (Ar = 4-
MeC6H4, 0.5 mmol) as the starting substrate. The reaction
was carried out using different ligands and various
10). It is noteworthy that aryl azides bearing either an
electron-donating or an electron-withdrawing group at the
N
CuI, ligand
solvent
N
CaC2
para position could give good product yields at room tem-
perature. Unlike para-substituted aryl azides, substrates
bearing ortho substituent suffered from slower reaction
rate due to steric hindrance effect, and cycloaddition reac-
tion lasted three or more days at room temperature. Im-
provements were obtained when the reaction was
conducted in sealed tube at 90 °C (Table 2, entries 2, 5, 9,
ArN3
+
Ar
N
2
1
Scheme 1 Synthesis of 1-monosubstituted aryl 1,2,3-triazoles 2
SYNLETT 2009, No. 19, pp 3163–3166
x
x
.x
x
.2
0
0
9
Advanced online publication: 03.11.2009
DOI: 10.1055/s-0029-1218346; Art ID: W13409ST
© Georg Thieme Verlag Stuttgart · New York

3164
Y. Jiang et al.
LETTER
Table 1 Synthesis of Compound 2a under Various Conditions
Entry
1
CaC2 (equiv) CuI (equiv)
Ligand (equiv)
Solvent (v/v)
Time (h)
24
Yield of 2a (%)a
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.8
1.3
1.1
1.3
1.3
1.3
1.3
1.3
0.05
0.05
0.10
0.20
0.20
0.20
0.20
0.20
0.20
0.30
0.40
0.30
0.30
0.30
0.30
0.30
0.30
0.30
0
Na ascorbate (0.05)
Na ascorbate (0.05)
Na ascorbate (0.10)
Na ascorbate (0.20)
L-proline (0.20)
THF–H20 (20:1)
THF–H20 (10:1)
THF–H20 (3:1)
THF–H20 (3:1)
THF–H20 (3:1)
THF–H20 (3:1)
MeCN–H20 (3:1)
MeCN–H20 (3:1)
MeCN–H20 (3:1)
MeCN–H20 (3:1)
MeCN–H20 (3:1)
MeCN–H20 (2:1)
MeCN–H20 (2:1)
MeCN–H20 (2:1)
MeCN–H20 (2:1)
EtOH–H20 (2:1)
EtOH–H20 (4:1)
EtOH–H20 (2:1)
MeCN–H20 (2:1)
MeCN (dry)
8
15
22
62
45
15
32
55
70
80
72
85
80
88
65
35
21
25
0
2
24
3
24
4
24
5
18
6
N,N-dimethlglycine (0.20)
N,N-dimethlglycine (0.20)
L-proline (0.20)
24
7
24
8
24
9
Na ascorbate (0.20)
Na ascorbate (0.30)
Na ascorbate (0.40)
Na ascorbate (0.30)
Na ascorbate (0.30)
Na ascorbate (0.30)
Na ascorbate (0.30)
Na ascorbate (0.30)
Na ascorbate (0.30)
L-proline (0.30)
24
10
11
12
13
14
15
16
17
18
19
20
24
16
20
20
20
24
24
24
24
0
24
0.30
Na ascorbate (0.30)
24
0
a Isolated yield.
11) in a shorter time. On the other hand, click reaction of
benzyl and alkyl azides using the present method gave
low product yields (<10%). The exact reason remained
unknown to us.
References and Notes
(1) (a) Kolb, H. C.; Finn, M. G.; Sharpless, K. B. Angew. Chem.
Int. Ed. 2001, 40, 2004. (b) Bock, V. D.; Hiemstra, H.;
Maarseveen, J. H. J. Org. Chem. 2006, 5, 919. (c) Fournier,
D.; Hoogenboom, R.; Schubert, U. S. Chem. Soc. Rev. 2007,
36, 1369. (d) Nandivada, H.; Jiang, X.; Lahann, J. Adv.
Mater. 2007, 19, 2197. (e) Lutz, J. F. Angew. Chem. Int. Ed.
2007, 46, 1018. (f) Tron, G. C.; Pirali, T.; Billington, R. A.;
Canonico, P. L.; Sorba, G.; Genazzani, A. A. Med. Res. Rev.
2008, 28, 278. (g) Hanelt, S.; Liebscher, J. Synlett 2008,
1058.
In summary, we have reported the first calcium carbide
participated 1,3-dipolar cycloaddition reaction. It pro-
vides a novel access to 1-monosubstitued 1,2,3-triazoles,
which are important classes of heterocycles in medicinal
chemistry and materials science.1
(2) (a) Rostovtsev, V. V.; Green, L. G.; Fokin, V. V.; Sharpless,
K. B. Angew. Chem. Int. Ed. 2002, 41, 2596. (b) Tornoe,
C. W.; Christensen, C.; Meldal, M. J. Org. Chem. 2002, 67,
3057. (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) Rasmussen, L. K.; Boren,
B. C.; Fokin, V. V. Org. Lett. 2007, 9, 5337. (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) Wu, L. Y.; Xie, Y. X.; Chen, Z. S.; Liu, Y. N.; Liang,
Y. M. Synlett 2009, 1453. (g) Yan, Z. Y.; Wei, H. L.; Wu,
L. Y.; Zhao, Y. B.; Liang, Y. M. Tetrahedron: Asymmetry
2006, 17, 3288. (h) Yan, Z. Y.; Zhao, Y. B.; Fan, M. J.; Liu,
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
Acknowledgment
The work was supported by Natural Science Foundation of China
(No. 30873153), the Key Projects of Shanghai in Biomedical
(No.08431902700), and the Scientific Research Foundation of State
Education Ministry for the Returned Overseas Chinese Scholars.
We would like to thank the Center for Instrumental Analysis, Tongji
University, P. R. of China.
Synlett 2009, No. 19, 3163–3166 © Thieme Stuttgart · New York

LETTER
Cu-Catayzed 1,3-Dipolar Cycloaddition of Calcium Carbide and Azides
3165
Table 2 Synthesis of Aryl 1,2,3-Triazoles 2
Entry
ArN3 1
Product 2
Conditionsa
A
Time (h)
20
Yields of 2 (%)b
N
N
N
N
1
1a
88
81
2a
N
N
N
2
1b
B
8
2b
N
N
3
4
1c
A
A
16
6
85
90
2c
Cl
N
N
N
N
1d
2d
N
N
5
1e
B
5
84
Cl
2e
N
N
F
N
6
7
8
1f
A
A
A
4
8
2
94
70
95
2f
N
N
H2NO2S
2g
N
1g
1h
N
N
O2N
2h
N
N
N
N
NO2
9
1i
1j
B
A
4
86
76
2i
Br
N
N
N
10
20
2j10
N
N
N
11
1k
B
10
72
Br
2k10
a Conditions A: azide (0.5 mmol), CaC2 (42 mg, 0.65 mmol), CuI (29 mg, 0.15 mmol), Na ascorbate (30 mg, 0.15 mmol), MeCN–H2O (12 mL)
in a flask at r.t.8 Conditions B: azide (0.5 mmol), CaC2 (42 mg, 0.65 mmol), CuI (29 mg, 0.15 mmol), Na ascorbate (30 mg, 0.15 mmol), MeCN–
H2O (12 mL) in a sealed tube at 90 °C.9
b Isolated yield.
W. M.; Liang, Y. M. Tetrahedron 2005, 61, 9331.
(i) Cristau, H. J.; Cellier, P. P.; Spindler, J. F.; Taillefer, M.
Chem. Eur. J. 2004, 10, 5607.
Stevens, M. F. G. Bioorg. Med. Chem. 2002, 10, 3001.
(c) Fletcher, J. T.; Walz, S. E.; Keeney, M. E. Tetrahedron
Lett. 2008, 49, 7030.
(3) De, O.; Ronaldo, N.; Sinou, D.; Srivastava, R. M.
(5) (a) Biagi, G.; Livi, O.; Scartoni, V.; Verugi, E. Farmaco
1988, 43, 597. (b) Haebich, D.; Barth, W.; Roesner, M.
Heterocycles 1989, 29, 2083. (c) Kadaba, P. K. J. Org.
Chem. 1992, 57, 3075. (d) Sasaki, T.; Eguchi, S.;
Yamaguchi, M.; Esaki, T. J. Org. Chem. 1981, 46, 1800.
J. Carbohydr. Chem. 2006, 25, 407.
(4) (a) Andersen, J.; Bolvig, S.; Liang, X. Synlett 2005, 2941.
(b) Chan, D. C. M.; Laughton, C. A.; Queener, S. F.;
Synlett 2009, No. 19, 3163–3166 © Thieme Stuttgart · New York

3166
Y. Jiang et al.
LETTER
over anhyd NaSO4. Evaporation of the solvent gave the
crude product, which was subjected to column
chromatography (silica gel, EtOAc–PE) to afford
1-substitued 1,2,3-triazoles 2.
(6) Naud, J.; Lemke, C.; Goudreau, N.; Beaulieu, E.; White,
P. D. Bioorg. Med. Chem. Lett. 2008, 18, 3400.
(7) Broggini, G.; De M, I.; Martinelli, M.; Paladino, G.; Polati,
T.; Terraneo, A. Synthesis 2005, 2246.
(8) General Procedure for the Synthesis of 2 (Conditions A)
To a flask were added MeCN–H2O mixture (12 mL
v/v = 2:1), azide (0.5 mmol), CuI (19 mg, 0.1 mmol), Na
ascorbate (20 mg, 0.1 mmol), CaC2 (42 mg, 0.65 mmol). The
mixture was stirred at r.t., and the reaction was monitored by
TLC. After reaction completed, the system was neutralized
to pH = 5 with aq HCl (6%), and the mixture was then
extracted with EtOAc (3 × 30 mL). The organic layer was
separated, washed with H2O and sat. brine, and dried over
anhyd NaSO4. Evaporation of the solvent gave the crude
product, which was subjected to column chromatography
(silica gel, EtOAc–PE) to afford 1-substitued 1,2,3-triazoles
2.
(9) General Procedure for the Synthesis of 2 (Conditions B)
To a sealed tube were added MeCN–H2O mixture (12 mL
v/v = 2:1), azide (0.5 mmol), CuI (19 mg, 0.1 mmol), Na
ascorbate (20 mg, 0.1 mmol), CaC2 (42 mg, 0.65 mmol). The
mixture was stirred at 90 °C, and the reaction was monitored
by TLC. After reaction completed, the system was
neutralized to pH = 5 with aq HCl (6%), and the mixture was
then extracted with EtOAc (3 × 30 mL). The organic layer
was separated, washed with H2O and sat. brine, and dried
(10) All compounds gave satisfactory analytical and spectral
data.
Selected Data
(E)-1-[4-(2-Bromovinyl)phenyl]-1H-1,2,3-triazole (2j):
yellow solid, mp 147.8–148.1 °C. IR (KBr): 1599, 1511,
1435, 977, 783 cm–1. 1H NMR (500 MHz, CDCl3): d = 8.00
(1 H, s), 7.85 (1 H, s), 7.73 (2 H, d, J = 9.0 Hz), 7.46 (2 H, d,
J = 9.0 Hz), 7.16 (1 H, d, J = 13.8 Hz), 6.88 (1 H, d, J = 13.8
Hz). 13C NMR (125 MHz, CDCl3): d = 136.5, 136.4, 135.7,
134.5, 127.3, 121.5, 120.8, 108.3. ESI-MS: m/z (%) =
251(99) [M + 2]+, 249(100) [M+]. HRMS: m/z calcd for
C10H879BrN3: 248.9902; found: 248.9906
(E)-1-[2-(2-Bromovinyl)phenyl]-1H-1,2,3-triazole (2k):
yellow solid, mp 100.9–101.5 °C. IR (KBr): 1609, 1496,
1507, 1447, 1193, 983, 783 cm–1. 1H NMR (500 MHz,
CDCl3): d = 7.89 (1 H, s), 7.80 (1 H, s), 7.59–7.57 (1 H, m),
7.52–7.46 (2H, m), 7.42 (1 H, d, J = 8.0 Hz), 6.84 (1 H, d,
J = 14.0 Hz), 6.78 (1 H, d, J = 14.0 Hz). 13C NMR (125
MHz, CDCl3): d = 134.3, 134.0, 131.7, 131.6, 130.1, 129.1,
127.1, 126.5, 125.7, 110.6. ESI-MS: m/z (%) = 251(99)
[M + 2]+, 249(100) [M+]. HRMS: m/z calcd for C10H879BrN3:
248.9902; found: 248.9908.
Synlett 2009, No. 19, 3163–3166 © Thieme Stuttgart · New York