Preparation of 1H-1,2,3-triazoles by cuprous ion mediated cycloaddition of terminal alkyne and sodium azide

Article abstract of DOI:10.1002/jccs.200800061

1H-1,2,3-triazoles can be prepared in good yield by the reaction of terminal alkyne and sodium azide in the presence of cuprous chloride at a temperature higher than 70 °C. The alkyne is unactivated and the reaction has to be carried out under inert gas.

Full text of DOI:10.1002/jccs.200800061

4
14
Journal of the Chinese Chemical Society, 2008, 55, 414-417
Preparation of 1H-1,2,3-Triazoles by Cuprous Ion Mediated Cycloaddition
of Terminal Alkyne and Sodium Azide
Li-Hui Lu (
Department of Chemistry, Chung-Yuan Christian University, Chung-Li 32023, Taiwan, R.O.C.
), Jia-Hao Wu (
) and Chia-Hsi Yang* (
)
1
H-1,2,3-triazoles can be prepared in good yield by the reaction of terminal alkyne and sodium azide
in the presence of cuprous chloride at a temperature higher than 70 °C. The alkyne is unactivated and the
reaction has to be carried out under inert gas. At room temperature, the reaction first gives a Cu(I)-azide
complex which is converted to a Cu-alkyne complex when the temperature is raised to higher than 70 °C.
The reaction of Cu(I)-alkyne complex and azide ion dissociated from or coordinated to Cu(I) then gives
1
H-1,2,3-triazoles.
Keywords: 1H-1,2,3-Triazole; Alkyne; Cuprous chloride; Sodium azide.
INTRODUCTION
N-substituted 1,2,3-triazoles are useful as dyestuffs,
applicable to their N-unsubstituted counterpart. Therefore,
methodologies for preparing N-substituted 1,2,3-triazoles
are still receiving attention. In the literature, the prepara-
tions of N-unsubstituted 1,2,3-triazoles can be classified
into three categories: (a) By the rearrangement of propargyl
photostabilizers, corrosion inhibitors, pharmaceuticals and
1
agrochemicals. Many methodologies for preparing these
1
compounds have been developed. Recently, the reaction
4
of alkyl azide and terminal alkyne catalyzed by Cu(I),
known as click chemistry, was often used to prepare N-sub-
stituted 1,2,3-triazoles for a variety of purposes (Scheme
azide (Banert cascade); (b) By the reaction of an alkyne
and an organic azide to obtain a preformed N-substituted
1,2,3-triazole followed by removing the substituent on ni-
2
5
trogen. The organic azides used therein include trimeth-
I(a)).
5
a,5c
5b
pivaloyloxymethyl azide, tropylium
ylsilyl azide,
5
azide and b-tosylethylazide; (c) By addition of hydra-
6
zoic acid or an azide ion to alkyne. In (c), the alkyne usu-
d
5e
Scheme I
ally is activated by an electron-withdrawing group and the
reaction is usually carried out at high temperature (> 90
°
C).
In this report, a convenient and efficient preparation
of N-unsubstituted 1,2,3-triazoles by cuprous ion mediated
cycloaddition of nonactivated terminal alkynes and sodium
azide is described.
(
(
a) N-substituted 1,2,3-triazoles prepared by click chemistry,
R = alkyl.
b) 1H-1,2,3-triazoles prepared by the reaction of terminal
alkyne and sodium azide, R = Na.
RESULTS AND DISCUSSION
4
-Phenyl-1H-1,2,3-triazole (2a) can be prepared in a
N-unsubstituted 1,2,3-triazoles also are found to have
3
many applications. For example, many N-unsubstitued 4-
yield of 81% by refluxing the mixture of phenylacetylene
(1 equivalent), cuprous chloride (1.0 equivalent) and so-
dium azide (1.5 equivalent) in a co-solvent of methanol and
1,4-dioxane (1:2) under nitrogen for two days. In studying
this reaction, we noticed:
aryl-1,2,3-triazoles are methionine aminopeptidase 2 in-
3
a
hibitors and can inhibit angiogenesis in vivo. Many com-
pounds having N-unsubstituted moiety are found to be bio-
logically active and useful as ihibitors against tuberculo-
(a) There is only one compound obtained in the crude
3
b
3c
1
product as observed by H-NMR spectroscopy. The H-
13
NMR and C-NMR spectra of this compound are identical
1
sis, as neurokinin-1 receptor antagonists, as HIV-prote-
3
d
3e
ase inhibitors, and as anticancer agents. The method
used to prepare N-substituted 1,2,3-triazoles may not be
6
to that of 4-phenyl-1H-1,2,3-triazole. Therefore, this re-
a

Preparation of 1H-1,2,3-Triazoles
action is regiospecific.
J. Chin. Chem. Soc., Vol. 55, No. 2, 2008 415
Table 1. The yields of 1H-1,2,3-triazoles from the reaction of
terminal alkynes and sodium azide in the presence of
cuprous chloride (Scheme I(b))
(
b) The reaction has to be carried out under inert gas;
otherwise, phenylacetylene dimer (1,4-diphenylbutadiyne)
produced from oxidative coupling is the major product and
7
R
1
Yield (%)
2
a is obtained only in less than 10% yield.
2a
C H -
5
81
91
82
91
78
75
78
70
72
6
2
2
2
2
b
c
4 9
n-C H -
(
c) The reaction temperature has to be higher than 70
C. If the reaction is carried out at 50 °C, the yield of 2a is
lower than 34%.
HOCH2-
°
d
e
1-(cyclohexanol)yl
1-cyclohexenyl
CH =C(CH )-
(
d) The yield of 2a is dependent on the amount of
2f
2
3
2
2
2
g
p-CH
3
O-C
6
H
4
-
cuprous chloride used in the reaction. If the molar ratio of
cuprous chloride to phenylacetylene in the reaction is 1:4,
then the yield of the triazole is down to 26%.
h
i
CH
3
CH
2
COOCH
2
-
p-CH
3
-C
6 4
H -
(
e) The color of the reaction mixture is changing in
the reaction. It is brownish-red at the beginning when the
mixture is at room temperature. As the reaction tempera-
ture is raised to 70 °C, the color of the slurry formed gradu-
ally changes to yellow. After refluxing for two days, a
white precipitate is obtained.
cipitate in dioxane-methanol co-solvent. After the reaction
temperature is raised to 70 °C, the color of the suspension
changes gradually from yellow to light yellow and eventu-
ally to white in two days. After work-up, 2a is obtained in a
yield of 79%. This yield is comparable to that when the re-
action is carried out in one pot. This result supports our
speculation that 2a is formed from the reaction of Cu(I)-
alkyne complex and coordinated or free azide ion.
(
f) Mixing only sodium azide and cuprous chloride
using methanol-dioxane as the solvent produces sparingly
soluble red-brown precipitate which presumably is a Cu(I)-
azide complex.
The same procedure was used to prepare several other
(
g) Mixing phenylacetylene and cuprous chloride us-
1
H-1,2,3-triazoles (2b-2i) in good yields from terminal al-
ing methanol-dioxane as the solvent produces insoluble
yellow precipitate which is presumably a Cu(I)-phenyl-
acetylene complex.
kynes, cuprous chloride and sodium azide (Table 1). In
these reactions, the color changes from red brown to white
or yellow for the mixture in the course of reaction are also
observed. Therefore, the same reaction path as in the prepa-
ration of 2a should also occur in these cases. The yields of
2a-2i by this method are comparable to that of the corre-
From (e), (f) and (g), it seems that at the beginning, a
Cu(I)-azide complex is formed. When the temperature is
raised to about 70 °C, a Cu-phenylacetylene complex is
produced at the expense of Cu(I)-azide complex. 2a is ob-
tained from the reaction of alkyne-Cu(I) complex and free
azide ion dissociated from Cu(I)-azide complex or azide
ion coordinated to Cu(I) (Scheme II).
4
d,5b,5c,6d,8
sponding cases by other methods.
For nonterminal alkynes such as diphenylacetylene
and 3-hexyne, only starting materials were recovered using
the same procedure. These negative results are further sup-
port for the mechanism proposed in Scheme II.
To test this hypothesis, CuCl and phenylacetylene are
first mixed under nitrogen to obtain a yellow precipitate;
sodium azide is then added to the suspension of yellow pre-
In our preparation of 1H-1,2,3-triazole, the reaction
conditions are mild, the alkynes are not activated and inex-
Scheme II

4
16 J. Chin. Chem. Soc., Vol. 55, No. 2, 2008
Lu et al.
pensive sodium azide, instead of organic azide as in cate-
gory (b), is used. Furthermore, the step of removing the N-
substituent group is also avoided.
procedure.
8
Compounds 2a, 2b, 2c, 2d, 2f and 2g are
6d
4d
8
5c
5b
known in the literature.
1H-1,2,3-Triazole, 4-(phenyl) (2a)
6
d
CONCLUSION
White solid. 81% yield: mp: 147-148 °C. (literature:
1
148 °C); H-NMR spectrum is identical to that reported in
In conclusion, 1H-1,2,3-triazoles can be prepared in
good yields by refluxing the mixture of nonactivated termi-
nal alkynes, cuprous chloride and sodium azide using meth-
anol and dioxane as the co-solvent. In this reaction, a Cu(I)-
azide complex is produced at low temperature; Cu-alkyne
complex is then formed when the temperature is raised to
higher than 70 °C, 1H-1,2,3-triazoles are finally produced
from the reaction of Cu(I)-alkyne complexes and azide ion
dissociated from or coordinated to Cu(I).
7
13
literature. C NMR (DMSO-d
128.7, 129.4, 130.2, 145.5.
6
, d ppm): 125.9, 127.1,
1H-1,2,3-Triazole, 4-(n-butyl) (2b)
1
Liquid, 91% yield. H-NMR (CDCl
3
, d ppm): 0.90 (t,
3H, J = 7.3 Hz), 1.36 (sextet, 2H, J = 7.7 Hz), 1.36 (quintet,
2H, J = 7.7 Hz), 2.74 (t, 2H, J = 7.7 Hz), 7.53 (s, 1H);
1
3
C-NMR (CD
3
OD, d ppm): 13.7, 22.2, 24.2, 31.2, 130.2,
+
146.0; MS m/z (EI): 125 (M , 6%).
1H-1,2,3-Triazole, 4-(hydroxymethyl) (2c)
1
Liquid, 82% yield. H-NMR and C-NMR spectra
13
EXPERIMENTAL SECTION
4
e
Commercially available reagents from Aldrich, Merck
or Acros were used without further purification. Solvents
were dried by standard procedures. NMR spectra were re-
corded using a Bruker ACE-300 FT-NMR spectrometer. J
values were recorded in Hz, and multiplicities were ex-
pressed by usual conventions. Mass spectra were obtained
with an Agilent 5973 mass spectrometer. HRMS were ob-
tained with a JMS-700 HRMS high resolution mass spec-
trometer. Melting points were determined on a Yanagimoto
micromelting point apparatus and are reported uncor-
rected.
are identical to that reported in literature.
1H-1,2,3-Triazole, 4-(1-hydroxy-1-cyclohexyl) (2d)
White solid, 91% yield: mp: 128~129 °C.
1
H-NMR spectrum is identical to that reported in lit-
9
erature. C-NMR (CD
13
3 2
OD, d ppm): 21.6 (CH ), 25.1
(CH ), 37.6 (CH ), 68.6 (C), 126.4 (CH), 152.5 (C); MS
2
2
+
m/z (EI): 168 (M+H , 30%).
1H-1,2,3-Triazole, 4-(1-cyclohexenyl) (2e)
1
White solid, 78% yield: mp: 103~104 °C. H-NMR
(CD
3
OD, d ppm): 1.70~1.57 (m, 4H), 2.13~2.10 (m, 2H),
1
2.34~2.30 (m, 2H), 7.68 (s, 1H). C-NMR (CD
3
3
OD, d
Procedure of preparing 4-phenyl 1H-1,2,3-triazole
ppm): 21.7, 22.0, 24.9, 25.8, 125.6, 125.9, 126.1, 145.5;
+
MS m/z (EI): 150 (M+H , 100%); HRMS calcd. for C H N :
8 11 3
(
2a)
The mixture of phenylacetylene (0.51 g, 5 mmole),
cuprous chloride (0.495 g, 7.5 mmole) and sodium azide
0.487 g, 7.5 mmole) in a mixed solvent of methanol and
149.0954; Found: 149.0956.
1H-1,2,3-Triazole, 4-(1-methylethenyl) (2f)
1
Yellow oil, 75% yield. H-NMR (CD
(
3
OD, d ppm):
dioxane (1:2, 50 mL) was purged with nitrogen gas. The
temperature of the mixture is raised to 80 °C and refluxed
for 2 days. The color of the mixture was red brown in the
beginning, gradually turned yellow and finally became
white in two days. The mixture then was bubbled with hy-
drogen sulfide and the precipitate was filtrated off. The sol-
vent was removed from the filtrate and a precipitate as
crude product was obtained. The crude product was then
dissolved in acetonitrile and insoluble solid was filtered
off. A yellowish white precipitate was obtained after evap-
oration of the solvent. The product can be further purified
by column chromatography using silica gel as the station-
ary phase and a mixture of ethyl acetate and n-hexane
2.12 (s, 3H), 5.15 (d, 1H, J = 1.0 Hz), 5.59 (d, 1H, J = 1.0
1
3
3
Hz), 7.74 (s, 1H). C-NMR (CD OD, d ppm): 20.6, 114.2,
+
128.3, 132.8, 146.7; MS m/z (EI): 109 (M , 100%).
1H-1,2,3-Triazole, 4-(4-methoxyphenyl) (2g)
5
b
White solid, 78% yield: mp: 168-169 °C (literature:
1
166 °C). H-NMR spectrum is identical to that reported in
5
b 13
literature.
3 3
C NMR (CDCl , d ppm): 54.4 (CH ), 114.0
(CH), 122.0 (C), 125.6 (C), 126.9 (CH), 145.0 (C), 160.0
(CH).
1H-1,2,3-Triazole-4-methanol propanoate (2h)
1
3
H-NMR (CD OD, d ppm): 1.07 (t, 3H, J = 7.2 Hz),
1
3
2.30 (q, 2H, J = 7.2 Hz), 5.22 (s, 2H), 7.74 (s, 1H);
NMR (CDCl , d ppm): 8.83 (CH ), 27.3 (CH ), 56.9 (CH
130.2 (CH), 141.8 (C), 174.6 (C=O); MS m/z (EI): 155.
C
3
3
2
2
),
(
1:1~6:1) as eluent.
b, 2c, 2d, 2e, 2f, 2g are prepared following the same
+
2
6 9 3 2
(M , 3%); HRMS calcd. for C H N O : 155.0695; Found:

Preparation of 1H-1,2,3-Triazoles
J. Chin. Chem. Soc., Vol. 55, No. 2, 2008 417
R. J. J. Med. Chem. 2001, 44, 4296. (d) Baures, P. W. Org.
Lett. 1999, 1, 249. (e) Komeda, S.:Lutz, M.; Spek, A. L.;
Yamanaka, Y.; Sato, T.; Chikuma, M.; Reedijk, J. J. Am.
Chem. Soc. 2002, 124, 4738.
1
55.0700.
1
H-1,2,3-Triazole-4-(p-tolyl) (2i)
1
13
mp: 134-136 °C, H-NMR and C NMR spectra are
5
c
identical to that in reported literature.
Received June 15, 2007.
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