Regioselective synthesis of 1,2,3-triazole derivatives via 1,3-dipolar
cycloaddition reactions in water†
Zhong-Xia Wang* and Hua-Li Qin
Department of Chemistry, University of Science and Technology of China, Hefei, Anhui 230026, P. R.
China. E-mail: zxwang@ustc.edu.cn
Received (in Cambridge, UK) 20th June 2003, Accepted 13th August 2003
First published as an Advance Article on the web 22nd August 2003
Reaction of an arylacetylene with an azide in hot water gave
1,4-disubstituted 1,2,3-triazoles in high yields, while similar
reaction between a terminal aliphatic alkyne and an azide
(except m-nitroazidobenzene) afforded a mixture of regioi-
somers with the ratio of 1,4- to 1,5-isomers ranging from 3 :
1 to 28.6 : 1. Reactions of m-nitroazidobenzene with either
arylalkynes or aliphatic alkynes formed only 1,4-disub-
stituted derivatives in excellent yields.
actions predominate. We also found that in most cases the yields
can be raised by prolonging the reaction time or elevating the
reaction temperature. For example, the yield of the reaction of
p-methylazidobenzene with phenylacetylene was 38% at 85 °C
for 24 h, 72% at 120 °C for 4 h and 85% at 120 °C for 24 h. If
an electron-withdrawing group attached to the phenyl ring of
the azide is present, the reaction proceeds more rapidly and
more efficiently as shown by the reactions with m-ni-
troazidobenzene (entries 6–9 in Table 1). This observation is not
very consistent with that in organic solvents. It has been
reported that in organic solvents electron-deficient dipolar-
ophiles react more easily with azides carrying electron-
releasing substituents and vice versa.11 However, we found that
reactions of m-nitroazidobenzene with either HC·CCOOEt or
HC·CCH2OC(O)Me in water at 85 °C proceeded smoothly and
afforded only 1,4-disubstituted triazoles in excellent yields.
This may be because the FMOs of the two reactants are
stabilised in water to different extent and this leads to a
reduction of the energy gap between the HOMO (dipole) and
the LUMO (dipolarophile).12 Reaction of aliphatic alkynes such
as HC·CCOOEt or HC·CCH2OC(O)Me with the aryl azides
except m-nitroazidobenzene usually gave a mixture of regioi-
somers (entries 10–15 in Table 1) with the ratio of 1,4- to
1,5-isomers ranging from 3 : 1 to 28.6 : 1 (reactions carried out
at 120 °C). It was also observed that higher reaction tem-
peratures not only increased product yields but also changed the
ratio of regioisomers. Namely, higher reaction temperature is
advantageous for the formation of 1,4-disubstituted triazole
derivatives.
1,2,3-Triazoles have attracted much attention in recent years
because of their biological activity and wide applications in
organic synthesis.1 Numerous synthetic methods for the
preparation of 1,2,3-triazole derivatives have been developed.
Among them 1,3-dipolar cycloaddition between an alkyne and
an azide is the traditional and extensively used method.2
However, the regioselectivities of these cycloaddition reactions
are generally low.3 The improvement of the regioselectivity of
the reactions is an attractive target.3,4
Recent studies have revealed that a number of organic
reactions proceed more rapidly and efficiently in aqueous
solution than in organic solvents. For example, Diels–Alder
reaction has been extensively studied in aqueous solution and
the reaction exhibits strong rate accelerations in water.5 It was
also found that the endo/exo ratio of the products and regio- or
diastereoselectivity can be changed when a reaction is per-
formed in water instead of in the usual organic solvents.6
1,3-Dipolar cycloadditions in water or aqueous media have also
been reported.7,8 However, research on the regioselectivities of
these dipolar cycloadditions in aqueous media is very rare. In
addition, the use of water has obvious environmental and
economic advantages. Therefore, it is synthetically interesting
to further investigate whether aqueous media can improve the
regioselectivity of 1,3-dipolar cycloadditions. Here we report
our investigations of 1,3-dipolar cycloaddition reactions be-
tween alkynes and azides in water and regioselective synthesis
of 1,2,3-triazole derivatives.
The reactions were carried out in distilled water. Heating an
equivalent mixture of an azide and an alkyne in water at 85 °C
or 120 °C (bath temperature) for 24 h afforded the correspond-
ing 1,2,3-triazoles. The products were separated by simple
filtration. The results are presented in Table 1. When a terminal
arylalkyne such as phenylacetylene or p-methylphenylacetylene
was employed (entries 1–7 in Table 1), only 1,4-disubstituted
1,2,3-triazoles were obtained in 81–97% yields. Similar reac-
tions in organic solvents usually yielded a mixture of regioi-
somers. For example, reaction of phenylacetylene with azido-
benzene in toluene under reflux gave two regioisomers in
approximately 1 : 1 ratio.9 This lack of regioselectivity is the
result of the reaction being controlled by both dipole–HOMO
and dipole–LUMO interactions simultaneously.3,10 When the
reactions were switched from organic to aqueous solvent, the
energies of the FMOs of the reactants changed. This change of
the relative levels of the HOMO and LUMO of both reactants
means that the dipole–HOMO dipolarophile–LUMO inter-
Recently Sharpless and coworkers reported CuI-catalysed
regioselective synthesis of 1,2,3-triazoles from azides and
terminal alkynes.4b For comparison, we carried out the reactions
of the substrate pairings used by Sharpless in water in the
absence of CuI catalyst (entries 16 and 17 in Table 1). The
reaction between AdN3 (Ad = adamantyl) and PhC·CH
formed 1,4-disubstituted triazole in 86% yield, while the
reaction between PhCH2N3 and Et2NCH2C·CH gave a mixture
of regioisomers in a ratio of 9 : 1 in favour of the 1,4-isomer.
This is consistent with the reactions shown in entries 10–15
(Table 1). We also tried the reactions of entries 1, 4, 11 and 13
in the presence of CuI catalyst either in a mixed solvent of water
and tert-butyl alcohol or in water. Each of the reactions gave
1,4-disubstituted 1,2,3-triazole in good yield.
Disubstituted acetylenes can also react with azides in hot
water. Reaction of diphenylacetylene with aryl azides (entries
18–20 in Table 1) afforded 1,4,5-trisubstituted 1,2,3-triazoles.
The results showed that the electronic effects of the substituents
attached to the phenyl ring of the azides affect the reactions, the
electron-withdrawing groups promoting the reaction and the
electron-donating groups impeding the reaction.
1
The compounds were characterised by H, 13C{1H} NMR
and IR spectroscopy and elemental analyses. The structures of
the 1,4-disubstituted compounds were proved by comparing the
13C{1H} NMR spectral data of the heterocyclic skeletons with
those of related compounds reported elsewhere.13 The 1,4- and
1,5-isomers in the mixture of regioisomers can be distinguished
by their 1H NMR spectra because the triazole proton in
1,4-disubstituted triazoles was always shifted considerably
† Electronic supplementary information (ESI) available: experimental
procedures, elemental analyses and spectroscopic data. See http:/
2450
CHEM. COMMUN., 2003, 2450–2451
This journal is © The Royal Society of Chemistry 2003
Wang, Zhong-Xia
