Tetrahedron Letters
Effect of temperature on triazole and bistriazole formation
through copper-catalyzed alkyne–azide cycloaddition
Jaime González, Víctor M. Pérez, David O. Jiménez, Germán Lopez-Valdez, David Corona,
⇑
Erick Cuevas-Yañez
Centro Conjunto de Investigación en Química Sustentable UAEM-UNAM, Carretera Toluca-Atlacomulco Km. 14.5, Toluca, Estado de México 52000, Mexico
a r t i c l e i n f o
a b s t r a c t
Article history:
Temperature is an important factor in the copper catalyzed alkyne azide cycloaddition under oxidative
conditions. 1,2,3-Triazoles were obtained in high yields when several alkynes and azides were reacted
at methanol reflux using catalytic amounts of both copper iodide and sodium hydroxide. On the other
hand, bistriazoles were major products when reactions were performed at À35 °C using excess sodium
hydroxide.
Received 16 March 2011
Revised 28 April 2011
Accepted 2 May 2011
Available online 10 May 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Copper-catalyzed alkyne–azide cycloaddition (CuAAC), a click
reaction, is one of the most important methods for ring formation
developed in this century.1–4 This reaction is the best route to ob-
tain 1,2,3-triazoles, which have been identified with interesting
biological properties and important applications in drug design.
In addition, CuAAC perfectly combines the use of mild reaction
conditions together with high efficiency in terms of regioselectivity
and atom economy.5
Recently, a novel kind of bistriazoles derived from CuAAC has
been reported. In contrast to that observed for 1,2,3-triazoles,
few reports describe the bistriazole formation, which occurs
mainly using inorganic bases under oxidative conditions.6–8
In connection with other projects, we some time ago initiated
studies about the influence of bases on CuAAC in order to find
the simplest inorganic bases to prepare 1,2,3-triazoles in high
yield. In these experiments, we observed bistriazole formation
with a dependence of temperature in these processes. Herein is de-
scribed a summary of our recent endeavors in this area.
After a week, we realized that bistriazole 4 was consumed and only
triazole 3 was detected in the reaction.
Motivated by this fact, we carried out experiments under differ-
ent temperatures and base concentrations. The results, summa-
rized in Table 1, show that temperature plays an important role
in this process. Initially, CuAAC reaction between phenylacetylene
1 and benzyl azide 2 at room temperature (96 h) afforded triazole 3
in 78% yield. When the reaction was carried out at methanol reflux
temperature, after 2.5 h, the yield was increased to 92%. As a minor
product, bistriazole 4 was obtained in 13% at room temperature,
however, this compound was not observed under methanol reflux
conditions.
Thus, this protocol was extended to several azides using phen-
ylacetylene, obtaining 1,2,3-triazoles as only reaction products (Ta-
ble 2). Volatile compounds were not suitable for CuAAC under
N
N
The initial studies were carried out on phenylacetylene (1) and
benzyl azide (2) using catalytic copper iodide in the presence of
several bases. In all cases, 1-benzyl-4-phenyl-1,2,3-triazole (3)
was obtained as major product. However, when inorganic bases
were used as additives, a mixture of triazole 3, bistriazole 4 and
bisphenylacetylene 5 was obtained, according to that described
by Angell and Burgess.6 A noteworthy feature is that we found that
NaOH gives the best yield of triazole 3 and, surprisingly, its use in
CuAAC has not been previously reported. For this reason, NaOH
was chosen as base in all our experiments (Scheme 1).
N
Ph
Ph
3
Ph
1
5% CuI
N
N
N
+
MeOH,
Base
Ph
N3
2
N
N
Ph
Ph
N
In addition, we detected by TLC in all reactions between alkyne
1 and azide 2 using NaOH as base at room temperature, bistriazole
4 is first formed, and subsequently, triazole 3 can be observed.
4
Ph
5
⇑
Corresponding author. Tel.: +52 722 276 66 10x7734; fax: +52 722 217 5109.
Scheme 1. Cu-catalyzed cycloaddition between azide 2 and alkyne 1.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.