Copper(II)-promoted regioselective synthesis of 1,4-disubstituted 1,2,3-triazoles in water

Article abstract of DOI:10.1055/s-2006-933134

A high-yielding synthesis of 1,2,3-triazole with cheaply available Cu(OAc)₂ without any additional reducing agents is explored, which provides an exclusive 1,4-regioselectivity at ambient conditions in an environmentally benign solvent - water.

Full text of DOI:10.1055/s-2006-933134

LETTER
957
Copper(II)-Promoted Regioselective Synthesis of 1,4-Disubstituted
1,2,3-Triazoles in Water
R
egioselective Syn
.
thesis of 1,4
R
-Disubstitute
d
1,
a
j
eater nder Reddy, K. Rajgopal, M. Lakshmi Kantam*
Inorganic and Physical Chemistry Division, Indian Institute of Chemical Technology, Hyderabad 500007, India
Fax +91(40)27160921; E-mail: mlakshmi@iict.res.in
Received 17 October 2005
R2
N
R2
N
Abstract: A high-yielding synthesis of 1,2,3-triazole with cheaply
N
N
N
+
N
available Cu(OAc)2 without any additional reducing agents is
explored, which provides an exclusive 1,4-regioselectivity at
ambient conditions in an environmentally benign solvent – water.
Key words: Cu(II) catalyst, regioselective, 1,2,3-triazole, water
R1
R1
N
R1
R2
N3
+
1,4-
N
1,5-
R2
N
Replacement of volatile organic solvents with environ-
mentally benign solvents has received considerable atten-
tion in organic synthesis due to increased environmental
regulations.1 Several solvent systems, including water,2
supercritical fluids,3 ionic liquids,4 soluble polymers,5 and
fluorous liquids,6 have been exploited over the last several
years as alternative media for organic synthesis. In recent
years significant progress has been made in the field of
organic chemistry in water/aqueous media, and several
organic transformations, e.g. aldol, allylation, Diels–
Alder, Michael, Heck and Suzuki reactions, have been
performed efficiently in water.7
1,3-Dipolar cycloaddition of azides with alkynes investi-
gated by Huisgen et al. is an important organic
transformation8 and the resulting five-membered 1,2,3-
triazoles have a wide range of industrial applications in
agrochemicals, corrosion inhibitors, dyes, optical bright-
eners and pharmaceuticals.9 The traditional method for
the synthesis of triazoles requires elevated temperatures
and this non-catalyzed reaction is poorly regioselective,
which gives a mixture of 1,4- and 1,5-disubstituted tri-
azoles (Scheme 1).
Recently, Sharpless and co-workers have reported a high
yielding synthesis of triazoles using a Cu(I) catalyst with
an excellent 1,4-regioselectivity.10 The reaction tolerates a
variety of functional groups and, being insensitive to
water and oxygen, makes it a candidate for use in click
chemistry.11 It is postulated that the reaction proceeds via
a copper acetylide intermediate, generated from Cu(I) and
the terminal alkyne, which then participates in a cycload-
dition process with the coordinated azide.12 The active
Cu(I) catalysts are introduced directly in the form of dif-
ferent copper(I) salts, generated in situ from Cu(II) salts
with reducing agents or by the in situ oxidation of copper
metal turnings. Herein we wish to report on the direct
Cu(II)-catalyzed regioselective synthesis of 1,4-triazole
Cu(I)
R1
Scheme 1 Synthesis of 1,4-disubstituted 1,2,3-triazole
derivatives in high yields under ambient conditions in
water without any additional reducing/oxidizing agents.
Initially, we evaluated the reaction between benzyl azide
and phenylacetylene (Table 1) with 20 mol% of the cop-
per catalyst. As expected, Cu(I) salts provided exclusive
1,4-regioselectivity irrespective of the source of copper.
On the other hand, a large difference in activity was ob-
served for different Cu(II) salts. Among several Cu(II)
salts, Cu(OAc)2·H2O was found to be the best in terms of
activity and selectivity and all further experiments were
carried out with this catalyst.
The results of the Cu(II)-catalyzed [3+2] cycloaddition of
various terminal alkynes with benzyl azide are summa-
rized in Table 2 and compared further with the blank as
well as Cu(I)-catalyzed reactions. The reaction of phenyl-
acetylene and benzyl azide in water with 20 mol% of the
catalyst resulted in 77% of product, while under similar
conditions a blank experiment provided only 20% of the
product (Table 2, entry 1). Slightly lower conversion
(71%) is observed for p-methylphenylacetylene and
benzyl azide reaction (Table 2, entry 2). On the other
hand, m-methoxyphenylacetylene having an electron-
donating group underwent quantitative conversion (Table
2, entry 3). In the case of aliphatic alkynes, propargyl
alcohol gave quantitative conversion (Table 2, entry 4);
whereas substituted derivatives resulted in lower yields
(Table 2, entries 5 and 6), which might be due to steric
factors. Irrespective of the nature of alkynes, complete
1,4-regioselectivity is observed in all the experiments
with the present catalyst. Higher conversions are observed
compared with the blank experiments, which clearly in-
dicates that the activity is associated with the Cu(II)
catalyst.
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Advanced online publication: 21.02.2006
DOI: 10.1055/s-2006-933134; Art ID: D31805ST
© Georg Thieme Verlag Stuttgart · New York

958
K. R. Reddy et al.
LETTER
Table 1 Synthesis of 1,2,3-Triazole from Phenylacetylene and
ever, in all the above cases utilization of Cu(II) salts for
the activation of terminal alkynes is not fully focused. To
probe further on the nature of the metal ion in solution, we
have recorded the electronic spectra before and after the
reaction and the spectral features clearly indicate no
change in formal oxidation state of the metal ion.
Moreover, the aqueous phase after extraction with ethyl
acetate is still active for further recycling experiments.
We observed no loss in activity even after two cycles.
These results clearly indicate that the activity is associated
with Cu(OAc)2. Further studies on the influence of
counter ions on the activation of alkynes are under inves-
tigation.
Benzyl Azide with Different Copper Sources in Watera
Entry Copper source
Yield (%)b Ratio of 1,4-:1,5-isomers
1
2
3
4
5
6
None (control)
CuI
20
100
100
5
91:9
100:0
100:0
28:72
100:0
100:0
CuBr
CuCl2
Cu(NO3)2·3H2O
Cu(OAc)2·H2O
13
77
a Reaction conditions: phenylacetylene (1.2 mmol), benzyl azide
(1 mmol), Catalyst (20 mol%), H2O (3 mL).
In conclusion, we have shown a simple protocol for the
synthesis of 1,4-disubstituted 1,2,3-triazoles in an en-
vironmentally benign solvent with copper(II) acetate
under ambient conditions in high yields.
b NMR yields based on benzyl azide starting material.
In the majority of reported procedures, activation of
terminal alkynes is achieved by the formation of Cu-
acetylide with the main catalyst precursor as a Cu(I) salt.
However, there is some precedent in the literature where
the nature of the Cu(II) salts do effect the activation of ter-
minal alkynes. For example, Yamamoto and co-workers
recently reported that the activity of CuBr2 and CuCl2 are
comparable to CuBr in the synthesis of glycinate-tethered
a,w-enynes, whereas, Cu(OAc)2 and CuI proved to be in-
effective.13 Similarly, simple Cu(ClO4)2 and oxazoline
ligand combination is utilized for the coupling of terminal
alkynes with nitrones.14
Acknowledgment
We wish to thank the CSIR for financial support under the Task
Force Project CMM-0005 and K.R thanks UGC for a Junior
Research Fellowship.
References and Notes
(1) Sheldon, R. A. Green Chem. 2005, 7, 267.
(2) Cornils, B.; Herrmann, W. A. Aqueous Phase
Organometallic Catalysis – Concepts and Applications;
Wiley-VCH: Weinheim, 1998.
Recently, Alper and co-workers also observed slightly
lower activity of Cu(OAc)2 with respect to Cu(I) salts for
the synthesis of propargylamines in ionic liquids.15 How-
(3) (a) Leitner, W. Top. Curr. Chem. 1999, 206, 107.
(b) Leitner, W. Acc. Chem. Res. 2002, 35, 746.
(c) Beckman, E. J. J. Supercrit. Fluids 2004, 28, 121.
(4) (a) Sheldon, R. A. Chem. Commun. 2001, 2399.
(b) Wasserscheid, P.; Keim, W. Angew. Chem. Int. Ed. 2000,
39, 3772. (c) Dupont, J.; de Souza, R. F.; Suarez, P. A. Z.
Chem. Rev. 2002, 102, 3667. (d) Song, C. E. Chem.
Commun. 2004, 1033.
Table 2 Formation of Triazoles from Different Alkynes in Watera
Entry Alkyne
Product Control
CuI
Cu(OAc)2
Yield (%)b,c Yield (%)b,c Yield (%)b,c
20 (91:9) 100 (100:0) 77 (100:0)
(5) (a) Haimov, A.; Neumann, R. Chem. Commun. 2002, 876.
(b) Alper, H.; Januszkiewicz, K.; Smith, D. J. H.
Tetrahedron Lett. 1985, 26, 2263. (c) Chanrasekhar, S.;
Narsihmulu, C.; Sultana, S. S.; Reddy, N. R. Org. Lett. 2002,
4, 4399.
1
1a
2a
3a
2
2 (100:0) 100 (100:0) 71 (100:0)
10 (100:0) 100 (100:0) 100 (100:0)
(6) Dobbs, A. P.; Rimberley, M. R. J. Fluorine Chem. 2002,
118, 3.
(7) Li, C. J. Chem. Rev. 2005, 105, 3095.
Me
(8) Huisgen, R. In 1,3-Dipolar Cycloaddition Chemistry;
Wiley: New York, 1984, 1–176.
3
(9) (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 Science: Oxford, 1996,
1–126. (b) Holla, B. S.; Mahalinga, M.; Karthikeyan, M. S.;
Poojary, B.; Akberali, P. M.; Kumari, N. S. Eur. J. Med.
Chem. 2005, 40, 1173. (c) Elmorsi, M. A.; Hassanein, A. M.
Corros. Sci. 1999, 41, 2337. (d) Kim, D. K.; Kim, J.; Park,
H. J. Bioorg. Med. Chem. Lett. 2004, 14, 2401.
(10) Rostovtsev, V. V.; Green, L. G.; Fokin, V. V.; Sharpless, K.
B. Angew. Chem. Int. Ed. 2002, 41, 2596.
OMe
4
4a
5a
0
0
87 (100:0) 100 (100:0)
100 (100:0) 83 (100:0)
OH
5
OH
OH
6
6a
0
91 (100:0) 77 (100:0)
Ph
(11) Kolb, H. C.; Sharpless, K. B. Drug Discov. Today 2003, 8,
1128.
a Reagents: alkyne (1.2 mmol), benzyl azide (1 mmol), catalyst
(20 mol%), H2O (3 mL).16
b NMR yields based on benzyl azide starting material.
c The 1,4- vs. 1,5-regioselectivities are shown in parenthesis.
(12) Himo, F.; Lovell, T.; Hilgraf, R.; Rostovtsev, V. V.;
Noodleman, L.; Sharpless, K. B.; Fokin, V. V. J. Am. Chem.
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Synlett 2006, No. 6, 957–959 © Thieme Stuttgart · New York

LETTER
Regioselective Synthesis of 1,4-Disubstituted 1,2,3-Triazoles in Water
959
(13) Yamamoto, Y.; Hayashi, H.; Saigoku, T.; Nishiyama, H. J.
Am. Chem. Soc. 2005, 127, 10804.
Compound 1a: 1H NMR (CDCl3): d = 5.55 (s, 2 H), 7.25–
7.37 (m, 8 H), 7.58 (s, 1 H), 7.75 (d, 2 H, J = 8.30 Hz).
Compound 2a: 1H NMR (CDCl3): d = 2.36 (s, 3 H), 5.55 (s,
2 H), 7.14–7.37 (m, 7 H), 7.55 (s, 1 H), 7.64 (d, 2 H, J = 8.3
Hz). Compound 3a: 1H NMR (CDCl3): d = 3.83 (s, 3 H),
5.52 (s, 2 H), 6.69 (m, 1 H), 7.19–7.38 (m, 8 H), 7.58 (s, 1
H). Compound 4a: 1H NMR (CDCl3): d = 3.12 (br, 1 H),
4.69 (s, 2 H), 5.48 (s, 2 H), 7.18–7.38 (m, 6 H). Compound
5a: 1H NMR (CDCl3): d = 1.52 (s, 6 H), 4.20 (br, 1 H), 5.39
(s, 2 H), 7.21–7.36 (m, 6 H). Compound 6a: 1H NMR
(CDCl3): d = 1.90 (s, 3 H), 2.93 (br, 1 H), 5.43 (s, 2 H), 7.15–
7.42 (m, 11 H).
(14) Ye, M. C.; Zhou, J.; Huang, Z. Z.; Tang, Y. Chem. Commun.
2003, 2554.
(15) Park, S. B.; Alper, H. Chem. Commun. 2005, 1315.
(16) Typical Procedure for the Synthesis of 1,2,3-Triazoles
To the stirred solution of alkyne (1.2 mmol) and copper
catalyst (20 mol%) in H2O (3 mL), was added alkyl azide
(1.0 mmol) in one portion at r.t. After 20 h of stirring, the
precipitated product was extracted with EtOAc (3 × 5 mL)
and the organic extract was dried. The crude product was
subjected to column chromatography to yield the desired
product. The products were characterized by 1H NMR.
Synlett 2006, No. 6, 957–959 © Thieme Stuttgart · New York