A novel and efficient strategy for the preparation of 2,4-disubstituted-1,2,3-triazoles

Article abstract of DOI:10.1081/SCC-120024731

We have developed a novel and efficient method for the preparation of 2,4-disubstituted-1,2,3-triazoles. These compounds 3a-3p were synthesized in good yield by refluxing α-aminoacetophenones and hydrazines in glacial acetic acid. The reaction proceeds under mild conditions and is compatible with various functional groups.

Full text of DOI:10.1081/SCC-120024731

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: http://www.tandfonline.com/loi/lsyc20
A Novel and Efficient Strategy for the Preparation
of 2,4-Disubstituted-1,2,3-triazoles
Yun Luo & Yongzhou Hu
To cite this article: Yun Luo & Yongzhou Hu (2003) A Novel and Efficient Strategy for the
Preparation of 2,4-Disubstituted-1,2,3-triazoles, Synthetic Communications, 33:20, 3513-3517,
DOI: 10.1081/SCC-120024731
To link to this article: http://dx.doi.org/10.1081/SCC-120024731
Published online: 15 Aug 2006.
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SYNTHETIC COMMUNICATIONSÕ
Vol. 33, No. 20, pp. 3513–3517, 2003
A Novel and Efficient Strategy for the
Preparation of 2,4-Disubstituted-1,2,3-triazoles
*
Yun Luo and Yongzhou Hu
Department of Medicinal Chemistry, School of
Pharmaceutical Science, Zhejiang University,
Hangzhou, P.R. China
ABSTRACT
We have developed a novel and efficient method for the preparation
of 2,4-disubstituted-1,2,3-triazoles. These compounds 3a–3p were
synthesized in good yield by refluxing a-aminoacetophenones and
hydrazines in glacial acetic acid. The reaction proceeds under mild
conditions and is compatible with various functional groups.
Key Words: Synthesis; 2,4-Disubstituted-1,2,3-triazoles.
*Correspondence: Yongzhou Hu, Department of Medicinal Chemistry, School
of Pharmaceutical Science, Zhejiang University, Hangzhou, 310031, P.R. China;
E-mail: huyz@zjuem.edu.cn.
3513
DOI: 10.1081/SCC-120024731
Copyright & 2003 by Marcel Dekker, Inc.
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com

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3514
Luo and Hu
INTRODUCTION
1,2,3-Triazole analogues are important intermediates in organic
synthesis especially in the synthesis of biologically active and medicinally
useful agent. For example, they were used in the synthesis of
antibiotics,[1] inhibitor of HIV-1 replication,[2] the human ß3-adrenergic
receptor agonist,[3] or potassium channel activator,[4–7] etc. During the
past five decades, the general method for the synthesis of 1,2,3-triazole
was the 1,3-dipolar cycloaddition of various azides(or salts there of) with
acetylenes or activated methylene compounds.[8,9] The main method
for the synthesis of 2,4-diaryl-1,2,3-triazoles was the intramolecular
condensation of bisarylhydrazones.[10–12]
As a part of our ongoing program aimed at searching for novel
synthesis of 1,2,3-triazoles, we found an efficient method to obtain a
series of 1,2,3-triazole by cyclization between a-aminoacetophenone
and hydrazine derivatives. The method is more satisfactory in terms of
the easy availability of starting materials and the simple one-pot
operation, as shown in Sch. 1.
RESULTS AND DISCUSSION
In the course of our research, we found useful information about the
influences of the reaction conditions and catalysts on this cyclization. It
was observed that glacial acetic acid was indispensable for the cyclization.
If ethanol was choosed as solvent only, the triazoles could not be
obtained. And if we using ethanol and glacial acetic acid as a mixed
solvent, the reaction time was longer and more side products was
formed. Although 2-methyl-4-phenyl-1,2,3-triazole was easily obtained
by refluxing the mixture of a-amimoacetophenone and methylhydrazine,
O
R
R
N
N R'
NNHR'
R
'
RNHNH2
CCH2NH2
+
CH
CCH2NH2
CH2NH2
1
2
R
[O]
N
'
R
N
N
3a-p
Scheme 1.

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2,4-Disubstituted-1,2,3-triazoles
3515
it was interesting that when a-aminoacetophenone was treated with
phenylhydrazine, the expected product, 2,4-diphenyl-1,2,3-triazole,
could not be obtained unless in the presence of cupric ion.
Various a-aminoacetophenones 1 bearing substituents on benzene
ring were reacted with hydrazine derivatives 2 to evaluate the scope of
this reaction. Fifteen 2,4-disubstituted-1,2,3-triazoles 3 were obtained in
moderate to good yields, as shown in Table 1.
EXPERIMENTAL
Melting points are uncorrected. 1H NMR spectra were recorded on a
Brucker ADVANCE-400 MHz spectrometers with SiMe4 as the internal
standard. Infrared spectra were recorded on a Bruck Vector 200
spectrophotometer and microanalyses were performed on a MOD-1106
elemental analyzer.
General Procedure
Suspension of the 0.05 mol of a-aminoacetophenone 1 and 0.06 mol
of phenylhydrazine 2 in 10 mL of glacial acetic acid was treated with
0.05 mol of cupric chloride (cupric chloride was not necessary when
methylhydrazine was used as starting material to prepare 2-methyl-4-
aryl-1,2,3-triazoles 3a–3d). The mixture was heated under reflux for 2 h
and filtrated. The filtrate was neutralized with 0.2 mol/L sodium hydro-
xide and then extracted twice with dichloromethylene. The combined
Table 1. The yields and melting points of compounds 3a–3p.
Yield M.p.
R0 (%) (ꢀC) No.
Yield M.p.
(%)
(ꢀC)
No.
R
R
R0
3a p-Cl
3b p-Br
CH3 54.5 96–98
3i 2,4-2F Ph
66.7 83–85
75.0 104–105
61.2 39–40
55.7 80–82
52.5 71–72
55.6 69–71
65.0 144–146
CH3 55.3 120–122 3j 3,4-2Cl Ph
Ph
3c p-CH3O CH3 50.1 104–106 3k
3d 2,4-2F CH3 58.9 36–38 3l p-Cl
3e 3,4-2Cl CH3 65.8 106–108 3m
H
o-CH3-Ph
o-CH3-Ph
H
3f p-Cl
3g p-Br
Ph
Ph
66.7 98–99 3n 2,4-2F o-CH3-Ph
68.0 110–111 3o p-CH3O p-Cl-Ph
3h p-CH3O Ph
58.5 90–92 3p p-Cl
p-CH3O-Ph 41.2 115–117

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3516
Luo and Hu
organic extraction was washed with water and dried over anhydrate
sodium sulfate. The solution was removed under reduced pressure. The
residue was purified by column chromatography on silica gel using ethyl
acetate: petroleum ether 1:30 as eluant to afford 3a–3p. The products
1
were characterized by IR, H NMR, and elemental analysis.[13]
REFERENCES
1. Zhong, Y.J. Hua Xue Shi Ji 2000, 22, 90–92.
2. Velazquez, S.; Alvarez, R.; Perez, C.; Gago, F.; De-Clercq, D.;
Balzarini, J.; Camarasa, M. J. Antivir. Chem. Chemother 1998, 9,
481–489.
3. Brockunier, L.L.; Parmee, E.R.; Ok, H.O.; Candelore, M.R.;
Cascieri, M.A.; Colwell, L.F.; Deng, L.P.; Feeney, Wyvratt, M.J.;
Fisher, M.H.; Weber, A.E. Bioorg. & Med. Chem. Lett. 2000, 10,
2111–2114.
4. Baragatti, B.; Biagi, G.; Calderone, V.; Giorgi, I.; Livi, O.;
Martinotti, E.; Scartoni, V. Eur. J. Med. Chem. 2000, 35, 949–955.
5. Biagi, G.; Calderone, V.; Giorgi, I.; Livi, O.; Scartoni, V.;
Baragatti, B.; Martinotti, E. Eur. J. Med. Chem. 2000, 35, 715–720.
6. Biagi,G.;Calderone,V.;Giorgi,I.;Livi,O.;Scartoni,V.;Baragatti,B.;
Martinotti, E. Farmaco 2001, 56, 841–849.
7. Biagi, G.; Giorgi, I.; Livi, O.; Scartoni, V.; Barili, P.L.; Calderone, V.;
Martinotti, E. Farmaco 2001, 56, 827–834.
8. Howell, S.J.; Spencer, N.; Philp, D. Tetrahedron 2001, 57,
4945–4954.
9. Journet, M.; Cai, D.; Kowal, J.J.; Larsen, R.D. Tetrahedron Letter
2001, 42, 9117–9118.
10. Eikhadem, H.; Ei-Sadik, M.M.; Meshreki, M.H. J. Chem. Soc. (C)
1968, 2097–2099.
11. Balachandran, K.S.; Hiryakkanavar, I.; George, M.V. Tetrahedron
1975, 31, 1171–1177.
12. Latif, N.; Meguid, S.A. J. Chem. Soc., Perkin Trans. 1 1972,
1095–1097.
13. For compound 3a. IR (KBr, cmꢁ1): 1471, 1377, 829. 1H NMR
(400 MHz ,CDCl3, ppm) ꢀ: 7.79 (s, 1H, ¼CH), 7.70 (m, 2H,
Ar-H), 7.39 (m, 2H, Ar-H), 4.23 (s, 3H, CH3). Anal. calcd. for
C9H8N3Cl: C 55.83, H 4.16, N 21.70. Found: C 55.69, H 4.01, N
21.45. For compound 3o. IR (KBr, cmꢁ1): 2923, 2853, 1614, 1547,
1495, 1453, 1376, 1030, 997, 830. 1H NMR (400 MHz ,CDCl3, ppm)

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2,4-Disubstituted-1,2,3-triazoles
3517
ꢀ: 8.09 (m, 2H, Ar-H), 8.00 (s, 1H, ¼CH), 7.84 (m, 2H, Ar-H), 7.48
(m, 2H, Ar-H), 7.02 (m, 2H, Ar-H), 3.89 (s, 3H, CH3O). Anal. calcd.
for C15H12N3Cl: C 66.79, H 4.45, N 15.58. Found: C 66.62, H 4.41,
N 15.52.
Received in Japan February 28, 2003

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