Simple and efficient one-pot synthesis of 2,4-diaryl-1,2,3-triazoles

Article abstract of DOI:10.1080/00397910600781216

A general and efficient method for the preparation of 2,4-diaryl-1,2,3- triazoles from α-hydroxyacetophenones and phenylhydrazines is reported. The essential characteristics of this method include mild reaction conditions, a straight-forward workup proced

Full text of DOI:10.1080/00397910600781216

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Simple and Efficient One‐Pot Synthesis of
2,4‐Diaryl‐1,2,3‐triazoles
Wen‐Jie Tang a & Yong‐Zhou Hu a
a Zhejiang University‐Ecole Normale Superieure Joint Laboratory of
Medicinal Chemistry, School of Pharmaceutical Sciences, Zhejiang
University, Hangzhou, China
Version of record first published: 27 Oct 2006.
To cite this article: Wen‐Jie Tang & Yong‐Zhou Hu (2006): Simple and Efficient One‐Pot Synthesis of
2,4‐Diaryl‐1,2,3‐triazoles, Synthetic Communications: An International Journal for Rapid Communication of
Synthetic Organic Chemistry, 36:17, 2461-2468
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Synthetic Communicationsw, 36: 2461–2468, 2006
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910600781216
Simple and Efficient One-Pot Synthesis
of 2,4-Diaryl-1,2,3-triazoles
Wen-Jie Tang and Yong-Zhou Hu
Zhejiang University-Ecole Normale Superieure Joint Laboratory of
Medicinal Chemistry, School of Pharmaceutical Sciences, Zhejiang
University, Hangzhou, China
Abstract: A general and efficient method for the preparation of 2,4-diaryl-1,2,3-
triazoles from a-hydroxyacetophenones and phenylhydrazines is reported. The
essential characteristics of this method include mild reaction conditions, a straight-
forward workup procedure, and comparatively higher yields.
Keywords: 2,4-Diaryl-1,2,3-triazoles, synthesis, 2,4,5-triaryl-1,2,3-triazoles
1,2,3-Triazoles are very important compounds because of their versatile bio-
logical activities. Members of this family have been widely used as antimicro-
bial agents,[1] antihypertensive agents,[2] anti-AIDS agents,[3] and potassium
channel activators.[4] A number of synthetic strategies have been developed
for the synthesis of 1H-1,2,3-triazoles through the years, and the most
classical ones are 1,3-dipolar cycloaddition of a wide variety of azides with
acetylenic compound[5–7] and alkenes with a suitable leaving group located
on the double bond.[8]
However, comparatively fewer methods are available for the preparation
of 2,4-diaryl-1,2,3-triazoles and 2,4,5-triaryl-1,2,3-triazoles, in which intra-
molecular cycloaddition of bisphenylhydrazones was often favored. This
procedure requires 1,2-diketones such as benzil,[9] phenylglyoxal, and glyoxal
Received in Japan December 12, 2005
Address correspondence to Yong-Zhou Hu, Zhejiang University-Ecole Normale
Superieure Joint Laboratory of Medicinal Chemistry, School of Pharmaceutical
Sciences, Zhejiang University, Hangzhou 310031, China. E-mail: huyz@zjuem.zju.
edu.cn
2461

2462
W.-J. Tang and Y.-Z. Hu
as starting materials,[10,11] which were further treated with phenylhydrazines
in acidic medium and under the catalysis of metallic salts to obtain the
title compounds.[9,11–13] In addition, 2-aroyl-4,5,6,7-tetrahalogeno-1,3-
benzodioxoles reacting with phenylhydrazine in boiling n-butanol can
afford the corresponding arylglyoxal bisphenylhydrazones, which were
cyclized readily by copper sulphate in aqueous dioxane, giving 2,4-diaryl-
1,2,3-triazoles.[14] 2,4,5-Triaryl-1,2,3-triazoles can also be obtained by
photocyclization of bisphenylazoethylenes[15] or by photolysis of 2,5-diphe-
nyltetrazole.[16] These multistep processes inevitably resulted in compromised
yields and sometimes involved tedious workup procedures. Therefore, the
development of new general methodologies for the synthesis of 2,4-diaryl-
1,2,3-triazoles and 2,4,5-triaryl-1,2,3-triazoles are of great interest.
As a part of our continuing effort toward the further development of new
synthetic methods for the title compounds, our work relied on previous
work.[17,18] a-Hydroxyacetophenones were found to undergo cupric chloride–
catalyzed cycloaddition with phenylhydrazines in refluxing glacial acetic
acid, affording corresponding 2,4-diaryl-1,2,3-triazoles or 2,4,5-triaryl-
1,2,3-triazoles in moderate to good yields (Scheme 1). Generally, the
starting a-hydroxyacetophenones can be obtained by convenient hydrolysis
of a-bromoacetophenones.[19,20]
RESULTS AND DISCUSSION
The optimization of the reaction condition commenced with investigation of
the reaction solvents and the catalysts. As in our previous work, we were
convinced that this reaction was readily achieved in a weak acidic medium
(Table 1). Although this reaction can be carried out in a variety of solvents,
such as HCOOH or HOAc–EtOH(3 : 1), the results disclosed that glacial
HOAc or 70% HOAc was a suitable solvent for the reaction, and the yield
of the product 1a could be improved up to 81% and 75%, respectively.
Meanwhile, various metallic salts were studied for promoting this reaction,
among which cupric chloride proved to be the most suitable catalyst
(Table 2). It should be mentioned that some salts such as K2CrO4 and
NaNO2 used to catalyze this reaction failed to afford the desired products
Scheme 1.

2,4-Diaryl-1,2,3-triazoles
Table 1. Solvent screeninga
2463
Entry
Solvent
Reaction time (h)
Yield (%)b
1
2
3
4
5
6
EtOH
Glacial HOAc
HOAc (70%)
4
Trace
81
75
1.5
1.5
1
HOAc-TFA (3 : 1)
HOAc-EtOH (3 : 1)
HCOOH
38
57
3.5
5
35
aReactions of a-hydroxyacetophenone (1 equiv) and phenylhydra-
zine (4 equiv) catalyzed by CuCl2 (1 equiv) in various solvents
under reflux conditions.
bIsolated yield after column chromatography.
under identical conditions.[9] The reason may be the oxidation ability of these
salts is so violent that the arylhydrazines react with these salts first.
According to the initial success of this reaction, we set out to determine
the scope and variability of the procedure and finally obtained twenty title
compounds (Table 3).
Furthermore, we hypothesized the plausible mechanism as follows:
a-hydroxyacetophenone 2a with phenylhydrazine 3a underwent a reaction
similar to the formation of sugar osazone to give phenylglyoxal bisphenylhy-
drazone 4a,[12,22] and then bisphenylhydrazone 4a lost a proton under the
oxidation of cupric chloride to form the intermediate 5a, which was trans-
formed to bisphenylazoethylene 6a. Finally, its mesoionic form lost a
Table 2. Catalyst screeninga
Entry
Catalyst
Reaction time (h)
Yield (%)b
1
2
3
4
5
6
7
8
9
K2CrO4
2
Trace
58
75
Cu(OAc)2
CuSO4
CuCl2
2.5
2.5
1.5
5
81
72
0c
CuBr2
NaNO2
FeCl3
ZnCl2
3.5
5
35
3
trace
12
.
InF3 3H2O
6
aReaction of a-hydroxyacetophenone (1 equiv) and phenylhy-
drazine (4 equiv) in refluxing glacial HOAc catalyzed by various
metallic salts (1 equiv).
bIsolated yield after column chromatography.
cNo product detected.

2464
W.-J. Tang and Y.-Z. Hu
Table 3. Synthesis of 2,4-diaryl-1,2,3-triazoles
Reaction Yield
time (h) (%)a
Compound
R1
R2
R3
Mp (8C)
1a
1b
1c
1d
1e
1f
H
4-F
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Ph
Ph
H
H
H
H
H
H
H
H
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
4
81
78
80
79
74
82
76
85
86
75
72
69
73
69
55
62
54
59
68
52
39–40 (40)[10]
100–101
101–102 (98–99)[18]
111–112 (111)[10]
177–179
92–93 (90–92)[18]
166–168
96–97
4-Cl
4-Br
4-HO
4-MeO
3,4-2HO
3,4-2MeO
H
1g
1h
1i
4-Cl
4-Cl
112–113
136–137
1j
4-Cl
1k
1l
4-HO
H
4-Cl
4-Cl
180–182
2-Me
2-Me
4-MeO
4-MeO
4-MeO
4-MeO
4-MeO
H
73–74 (71–72)[18]
80–82 (80–82)[18]
76–77 (75–76)[21]
115–117 (115–117)[18]
135–136
1m
1n
1o
1p
1q
1r
1s
4
H
4-Cl
1
1
4-MeO
3,4-2HO
3,4-2MeO
H
1
1
152–153
93–95
123–124 (124)[11]
131–132 (132)[9]
1
8
1t
4-MeO
H
8
aIsolated yield after column chromatography.
phenylnitrene to obtain 2,4-diphenyl-1,2,3-triazole under thermal condition
(Scheme 2).[11,23] This mechanism was testified by the separation of inter-
1
mediate 4a, which was assigned on the basis of its H NMR and MS data.
In summary, we have demonstrated a simple and efficient general
procedure for the preparation of functionalized 2,4-diaryl-1,2,3-triazoles or
2,4,5-triaryl-1,2,3-triazoles via a one-pot reaction of easily available
materials. The essential characteristics of this method include mild reaction
conditions, straightforward workup procedures, and comparatively higher
1
yields. The selected products were characterized by H NMR, 13C NMR,
elemental analysis, and MS data.
EXPERIMENTAL
´´
Melting points were obtained on B-540 Buchi melting-point apparatus and
1
were uncorrected. H and 13C NMR spectra were recorded on Brucker AM
400-MHz spectrometer (at 400 and 100 MHz, respectively) with SiMe4 as
the internal standard in CDCl3. Element analysis were performed on

2,4-Diaryl-1,2,3-triazoles
2465
Scheme 2. Plausible reaction mechanism for the synthesis of 2,4-diphenyl-1,2,3-
triazole.
EA-1110 instrument. Infrared spectra were recorded on Bruck Vector 200
spectrophotometer.
General Procedure for the Preparation of 2,4-Diphenyl-1,2,3-
triazole (1a)
a-Hydroxyacetophenone (5 mmol, 0.681 g), cupric chloride (5 mmol,
0.673 g) and phenylhydrazine (20 mmol, 2.163 g) were added to 6.7 mL of
glacial acetic acid. The mixture was heated to reflux for 1.5 h and filtrated.

2466
W.-J. Tang and Y.-Z. Hu
The filtrate was neutralized with saturated sodium carbonate solution and
extracted with dichloromethylene (3 ꢀ 5 mL). The organic layer was
washed with water (3 mL) and dried over anhydrate sodium sulfate. The
organic layer was filtered, concentrated in vacuo, and purified by
column chromatography on silica gel using petroleum ether–EtOAc
(30 : 1) as eluent. The yields in Table 3 represent the average of two or
more runs.
Data for Intermediate 4a
Mp 148–1508C (1488C, Ref. 10); 1H NMR (400 MHz, CDCl3): d 6.98 (m, 1H,
Ar–H), 7.05 (m, 2H, Ar–H), 7.31 (s, 9H, Ar–H), 7.33 (s, 1H, 55CH–), 7.68
(m, 3H, Ar–H), 7.89 (s, 1H, 55N–H), 12.67 (s, 1H, 55N–H); MS (ESI): m/
z ¼ 313 [Mþ 2 1].
Data for Selected Compounds
1
Compound 1b: H NMR (400 MHz, CDCl3): d 7.14 (m, 2H, Ar–H), 7.33
(m, 1H, Ar–H), 7.47 (m, 2H, Ar–H), 7.85 (m, 2H, Ar–H), 8.00 (s, 1H,
55CH–), 8.11 (m, 2H, Ar–H); 13C NMR (100 MHz, CDCl3): d 115.8, 116.1
(J ¼ 21.0 Hz), 118.8, 126.2, 126.3 (J ¼ 3.6 Hz), 127. 5, 127.8, 127.9
(J ¼ 8.3 Hz), 129.3, 132.2, 139.8, 147.9, 161.8, 164.3 (J ¼ 246.0 Hz). Anal.
calcd. for C14H10FN3: C, 70.28; H, 4.21; N, 17.56. Found: C, 70.49; H,
4.22; N, 17.60. MS(ESI): m/z ¼ 240 [Mþ þ 1].
1
Compound 1h: H NMR (400 MHz, CDCl3): d 3.94 (s, 3H, CH3O), 4.00
(s, 3H, CH3O), 6.94 (m, 1H, Ar–H), 7.33 (m, 1H, Ar–H), 7.40 (m, 1H,
Ar–H), 7.47 (m, 3H, Ar–H), 7.99 (s, 1H, 55CH–), 8.12 (m, 2H, Ar–H);
13C NMR (100 MHz, CDCl3): d 55.9, 55.9, 109.0, 111.2, 118.7, 118.8,
122.8, 127.2, 129.2, 132.1, 139.8, 148.7, 149.3, 149.6. Anal. calcd. for
C16H15N3O2: C, 68.31; H, 5.37; N, 14.94. Found: C, 68.51; H, 5.36; N,
14.98; MS(ESI): m/z ¼ 282 [Mþ þ 1].
1
Compound 1i: H NMR (400 MHz, CDCl3): d 7.38 (m, 1H, Ar–H), 7.43
(m, 4H, Ar–H), 7.86 (m, 2H, Ar–H), 8.02 (s, 1H, 55CH–), 8.05 (m, 2H,
Ar–H); 13C NMR (100 MHz, CDCl3): d 119.9, 120.1, 128.9, 129.3,
129.7, 132.8, 132.9, 138.3, 149.1. Anal. calcd. for C14H10ClN3: C, 65.76;
H, 3.94; N, 16.43. Found: C, 65.93; H, 3.93; N, 16.47; MS(ESI): m/
z ¼ 256 [Mþ þ 1].
1
Compound 1o: H NMR (400 MHz, CDCl3): d 3.87 (s, 3H, CH3O), 7.00
(m, 2H, Ar–H), 7.42 (m, 2H, Ar–H), 7.81 (m, 2H, Ar–H), 7.99 (s, 1H,
55CH–), 8.02 (m, 2H, Ar–H); 13C NMR (100 MHz, CDCl3): d 55.5, 114.3,

2,4-Diaryl-1,2,3-triazoles
2467
120.2, 127.2, 128.7, 129.1, 131.9, 133.54, 134.4, 147.3, 159.0. Anal. calcd. for
C15H12ClN3O: C, 63.05; H, 4.23; N, 14.71. Found: C, 63.21; H, 4.24; N,
14.67; MS(ESI): m/z ¼ 286 [Mþ þ 1].
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