Microwave assisted direct arylation of 1-benzyl-1,2,3-triazole

Article abstract of DOI:10.1016/j.tetlet.2019.151390

A new efficient pathway for synthesis of 1-benzyl-5-aryl-1,2,3-triazoles by regioselective direct arylation between 1-benzyl-1,2,3-triazole and Ar-Br is developed. The microwave assisted reaction proceeded smoothly with good yield with high C5 position se

Full text of DOI:10.1016/j.tetlet.2019.151390

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Microwave Assisted Direct Arylation of 1-Benzyl-1,2,3-Triazole
Wei Liu, Yuanyuan Li, Rong Wang, Yubo Jiang, Chunxiang Kuang
PII:
S0040-4039(19)31181-5
DOI:
https://doi.org/10.1016/j.tetlet.2019.151390
TETL 151390
Reference:
Tetrahedron Letters
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11 September 2019
4 November 2019
11 November 2019
Please cite this article as: Liu, W., Li, Y., Wang, R., Jiang, Y., Kuang, C., Microwave Assisted Direct Arylation of
1-Benzyl-1,2,3-Triazole, Tetrahedron Letters (2019), doi: https://doi.org/10.1016/j.tetlet.2019.151390
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1
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Microwave Assisted Direct Arylation of 1-Benzyl-1,2,3-Triazole
Wei Liu a*, Yuanyuan Lib, Rong Wangb, Yubo Jiangc, Chunxiang Kuangb
a School of Pharmacy, Nantong University, Qixiu Road 19, Nantong 226001, China
b Department of Chemistry, Tongji University, Siping Road 1239, Shanghai 200092, China
c Faculty of Science, Kunming University of Science and Technology, Kunming 650500, China
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A new efficient pathway for synthesis of 1-benzyl-5-aryl-1,2,3-triazoles by regioselective
direct arylation between 1-benzyl-1,2,3-triazole and Ar-Br is developed. The microwave
assisted reaction proceeded smoothly with good yield with high C5 position selectivity and
a possible pathway of direct arylation is discussed. This methodology provides a simple
way to construct 1, 5-disubstituted 1,2,3-triazoles moiety.
Available online
Keywords:
2009 Elsevier Ltd. All rights reserved.
1-benzyl-1,2,3- triazoles
1,5-disubstituted 1,2,3-triazoles
Direct arylation
Pd-catalyzed

2
Introduction
Recently, 1,2,3-triazoles have attracted increasing attention as an important class of heterocycles with numerous
applications in medicinal chemistry and other chemistry(Figure 1) [1]. The rapidly increasing number of
requirements for the synthesis of these heterocycles has led to a need to develop effective methods for the
preparation of diverse 1,2,3-triazole derivatives [2]. Various protocols that involve the synthesis of 1,2,3-triazole
derivatives have been developed [3]. The Meta-catalyzed “click chemistry” reaction between azide and terminal
alkyne or alkene is extensively used for the practical and efficient preparation of 1,4-disubstituted 1,2,3-triazoles
since the robust Huisgen 1,3-dipolar cycloaddition was established. However, click chemistry on the synthesis
methods of 1,5-disubstituted 1,2,3-triazoles are limited because of the poor compatibility of the substrates and low
yeild (Entries 1, Scheme 1) [4]. Developing reaction conditions is necessary in widening the applicability of these
transformations.
HO C
2
O
N
N
N
S
O
O
H
N
N
N
Tazobatam
(antibiotic)
N
O
CF
3
Mubritinib
(breast cancer)
O
Figure 1. Drugs containing the 1,2,3-triazole ring.
Previous work
Click Chemistry
Scheme 1. The strategy to prepare disubstituted 1,2,3-triazoles by C-H activation
N
3
N
1)
Oveorr the past decade, C–H bond activation reactions have recently emerged as an attractive alternative to the
N
NO
Fe, Ag, Ru or Ce cat
2
N
use of organometallic reagents in the preparation of biaryl compounds [5]. To our knowledge, most of direct
arylation of 1-benzyl-1,2,3-triazole derivatives has rarely been developed due to the difficulty in reactivity and
C-H bond activation
Br
selectivity [6] or low yied [7] (Entries 2, Scheme 1). With a continuing interest in direct arylation of 1,2,3-triazole
2)
N
derivativeNs [8], we continued our efforts to expand the reaction of direct arylation for the formation of 1,5-
N
N
+
N
N
N
disubstituNted 1,2,3-CturIi,aLizOo(t-lBeus),.NMInP this paper, we report an efficient synthesis of 1-benzyl-5-aryl-1,2,3-triazoles based
N
o
140 C, 24h
main product
byproduct
on microwave assisted direct arylation between arylhalide and 1-benzyl-1,2,3-triazole many of which were obtained
in good yields.
This work
RCe-sHublotnsd aacntivdatDioniscussion
Br
Table 1. ScrNeening for optimal reaction conditions[a]
N
N
3)
N
high C-5 selectivity
N
Pd(OAc) , P(t-Bu) -HBF
4
N
2
3
Pdo(OAc)
Br
2
88%yield
K CO , DMF, 100 C, 0.5h
2
3
H
MicrowavLeiAgsasinstded
N
N
N
N
Base
Solvent
N
N
1a
2a
3a
d
Entry
Ligand
Base
Sovent
Yield of 3a (%)
1
2
3
4
5
P(t-Bu) -HBF
PCy
3
K CO
2
Dioxane
Dioxane
56%
43%
3
3
4
K CO
2
3
P(Ph)
3
K CO
2
Dioxane
Dioxane
Dioxane
18%
24%
28%
3
P(t-Bu) -HBF
DBU
3
4
P(t-Bu) -HBF
Pyridine
3
4

3
[a] Conditions: 1 (0.50 mmol), 2a (0.60 mmol), Pd(OAc)2 (5.0 mol%) ,ligand (5.0 mol%), base (1.0) solvent (2.0 ml),100℃, and 0.5 h in
microwave reactor under an atmosphere of N2. [b] Iodobenzene was used as the aryl halide. [c] Chlorobenzene was used as the aryl
halide. [d] Yield of isolated product.
Based on the results of published methods for the typical direct arylation reaction conditions [2c], we tested the
microwave assisted reaction of 2-(p-methylbenzyl)-1,2,3-triazole (1a) and phenyl bromide (2a) (Table 1). It was
found that P(tBu)3-HBF4 was more effective than P(Ph)3, P(Cy)3 (entries 1-3). Moreover, it was found that K2CO3 was
more effective than DBU, pyridine and Et3N as base (entries 3-6). it was found that DMF was more effective than
1,4-dioxane, DMSO and toluene as solvent (entries 6-9). Although the desired arylation conditions for 2-(p-
methylbenzyl) -1,2,3-triazole (1a) with iodobenzene provided the direct product 3a in 90% isolated yield (entry 10),
we investigated whether the reaction might be performed when using phenylchloride in stead of phenylbromide
(2a) (entries 10). Surprisely, no desired product was obtained (entry 11).
With the optimized conditions in hand, we tested the scope of the reaction of 1-benzyl-1,2,3-triazole 1 and aryl
halides 2 (Table 2). Diverse decorated products 3b–n formed in good to excellent yields. Both electron-rich (entries
6, 7, 9, 10, 11 ,13 and 14) and electron-poor (entries 8, 12, 15, 16 and 17) aryl halides were compatible.
Moreover; we also tested 2-bromo5-phenylthiophene and compound 3r was obtained. However, when we test
2-bromopyridine and 2-bromothiophene as substrates, no desired products were afforded under our catalytic
system. Notably, benzyl groups at the N-1 position of a triazole ring bearing 4-methyl-benzyl (entry 1, 6-10, 15-
18), 3-methyl-phenyl (entries 2, 13), 4-trifluoromethyl-benzyl (entry 4), 3-methoxyl-benzyl (entries 5, 14), and the
2-fluoro-benzyl (entries 3, 11, 12) moiety can also be used for this reaction.
Further studies on the influence of the aryl halide was conducted by a competition experiment (Scheme 2).
Under the above reaction conditions, 1a was reacted with both phenyl bromides 2d and 2e. It is found that the main
product, as detected by analysis of the crude reaction mixture by HPLC
Table 2. C-5 Arylation of 1-benzyl-1,2,3-triazole[a]

4
R
1
1
Pd(OAc)
Ar
2
R
2
Br
Ar
H
P(t-Bu) -HBF
3 4
N
N
N
N
2
N
N
K CO
2
3
o
DMF, 100 C, 0.5h
1
2
3
b
1
2
Yield (%)
Ar
Ar
Entry
1
2
3
1
3
2
4-MeC H
6
C H
6
C H
6
3a
3b
3c
1a
1b
1c
2a
2a
2a
88
86
83
82
4
4
5
5
3-MeC H
6
2-FC H
C H
6
6
4
5
5
5
4
5
4-CF C H
3 6 4
1d
1e
3d
3e
C H
6
C H
6
2a
2a
3-MeOC H
6
4
80
85
85
4-MeC H
6
7
1a
1a
3-MeC H
6
3f
6
4
2b
2c
5
4-MeC H
6
3g
2-MeC H
6
4
5
4-MeC H
6
4-MeC H
6
1a
1a
3,5-(CF ) C H
8
9
89
76
4
4
3h
3i
2d
2e
3 2
6
5
4-MeOC H
6
5
10
1a
4-MeC H
6
86
87
2f
2f
4
3j
3k
4-MeC H
6
5
5
2-FC H
4-MeC H
11
12
1c
1c
6
4
6
2-FC H
6
4
92
77
2d
2e
3l
3m
3,5-(CF ) C H
3 2
6
5
13
1b 3-MeC H
6
4-MeOC H
6
4
5
14
15
16
1e
1e
1e
1e
1e
3-MeOC H
6
79
86
85
3n
3o
3p
4-MeOC H
6
4
2e
2g
2h
5
4-MeC H
4-ClC H
6
4
4
4
4
6
4
4-MeC H
6
4-MeO CC H
6 4
2
17
18
4-MeC H
6
86
76
3q
3r
3-MeO CC H
6 4
2i
2j
2
4-MeC H
6
2-(5-phenyl)thienyl
[a] Conditions: 1 (0.50 mmol), 2 (0.60 mmol), Pd(OAc)2 (5.0 mol%), P(tBu)3-HBF4 (5.0 mol%), K2CO3 (1.0 mmol), DMF (2.0 ml), 100℃,
and 0.5 h in microwave reactor under an atmosphere of N2. [b] Yield of isolated product.
F C
3
O
CF
3
Br
Br
O
Pd(OAc)
N
2
N
N
N
N
P(t-Bu) -HBF
N
3
4
H
N
N
K
CO
3
N
2
F C
CF
3
3
o
DMF, 100 C, 0.5h
Microwave Reaction
3i
3h
3h/3i = > 13:1
1a
2d
2e
Scheme 2. Competition experiment
.
Ar -X
2
(0)
N
N
N
(t-BuP) Pd
2
Ar
2
KHCO
3
Ar
1
K CO
2
3
N
N
(t-BuP) Pd(Ar )X
2
2
AcOK
N
1
Ar (t-BuP) Pd
2
2
Ar
KBr
2
Ar
1
4
t-Bu P
3
AcOH
Pd O
O
Me
N
2
Concerted Metallation-
Deprotonation
N
N
N
Ar
2
t-Bu P
N
3
Pd
O
N
Ar
1
H
Ar
1
O
H
Me

5
Scheme 3. Possible pathway
spectroscopy, was 3h, which arises from reaction of phenyl bromide 2d with an electronwithdrawing group. The
result from the competition experiment indicates that, relative to phenyl bromides with electron-donating groups,
phenyl bromides with electron-withdrawing groups should have higher reactivity and show a higher reaction rate in
the formation of intermediate 1 in Scheme 3 for the direct arylation in this system.
Despite the rather fragmented information on the mechanism at present, We propose that the direct arylation
reaction proceeds through a plausible reaction mechanism similar to the typical mechanism of the direct arylation
reaction of pyridine N-oxide [9]. The reaction was proposed to involve a concerted metalation-deprotonation (CMD)
mechanism for the C–H activation step as shown in Scheme 3. Further studies are needed to understand the
mechanism of arylation reaction of 1-benzyl-1,2,3-triazole. Although a few reports have developed the synthesis of 1-
benzyl-5-aryl-1,2,3-triazoles with low yield and site-selectivity [10], this protocol can provide an valuable alternative
for the synthesis of 1-benzyl-5-aryl-1,2,3-triazoles.
Conclusion
In conclusion, we repeorted an efficient microwave assisted coupling between 1-benzyl-1,2,3-triazoles and
arylhalides in synthesizing 1-benzyl-5-aryl-1,2,3-triazoles. The method provided a useful alternative for synthesis of
1-benzyl-5-aryl-1,2,3-triazoles in organic chemistry and medical chemistry.
Acknowledgements
This work was supported by the Nantong University for Returned Overseas Chinese Scholars (17R37) and
Zhejiang Province Pinghu Leading Academic Discipline Project (2018).
Supplementary data
1
Supplementary data (Experimental details, H NMR data and spectra, 13C NMR data and spectra, FT-IR data and
spectra) associated with this article can be found, in the online version, at http://dx.doi.org/000000.
References and notes
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6
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Table 1.
Entry Ligand
Base
Sovent
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Toluene
DMSO
Yield of 3a (%)d
1
2
K2CO3
K2CO3
K2CO3
DBU
Pyridine
Et3N
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
56%
43%
18%
24%
28%
12%
57%
68%
88%
90%
None
P(t-Bu)3-HBF4
PCy3
3
P(Ph)3
4
5
6
7
8
9
10b
11c
P(t-Bu)3-HBF4
P(t-Bu)3-HBF4
P(t-Bu)3-HBF4
P(t-Bu)3-HBF4
P(t-Bu)3-HBF4
P(t-Bu)3-HBF4
P(t-Bu)3-HBF4
P(t-Bu)3-HBF4
DMF
DMF
DMF
Table 2
Entry 1a Ar1
2 Ar2
3 Yield (%)b
3a 88
3b 86
123
45
6
1d 4-MeC6H4
1e 3-MeC6H4
1a 2-FC6H4
2a C6H5
2a C6H5
2a C6H5
3c 83
7
1a 4-CF3C6H4 2a C6H5
1a 3-MeOC6H4 2a C6H5
3d 82
3e 80
3f 85
3g 85
3h 89
3i 76
89
10
11
12
13
1a 4-MeC6H4
1a 4-MeC6H4
1c 4-MeC6H4
1b 4-MeC6H4
2b 3-MeC6H5
2c 2-MeC6H5
2d 3,5-(CF3)2C6H5
2e 4-MeC6H5

7
14
15
16
17
18
1c 4-MeC6H4
1 2-FC6H4
1c 2-FC6H4
1b 3-MeC6H4
2f 4-MeOC6H5
2f 4-MeC6H5
2d 3,5-(CF3)2C6H5
2e 4-MeOC6H5
3j 86
3k 87
3l 92
3m 77
3n 79
3o 86
3p 85
3q 86
1e 3-MeOC6H4 2e 4-MeOC6H5
1e 4-MeC6H4
1e 4-MeC6H4
1e 4-MeC6H4
1e 4-MeC6H4
2g 4-ClC6H4
2h 4-MeO2CC6H4
2i 3-MeO2CC6H4
2j 2-(5-phenyl)thienyl 3r 76