Room-temperature oxidative Suzuki coupling reaction of 1,2,3-triazole N-oxides

Article abstract of DOI:10.1016/j.tetlet.2017.06.051

This study develops a new efficient pathway for synthesis of 2,4-disubstituted 1,2,3-triazoles through regioselective direct arylation between 2-aryl-1,2,3-triazole N-oxides and Ar-B(OH)₂. The reaction proceeds smoothly at room temperature and exhibits good yield and high C5 position selectivity. The possible pathway of oxidative Suzuki coupling is also discussed. This simple methodology can be used to construct 2,4-disubstituted 1,2,3-triazole moiety.

Full text of DOI:10.1016/j.tetlet.2017.06.051

Accepted Manuscript
Room-Temperature Oxidative Suzuki Coupling Reaction of 1,2,3-Triazole N-
Oxides
Wei Liu, Yanyan Yu, Boyi Fan, Chunxiang Kuang
PII:
S0040-4039(17)30782-7
DOI:
http://dx.doi.org/10.1016/j.tetlet.2017.06.051
TETL 49043
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
4 May 2017
15 June 2017
16 June 2017
Please cite this article as: Liu, W., Yu, Y., Fan, B., Kuang, C., Room-Temperature Oxidative Suzuki Coupling
Reaction of 1,2,3-Triazole N-Oxides, Tetrahedron Letters (2017), doi: http://dx.doi.org/10.1016/j.tetlet.
2017.06.051
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1
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Room-Temperature Oxidative Suzuki Coupling Reaction of 1,2,3-Triazole N-
Oxides
Wei Liua,*, Yanyan Yua, Boyi Fana, 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
ARTICLE INFO
ABSTRACT
Article history:
Received
This study develops a new efficient pathway for synthesis of 2,4-disubstituted 1,2,3-
triazoles through regioselective direct arylation between 2-aryl-1,2,3-triazole N-oxides and
Ar-B(OH)2. The reaction proceeds smoothly at room temperature and exhibits good yield
and high C5 position selectivity. The possible pathway of oxidative Suzuki coupling is also
discussed. This simple methodology can be used to construct 2,4-disubstituted 1,2,3-
triazole moiety.
Received in revised form
Accepted
Available online
Keywords:
Room-temperature reaction
1,2,3-Triazoles
2009 Elsevier Ltd. All rights reserved.
Oxidative Suzuki coupling
Direct arylation
Pd catalyzed
Introduction
1,2,3-Triazoles, which exhibit unique chemical and structural
properties, are an important class of heterocycles with numerous
applications in materials and medicinal chemistry.1–4
Considering the rapidly increasing number of requirements for
synthesis of these heterocycles, scholars must develop effective
methods for preparation of diverse 1,2,3-triazole derivatives.5–8
Various protocols involving coupling with 1,2,3-triazole
derivatives have been established.9–11
C–H bond activation reactions have gained increasing
attention from academic and industrial chemists12–14 because
these reactions can shorten the synthesis route and allow the
utilization of affordable and readily available starting materials.
The Pd-catalyzed direct cross coupling of arenes and arylboronic
acid, also called oxidative Suzuki-type reaction, is
a
representative of C–H bond activation reactions. Previous studies
reported that these reactions require elevated temperatures,15,16,18
which severely limit the compatibility of the substrates and their
large-scale applications. Thus, identifying mild reaction
conditions that can proceed at ambient temperature is necessary
to broaden the applicability of these transformations (Scheme
1).15,18
Scheme 1. Strategy for preparing 2,4-bisaryl 1,2,3-triazoles by C–H
activation.
To our knowledge, most direct arylation methods of 1,2,3-
triazole rings are mainly limited to 1-substituted 1,2,3-triazole
derivatives; moreover, the direct arylation of 2-substituted 1,2,3-
triazoles has been rarely investigated due to their complex
reactivity and selectivity20. In this study, we report an efficient
method for synthesis of 2,4-disubstituted 1,2,3-triazoles through
direct arylation between arylboronic acid and 2-aryl-1,2,3-
Focusing on the direct arylation of 1,2,3-triazole N-
oxides,17–19 we aim to expand the reaction at room
temperature for the formation of 2,4-bisaryl 1,2,3-triazoles.

2
Table 1. Screening for optimal reaction conditions[a]
Table 2. C-5 arylation of 2-aryl-1,2,3-triazole N-oxides[a]
.
OH
HO
B
Pd(OAc)2
O
Pd(OAc)2
Oxidant
O
N
Ar2
N
N
Ar1
N
AgOAc
+
N
N
+
N
B(OH)2
Ar2
Ar1
N
N
N
DMF
rt, 16h
solvent
H
H
N
N
O
O
1
2
3
3a
1a
Entry Oxidant(1.3equiv)
2a
b
Yield of 3a (%)b
1
3
Yield of (%)
Entry
1
2
3
solvent
Temperature
O
N
N
1
2
Ag2CO3
AgOAc
25oC
25oC
Dioxane
Dioxane
35%
56%
N
3b
3c
84%
B(OH)2
O
25oC
25oC
Dioxane
Dioxane
8%
1a
2b
3
4
Ag2O
N
AgNO3
trace
87%
N
2
3
25oC
25oC
Dioxane
Dioxane
trace
trace
N
B(OH)2
5
6
Ag2SO4
CuSO4
1a
O
2c
2d
N
N
AgOAc
AgOAc
AgOAc
25oC
25oC
25oC
25oC
77%
87%
70%
22%
7
Dioxane
DMF
N
3d
3e
81%
78%
8
MeOOC
F3C
B(OH)2
B(OH)2
1a
O
9
DMSO
N
AgOAc
10
Toluene
DMF
N
4
5
11c
12c
13
70oC
100oC
25oC
N
AgOAc
AgOAc
none
23%
1a
1a
2e
O
DMF
trace
trace
N
DMF
N
3f
89%
64%
N
[a] Conditions: 1 (0.50 mmol), 2a (0.60 mmol), Pd(OAc)2 (5.0 mol%),
Oxidant (5.0 mol%), solvent (2.0 ml), rt, and 16 h, under air. [b] Yield of
isolated product. [c] Biphenyl was obtained.
B(OH)2
2f
O
N
N
N
N
N
6
3g
B(OH)2
B(OH)2
1a
2g
2h
O
triazole N-oxides at room temperature, many of which were
N
obtained in good yields.
7
8
3h
3i
85%
83%
N
S
1a
1b
O
Results and Discussion
Cl
N
O
Basing on the results of published methods for the typical
reaction conditions for direct arylation,7 we tested the reaction of
2-(p-tolyl)-1,2,3-triazole N-oxide (1a) and phenylboronic acid at
room temperature (Table 1). AgOAc was more effective than
Ag2CO3, Ag2O, Ag2SO4, AgNO3, and CuSO4 (entries 1–7).
Moreover, DMF was more effective than 1,4-dioxane, DMSO,
and toluene as solvent (entries 7–10). Although the desired
conditions for 2-substituted 1,2,3-triazole N-oxide arylation
provided the direct product 3a in 87% isolated yield at room
temperature (entry 7), we investigated whether the reaction
might be performed at high temperatures (entries 4–6). Notably,
only 23% product yield was obtained, and 45% biphenyl yield
was detected at 70 °C (entry 11). No desired product was
obtained, and 95% biphenyl yield was observed when the
temperature was changed to 100 °C (entry 12).
F
N
B(OH)2
O
2b
N
9
3j
80%
N
N
O
MeOOC
B(OH)2
1c
2d
N
Cl
N
10
11
3k
3l
88%
79%
N
B(OH)2
2a
O
1d
N
F3C
N
N
B(OH)2
O
1e
2e
[a] Conditions: 1 (0.50 mmol), 2a (0.60 mmol), Pd(OAc)2 (5.0 mol%),
AgOAc (1.0 mmol), DMF (2.0 ml), rt, and 16 h. [b] Yield of the isolated
product.
B(OH)2
chloro-4-fluoro-phenyl (entry 8) moiety can be used for the
reaction. Moreover, (E)-styreneboronic acid 2i can be used for
this reaction with 2-aryl-1,2,3-triazole N-oxides 1a. The product
4a was formed in moderate yield (Scheme 2).
O
Pd(OAc)2
AgOAc
N
N
N
+
N
N
DMF
rt, 16h
.
H
N
O
4a
1a
2I
78% yield
In this study, we propose a Pd-catalyzed direct arylation that
proceeds through a pathway similar to the typical mechanism of
direct arylation between pyridine N-oxides and arylboronic acids
(Scheme 3).21,22 We performed a control experiment using
phenylboronic acid and iodobenzene or bromobenzene as
coupling partner under standard conditions. No desired product
was observed, indicating that the activity of C–H bond on the C-
5 position in 2-aryl-1,2,3-triazole N-oxides should be higher than
the C–Br or C–I bond on aryl halides under this condition.
Further studies must be performed to elucidate the mechanism of
Scheme 2. Reaction between (E)-styreneboronic acid and 1a.
Under the optimized conditions, we tested the scope of the
reaction of 2-aryl-1,2,3-triazole N-oxides 1 and arylboronic acids
2 (Table 2). Diverse decorated products 3b–l were formed, with
good to excellent yields. Both electron-rich (entries 1, 2, 5, 6,
and 8) and electron poor (entries 3 and 4) arylboronic acids were
compatible. Thiopheneboronic acids were also applied to this
system (entries 7). Notably, aryl groups at the N-2 position of the
triazole ring bearing m-tolyl (entries 1–7), phenyl (entries 11), 1-
naphthyl (entries 9), 4-chloro-phenyl (entry 10), and the 3-

7
8
Yeung, C. -S.; Dong, V. -M. Chem. Rev. 2011, 111, 1215-1292;
Duan, H.; Sengupta, S.; Petersen, J. L.; Shi, X. Organometallics. 2009, 28,
2352-2355.
the oxidative Suzuki coupling of 1,2,3-triazole N-oxides with
arylboronic acids at room temperature.
9. Guo, X.-Q.; Zhu, X.-H.; Zhong, R.; Cai, Li.-H.; Hou, X.-F. Chem.
Commun. 2012, 48, 10437-10439;
The deoxygenation of the arylated N-oxides to the desired
1,2,3-triazoles can be conveniently achieved with high yields
through the Pd-catalyzed reduction with ammonium formate or
PBr3.19,23 Although few scholars have developed the synthesis of
2,4-disubstituted 1,2,3-triazoles,24 this protocol can provide a
valuable alternative for synthesis of 2,4-disubstituted 1,2,3-
triazoles.
10. Ackermann, L. Pure. Appl. Chem. 2010, 82, 1403-1413;
11. Hirano, K.; Miura, M. Synlett. 2011, 3, 294-307;
12. Campeau, L. C.; Rousseaux, S.; Fagnou, K. J. Am. Chem. Soc. 2005, 127,
18020-18023.
13 Leclerc, J.-P.; Fagnou, K. Angew. Chem., Int. Ed. 2006, 45, 7781-7784.
14 Fu, X.-P.; Xuan, Q.-Q.; Liu, L.; Wang, D.; Chen, Y.-J.; Li, C.-J.
Tetrahedron. 2013, 69, 4436-4439.
H
Pd(OAc)2
O
15. Elisabeth, N.; Ghenia, B.; Mathieu, A. S.; Floris, C.; Stephanie. P.;
Stephane. F.; Raphael, E. D.; Yury, H.; Oleg, S. I.; Vadim, E. A, M.
Bioorganic & Medicinal Chemistry. 2015, 23, 6355-6363. .
16. Zhang, S.; Li, B.; Cheng, W.; Fang, Z.; Cao, B.; Qin, C. Angew. Chem.,
Int. Ed. 2007, 46, 5554-5558;
N
Ag
N
Ar1
N
Ag2+
(OAc)Pd
17. Liu, W.; Li, Y.-H.; Xu, B.; Kuang, C. -X. Org. Lett. 2013.15, 2342-2345;
18. Liu, W.; Li, Y. H.; Wang, Y.; Kuang, C. -X. Euro. J. Org. Chem. 2013,
15, 5272-5275.
O
HPdOAc
N
N
3
Ar1
N
19. Liu, W.; Li, Y. -H.; Wang, Y.; Kuang, C. -X. Org. Lett. 2013, 16, 4682-
4685;
Ar2
1
O
N
20. Kozhushkov, S. I.; Potukuchi, H. K.; Ackermann, L. Catal. Sci. Technol.
2013, 3, 562-566.
N
Ar2
Ar1
N
(OAc)Pd
Ar2-B(OH)2
O
TM
N
21. Shen, Y.; Chen, J.-X.; Liu, M.-C; Ding, J.-C; Gao, W.-X; Huang, X.-B;
Wu, H.-Y. Chem. Commun. 2014, 50, 4292-4295.
N
Ar1
N
22. Mai, W.-P.; Yuan, J.-W.; Li, Z.-C.; S, G.-C.; Qu, L.-B. Synlett. 2012, 23,
145-149;
2
Scheme 3. Possible pathway for oxidative Suzuki coupling.
23. Sasa, D.; Christoph. Tzschucke, C. Org. Lett. 2011, 13, 2310-2313;
24. Ueda, S.; Su, M.-J.; Buchwald, S.-L. Angew. Chem., Int. Ed. 2011, 50,
8944-8947;
.
Conclusion
We reported an efficient direct coupling reaction between 2-
aryl-1,2,3-triazole N-oxides and arylboronic acids at room
temperature for synthesis of 2,4-disubstituted 1,2,3-triazoles. The
protocol can be applied to obtain moderate yields of
styreneboronic acid and 1,2,3-triazole N-oxides. The proposed
method can be used as an alternative to existing procedures for
synthesis of 2,4-disubstituted 1,2,3-triazoles in organic chemistry
and medical chemistry.
Acknowledgements
This work was supported by the National Natural Science
Foundation of China (No. 21476071) and Shanghai Leading
Academic Discipline Project (B502).
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, 2853-2856.
6
Liu, D.; Gao, W. -Z.; Dai, Q.; Zhang, X.-M. Org. Lett. 2005, 7, 4907-
4910.

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Room-Temperature Oxidative Suzuki Coupling Reaction of 1,2,3-Triazole N-Oxides
Wei Liu, Yan-Yan Yu, Bo-Yi Fan and Chun-Xiang Kuang
This study develops a new efficient pathway for synthesis of 2,4-disubstituted 1,2,3-triazoles through
regioselective direct arylation between 2-aryl-1,2,3-triazole N-oxides and Ar-B(OH)2. The reaction
proceeds smoothly at room temperature and exhibits good yield and high C5 position selectivity. The
possible pathway of oxidative Suzuki coupling is also discussed. This simple methodology can be used

Highlight
）
1
A new efficient method for synthesis of 2,4-
disubstituted 1,2,3-triazoles through oxidative
Suzuki reaction is developed.
）
）
2
3
The reaction can be carried out smoothly at
room temperature with good yield.
The possible mechanism of the oxidative
Suzuki reaction is discussed.