Sodium hydride-mediated synthesis of 1,5-diaryl-1,2,3-triazoles from anti-3-aryl-2,3-dibromopropanoic acids and organic azides

Article abstract of DOI:10.1016/j.cclet.2013.05.007

A series of 1,5-disubstituted 1,2,3-triazoles are synthesized by a one-pot process from anti-3-aryl-2,3-dibromopropanoic acids and organic azides mediated by sodium hydride in dimethyl sulfoxide. The reaction is mild and simple, does not require a transition-metal catalyst, and gives products in good to excellent yields.

Full text of DOI:10.1016/j.cclet.2013.05.007

Chinese Chemical Letters 24 (2013) 764–766
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Chinese Chemical Letters
journal homepage: www.elsevier.com/locate/cclet
Original article
Sodium hydride-mediated synthesis of 1,5-diaryl-1,2,3-triazoles from
anti-3-aryl-2,3-dibromopropanoic acids and organic azides
Xue-Zhi Cheng a, Wei Liu a, Zhen-Dong Huang b, Chun-Xiang Kuang a,c,
*
a Department of Chemistry, Tongji University, Shanghai 200092, China
b Zhejiang Citrus Research Institute, Taizhou 318020, China
c Key Laboratory of Yangtze River Water Environment, Ministry of Education, Shanghai 200092, China
A R T I C L E I N F O
A B S T R A C T
Article history:
A series of 1,5-disubstituted 1,2,3-triazoles are synthesized by a one-pot process from anti-3-aryl-2,3-
dibromopropanoic acids and organic azides mediated by sodium hydride in dimethyl sulfoxide. The
reaction is mild and simple, does not require a transition-metal catalyst, and gives products in good to
excellent yields.
Received 28 March 2013
Received in revised form 25 April 2013
Accepted 27 April 2013
Available online 2 June 2013
ß 2013 Chun-Xiang Kuang. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights
reserved.
Keywords:
Cyclizations
Heterocycles
Sodium hydride
Triazoles
1. Introduction
anti-3-aryl-2,3-dibromopropanoic acids and organic azides medi-
ated by sodium hydride (Scheme 1). In this reaction, the anti-3-
1,2,3-Triazoles are attractive compounds because of their
unique chemical properties and structures that find many
applications in medical [1], material [2], and biological research
[3]. The use of 1,2,3-triazole moieties as catalysts and ligands in
transition-metal catalysis systems is also emerging [4]. 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.
aryl-2,3-dibromopropanoic acids serve as precursors of reactive
acetylides, which readily react with organic azides. The result is the
exclusive formation of 1,5-disubstituted triazoles in a one-pot
process. To verify the final products are 1,5-diaryl-1,2,3-triazoles,
not the 1,4-isomers, we compare the 1H NMR and 13C NMR spectra
of the final products (for details see the Supporting information)
with the standard spectra in the existing literature [6–10].
Copper(I)-catalyzed azide–alkyne cycloaddition (CuAAC) is an
important advancement in the chemistry of 1,2,3-triazoles [5].
However, the CuAAC process works only with terminal alkynes and
produces various kinds of 1,4-disubstituted 1,2,3-triazoles. In
contrast to 1,4-disubstituted 1,2,3-triazoles, general and regiose-
lective routes leading to 1,5-regioisomers are not as well
developed. Among the available methods are the reactions of
stabilized phosphonium ylides [6] or enamines [7] with aryl azides,
the nucleophilic attack of acetylide on the electrophilic terminal
nitrogen of the azide [8,9], and ruthenium-catalyzed azide–alkyne
cycloaddition [10]. However, these methods have limitations that
cannot be neglected.
2. Experimental
1H NMR and 13C NMR spectra were recorded using Bruker AM-
400 spectrometer in CDCl3 with TMS as an internal standard.
Commercially obtained reagents were used without further
purification. All reactions were monitored by TLC with Huanghai
GF 254 silica gel coated plates. Column chromatography was
carried out using 300–400 mesh silica gel at medium pressure. The
synthesis of anti-3-aryl-2,3-dibromopropanic acids 1 and organic
azides 2 was achieved according to literature procedures [11,12].
(CAUTION! Aryl azides are poisonous and potentially explosive
when subjected to heat, light, and pressure. Any azide synthesized
should be stored below 0 8C in the dark.)
In this paper, we report a mild and simple method for the
generation of 1,5-disubstituted triazoles from readily available
2.1. 1,5-Disubstituted 1,2,3-triazoles (3a)
A
solution of anti-3-aryl-2,3-dibromopropanic acid
1
* Corresponding author at: Department of Chemistry, Tongji University, Shanghai
200092, China.
(0.6 mmol), organic azides 2 (0.5 mmol), NaH (60 mg, 2.5 mmol),
E-mail address: kuangcx@tongji.edu.cn (C.-X. Kuang).
and DMSO (5 mL) were placed in a sealed tube. The mixture was
1001-8417/$ – see front matter ß 2013 Chun-Xiang Kuang. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
http://dx.doi.org/10.1016/j.cclet.2013.05.007

[
X.-Z. Cheng et al. / Chinese Chemica
T
l Letters 24 (2013) 764–766
765
R1
Previous method
Br
N
R2
N
Ru/L
N
CO2H
R1
2
N
N
R
N
2
2
N
1
Br
R
N
N
R
+
3
NaH
N
R2
1
1
II
R
NaH
R2
NMe OH
4
R1
H
R1
N
R2
R1
N
N
I
NaH
This work
Br
Br
N
R1
2
N
N
R
H
III
NaH
N
2
N
N
R
H
CO H
2
3
R1
B
H
+
1
R
R1
H
N
DMSO, r.t.
1
R
3
Br
Br
Scheme 1. One-pot synthesis of 1,5-disubstituted 1,2,3-triazoles.
Scheme 2. Proposed mechanism of the one-pot reaction.
stirred at room temperature for 12 h. The mixture was then
quenched with H2O (25 mL). The mixture was extracted with
EtOAc (3Â 30 mL), and the combined organic layers were washed
with brine (3Â 10 mL). The extract was dried over Na2SO4 and
concentrated under reduced pressure to afford a crude product.
Purification by column chromatography on silica gel (EtOAc–PE)
afforded the desired 1,5-disubstituted-1,2,3-triazole 3a. Yield:
100 mg (85%), yellow solid.
synthesis of 1,5-diaryl-1,2,3-triazoles (Table 1). The necessary anti-
3-aryl-2,3-dibromopropanoic acids were easily prepared by
bromination of the corresponding trans-a,b-unsaturated carbox-
ylic acids [11], and the organic azides were obtained from the
corresponding organic amine or organic halide [12]. As shown in
Table 1, the method can be used to synthesize 1,5-diaryl-1,2,3-
triazoles carrying either an electron-donating substituent (such as
methyl, tert-butyl, or methoxy; entries 1–4) or an electron-
withdrawing group (entries 5–11). Aryl azides with sterically
demanding ortho-substituents gave slightly lower yields (entries 9
and 11). The electronic properties of both reactants also influenced
the reaction outcome. Electron-deficient reactants give slightly
lower yields on average than electron-rich reactants (compare
entries 1–4 with entries 9–11).
3. Results and discussion
The reaction was determined to proceed best using dimethyl-
sulfoxide (DMSO) as solvent at room temperature. Then, we
examined the substrate scope of the sodium hydride-mediated
Table 1
Sodium hydride-mediated synthesis of 1,4-disubstituted-1,2,3-triazoles from anti-3-aryl-2,3-dibromopropanoic acids and organic azides.
[TD$INLE]
R2
Br
NaH
N
N3 R2
N
CO2H
R1
+
N
DMSO, r.t.
R1
Br
.
Entrya
Product
Yield (%)b
Entrya
5
Product
Yield (%)b
82
Entrya
9
Product
Yield (%)b
75
1
85
Br
N
N
N
N
[TD$INLE]
N
N
N
[
N
3i
[DT$INLE]
3e
3a
N
Br
2
86
6
79
10
78
Br
N
N
N
N
N
N
N
[DT$INLE]
]
[TD$INLE]
3f
3b
N
N
3j
Br
Br
3
87
7
76
11
73
MeO
Br
N
N
N
N
[DT$INLE]
3k
[DT$INLE]
N
N
E
3g
N
N
N
Cl
Cl
Cl
Br
Cl
4
MeO
91
8
83
N
N
N
N
[DT$INLE]
N
3d
[TD$INLINE]
3h
N
a
1 (0.6 mmol), 2 (0.5 mmol), NaH (2.5 mmol), DMSO (5 mL), r.t., and 12 h.
Isolated yield based on substrate 2.
b

766
X.-Z. Cheng et al. / Chinese Chemical Letters 24 (2013) 764–766
To study the reaction mechanism, we carried out a control
Appendix A. Supplementary data
experiment with anti-3-phenyl-2,3-dibromopropanoic acids in the
absence of the azide partner and obtained the corresponding
terminal alkyne in 89% yield. This finding suggested that an
aralkyne was generated in situ in the one-pot reaction. The
proposed pathway of this reaction is shown in Scheme 2, as
previously described [9,13]. Initially, the trans-elimination reac-
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.cclet.2013.05.007.
References
tion of anti-3-aryl-2,3-dibromopropanoic acid 1, involving
simultaneous loss of carbon dioxide and bromide ions, occurs to
generate the intermediate (Z)- -arylvinyl bromide. A subsequent
E2 trans-elimination gives the terminal alkyne. Reversible
deprotonation of the terminal alkyne generates an aryl acetylide
I, which acts as a nucleophile to attack the terminal nitrogen of aryl
a
[1] R. Moumne, V. Larue, B. Seijo, et al., Tether influence on the binding properties of
tRNAL3ys ligands designed by a fragment-based approach, Org. Biomol. Chem. 8
(2010) 1154–1159.
[2] G.K. Rawal, P. Zhang, C. Ling, Controlled synthesis of linear a-cyclodextrin
oligomers using copper-catalyzed Huisgen 1,3-dipolar cycloaddition, Org. Lett.
12 (2010) 3096–3099.
[3] M.P. Ahsanullah, P. Schmieder, R. Kuhne, J. Rademann, Metal-free, regioselective
triazole ligations that deliver locked cis peptide mimetics, Angew. Chem. Int. Ed.
48 (2009) 5042–5045.
b
azide 2. The triazenide intermediate II then undergoes either 6p-
electrocyclization or 5-endo-dig cyclization to form 1,5-disubsti-
tuted-1,2,3-triazolyl anion III, which gives products 3 by the
deprotonation of a DMSO molecule, terminal alkyne, or water.
[4] H. Duan, S. Sengupta, J.L. Petersen, N.G. Akhmedov, X. Shi, Triazole-Au(I) com-
plexes: a new class of catalysts with improved thermal stability and reactivity for
intermolecular alkyne hydroamination, J. Am. Chem. Soc. 131 (2009)
12100–12102.
[5] C.W. Tornøe, C. Christensen, M. Meldal, Peptidotriazoles on solid phase: [1,2,3]-
triazoles by regiospecific copper(I)-catalyzed 1,3-dipolar cycloadditions of termi-
nal alkynes to azides, J. Org. Chem. 67 (2002) 3057–3064.
4. Conclusion
[6] G. Labbe, P. Ykman, G. Smets, Reactions of azides with a-ester phosphorus ylids,
Tetrahedron 25 (1969) 5421–5426.
[7] S. Fioravanti, L. Pellacani, D. Ricci, P.A. Tardella, Stereoselective azide cycloaddi-
We developed a simple and efficient one-pot method for the
preparation of 1,5-disubstituted 1,2,3-triazoles 3 from anti-3-aryl-
2,3-dibromopropanoic acids 1 and organic azides 2. The reaction
was mediated only by the inexpensive sodium hydride, and good
to excellent yields were obtained. The process had considerable
advantages in terms of readily available substrates and mild,
transition-metal-free conditions.
tion to chiral cyclopentanone enamines, Tetrahedron: Asymmetry
2261.
8 (1997)
[8] A. Krasinski, V.V. Fokin, K.B. Sharpless, Direct synthesis of 1,5-disubstituted-4-
magnesio-1,2,3-triazoles, revisited, Org. Lett. 6 (2004) 1237–1240.
[9] S.W. Kwok, J.R. Fotsing, R.J. Fraser, V.O. Rodionov, V.V. Fokin, Transition-metal-
free catalytic synthesis of 1,5-diaryl-1,2,3-triazoles, Org. Lett. 12 (2010)
4217–4219.
[10] B.C. Boren, S. Narayan, L.K. Rasmussen, et al., Ruthenium-catalyzed azide–alkyne
cycloaddition: scope and mechanism, J. Am. Chem. Soc. 130 (2008) 8923–8930.
[11] M. Zhao, C. Kuang, X.Z. Cheng, Q. Yang, Iron-catalyzed ketonization of 2-aryl-1,1-
dibromoalkenes with KOAc: synthesis of a-acetoxy aryl ketones via a Michael-
like addition process, Chin. Chem. Lett. 22 (2011) 571–574.
[12] S. Brase, C. Gil, K. Knepper, V. Zimmermann, Organic azides: an exploding
diversity of a unique class of compounds, Angew. Chem. Int. Ed. 44 (2005)
5188–5240.
Acknowledgments
The present work was supported by the Natural Science
Foundation of China (No. 21272174), the Key Projects of Shanghai
in Biomedicine (No. 08431902700), and the Scientific Research
Foundation of the State Education Ministry for Returned Overseas
Chinese Scholars. We would also like to thank the Center for
Instrumental Analysis, Tongji University, China.
[13] X.Z. Cheng, Y. Yang, C. Kuang, Q. Yang, Copper(I) iodide catalyzed synthesis of 1,4-
disubstituted 1,2,3-triazoles from anti-3-aryl-2,3-dibromopropanoic acids and
organic azides, Synthesis 18 (2011) 2907–2912.