Stereoselective synthesis of phenyl-1,2,3-triazoles containing (E)-vinyl halide group via a one-pot, three-component reaction

Article abstract of DOI:10.1080/00397911.2010.481746

Phenyl-1,2,3-triazoles containing (E)-vinyl halide were readily synthesized via a one-pot, three-component reaction of 3-(4- or 2-azidophenyl)acrylic acid, NXS(X=Cl, Br and I) and 1-alkynes in MeCN-H2O (9:1v/v) catalyzed by LiOAc/CuI-sodium ascorbate syst

Full text of DOI:10.1080/00397911.2010.481746

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Stereoselective Synthesis of
Phenyl-1,2,3-triazoles Containing (E)-
Vinyl Halide Group via a One-Pot, Three-
Component Reaction
Wensheng Zhang a , Changhui Su a , Chunxiang Kuang a & Qing Yang b
a Department of Chemistry , Tongji University , Shanghai , China
b Department of Biochemistry, School of Life Sciences , Fudan
University , Shanghai , China
Published online: 30 Mar 2011.
To cite this article: Wensheng Zhang , Changhui Su , Chunxiang Kuang & Qing Yang (2011)
Stereoselective Synthesis of Phenyl-1,2,3-triazoles Containing (E)-Vinyl Halide Group via a One-
Pot, Three-Component Reaction, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 41:9, 1267-1275, DOI: 10.1080/00397911.2010.481746
To link to this article: http://dx.doi.org/10.1080/00397911.2010.481746
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Synthetic Communications1, 41: 1267–1275, 2011
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2010.481746
STEREOSELECTIVE SYNTHESIS OF PHENYL-1,2,
3-TRIAZOLES CONTAINING (E)-VINYL HALIDE GROUP
VIA A ONE-POT, THREE-COMPONENT REACTION
Wensheng Zhang,1 Changhui Su,1 Chunxiang Kuang,1 and
Qing Yang2
1Department of Chemistry, Tongji University, Shanghai, China
2Department of Biochemistry, School of Life Sciences, Fudan University,
Shanghai, China
GRAPHICAL ABSTRACT
Abstract Phenyl-1,2,3-triazoles containing (E)-vinyl halide were readily synthesized via a
=
one-pot, three-component reaction of 3-(4- or 2-azidophenyl)acrylic acid, NXS(X Cl,
Br and I) and 1-alkynes in MeCN-H2O (9:1 v/v) catalyzed by LiOAc/CuI–sodium ascor-
bate system.
Keywords 1,3-Dipolar cycloaddition; one pot; stereoselective synthesis; 1,2,3-triazole;
vinyl halide
1,2,3-Triazoles have found widespread applications in pharmaceuticals and agro-
chemicals.[1] The discovery[2] of Cu(I)-catalyzed 1,3-dipolar cycloaddition of azides
and terminal alkynes has further triggered the use of 1,2,3-triazoles in bioconjunga-
tion, drug discovery,[3] material science,[4] and combinatorial chemistry.[5] In
addition, a number of compounds containing 1,2,3-triazoles have shown a broad
spectrum of biological activities such as antibacterial,[6] herbicidal, fungicidal,[7]
antiallergic,[8] and anti-HIV activities.[9]
(E)-Vinyl halides are extremely useful synthetic intermediates in organic
synthesis. Their use as precursors of vinyl anions[10] and as coupling components in
a wide range of transition metal–catalyzed coupling reactions[11] has stimulated a great
deal of interest in their synthesis. There are many methods for the synthesis of (E)-vinyl
halides. Among them, the most efficient one is a Hunsdiecker-type reaction of cinnamic
acid derivatives and N-halosuccinimide (NXS) catalyzed by LiOAc.[12]
The multicomponent reaction (MCR), offering an efficient route to generate
complex molecular frameworks from simple and readily available substrates, is a
Received September 1, 2009.
Address correspondence to Chunxiang Kuang, Department of Chemistry, Tongji University,
Siping Road 1239, Shanghai 200092, China. E-mail: Kuangcx@tongji.edu.cn
1267

1268
W. ZHANG ET AL.
powerful tool in modern organic synthesis as well as in the field of combinatorial
chemistry and drug discovery.[13]
In this paper, we developed a facile method for the stereoselective synthesis of
phenyl-1,2,3-triazoles containing (E)-vinyl halide via a one-pot, three-component
=
reaction of 3-(4- or 2-azidophenyl)acrylic acid 1, NXS (X Cl, Br and I) 2, and ter-
minal alkyne 3 in MeCN-H2O (9:1 v=v) catalyzed by LiOAc=CuI–sodium ascorbate
system (Scheme 1).
In our one-pot, three-component procedure for the synthesis of (E)-1-(4-(2-
bromovinyl)phenyl)-1,2,3-triazoles 4, N-bromosuccinimide (NBS) was first chosen
as a model NXS substrate 2. Reaction of (E)-3-(4-azidophenyl)acrylic acid 1a with
NBS 2a and terminal alkyne 3a in MeCN-H2O (9:1 v=v) under a nitrogen atmos-
phere catalyzed by LiOAc=CuI–sodium ascorbate system at ambient temperature
for 8 h afforded 4a in a yield of94% (Table 1, entry 1). It is vital that LiOAc and
NBS be added to the reaction system before the addition of terminal alkynes,
CuI, and sodium ascorbate; otherwise, the yields of product 4 would decrease
dramatically.
The generality and scope of this method was thoroughly investigated under the
same conditions as those for 3a using a diverse range of terminal alkynes 3b–e. The
results are given in Table 1. The aliphatic terminal alkynes such as prop-2-yn-1-ol 3b
and hept-1-ne 3c furnished the corresponding triazoles 4b and 4c in a prospective
yield of 86% and 84%, respectively (entries 2 and 3). The aromatic terminal alkynes
such as ethynylbenzene 3d and 1-bromo-4-ethynylbenzene 3e afforded products 4d
and 4e in 87% and 84% yield (entries 4 and 5).
N-Iodosuccinimide (NIS) 2b and N-chlorosuccinimide (NCS) 2c were also
tested instead of NBS 2a to react with 1a and 3a. Under the same reaction conditions
as for 1a, almost no conversion was observed. In contrast, 4f and 4g were obtained in
satisfactory yields of 91% and 90% when the reaction temperature was increased to
80 ꢀC (Table 1, entries 6 and 7).
(E)-3-(2-Azidophenyl)acrylic acid 1b instead of 1a was next examined to react
with NBS 2a and terminal alkynes 3a and b at 80 ꢀC, and good yields of 4h and 4i
were realized. The results are also given in Table 1 (Table 1, entries 8 and 9).
The proposed pathways for the present halodecarboxylation and cycloaddition
reactions are shown in Scheme 2. Reaction of lithium carboxylate of 1 with NXS
gives the intermediate A, which is immediately converted to a zwitterion B. Zwitter-
ion B would then eliminate carbon dioxide to give the corresponding vinyl halides C.
[3 þ 2] Cycloaddition of C with Cu(I) acetylide F, which is generated by the reaction
of alkynes 3 and Cu(I) complex E, afforded the copper-containing intermediate D.
Proteolysis of the reactive intermediate D, upon release of the Cu (I) complex E
to complete the catalytic cycle, gives rise to the desired products 4.
Scheme 1. Synthesis of phenyl-1,2,3-triazoles containing (E)-vinyl halide 4 from 1, 2, and 3.

PHENYL-1,2,3-TRIAZOLES
1269
Table 1. Synthesis of phenyl-1,2,3-triazoles containing (E)-vinyl halide 4 from azide 1
Entry
1
1
2
3
Product 4a,b
Yield of 4c (%)
1a
2a
94
2
3
4
5
6
7
8
9
1a
1a
1a
1a
1a
1a
1b
1b
2a
2a
2a
2a
2b
2c
2a
2a
86
84
87
84
91
90
83
81
aReaction conditions: azide 1 (1 mmol), NXS 2 (1.05 mmol), LiOAc (0.2 mmol), MeCN-H2O (10 mL, 9:1
v=v), terminal alkynes 3 (1.05 mmol), sodium ascorbate (0.15 mmol), CuI (0.15 mmol); rt (for entries 1–5)
or 80 ꢀC (for entries 6–9); 8 h.
bE=Z: >99=1, determined by 1H NMR analysis.
cIsolated yields based on azides 1.

1270
W. ZHANG ET AL.
Scheme 2. Proposed pathways for the halodecarboxylation and cyclozddition course.
In summary, a series of phenyl-1,2,3-triazoles containing (E)-vinyl halide were
synthesized via a one-pot, three-component reaction of 3-(4- or 2-azidophenyl)-
=
acrylic acid, NXS (X Cl, Br and I), and terminal alkyne in 81–94% yields. The
synthetic applications of these compounds are in progress in our laboratory.
EXPERIMENTAL
Melting points were recorded using a Kruss Optronic GmbH KSPII
¨
melting-point meter and were uncorrected. Infrared (IR) spectra were performed
on a Nexus Fourier transform (FT)–IR spectrophotometer. 1H NMR and13C
NMR spectra were recorded using a Bruker AM-500 spectrometer in CDCl3 with
SiMe4 as an internal standard. Elemental analyses were performed with a
Perkin-Elmer 2400 CHNS elemental analyzer. Commercially obtained reagents were
used without further purification. All reactions were monitored by thin-layer chro-
matography (TLC) with Huanghai GF 254 silica-gel-coated plates. Column chroma-
tography was carried out using silica gel (300–400 mesh) at medium pressure.
Preparation of 3-(4-Azidophenyl) Acrylic Acid (1a) and
3-(2-Azidophenyl) Acrylic Acid (1b)
Zinc powder (3.900 g, 60 mmol) was added to 100 mL of stirred HOAc–H2O
(9:1 v=v) suspension of 3-(4- or 2-nitrophenyl)acrylic acid (5.790 g, 30 mmol), which
was prepared from 4- or 2-nitrobenzaldehyde according to a conventional synthetic
route.[14] The reaction system was stirred at ambient temperature for 0.5 h and
filtered. The filtrate was cooled to 0 ꢀC in an ice bath. A solution of sodium nitrite

PHENYL-1,2,3-TRIAZOLES
1271
(2.484 g, 36 mmol) in 20 mL of water was added dropwise to the reaction system. The
mixture was stirred at 0 ꢀC for 10 min. Sodium azide (2.340 g, 36 mmol) in 20 mL
water was added dropwise to the reaction system. After the reaction completed,
the solvent was evaporated. The combined organic layers were washed with brine
(100 ꢁ 2 mL) and cooled water (100 mL) and then dried over anhydrous Na2SO4.
Evaporation of the solvent gave a crude product, which was recrystallized from
EtOAc–hexane to yield 1a or 1b as a brown solid (90%): 1a mp 197.3–197.5 ꢀC
(lit.[15] 195–196 ꢀC); 1b mp 185.5–186.1 ꢀC (lit.[15] 186 ꢀC).
General Procedure for the Synthesis of
(E)-1-(4-(2-Bromovinyl)phenyl)-1,2,3-triazoles (4a–4e)
Compound 2a (1.05 mmol), alkynes 3 (1.05 mmol), sodium ascorbate
(0.15 mmol), and CuI (0.15 mmol) were added to a stirred MeCN-H2O (5 mL, 9:1
v=v) suspension of 3-(4-azidophenyl)acrylic acid 1a (1 mmol) and LiOAc (0.2 mmol).
The reaction mixture was stirred at ambient temperature under a nitrogen atmos-
phere for 8 h. The solvent was evaporated. EtOAc (30 mL) was added to the residue
and filtered. The filtrate was washed with brine (30 ꢁ 2 mL) and cooled water
(30 mL) and then dried over anhydrous Na2SO4. Evaporation of the solvent gave
the crude product, which was subjected to column chromatography (silica gel,
EtOAc=petroleum ether) to afford products 4a–4e.
Selected Data (4a–4e)
(E)-1-[4-(2-bromovinyl)phenyl-[1,2,3]triazole-4-carboxylic Acid Ethyl
Ester (4a). Light yellow solid; mp 179.2–179.6 ꢀC. IR (KBr): 3143, 2981, 1716,
1609, 1548, 1517, 1469 cmꢂ1. 1H NMR (500 MHz, CDCl3): d 1.37 (3H, t, J ¼ 7.0 Hz),
4.40 (2H, q, J ¼ 7.0 Hz), 6.84 (1H, d, J ¼ 14.0 Hz), 7.09 (1H, d, J ¼ 14.0 Hz), 7.42
(2H, d, J ¼ 8.5 Hz), 7.67 (2H, d, J ¼ 8.5 Hz), 8.44 (1H, s). 13C NMR (125 MHz,
CDCl3): d 14.31, 61.55, 108.89, 121.06, 125.21, 127.46, 135.56, 135.79, 137.15,
140.97, 160.53. Anal. calcd. for C13H12BrN3O2: C, 48.47; H, 3.75; N, 13.04. Found:
C, 48.44; H, 3.73; N, 13.02.
(E)-(1-(4-(2-Bromovinyl)phenyl)-1,2,3-triazol-4-yl)methanol (4b). White
solid; mp 166.8–167.2 ꢀC. IR (KBr): 1618, 1518, 1478, 1446 cmꢂ1 1H NMR
.
(300 MHz, DMSO-d6): d 4.71 (2H, s), 7.11 (1H, d, J ¼ 14.0 Hz), 7.18 (1H, d,
J ¼ 14.0 Hz), 7.56 (2H, d, J ¼ 9.0 Hz), 7.82 (2H, d, J ¼ 9.0 Hz), 8.40 (1H, s). 13C
NMR (125 MHz, CDCl3): d 55.62, 108.69, 120.30, 120.44, 127.55, 135.78, 135.85,
136.53, 149.49. Anal. calcd. for C11H10BrN3O: C, 47.16; H, 3.60; N, 15.00. Found:
C, 47.11; H, 3.57; N, 15.01.
(E)-1-(4-(2-Bromovinyl)phenyl)-4-pentyl-1,2,3-triazole (4c). White solid;
1
mp 99.6–100.1 ꢀC. IR (KBr): 2930, 2854, 1609, 1549, 1517, 1462 cmꢂ1. H NMR
(300 MHz, DMSO-d6): d 0.91 (1H, t, J ¼ 7.0 Hz), 1.24–1.26 (2H, m), 1.23–1.40
(4H, m), 1.72–1.77 (2H, m), 2.79 (2H, t, J ¼ 8.0 Hz), 6.86 (1H, d, J ¼ 14.0 Hz),
7.17 (1H, d, J ¼ 14.0 Hz), 7.43 (2H, d, J ¼ 8.5 Hz), 7.70 (2H, d, J ¼ 8.5 Hz), 7.71
(1H, s). 13C NMR (125 MHz, CDCl3): d 13.95, 22.39, 25.60, 29.03, 31.04, 107.96,

1272
W. ZHANG ET AL.
118.47, 120.52, 127.24, 135.81, 135.98, 136.76, 149.34. Anal. calcd. for C15H18BrN3:
C, 56.26; H, 5.67; N, 13.12. Found: C, 56.22; H, 5.65; N, 13.09.
(E)-1-[4-(2-Bromovinyl)phenyl]-4-phenyl-[1,2,3]triazole
solid; mp 215.4–216.0 ꢀC. IR (KBr): 1609, 1517, 1478, 1447 cmꢂ1
(4d). Yellow
1H NMR
.
(500 MHz, CDCl3): d 6.90 (1H, d, J ¼ 14.0 Hz), 7.16 (1H, d, J ¼ 14.0 Hz),
7.37–7.49 (5H, m), 7.78 (2H, d, J ¼ 8.5 Hz), 7.91 (2H, d, J ¼ 8.5 Hz), 8.19 (1H, s).
13C NMR (125 MHz, CDCl3): d 108.28, 117.25, 120.73, 125.90, 127.38, 128.53,
128.95, 130.89, 135.79, 136.41, 136.57, 146.62. Anal. calcd. for C16H12BrN3: C,
58.91; H, 3.71; N, 12.88. Found: C, 58.89; H, 3.70; N, 12.85.
(E)-4-(4-Bromophenyl)-1-[4-(2-bromovinyl)-phenyl-[1,2,3]triazole (4e).
Yellow solid; mp 206.3–206.9 ꢀC. IR (KBr): 1606, 1518, 1476, 1450 cmꢂ1 1H
.
NMR (300 MHz, DMSO-d6): d 7.32 (1H, d, J ¼ 14.0 Hz), 7.46 (1H, d, J ¼ 14.0 Hz),
7.72 (2H, d, J ¼ 8.1 Hz), 7.75 (2H, d, J ¼ 8.1 Hz), 7.90 (2H, d, J ¼ 8.5 Hz), 7.94 (2H,
d, J ¼ 8.5 Hz), 9.38 (1H, s). 13C NMR (125 MHz, CDCl3): d 109.41, 120.33, 121.63,
127.53, 127.85, 128.88, 129.81, 131.49, 132.09, 136.18, 136.37, 146.75. Anal. calcd.
for C16H11Br2N3: C, 47.44; H, 2.74; N, 10.37. Found: C, 47.40; H, 2.72; N, 10.33.
General Procedure for the Synthesis of (E)-1-[4-(2-Halovinyl)phenyl]-
[1,2,3]triazole-4-carboxylic Acid Ethyl Ester (4f–4g)
Compound 2b/2c (1.05 mmol), alkynes 3a (1.05 mmol), sodium ascorbate
(0.15 mmol), and CuI (0.15 mmol) were added to a stirred MeCN-H2O (5 mL, 9:1
v=v) suspension of 3-(4-azidophenyl)acrylic acid 1a (1 mmol) and LiOAc (0.2 mmol).
The reaction mixture was stirred at 80 ꢀC under a nitrogen atmosphere for 8 h. The
solvent was evaporated. EtOAc (30 mL) and filtered was added to the residue. The
filtrate was washed with brine (30 ꢁ 2 mL) and cooled water (30 mL) and then dried
over anhydrous Na2SO4. Evaporation of the solvent gave the crude product, which
was subjected to column chromatography (silica gel, EtOAc=petroleum ether) to
afford products 4f and 4g.
(E)-1-[4-(2-Iodovinyl)phenyl]-[1,2,3]triazole-4-carboxylic acid ethyl ester
(4f). Light yellow solid; mp 187.1–187.4 ꢀC. IR (KBr): 3142, 2980, 1716, 1606, 1544,
1511, 1472 cmꢂ1
.
1H NMR (500 MHz, CDCl3): d 1.44 (3H, t, J ¼ 7.0 Hz),
4.47 (2H, q, J ¼ 7.0 Hz), 7.02 (1H, d, J ¼ 15.0 Hz), 7.47 (2H, d, J ¼ 8.5 Hz), 7.48
(1H, d, J ¼ 15.0 Hz), 7.74 (2H, d, J ¼ 8.5 Hz), 8.52 (1H, s). 13C NMR (125 MHz,
CDCl3): d 14.28, 61.50, 79.23, 120.91, 125.19, 127.31, 135.77, 138.72, 140.91,
143.22, 160.48. Anal. calcd. for C13H12IN3O2: C, 42.30; H, 3.28; N, 11.38. Found:
C, 42.25; H, 3.26; N, 11.36.
(E)-1-[4-(2-Chlorovinyl)phenyl]-[1,2,3]triazole-4-carboxylic acid ethyl
ester (4g). Light yellow solid; mp 161.3–162.7 ꢀC. IR (KBr): 3137, 2981, 1716,
1604, 1544, 1514, 1468 cmꢂ1. 1H NMR (500 MHz, CDCl3): d 1.44 (3H, t, J ¼ 7.0 Hz),
4.47 (2H, q, J ¼ 7.0 Hz), 6.77 (1H, d, J ¼ 14.0 Hz), 6.88 (1H, d, J ¼ 14.0 Hz), 7.48
(2H, d, J ¼ 8.5 Hz), 7.74 (2H, d, J ¼ 8.5 Hz), 8.51 (1H, s). 13C NMR (125 MHz,
CDCl3): d 14.30, 61.52, 120.96, 121.04, 125.21, 127.46, 131.69, 135.72, 136.13,
140.94, 160.52. Anal. calcd. for C13H12ClN3O2: C, 56.22; H, 4.36; N, 15.13. Found:
C, 56.20; H, 4.35; N, 15.10.

PHENYL-1,2,3-TRIAZOLES
1273
Genreal Procedure for the Synthesis of
(E)-1-(2-(2-Bromovinyl)phenyl)-1,2,3-triazoles (4h–4i)
To a stirred MeCN-H2O (5 mL, 9:1 v=v) suspension of 3-(2-azidophenyl)acrylic
acid 1b (1 mmol) and LiOAc (0.2 mmol) was added 2a (1.05 mmol), alkynes 3a/3b
(1.05 mmol), sodium ascorbate (0.15 mmol) and CuI (0.15 mmol). The reaction mix-
ture was stirred at 80 ꢀC under nitrogen atmosphere for 8 h. The solvent was evapo-
rated. EtOAc (30 mL) was added to the residue and filtered. The filtrate was washed
with brine (30 ꢁ 2 mL) and cooled water (30 mL) and then dried over anhydrous
Na2SO4. Evaporation of the solvent gave the crude product, which was subjected
to column chromatography (silica gel, EtOAc=petroleum ether) to afford products
4h and 4i.
Selected Data (4h and 4i)
(E)-Ethyl 1-(2-(2-bromovinyl)phenyl)-1,2,3-triazole-4-carboxylate (4h).
Brown oil; IR (KBr): 3143, 2983, 1720, 1601, 1546, 1515, 1468 cmꢂ1.1H NMR
(500 MHz, CDCl3): d 1.45 (3H, t, J ¼ 7.0 Hz), 4.48 (2H, q, J ¼ 7.0 Hz), 6.84 (2H,
s), 7.41 (1H, d, J ¼ 7.5 Hz), 7.50 (1H, t, J ¼ 7.5 Hz), 7.55 (1H, t, J ¼ 7.5 Hz), 7.61
(1H, d, J ¼ 7.5 Hz), 8.31 (1H, s). 13C NMR (125 MHz, CDCl3): d 14.24, 61.50,
111.30, 126.39, 127.16, 129.20, 129.33, 130.75, 130.96, 131.83, 133.37, 140.45,
160.44. Anal. calcd. for C13H12BrN3O2: C, 48.47; H, 3.75; N, 13.04. Found: C,
48.42; H, 3.74; N, 13.03.
(E)-(1-(2-(2-Bromovinyl)phenyl)-1,2,3-triazol-4-yl)methanol (4i). Brown
oil; IR (KBr): 1615, 1517, 1483, 1450 cmꢂ1.1H NMR (500 MHz, CDCl3): d 4.85
(2H, s), 6.72 (1H, d, J ¼ 14.0 Hz), 6.81 (1H, d , J ¼ 14.0 Hz), 7.31–7.50 (4H, m),
7.71 (1H, s).13C NMR (125 MHz, CDCl3): d 56.16, 110.57, 123.99, 126.42, 127.00,
129.09, 130.15, 131.47, 131.64, 134.14, 147.97. Anal. calcd. for C11H10BrN3O: C,
47.16; H, 3.60; N, 15.00. Found: C, 47.12; H, 3.58; N, 15.02.
ACKNOWLEDGMENTS
This work was supported by Natural Science Foundation of China (No.
30873153), the Key Projects of Shanghai in Biomedicine (No. 08431902700), and
the Scientific Research Foundation of State Education Ministry for the Returned
Overseas Chinese Scholars. We thank the Center for Instrumental Analysis, Tongji
University, China.
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