Preparation of 4,5 disubstituted-2H-1,2,3-triazoles from (Z)-2,3-diaryl substituted acrylonitriles

Article abstract of DOI:10.1016/j.tetlet.2014.05.045

2H-1,2,3-Triazoles (2) were synthesized by [3+2] cycloaddition of (Z)-2,3-diaryl substituted acrylonitriles (1) with sodium azide and ammonium chloride in DMF/water. This method represents a facile and efficient reaction procedure for the synthesis of 4,5

Full text of DOI:10.1016/j.tetlet.2014.05.045

Tetrahedron Letters xxx (2014) xxx–xxx
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Tetrahedron Letters
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Preparation of 4,5 disubstituted-2H-1,2,3-triazoles from (Z)-2,
3-diaryl substituted acrylonitriles
⇑
Nikhil Reddy Madadi, Narsimha Reddy Penthala, Lin Song, Howard P. Hendrickson, Peter A. Crooks
Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
2H-1,2,3-Triazoles (2) were synthesized by [3+2] cycloaddition of (Z)-2,3-diaryl substituted acrylonitriles
(1) with sodium azide and ammonium chloride in DMF/water. This method represents a facile and
efficient reaction procedure for the synthesis of 4,5-diaryl-2H-1,2,3-triazoles in modest to good yields.
Ó 2014 Published by Elsevier Ltd.
Received 18 April 2014
Revised 6 May 2014
Accepted 7 May 2014
Available online xxxx
Keywords:
Sodium azide
Triazole synthesis
Acrylonitrile
Huisgen cycloaddition
1,2,3-Triazoles are an important class of heterocycles which
have a wide range of applications in agricultural,1 industrial,2
and pharmaceutical industries.3 This ring system is present in a
number of drugs with biological properties, such as anti-cancer,4
anti-fungal,5 anti-viral,6 anti-consulvant,7 and anti-HIV agents.8
Industrial applications include dyes,9 photostabilizers, photo-
graphic materials,9 and anti-corrosives.2 Our laboratory is cur-
rently focusing on the development of anticancer agents
structurally related to combretastatin A4 (CA4) and trans-cyano-
combretastatin A4 (cyano-CA4) (Fig. 1e).10,11 CA4 and cyano-CA4
suffer from chemical instability in solution, due to cis-trans isomer-
ism.12 We are currently involved in identifying chemically stable
cis-cyano-CA4 analogs. One approach we are exploring is the
replacement of the acrylonitrile moiety in these active anticancer
agents with a triazole moiety to afford geometrically stable triazole
analogs of cyano-CA4 (Figs. 1 and 2e).
The conventional route for preparing 1,2,3-triazoles is via Huis-
gen 1,3-dipolar cycloaddition of azides with alkynes. However, the
disadvantages of this synthetic approach are poor regioselectivity
and long reaction times. A variety of triazoles can also be synthe-
sized by the click chemistry methodologies developed by Sharpless
et al. between azides and alkynes, to yield 1,5-disubstituted 1,2,3-
triazoles.13 However, inorganic azides (NaN3) are not good sub-
strates for this reaction, and these methods cannot be applied to
the synthesis of internal alkynes. Recently, Majireck et al.14 and
Tsai et al.15 have reported the synthesis of 4,5-disubstituted 2H-
1,2,3-triazoles by cycloaddition of internal alkynes with alkyl
azides or metal azides, but the disadvantage is the low yielding
synthesis of the alkyne reactant, especially when an electron
donating group is attached to the alkyne terminus.
A less explored route for the synthesis of 2H-1,2,3-triazoles is
the cycloaddition of azides with alkenes bearing a good leaving
group. Zard et al.16 reported the synthesis of 4,5-disubstituted-
1H-1,2,3-triazoles from nitroalkenes, but did not report any
formation of 4,5-disubstituted 2H-1,2,3-triazoles via this approach.
Sengupta et al.17 have reported the synthesis of 4,5-disubstituted
2H-1,2,3-triazoles from nitroalkenes; however, the presence of a
vinyl group was necessary for the reaction to proceed.
Herein, we report a novel synthetic procedure for the synthesis
of 4,5-disubstituted 2H-1,2,3-triazoles from (Z)-2,3-diaryl-substi-
tuted acrylonitriles by treatment with NaN3/NH4Cl in aqueous
DMF (Scheme 1). The advantage of this methodological approach
is that cyano-CA4 analogs bearing a broad range of aromatic func-
tionalities can be easily converted to their corresponding 2H-1,2,3-
triazole derivatives in one step.
Utilizing (Z)-3-(3,4-dichlorophenyl)-2-(3,4-dimethoxyphenyl)
acrylonitrile as a model reactant, it was observed that using a com-
bination of 10:1 volumes of DMF/H2O as solvent significantly
improved the yield of 4-(3,4-dichlorophenyl)-5-(3,4-dimethoxy-
phenyl)-2H-1,2,3-triazole compared to using DMF alone
(Scheme 2). The reaction did not proceed in anhydrous THF. The
rate of the reaction was found to be dependent on the molar
amount of NaN3/NH4Cl used (Table 1). The optimum conditions
for this reaction are: heating the reactant under reflux with 3
molar equivalents of NH4Cl and 3 molar equivalents of NaN3 in
⇑
Corresponding author. Tel.: +1 501 686 6495; fax: +1 501 686 6057.
E-mail address: pacrooks@uams.edu (P.A. Crooks).
http://dx.doi.org/10.1016/j.tetlet.2014.05.045
0040-4039/Ó 2014 Published by Elsevier Ltd.
Please cite this article in press as: Madadi, N. R.; et al. Tetrahedron Lett. (2014), http://dx.doi.org/10.1016/j.tetlet.2014.05.045

2
N. R. Madadi et al. / Tetrahedron Letters xxx (2014) xxx–xxx
Figure 1. Structures of combretastatin A-4 (CA4), trans-cyano CA4 (1e) and the 2H-1,2,3-triazole analog of CA4 (2e).
Figure 2. X-ray Crystal structures of compounds 2b and 3a.
Table 1
Optimization of the reaction conditions for the synthesis of 4-(3,4-dichloro)-5-(3,4-
dimethoxyphenyl)-2H-1,2,3-triazole
Entry
Solvent
Reaction conditions
Yielda (%)
1
2
3
4
5
DMFc
Reflux, 5 h, 3 equiv NH4Cl/3 equiv NaN3
Reflux, 5 h, 3 equiv NH4Cl/3 equiv NaN3
Reflux, 5 h, 1 equiv NH4Cl/1 equiv NaN3
Reflux, 5 h, 3 equiv NaN3
24
81
45
32
0
DMF/H2Ob
DMF/H2Ob
DMF/H2Ob
THFc
Reflux, 5 h, 3 equiv NH4Cl/3 equiv NaN3
a
b
c
Isolated yields.
10:1 volumes of DMF/H2O.
Anhydrous.
Scheme 1. Synthesis of 4,5-disubstituted 2H-1,2,3-triazoles from (Z)-2,3-
diarylacrylonitriles.
N
N
N
N
OCH3
N
C
N3
N
NaN3, NH4Cl
OCH3
C
OCH3
OCH3
OCH3
OCH3
Cl
N
DMF/ H2O
reflux, 5 h
C
N
Cl
Cl
Cl
H
N
X
O
Cl
Y
Cl
1a
H
H
-HCN
H
O
CH3
N
H
N
H
H
N
N
N
N
N
N
N
K2CO3/ Acetone
MeI
OCH3
H
Cl
OCH3
Cl
Cl
OCH3
Cl
OCH3
OCH3
OH2
Cl
Cl
OCH3
3a
2a
Z
Scheme 2. Proposed mechanism and optimization of the reaction conditions for the synthesis of 4-(3,4-dichloro)-5-(3,4-dimethoxyphenyl)-2H-1,2,3-triazole and synthesis
of its methylated product.
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N. R. Madadi et al. / Tetrahedron Letters xxx (2014) xxx–xxx
3
Table 2
Synthesis of 4,5-disubstituted-2H-1,2,3-triazoles from their corresponding (Z)-2,3-diaryl substituted acrylonitriles with reaction times and isolated yields
Entry
Substrate
Time (h)
Triazole
Yield (%)
OCH3
OCH3
H
N
N
N
CN
Cl
Cl
OCH3
OCH3
1
5
81
Cl
Cl
1a
2a
H
N
OCH3
N
N
OCH
3
H3CO
H3CO
H
3
CO
OCH3
OCH3
OCH3
2
CN
12
65
H3CO
OCH
3
OCH3
OCH3
1b
H3CO
OCH3
2b
H
OCH3
N
N
N
OCH3
OCH3
CN
3
5
69
N
N
H3CO
1c
2c
H
N
N
OCH3
N
OCH3
N
N
OCH3
OCH3
OCH
3
4
5
74
CN
1d
H3CO
2d
OCH3
H
N
OCH
3
N
N
H3CO
H3CO
OCH3
5
6
12
12
59
21
CN
OCH3
H3CO
OCH
3
OH
OH
OH
NC
2e
1e
H
N
N
N
H3CO
H3CO
H3CO
H3CO
OH
OCH3
OCH3
OCH
3
OCH
N
3
1f
2f
S
H
N
N
CN
Cl
7
8
5
5
64
78
Cl
F
S
1g
F
2g
H
Cl
N
Cl
N
N
N
CN
Cl
N
Cl
1h
2h
(continued on next page)
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N. R. Madadi et al. / Tetrahedron Letters xxx (2014) xxx–xxx
Table 2 (continued)
Entry
Substrate
Time (h)
Triazole
Yield (%)
OCH3
H
N
OCH3
OCH3
N
N
O
O
OCH3
OCH3
O
O
9
12
60
CN
OCH3
1i
2i
NO 2
H
N
N
N
H3CO
H3CO
H3CO
H3CO
CN
10
11
12
3
80
66
78
OCH3
NO2
OCH3
1j
2j
H
N
N
N
O
O
O
O
CN
12
1k
2k
Br
Br
H
N
H3CO
N
N
OCH
3
Br
NC
5
1l
Br
2l
OCH3
H
N
OCH
3
N
N
OCH3
13
5
OCH3
OCH3
87
CN
S
S
1m
H3CO
2m
H3CO
H3CO
H
N
N
N
H3CO
OCH3
14
15
12
12
0
0
OCH3
1n
OCH3
2n
H
N
N
N
H3CO
H3CO
OCH3
OCH3
OCH3
1o
OCH3
2o
10:1 volumes of DMF/H2O. X-ray crystallographic studies on com-
pounds 2b and 3a confirmed the presence of a 2H-1,2,3-triazole
ring system and the position of N-methylation (Fig. 2).
5-trimethoxyphenyl)-acrylonitrile, the corresponding (E)-isomer
of 1e, was used as a starting material for the synthesis of com-
pound 2e. The yield of the resulting 2H-1,2,3-triazole 2e was 21%
compared to 59% when the (Z)-isomer was utilized under similar
reaction conditions (Table 2, entry 5), indicating that (E)-2,3-diary-
lacrylonitriles are less useful than their (Z)-counterparts in the syn-
thesis of 2H-1,2,3-triazoles of structure 2.
A variety of cyano-CA4 analogs were subjected to treatment
with NaN3/DMF/H2O under the above optimized reaction condi-
tions, and their corresponding 4,5-disubstituted 2H-1,2,3-triazoles
(2a–2m) were obtained in modest to good yields (Table 2). No sig-
nificant side products are formed in the reactions shown in Table 2.
It should be noted that when either E- or Z-diarylstilbenes that lack
the cyano group (Table 2, entries 14 and 15, 1n and 1o) are utilized
Previous reports have not elaborated on the mechanism of for-
mation of the 2H-1,2,3-triazole ring in cyanostilbenes of structure
1.14,15 Triazole ring formation initially involves Michael addition of
azide ion at the unsubstituted sp2 olefinic carbon to afford X fol-
lowed by cyclization to Y (Scheme 2). Acid-catalyzed elimination
of the cyano moiety then affords 2a. It is evident from the optimi-
zation studies that NH4Cl and water are essential components
in the reaction (Scheme 2). All the reactions were conducted
with (Z)-2,3-diarylacrylonitriles. However, we did examine the
relative usefulness of utilizing (E)-2,3-diarylacrylonitriles in
these reactions. Thus, (E)-3-(3-hydroxy-4-methoxyphenyl)-2-(3,4,
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N. R. Madadi et al. / Tetrahedron Letters xxx (2014) xxx–xxx
5
disappeared, cold water was added and the mixture stirred over 10–15 min,
during which the final product precipitated out. In the absence of a precipitate,
the product was extracted into ethyl acetate, the organic extract washed with
copious amounts of water, and the resulting organic liquor evaporated to
dryness on a rotavaporator. The residue obtained was purified by flash column
chromatography to afford the corresponding triazole (2). Yields of the
synthesized triazoles are presented in Table 2.
in the above reaction no detectable amounts of the corresponding
2H-1,2,3-triazole were observed.
In summary, we have developed a facile procedure for the syn-
thesis of 4,5-diaryl-2H-1,2,3-triazoles bearing a broad range of aryl
moieties from their corresponding (Z)-2,3-diarylacrylonitriles. The
method does not require an inert atmosphere, is economical, can
be applied to a wide range of aryl groups and aromatic ring substi-
tutions, and is a viable alternative to the Huisgen cycloaddition
reaction of alkynes with azides.
Spectral
data
for
selected
products:
5-(3,4-dichlorophenyl)-4-(3,4-
dimethoxyphenyl)-2H-1,2,3-triazole (2a): Yellow solid; 1H NMR (400 MHz,
CDCl3-d): d 3.82 (s, 3H, –OCH3), d 3.93 (s, 3H, –OCH3), 6.87–6.89 (d, J = 8 Hz,
1H, ArH), 7.05–7.07 (d, J = 12 Hz, 2H, ArH),), 7.42 (s, 2H, ArH), 7.78 (s, 1H, ArH).
13C NMR (100 MHz, DMSO-d6): 55.87, 55.96, 111.05, 127.31, 129.80, 129.89,
130.54, 132.60, 132.86, 149.15, 149.754. HRMS (ESI): m/z calcd for
C
16H14Cl2N3O2 [MÀH] 350.0463; found 350.0480.
Acknowledgments
4,5-Bis(3,4,5-trimethoxyphenyl)-2H-1,2,3-triazole (2b): Yellow solid; 1H NMR
(400 MHz, CDCl3-d): d 3.77 (s, 12H, –OCH3), 3.88 (s, 6H, –OCH2), 6.85 (s, 4H,
ArH). 13C NMR (100 MHz, DMSO-d6): 56.09, 60.97, 105.58, 125.59, 138.28,
The authors thank the NIH/National Cancer Institute
(CA140409) United States, and the Arkansas Research Alliance for
financial support, and acknowledge Grants UL1TR000039 and
KL2TR000063 for the UAMS Translational Research Institute
support of the Bioanalytical Core.
153.27. HRMS (ESI): m/z calcd for
402.1659.
C
20H24N3O6 [MÀH] 402.1665; found
4-(4-(3,4,5-Trimethoxyphenyl)-2H-1,2,3-triazol-5-yl)quinoline (2c): Yellow solid;
1H NMR (400 MHz, CDCl3-d): d 3.47 (s, 6H, –OCH3), 3.81 (s, 3H, –OCH3), 6.65 (s,
2H, ArH), 7.50–7.52 (t, J = 8 Hz, 1H, ArH), 7.54–7.56(d, J = 4.4 Hz, 1H, ArH),
7.76–7.77 (t, J = 1.6 Hz, 1H, ArH), 7.82–7.84 (d, J = 8 Hz, 1H, ArH), 8.27–8.29 (d,
J = 8.8 Hz, 1H, ArH), 9.03–9.04 (d, J = 4.4 Hz, 1H, ArH). 13C NMR (100 MHz,
DMSO-d6):55.70, 55.79, 0.85, 60.95, 104.47, 104.55, 122.68, 122.76, 124.69,
125.95, 126.66, 127.52, 129.42, 130.21, 138.21, 138.45, 148.15, 149.63, 149.69,
References and notes
153.24. HRMS (ESI): m/z calcd for
363.1445.
5-(Benzo[b]thiophen-3-yl)-4-(3,4,5-trimethoxyphenyl)-2H-1,2,3-triazole
C
20H19N4O3 [MÀH] 363.1457; found
1. Fan, W. In Comprehensive Heterocyclic Chemistry II; Katritzky, A. R., Rees, C. W.,
Scriven, E. F. V., Eds.; ; Pergamon: Oxford, U.K., 1996; Vol. 4, pp 1–126.
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3. Cai, D.; Journet, M.; Larsen, R. D. U.S. Patent US 6051707, 2000.
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7. Palhagen, S.; Canger, R.; Henriksen, O.; van Parys, J. A.; Riviere, M. E.; Karolchyk,
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(2m):
Yellow solid; 1H NMR (400 MHz, CDCl3-d): d 3.57 (s, 6H, –OCH3), d 3.84 (s,
3H, –OCH3), 6.80 (s, 2H, ArH), 7.34–7.39 (m, J = 20 Hz, 1H, ArH), 7.61 (s, 1H,
ArH), 7.75–7.77 (d, J = 7.6 Hz, 1H, ArH), 7.90–7.92(d, J = 8 Hz, 1H, ArH). 13C
NMR (100 MHz, DMSO-d6):55.72, 55.85, 60.85, 60.99, 104.57, 104.64, 122.61,
122.73, 123.65, 123.77, 124.66, 124.74, 124.83, 124.94, 125.28, 127.21, 127.37,
137.56, 138.12, 139.89, 153.24. HRMS (ESI): m/z calcd for C19H18N3O3S [MÀH]
368.1069; found 368.1075.
5-(Benzo[d][1,3]dioxol-5-yl)-4-phenyl-2H-1,2,3-triazole (2i): Yellow solid; 1H
NMR (400 MHz, CDCl3-d): d 6.00 (s, 2H, –CH2), 6.80–6.82 (d, J = 8.8 Hz, 1H,
ArH), 7.03–7.05 (d, J = 6.8 Hz, 2H, ArH), 7.38–7.40 (t, J = 5.2 Hz, 3H, ArH), 7.56–
7.58 (m, J = 9.6 Hz, 1H, ArH). 13C NMR (100 MHz, DMSO-d6): 101.25, 108.58,
108.70, 122.23, 128.24, 128.70, 147.85. HRMS (ESI): m/z calcd for C15H12N3O2
[MÀH] 266.0930; found 266.0918.
10. Pettit, G. R.; Singh, S. B.; Boyd, M. R.; Hamel, E.; Pettit, R. K.; Schmidt, J. M.;
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Zisterer, D. Oncol. Rep. 2013, 29, 2451–2458.
4-(3,4-Dichlorophenyl)-5-(3,4-dimethoxyphenyl)-2-methyl-2H-1,2,3-triazole
(3a): A mixture of 5-(3,4-dichlorophenyl)-4-(3,4-dimethoxyphenyl)-2H-1,2,3-
triazole (2a) (1 mmol), K2CO3 (10 mmol) and MeI (2 mmol) in 10 volumes of
acetone was refluxed for 5 h. 2M aqueous HCl was then added to quench the
reaction and the resulting mixture was evaporated to dryness on
a
rotavaporator. The resulting residue was dissolved in ethyl acetate, filtered,
and the filtrate submitted to ethyl acetate/hexane flash column
chromatography to yield 4-(3,4-dichlorophenyl)-5-(3,4-dimethoxyphenyl)-2-
13. Krasinki, A.; Fokin, V. V.; Sharpless, K. B. Org. Lett. 2004, 6, 1237–1240.
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1494
methyl-2H-1,2,3-triazole (3a) as
a
pale yellow solid; 85% yield. 1H NMR
(400 MHz, CDCl3-d): d 3.83 (s, 3H, –OCH3), 3.92 (s, 3H, –OCH3), 4.25 (s, 3H, –
CH3), 6.86–6.88 (d, J = 8 Hz, 1H, ArH), 7.05–7.07 (dd, J = 15.2 Hz, 2H, ArH),),
7.42–7.26 (dd, J = 16.8 Hz, 2H, ArH), 7.74–7.74 (d, J = 1.6 Hz, 1H, ArH). 13C NMR
(100 MHz, CDCl3-d): 41.98, 56.08, 111.40, 121.07, 123.09, 127.45, 129.97,
130.59, 131.376, 132.41, 132.91, 141.99, 144.87, 149.25, 149.63.
General experimental procedure: A typical experimental procedure entailed
refluxing a mixture of the (Z)-2,3-diarylacrylonitrile (1), NaN3, and NH4Cl in a
mole ratio of 1:3:3 in 10:1 volumes of DMF/H2O for 5–12 h. The reaction was
monitored by TLC and GC. When the starting material had completely
Please cite this article in press as: Madadi, N. R.; et al. Tetrahedron Lett. (2014), http://dx.doi.org/10.1016/j.tetlet.2014.05.045