A Green and Facile Synthesis of Biopertinent Pyrazole-Decorated Nitriles and Acrylates under Catalyst-Free Conditions

Article abstract of DOI:10.1055/s-0034-1380742

A green and efficient methodology has been developed for the construction of 2-[(1,3-diaryl-4-pyrazolyl)methylene]malononitriles, potent antioxidant molecules, in good to excellent yields in five minutes from 1,3-diarylpyrazole-4-carbaldehydes and malonon

Full text of DOI:10.1055/s-0034-1380742

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© Georg Thieme Verlag Stuttgart · New York
2015, 26, A–E
letter
A
L. N. Jayalakshmi et al.
Letter
Synlett
A Green and Facile Synthesis of Biopertinent Pyrazole-Decorated
Nitriles and Acrylates under Catalyst-Free Conditions
Lakshmi Narayanan Jayalakshmi
Kesavan Stalindurai
Ayyanar Karuppasamy
Ramar Sivaramakarthikeyan
R1
R1
Vellasamy Devadoss
PEG-400–H2O (3:1)
ambient temp.
Chennan Ramalingan*
N
N
H
H
Centre for Nanotechnology/Department of Chemistry,
Kalasalingam University, Krishnankoil – 626 126, Tamilnadu,
India
N
N
R2
R2
O
N
ramalinganc@gmail.com
N
R1, R2 = H, alkyl, alkoxy, halogens
Received: 17.03.2015
Accepted after revision: 14.04.2015
Published online: 21.05.2015
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DOI: 10.1055/s-0034-1380742; Art ID: st-2015-d0188-l
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NC
NC
NC
Abstract A green and efficient methodology has been developed for
the construction of 2-[(1,3-diaryl-4-pyrazolyl)methylene]malononi-
triles, potent antioxidant molecules, in good to excellent yields in five
minutes from 1,3-diarylpyrazole-4-carbaldehydes and malononitrile us-
ing PEG-400 and water at ambient temperature under catalyst-free
conditions. The PEG-400 could be reused without appreciable loss in
the yield. The methodology has been extended to the synthesis of a di-
verse range of homo/heteroaryl-based nitriles and acrylates, reflecting
its versatility.
N
N
NC
N
N
1a
1b
Figure 1 Pyrazole-based nitriles with antioxidant activity
Key words pyrazoles, green chemistry, condensation
metal-based/encapsulated nanoparticles, ionic liquids, in-
organic/organic bases, metal organic frameworks, ammoni-
um salts, and mesoporous materials as catalysts.4–6 We
herein report a green and simple process for the construc-
tion of a diverse range of homo-/heteroaryl-based nitriles
and acrylates.
Reaction between 3-(4-bromophenyl)-1-phenylpyra-
zolecarbaldehyde and malononitrile was chosen as a model
one in this study (Scheme 1,Table 1).
Pyrazole-based chemical entities are one of the most
important classes of nitrogen heterocycle possessing a di-
verse range of biological activities.1 In continuation of our
research on the synthesis of heterocycles and methodology
development,2 we initially synthesized 2-{[3-(4-bromophe-
nyl)-1-phenyl-1H-pyrazol-4-yl]methylene}malononitrile
(1a) and 2-{[3-(4-fluorophenyl)-1-phenyl-1H-pyrazol-4-
yl]methylene}malononitrile (1b) from their corresponding
aldehyde precursors and malononitrile using sodium
ethoxide and ethanol with a view to evaluate their antioxi-
dant activities (Figure 1). Since 1a and 1b showed good an-
tioxidant properties in their preliminary screening, we de-
cided to synthesize an array of 2-[(1,3-diaryl-4-pyra-
zolyl)methylene]malononitriles for further exploration of
antioxidant and anticancer activities.
R1
R1
H
H
N
N
N
O
aq PEG-400
N
N
+
ambient temp
N
N
N
Such an approach involving condensation between al-
dehydes and active methylene compounds, first reported in
1894,3 can be effected using either a base or an acid. Vari-
ous synthetic protocols include exploitation of zeolites,
1
R2
R2
Scheme 1 Synthesis of 2-[(1,3-diaryl-4-pyrazolyl)methylene]malono-
nitriles 1
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, A–E

B
L. N. Jayalakshmi et al.
Letter
Synlett
Table 1 Optimization of the Model Reaction
to the use of PEG-400 alone, and the reaction was also com-
plete within two minutes (Table 1). Further increase in the
proportion of water (PEG-400/H2O ratio to 2:1) resulted in
almost no appreciable change in the yield. Thus, stirring
equimolar amounts of 3-(4-bromophenyl)-1-phenylpyra-
zolecarbaldehyde and malononitrile in aqueous PEG-400
(3:1 ratio) at ambient temperature was found to be the op-
timal conditions for the efficient synthesis of 1a.9 Luo et
al.,10 Ye et al.,11 and Siddiqui et al.12 reported the reaction of
commercially available simple aldehydes with malononi-
trile to produce their corresponding olefins using PEG, how-
ever, modification of PEG (i.e., tertiary amine functionalized
ionic liquid, diethylamine-functionalized PEG, and sulfuric
acid modified PEG, respectively) was required prior to use.
The effect of variation in the substrate structure was
then investigated. Although the model reaction was com-
plete within a couple of minutes, all the reactions were car-
ried out for five minutes as some unreacted starting alde-
hyde was observed in a few cases after two minutes. Akin to
the model aldehyde, all the other pyrazole-based carbalde-
hydes also produced the corresponding (pyrazolylmethy-
lene)malononitriles 1b–j in good to excellent yields irre-
spective of the nature of the substituents (Table 2).13 To in-
vestigate the reactivity on a larger scale, the model reaction
was then performed with fivefold increase in the concen-
tration of the substrates (i.e., 5.0 mmol). In this case, the
corresponding product 1a was formed in good yield (83%)
within five minutes.
Entry
Cat. (0.5 equiv)
Solvent
Yield 1a (%)
1
2
–
H2O
–
–
H2O (50 °C)
H2O (100 °C)
H2O
trace
trace
trace
<10
trace
<10
trace
<10
trace
<10
trace
<10
86
3
–
4
(n-Bu)4N+Br–
(n-Bu)4N+Br–
Bn(Et)3N+Cl–
Bn(Et)3N+Cl–
NH4OAc
NH4OAc
K2CO3
5
H2O (100 °C)
H2O
6
7
H2O (100 °C)
H2O
8
9
H2O (100 °C)
H2O
10
11
12
13
14
15
16
K2CO3
H2O (100 °C)
H2O
KOH
KOH
H2O (100 °C)
PEG-400
PEG-400a
PEG-400b
–
–
97
–
96
a Reactants were stirred in a PEG-400–H2O (3:1) mixture at ambient tem-
perature.
b Reactants were stirred in a PEG-400–H2O (2:1) mixture at ambient tem-
perature.
When equimolar amounts of model reactants were
stirred under catalyst-free conditions in water at ambient
temperature, the product 1a was not formed even after 12
hours. Elevating the reaction temperatures (i.e., at 50 °C and
100 °C) also led to no reaction. Attempts utilizing phase-
transfer catalysts such as tetrabutylammonium bromide
and benzyltriethylammonium chloride as well as common
bases such as ammonium acetate, potassium carbonate,
and potassium hydroxide in water (at ambient temperature
and 100 °C) were also ineffective. However, Fujita et al., Xie
et al., and Zhang et al. have performed this type of reaction
efficiently in water,6b,7 but very specific catalysts are vital.
Polyethylene glycols (PEG) have a diversity of benign
properties as they are nonvolatile and biocompatible, have
low flammability, and show good stability towards bases,
acids, elevated temperatures, and some of the oxidation/re-
duction systems.8 When the model reaction was performed
in PEG-400 under catalyst-free conditions at ambient tem-
perature, to our satisfaction, the target 1a was obtained in
86% yield in just a few minutes. The model reaction was
also executed using some common protic solvents. When
the reaction was performed either in ethanol or methanol
at ambient temperature for two hours, no significant im-
provement in the yield was observed. In addition, use of
branched alcohols, such as isopropanol and tertiary buta-
nol, also resulted in poor yields though slightly higher than
the former. Surprisingly, addition of water to PEG-400 (i.e.,
PEG–H2O = 3:1) improved the yield significantly compared
Table 2 Green and Facile Synthesis of Pyrazole-Decorated Nitriles in
PEG400–H2O (3:1) at Ambient Temperature
Entry
1
Reactant
Product
Yield (%)
97
Br
Br
H
H
NC
NC
O
N
N
N
N
1a
2
95
F
F
H
H
NC
NC
O
N
N
N
N
1b
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, A–E

C
L. N. Jayalakshmi et al.
Letter
Synlett
Table 2 (continued)
Entry
8
Reactant
Product
Yield (%)
88
Entry
3
Reactant
Product
Yield (%)
92
Cl
Cl
H
H
NC
NC
O
N
N
N
N
H
H
N
N
NC
O
N
N
NC
N
N
NO2
NO2
1h
1c
9
92
4
94
OMe
OMe
H
H
NC
NC
Cl
Cl
O
N
H
H
N
N
NC
O
N
N
NC
N
N
1i
10
89
Cl
Cl
1d
5
96
Me
Me
H
H
NC
NC
Cl
Cl
O
N
H
H
N
N
NC
O
N
N
NC
N
N
1j
For further exploration of the reaction scope, substitut-
ed benzaldehydes were also utilized in place of the pyra-
zole-based carbaldehydes. Notably, all furnished the corre-
sponding arylidenemalononitriles 2a–f in good to excellent
yields within five minutes irrespective of the nature of the
substituents (Table 3).
To demonstrate the system’s versatility, reactions of
various pyrazole-based heteroaromatic aldehydes (1.0
mmol) with ethyl 2-cyanoacetate (1.0 mmol) were execut-
ed under the optimal conditions, and the results are sum-
marized in Table 4.16 In all the cases, the reactions proceed-
ed smoothly at ambient temperature and culminated in the
formation of the corresponding acrylates in good to excel-
lent yields, albeit with longer reaction times (4 h). The lon-
ger reaction time is due to the lower reactivity of ethyl 2-
cyanoacetate compared to malononitrile.
1e
6
96
H
H
NC
O
N
N
NC
N
N
1f
7
94
Br
Br
H
H
NC
O
N
N
NC
N
The recyclability of the PEG400 for the model reaction
was subsequently explored. After separating the product by
filtration, the filtrate was subjected to distillation under re-
duced pressure to separate the PEG400 and water. The
PEG400 was then reused along with the required amount of
water for further consecutive runs. The PEG400 could be re-
N
1g
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, A–E

D
L. N. Jayalakshmi et al.
Letter
Synlett
Table 4 (continued)
used for six consecutive runs with no appreciable loss in
Yield (%)a
92
the yield of 1a.
Entry Reactant
3
Product
Me
Me
Table 3 Green and Facile Synthesis of 2-Arylidenemalononitriles in
PEG400–H2O (3:1) at Ambient Temperature
H
H
H
H
EtOOC
Entry Reactant
Product
Yield (%)
948c
O
NC
N
N
N
N
1
NC
O
N
N
N
N
CN
2a
2
976a
9514
9215
886a
NC
3c
O
4
96
Br
Br
CN
CN
Br
Cl
Br
Cl
2b
H
3
EtOOC
NC
O
O
NC
N
N
2c
4
NC
O
CN
OMe
3d
OMe
2d
5
94
OMe
OMe
5
NO2
NO2
NC
H
O
EtOOC
CN
CN
O
2e
NC
N
N
6
938c
NC
O
Me
Me
2f
3e
a The reaction period was 4 h.
Table 4 Green and Facile Synthesis of Pyrazole-Decorated Acrylates in
PEG400–H2O (3:1) at Ambient Temperature
The expediency of this methodology lies in the fact that
the reaction occurs in a rapid manner to furnish (pyrazolyl-
methylene)malononitriles in good to excellent yields using
an aqueous PEG-400 solvent system under catalyst-free
conditions. This method is applicable to the synthesis of a
diverse range of aryl/heteroaryl-decorated malononitriles
and acrylates from their corresponding aldehydes showing
compatibility for various substituents such as halogen, al-
kyl, alkoxy, and nitro substituents in the substrates. PEG-
400 is a cost effective, nonvolatile, biocompatible, and sta-
ble liquid with low flammability, and so this protocol is
Entry Reactant
1
Product
Yield (%)a
97
Cl
Cl
H
H
EtOOC
O
NC
N
N
N
N
likely to have
arylidene/heteroarylidenemalononitriles and acrylates.
a broad scope for the synthesis of
3a
2
95
H
H
EtOOC
Acknowledgment
O
NC
N
N
Financial support provided by the Department of Science and Tech-
nology (DST-SERB), New Delhi, India under the Fast-Track Scheme
[SR/FT/CS-149/2011] and the Council of Scientific and Industrial Re-
search (CSIR), New Delhi, India [02(0099)/12/EMR II] is gratefully ac-
knowledged.
N
N
3b
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, A–E

E
L. N. Jayalakshmi et al.
Letter
Synlett
Supporting Information
(9) Typical Experimental Procedure
An equimolar quantity of 3-(4-bromophenyl)-1-phenylpyra-
zolecarbaldehyde (1.0 mmol) and malononitrile (1.0 mmol)
was stirred in polyethylene glycol (PEG-400)–H2O (3:1) mixture
at ambient temperature for 5 min when a solid was obtained.
H2O was then added, and the mixture was filtered and dried
under reduced pressure to give 2-{[3-(4-bromophenyl)-1-phen-
ylpyrazolyl]methylene}malononitrile (1a). Recrystallization
from an EtOH–DMF mixture afforded analytically pure product
as a pale yellow solid; mp 199–200 °C. IR (KBr): ν = 2362.8,
2223.9, 1570.1, 1518.0, 1436.9, 1402.2, 1338.6, 1240.2, 1076.3,
1008.8, 974.1, 954.8, 831.2, 812.0, 754.2, 729.1, 705.9, 682.8,
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0034-1380742.
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References and Notes
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2889. (b) Ramalingan, C.; Park, S.-J.; Lee, I.-S.; Kwak, Y.-W. Tetra-
hedron 2010, 66, 2987. (c) Ramalingan, C.; Park, Y.-T. J. Org.
Chem. 2007, 72, 4536.
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Synthesis; Vol. 2; Trost, B. M.; Fleming, I., Eds.; Pergamon Press:
Oxford, 1991, 341.
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Hosseinabadi, R.; Petrov, S.; Migliori, A. RSC Adv. 2013, 3, 22353.
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M. M.; Ondruschka, B. Green Chem. 2008, 10, 767. (d) Pratap, U.
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1
630.7, 609.5 cm–1. H NMR (300 MHz, CDCl3): δ = 9.01 (s, 1 H),
7.74–7.63 (m, 5 H), 7.50–7.41 (m, 5 H). 13C NMR (75 MHz,
CDCl3): δ = 156.2, 151.3, 138.6, 132.5, 131.5, 130.2, 129.4, 128.9,
126.5, 123.9, 120.0, 115.0, 114.7, 114.0, 78.3. GC–MS: m/z = 374
[M+]. Anal. Calcd for C19H11BrN4: C, 60.82; H, 2.95; N, 14.93.
Found: 60.85; H, 2.91; N, 14.91.
(10) Luo, J.; Xin, T.; Wang, Y. New J. Chem. 2013, 37, 269.
(11) Ye, W.; Jiang, H.; Yang, X.-C. J. Chem. Sci. 2011, 123, 331.
(12) Siddiqui, Z. N.; Khan, T. Tetrahedron Lett. 2013, 54, 3759.
(13) Characterization Data of Representative Unsubstituted
Nitrile 1f
Pale yellow solid; mp 214–215 °C. IR (KBr): ν = 2357.0, 2223.9,
1581.6, 1521.8, 1502.6, 1469.8, 1448.5, 1344.4, 1238.3, 1184.3,
.
1018.4, 952.8, 821.7, 758.0, 715.6, 678.9, 611.4 cm–1 1H NMR
(300 MHz, CDCl3): δ = 9.06 (s, 1 H), 7.84–7.80 (m, 3 H), 7.58–
7.52 (m, 7 H), 7.47–7.44 (m, 1 H). 13C NMR (75 MHz, CDCl3): δ =
156.3, 151.0, 138.5, 130.6, 129.6, 129.5, 129.3, 129.1, 128.9,
119.9, 114.9, 113.8, 78.5. GC–MS: m/z = 296 [M+]. Anal. Calcd for
C
19H12N4: C, 77.01; H, 4.08; N, 18.91. Found: 77.05; H, 4.11; N,
18.88.
(14) Xu, D. Z. C.; Liu, Y.; Shi, S.; Wang, Y. Green Chem. 2010, 12, 514.
(15) Balalaie, S.; Bararjanian, M.; Hekmat, S.; Salehi, P. Synth.
Commun. 2006, 36, 2549.
(16) Characterization Data of Representative Acrylate 3a
Off-white solid; mp 106–107 °C. IR (KBr): ν = 2987.7, 2218.1,
1726.3, 1643.4, 1593.2, 1519.9, 1429.3, 1373.3, 1267.2, 1236.4,
1190.1, 1093.6, 1020.3, 947.1, 887.3, 817.8, 721.2, 673.2, 578.6,
526.6 cm–1. 1H NMR (300 MHz, CDCl3): δ = 9.14 (s, 1 H), 8.24 (s,
1 H), 7.82 (d, J = 8.0 Hz, 2 H), 7.55–7.47 (m, 7 H), 7.41 (t, J = 6.9
Hz, 1 H), 4.37–4.32 (m, 2 H), 1.37 (t, J = 7.2 Hz, 3 H). 13C NMR (75
MHz, CDCl3): δ = 162.6, 155.1, 145.7, 138.8, 135.7, 130.4, 129.7,
129.4, 129.3, 128.3, 120.0, 116.6, 114.9, 100.2, 62.5, 14.2. MS:
m/z = 377 [M+]. Anal. Calcd for C21H16ClN3O2: C, 66.76; H, 4.27;
N, 11.12. Found: C, 66.85; H, 4.33; N, 11.01.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, A–E