Catalyst-free one-pot synthesis and antioxidant evaluation of highly functionalized novel 1,4-dihydropyridine derivatives

Article abstract of DOI:10.1007/s11164-014-1887-z

A catalyst-free greener protocol for the most effective one-pot synthesis of 2,6-diamino-4-aryl-1-propyl/cyclohexyl-1,4-dihydropyridine-3,5-dicarbonitrile derivatives has been developed using a simple three-component reaction of structurally diverse aldeh

Full text of DOI:10.1007/s11164-014-1887-z

Res Chem Intermed
DOI 10.1007/s11164-014-1887-z
Catalyst-free one-pot synthesis and antioxidant
evaluation of highly functionalized novel 1,4-
dihydropyridine derivatives
Rathinam Ramesh Subramani Maheswari
·
·
·
Senniappan Murugesan Raman Sandhiya
·
Appaswami Lalitha
Received: 15 September 2014 / Accepted: 30 November 2014
© Springer Science+Business Media Dordrecht 2014
Abstract A catalyst-free greener protocol for the most effective one-pot synthesis
of 2,6-diamino-4-aryl-1-propyl/cyclohexyl-1,4-dihydropyridine-3,5-dicarbonitrile
derivatives has been developed using a simple three-component reaction of struc-
turally diverse aldehydes, malononitrile and n-propylamine/cyclohexylamine at an
ambient temperature. The formation of 1,4-dihydropyridines could be achieved in
aqueous methanol in a single synthetic process involving no chromatography. The
newly synthesized highly functionalized 1,4-DHPs have been screened for their
in vitro antioxidant activity using the DPPH radical scavenging technique and the
results were good in comparison with a standard drug.
Keywords 1,4-Dihyropyridine · n-Propylamine · Cyclohexylamine ·
DPPH radical scavenging · Antioxidant activity
Introduction
The development of greener methodologies to facilitate the construction of
biologically diverse heterocyclic scaffolds based on privileged structures is an
intense materialization of organic synthesis [1]. In the past decade, functionalization
of C–H bond has been one of the most attractive and existing approaches in which
environmentally benign processes to build newer chemical bonds have attracted the
most attention. Multicomponent reactions (MCRs) have been considered as
important tools in combinatorial chemistry due to their ability to synthesize novel
‘drug-like’ small molecules with superior applications [2–4]. In recent years,
pollution-free chemical processes using metal-free catalysts have become highly
R. Ramesh · S. Maheswari · S. Murugesan · R. Sandhiya · A. Lalitha (&)
Department of Chemistry, Periyar University, Periyar Palkalai Nagar,
Salem 636 011, Tamil Nadu, India
e-mail: lalitha2531@yahoo.co.in
123

R. Ramesh et al.
desirable and some equivalent metal-free bases are easily available making the
reaction costs lower.
Synthesis of pyridine-based heterocyclic compounds has predominant impor-
tance from the viewpoint of the discovery of novel drug molecules for the treatment
of cancer, asthma, hypoxia, kidney disease, epilepsy, Parkinson’s diseases [5] and
Prion-induced fatal neurodegenerative diseases, such as Creutzteldt-Jacob disease in
humans, bovine spongiform encephalopathy and scrapie in sheep [6]. 2-Amino-3-
cyanopyridine scaffolds have diverse applications, such as anti-tumor [7], cardio-
tonic [8], and anti-inflammatory, and as novel IKK-β inhibitors [9], A2A adenosine
receptor antagonists [10] and potent inhibitors of HIV-1 integrase [11]. The
synthesized pyridine derivatives bearing nitrile functionality are used as valuable
intermediates for the synthesis of various N-heterocycles [12, 13]. In terms of the
synthetic community, the high reactivity connected with 1,4-DHPs possesses vital
applications in modern drug discovery. Generally, 1,4-dihydropyridines have been
synthesized by the Hantzsch method, which involves the cyclocondensation of β-
ketoester, aldehyde and ammonia in refluxing alcohol for long reaction times
leading to only moderate yields [14–16]. Although a number of synthetic methods
have been reported for 2-amino-3-cyanopyridines, with catalysts like nano ZnO
[17], Et3N [18, 19], piperidine [20], KOH [21], cellulose-SO3H [22], SiO2-sulfonic
acid [23], etc., many of them suffer from any one of demerits such as prolonged
reaction time, unsatisfactory yield, high temperature and harsh reaction conditions.
During the metabolic reactions, a variety of free radicals are generated and
quenched by an efficient antioxidant network in the body. When the production of
these species crosses their antioxidant mechanism, it leads to oxidative damage of
tissues leading to diseases, especially degenerative diseases [24]. In this paper, we
are reporting a greener protocol for the synthesis of highly functionalized 1,4-
dihydropyridine derivatives and their antioxidant properties, evaluated using the
DPPH (2,2´-diphenyl-1-picrylhydrazyl) method. The DPPH radical scavenging
evaluation is a standard and rapid technique for the potent antioxidant studies of the
synthesized compounds by a photometric method [25].
Experimental
Reagents and equipments
All the reagents and solvents were purchased from commercial sources and were
freshly used after being purified by standard techniques. Reactions were
monitored by TLC using silica gel-coated plates with ethyl acetate/hexanes as
the mobile phase. Melting points were measured with an electrothermal apparatus
and are uncorrected. 1H NMR and 13C NMR were recorded on a BRUKER DRX-
400 spectrometer in CDCl3 and chemical shifts are expressed in δ units using
TMS as an internal standard. IR spectra were recorded on a Bruker FT-IR27
spectrophotometer using KBr optics. Mass spectrum was recorded on GCMS-Q-
TOF spectrometer.
123

Catalyst-free one-pot synthesis and antioxidant evaluation
Typical procedure for the synthesis of 2,6-diamino-1,4-dihydropyridine-3,5-
dicarbonitrile derivatives
To a stirred mixture of aromatic aldehyde (3.0 mmol) and malononitrile (6.0 mol) in
aqueous methanol (60 %, 20 ml), n-propylamine/cyclohexylamine (3.5 mmol) was
added at room temperature and, from the resulting solution, the products were
precipitated within the time mentioned in Tables 1 and 2. After this (monitored by
TLC using ethyl acetate: hexanes 1:2), the desired products were filtered, air-dried
and recrystallized from methanol.
Table 1 Synthesis of 2,6-diamino-4-(aryl)-1-propyl-1,4-dihydropyridine-3,5-dicarbonitriles
Entry
R
Producta
Time (h)
Yield (%)b
M.pt (°C)
1
2
3
4
5
6
7
8
9
a
H
4a
4b
4c
4d
4e
4f
3.0
2.5
3.0
2.5
2.5
3.0
3.0
2.5
3.0
84
88
83
86
87
82
80
86
84
182–184
220–222
218–220
172–174
230–232
226–228
240–242
244–246
250–252
4-Cl
4-OMe
4-F
4-Br
4-CH3
4-OH
3-NO2
2-Cl
4g
4h
4i
Reaction of aromatic aldehyde (3 mmol), malononitrile (3 mmol) and n-propylamine (3.5 mmol) in
aqueous methanol (60 %, 20 ml) at room temperature
b
Isolated yield
Table 2 Synthesis of 2,6-diamino-4-(aryl)-1-cyclohexyl-1,4-dihydropyridine-3,5-dicarbonitriles
Entry
R
Producta
Time (h)
Yield (%)b
M.pt (°C)
1
2
3
4
5
6
7
8
9
a
H
6a
6b
6c
6d
6e
6f
3.0
2.5
3.0
2.5
2.5
3.0
3.0
2.5
3.0
82
85
81
84
82
81
79
84
83
224–226
228–230
220–222
262–264
242–244
238–240
248–250
266–268
262–264
4-Cl
4-OMe
4-F
4-Br
4-CH3
4-OH
3-NO2
2-Cl
6g
6h
6i
Reaction of aromatic aldehyde (3 mmol), malononitrile (3 mmol) and cyclohexylamine (3.5 mmol) in
aqueous methanol (60 %, 20 ml) at room temperature
b
Isolated yield
123

R. Ramesh et al.
DPPH assay
The evaluation of antioxidant activity of the synthesized 1,4-DHPs has been
performed by stable DPPH-free radicals, according to a modified procedure from
that reported by Keshwal et al. [26] using DPPH (0.59 mg/250 ml) in methanol.
Based on this, 0.1 ml of the test compound (in five different concentrations), 1.5 ml
of methanol and 0.5 ml of DPPH solution were added and mixed thoroughly. The
mixture was incubated at 25 °C for 60 min in the dark and the absorbance of
reaction liquid was measured at 517 nm.
The percentage of scavenging activity of the tested compounds was calculated by
using the formula.
Scavenging effect ð%Þ ¼ ðA0 ꢀ A1Þ=A0 ꢁ 100
where A0 is the absorbance of the control (water instead of sample) and A1 is the
absorbance of the sample.
Characterization data
2,6-Diamino-4-phenyl-1-propyl-1,4-dihydropyridine-3,5-dicarbonitrile (4a): Yel-
low crystals; mp 182–184 °C; IR (KBr) (ʋmax, cm−1): 3,344, 3,312 (NH2), 2,170
(CN), 1,063 (C–N); 1H NMR (400 MHz, CDCl3): δ (ppm) 0.98 (t, 3H, CH3,
J = 7.4 Hz) 1.52 (h, 2H, CH2, J = 7.2 Hz) 3.46 (t, 2H, CH2 J = 6.0 Hz), 4.08 (s, 1H,
CH), 5.72 (s, 2H, NH2), 7.28 (d, 2H, ArH, J = 8.0 Hz), 7.32 (t, 1H, ArH,
J = 7.6 Hz), 7.37 (t, 2H, ArH J = 7.6 Hz); 13C NMR (100 MHz, CDCl3): δ (ppm)
12.10, 21.52, 36.14, 45.62, 56.41, 116.21, 125.80, 127.72, 130.10, 148.47, 162.58;
MS(ESI) m/z 280 (M + H)+; Anal. Calcd for C16H17N5: C, 68.79; H, 6.13; N,
25.07 %. Found: C, 68.72; H, 6.07; N, 25.01 %.
2,6-Diamino-4-(4-bromophenyl)-1-propyl-1,4-dihydropyridine-3,5-dicarbonitrile
(4e): Yellow crystals; mp 230–232 °C; IR (KBr) (ʋmax, cm−1): 3,357, 3,329 (NH2),
1
2,203 (CN), 1,024 (C–N); H NMR (400 MHz, CDCl3), δ (ppm) 0.99 (t, 3H, CH3,
J = 7.6 Hz), 1.59 (h, 2H, CH2, J = 7.2 Hz) 3.46 (t, 2H, CH2, J = 6.0 Hz) 3.97 (s, 1H,
CH), 5.41 (s, 2H, NH2), 7.42 (d, 2H, ArH, J = 8.8 Hz), 7.69 (d, 2H, ArH,
J = 8.8 Hz); 13C NMR (100 MHz, CDCl3): δ (ppm) 10.32, 21.50, 42.31, 79.03,
115.42, 128.72, 131.63, 135.83, 156.86, 158.57, 159.96; MS(ESI) m/z 359
(M + H)+; Anal. Calcd for C16H16BrN5: C, 53.64; H, 4.50; N, 19.55 %. Found:
C, 53.60; H, 4.42; N, 19.52 %.
2,6-Diamino-1-propyl-4-(p-tolyl)-1,4-dihydropyridine-3,5-dicarbonitrile
(4f):
Yellow crystals; mp 226–228 °C; IR (KBr) (ʋmax, cm−1): 3,352, 3,306 (NH2),
1
2,207 (CN), 1,027 (C–N); H NMR (400 MHz, CDCl3): δ (ppm) 0.92 (t, 3H, CH3,
J = 7.6 Hz) 1.56 (h, 2H, CH2, J = 7.2 Hz) 2.34 (s, 3H, CH3), 3.38 (t, 2H, CH2,
J = 6.8 Hz) 3.92 (s, 1H, CH), 5.37 (s, 2H, NH2), 7.25 (d, 2H, ArH, J = 8.0 Hz), 7.35
(d, 2H, ArH, J = 8.0 Hz); 13C NMR (100 MHz, CDCl3): δ (ppm) 11.36, 21.47,
22.58, 43.30, 116.71, 116.85, 128.23, 129.57, 131.40, 140.84, 159.29, 161.05; MS
(ESI) m/z 294 (M + H)+; Anal. Calcd for C17H19N5: C, 69.60; H, 6.53; N, 23.87 %.
Found: C, 69.50; H, 6.47; N, 23.83 %.
123

Catalyst-free one-pot synthesis and antioxidant evaluation
2,6-Diamino-1-cyclohexyl-4-phenyl-1,4-dihydropyridine-3,5-dicarbonitrile (6a):
Dark Yellow crystals; mp 224–226 °C; IR (KBr) (ʋmax, cm−1): 3,352, 3,317 (NH2),
2,203 (CN), 1,096 (C–N); 1H NMR (400 MHz, CDCl3): δ (ppm) 1.22 (m, 4H, CH2),
1.50 (m, 2H, CH2), 1.72 (m, 4H, CH2), 2.48 (p, 1H, CH), 4.14 (s, 1H, CH), 5.92
(s, 2H, NH2), 7.25 (d, 2H, ArH, J = 7.8 Hz), 7.36 (t, 2H, ArH, J = 7.2 Hz), 7.37
(t, 1H, ArH, J = 7.2 Hz); 13C NMR (100 MHz, CDCl3): δ (ppm) 24.53, 27.21,
32.04, 36.15, 57.01, 116.27, 125.42, 127.92, 130.21, 146.71, MS(ESI) m/z 320
(M + H)+; Anal. Calcd for C19H21N5: C, 71.45; H, 6.63; N, 21.93 %. Found: C,
71.40; H, 6.58; N, 21.90 %.
2,6-Diamino-4-(4-bromophenyl)-1-cyclohexyl-1,4-dihydropyridine-3,5-dicarbo-
nitrile (6e): Yellowish white crystals; mp 242–244 °C; IR (KBr) (ʋmax, cm−1):
1
3,396, 3,338 (NH2), 2,220 (CN), 1,016 (C–N); H-NMR (400 MHz, CDCl3): δ
(ppm) 0.98 (m, 4H, CH2), 1.52 (m, 4H, CH2), 1.68 (m, 4H, CH2), 3.38 (m, 1H, CH),
4.12 (s, 1H, CH), 5.58 (s, 2H, NH2), 7.12 (d, 2H, ArH, J = 8.4 Hz), 7.58 (d, 2H,
ArH, J = 8.4 Hz); 13C NMR (100 MHz, CDCl3): δ (ppm) 25.72, 31.64, 36.37,
50.77, 55.30, 83.83, 115.34, 125.59, 130.04, 132.32, 159.54, 166.70; MS(ESI) m/z
399 (M + H)+; Anal. Calcd for C19H20BrN5: C, 57.29; H, 5.06; N, 17.58 %. Found:
C, 57.22; H, 5.01; N, 17.55 %.
2,6-Diamino-1-cyclohexyl-4-(p-tolyl)-1,4-dihydropyridine-3,5-dicarbonitrile (6f):
Dark Yellow crystals; mp 238–240 °C; IR (KBr) (ʋmax, cm−1): 3,343, 3,312 (NH2),
2,210 (CN), 1,019 (C–N); 1H NMR (400 MHz, CDCl3): δ (ppm) 1.24 (m, 4H, CH2),
1.53 (m, 2H, CH2), 1.68 (m, 4H, CH2), 2.56 (p, 1H, CH), 3.83 (s, 1H, OCH3), 4.46 (s,
1H, CH), 5.73 (s, 2H, NH2), 6.89 (d, 2H, ArH, J = 8.0 Hz), 7.14 (d, 2H, ArH,
J = 8.0 Hz); 13C NMR (100 MHz, CDCl3): δ (ppm) 25.32, 27.10, 32.41, 36.30, 55.54,
57.62, 114.24, 116.05, 130.23, 134.63, 156.76, 161.36; MS(ESI) m/z 334 (M + H)+;
Anal. Calcd for C20H23N5: C, 72.04; H, 6.95; N, 21.00 %. Found: C, 71.95; H, 6.90; N,
20.89 %.
Results and discussion
To optimize the reaction conditions, initially we have tried the reaction of 4-
chlorobenzaldehyde (1b) with two equivalents of malononitrile (2) and n-
propylamine (3) in ethanol as a model reaction without any added catalysts. The
reaction proceeded smoothly even at room temperature resulting in the formation of
the target molecule (4b) with 58 % of yield in more than 5 h of reaction time. Then,
we tried the same reaction with various solvents and the best results were obtained
while using 60 % aqueous methanol as the solvent with a slight excess of amine.
In this reaction, the initial Knoevenagel condensation step might be promoted by
one of the excess reagents, namely, the n-propylamine (3) instead of using any other
external base as a catalyst. With these optimized reaction conditions, a variety of
substituted aromatic aldehydes (1a–i) have been utilized for the synthesis of a series
of 2,6-diamino-1-propyl-3,5-dicyano-1,4-dihydropyridine derivatives (Scheme 1).
The reactions of different aldehydes possessing either electron-withdrawing or
electron-donating substituents produced heterocyclic compounds with good yields,
123

R. Ramesh et al.
Scheme 1 Synthesis of 2,6-diamino-3,5-dicyano-1,4-dihydropyridine derivatives
Scheme 2 Synthesis of 2,6-diamino-3,5-dicyano-1,4-dihydropyridine derivatives
Scheme 3 The suggested mechanism for the one-pot synthesis of highlyfunctionalized 1,4-dihydropyridines
ranging from 80 to 88 %. The unsubstituted benzaldehyde provided the corresponding
1,4-DHP of about 84 % yield (Table 1, Entry 1).
1
The formation of cyclized 1,4-DHP molecule was confirmed by the H NMR
spectrum, in which the two singlets appeared at δ 3.92 and 5.37 ppm, corresponding
123

Catalyst-free one-pot synthesis and antioxidant evaluation
to the methine proton (–CH–) and the free amine proton (–NH2). IR shows a peak at
2,207 cm−1 that specifies the presence of nitrile moiety and peaks at 3,352 and
3,306 cm−1 representing the presence of –NH2 group. Impressed by the results
obtained in the above case, we extended the utility of this MCR with cyclohexylamine
(5) in the place of n-propylamine (3) (Scheme 2). Under the above optimized reaction
conditions, the three-component reaction of aromatic aldehydes, malononitrile and
cyclohexylamine gave the corresponding 2,6-diamino-1-cyclohexyl-1,4-dihydropyr-
idine-3,5-dicarbonitriles in 79–85 % (Table 2).
Table 3 Free radical scavenging activity of the synthesized 1,4-DHPs (4a–i) using DPPH assay
Entry
Compound
DPPH RSAa (2 mg/ml)
(%)
IC50 value (mg)
1
2
3
4
5
6
7
8
9
10
a
4a
73.59 0.87
90.44 1.28
51.25 1.12
74.38 1.02
76.25 1.04
57.67 1.24
50.31 0.93
68.11 1.15
86.43 1.11
92.22 1.13
0.887
0.196
1.953
0.422
0.248
1.260
1.988
0.993
0.210
0.143
4b
4c
4d
4e
4f
4g
4h
4i
Ascorbic acid
Antioxidant activities were expressed in percentage compared with ascorbic acid. The data represent
mean value (SEM) of three duplicates
Table 4 Free radical scavenging activity of the synthesized 1,4-DHPs (6a–i) using DPPH assay
Entry
Compound
DPPH RSAa (2 mg/ml)
(%)
IC50 value (mg)
1
2
3
4
5
6
7
8
9
10
a
6a
62.14 1.39
81.71 1.23
56.34 1.09
70.94 0.59
73.45 1.32
55.60 1.19
57.08 1.32
62.38 1.45
76.70 1.28
92.22 1.37
0.922
0.231
1.139
0.646
0.238
1.387
1.086
1.388
0.280
0.143
6b
6c
6d
6e
6f
6g
6h
6i
Ascorbic acid
Antioxidant activities were expressed in percentage compared with standard ascorbic acid. The data
represent mean value (SEM) of three duplicates
123

R. Ramesh et al.
Fig.
dicarbonitriles
1
Free radical scavenging activity of 2,6-diamino-4-aryl-1-propyl-1,4-dihydropyridine-3,5-
Fig. 2 Free radical scavenging activity of 2,6-diamino-4-aryl-1-cyclohexyl-1,4-dihydropyridine-3,
5-dicarbonitriles
123

Catalyst-free one-pot synthesis and antioxidant evaluation
Scheme 4 Plausible steps for all synthesized 1,4-DHP’s interacting with DPPH radical
A plausible mechanism for the three-component synthesis of diamino-1,4-
dihydropyridine-dicarbonitrile derivatives at ambient temperature is presented in
Scheme 3. Initially, the amine promotes the Knoevenagel condensation between
aromatic aldehyde and malononitrile producing an arylidenemalononitrile which
undergoes Michael addition with another mole of malononitrile, resulting in the
formation of tetracyano intermediate A. In the second step, amine acting as a
stronger nucleophile attacks the cyano group of intermediate A to give B. The third
step involves the intra-molecular nucleophilic addition of the imino group to one of
the cyano groups through a 1,3-proton shift to give nitrogen containing intermediate
C. Finally, C undergoes tautomerization (i.e., imino to enamino) resulting in the
formation of highly functionalized 1,4-dihydropyridine (D).
Radical scavenging activities of the synthesized compounds were screened by
following the interacting ability of DHP derivatives with DPPH as the stable free
radical. Decreased absorbance of the synthesized compounds with different
concentrations indicated that the compounds possess significant radical scavenging
abilities. The results obtained for the synthesized 1,4-DHPs are depicted in Tables 3
and 4 and graphically represented in Figs. 1 and 2. The values are expressed in
percentage of inhibition and 50 % inhibitory concentration (the concentration of the
test sample required the scavenging of 50 % free radicals) and compared with the
ascorbic acid as standard. Initially, compound 4b was selected as a model compound
for evaluating its DPPH radical scavenging activity in five different concentrations,
i.e. 2, 4, 6, 8, 10 mg/ml, and better activity was observed with 2 mg/ml. All the
other compounds were screened for their antioxidant activity using 2 mg/ml
concentrations.
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R. Ramesh et al.
The antioxidant activity of compounds in the series 4a–i and 6a–i is perhaps due to
the presence of an N–H group, which can donate a hydrogen atom to the DPPH radical.
After donating a hydrogen atom, compounds 4a–i and 6a–i exist in a radical form
that is stabilized by resonance as shown in Scheme 4. Due to the greater
electronegativity, the antioxidant properties of compounds with halogens are high.
The results indicated that some of the tested compounds are noteworthy for their
antioxidant properties. Particularly, halogen-containing compounds 4b, 6b, 4d, 6d,
4e, 6e, 4i and 6i were most efficient with enhanced activity, whereas the insertion of
the electron-donating OMe, CH3 and OH groups, in 4c, 4f and 4 g, respectively,
decreased their radical scavenging ability. Among the compounds tested, 4b and 6b
exhibited good antioxidant activities closer to the standard drug which may be
attributed to the presence of a chlorine moiety on the aryl ring.
Conclusion
In summary, we have developed a greener and effective protocol leading to
selective and high yielding novel 2,6-diamino-4-aryl-1-propyl/cyclohexyl-1,4-
dihydropyridine-3,5-dicarbonitrile derivatives using a one-pot three-component
reaction of aromatic aldehydes, malononitrile and n-propyl/cyclohexylamines
without using any external catalysts at ambient temperature. This method provided
several notable advantages such as operational simplicity, milder conditions and
good yields. Antioxidant activities of all the synthesized compounds were measured
using DPPH radical technique in which chlorine containing 1,4-DHPs showed
maximum radical scavenging activity.
Acknowledgments R.R. gratefully acknowledges the financial support from the DST-Inspire Fellow-
ship (No: DST/INSPIRE Fellowship/2012/690) New Delhi, India. We thank Dr. V. Sujatha for providing
UV–Vis spectral facilities.
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