Microwave irradiation: A green approach for the synthesis of functionalized: N -methyl-1,4-dihydropyridines

Article abstract of DOI:10.1039/c8ra09155b

An eco-friendly and cost-effective, microwave-assisted green approach has been developed for the synthesis of diverse functionalized N-methyl-1,4-dihydropyridines (1,4-DHPs). This pseudo three-component reaction was carried out between two equivalents of

Full text of DOI:10.1039/c8ra09155b

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Microwave irradiation: a green approach for the
synthesis of functionalized N-methyl-1,4-
dihydropyridines†
Cite this: RSC Adv., 2018, 8, 41892
a
Saigal,a Sarfaraz Khan,a Sumbulunnisan Shareefa
*
M. Musawwer Khan,
and Subash C. Sahoo
b
An eco-friendly and cost-effective, microwave-assisted green approach has been developed for the
synthesis of diverse functionalized N-methyl-1,4-dihydropyridines (1,4-DHPs). This pseudo three-
component reaction was carried out between two equivalents of (E)-N-methyl-1-(methylthio)-2-
nitroethenamine (NMSM) and one equivalent of aromatic aldehydes under microwave irradiation at
100 ꢀC without catalyst and solvent. Short reaction times, avoidance of toxic solvents or expensive,
metallic and corrosive catalysts and no need for column chromatographic purification are among the
valuable features of the presented method. Moreover, the “greenness” of the method was evaluated
within the ambits of the defined green metrics such as atom economy, carbon efficiency, E-factor,
reaction mass efficiency, overall efficiency, process mass intensity and solvent intensity and the method
exhibited a good to excellent score.
Received 5th November 2018
Accepted 28th November 2018
DOI: 10.1039/c8ra09155b
rsc.li/rsc-advances
high bond efficiency, convergence and step economy, short
synthetic period, reduction in waste products, high selectivity as
well as operational simplicity.6 On the other hand, the micro-
wave irradiation assisted synthetic protocol has also gained
importance, mainly in developing sustainable solvent- and
catalyst-free alternatives to laborious reactions. Additionally,
these approaches give better results in contrast to traditional
synthesis in terms of waste reduction, extreme drop in reaction
times, and relatively isolated pure products, thereby avoiding
tedious column chromatographic purication. Hence they
Introduction
The development of novel, green and sustainable synthetic
procedures has received substantial attention because of the
growing environmental pollution and its overwhelming effect
on human life. Therefore, the design of synthetic protocols with
efficient atom economy under catalyst- and solvent-free condi-
tions based on the microwave utilizing multicomponent reac-
tion (MCR) strategy has become a central theme in the evolution
of green chemistry.1 MCRs have the ability to generate conve-
niently only one product from three or more components in
a single synthetic operation with multiple bond formation and
high atom economy.2 Over the past decade, several classes of
heterocycles including natural and unnatural compounds have
been successfully synthesized through MCRs.3 Owing to the
simple experimental processes and one-pot procedure, the
application of catalytic methods involving MCR has gained
remarkable attention as it allows simple and straightforward
access to novel heterocyclic libraries of small molecules.4 MCRs
are now renowned and considered as an efficient tool for
generating complex and diverse molecules of medicinal
importance.5 They also have some inherent advantages such as
embody a prevailing green alternative to conventional
synthesis.7
Among the nitrogen containing heterocyclic compounds,
functionalized 1,4-dihydropyridines are considered as invalu-
able scaffolds because of their abundance in natural products8
and exhibit a variety of biological activities such as anti-
hypertension,9 anticancer,10 antioxidant,11 antiviral,12 anti-
tumor,13 anti-inammatory,14 analgesic15 and potential calcium
channel antagonist activities.16 1,4-Dihydropyridines (1,4-
DHPs), particularly 4-aryl-substituted-1,4-dihydropyridines,
also possess various pharmacological activities like vaso-
dilatory, anti-atherosclerotic, bronchodilatory, antiradical,
antitumor and anti-diabetic effects.17 Extensive studies have
revealed that these compounds display other therapeutic
properties including HIV protease inhibition, radioprotection,
neuroprotection, platelet and antiaggregatory activities etc.18
For example, compound I was found to be an anticonvulsant
while compound II exhibits antileishmanial properties.19
Recently, sugar derived 1,4-dihydropyridine III was revealed
to show antitumor activity against two types of tumor cell lines,
aDepartment of Chemistry, Aligarh Muslim University, Aligarh 202002, India. E-mail:
musawwer@gmail.com
bDepartment of Chemistry, Center of Advanced Studies in Chemistry, Panjab
University, Chandigarh-160014, India
† Electronic supplementary information (ESI) available. CCDC 1841358. For ESI
and crystallographic data in CIF or other electronic format see DOI:
10.1039/c8ra09155b
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Results and discussion
In our initial studies, a trial reaction was performed with
benzaldehyde 1a (1.0 mmol) and NMSM 2a (2.0 mmol) in the
presence of 10 mol% ZnCl2 under reuxing ethanol. The reac-
tion progress and consumption of starting materials was
checked by TLC. Aer completion of the reaction as monitored
by TLC, the highly substituted N-methyl-1,4-DHP derivative 3a
was isolated in 62% yield and the product was characterized by
physical properties24 and spectroscopic techniques including
1
IR, H and 13C NMR (Table 1, entry 1). Next, we focused on an
Fig. 1 Some biologically active highly substituted 1,4-DHPs.
optimization study to obtain the best results in terms of yield
and time. To this end, different catalysts including FeCl3,
SnCl2$2H2O, p-toluenesulfonic acid (p-TSA), piperidine and
DBU (10 mol%) were screened in the model reaction under
reuxing ethanol. Unfortunately, we did not obtain any
improvement in results (Table 1, entries 2–6). Next, we
attempted the same reaction in the presence of 10 mol% ZnCl2
under solvent-free conditions at 80 ꢀC and isolated 70% yield of
the product (Table 1, entry 7). Similarly, we have also executed
the same reaction under microwave irradiation at 80 ꢀC without
solvent in the presence of 10 mol% ZnCl2, and isolated 79%
yield of the product within 20 min. Then the same reaction was
also attempted in catalyst- and solvent-free conditions under
microwave irradiation at 80 ꢀC. Unexpectedly, this gave a better
result in comparison with the above experiments (Table 1, entry
9). Next, to optimize the reaction temperature of this trans-
formation, the above model reaction was executed at different
temperatures including 90 ꢀC, 100 ꢀC, 105 ꢀC, 110 ꢀC and 120 ꢀC
under microwave irradiation excluding catalyst and solvent
(Table 1, entries 10–14). From the above observations, the
reaction performed without catalyst and solvent under micro-
wave irradiation at 100 ꢀC emerged as the optimal reaction
conditions in terms of the yields and time (Table 1, entry 11).
The optimization of reaction yields vs. the reaction temperature
is depicted in Fig. 2.
HepG2 and HeLa (Fig. 1).20 Therefore, the preparation of 1,4-
dihydropyridines is one of the most attractive areas of research
for synthetic and medicinal chemists due to their diverse
applications. For the synthesis of 1,4-DHPs, starting from the
classical Hantzsch reaction,21 a number of protocols have been
reported.22
In recent times, (E)-N-methyl-1-(methylthio)-2-nitroethenamine
(NMSM) has been found to be a very attractive building block for
the synthesis of a variety of nitrogen and oxygen containing
heterocyclic compounds.23 To the best of our knowledge, only one
protocol has been reported in the literature so far for the synthesis
of N-methyl-1,4-dihydropyridines by using NMSM and aromatic
aldehydes in presence of a 2-aminopyridine catalytic system.24
However, the above method suffered from some limitations, like
very long reaction time, used of toxic catalyst, used of solvent, and
lower yields for some of the products. Hence, the need to develop
a rapid, efficient, and environmentally benign synthetic protocol
for the preparation of such 1,4-DHP derivatives is paramount and
justied.
Very recently, we have reported a green approach for the
synthesis of 4H-chromen-5-ones by using NMSM, dimedone
and aromatic aldehydes under catalyst- and solvent-free
conditions25 and our group also developed green protocols for
the synthesis of biologically active heterocycles such as N-
substituted-1,4-dihydropyridines, coumarin-fused 1,4-dihy-
dropyridines, tetrahydropyridines, functionalized furan-2-one
and pyrrol-2-one.26 In continuation of our research interest to
develop newer synthetic methodologies under greener condi-
tions, this paper describes an environmentally benign and
sustainable method for the synthesis of highly functionalized N-
methyl-1,4-DHPs under microwave irradiation without catalyst
and solvent as depicted in Scheme 1.
Aer establishing the optimized conditions, we examined
the reaction of NMSM with 4-nitrobenzaldehyde and obtained
the desired N-methyl-1,4-dihydropyridine derivative 3b in 85%
yield within 10 min. Next, we proceeded to investigate the
substrate scope for the presented method with various aromatic
aldehydes having substituents including NO2, Cl, Br, F, OMe,
Me and Et under the optimal reaction conditions, and the
reaction time and yield of the isolated products 3c–3o are
summarized in Table 2.
Scheme 1 Synthesis of highly functionalized N-methyl-1,4-dihydropyridines.
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Table 1 Optimization study for the synthesis of N-methyl-1,4-DHP 3aa
Entry
Catalyst (mol%)
Solvent
Temp. (ꢀC)
Time
Yieldb (%)
1
2
3
4
5
6
7
8
ZnCl2 (10)
FeCl3 (10)
SnCl2$2H2O (10)
p-TSA (10)
Piperidine (10)
DBU (10)
ZnCl2 (10)
ZnCl2 (10)
None
None
None
None
None
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
Neat
Neat
Neat
Neat
Neat
Neat
Neat
Neat
80
80
80
80
80
80
80
80 (mw)
80 (mw)
90 (mw)
100 (mw)
105 (mw)
110 (mw)
120 (mw)
5 h
7 h
8 h
12 h
15 h
10 h
50 min
20 min
20 min
15 min
10 min
10 min
10 min
10 min
62
52
57
32
22
10
70
79
82
89
94
93
91
89
9
10
11
12
13
14
None
a
Reaction conditions: NMSM (1a 2.0 mmol), benzaldehyde (2a 1.0 mmol). b Isolated yields. mw ¼ microwave irradiation.
In general, the reaction proceeded smoothly under the
optimized conditions to afford the desired products in good to hydes
Furthermore, the reactions of NMSM with heteroaryl alde-
including thiophene-2-carbaldehyde, pyridine-3-
excellent yields. It was observed that several functionalities, carbaldehyde and indole-3-carbaldehyde were executed under
including both electron donating and electron withdrawing this protocol and yielded the corresponding products 3p–3r in
groups, in the aromatic ring were compatible with the reaction 80–86% yield. In addition, 2-naphthaldehyde also gave the
conditions.
desired product 3s in 88% yield on heating with NMSM under
microwave irradiation at 100 ꢀC as shown in Table 2. Aer
achieving excellent results in terms of yields and time, we
moved to practical testing and explored our protocol on the
gram-scale level under the optimized conditions.
The gram scale preparation of 3a was carried out, wherein
benzaldehyde (5.0 mmol) successfully reacted with NMSM (10.0
mmol) under the optimized conditions to yield the desired
product in 88% yield (1.48 g) aer 15 min as depicted in Scheme
1. The newly synthesized compounds were conrmed by their
1
melting points, spectroscopic techniques (FTIR, H NMR, 13C
NMR, HRMS) and elemental analysis, and matched well with
the reported data.24 The spectroscopic data are in good agree-
ment with the proposed structure and some characteristic NMR
peaks assigned for compound 3n are shown in Fig. S2 (see ESI†).
Finally, the structure as well as the relative stereochemistry of
1,4-dihydropyridine 3n was conrmed by X-ray crystallographic
analysis (CCDC 1841358). From the crystal structure, it was
found that the 1,4-dihydropyridine ring adopted a boat
conformation in which the ag pole positions 1 and 4 are
occupied by the –N–CH3 and –Ph–CH3 group respectively. The
ORTEP representation of compound 3n is presented in Fig. 3.
Fig. 2 % yield of reaction vs. reaction temperature for the synthesis of
3a.
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Table 2 Substrate scope for the synthesis of N-methyl-1,4-DHPs (3a–s)a
Entry
Ar
Product
Time
% yieldb
Mp (ꢀC)
Reported mp (ꢀC)24
1
10 min
94
198–200
201
2
10 min
85
218–220
—
3
15 min
86
216–218
—
4
15 min
85
226–228
226
5
10 min
87
210–212
213
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Table 2 (Contd.)
Entry
Ar
Product
Time
% yieldb
Mp (ꢀC)
Reported mp (ꢀC)24
6
10 min
85
208–210
—
7
8
9
10 min
15 min
10 min
86
88
90
218–220
206–208
230–232
219
—
230
10
10 min
92
200–202
203
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Table 2 (Contd.)
Entry
Ar
Product
Time
% yieldb
Mp (ꢀC)
Reported mp (ꢀC)24
11
15 min
88
236–238
—
12
13
14
15
10 min
10 min
10 min
10 min
90
92
94
92
242–244
260–262
212–214
236–238
—
—
214
—
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Table 2 (Contd.)
Entry
16
Ar
Product
Time
% yieldb
Mp (ꢀC)
Reported mp (ꢀC)24
15 min
86
208–210
209
17
15 min
80
158–160
149
18
15 min
86
228–230
229
19
10 min
88
222–224
217
a
NMSM and aromatic aldehydes in a 2 : 1 ratio, microwave irradiation (200 W) at 100 ꢀC. b Isolated yields.
A single crystal was mounted on a glass bre and used for
Finally, a plausible reaction mechanism for the synthesis of
data collection. A metallic light yellow coloured crystal of N-methyl-1,4-dihydropyridine was proposed, as shown in
compound 3n was grown by slow evaporation of acetonitrile Scheme 2. We consider that the rst step involves the Knoeve-
solvent for X-ray analysis. The single crystal X-ray diffraction nagel condensation of one molecule of NMSM and aromatic
data were collected from a SuperNova diffractometer, single aldehyde to form intermediate I. To study the formation of
source at offset/far, with a HyPix3000 detector using graphite- proposed intermediate I and to isolate it, we have also con-
˚
monochromated MoKa radiation (l ¼ 0.71073 A) at 293 K. ducted a reaction with NMSM (1.0 mmol) and benzaldehyde (1.0
The crystallized compound has a triclinic crystal system, space mmol) under the optimised reaction conditions, but unfortu-
˚
ꢀ
group P1, and unit cell dimensions a ¼ 7.3596(3) A, b ¼ nately we unable to isolate the intermediate I. In this control
˚
˚
9.2464(6) A, c ¼ 14.1726(5) A. The unit cell packing of the case we obtained the proposed product in lower yield. None-
compound 3n is shown in Fig. 4.
theless, we proceed on the assumption that the intermediate I
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was formed, which acted as a Michael acceptor and reacted with
the Michael donor compound NMSM.23b,24
Another molecule of NMSM reacted with Knoevenagel
product I and formed Michael adduct II, which underwent
rotation to give conformer III. Then, the key intermediate III
underwent intra-molecular N-cyclization to form species IV.
Finally the species IV afforded the desired product by the
elimination of –MeSH. In contrast the elimination of –MeNH2
and formation of 3a0 (2,6-bismethylthio derivative) were not
observed. Comparing the leaving capacity of –MeNH2 and
–MeSH, the latter is more labile and has a greater leaving
tendency.
In the context of green chemistry, it was required to validate
our synthetic method as environmentally benign, which was
performed through the evaluation of green chemistry metrics
for this one-pot synthesis of N-methyl-1,4-dihydropyridines.27–29
Several green metrics, including atom economy (AE), carbon
efficiency (CE), reaction mass efficiency (RME), overall efficiency
(OE), process mass intensity (PMI), E-factor and solvent inten-
sity (SI), have been evaluated for all the synthesized compounds,
which empowers us to assess the present synthetic method in
terms of waste, carbon efficiency and energy usage. The calcu-
lated values of the green metrics of all the synthesized
compounds are summarized in Table S2 (see ESI†).
Fig. 3 ORTEP diagram of compound 3n (CCDC 1841358).
The calculated values, including high atom economy (83–
86%), carbon efficiency (93–94%), overall efficiency (85–94%),
and small E-factor (4–3), solvent intensity (4–3) and PMI (5–4),
endorse this presented method as green and sustainable.
Conclusion
In summary, the present study demonstrated the development
of a rapid, sustainable, environmentally benign and highly
efficient synthetic protocol for the preparation of N-methyl-1,4-
dihydropyridine derivatives under microwave irradiation
Fig. 4 Unit cell packing of compound 3n.
Scheme 2 Plausible reaction mechanism for the synthesis of N-methyl-1,4-DHPs.
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without catalyst and solvent. This protocol offers noteworthy (t, J ¼ 8 Hz, 2H), 10.12 (s, 1H), 13C NMR (100 MHz, DMSO-d6)
advantages such as good to excellent yields, short reaction time, d 16.6, 32.4, 41.0, 43.3, 113.3, 127.2, 128.0, 129.4, 137.7, 140.3,
avoidance of toxic catalyst and solvent, wide range of applica- 155.5, 156.5; anal. calcd (%) for C14H16N4O4S: C, 49.99; H,
bility, purication by crystallization, easily available starting 4.79; N, 16.66; S, 9.53. Found: C, 49.90; H, 4.77; N, 16.62, S, 9.50.
materials, low cost, clean reaction proles and good amena-
N,1-Dimethyl-6-(methylthio)-3,5-dinitro-4-(4-nitrophenyl)-1,4-
bility with the principles of green chemistry. In addition, the dihydropyridin-2-amine (3b). Isolated as yellow solid; yield:
presented methodology produced smaller amounts of waste, 85%; 325 mg; mp: 218–220 ꢀC; IR (KBr, cmꢁ1): 3214, 3024, 2958,
1
with good to excellent values of green chemistry metrics (AE, 1628, 1560, 1492, 1356, 1270, 1158, 1060, 720 cmꢁ1; H NMR
CE, RME, OE, PMI, SI and E-factor), and our method stands as (400 MHz, DMSO-d6) d 2.61 (s, 3H), 3.11 (d, J ¼ 4.8 Hz, 3H), 3.49
an exemplary choice in this framework.
(s, 3H), 6.09 (s, 1H), 7.45 (d, J ¼ 8.4 Hz, 2H), 8.17 (d, J ¼ 8.8 Hz,
2H), 10.13 (s, 1H), 13C NMR (100 MHz, DMSO-d6) d 16.8, 32.4,
41.1, 43.5, 112.5, 124.6, 128.8, 136.1, 147.3, 147.5, 156.4, 157.3;
anal. calcd (%) for C14H15N5O6S: C, 44.09; H, 3.96; N, 18.36, S,
8.41. Found: C, 43.96; H, 3.94; N, 18.32, S, 8.44; ESI-HRMS: anal.
calcd for [C14H15N5O6S + H+]: calcd: 382.0815, found: 382.0816.
N,1-Dimethyl-6-(methylthio)-3,5-dinitro-4-(3-nitrophenyl)-1,4-
dihydropyridin-2-amine (3c). Isolated as yellow solid; yield: 86%;
329 mg; mp: 216–218 ꢀC; IR (KBr, cmꢁ1): 3226, 3021, 2954, 1623,
Experimental section
General information
Commercially available solvents and chemicals were obtained
from suppliers and used to execute this work as received unless
otherwise mentioned. All the reactions were performed on
a Monowave 300 microwave synthesizer (Anton Paar) by
employing a glass vial G10. TLC analysis was performed using
silica gel GF-254 from SRL. Stuart digital melting point appa-
ratus (SMP10) was used for the measurement of melting points,
which are uncorrected. FTIR spectra were recorded in potas-
sium bromide pellets on a Perkin-Elmer 10.4.00 IR spectro-
photometer. 1H-NMR and 13C-NMR spectral analysis were
carried out on Bruker (Avance-II 400 MHz, Varian-AS400 NMR)
spectrometers using TMS as an internal standard and DMSO-d6
as a solvent. Crystal data were collected with a SuperNova
diffractometer, single source at offset/far, with a HyPix3000
detector (CCD) at 293 K using graphite monochromated MoKa
1563, 1490, 1356, 1272, 1156, 1062, 725 cmꢁ1 1H NMR (400
;
MHz, DMSO-d6) d 2.61 (s, 3H), 3.11 (d, J ¼ 4.0 Hz, 3H), 3.51 (s,
3H), 6.06 (s, 1H), 7.65 (t, J ¼ 7.6 Hz, 2H), 7.95 (s, 1H), 8.12–8.15
(m, 1H), 10.17 (s, 1H), 13C NMR (100 MHz, DMSO-d6) d 16.8,
32.5, 41.0, 43.7, 107.2, 122.1, 123.1, 131.1, 134.0, 136.2, 142.2,
148.4, 156.4, 157.6; anal. calcd (%) for C14H15N5O6S: C, 44.09; H,
3.96; N, 18.36, S, 8.41. Found: C, 44.18; H, 3.98; N, 18.39, S, 8.44.
4-(4-Chlorophenyl)-N,1-dimethyl-6-(methylthio)-3,5-dinitro-
1,4-dihydropyridin-2-amine (3e). Isolated as yellow solid; yield:
87%; 323 mg; mp: 210–212 ꢀC; IR (KBr, cmꢁ1): 3203, 3016, 2938,
1
1630, 1564, 1485, 1395, 1270, 1184, 1076, 722 cmꢁ1; H NMR
˚
(400 MHz, DMSO-d6) d 2.58 (s, 3H), 3.09 (s, 3H), 3.45 (s, 3H), 5.95
(s, 1H), 7.11 (d, J ¼ 8.4 Hz 2H), 7.51 (d, J ¼ 8.4 Hz, 2H), 10.11 (s,
1H), 13C NMR (100 MHz, DMSO-d6) d 16.5, 32.5, 40.6, 43.3,
113.5, 114.7, 128.4, 132.2, 138.0, 155.0, 156.5, 159.1; anal. calcd
(%) for C14H15ClN4O4S: C, 45.35; H, 4.08; N, 15.11, S, 8.65.
Found: C, 45.25; H, 4.06; N, 15.07, S, 8.62.
radiation (l ¼ 0.71073 A). Elemental analysis was performed on
a Perkin-Elmer-2400 CHN/S analyser and Thermo Scientic
(FLASH 2000) analyser while high resolution mass spectra were
recorded on an ORBITRAP mass analyser (Thermo Scientic, Q
Exactive) under electrospray ionisation (ESI) conditions.
4-(4-Methoxyphenyl)-N,1-dimethyl-6-(methylthio)-3,5-dinitro-
1,4-dihydropyridin-2-amine (3f). Isolated as yellow solid; yield:
85%; 316 mg; mp: 208–210 ꢀC; IR (KBr, cmꢁ1): 3230, 3025, 2942,
General procedure for the preparation of N-methyl-1,4-
dihydropyridines (3a–s)
A mixture of aromatic aldehydes (1.0 mmol) and (E)-N-methyl-1-
(methylthio)-2-nitroethenamine (NMSM) (2.0 mmol) was taken
in a glass vial G10 and irradiated with microwave radiation (200
W) at 100 ꢀC on a Monowave 300 synthesizer for 10–15 min. The
reaction progress and consumption of starting materials were
checked by TLC. Aer completion of the reaction as indicated
by TLC, the resulting precipitate-containing glass vial was
withdrawn from the microwave oven and allowed to cool. Then
the precipitate was washed with 1.5 mL of cold ethanol and
dried. Recrystallization was performed from hot ethanol to
provide the pure products.
1
2834, 1632, 1560, 1489, 1350, 1282, 1170, 1072, 786 cmꢁ1; H
NMR (400 MHz, DMSO-d6) d 2.59 (s, 3H), 3.11 (d, J ¼ 5.2 Hz, 3H),
3.47 (s, 3H), 5.97 (s, 1H), 7.09 (d, J ¼ 6.4 Hz, 1H), 7.17 (s, 1H),
7.07 (q, J ¼ 7.6 Hz, 2H), 10.15 (s, 1H), 13C NMR (100 MHz,
DMSO-d6) d 16.7, 32.4, 40.8, 43.5, 112.8, 125.8, 127.3, 128.1,
131.4, 133.8, 136.8, 142.6, 156.4, 156.6; anal. calcd (%) for C14
-
H15ClN4O4S: C, 45.35; H, 4.08; N, 15.11, S, 8.65 found: C, 45.21;
H, 4.10; N, 15.08; S, 8.61; anal. calcd for [C14H15ClN4O4S + H+]:
calcd: 371.0575, found: 371.0575.
4-(4-Bromophenyl)-N,1-dimethyl-6-(methylthio)-3,5-dinitro-
1,4-dihydropyridin-2-amine (3g). Isolated as light yellow solid;
yield: 86%; 358 mg; mp: 218–220 ꢀC; IR (KBr, cmꢁ1): 3239, 3016,
Spectral data of synthesized compounds
1
2931, 1631, 1561, 1485, 1396, 1283, 1164, 1039, 726 cmꢁ1; H
N,1-Dimethyl-6-(methylthio)-3,5-dinitro-4-phenyl-1,4-
NMR (400 MHz, DMSO-d6) d 2.52 (s, 3H), 3.19 (s, 3H), 3.46 (s,
dihydropyridin-2-amine (3a). Isolated as yellow solid; yield: 3H), 6.11 (s, 1H), 6.97 (d, J ¼ 6.8 Hz, 2H), 7.18 (d, J ¼ 8 Hz, 2H),
94%; 317 mg; mp: 198–200 ꢀC; IR (KBr, cmꢁ1): 3238, 3014, 2954, 10.06 (s, 1H), 13C NMR (100 MHz, DMSO-d6) d 16.3, 31.6, 40.6,
1
2934, 1621, 1561, 1496, 1356, 1246, 1172, 1070, 721 cmꢁ1; H 42.7, 111.2, 115.5, 115.7, 128.5, 128.6, 142.8, 146.5, 156.0; anal.
NMR (400 MHz, DMSO-d6) d 2.58 (s, 3H), 3.10 (s, 3H), 3.46 (s, calcd (%) for C14H15BrN4O4S: C, 40.49; H, 3.64; N, 13.49, S, 7.72.
3H), 5.99 (s, 1H), 7.16 (d, J ¼ 8.4 Hz, 2H), 7.23–7.28 (m, 1H), 7.32 Found: C, 40.40; H, 3.62; N, 13.45, S, 7.69.
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4-(3-Bromophenyl)-N,1-dimethyl-6-(methylthio)-3,5-dinitro-
RSC Advances
N,1-Dimethyl-6-(methylthio)-3,5-dinitro-4-(3,4,5-trimethoxyphenyl)-
1,4-dihydropyridin-2-amine (3h). Isolated as yellow solid; yield: 1,4-dihydropyridin-2-amine (3m). Isolated as yellow solid; yield:
88%; 366 mg; mp: 206–208 ꢀC; IR (KBr, cmꢁ1): 3206, 3053, 2932, 92%; 393 mg; mp: 260–262 ꢀC; IR (KBr, cmꢁ1): 3237, 2995, 2938,
2854, 1635, 1560, 1490, 1361, 1279, 1168, 1070, 775 cmꢁ1; H 2839, 1636, 1562, 1492, 1367, 1277, 1162, 1068, 719 cmꢁ1; H
NMR (400 MHz, DMSO-d6) d 2.59 (s, 3H), 3.10 (s, 3H), 3.46 (s, NMR (400 MHz, DMSO-d6) d 2.58 (s, 3H), 3.11 (s, 3H), 3.52 (s,
3H), 5.95 (s, 1H), 7.13 (d, J ¼ 8 Hz, 1H), 7.28–7.32 (m, 2H), 7.48 3H), 3.62 (s, 3H), 3.74 (s, 6H), 5.94 (s, 1H), 6.37 (s, 2H), 10.12 (s,
(d, J ¼ 8 Hz, 1H), 10.10 (s, 1H), 13C NMR (100 MHz, DMSO-d6) 1H), 13C NMR (100 MHz, DMSO-d6) d 16.6, 32.3, 41.2, 43.4, 56.3,
d 16.7, 32.4, 40.9, 43.4, 112.8, 122.4, 126.1, 130.2, 131.0, 131.7, 60.40, 104.3, 113.2, 128.2, 135.9, 137.4, 137.6, 153.5, 155.4,
136.7, 142.9, 156.4, 156.6; anal. calcd (%) for C14H15BrN4O4S: C, 156.5; anal. calcd (%) for C17H22N4O7S: C, 47.88; H, 5.20; N,
40.49; H, 3.64; N, 13.49; S, 7.72. Found: C, 40.38; H, 3.66; N, 13.14; S, 7.52; found: C, 47.76; H, 5.17; N, 13.10; S, 7.49.
1
1
13.52; S, 7.75; anal. calcd for [C14H15BrN4O4S + H+]: calcd:
415.0070, found: 415.0070.
N,1-Dimethyl-6-(methylthio)-3,5-dinitro-4-(p-tolyl)-1,4-
dihydropyridin-2-amine (3n). Isolated as light yellow solid;
yield: 94%; 330 mg; mp: 212–214 ꢀC; IR (KBr, cmꢁ1): 3163, 3013,
4-(4-Fluorophenyl)-N,1-dimethyl-6-(methylthio)-3,5-dinitro-
1,4-dihydropyridin-2-amine (3i). Isolated as light yellow solid; 2954, 2854, 1628, 1564, 1488, 1390, 1270, 1186, 1077, 787 cmꢁ1
;
yield: 90%; 319 mg; mp: 230–232 ꢀC; IR (KBr, cmꢁ1): 3216, 3020, 1H NMR (400 MHz, DMSO-d6) d 2.25 (s, 3H), 2.57 (s, 3H), 3.09 (d,
1
2958, 1620, 1562, 1480, 1395, 1277, 1180, 1074, 778 cmꢁ1; H J ¼ 5.2 Hz, 3H), 3.44 (s, 3H), 5.95 (s, 1H), 7.02 (d, J ¼ 8 Hz, 2H),
NMR (400 MHz, DMSO-d6) d 2.60 (s, 3H), 3.11 (d, J ¼ 4.8 Hz, 3H), 7.12 (d, J ¼ 8 Hz, 2H), 10.11 (s, 1H), 13C NMR (100 MHz, DMSO-
3.48 (s, 3H), 6.08 (s, 1H), 7.45 (d, J ¼ 8.8 Hz, 2H), 8.17 (d, J ¼ d6) d 16.5, 21.0, 32.3, 40.8, 43.3, 113.3, 127.0, 129.9, 137.2, 137.4,
8.8 Hz, 2H), 10.15 (s, 1H), 13C NMR (100 MHz, DMSO-d6) d 16.8, 137.9, 155.2, 156.5 anal. calcd (%) for C15H18N4O4S: C, 51.42; H,
32.5, 41.1, 43.6, 112.5, 124.6, 128.8, 136.1, 147.3, 147.5, 156.4, 5.18; N, 15.99, S, 9.15. Found: C, 51.30; H, 5.16; N, 15.95, S, 9.12.
157.4; anal. calcd (%) for C14H15FN4O4S: C, 47.45; H, 4.27; N,
15.81, S, 9.05. Found: C, 47.35; H, 4.25; N, 15.78, S, 9.02.
4-(4-Methoxyphenyl)-N,1-dimethyl-6-(methylthio)-3,5-dinitro-
4-(4-Ethylphenyl)-N,1-dimethyl-6-(methylthio)-3,5-dinitro-1,4-
dihydropyridin-2-amine (3o). Isolated as light yellow solid; yield:
92%; 336 mg; mp: 236–238 ꢀC; IR (KBr, cmꢁ1): 3230, 3010, 2928,
1
1,4-dihydropyridin-2-amine (3j). Isolated as yellow solid; yield: 2856, 1623, 1564, 1480, 1395, 1278, 1180, 1076, 787 cmꢁ1; H
92%; 338 mg; mp: 200–202 ꢀC; IR (KBr, cmꢁ1): 3208, 3012, 2924, NMR (400 MHz, DMSO-d6) d 1.13 (t, J ¼ 8 Hz, 3H), 2.53 (q, J ¼
1
2832, 1620, 1564, 1482, 1377, 1267, 1160, 1065, 710 cmꢁ1; H 7.6 Hz, 2H), 2.57 (s, 3H), 3.09 (d, J ¼ 5.2 Hz, 3H), 3.45 (s, 3H),
NMR (400 MHz, DMSO-d6) d 2.57 (s, 3H), 3.10 (s, 3H), 3.45 (s, 5.95 (s, 1H), 7.05 (d, J ¼ 8 Hz, 2H), 7.15 (d, J ¼ 8 Hz, 2H), 10.11 (s,
3H), 3.71 (s, 3H), 5.91 (s, 1H), 6.86 (d, J ¼ 8.8 Hz, 2H), 7.06 (d, J ¼ 1H), 13C NMR (100 MHz, DMSO-d6) d 15.9, 16.5, 28.2, 32.3, 40.7,
8.8 Hz, 2H), 10.11 (s, 1H), 13C NMR (100 MHz, DMSO-d6) d 16.5, 43.3, 112.4, 127.2, 128.7, 137.6, 137.9, 143.5, 155.2, 156.5; anal.
32.3, 40.6, 43.3, 55.5, 113.5, 114.7, 128.4, 132.2, 138.1, 155.0, calcd (%) for C16H20N4O4S: C, 52.73; H, 5.53; N, 15.37, S, 8.80.
156.5, 159.1; anal. calcd (%) for C15H18N4O5S: C, 49.17; H, Found: C, 52.60; H, 5.51; N, 15.33, S, 8.77.
4.95; N, 15.29; S, 8.75. Found: C, 49.05; H, 4.93; N, 15.25; S, 8.72.
N,1-Dimethyl-6-(methylthio)-3,5-dinitro-4-(thiophen-2-yl)-1,4-
dihydropyridin-2-amine (3p). Isolated as light yellow solid; yield:
4-(3-Methoxyphenyl)-N,1-dimethyl-6-(methylthio)-3,5-dinitro-
1,4-dihydropyridin-2-amine (3k). Isolated as yellow solid; yield: 86%; 295 mg; mp: 208–210 ꢀC; IR (KBr, cmꢁ1): 3103, 3011, 2928,
88%; 323 mg; mp: 236–238 ꢀC; IR (KBr, cmꢁ1): 3237, 3015, 2940, 1633, 1564, 1489, 1395, 1276, 1187, 1070, 778 cmꢁ1; H NMR
1
1
2837, 1618, 1562, 1489, 1358, 1285, 1174, 1072, 739 cmꢁ1; H (400 MHz, DMSO-d6) d 2.52 (s, 3H), 3.19 (s, 3H), 3.45 (s, 3H), 6.39
NMR (400 MHz, DMSO-d6) d 2.58 (s, 3H), 3.10 (s, 3H), 3.45 (s, (s, 1H), 6.92 (d, J ¼ 16 Hz, 2H), 7.42 (s, 1H), 9.98 (s, 1H), 13C NMR
3H), 3.72 (s, 3H), 5.97 (s, 1H), 6.64 (s, 1H), 6.70 (d, J ¼ 8 Hz, 1H), (100 MHz, DMSO-d6) d 16.3, 31.6, 36.4, 42.6, 124.3, 124.9, 127.2,
6.84 (dd, J ¼ 8 Hz, 3.2 Hz, 1H), 7.24 (t, J ¼ 8 Hz, 1H), 10.10 (s, 137.7, 142.7, 152.8, 155.8; anal. calcd (%) for C12H14N4O4S2: C,
1H), 13C NMR (100 MHz, DMSO-d6) d 16.6, 32.4, 40.6, 43.3, 55.5, 42.09; H, 4.12; N, 16.36, S, 18.73. Found: C, 42.19; H, 4.14; N,
113.0, 113.2, 119.2, 130.6, 137.6, 141.9, 155.4, 156.5, 159.9; anal. 16.33, S, 18.70.
calcd (%) for C15H18N4O5S: C, 49.17; H, 4.95; N, 15.29; S, 8.75.
Found: C, 49.08; H, 4.97; N, 15.32; S, 8.77; anal. calcd for
[C15H18N4O5S + H+]: calcd: 367.1070, found: 365.1278.
Conflicts of interest
4-(3,4-Dimethoxyphenyl)-N,1-dimethyl-6-(methylthio)-3,5-
dinitro-1,4-dihydropyridin-2-amine (3l). Isolated as yellow
solid; yield: 90%; 357 mg; mp: 242–244 ꢀC; IR (KBr, cmꢁ1): 3238,
3002, 2842, 2930, 1618, 1563, 1470, 1361, 1234, 1162, 1074,
775 cmꢁ1; 1H NMR (400 MHz, DMSO-d6) d 2.57 (s, 3H), 3.09 (d, J
¼ 4.4 Hz, 3H), 3.47 (s, 3H), 3.69 (s, 3H), 3.70 (s, 3H), 5.91 (s, 1H),
6.62–6.66 (m, 2H), 6.87 (d, J ¼ 6.6 Hz, 1H), 10.13 (s, 1H), 13C
NMR (100 MHz, DMSO-d6) d 16.1, 31.9, 40.1, 42.9, 55.3, 55.5,
110.1, 111.9, 118.9, 132.1, 137.5, 148.2, 148.9, 154.7, 156.0; anal.
calcd (%) for C16H20N4O6S: C, 48.48; H, 5.09; N, 14.13, S, 8.09;
found: C, 48.38; H, 5.07; N, 14.09, S, 8.06; anal. calcd. for
[C16H20N4O6S + H+]: calcd: 397.1176, found: 397.1176.
There are no conicts to declare.
Acknowledgements
Saigal and SK acknowledge the CSIR and UGC, New Delhi
respectively, for their Fellowship. S. C. Sahoo acknowledge to
DST-FIST for single crystal XRD facility. The authors are also
thankful to IIT Patna, NCL Pune for providing NMR and HRMS
facility. The authors are also grateful to the Chairman, Depart-
ment of Chemistry, AMU, Aligarh, for providing necessary
research facilities to complete this work. We are also thankful to
the referees for their valuable suggestions.
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