One-pot pseudo three-component reaction of nitroketene-N,S-acetals and aldehydes for synthesis of highly functionalized hexa-substituted 1,4-dihydropyridines

Article abstract of DOI:10.1039/c4ob00628c

We have described the simple, convenient and high yielding one-pot synthesis of a library of highly functionalized hexa-substituted 1,4-dihydropyridines (1,4-DHPs) by 2-aminopyridine catalysed pseudo three-component reaction of nitroketene-N,S-acetals and aldehydes. This domino transformation involves formation of dihydropyridine ring by creation of two C-C bonds and one C-N bond, all of them taking place in a single synthetic operation. As the products precipitate out of the reaction simple filtration is enough to gather the products and thus, there is no need for work-up or column-chromatography. The C6-methylsulfanyl group in the product 1,4-DHPs was substituted with primary and secondary amines to provide 1,4-DHPs with further possibilities in structural diversity. As a demonstration of application of the method we have synthesised an analogue of nitenpyram, a neonicotinoid insecticide. This journal is the Partner Organisations 2014.

Full text of DOI:10.1039/c4ob00628c

Organic &
Biomolecular Chemistry
View Article Online
View Journal | View Issue
PAPER
One-pot pseudo three-component reaction of
nitroketene-N,S-acetals and aldehydes for
synthesis of highly functionalized hexa-substituted
1,4-dihydropyridines†
Cite this: Org. Biomol. Chem., 2014,
12, 6223
H. Surya Prakash Rao* and A. Parthiban
We have described the simple, convenient and high yielding one-pot synthesis of a library of highly func-
tionalized hexa-substituted 1,4-dihydropyridines (1,4-DHPs) by 2-aminopyridine catalysed pseudo three-
component reaction of nitroketene-N,S-acetals and aldehydes. This domino transformation involves for-
mation of dihydropyridine ring by creation of two C–C bonds and one C–N bond, all of them taking
place in a single synthetic operation. As the products precipitate out of the reaction simple filtration is
enough to gather the products and thus, there is no need for work-up or column-chromatography. The
C6-methylsulfanyl group in the product 1,4-DHPs was substituted with primary and secondary amines to
provide 1,4-DHPs with further possibilities in structural diversity. As a demonstration of application of the
method we have synthesised an analogue of nitenpyram, a neonicotinoid insecticide.
Received 24th March 2014,
Accepted 5th June 2014
DOI: 10.1039/c4ob00628c
www.rsc.org/obc
Introduction
The multicomponent reactions (MCRs) are among the sim-
plest, atom-economic and eco-friendly reactions used for syn-
thesis of complex molecules from readily available bench-top
organic chemicals.1 On their way to generation of complex pro-
ducts, MCRs go through cascade reactions resulting in for-
mation of several bonds within a single pot. Owing to such
highly desirable reaction features that include chemo- and
regioselective formation of the products in high yield and
purity, in recent years, MCRs have garnered a great deal of
attention for synthesis of structurally diverse and densely func-
tionalized biologically and medicinally important products.2
Classical Hantzsch 1,4-dihydropyridine (1,4-DHP) synthesis in
which one unit each of an aldehyde 1, an amine 2 and two
units of acetoacetic ester 3, undergo four-component MCRs to
provide 1,4-DHPs 4 is a quintessential reaction for synthesis of
Scheme 1 Hantzsch 1,4-dihydropyridine synthesis and limitations.
adenine dinucleotide phosphate (NADPH), both of which are
cofactors in the enzymes that perform oxidation–reduction
reactions.4 Synthetic 1,4-DHPs found extensive medicinal
applications5 including use as calcium channel blockers,6 anti-
tumor agents,7 and anti-inflammatory molecules.8 Due to the
highly specific activity of 1,4-DHPs as calcium channel block-
ing agents and ease in bulk-scale synthesis, their derivatives,
for example nifedipine, became standard drugs for treatment
of coronary heart diseases.9 In addition to medicinal appli-
cations, some 1,4-DHPs, like neonicotinoids, exhibit insectici-
dal activity without being very toxic to humans.10 Apart from
the above applications 1,4-DHPs are used as a hydride source
in reduction reactions11 and as synthetic intermediates in alka-
loid syntheses.12 Owing to diverse applications, 1,4-DHP has
become a privileged scaffold and the group has attracted con-
siderable attention for the preparation of structurally diverse
six-member nitrogen heterocycles and equally for methodology
development.13 Although, Hantzsch 1,4-DHP synthesis is
a
large library of six-member nitrogen heterocycles
(Scheme 1).3 The 1,4-DHPs are of immense biological impor-
tance, as they are analogues of the reactive portion of nicotin-
amide adenine dinucleotide (NADH) and nicotinamide
Department of Chemistry, Pondicherry University, Puducherry – 605 014, India.
E-mail: hspr.che@pondiuni.edu.in, hspr@yahoo.com; Fax: +91-413-2656230;
Tel: +91-413-2654411
†Electronic supplementary information (ESI) available: Copies of 1H and 13C
NMR spectra for all new compounds. CCDC 992572 and 918142. For ESI and
crystallographic data in CIF or other electronic format see DOI: 10.1039/
c4ob00628c
This journal is © The Royal Society of Chemistry 2014
Org. Biomol. Chem., 2014, 12, 6223–6238 | 6223

View Article Online
Paper
Organic & Biomolecular Chemistry
Results and discussion
Our initial studies were focused on identification of optimal
reaction conditions for the pseudo MCR of benzaldehyde 1a
and NMSM 5a to afford 1,4-DHP 8a (Table 1). The reaction did
not take place in the absence of a base catalyst (Table 1,
entry 1). A series of the reactions was then performed with a
catalytic amount (10 mol%) of base which included non-
nucleophilic tertiary amines like 4-(dimethylamino)pyridine
Fig. 1 Structure and reactivity profile of NMSM 5a.
hugely popular, it has some limitations like being restricted to
alkyl acetoacetates, the need for a separate nitrogen source,
difficulty in further functionalization of the alkyl group, etc.
(Scheme 1). Hence, development of new methods by overcom-
ing such difficulties for diversity oriented synthesis of polysub-
stituted 1,4-DHPs is of great interest.
Table 1 Optimization of reaction conditions for pseudo MCRs leading
to 8a
In continuation of our efforts in exploring the chemistry of
nitroketene-N,S-acetals,14 we conceived a simple and con-
venient synthesis of highly functionalized 1,4-DHPs by pseudo
MCR of aldehydes and (E)-N-methyl-1-(methylthio)-2-nitroethe-
namine (N-methyl-S-methyl nitroethylene, NMSM) 5a (Fig. 1)
and their analogues. For their simplicity and reactivity pattern
(Fig. 1) nitroenamines like NMSM are attractive substrates for
synthesis of a variety of heterocyclic compounds.15 Recently,
Tobe and co-workers reported the synthesis of C4-substituted
3,5-dinitro-1,4-DHPs, molecules relevant to the present study,
by pseudo three-component condensation involving two
equivalents of 2-formyl-2-nitroenamine (specifically 2-nitro-3-
(propylamino)acrylaldehyde) and one equivalent electron-rich
aromatic compound.16 By taking the reactivity pattern of
NMSM 5a as enumerated in Fig. 1 into consideration, we per-
formed a Hantzsch type pseudo four-component condensation
of two mole equivalents of NMSM 5a with one mole equivalent
each of benzaldehyde 1a and benzylamine 2a in refluxing
ethanol with the intention to generate 1,4-DHP 6 (Scheme 2). 13
The reaction, surprisingly however, provided its regioisomer
1,4-DHP 7a exclusively. In the formation of 7a benzylamine
appeared to replace the methylsulfanyl group located on the 17
initially formed 1,4-DHP 8a. When the reaction of NMSM 5a
and benzaldehyde 1a was conducted in the presence of a cata-
lytic amount of benzylamine 2a (10 mol%) the 1,4-DHP 8a was 21
the major product (71%) and 7a was the minor product (9%).
Entry
Basea (equivalents)
Solvent
Time (h)
Yield (%)
1
2
3
4
5
6
7
8
No catalyst
DMAP (0.1)
DBU (0.1)
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
H2O
24
15
20
20
10
15
10
15
20
12
15
5
10
15
20
15
25
2
—
30
10
26
20
38
36
46
71
62
62
92
71
23
70
62
60
92
40
75
85
62
65
Et3N (0.1)
Pyridine (0.1)
Piperidine (0.1)
Pyrrolidine (0.1)
L-Proline (0.1)
Benzylamine (0.1)
Ethyl amine (0.1)
Aniline (0.1)
2-AP (0.1)
9
10
11
12
4-AP (0.1)
14
15
16
K2CO3 (0.1)
2-AP (0.05)
2-AP (0.01)
2-AP (0.001)
2-AP (1)
2-AP (0.1)
2-AP (0.1)
2-AP (0.1)
2-AP (0.1)
2-AP (0.1)
18
19
20
20
15
10
15
24
EtOH–H2O
MeOH
DMF
22
23
Toluene
We explored the reaction further and present here its scope for
the synthesis of a library of 1,4-DHPs 7 and 8 and for the facile
synthesis of an analogue of neonicotinoid insecticide.
a DMAP: 4-(dimethylamino)pyridine; DBU: 1,8-diazabicycloundec-7-ene;
AP: aminopyridine; DMF: N,N-dimethylformamide.
Scheme 2 The pseudo four-component reaction of aldehyde 1a, NMSM 5a and benzylamine 2a for the synthesis of 1,4-DHP 7a.
6224 | Org. Biomol. Chem., 2014, 12, 6223–6238
This journal is © The Royal Society of Chemistry 2014

View Article Online
Organic & Biomolecular Chemistry
Paper
(DMAP; entry 2), 1,8-diazabicycloundec-7-ene (DBU; entry 3),
With 1 equivalent of 2-AP the product 8a was formed in
triethylamine (entry 4) and pyridine (entry 5) in EtOH over 92% yield within 2 h (entry 18), but the product required
medium. In each case 1,4-DHP 8a was obtained in poor yield. chromatographic purification. Although the reaction pro-
Although the yield of the desired product 8a improved when ceeded in various solvents like water (entry 19), 1 : 1 mixture of
secondary amines like piperidine (entry 6), pyrrolidine (entry water and ethanol (entry 20), methanol (entry 21), dimethyl-
7) and L-proline (entry 8) were employed, still the yield was formamide (entry 22) and toluene (entry 23) at respective
only moderate and much lower than when primary amine solvent reflux temperature, refluxing ethanol was selected for
bases like benzyl amine (entry 9), 30% aq. solution of ethyl optimized reaction conditions. Under these conditions, yellow
amine (entry 10) or aniline (entry 11) were employed. The real colored product 8a precipitated from the reaction mixture and
breakthrough appeared when we employed 10 mol% of simple filtration was enough to collect the spectroscopic grade
2-aminopyridine (2-AP; entry 12) and the reaction provided product.
over 92% yield consistently. The yield of 8a was lower when 4-
The 1,4-DHP 8a was characterized on the basis of IR,
aminopyridine (entry 13) or inorganic bases, e.g. potassium 1H NMR, 13C NMR spectral data and HRMS analysis. The H
carbonate (entry 14), were employed. Next, we varied the NMR spectrum of 8a displayed a characteristic signal for C4H
amount of the 2-AP to evaluate the minimum amount required at 5.94 ppm. The signals located at δ 2.53, 3.09 and 3.42
to furnish 8a in near quantitative yield. The set of experiments attributable to SMe, NHMe and NMe, respectively, supported
(entries 15–17) showed that 10 mol% of 2-AP provides products the assigned structure. The 13C NMR spectrum of 8a displayed
1
in high purity in over 92% yield.
the anticipated 12 signals out of which four were located in
the aliphatic region. The structure of 8i was unequivocally
assigned on the basis of single crystal X-ray structure analysis
(Fig. 2).
Based on the above results, a plausible mechanism was pro-
posed as shown in Scheme 3. In the first step benzaldehyde 1a
reacts with 2-AP to form the iminium ion 9. The iminium ion
then reacts with NMSM 5a to generate intermediate 10 which
quickly rearranges to the more stable intermediate 11 where
the nitroketene-N,S-acetal substructure has been restored. The
intermediate 11 reacts with one more unit of NMSM 5a to
generate intermediate 12 and 2-AP. Finally, an intramolecular
elimination of methanethiol furnishes 1,4-DHP 8a. Formation
of iminium ion 9 as the initial intermediate is indicated by the
fact that primary amines efficiently promote the pseudo MCR
(Table 1). Nucleophilic base 2-AP appears to have the unique
ability to form an imine by reacting with benzaldehyde 1a but
not displace the methylsulfanyl group in 8a. The reaction of
intermediate 11 with a second unit of NMSM 5a could go
Fig. 2 ORTEP diagram of the 4-(2,4-dimethoxyphenyl)-N,1-dimethyl-
6-(methylthio)-3,5-dinitro-1,4-dihydropyridin-2-amine 8i.
Scheme 3 Plausible mechanism for the formation of 1,4-DHP 8a.
This journal is © The Royal Society of Chemistry 2014
Org. Biomol. Chem., 2014, 12, 6223–6238 | 6225

View Article Online
Paper
Organic & Biomolecular Chemistry
through several pathways, like formation of C–C bond (route a, cated that the α,β-unsaturation does not have much influence.
Scheme 3) ahead of C–N bond formation (route b, Scheme 3) or An aliphatic aldehyde, e.g. hexanal (entry 13), furnished 1,4-
the other way. Although confirmative evidences are not available DHP 8m in good yield. The pseudo MCR was next performed
at present, we presume that route a is more feasible than b with various heterocyclic aromatic aldehydes like thiophene-
(Scheme 3) as nucleophilic primary amines like benzyl amine 2-carbaldehyde 1n, furan-2-carbaldehyde 1o, 1,3-diphenyl-1H-
did not react with NMSM to provide 6 or 7a as the primary pyrazole-4-carbaldehyde 1p, pyridine-3-carbaldehyde 1q and
product (Scheme 2). The reaction of intermediate 11 with 5a indole-3-carbaldehyde 1r (entries 14–18) to result in the corres-
could go through an aza-Diels–Alder pathway. However, taking ponding 1,4-DHPs 8n–r in good yield.
into consideration the low reactivity of NMSM 5a towards Diels–
After demonstrating the ease of synthesis of 1,4-DHPs 8b–r
by incorporating various changes in the aldehyde portion, we
Alder reactions17 we assume this pathway is unlikely.
The 1,4-DHPs 8 have two potential areas for development of have taken up the synthesis of 1,4-DHPs where diversity is
structural diversity, namely the aldehyde and the N-alkyl built into N-alkyl group. The reaction of nitroketene-N,S-
groups, which can be exploited for preparation of a library of acetals with N-benzyl 5b, N-4-methoxyphenylethyl 5c and
two-dimensional matrix. We employed the optimized reaction n-butyl 5d groups afforded the corresponding 1,4-DHPs 8s–u
conditions for construction of a small library of 1,4-DHPs 8a–u (entries 19–21) without much difficulty. However, the reaction
(Table 2, Fig. 3). Initially, variations were incorporated in the with the nitroketene-N,S-acetal with N-phenyl group did not
benzaldehyde ring by placing electron-withdrawing or elec- furnish the desired 1,4-DHP, possibly due to steric repulsion
tron-donating groups in the C4 position (Table 2, entries 2–8) that gets inbuilt when the product is formed. Spectroscopic
and the products 8b–h were obtained in good yields. The data of 1,4-dihydropyridines 8b–u compared well with those of
results indicated that the electron-donating or withdrawing the parent compound 8a.
groups had little influence on the outcome of the reaction.
The 1,4-dihydropyridines 8 possess a highly labile SMe
Introduction of steric effects at the C2-position of benz- group, which can be replaced with a variety of nucleophiles by
aldehyde (entries 9–10) in the form of OMe group did not have SNV substitution.18 For the present study, we have selected to
any effect on the formation of 1,4-DHPs 8i–j. Similarly, replace the C6 methylsulfanyl group in 8a with a variety of ali-
naphthaldehyde (entry 11) provided the 1,4-DHP 8k without much phatic primary and secondary amines. Thus, the reaction of
difficulty. This methodology was tested with cinnamaldehyde 1,4-DHP 8a with 1 equivalent of primary amines like benzyl
(entry 12) for the formation of 1,4-DHP 8l and the results indi- amine 2a, phenylethyl amine 2b, n-butyl amine 2c, and n-hexyl
Table 2 Synthesis of hexa-substituted 1,4-dihydropyridines (8a–8u)a
Entry
R1 in 1
R2 in 5
1,4-DHP 8
Time (h)
Yieldb (%)
1
2
3
4
5
6
7
8
Ph
p-FC6H4
p-ClC6H4
p-BrC6H4
o-O2NC6H4
p-MeC6H4
p-MeOC6H4
p-HOC6H4
o,p-(MeO)2C6H3
p-HO,o-MeOC6H3
Naphthalene-2-yl
Styryl
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
8a
8b
8c
8d
8e
8f
8g
8h
8i
8j
8k
8l
8m
8n
8o
8p
8q
8r
5
6
12
12
20
10
6
15
5
15
6
18
20
10
15
12
15
15
20
10
15
92
89
60
86
56
75
85
62
88
82
90
73
64
70
90
78
76
69
84
86
70
9
10
11
12
13
14
15
16
17
18
19
20
21
Pentyl
Thiophen-2-yl
Furan-2-yl
1,3-Biphenyl-1H-pyrazol-4-yl
Pyridine-3-yl
Indol-3-yl
Ph
Me
Me
Bn
8s
8t
8u
Ph
Ph
4-MeOC6H4CH2CH2
n-Butyl
a General conditions: 1 (1 equivalent), 5 (2 equivalents) and 2-aminopyridine (0.1 equivalent) in refluxing ethanol. b Isolated yield after triturating
with cold (0–5 °C) ethanol.
6226 | Org. Biomol. Chem., 2014, 12, 6223–6238
This journal is © The Royal Society of Chemistry 2014

View Article Online
Organic & Biomolecular Chemistry
Paper
Fig. 3 Library of diversity incorporated 1,4-DHPs with C6-methylthio group.
amine 2d in refluxing EtOH afforded the corresponding 1,4-
DHPs 7a–d in good yields (Scheme 4, Table 3, entries 1–4). The
above experiments showed that it is possible to synthesise a
library of 1,4-DHPs that possess three areas of structural diver-
sity, derived from the aldehydes 1, amine in N,S-acetals 5 and
amines 2 (Scheme 4). To demonstrate this premise on one
Table 3 Replacement of SMe in 8a and 8g by primary and secondary
amines
Entry R1
R2 in 2
R3 in 2 Product Time (h) Yield (%)
1
2
3
4
5
6
7
8
H
H
H
H
Bn
H
H
H
H
7a
7b
7c
7d
7e
7f
1
1
2
5
2
5
6
10
98
90
81
80
96
92
82
81
Phenylethyl
n-Bu
n-Hexyl
OMe Bn
H
H
H
H
Me
Et
Morpholine
Me
Et
H
7g
7h
example, the 1,4-DHP 8g where the C4-aryl ring is derived
from 4-methoxybenzaldehyde was subjected to reaction with
benzylamine and the product 7e was isolated without any
difficulty (Table 3, entry 5). Although the reaction took longer,
the methylsulfanyl group in 1,4-DHP 8a, could be replaced
with secondary amines like N,N-dimethylamine 2e, N,N-diethyl-
amine 2f and morpholine 2g afforded the corresponding
Scheme 4 Synthesis of 1,4-dihydropyridines (7a–h) by nucleophilic
displacement of the C6 methylsulfanyl group in 8a with primary or
secondary amines and 8g with benzylamine.
This journal is © The Royal Society of Chemistry 2014
Org. Biomol. Chem., 2014, 12, 6223–6238 | 6227

View Article Online
Paper
Organic & Biomolecular Chemistry
Fig. 4 Library of 1,4-DHPs 7 with diversity incorporated by replacement of C6-SMe in 8a and 8g.
Scheme 5 Synthesis of neonicotinoid insecticide analogue 9 from 8a.
1,4-DHPs 7f–h in good yields (Table 3, entries 6–8). The library common pest Aphis medicaginis is better.23 We have taken up
of 1,4-DHPs of type 7 that was prepared in this study is shown synthesis of the neonicotinoid analogue 9 to demonstrate an
in Fig. 4. Although it is possible to prepare dihydropyridines application of our newly developed pseudo MCR for the syn-
like 7 via a pseudo four-component MCR of one equivalent of thesis of 1,4-DHPs. The reaction of 8a with 1-(6-chloropyridin-
primary amine, two equivalents of NMSM and one equivalent of 3-yl)-N-methylmethanamine 2h furnished the neonicotinoid
the aldehyde, we found that the transformation is restricted to analogue 9 in excellent yield. The structure of 9 was assigned
reactive and high boiling primary amines like benzyl amine. For on the basis of spectroscopic data and confirmed by single
other primary amines like butyl and hexylamine or secondary crystal X-ray diffraction analysis (Fig. 5, given in the Experi-
1
amines like piperidine the reaction was slow and low yielding.
mental section). Interestingly, the room-temperature H NMR
To demonstrate an application of the present study, we spectrum of 9 showed broad peaks for methylene hydrogens.
designed a synthesis of neonicotinoid analogue 9 (Scheme 5). On heating to 80 °C the spectrum became clear (see ESI†).
Neonicotinoids, for example nitenpyram 10 are a group of
newer class of insecticides used in agriculture and flea control
in domestic animals.19 They exhibit lower toxicity in mammals
than in insects compared to organochlorides, organophos-
phates and carbamates.20 Although neonicotinoids have
become hugely popular, there are some concerns about their
activity against humans and also on human-friendly insects
like honey bees.21 Moreover acquisition of resistance to the
neonicotinoid insecticides is on the rise.22 Therefore there is a
requirement to design suitable analogues with favourable pro-
perties. Chuanwen and co-workers synthesized a few 1,4-DHPs
incorporating the nitenpyram structural motif and showed
that when the nitro group and the secondary amine are locked
in a cis configuration, the insecticide activity against the
Fig. 5 ORTEP diagram of the N2-((6-chloropyridin-3-yl)methyl)-N2,
N6,1-trimethyl-3,5-dinitro-4-phenyl-1,4-dihydropyridine-2,6-diamine 9.
6228 | Org. Biomol. Chem., 2014, 12, 6223–6238
This journal is © The Royal Society of Chemistry 2014

View Article Online
Organic & Biomolecular Chemistry
Paper
This result indicated slow rotation around the C2–N bond at stirred at 80 °C until the reaction was complete, as monitored
room temperature owing to steric hindrance between by thin-layer chromatography (TLC, hexanes–EtOAc, 3 : 2). The
ArCH2NMe and NO2 groups.
reaction mixture was cooled to room temperature and the
resulting solid was filtered off and recrystallized from dichloro-
methane and hexane to obtain pure products 8.
Conclusion
Representative procedure for preparation of hexa substituted
1,4-dihydropyridines 8a
In summary, we have discovered and described new pseudo
three-component reactions for regio- and chemoselective,
high-yielding and experimentally convenient one-pot synthesis
of diversely functionalized hexa-substituted 1,4-dihydropyri-
dines 8 from readily available aldehydes 1 and nitroketene-N,S-
acetals 5. The primary amine 2-AP acted as a tailor-made cata-
lyst for the pseudo MCR. Conveniently the product 1,4-DHPs
precipitated out of the reaction and simple filtration was
enough to isolate pure products. Nucleophilic displacement of
the C6 methylsulfanyl group in 8 with different primary and
N,1-Dimethyl-6-(methylthio)-3,5-dinitro-4-phenyl-1,4-dihydro-
pyridin-2-amine 8a.
secondary amines afforded 1,4-dihydropyridines
7 with
additional structural diversity. The newly developed protocol
allowed a convenient and high-yielding synthesis of neonicoti-
noid insecticide analogue 9.
In a round-bottomed flask a solution of benzaldehyde 1a
(105 mg, 0.94 mmol) NMSM 5a (279 mg, 1.88 mmol) and
10 mol% of 2-aminopyridine (10 mg, 0.09 mmol) in ethanol
(3 mL) were mixed and stirred at 80 °C until the reaction was
complete, as monitored by thin-layer chromatography (TLC,
hexanes–EtOAc, 3 : 2). After 5 h yellow solid was obtained
which was filtered to afford N,1-dimethyl-6-(methylthio)-3,5-
dinitro-4-phenyl-1,4-dihydropyridin-2-amine 8a. Good crystals
were obtained by recrystallization with a solution of dichloro-
methane–hexane (9 : 3 v/v). Yield (292 mg 92%; mp 201 °C;
IR Data (ν) (KBr) 3057, 2995, 2928, 1631, 1497, 1440, 1358,
Experimental
General experimental
All melting points were uncorrected and were determined
using open-ended capillary tubes on VEEGO VMP-DS instru-
ment. All the reactions and chromatographic separations were
observed by thin layer chromatography. Glass plates coated
with silica gel (60–120 mesh SRL chemicals) were employed for
thin layer chromatography (TLC). Infra Red (IR) spectra were
recorded as KBr pellets on a Nicolet-6700 spectrometer. 1H
NMR (400 MHz), 13C NMR (100 MHz) and DEPT-135 spectra
were recorded for (CDCl3) or (DMSO-d6 + CCl4, 1 : 1) solutions
on a BrukerAvance 400 spectrometer with tetramethylsilane
(TMS) as internal standard; J values are in Hz. 1H NMR data
are reported as follows: chemical shift, multiplicity (s = singlet,
d = doublet, t = triplet, q = quartet and m = multiplet), coup-
ling constant, integration. High resolution mass spectra were
recorded on a Water Q-TOF micro mass spectrometer using
electron spray ionization mode. The X-ray diffraction measure-
ments were performed at 298 K on Oxford CrysAlis CCD area
detector system equipped with a graphite monochromator and
a Mo-Kα fine-focus sealed tube (λ = 0.71073 Å). Benzaldehydes
and amines was purchased from Sigma Aldrich Chemicals
Private Limited and (E)-N-methyl-1-(methylthio)-2-nitroethen-
amine NMSM 5a was gifted by Shasun Chemical Company,
Chennai. We synthesized NMSM derivatives like (E)-N-benzyl-
1-(methylthio)-2-nitroethenamine 5b, (E)-N-(4-methoxyphe-
nethyl)-1-(methylthio)-2-nitroethenamine 5c and (E)-N-(1-
(methylthio)-2-nitrovinyl)butan-1-amine 5d in our laboratory.
1244, 1069, 721 cm−1 1H NMR (400 MHz, DMSO-d6 + CCl4,
;
1 : 1) δ 10.05 (s, 1H), 7.28 (t, J = 10.8 Hz, 2H), 7.23 (d, J =
7.2 Hz, 1H), 7.12 (d, J = 7.1 Hz, 2H), 5.94 (s, 1H), 3.42 (s, 3H),
3.09 (d, J = 5.2 Hz, 3H), 2.53 (s, 3H); 13C NMR (100 MHz,
DMSO-d6 + CCl4, 1 : 1) δ 156.3 (C), 154.8 (C), 139.9 (C), 137.6
(C), 129.1 (CH), 127.8 (CH), 126.9 (CH), 113.2 (C), 43.2 (NMe),
40.8 (NHMe), 32.1 (CH), 16.4 (SMe); HRMS (ESI) Calcd for
C14H16N4O4SNa [M + Na] 359.0790 amu, found 359.0791 amu.
4-(4-Fluorophenyl)-N,1-dimethyl-6-(methylthio)-3,5-dinitro-
1,4-dihydropyridin-2-amine 8b.
Following the representative procedure, the solution of 4-fluoro-
benzaldehyde 1b (202 mg, 1.62 mmol), NMSM 5a (454 mg,
3.29 mmol) and 10 mol% of 2-aminopyridine (15 mg,
0.161 mmol in ethanol (3 mL) afforded 4-(4-fluorophenyl)-N,1-
General procedure for synthesis of 1,4-dihydropyridines 8
A solution of aldehydes (1.0 equiv.), NMSM (2.0 equiv.) and dimethyl-6-(methylthio)-3,5-dinitro-1,4-dihydropyridin-2-amine
2-aminopyridine (0.1 equiv.) in ethanol (3 mL) were mixed and 8b. Yield (400 mg, 89%); mp 230 °C; IR Data (ν) (KBr) 3067,
This journal is © The Royal Society of Chemistry 2014
Org. Biomol. Chem., 2014, 12, 6223–6238 | 6229

View Article Online
Paper
Organic & Biomolecular Chemistry
2934, 1630, 1486, 1440, 1393, 1299, 1193, 1069, 802 cm−1
;
775 cm−1
;
1H NMR (400 MHz, DMSO-d6 + CCl4, 1 : 1) δ 10.04
1H NMR (400 MHz, DMSO-d6 + CCl4, 1 : 1) δ 10.06 (s, 1H), (s, 1H), 7.46 (d, J = 8.4 Hz, 2H), 7.12 (d, J = 8.4 Hz, 2H), 5.94 (s,
7.38–7.32 (m, 1H), 7.07–7.02 (m, 1H), 6.98 (d, J = 7.8 Hz, 1H), 1H), 3.44 (s, 3H), 3.10 (s, 3H), 2.56 (s, 3H); 13C NMR (100 MHz,
6.89 (td, J = 9.8, 2.9 Hz, 1H), 5.98 (s, 1H), 3.45 (s, 3H), 3.10 (d, DMSO-d6 + CCl4, 1 : 1) δ 155.7 (C), 154.8 (C), 138.9 (C), 136.6 (C),
J = 5.3 Hz, 3H), 2.56 (s, 3H),13C NMR (100 MHz, DMSO-d6
+
131.6 (CH), 128.8 (CH), 120.6 (C), 112.4 (C), 42.7 (NMe), 39.9
CCl4, 1 : 1) δ 162.2 (C), 155.5 (C), 142.5 (C), 136.6 (C), 130.8 (NHMe), 31.7 (CH), 16.0 (SMe); HRMS (ESI) Calcd for
(CH), 122.5 (CH), 114.4 (C), 113.7 (C), 42.8 (NMe), 39.9 (NHMe), C14H15BrN4O4SNa [M + Na] 436.9895 amu, found 436.9897 amu.
31.8 (CH), 16.1 (SMe); HRMS (ESI) Calcd for C14H15FN4O4SNa
[M + Na] 377.0696 amu, found 377.0694 amu.
N,1-Dimethyl-6-(methylthio)-3,5-dinitro-4-(2-nitrophenyl)-1,4-
dihydropyridin-2-amine 8e.
4-(4-Chlorophenyl)-N,1-dimethyl-6-(methylthio)-3,5-dinitro-
1,4-dihydropyridin-2-amine 8c.
Following the representative procedure, the solution of 2-nitro-
benzaldehyde 1e (204 mg, 1.32 mmol), NMSM 5a (353 mg,
2.64 mmol) and 10 mol% of 2-aminopyridine (26 mg,
0.13 mmol) in ethanol (3 mL) afforded N,1-dimethyl-6-
(methylthio)-3,5-dinitro-4-(2-nitrophenyl)-1,4-dihydropyridin-2-
amine 8e. Yield (250 mg, 56%); mp 226 °C; IR Data (ν) (KBr)
2994, 2934, 1628, 1568, 1529, 1492, 1367, 1277, 1162, 1068,
Following the representative procedure, the solution of 4 chloro-
benzaldehyde 1c (255 mg, 1.78 mmol), NMSM 5a (498 mg,
3.57 mmol) and 10 mol% of 2-aminopyridine (20 mg,
0.17 mmol) in ethanol (3 mL) afforded 4-(4-chlorophenyl)-N,1-
dimethyl-6-(methylthio)-3,5-dinitro-1,4-dihydropyridin-2-amine
8c. Yield (250 mg, 60%); mp 213 °C; IR Data (ν) (KBr) 3188,
3067, 2996, 2932, 1626, 1580, 1448, 1392, 1361, 1322, 1283,
1
719 cm−1; H NMR (400 MHz, DMSO-d6 + CCl4, 1 : 1) δ 10.15
(s, 1H), 7.80 (dd, J = 8.0, 1.1 Hz, 1H), 7.67 (td, J = 7.9, 1.2 Hz,
1H), 7.45 (t, J = 11.5 Hz, 1H), 7.26 (dd, J = 8.0, 1.2 Hz, 1H), 6.49
(s, 1H), 3.59 (s, 3H), 3.12 (d, J = 3.1 Hz, 3H), 2.56 (s, 3H);
13C NMR (100 MHz, DMSO-d6 + CCl4, 1 : 1) δ 156.0 (C), 152.5
(C), 149.1 (C), 136.2 (C), 133.4 (CH), 132.6 (C), 129.6 (CH),
128.8 (CH), 124.3 (CH), 112.4 (CH), 42.9 (NMe), 36.6 (NHMe),
32.0 (CH), 16.1 (SMe); HRMS (ESI) Calcd for C14H15N5O6SNa
[M + Na] 404.0641 amu, found 404.0639 amu.
1070, 778 cm−1 1H NMR (400 MHz, DMSO-d6 + CCl4, 1 : 1)
.
δ 10.05 (s, 1H), 7.32 (d, J = 8.5 Hz, 2H), 7.17 (d, J = 8.5 Hz, 2H),
5.96 (s, 1H), 3.45 (s, 3H), 3.11 (d, J = 5.2 Hz, 3H), 2.57 (s, 3H);
13C NMR (100 MHz, DMSO-d6 + CCl4, 1 : 1) δ 155.7 (C),
154.8 (C), 138.5 (C), 136.7 (C), 132.2 (C), 128.6 (CH), 128.4
(CH), 112.5 (C), 42.7 (NMe), 39.9 (NHMe), 31.7 (CH), 16.0
(SMe); HRMS (ESI) Calcd for C14H15ClN4O4SNa [M + Na]
393.0400 amu, found 393.0400 amu.
N,1-Dimethyl-6-(methylthio)-3,5-dinitro-4-(p-tolyl)-1,4-dihydro-
pyridin-2-amine 8f.
4-(4-Bromophenyl)-N,1-dimethyl-6-(methylthio)-3,5-dinitro-
1,4-dihydropyridin-2-amine 8d.
Following the representative procedure, the solution of
4 methyl benzaldehyde 1f (502 mg, 4.16 mmol), NMSM 5a
Following the representative procedure, the solution of (798 mg, 8.33 mmol) and 10 mol% of 2-aminopyridine (41 mg,
4-bromo benzaldehyde 1d (101 mg, 0.54 mmol), NMSM 5a 0.41 mmol) in ethanol (5 mL) afforded N,1-dimethyl-6-
(173 mg, 1.08 mmol) and 10 mol% of 2-aminopyridine (12 mg, (methylthio)-3,5-dinitro-4-(p-tolyl)-1,4-dihydropyridin-2-amine 8f.
0.05 mmol) in ethanol (3 mL) afforded 4-(4-bromophenyl)-N,1- Yield (1.1 g, 75%); mp 214 °C; IR Data (ν) (KBr) 3176, 2999, 2927,
dimethyl-6-(methylthio)-3,5-dinitro-1,4-dihydropyridin-2-amine 1630, 1489, 1443, 1389, 1358, 1197, 1168, 1069, 777 cm−1 1H
;
8d. Yield (180 mg, 86%); mp 219 °C; IR Data (ν) (KBr) 3198, NMR (400 MHz, DMSO-d6 + CCl4, 1 : 1) δ 9.96 (s, 1H), 7.04 (d, J =
3068, 2995, 2933, 1627, 1484, 1361, 1281, 1239, 1192, 1068, 8.0 Hz, 2H), 6.98 (d, J = 8 Hz, 2H), 5.92 (s, 1H), 3.39 (s, 3H), 3.09
6230 | Org. Biomol. Chem., 2014, 12, 6223–6238
This journal is © The Royal Society of Chemistry 2014

View Article Online
Organic & Biomolecular Chemistry
Paper
(s, 3H), 2.49 (d, J = 9.2 Hz, 3H), 2.25 (s, 3H); 13C NMR (100 MHz, 5.6 Hz, 3H), 2.51 (s, 3 H); 13C NMR (100 MHz, DMSO-d6
+
DMSO-d6 + CCl4, 1 : 1) δ 155.7 (C), 152.8 (C), 137.9 (C), 136.8 (C), CCl4, 1 : 1) δ 156.8 (C), 155.8 (C), 152.6 (C), 138.3 (C), 129.8 (C),
136.4 (C), 129.1 (CH), 126.4 (CH), 113.1 (C), 42.5 (NMe), 40.2 127.6 (CH), 115.5 (CH), 113.5 (C), 42.6 (NMe), 39.7 (NHMe),
(NHMe), 31.6 (CH), 20.6 (CH3), 15.9 (SMe); HRMS (ESI) Calcd for 31.6 (CH), 15.9 (SMe); HRMS (ESI) Calcd for C14H16N4O5SNa
C15H18N4O4SNa [M + Na] 373.0946 amu, found 373.0945 amu.
4-(4-Methoxyphenyl)-N,1-dimethyl-6-(methylthio)-3,5-dinitro-
1,4-dihydropyridin-2-amine 8g.
[M + Na] 375.0739 amu, found 375.0738 amu.
4-(2,4-Dimethoxyphenyl)-N,1-dimethyl-6-(methylthio)-3,5-
dinitro-1,4-dihydropyridin-2-amine 8i.
Following the representative procedure, the solution of 2,4-
dimethoxy benzaldehyde 1i (501 mg, 3.01 mmol), NMSM 5a
(891 mg, 6.02 mmol) and 10 mol% of 2-aminopyridine (25 mg,
6.02 mmol) in ethanol (5 mL) afforded 4-(2,4-dimethoxy-
phenyl)-N,1-dimethyl-6-(methylthio)-3,5-dinitro-1,4-dihydropyri-
din-2-amine 8i. Yield (1.1 g, 88%); mp 204 °C; IR Data (ν) (KBr)
3165, 2959, 2836, 1628, 1485, 1391, 1362, 1205, 1165, 1047,
Following the representative procedure, the solution of 4-meth-
oxybenzaldehyde 1g (252 mg, 1.83 mmol), NMSM 5a (531 mg,
3.67 mmol) and 10 mol% of 2-aminopyridine (21 mg,
0.18 mmol) in ethanol (3 mL) afforded 4-(4-methoxyphenyl)-
N,1-dimethyl-6-(methylthio)-3,5-dinitro-1,4-dihydropyridin-2-
amine 8g. Yield (570 mg, 85%); mp 203 °C; IR Data (ν) (KBr)
3192, 2994, 2935, 1624, 1497, 1363, 1287, 1249, 1174,
1
770 cm−1; H NMR (400 MHz, DMSO-d6 + CCl4, 1 : 1) δ 10.12
1
1064 cm−1; H NMR (400 MHz, DMSO-d6 + CCl4, 1 : 1) δ 9.96
(s, 1H), 6.69 (d, J = 2.3 Hz, 1H), 6.49 (d, J = 2.4 Hz, 1H), 6.41
(dd, J = 8.4, 2.3 Hz, 1H) 5.86 (s, 1H), 3.73 (s, 3 H), 3.70 (s, 3H),
3.38 (s, 3H), 3.12 (d, J = 5.2 Hz, 3H), 2.47 (s, 3H); 13C NMR
(100 MHz, DMSO-d6 + CCl4, 1 : 1) δ 159.9 (C), 158.1 (C), 156.8
(C), 148.3 (C), 137.9 (C), 129.5 (CH), 118.4 (C), 111.3 (C), 104.4
(CH), 98.8 (CH), 55.3 (OMe), 54.9 (OMe), 41.8 (NMe), 37.9
(NHMe), 31.8 (CH), 15.6 (SMe); HRMS (ESI) Calcd for
C16H20N4O6SNa [M + Na] 419.1001 amu, found 419.1002 amu.
Empirical formula, C16H20N4O6S; formula weight, 396.41;
crystal colour, light yellow; crystal dimensions a = 7.6554(3) Å,
b = 9.9905(4) Å, c = 12.4133(5) Å; α = 84.570(4), β = 88.088(3),
γ = 67.987(4); crystal system, triclinic; V = 876.22(7) A3; space
(s, 1H), 7.05 (d, J = 8.4 Hz, 2H), 6.79 (d, J = 8.4 Hz, 2H), 5.91
(s, 1H), 3.72 (s, 3H), 3.43 (s, 3H), 3.12 (d, J = 5.2 Hz, 3 H), 2.58
(s, 3H); 13C NMR (100 MHz, DMSO-d6 + CCl4, 1 : 1) δ 158.4 (C),
155.6 (C), 152.2 (C), 138.1 (C), 131.4 (CH), 127.6 (CH), 113.8
(C), 113.3 (C), 54.6 (OMe), 42.4 (NMe), 40.1 (NHMe), 31.4 (CH),
15.8 (SMe); HRMS (ESI) Calcd for C15H18N4O5SNa [M + Na]
389.0896 amu, found 389.0894 amu.
4-(1-Methyl-2-(methylamino)-6-(methylthio)-3,5-dinitro-1,4-
dihydropyridin-4-yl)phenol 8h.
group P1; Z = 2; Dcalcd = 1.495 g cm−3; F(000) = 414.0; R(I ≥ 2σ1)
ˉ
= 0.1010, wR2 = 0.2675. Detailed X-ray crystallographic data
was available from the Cambridge Crystallographic Data
Centre (for compound 8i CCDC 992572; see Fig. 2).
3-Methoxy-4-(1-methyl-2-(methylamino)-6-(methylthio)-3,5-
dinitro-1,4-dihydropyridin-4-yl)phenol 8j.
Following the representative procedure, the solution of
4-hydroxybenzaldehyde 1h (510 mg, 2.04 mmol), NMSM 5a
(605 mg, 4.09 mmol) and 10 mol% of 2-aminopyridine (20 mg,
0.20 mmol) in ethanol (3 mL) afforded 4-(1-methyl-2-(methyl-
amino)-6-(methylthio)-3,5-dinitro-1,4-dihydropyridin-4-yl)phenol
8h. Yield (240 mg, 62%); mp 221 °C; IR Data (ν) (KBr) 3244,
3014, 2940, 1624, 1511, 1478, 1394, 1353, 1322, 1278, 1239,
1
1195, 1162, 1122 cm−1; H NMR (400 MHz, DMSO-d6 + CCl4,
1 : 1) δ 9.99 (s, 1H), 9.25 (s, 1H), 6.90 (d, J = 8.8 Hz, 2H), 6.66 Following the representative procedure, the solution of
(dd, J = 6.6, 1.8 Hz, 2H), 5.85 (s, 1H), 3.41 (s, 3H), 3.09 (d, J = 4-hydroxy-2-methoxybenzaldehyde 1j (502 mg, 3.28 mmol),
This journal is © The Royal Society of Chemistry 2014
Org. Biomol. Chem., 2014, 12, 6223–6238 | 6231

View Article Online
Paper
Organic & Biomolecular Chemistry
NMSM 5a (973 mg, 6.57 mmol) and 10 mol% of 2-aminopyri- Following the representative procedure, the solution of cinna-
dine (30 mg, 0.32 mmol) in ethanol (5 mL) afforded maldehyde 1l (203 mg, 1.51 mmol), NMSM 5a (448 mg,
3-methoxy-4-(1-methyl-2-(methylamino)-6-(methylthio)-3,5- 3.03 mmol) and 10 mol% of 2-aminopyridine (14 mg,
dinitro-1,4-dihydropyridin-4-yl)phenol 8j. Yield (980 mg, 82%); 0.15 mmol) in ethanol (5 mL) afforded (E)-N,1-dimethyl-6-
mp 229 °C; IR Data (ν) (KBr) 3442, 3014, 2934, 1629, 1484, (methylthio)-3,5-dinitro-4-styryl-1,4-dihydropyridin-2-amine 8l.
1445, 1363, 1324, 1241, 1193, 741 cm−1 1H NMR (400 MHz, Yield (400 mg, 73%); mp 206 °C; IR Data (ν) 3436, 3241, 3009,
;
DMSO-d6 + CCl4, 1 : 1) δ 10.03 (s, 1H), 8.84 (s, 1H), 6.68 (d, J = 2926, 1621, 1549, 1511, 1442, 1390, 1360, 1270, 1244, 1190,
1
8 Hz, 1H), 6.62 (d, J = 1.6 Hz, 1H), 6.50 (dd, J = 8, 1.6 Hz, 1H), 1115 cm−1; H NMR (400 MHz, DMSO-d6 + CCl4, 1 : 1) δ 10.02
5.90 (s, 1H), 3.74 (s, 3H) 3.44(s, 3H), 3.12 (d, J = 5.2 Hz, 3H), (s, 1H), 7.40 (d, J = 7.2 Hz, 2H), 7.28 (t, J = 10.8 Hz, 2H). 7.20 (t,
2.54 (s, 3H); 13C NMR (100 MHz, DMSO-d6 + CCl4, 1 : 1) δ 155.8 J = 10.4 Hz, 1H), 6.36 (d, J = 15.6 Hz, 1H), 6.05 (dd, J = 15.6,
(C), 153.3 (C), 147.5 (C), 146.1 (C), 137.9 (C), 130.4 (CH), 118.8 6.8 Hz, 1H), 5.48 (d, J = 6.8 Hz, 1H), 3.44 (s, 3H), 3.20 (s, 3H),
(CH), 115.5 (C), 113.2 (CH), 110.7 (C), 55.4 (OMe), 42.6 (NMe), 2.55 (s, 3H); 13C NMR (100 MHz, DMSO-d6 + CCl4, 1 : 1) δ 155.8
39.9 (NHMe), 31.6 (CH), 15.9 (SMe); HRMS (ESI) Calcd for (C), 155.0 (C), 136.2 (C), 135.9 (C), 130.2 (CH), 128.2 (CH),
C15H18N4O6SNa [M + Na] 405.0845 amu, found 405.0847 amu.
127.5 (CH), 126.3 (CH), 125.8 (CH), 119.9 (C), 42.6 (NMe), 38.4
N,1-Dimethyl-6-(methylthio)-4-(naphthalen-2-yl)-3,5-dinitro- (NHMe), 31.4 (CH), 15.7 (SMe); HRMS (ESI) Calcd for
1,4-dihydropyridin-2-amine 8k.
C16H18N4O4SNa [M + Na] 385.0946 amu, found 385.0942 amu.
N,1-Dimethyl-6-(methylthio)-3,5-dinitro-4-pentyl-1,4-dihydro-
pyridin-2-amine 8m.
Following the representative procedure, the solution of hexa-
naldehyde 1m (101 mg, 1.00 mmol), NMSM 5a (296 mg,
2.00 mmol) and 10 mol% of 2-aminopyridine (20 mg,
0.20 mmol) in ethanol (3 mL) afforded N,1-dimethyl-6-
(methylthio)-3,5-dinitro-4-pentyl-1,4-dihydropyridin-2-amine
8m. Yield (220 mg, 64%); mp 195 °C; IR Data (ν) 3445, 3202,
3167, 2928, 2851, 1629, 1491, 1442, 1353, 1322, 1240, 1193,
Following the representative procedure, the solution of
2-naphthaldehyde 1k (501 mg, 3.20 mmol) NMSM 5a (948 mg,
6.41 mmol) and 10 mol% of 2-aminopyridine (30 mg,
0.32 mmol) and in ethanol (5 mL) afforded N,1-dimethyl-
6-(methylthio)-4-(naphthalen-2-yl)-3,5-dinitro-1,4-dihydropyridin-
2-amine 8k. Yield (1.1 g, 90%); mp 217 °C; IR Data (ν) (KBr)
3421, 3200, 3049, 2928, 1629, 1576, 1481, 1446, 1370, 1290,
1
1167, 1102, 1059 cm−1; H NMR (400 MHz, CDCl3) δ 9.98 (d,
J = 4.8 Hz, 1H), 4.97 (t, J = 9.2 Hz, 1H), 3.36 (s, 3H), 3.12 (d, J =
5.2 Hz, 3H), 2.44 (s, 3H), 1.48–1.42 (m, 2H), 1.23–1.11 (m, 6H),
0.82 (t, J = 11.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 156.5
(C), 150.3 (C), 139.9 (C), 114.9 (C), 42.6 (NMe), 36.2 (NHMe),
34.2 (CH2), 31.7 (CH2), 31.5 (CH), 25.6 (CH2), 22.6 (CH2),
16.4 (SMe), 14.1 (Me); HRMS (ESI) Calcd for C13H22N4O4SNa
[M + Na] 353.1259 amu, found 353.1258 amu.
1
1245, 1195, 1068 cm−1; H NMR (400 MHz, DMSO-d6 + CCl4,
1 : 1) δ 10.11 (s, 1H), 7.87 (dd, J = 21.8, 7.9 Hz, 3H), 7.63
(s, 1H), 7.47 (dd, J = 9.1, 5.3 Hz, 2H), 7.32 (d, J = 8.4 Hz, 1H),
6.20 (s, 1H), 3.50 (s, 3H), 3.14 (d, J = 3.9 Hz, 3H), 2.58 (s, 3H);
13C NMR (100 MHz, DMSO-d6 + CCl4, 1 : 1) δ 155.9 (C), 154.7
(C), 137.2 (C), 137.1 (C), 132.8 (C), 132.2 (C), 128.6 (CH), 127.7
(CH), 127.3 (CH), 126.2 (CH), 125.9 (CH), 125.1 (CH), 124.9
(CH), 112.8 (C), 42.8 (NMe), 40.6 (CH), 31.8 (NHMe), 16.1
(SMe); HRMS (ESI) Calcd for C18H18N4O4SNa [M + Na]
409.0946 amu, found 409.0946 amu.
N,1-Dimethyl-6-(methylthio)-3,5-dinitro-4-(thiophen-2-yl)-1,4-
dihydropyridin-2-amine 8n.
(E)-N,1-Dimethyl-6-(methylthio)-3,5-dinitro-4-styryl-1,4-di-
hydropyridin-2-amine 8l.
Following the representative procedure, the solution of thio-
phene-2-carbaldehyde 1n (202 mg, 1.78 mmol) NMSM 5a
(501 mg, 3.56 mmol) and 10 mol% of 2-aminopyridine (20 mg,
0.17 mmol) in ethanol (3 mL) afforded N,1-dimethyl-
6-(methylthio)-3,5-dinitro-4-(thiophen-2-yl)-1,4-dihydropyridin-
6232 | Org. Biomol. Chem., 2014, 12, 6223–6238
This journal is © The Royal Society of Chemistry 2014

View Article Online
Organic & Biomolecular Chemistry
Paper
1
2-amine 8n. Yield (410 mg, 70%); mp 209 °C; IR Data (ν) (KBr) 1300, 1276, 1242, 1174, 1202, 1118, 1065, 785 cm−1; H NMR
3419, 3196, 2994, 2927, 1627, 1576, 1480, 1427, 1392, 1363, (400 MHz, DMSO-d6 + CCl4, 1 : 1) δ 10.10 (s, 1H), 8.12 (s, 1H),
1287, 1158, 1066, 812 cm−1
;
1H NMR (400 MHz, DMSO-d6
+
7.83 (dd, J = 8.6, 1.0 Hz, 2H), 7.69–7.67 (m, 2H), 7.47–7.43
CCl4, 1 : 1) δ 9.98 (s, 1H), 7.32 (dd, J = 5.0, 1.2 Hz, 1H), (m, 5H), 7.28 (t, J = 11.1 Hz, 1H), 6.18 (s, 1H), 3.46 (s, 3H), 3.08
6.92 (dd, J = 5.10, 3.5 Hz, 1H), 6.83 (t, 2.1 Hz, 1H), 6.21 (s, 1H), (d, J = 5.2 Hz, 3H), 2.49 (s, 3H); 13C NMR (100 MHz, DMSO-
3.40 (s, 3H), 3.10 (d, J = 4.9 Hz, 3H), 2.57 (s, 3H); 13C NMR d6 + CCl4, 1 : 1) δ 155.7 (C), 152.1 (C), 150.9 (C), 139.2 (C),
(100 MHz, DMSO-d6 + CCl4, 1 : 1) δ 155.5 (C), 143.1 (C), 137.7 (C), 133.3 (C), 129.1 (CH), 128.2 (CH), 127.9 (CH),
136.6 (C), 126.9 (CH), 124.8 (CH), 124.2 (CH), 112.9 (C), 127.8 (CH), 126.9 (CH), 126.1 (CH), 120.4 (C), 118.4 (CH), 112.9
42.7 (NMe), 36.1 (CH), 31.7 (NHMe), 16.0 (SMe); HRMS (ESI) (C), 41.9 (NMe), 39.9 (NHMe), 31.8 (CH), 15.9 (SMe); HRMS
Calcd for C12H14N4O4S2Na [M + Na] 365.0354 amu, found (ESI) Calcd for C23H22N6O4SNa [M + Na] 501.1321 amu, found
365.0354 amu.
501.1321 amu.
4-(Furan-2-yl)-N,1-dimethyl-6-(methylthio)-3,5-dinitro-1,4-
dihydropyridin-2-amine 8o.
N,1′-Dimethyl-6′-(methylthio)-3′,5′-dinitro-1′,4′-dihydro-[3,4′-
bipyridin]-2′-amine 8q.
Following the representative procedure, the solution of furfur-
aldehyde 1o (502 mg, 5.31 mmol), NMSM 5a (801 mg,
10.63 mmol) and 10 mol% of 2-aminopyridine (49 mg,
0.53 mmol) in ethanol (5 mL) afforded 4-(furan-2-yl)-N,1-
dimethyl-6-(methylthio)-3,5-dinitro-1,4-dihydropyridin-2-amine
8o. Yield (990 mg, 90%); mp 200 °C; IR Data (ν) Data 3197,
3110, 2945, 1635, 1569, 1569, 1487, 1442, 1393, 1301, 1278,
Following the representative procedure, the solution of pyri-
dine-3-carbaldehyde 1q (251 mg, 2.35 mmol), NMSM 5a
(501 mg, 4.71 mmol) and 10 mol% of 2-aminopyridine (31 mg,
0.23 mmol) in ethanol (3 mL) afforded N,1′-dimethyl-6′-
(methylthio)-3′,5′-dinitro-1′,4′-dihydro-[3,4′-bipyridin]-2′-amine
8q. Yield (600 mg, 76%); mp 149 °C; IR Data (ν) (KBr)
3443, 3204, 3069, 2931, 2810, 2742, 1693, 1631, 1476, 1446,
1156, 1066, 1010, 777 cm−1 1H NMR (400 MHz, DMSO-d6
; +
1394, 1299, 1281, 794 cm−1 1H NMR (400 MHz, DMSO-d6
; +
CCl4, 1 : 1) δ 9.95 (s, 1H), 7.46 (s, 1H), 6.32 (s, 1H), 6.16 (s, 1H),
6.05 (s, 1H), 3.38 (s, 3H), 3.12 (d, J = 2.4 Hz, 3H), 2.56 (s, 3H);
13C NMR (100 MHz, DMSO-d6 + CCl4, 1 : 1) δ 155.8 (C), 155.1
(C), 150.7 (C), 142.2 (C), 135.0 (CH), 110.72 (CH), 110.2 (CH),
106.1 (C), 42.4 (NMe), 34.8 (NHMe), 31.3 (CH), 15.8 (SMe);
HRMS (ESI) Calcd for C12H14N4O5SNa [M + Na] 349.0583 amu,
found 349.0582 amu.
CCl4, 1 : 1) δ 10.09 (s, 1H), 8.43 (td, J = 7.9, 1.9 Hz, 2H),
7.56–7.53 (m, 1H), 7.34–7.30 (m, 1H), 5.94 (s, 1H), 3.52 (s, 3H),
3.14 (s, 3H), 2.59 (s, 3H); 13C NMR (100 MHz, DMSO-d6
+
CCl4, 1 : 1) δ 155.8 (C), 155.5 (C), 148.4 (C), 148.2 (C),
136.1 (CH), 135.1 (CH), 134.4 (CH), 123.7 (CH), 112.1 (C),
42.9 (NMe), 40.1 (NHMe), 31.7 (CH), 16.1 (SMe); HRMS (ESI)
Calcd for C13H15N5O4SNa [M + Na] 360.0742 amu, found
360.0744 amu.
4-(1,3-Biphenyl-1H-pyrazol-4-yl)-N,1-dimethyl-6-(methylthio)-
3,5-dinitro-1,4-dihydropyridin-2-amine 8p.
4-(1H-indol-3-yl)-N,1-dimethyl-6-(methylthio)-3,5-dinitro-1,4-
dihydropyridin-2-amine 8r.
Following the representative procedure, the solution of 1,3-
diphenyl-1H-pyrazole-4-carbaldehyde 1p (101 mg, 0.40 mmol), Following the representative procedure, the solution of indole-
NMSM 5a (202 mg, 0.80 mmol) and 10 mol% of 2-aminopyri- 3-carbaldehyde 1r (101 mg, 0.68 mmol), NMSM 5a (202 mg,
dine (7 mg, 0.040 mmol) in ethanol (3 mL) afforded 4-(1,3- 1.37 mmol) and 10 mol% of 2-aminopyridine (12 mg,
diphenyl-1H-pyrazol-4-yl)-N,1-dimethyl-6-(methylthio)-3,5-dinitro- 0.06 mmol) in ethanol (3 mL) afforded 4-(1H-indol-3-yl)-N,1-
1,4-dihydropyridin-2-amine 8p. Yield (110 mg, 78%); mp dimethyl-6-(methylthio)-3,5-dinitro-1,4-dihydropyridin-2-amine
216 °C; IR Data (ν) (KBr) 3125, 1622, 1534, 1493, 1450, 1372, 8r. Yield (180 mg, 69%); mp 229 °C; IR Data (ν) (KBr) 3419,
This journal is © The Royal Society of Chemistry 2014
Org. Biomol. Chem., 2014, 12, 6223–6238 | 6233

View Article Online
Paper
Organic & Biomolecular Chemistry
1619, 1456, 1364, 1230, 1166, 1114, 780 cm−1
;
1H NMR 3,5-dinitro-4-phenyl-1,4-dihydropyridin-2-amine
8t.
Yield
(400 MHz, DMSO-d6 + CCl4, 1 : 1) δ 10.93 (s, 1H), 9.93 (s, 1H), (550 mg, 86%); mp 210 °C; IR Data (ν) 3128, 3064, 2997, 2935,
7.49 (d, J = 7.9 Hz, 1H), 7.31 (d, J = 8.0 Hz, 1H), 7.06 (t, 1634, 1487, 1359, 1282, 1067, 818, 770 cm−1 1H NMR
;
16.7 Hz, 1H), 6.98–6.92 (m, 2H), 6.28 (s, 1H), 3.40 (s, 3H), 3.08 (400 MHz, CDCl3 + CCl4, 1 : 1) δ 9.81 (s, 1H), 7.26–6.75 (m,
(s, 3H), 2.53 (s, 3H); 13C NMR (100 MHz, DMSO-d6 + CCl4, 13H) 6.40 (s, 1H),3.80 (td, J = 18.3, 4.94 Hz, 1H), 3.60 (d, J =
1 : 1) δ 156.0 (C), 152.5 (C), 138.5 (C), 136.5 (CH), 125.4 (C), 10.8 Hz, 6H), 3.53–3.50 (m, 3H), 2.94–2.90 (m, 2H), 2.38 (s,
122.0 (C), 121.3 (CH), 118.9 (CH), 118.8 (CH), 114.4 (C), 113.4 3H), 2.18 (td, J = 18, 4.98 Hz, 1H), 1.94 (dd, J = 17.5, 4.9 Hz,
(C), 111.5 (CH), 41.9 (NMe), 39.9 (NHMe), 31.8 (CH), 15.9 1H); 13C NMR (100 MHz, CDCl3 + CCl4, 1 : 1) δ 159.0 (C), 158.8
(SMe); HRMS (ESI) Calcd for C16H17N5O4SNa [M + Na] (C), 154.6 (C), 139.9 (C), 139.6 (C), 129.8 (CH), 129.5 (CH),
398.0899 amu, found 398.0898 amu.
128.9 (CH), 128.6 (CH), 127.8 (CH), 126.3 (CH), 116.1 (CH),
N,1-Dibenzyl-6-(methylthio)-3,5-dinitro-4-phenyl-1,4-dihydro- 114.6 (CH), 114.3 (CH), 55.5 (OMe), 55.4 (OMe), 55.4 (CH2),
pyridin-2-amine 8s.
48.3 (CH2), 40.1 (CH2), 36.0 (CH2), 34.3 (CH), 17.2 (SMe);
HRMS (ESI) Calcd for C30H32N4O6SNa [M + Na] 599.6940 amu,
found 599.1942 amu.
N,1-Dibutyl-6-(methylthio)-3,5-dinitro-4-phenyl-1,4-dihydro-
pyridin-2-amine 8u.
Following the representative procedure, the solution of benz-
aldehyde 1a (102 mg, 0.94 mmol), (E)-N-benzyl-1-(methylthio)-
2-nitroethenamine 5b (402 mg, 1.88 mmol) and 10 mol% of
2-aminopyridine (20 mg, 0.09 mmol) in ethanol (3 mL)
afforded N,1-dibenzyl-6-(methylthio)-3,5-dinitro-4-phenyl-1,4-
dihydropyridin-2-amine 8s. Yield (250 mg, 84%); mp 224 °C;
IR Data (ν) 3060, 3033, 2924, 1614, 1415, 1376, 1294, 1133,
Following the representative procedure, the solution of benz-
aldehyde 1a (101 mg, 0.94 mmol), (E)-N-(1-(methylthio)-2-nitro-
vinyl)butan-1-amine 5d (322 mg, 1.88 mmol) and 10 mol% of
2-aminopyridine (20 mg, 0.18 mmol) in ethanol (3 mL)
963, 755 cm−1 1H NMR (400 MHz, CDCl3) δ 10.13 (t, J =
;
afforded
N,1-dibutyl-6-(methylthio)-3,5-dinitro-4-phenyl-1,4-
8.4 Hz, 1H), 7.44–7.36 (m, 5H), 2.26 (s, 1H), 7.15–7.03 (m, 5H),
6.94 (t, J = 11.6 Hz, 2H), 6.43 (d, J = 7.2 Hz, 2H), 6.16 (s, 1H),
5.08 (d, J = 14.4 Hz, 1H), 4.87 (d, J = 14.4 Hz, 1H), 4.73–4.71
(m, 2H), 2.28 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 154.1 (C),
146.6 (C), 140.9 (C), 138.4 (C), 136.0 (C), 133.8 (C), 129.6 (CH),
129.5 (CH), 129.3 (CH), 128.8 (C), 128.6 (CH), 127.1 (CH), 126.9
(CH), 117.2 (C), 56.9 (CH2), 50.4 (CH2), 41.3 (CH), 16.9 (SMe);
HRMS (ESI) Calcd for C26H24N4O4SNa [M + Na] 511.1416 amu,
found 511.1418 amu.
dihydropyridin-2-amine 8u. Yield (220 mg, 70%); mp 225 °C;
IR Data (ν) 3445, 2962, 2929, 2872, 1623, 1493, 1422, 1372,
1
1237, 1207, 1182, 1160, 740 cm−1; H NMR (400 MHz, CDCl3)
δ 9.91 (d, J = 3.6 Hz, 1H), 7.26–7.20 (m, 3H), 7.06–7.04 (dd, J =
7.3, 1.0 Hz, 2H), 6.41 (s, 1H), 3.74–3.34 (m, 1H), 3.33–3.32 (m,
2H), 3.30–3.27 (m, 1H), 2.42 (s, 3H), 1.72–1.46 (m, 2H), 1.46 (s,
1H), 1.46–1.44 (m, 2H), 1.03–0.94 (m, 6H), 0.64 (t, J = 10.6 Hz,
3H); 13C NMR (100 MHz, CDCl3) δ 155.1 (C), 149.6 (C), 139.99
(C), 139.91 (C), 128.8 (CH), 127.6 (CH), 126.4 (CH), 115.9 (C),
54.2 (CH2), 46.9 (CH2), 40.0 (NMe), 32.2 (CH2), 31.0 (CH2), 19.9
(CH2), 19.8 (CH2), 16.9 (SMe), 13.6 (Me), 13.3 (Me); HRMS (ESI)
Calcd for C20H28N4O4SNa [M + Na] 443.1729 amu, found
443.1729 amu.
N,1-Bis(4-methoxyphenethyl)-6-(methylthio)-3,5-dinitro-4-
phenyl-1,4-dihydropyridin-2-amine 8t.
General procedure for synthesis of 1,4-dihydropyridine 7
A solution of N,1-dimethyl-6-(methylthio)-3,5-dinitro-4-phenyl-
1,4-dihydropyridin-2-amine (1 equiv.) and aliphatic amine
(1 equiv.) in ethanol (5 mL) were mixed and stirred at 80 °C
Following the representative procedure, the solution of benz- until the reaction was complete, as monitored by thin-layer
aldehyde 1a (202 mg, 1.88 mmol), (E)-N-(4-methoxyphenethyl)- chromatography (TLC). The reaction mixture was cooled to
1-(methylthio)-2-nitroethenamine 5c (501 mg, 3.77 mmol) and room temperature and the resulting solid was filtered off and
10 mol% of 2-aminopyridine (42 mg, 0.37 mmol) in ethanol recrystallized from dichloromethane and hexane to obtain
(3 mL) afforded N,1-bis(4-methoxyphenethyl)-6-(methylthio)- pure products 7.
6234 | Org. Biomol. Chem., 2014, 12, 6223–6238
This journal is © The Royal Society of Chemistry 2014

View Article Online
Organic & Biomolecular Chemistry
Paper
N2-Benzyl-N6,1-dimethyl-3,5-dinitro-4-phenyl-1,4-dihydropyri- 113.8 (C), 46.8 (CH2), 43.1 (NMe), 40.2 (CH2), 38.4 (CH),
dine-2,6-diamine 7a. 35.6 (NHMe); HRMS (ESI) Calcd for 21H23N5O4Na
[M + Na] 432.1648 amu, found 432.1648 amu.
C
N2-Butyl-N6,1-dimethyl-3,5-dinitro-4-phenyl-1,4-dihydropyri-
dine-2,6-diamine 7c.
In
a round-bottomed flask a solution of N,1-dimethyl-
6-(methylthio)-3,5-dinitro-4-phenyl-1,4-dihydropyridin-2-amine
8a (502 mg, 1.48 mmol) and benzyl amine 2a (159 mg,
1.48 mmol) in ethanol (5 mL) were mixed and stirred at 80 °C
until the reaction was complete, as monitored by thin-layer
chromatography (TLC, hexanes–EtOAc, 2 : 3). After 1 h white
solid was obtained which was filtered to afford N2-benzyl-N6,1-
dimethyl-3,5-dinitro-4-phenyl-1,4-dihydropyridine-2,6-diamine
7a. Yield (510 mg, 98%); mp 218 °C; IR Data (ν) 3023, 2995,
2945, 2837, 1639, 1504, 1463, 1375, 1287, 1155, 1052,
Following the representative procedure, the solution of N,1-
dimethyl-6-(methylthio)-3,5-dinitro-4-phenyl-1,4-dihydropyridin-
2-amine 8a (202 mg, 0.59 mmol) and butyl amine 2c (43 mg,
0.59 mmol) in ethanol (3 mL) afforded N2-butyl-N6,1-dimethyl-
3,5-dinitro-4-phenyl-1,4-dihydropyridine-2,6-diamine 7c. Yield
(180 mg, 81%); mp 215 °C; IR Data (ν) 3148, 2954, 2868, 1638,
1498, 1466, 1369, 1284, 1284, 1159, 1052, 732 cm−1 1H NMR
;
1
699 cm−1; H NMR (400 MHz, DMSO-d6 + CCl4, 1 : 1) δ 10.44
(400 MHz, CDCl3) δ 10.03 (d, J = 4.4 Hz, 2H), 7.26–7.17 (m, 5H),
6.01 (s, 1H), 3.45–3.29 (m, 4H), 2.98 (d, J = 5.2 Hz, 3H),
1.70–1.65 (m, 3H), 1.46–1.40 (m, 2H), 0.95 (t, J = 10.9 Hz, 3H);
13C NMR (100 MHz, CDCl3 + CCl4, 1 : 1) δ 156.2 (C), 155.4 (C),
140.9 (C), 128.7 (CH), 127.42 (CH), 127.40 (CH), 116.0 (C), 115.9
(C), 45.6 (NMe), 42.6 (CH2), 38.9 (CH2), 31.9 (CH), 31.7 (CH2),
20.1 (NHMe), 13.7 (Me); HRMS (ESI) Calcd for C17H23N5O4Na
[M + Na] 384.1648 amu, found 384.1646 amu.
(s, 1H), 10.20 (s, 1H), 7.41–7.38 (m, 4H), 7.35 (d, J = 3.4 Hz,
1H), 7.33–7.25 (m, 2H), 7.21 (t, J = 12.3 Hz, 3H), 5.90 (s, 1H),
4.78–4.72 (m, 2H), 3.38 (s, 3H), 2.56 (s, 3H); 13C NMR
(100 MHz, DMSO-d6 + CCl4, 1 : 1) δ 155.8 (C), 155.2 (C), 141.5
(C), 136.8 (C), 128.7 (CH), 128.4 (CH), 127.8 (CH), 127.3 (CH),
126.8 (CH), 126.7 (CH), 114.8 (C), 114.1 (C), 48.5 (NMe), 42.2
(CH2), 38.5 (CH), 31.7 (NHMe); HRMS (ESI) Calcd for
C20H21N5O4Na [M + Na] 418.1491 amu, found 418.1494 amu.
N2,1-Dimethyl-3,5-dinitro-N6-phenethyl-4-phenyl-1,4-dihydro-
pyridine-2,6-diamine 7b.
N2-Hexyl-N6,1-dimethyl-3,5-dinitro-4-phenyl-1,4-dihydropyri-
dine-2,6-diamine 7d.
Following the representative procedure, the solution of N,1-
Following the representative procedure, the solution of N,1- dimethyl-6-(methylthio)-3,5-dinitro-4-phenyl-1,4-dihydropyridin-
dimethyl-6-(methylthio)-3,5-dinitro-4-phenyl-1,4-dihydropyridin- 2-amine 8a (251 mg, 0.74 mmol) and hexylamine 2d (76 mg,
2-amine 8a (501 mg, 1.48 mmol) and phenylethyl amine 2b 0.74 mmol) in ethanol (3 mL) afforded N2-hexyl-N6,1-
(182 mg, 1.48 mmol) in ethanol (5 mL) afforded N2,1-dimethyl- dimethyl-3,5-dinitro-4-phenyl-1,4-dihydropyridine-2,6-diamine
3,5-dinitro-N6-phenethyl-4-phenyl-1,4-dihydropyridine-2,6- 7d. Yield (250 mg, 80%); mp 208 °C; IR Data (ν) 3146, 3007,
1
diamine 7b. Yield (600 mg, 90%). mp 220 °C; IR Data (ν) 2930, 2859, 1641; H NMR (400 MHz, CDCl3) δ 10.11 (s, 2H),
3607, 3518, 1493, 1450, 1408, 1377, 737 cm−1 1H NMR 7.33 (d, J = 4 Hz, 2H), 7.27 (d, J = 4 Hz, 3H), 6.09 (s, 1H),
;
(400 MHz, DMSO-d6 + CCl4, 1 : 1) δ 10.18 (s, 1H), 10.08 (s, 3.50–3.39 (m, 4H), 3.06 (d, J = 4.8 Hz, 3H), 1.78–1.73 (m, 3H),
1H), 7.29–7.26 (m, 4H), 7.24 (d, J = 1.2 Hz, 2H), 7.19 (d, J = 1.48–1.33 (m, 6H), 0.96 (d, J = 6.4 Hz, 3H); 13C NMR (100 MHz,
7.2 Hz, 2H), 7.13 (d, J = 7.2 Hz, 2H), 5.83 (s, 1H), 3.75–3.74 CDCl3 + CCl4, 1 : 1) δ 156.2 (C), 155.3 (C), 140.9 (C), 128.7 (CH),
(m, 2H), 3.28 (s, 3H), 3.01 (s, 3H), 2.50–2.49 (m, 2H); 127.42 (CH), 127.40 (CH), 116.0 (C), 115.9 (CH), 45.9 (NMe),
13C NMR (100 MHz, DMSO-d6 + CCl4, 1 : 1) δ 155.8 (C), 42.5 (CH2), 38.9 (CH2), 31.7 (CH2), 31.3 (CH2), 29.9 (CH2), 26.6
155.5 (C), 141.5 (C), 137.8 (C), 128.7 (CH), 128.3 (CH), (NHMe), 22.5 (CH2), 14.1 (Me); HRMS (ESI) Calcd for
128.3 (CH), 126.7 (CH), 126.6 (CH), 126.5 (CH), 114.5 (C), C19H27N5O4Na [M + Na] 412.1961 amu, found 412.1960 amu.
This journal is © The Royal Society of Chemistry 2014
Org. Biomol. Chem., 2014, 12, 6223–6238 | 6235

View Article Online
Paper
Organic & Biomolecular Chemistry
N2-Benzyl-4-(4-methoxyphenyl)-N6,1-dimethyl-3,5-dinitro-1,4-
dihydropyridine-2,6-diamine 7e.
40.15 (CH), 32.06 (NHMe), 39.52 (Me); HRMS (ESI) Calcd for
C15H19N5O4Na [M + Na] 356.1335 amu, found 356.1338 amu.
N2,N2-Diethyl-N6,1-dimethyl-3,5-dinitro-4-phenyl-1,4-dihydro-
pyridine-2,6-diamine 7g.
Following the representative procedure, the solution of N,1-
dimethyl-6-(methylthio)-3,5-dinitro-4-phenyl-1,4-dihydropyridin-
2-amine 8a (102 mg, 0.27 mmol) benzyl amine 2a (35 mg,
0.27 mmol) in ethanol (2 mL) afforded N2-benzyl-4-(4-
methoxyphenyl)-N6,1-dimethyl-3,5-dinitro-1,4-dihydropyridine-
2,6-diamine 7e. Yield (120 mg, 96%); mp 198 °C; IR Data (ν)
3444, 3002, 2952, 2923, 1638, 1507, 1469, 1370, 1161, 1194,
Following the representative procedure, the solution of N,1-
dimethyl-6-(methylthio)-3,5-dinitro-4-phenyl-1,4-dihydropyridin-
2-amine 8a (202 mg, 0.59 mmol) and N,N-diethylamine 2f
(44 mg, 0.59 mmol) in ethanol (3 mL) afforded N2,N2-diethyl-
N6,1-dimethyl-3,5-dinitro-4-phenyl-1,4-dihydropyridine-2,6-
diamine 7g. Yield (200 mg, 90%); mp 215 °C; IR Data (ν) 3025,
3000, 2982, 2840, 1666, 1516, 1472, 1386, 1290, 1170, 1062,
1054, 779 cm−1 1H NMR (400 MHz, DMSO-d6 + CCl4, 1 : 1)
;
700 cm−1 1H NMR (400 MHz, DMSO-d6) δ 10.26 (s, 1H),
;
δ 10.41 (s, 1H), 10.17 (s, 1H), 7.40–7.31 (m, 5H), 7.09 (d, J = 8.5
Hz, 2H), 6.80 (d, J = 8.6 Hz, 2H), 5.82 (s, 1H), 4.78–4.66 (m,
2H), 3.71 (s, 3H), 3.37 (s, 3H), 3.23 (s, 3H), 2.93 (d, J = 5.2 Hz,
3H); 13C NMR (DMSO-d6 + CCl4, 1 : 1) δ 158.1 (C), 155.7 (C),
155.1 (C), 136.8 (C), 133.3 (C), 128.6 (CH), 127.7 (CH), 127.6
(CH), 127.2 (CH), 115.0 (CH), 114.3 (C), 113.7 (C), 54.9 (OMe),
48.4 (CH2). 42.1 (NMe), 37.7 (CH), 31.6 (NHMe). HRMS (ESI)
Calcd for C21H23N5O5Na [M + Na] 448.1597 amu, found
448.1594 amu.
7.30–7.25 (m, 2H), 7.22–7.18 (m, 2H), 7.16–7.12 (m, 2H), 5.98
(s, 1H), 3.44–3.35 (m, 4H), 3.34 (s, 3H), 3.12 (s, 3H), 3.10 (s,
3H), 1.10 (d, J = 6.9 Hz, 6H); (t, J = 7.2 Hz, 2H), 7.20 (t, J =
7.1 Hz, 1H), 7.14 (d, J = 7.5 Hz, 2H), 6.0 (s, 1H), 3.33 (s, 3H),
3.11 (d, J = 4.8 Hz, 3H), 2.88 (s, 6H); 13C NMR (100 MHz,
DMSO-d6) δ 156.4 (C), 156.2 (C), 142.0 (C), 128.6 (CH), 126.8
(CH), 125.9 (CH), 116.3 (C), 113.8 (C), 45.1 (CH2), 40.7 (NMe),
32.1 (NHMe), 31.9 (CH), 13.6 (Me); HRMS (ESI) Calcd for
C17H23N5O4Na [M + Na] 384.1648 amu, found 384.1648 amu.
N,1-Dimethyl-6-morpholino-3,5-dinitro-4-phenyl-1,4-dihydro-
pyridin-2-amine 7h.
N2,N2,N6,1-Tetramethyl-3,5-dinitro-4-phenyl-1,4-dihydropyri-
dine-2,6-diamine 7f.
In a round-bottomed flask a solution of N,1-dimethyl-6- Following the representative procedure, the solution of N,1-
(methylthio)-3,5-dinitro-4-phenyl-1,4-dihydropyridin-2-amine 8a dimethyl-6-(methylthio)-3,5-dinitro-4-phenyl-1,4-dihydropyridin-
(201 mg, 0.59 mmol) and N,N-dimethylamine 2e (24 mg, 2-amine 8a (102 mg, 0.95 mmol) and morpholine 2g (75 mg,
1.48 mmol) in ethanol (3 mL) were mixed and stirred at 80 °C 0.95 mmol) in ethanol (3 mL) afforded N, 1-dimethyl-6-mor-
until the reaction was complete, as monitored by thin-layer pholino-3,5-dinitro-4-phenyl-1,4-dihydropyridin-2-amine
7h.
chromatography (TLC, hexanes–EtOAc, 2 : 3). After 5 h yellow Yield (140 mg, 81%); mp 222 °C; IR Data (ν) 3045, 3010, 2988,
1
solid was obtained which was filtered to afford N2,N2,N6, 1-tetra- 2870, 1666, 1520, 1488, 1396, 1289, 1172, 1080, 720 cm−1; H
methyl-3,5-dinitro-4-phenyl-1,4-dihydropyridine-2,6-diamine 7f. NMR (400 MHz, DMSO-d6) δ 10.25 (s, 1H), 7.31–7.27(m, 2H),
Yield (220 mg, 92%); mp 220 °C; IR Data (ν) 3023, 2995, 2945, 7.22–7.21 (m, 1H), 7.17–7.13 (m, 2H), 5.96 (s, 1H), 3.82–3.35 (s,
2837, 1639, 1504, 1463, 1375, 1287, 1155, 1052, 699 cm−1 1H 6H), 3.33(s, 3H), 3.1 (d, J = 5.4 Hz, 3H), 3.13 (s, 2H), 3.10 (s,
;
NMR (400 MHz, DMSO-d6) δ 10.29 (s, 1H), 7.28 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, DMSO-d6) δ 156.2 (C), 142.9 (C),
2H), 7.20 (t, J = 7.1 Hz, 1H), 7.14 (d, J = 7.5 Hz, 2H), 6.0 (s, 1H), 128.7 (CH), 128.4 (CH), 126.8 (CH), 125.9 (CH), 116.3 (C), 113.8
3.33 (s, 3H), 3.11 (d, J = 4.8 Hz, 3H), 2.88 (s, 6H); 13C NMR (C), 65.3 (CH2), 54.9 (CH2), 41.3 (NMe), 39.5(CH), 32.1 (NHMe);
(100 MHz, DMSO-d6) δ 156.4 (C), 156.3 (C), 142.4 (C), 128.7 HRMS (ESI) Calcd for C17H21N5O5Na [M + Na] 398.1440 amu,
(CH), 126.8 (CH), 125.8 (CH), 116.4 (C), 114.2 (C), 40.8 (NMe), found 398.1441 amu.
6236 | Org. Biomol. Chem., 2014, 12, 6223–6238
This journal is © The Royal Society of Chemistry 2014

View Article Online
Organic & Biomolecular Chemistry
Paper
N2-((6-Chloropyridin-3-yl)methyl)-N2,N6,1-trimethyl-3,5-dinitro-
4-phenyl-1,4-dihydropyridine-2,6-diamine 9.
(c) A. Dömling and I. Ugi, Angew. Chem., Int. Ed., 2000, 39,
3168–3210; (d) A. Dömling, Chem. Rev., 2006, 106, 17–89;
(e) H. L. Wei, Z. Y. Yan, Y. L. Niu, G. Q. Li and Y. M. Liang,
J. Org. Chem., 2007, 72, 8600–8603; (f) X. H. Duan,
X. Y. Liu, L. N. Guo, M. C. Liao, W. M. Liu and Y. M. Liang,
J. Org. Chem., 2005, 70, 6980–6983; (g) B. Jiang, S. J. Tu,
P. Kaur, W. Wever and G. G. Li, J. Am. Chem. Soc., 2009,
131, 11660–11661; (h) B. Jiang, T. Rajale, W. Wever, S. J. Tu
and G. G. Li, Chem. – Asian J., 2010, 5, 2318–2335;
(i) C. Cheng, B. Jiang, S. J. Tu and G. G. Li, Green Chem.,
2011, 13, 2107–2115; ( j) X. F. Lin, Z. J. Mao, X. X. Dai, P. Lu
and Y. G. Wang, Chem. Commun., 2011, 47, 6620–6622;
(k) D. Hong, Y. X. Zhu, Y. Li, X. F. Lin, P. Lu and
Y. G. Wang, Org. Lett., 2011, 13, 4668–4671; (l) Y. X. Zhu,
G. W. Yin, D. Hong, P. Lu and Y. G. Wang, Org. Lett., 2011,
13, 1024–1027.
3 (a) A. Hantzsch, Justus Liebigs Ann. Chem., 1882, 215, 1–82;
(b) D. M. Stout and A. I. Meyers, Chem. Rev., 1982, 82, 223–
243; (c) C. O. Kappe, Tetrahedron, 1993, 49, 6937–7168.
4 (a) Y. Sambongi, H. Nitta, K. Ichihashi, M. Futai and
I. Ueda, J. Org. Chem., 2002, 67, 3499–3501; (b) T. Itoh,
K. Nagata, A. Kurihara, M. Miyazaki and A. Ohsawa, Tetra-
hedron Lett., 2002, 43, 3105–3108.
Following the representative procedure, the solution of N,1-
dimethyl-6-(methylthio)-3,5-dinitro-4-phenyl-1,4-dihydropyridin-
2-amine 8a (101 mg, 0.30 mmol) and 1-(6-chloropyridin-3-yl)-
N-methylmethanamine 2h (52 mg, 0.30 mmol) in ethanol
(3 mL) afforded N2-((6-chloropyridin-3-yl)methyl)-N2,N6,1-tri-
methyl-3,5-dinitro-4-phenyl-1,4-dihydropyridine-2,6-diamine 9.
Yield (120 mg, 98%); mp 231 °C; IR Data (ν) 3023, 2926, 1628,
1593, 1454, 1388, 1344, 1245, 1166, 1111, 1047, 931, 757 cm−1
;
1H NMR (400 MHz, DMSO-d6) δ 10.05 (s, 1H), 8.31 (s, 1H), 7.71
(d, J = 7.2 Hz, 1H), 7.40 (dd, J = 8.4 Hz, 1H), 7.29–7.20 (m, 3H),
7.12 (d, J = 7.6 Hz, 2H), 5.99 (s, 1H), 4.54 (d, J = 14.8 Hz, 1H),
4.41 (d, J = 14.8 Hz, 1H), 3.10 (d, J = 7.2 Hz, 6H), 2.80 (s, 3H);
13C NMR (100 MHz, DMSO-d6) δ 156.5 (C), 156.7 (C), 156.0(C),
150.0 (C), 149.9 (C), 142.2 (C), 140.3 (CH), 130.5 (CH), 128.7
(CH), 126.8 (CH), 125.8 (CH), 124.1 (CH), 116.2 (C), 54.2 (CH2),
53.4 (NMe), 40.8 (NMe), 39.1 (CH), 32.2 (NMe); HRMS (ESI)
Calcd for C20H21ClN6O4Na [M + Na] 467.1211 amu, found
467.1211 amu.
5 (a) G. Swarnalatha, G. Prasanthi, N. Sirisha and
C. M. Chetty, Int. J. ChemTech Res., 2011, 3, 75–89;
(b) A. Boumendjel, H. Baubichon-Cortay, D. Trompier,
T. Perrotton and A. Di Pietro, Med. Res. Rev., 2005, 25, 453–
472; (c) A. Hilgeroth, Med. Chem., 2002, 2, 235–245;
(d) G. Prasanthi, K. V. S. R. G. Prasad and K. Bharathi,
Eur. J. Med. Chem., 2014, 73, 97–104.
Empirical formula, C20H21ClN6O4; formula weight,
444.8715; crystal colour, light yellow; crystal dimensions a =
11.9749(6) Å, b = 15.2082(6) Å, c = 12.0561(8) Å; α = 90, β =
106.909(6), γ = 90; crystal system, monoclinic; V = 2100.7(2) A3;
space group P21/c; Z = 4; Dcalcd = 1.406 g cm−3; F(000) = 928.0;
R(I ≥ 2σ1) = 0.0423, wR2 = 0.1404. Detailed X-ray crystallo-
graphic data was available from the Cambridge Crystallo-
graphic Data Centre (for compound 9 CCDC 918142).
6 J. T. David, Biochem. Pharmacol., 2007, 74, 1–9.
7 R. Boer and V. Gekeler, Drugs Future, 1995, 20, 499–509.
8 (a) V. M. Briukhanov, Exp. Clin. Pharmacol., 1994, 57,
47–49; (b) S. Bahekar and D. Shinde, Acta Pharm. A, 2002,
52, 281–287.
9 (a) N. Edraki, A. R. Mehdipour, M. Khoshneviszadeh and
R. Miri, Drug Discovery Today, 2009, 14, 1058–1066;
(b) F. Bossert and W. Vater, Med. Chem. Rev., 1989, 9,
291–324; (c) G. P. Young, Ann. Emerg. Med., 1984, 13,
712–722.
Acknowledgements
10 (a) S. Chuanwen, C. Yanxia, L. Tianyan, W. Ying, F. Ting,
W. Jing and X. Jiahua, Chin. J. Chem., 2012, 30, 1415–1422;
(b) W. Zhang, X. Yang, W. Chen, X. Xu, L. Li, H. Zhai and
Z. Li, J. Agric. Food Chem., 2010, 58, 2741–2745; (c) S. Lu,
X. Shao, Z. Li, Z. Xu, S. Zhao, Y. Wu and X. Xu, J. Agric.
Food Chem., 2012, 60, 322–330; (d) Z. Ye, L. Shi, X. Shao,
X. Xu, Z. Xu and Z. Li, J. Agric. Food Chem., 2013, 61,
312–319.
11 (a) S. G. Ouellet, A. M. Walji and D. W. C. Macmillan, Acc.
Chem. Res., 2007, 40, 1327–1339; (b) S. Hoffmann,
M. Nicoletti and B. List, J. Am. Chem. Soc., 2006, 128,
13074–13075; (c) G. Li and J. C. Antilla, Org. Lett., 2009, 11,
1075–1078; (d) R. He, P. H. Toy and Y. Lama, Adv. Synth.
Catal., 2008, 350, 54–60.
H.S.P.R. thanks UGC, UGC-SAP and DST-FIST for financial
assistance. AP thanks Pondicherry University for fellowship.
We thank CIF, Pondicherry University and IISc, Bangalore for
recording spectra. We thank Shasun Chemicals and Drugs Ltd,
Chennai, for generous gift of NMSM.
References
1 (a) L. F. Tietze, G. Brasche and K. Gericke, in Domino Reac-
tions in Organic Synthesis, Wiley-VCH, Weinheim, 2006;
(b) J. Zhu and H. Bienaymé, in Multicomponent Reactions,
Wiley-VCH, Weinheim, 2005.
2 (a) S. Ali and B. A. H. Pourasad, J. Chem. Res., 2014, 38,
62–63; (b) F.-L. Yang, F.-X. Wang, T.-T. Wang, Y.-J. Wang 12 (a) A. B. Charette, S. Mathieu and J. Martel, Org. Lett., 2005,
and S.-K. Tian, Chem. Commun., 2014, 50, 2111–2113;
7, 5401–5404; (b) L. Z. Chai, Y. K. Zhao, Q. J. Sheng and
This journal is © The Royal Society of Chemistry 2014
Org. Biomol. Chem., 2014, 12, 6223–6238 | 6237

View Article Online
Paper
Organic & Biomolecular Chemistry
Z.-Q. Liu, Tetrahedron Lett., 2006, 47, 9283–9285; 15 (a) P. Metzner and A. Thuillier, in Sulfur Reagents in Organic
(c) J. Chen and A. J. McNeil, J. Am. Chem. Soc., 2008,
130, 16496–16497; (d) R. Lavilla, M. C. Bernabeu,
I. Carranco and J. L. Diaz, Org. Lett., 2003, 5, 717–720;
(e) I. Carranco, J. L. Diaz, O. Jimenez, M. Vendrell,
F. Albericio, M. Royo and R. Lavilla, J. Comb. Chem.,
2005, 7, 33–41; (f) E. Vicente-Garcia, F. Catti, R. Ramon
Synthesis, Academic Press, New York, 1994; (b) M. Kolb,
Synthesis, 1990, 171–190; (c) Y. Tominaga and Y. Matsuda,
J. Heterocycl. Chem., 1985, 22, 937–949; (d) H. Ila,
H. Junjappa and P. K. Mohanta, in Progress in Heterocyclic
Chemistry, ed. G. W. Gribble and T. L. Gilchrist, Pergamon
Press, Oxford, 2001, vol. 13, pp. 1–24.
and R. Lavilla, Org. Lett., 2010, 12, 860–863; (g) S. Maiti, 16 Y. Nakaike, N. Nishiwaki, M. Ariga and Y. Tobe, J. Org.
V. Sridharan and J. C. Menéndez, J. Comb. Chem., 2010,
12, 713–722.
13 (a) J.-P. Wan and Y. Liu, RSC Adv., 2012, 2, 9763–9777;
(b) S. Ghosh, F. Saikh, J. Das and A. K. Pramanik, Tetra-
hedron Lett., 2013, 54, 58–62; (c) S. S. Kahandal, S. R. Kale,
Chem., 2014, 79, 2163–2169.
17 (a) S. E. Denmark and J. A. Sternberg, J. Am. Chem. Soc.,
1986, 108, 8277–8279; (b) L. F. Tietze and A. Schuffenhauer,
Eur. J. Org. Chem., 1998, 1629–1637; (c) D. Cheng, J. Zhou,
E. Saiah and G. Beaton, Org. Lett., 2002, 4, 4411–4414.
M. B. Gawande and R. V. Jayaram, Catal. Sci. Technol., 2014, 18 C. F. Bernasconi and Z. Rappoport, Acc. Chem. Res., 2009,
4, 672–680; (d) T. D. Ananda Kumar, P. Mohana, 42, 993–1003.
C. V. S. Subrahmanyam and K. Satyanarayana, Synth. 19 J. Peter and N. Ralf, Pestic. Sci., 2008, 64, 1084–1098.
Commun., 2014, 44, 574–582; (e) M. Nasr-Esfahani, 20 Y. Kashiwada, Agrochem. Jpn., 1996, 68, 18–19.
S. J. Hoseini, M. Montazerozohori, R. Mehrabi and 21 T. Iwasa, N. Motoyama, J. T. Ambrose and M. R. Roe, Crop
H. Nasrabadi, J. Mol. Catal. A: Chem., 2014, 382, 99–105;
Prot., 2004, 23, 371–378.
(f) C. G. Evans and J. E. Gestwicki, Org. Lett., 2009, 11, 22 (a) A. Elbert and R. Nauen, Pest Manage. Sci., 2000, 56, 60–
2957–2959.
64; (b) K. D. Ninsin, Pest Manage. Sci., 2004, 60, 839–841;
(c) D. M. Sanchez, R. M. Hollingworth, E. J. Grafius and
D. D. Moyer, Pest Manage. Sci., 2006, 62, 30–37;
(d) K. G. Gorman, G. Devine, J. Bennison, P. Coussons,
N. Punchard and I. Denholm, Pest Manage. Sci., 2007, 63,
555–558.
14 (a) H. S. P. Rao and K. Geetha, Tetrahedron Lett., 2009, 50,
3836–3839; (b) H. S. P. Rao, K. Geetha and M. Kamalraj,
RSC Adv., 2011, 1, 1050–1059; (c) H. S. P. Rao, K. Geetha
and M. Kamalraj, Tetrahedron, 2011, 67, 8146–8154;
(d) A. Parthiban, J. Muthukumaran, A. Moushumi Priya,
S. Jayachandran, R. Krishna and H. S. P. Rao, Med. Chem. 23 S. Chuanwen, C. Yanxia, L. Tianyan, W. Ying, F. Ting,
Res., 2013, 23, 642–659.
W. Jing and X. Jiahua, Chin. J. Chem., 2012, 30, 1415–1422.
6238 | Org. Biomol. Chem., 2014, 12, 6223–6238
This journal is © The Royal Society of Chemistry 2014