Lewis acid mediated three-component one-flask regioselective synthesis of densely functionalized 4-amino-1,2-dihydropyridines via cascade Knoevenagel/Michael/cyclization sequence This paper is dedicated to Professor Ganesh Pandey on the occasion of his 60th birthday

Article abstract of DOI:10.1016/j.tet.2014.11.052

A highly convergent and regioselective one-pot synthesis of hitherto unreported 4-amino-1,2-dihydropyridines has been achieved via three-component domino coupling (3CDC) of α-oxoketene-N,S-arylaminoacetals, aldehydes, and malononitrile in the presence of InCl₃ under solvent-free conditions. The merit of this cascade Knoevenagel condensation/Michael addition/cyclization sequence is highlighted by its atom-economy, efficacy of forming consecutive three new bonds (two C-C and one C-N), and one ring in a single operation. Noteworthy, the presence of nitrile and amino groups at 3- and 4-positions of 1,2-dihydropyridine ring makes these compounds excellent precursors for further synthetic renovations. Remarkably, one of the newly synthesized 4-amino-1,2-dihydropyridine exhibited high selectivity and sensitivity for Fe³⁺ ion over other metal ions.

Full text of DOI:10.1016/j.tet.2014.11.052

Accepted Manuscript
Lewis-acid mediated three-component one-flask regioselective synthesis of densely
functionalized 4-amino-1,2-dihydropyridines via cascade Knoevenagel/Michael/
cyclization sequence
Suvajit Koley , Sushobhan Chowdhury , Tanmoy Chanda , B. Janaki Ramulu ,
Subhasis Samai , Lerato Motisa , Maya Shankar Singh
PII:
S0040-4020(14)01636-6
10.1016/j.tet.2014.11.052
TET 26201
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 28 July 2014
Revised Date: 1 November 2014
Accepted Date: 19 November 2014
Please cite this article as: Koley S, Chowdhury S, Chanda T, Janaki Ramulu B, Samai S, Motisa
L, Singh MS, Lewis-acid mediated three-component one-flask regioselective synthesis of densely
functionalized 4-amino-1,2-dihydropyridines via cascade Knoevenagel/Michael/cyclization sequence,
Tetrahedron (2014), doi: 10.1016/j.tet.2014.11.052.
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Knoevenagel/Michael/cyclization sequence†
a
a
a
a
b
Suvajit Koley , Sushobhan Chowdhury , Tanmoy Chanda , B. Janaki Ramulu , Subhasis Samai , Lerato
c
a
Motisa , and Maya Shankar Singh ,*
a
Department of Chemistry, Faculty of Science, Banaras Hindu University, Varanasi-221005, India
School of Physics and Chemistry, University of Kwa-Zulu Natal, Durban-4000, South Africa
School of Pharmacy and Pharmacology, University of Kwa-Zulu Natal, Durban-4000, South Africa
b
c

1
ACCEPTED MANUSCRIPT
Tetrahedron
journal homepage: www.elsevier.com
Lewis-acid mediated three-component one-flask regioselective synthesis of densely
functionalized 4-amino-1,2-dihydropyridines via cascade
Knoevenagel/Michael/cyclization sequence†
a
a
a
a
b
Suvajit Koley , Sushobhan Chowdhury , Tanmoy Chanda , B. Janaki Ramulu , Subhasis Samai , Lerato
c
a,
Motisa , and Maya Shankar Singh ∗
a
Department of Chemistry, Faculty of Science, Banaras Hindu University, Varanasi-221005, India
School of Physics and Chemistry, University of Kwa-Zulu Natal, Durban-4000, South Africa
b
c
School of Pharmacy and Pharmacology, University of Kwa-Zulu Natal, Durban-4000, South Africa
ARTICLE INFO
ABSTRACT
Article history:
Received
A highly convergent and regioselective one-pot synthesis of hitherto unreported 4-amino-1,2-
dihydropyridines has been achieved via three-component domino coupling (3CDC) of α-
Received in revised form
Accepted
Available online
3
oxoketene-N,S-arylaminoacetals, aldehydes, and malononitrile in the presence of InCl under
solvent-free conditions. The merit of this cascade Knoevenagel condensation/Michael
addition/cyclization sequence is highlighted by its atom-economy, efficacy of forming
consecutive three new bonds (two C−C and one C−N), and one ring in a single operation.
Noteworthy, the presence of nitrile and amino groups at 3- and 4-positions of 1,2-
dihydropyridine ring makes these compounds excellent precursors for further synthetic
renovations. Remarkably, one of the newly synthesized 4-amino-1,2-dihydropyridine exhibited
Keywords:
Multicomponent cascade reactions
4
-Amino-1,2-dihydropyridines
3
+
Regioselective annulation
Solvent-free conditions
high selectivity and sensitivity for Fe ion over other metal ions.
2
009 Elsevier Ltd. All rights reserved.
3
+
Selective Fe sensing
1
. Introduction
pyridine based derivatives have broad applications in
10a 10b,c
coordination chemistry, supra-molecular chemisty,
artificial
To achieve pre-eminent goal of organic synthesis, the
10d
10e
photosynthesis systems, luminescent sensor materials, and
development of pot, step, and atom economic sustainable
methods is highly desirable. One of the important challenges of
synthesis is to design well-organized cascades that provide
structural and functional complexity as well as diversity with
remarkable properties. One approach to address this challenge
10f
non-linear optical materials. Additionally, pyridines consisting
of pendant chiral substituents, often used as ligands in several
11
metal-catalyzed asymmetric syntheses.
In view of above significant applications, synthesis of pyridine
derivatives has received much attention. The development of
synthetic routes to pyridine derivatives has been the focus for
decades and continues to be an active area of research even
1-3
involves the development of multicomponent domino reactions
MDRs), particularly those performed in aqueous media or under
(
solvent-free conditions. Due to their simplified reaction design,
convergent nature, extensive minimization of waste, labor, time,
energy and cost, the MDRs have emerged as one of the important
tools for modern organic synthesis, and have realized exponential
growth over the past two decades. As a consequence, solvent-
free MDRs and related reactions are witnessing a new spring.
12
today. Among the reported methods for the synthesis of
pyridine derivatives, the commonly utilized are cycloaddition
14
13
reactions, condensation of amine with carbonyl compounds,
15a
4,5
iminoannulation, coupling of N-vinyl amides with alkenes or
6,7
15b
16
alkynes, ring closing metathesis, and annulations via C−H
17
activation. However, most of the reported methods suffer from
For the past several decades, the synthesis of nitrogen
heterocycles has been a key goal because of their ubiquitous
presence in natural products and drugs. Pyridines, one of the
prominent and privileged N-heterocyclic pharmacophore, exhibit
diverse biological and therapeutic activities, and constitute the
core structural motif of numerous natural products. Furthermore,
18
some drawbacks like poor yields,
solvents/reagents
use of hazardous
15b,17a
that are difficult to degrade or remove
8
from the reaction media. Directed toward such challenging goals,
we focus our attention toward the use and design of domino
reactions for the construction of highly functionalized pyridine
derivatives. The planning of domino reactions is like playing
chess.
9
—
——
∗
Corresponding author. Tel.: +91-542-670-2502; fax: (+91) 542-2368127; e-mail: mssinghbhu@yahoo.co.in (M. S. Singh).

2
Tetrahedron
ACCEPTED MANUSCRIPT
2
. Results and discussion
in EtOH at room temperature. Unfortunately, the reaction did not
proceed at all even after 24 h of stirring, and the starting
materials remained completely unconsumed (Table 1, entry 1).
Next, upon increasing the temperature of the above reaction to
reflux, the Knoevenagel condensation product between aldehyde
Sustainable development has become one of the hottest terms
in the current century. With regard to sustainability,
methodologies based on domino raections are a highly efficient
strategy for the construction of carbon-carbon and carbon-
heteroatom bonds. Ambiphilic synthons have shown a great
potential in the development of new reaction pathways. α-
Oxoketene-N,S-arylaminoacetals containing promising structural
features have demonstrated incredible utility as versatile
intermediates in organic synthesis. Depending upon the reaction
conditions and counter reagents, α-oxoketene-N,S-acetal can
apply its reactive centers in different modes as depicted in
Scheme 1a.
2
a and malononitrile 3 was obtained whereas the N,S-acetal 1a
remained unconsumed even after 24 h (Table 1, entry 2). Next,
the above model reaction was carried out in ethanol under reflux
in the presence of InCl (10 mol % with respect to 1a). In this
case also the reaction stopped at the Knoevenagel condensation
step (Table 1, entry 3). A brief screen of some polar aprotic
solvents like CH CN and THF also did not provide any further
3
19
20
3
improvement (Table 1, entries 4 and 5). With above failures, we
next performed the model reaction in the non-polar solvents like
toluene and benzene in the presence of 10 mol % of InCl (Table
3
1
, entries 6 and 7). Notably, the workup of the reaction provided
the desired pyridine 4a in 40% and 32% yields, respectively
along with Knoevenagel product as predominant one.
Scheme 1. (a) Reaction modes of α-oxoketene-N,S-
arylaminoacetals. (b) Synthetic strategy for hexasubstituted
1
,2-dihydropyridines.
As a part of our research interest toward the development of
new methodologies via MCRs for the synthesis of novel
21,22
heterocyclic compounds,
this time, we envisioned to explore
and
Scheme 2. Synthesis of 4-amino-1,2-dihydropyridines.
α-oxoketene-N,S-arylaminoacetals (using its
C
N
nucleophilic centers) for the straightforward construction of 4-
aminopyridine derivatives. To the best of our knowledge, there is
no report on the synthesis of 4-amino-pentasubstituted 1,2-
Solvent-free reactions play an ever-increasing and important
role in organic synthesis. Interestingly, the power of solvent-free
reactions is even more visible in the area of domino reactions, so
we decided to carry out the reaction under solvent-free
conditions. Thus, the above MCR was performed under solvent-
dihydropyridine
derivatives
from
α-oxoketene-N,S-
arylaminoacetals. With regard to develop a new method for the
synthesis of highly functionalized pyridines, we devised a
cascade cross-dehydrative coupling strategy as outlined in
Scheme 1b. We envisaged that one-pot three-component
synthesis of 1,2-dihydropyridine derivatives from simple and
easily available synthons such as binucleophilic α-oxoketene-
free conditions at 80 °C in the presence of 10 mol % of InCl . To
3
our pleasure, the desired product 4a was obtained in 80% yield
within 6 h (Table 1, entry 8). With a view to optimize the
reaction conditions, experiments were conducted by varying
Lewis acid catalysts and temperature. However, increasing or
decreasing the reaction temperature showed no improvement
N,S-arylaminoacetal
and
bielectrophilic
Knoevenagel
condensation product derived from aromatic aldehyde and
malononitrile could be handy in the present case (Scheme 1b).
The precursor α-oxoketene-N,S-arylaminoacetals are not
commercially sourced and have been synthesized by literature
(
Table 1, entries 9 and 10). Next, some other common Lewis
acids such as FeCl , AlCl , InBr , Sc(OTf) , and Y(OTf) were
3
3
3
3
3
also screened to check their competence (Table 1, entries 11-15)
but none of them provided better result than InCl . Thus, InCl
23a
3
3
methods.
This strategy provided fully substituted 1,2-
was found to be most efficient and effective Lewis acid for the
current MCR.
dihydropyridines by the coupling of α-oxoketene-N,S-
arylaminoacetals, aldehydes, and malononitrile in the presence of
Lewis acid under solvent-free conditions at 80 °C. It involves
domino Knoevenagel/Michael /cyclization sequence, in which
three new σ bonds and one six-membered ring could be
straightforwardly formed (Scheme 2).
With InCl Lewis acid as good promoter in hand, next we
3
intended to optimize its loading, and it was found that the use of
10 mol % of InCl provided the best result (Table 1, entry 8).
3
Reducing the mol % of InCl3 in the reaction increased the
reaction time and lowered the yield, and increasing the catalyst
loading did not show any improvement (Table 1, entries 16 and
To optimize the reaction conditions for the synthesis of 4-
amino-1,2-dihydropyridines,
3-(methylthio)-1-phenyl-3-
1
7). Next, to see the feasibility of this one-pot three-component
(phenylamino)prop-2-en-1-one 1a, benzaldehyde 2a, and
cascade coupling in water, we performed the model reaction in
water at 100 °C, but the reaction stopped at its intermediate
Knoevenagel condensation step (Table 1, entry 18). Obviously,
screening of various parameters revealed that the reaction
malononitrile 3 were taken as test substrates. The equimolar
amounts of 1a, 2a, and 3 were examined under the array of
different conditions and the results are listed in Table 1. Initially,
one-pot three-component reaction of 1a, 2a, and 3 was performed

3
proceeded well in the presence of InCl u
conditions. Thus, the optimum reaction condition for the
synthesis of 4a was found to be equimolar amounts of 1a, 2a, and
A
nd
C
er
C
s
E
ol
P
ve
T
nt
E
-fr
D
ee MATo
N
i
U
llu
S
st
C
rat
R
e
I
the broad synthetic utility and generality of our
P
T
3
developed methodology, diverse aromatic aldehydes (4a–o),
aliphatic aldehydes (4p, q), and one heteroaromatic aldehyde (4r)
were examined and tolerated well under the optimized reaction
conditions to give the desired products 4.
3
in the presence of 10 mol % of InCl at 80 °C under solvent-
3
free conditions (Table 1, entry 8).
Table 1
Table 2
a
a
Optimization of reaction conditions for the synthesis of 4a
Substrates scope for the synthesis of 4
O
NH2
InCl3
(10 mol %)
O
SR2
NH
CN
CN
CN
R3
R1
+
R3 CHO
+
R1
solvent-free
2
2
o
R S
N
Ar
1
Ar
80
C
3
b
4
( time, yield
)
b
Entry
Catalyst
mol %)
Solvent
Temp
(° C)
rt
Time
(h)
24
24
24
24
24
24
24
6
Yield
(%)
O
NH2
O
NH2
O
NH2
CN
CN
CN
(
N
Ph
N
Ph
MeS
N
Ph
c
MeS
MeS
1
2
3
4
5
6
7
8
9
none
none
EtOH
EtOH
EtOH
nr
OMe
F
d
4a (6 h, 80%)
4b (6.5 h, 77%)
4c (7 h, 71%)
reflux
reflux
reflux
reflux
reflux
reflux
80
Kp
O
NH2
d
O
NH2
O
NH2
InCl
InCl
InCl
InCl
InCl
InCl
InCl
InCl
3
(10)
(10)
(10)
(10)
(10)
(10)
(10)
(10)
(10)
(10)
(10)
Kp
CN
CN
Br
CN
d
F
3
3
3
3
3
3
3
CH
3
CN
Kp
Me
N
Ph
Me
N
Ph
Me
OMe
N
Ph
MeS
MeS
MeS
d
Cl
THF
Kp
4
d (7 h, 72%)
4e (6 h, 79%)
4f (7.5 h, 69%)
Toluene
Benzene
none
40
32
80
76
65
30
38
72
52
59
61
80
O
NH2
O
NH2
O
NH2
CN
CN
CN
MeO
MeO
N
Ph
MeO
OMe
N
Ph
MeO
Br
N
Ph
MeS
MeS
PentS
4
g (6 h, 78%)
4h (7 h, 75%)
4i (6.5 h, 78%)
none
90
6
O
NH2
O
NH2
CN
Cl
O
NH2
1
1
1
1
1
1
1
1
1
0
1
2
3
4
5
6
7
8
none
70
12
24
24
24
24
24
10
6
CN
CN
O
O
NO2
FeCl
3
3
none
80
N
Ph
N
Ph
N
Ph
BuS
EtS
EtS
Me
Cl
AlCl
none
80
4j (6 h, 79%)
4
k (7 h, 73%)
4l (7 h, 70%)
InBr
Sc(OTf)
Y(OTf)
3
none
80
O
NH2
CN
O
NH2
O
NH2
CN
CN
3
(10)
none
80
O
EtS
S
Cl
N
Ph
S
N
Ph
N
Ph
PrS
3
(10)
none
80
PrS
Me
NO2
InCl
InCl
InCl
3
3
3
(5)
none
80
4m (6.5 h, 71%)
4o (7 h, 74%)
4
n (7.5 h, 76%)
Cl
O
NH2
(20)
(10)
none
80
O
NH2
O
NH2
CN
CN
CN
d
H
2
O
reflux
24
Kp
O
N
Me
MeS
Br
N
Ph
N
CH2
6
a
MeS
MeS
All reactions were carried out using 1.0 mmol of each 1a, 2a,
Ph
and 3 in 5 mL of each solvent.
4p (8 h, 68%)
4q (8 h, 66%)
4r (8 h, 69%)
a
b
All reactions were performed using 1.0 mmol of each 1, 2 and 3.
Isolated pure yield.
b
c
Isolated pure yield.
No reaction.
d
Intermediate Knoevenagel condensation product of 2a and 3.
To prove the intermediacy of the Knoevenagel product
2
3b
(obtained from the corresponding aldehyde and malononitrile),
Experiments probing the scope and generality of this one-pot
three-component cross-dehydrative coupling reaction between α-
oxoketene-N,S-acetals 1, aldehydes 2, and malononitrile 3 under
optimized conditions are summarized in Table 2. A broad
we isolated it and allowed to react with α-oxoketene-N,S-
arylaminoacetal under the previously optimized reaction
conditions. As per our expectation, the fully substituted 1,2-
dihydropyridine was obtained almost in comparable yield to that
of three-component reaction. To explore the scope and
1
spectrum of α-oxoketene-N,S-acetals 1, bearing R as aryl
(
containing both electron-donating and electron-withdrawing
limitations of the InCl catalyst, and to add further diversity to
3
2
groups) and hetaryl, and R as methyl, ethyl, iso-propyl, n-butyl
and n-pentyl groups could be employed to afford 1,2-
dihydropyridines 4 in good to excellent yields. As can be seen
from Table 2, all reactions proceeded smoothly resulting the
corresponding products 4 in high yields. Steric and electronic
effects of the substituents had no noticeable impact on the yield
as well as on the rate of the reaction. In all products 6-thioalkyl
substituent that stem from α-oxoketene-N,S-acetals was also well
tolerated under these reaction conditions and was kept constant.
the 1,2-dihydropyridine framework, we used methyl/ethyl
cyanoacetate as a coupling partner instead of malononitrile under
optimized reaction conditions. To our surprise, a number of
overlapping inseparable spots were observed on the TLC plate
and no desired product was observed, thus limiting the scope and
generality of this protocol to some extent. To overcome the
above problems, the test reaction was performed under a variety
of conditions, but to no avail.

4
Tetrahedron
TEwe
The structures of all 1,2-dihydropyrid
A
in
C
es
C
4
E
a–
P
r
D
re MAtra
N
ns
U
iti
S
on
C
m
R
et
I
a
P
ls and attributable to its important role in many
T
1
13
25
deduced from their satisfactory spectroscopic data (IR, H, &
C
biological processes, it is very much necessary to find out a
NMR and MS) and unequivocally established by the X-ray single
crystal diffraction analysis of some representative molecules such
suitable sensor for iron, which can be applied for several realistic
purposes. In this circumstance our new discovery about the
selective Fe sensing ability of 4-amino-1,2-dihydropyridine
possibly will find potential application in the advancement of
different metal sensors.
24
3+
as 4b (Figure 1), 4d, 4j and 4m (see supporting information).
The introduction of nitrile and amino functional groups at 3-and
-positions of the newly formed 1,2-dihydropyridine is of special
4
interest as it can act as an effective chemical handle for further
functionalization and diversification.
Fig. 1. ORTEP diagram of 4b.
Taking into consideration the entire outcome, a plausible
mechanistic pathway for the one-pot three-component cross-
dehydrative coupling protocol is depicted in Scheme 3. The first
step would be the Knoevenagel condensation between aldehyde 2
and malononitrile 3 to give the Knoevenagel product A, which
could serve as Michael acceptor. In the next step, Michael
acceptor A reacts with α-oxoketene-N,S-acetal 1 in a Lewis-acid
assisted Michael addition process. It is likely that the attack of α-
oxoketene-N,S-acetal can take place in two ways (path I & II) to
furnish the open chain intermediates B and B , respectively. The
-5
Figure 2. Changes in the absorption spectra of 4f (1.1 X 10 M) in the
presence of different metal ions in CH CN-H O (9:1).
3
2
1
2
intermediates B1 and B2 immediately would undergo
intramolecular N-cyclization to furnish compounds 4 and 5. But
during our investigation, we did not observe even a trace of 5,
and 4 was obtained exclusively suggesting that the protocol is
highly regioselective.
R3 CHO
2
+
NC
CN
3
LA
Knoevenagel condensation
N
C
O
H
N
NH2
O
LA
N
C
R1
Path I
NC
R1
cyclization
C
R3
N
SR2
O
R3
N
SR2
-5
Figure 3. Changes in the absorption spectra of 4f (1.1 X 10 M) in
R3
Michael
C
B1 Ar
4
5
Ar
-2
III
3 2
CH CN-H O (9:1) upon titration with (1.1 X 10 M) of Fe (0-16 equiv have
A
R3
N
addition
N
H
R3
LA
O
been employed). Inset: plots according to the method for continuous
O
C
R1
III
Ar
Path II
X
NC
R1
variations indicating the 1:1 stoichiometry for 4f-Fe (the total concentration
cyclization
N
R1
C
3+
SR2
SR2
SR2
of 4f and Fe is 3mL).
H
N
H2N
N
N
Ar
B2
1
Ar
LA = InCl3
LA
3
. Conclusion
Scheme 3. Plausible reaction scenario for the formation of 4.
In summary, we have developed a highly efficient and
regioselective synthesis of 4-amino-5-aroyl-6-thioalkyl-1,2-
disubstituted-1,6-dihydropyridine-3-carbonitrile frameworks
through three-component cross-dehydrative coupling of α-
oxoketene-N,S-acetals, aldehydes, and malononitrile in the
presence of InCl3 under solvent-free conditions. This atom-
Following a comprehensive investigation for the one-pot
synthesis of 4-amino-1,2-dihydropyridine, we became interested
to find out its application in metal sensing. To do that we
involved one of the 4-amino-1,2-dihydropyridine 4f in metal ion
sensing. Figure 1 shows UV-vis spectra of 4f measured in
CH CN-H O (9:1) with respective metal cations. Because of the
economic
domino
protocol
involves
Knoevenagel
3
2
condensation/Michael addition/cyclization sequence forming
three new bonds (two C–C and one C–N), and one stereocenter in
a single operation with all reactants efficiently being utilized.
non-fluorescent nature of 4f, we executed the whole sensing
experiment with the help of UV-vis spectroscopy over a wide
+
+
2+
2+
2+
2+
2+
range of metal ions like Na , K , Zn , Cd , Hg , Cu , Pb ,
3+
3+
3+
3+
Cheap and easily available InCl worked efficiently with diversly
3
Al , Cr and Fe . To our pleasure, 4f senses the Fe ion
selectively over the other metal ions (Figure 2). Due to the
maximum abundance of iron in biological systems among the
substituted α-oxoketene-N,S-acetals and aromatic aldehydes. The
remarkable renovation of these pyridine derivatives could be

5
-
1
achieved toward their diversification for var
A
iet
C
y
C
of
E
p
P
u
T
rp
E
os
D
es. MAN
Y
U
ell
S
owCRso
I
li
P
d, mp 145-147 °C; FT IR (KBr, cm ): 3463,
T
3+
1
Importantly, the selective Fe sensing capability of one of its
representative compound may be of value for both synthetic and
material chemists for academic research and practical
applications.
3348, 2922, 2139, 1651, 1436, 1021; H NMR (300 MHz,
CDCl ): δ 7.64 (t, J = 6.4 Hz, 2H, Ar), 7.40-7.33 (m, 6H, Ar),
7.20-7.10 (m, 4H, Ar), 7.00 (d, J = 7.5 Hz, 2H, Ar), 5.95 (br, 2H,
NH ), 5.48 (s, 1H, Chiral CH), 1.73 (s, 3H, SCH ); C NMR (75
3
13
2
3
MHz, CDCl ): δ 194.89, 154.61, 152.58, 144.16, 139.87, 136.66,
3
1
1
32.17, 129.56, 128.85, 128.63, 127.94, 127.17, 125.25, 120.21,
15.36 (d, JCF = 21.7Hz), 114.80, 114.75, 65.03, 63.06, 15.95
;
4
4
. Experimental section
+
HRMS [M+H] calcd. For C H FN OS 442.1389, found
442.1410.
26
21
3
.1. General
The commercially available starting materials were used as
4.2.4. 4-Amino-2-(2-bromophenyl)-5-(4-
methylbenzoyl)-6-methylthio-1-phenyl-1,2-
dihydropyridine-3-carbonitrile (4d).
received without further purification. α-Oxoketene-N,S-
23a
arylaminoacetals 1 were prepared by the known procedure.
Thin-layer chromatography (TLC) was performed using silica gel
0 F254 precoated plates. Infrared (IR) spectra are measured in
-
1
Yellow solid, mp 209-211 °C; FT IR (KBr, cm ): 3472, 3353,
1
6
2935, 2158, 1644, 1436, 1067; H NMR (300 MHz, CDCl
7.68-7.63 (m, 2H, Ar), 7.51 (d, J = 8.1 Hz, 2H, Ar), 7.30-7.23
(m, 7H, Ar), 7.12 (d, J = 7.8 Hz, 2H, Ar), 5.94 (br, 2H, NH ),
5.84 (s, 1H, Chiral CH), 2.37 (s, 3H, CH ), 1.82 (s, 3H, SCH );
): δ 193.95, 158.55, 153.48, 144.31,
3
): δ
-
1
1
13
KBr, and wavenumber (ῡ) are reported in cm . H and C NMR
spectra were recorded on NMR spectrometers operating at 300
and 75 MHz, respectively. Chemical shifts (δ) are given in parts
per million (ppm) using the residue solvent peaks as reference
relative to TMS. J values are given in Hz. Mass spectra were
recorded using electrospray ionization (ESI) mass spectrometry.
The melting points are uncorrected.
2
3
3
13
C NMR (75 MHz, CDCl
3
143.26, 138.59, 137.07, 134.03, 130.44, 130.21, 129.34, 129.11,
128.87, 127.68, 127.57, 127.15, 123.35, 119.87, 112.46, 64.75,
+
63.45, 21.55, 17.33; HRMS [M+Na]
C H BrN OSNa 538.0559, found 538.0563.
calcd. For
27
22
3
4
.2. General procedure for the synthesis of the 4-amino-1,2-
dihydropyridine (4a-r):
4.2.5. 4-Amino-2-(4-methoxyphenyl)-5-(4-
methylbenzoyl)-6-methylthio-1-phenyl-1,2-
To a mixture of α-oxoketene-N,S-arylaminoacetals (1.0
mmol), aldehyde (1.0 mmol) and malononitrile (1.0 mmol),
dihydropyridine-3-carbonitrile (4e).
-1
Yellow solid, mp 168-169 °C; FT IR (KBr, cm ): 3438, 3328,
InCl (0.1 mmol) was added and the reaction mixture was heated
1
3
2
7
925, 2180, 1623, 1413, 1058; H NMR (300 MHz, CDCl ): δ
3
at 80 °C till the completion of the reaction. After completion of
the reaction (monitored by TLC), water (20 mL) was added to the
reaction mixture followed by extraction with ethyl acetate (2 × 10
mL). The combined organic layer was dried over anhydrous
Na SO and evaporated under vacuo. The crude residue thus
.50 (d, J = 8.1 Hz, 2H, Ar), 7.34-7.18 (m, 5H, Ar), 6.93-6.84
(
3
m, 6H, Ar), 5.80 (br, 2H, NH ), 5.40 (s, 1H, Chiral CH), 3.79 (s,
2
13
H, OCH ), 2.22 (s, 3H, CH ), 1.18 (s, 3H, SCH ); C NMR (75
3 3 3
MHz, CDCl ): δ 194.86, 174.92, 159.83, 152.50, 144.30, 137.21,
3
2
4
1
1
1
4
32.61, 129.66, 129.45, 129.31, 129.15, 129.02, 128.63, 128.30,
26.93, 126.89, 125.32, 113.80, 64.92, 63.24, 55.44, 21.50,
obtained was purified by column chromatography over silica gel
using ethyl acetate/hexane as eluent to afford pure 4-amino-1,2-
dihydropyridines 4.
+
5.78; HRMS [M+H] calcd. For C H N O S 468.1745, found
28
26
3
2
68.1760.
4
.2.1. 4-Amino-5-benzoyl-6-methylthio-1,2-
4
.2.6. 4-Amino-2-(4-chloro-3-fluorophenyl)-5-(4-
diphenyl-1,2-dihydropyridine-3-carbonitrile (4a).
methylbenzoyl)-6-methylthio-1-phenyl-1,2-
dihydropyridine-3-carbonitrile (4f).
-
1
Yellow solid, mp 173-175 °C; FT IR (KBr, cm ): 3471, 3354,
1
2
7
936, 2157, 1643, 1438, 1057; H NMR (300 MHz, CDCl ): δ
-1
3
Yellow solid, mp 161-163 °C; FT IR (KBr, cm ): 3479, 3350,
.62 (d, J = 6.3 Hz, 2H, Ar), 7.42-7.24 (m, 9H, Ar), 7.04-6.99
1
2
7
923, 2173, 1624, 1471, 1033; H NMR (300 MHz, CDCl ): δ
3
(m, 2H, Ar), 6.88 (d, J = 7.2 Hz, 2H, Ar), 5.89 (br, 2H, D O
2
.53-7.31 (m, 9H, Ar), 6.95 (br, 3H, Ar), 5.92 (br, 2H, NH ), 5.45
2
Exchangeable, NH ), 5.47 (s, 1H, Chiral CH), 2.10 (s, 3H,
SCH3); C NMR (75 MHz, CDCl ): δ 195.06, 154.54, 152.60,
1
1
HRMS [M+H] calcd. For C H N OS 424.1483, found
4
13
2
(s, 1H, Chiral CH), 2.32 (s, 3H, CH ), 1.79 (s, 3H, SCH );
C
13
3
3
3
NMR (75 MHz, CDCl ): δ 194.32, 159.76, 156.44, 154.15,
3
44.16, 140.86, 131.93, 129.47, 128.73, 128.65, 128.47, 128.32,
27.85, 126.97, 125.19, 120.41, 114.78, 65.33, 63.05, 15.74
1
1
1
52.53, 143.94, 143.35, 142.69, 136.79, 130.57, 129.57, 128.73,
27.20, 125.11, 123.36, 120.01, 115.33 (d, JCF = 22.9Hz),
14.78, 111.73, 64.74, 62.51, 21.53, 15.97; HRMS [M+H]
;
+
+
26
22
3
24.1490.
calcd. For C H ClFN OS 490.1156, found 490.1168.
27
22
3
4
.2.2. 4-Amino-5-benzoyl-2-(4-methoxyphenyl)-6-
4
.2.7. 4-Amino-5-(4-methoxybenzoyl)-2-(4-
methylthio-1-phenyl-1,2-dihydropyridine-3-
carbonitrile (4b).
methoxyphenyl)-6-methylthio-1-phenyl-1,2-
dihydropyridine-3-carbonitrile (4g).
-
1
Yellow solid, mp 170-172 °C; FT IR (KBr, cm ): 3482,
-1
Yellow sticky solid; FT IR (KBr, cm ): 3452, 3332, 2937,
1
3
337, 2932, 2160, 1628, 1446, 1025; H NMR (300 MHz,
1
2
168, 1629, 1447, 1021; H NMR (300 MHz, CDCl ): δ 7.58 (d,
3
CDCl ): δ 7.58-7.31 (m, 8H, Ar), 7.17-6.98 (m, 6H, Ar), 5.92 (br,
3
J = 8.4 Hz, 2H, Ar), 7.41 (d, J = 4.5 Hz, 4H, Ar), 7.32-7.25 (m,
H, Ar), 7.00-6.97 (m, 4H, Ar), 6.60 (d, J = 8.7 Hz, 2H, Ar), 5.83
br, 2H, NH ), 5.47 (s, 1H, Chiral CH), 3.85 (s, 3H, OCH ), 3.78
2
3
1
1
6
4
H, NH ), 5.48 (s, 1H, Chiral CH), 3.86 (s, 3H, OCH ), 1.71 (s,
2
3
1
13
H, SCH3); C NMR (75 MHz, CDCl ): δ 195.02, 159.79,
3
(
(
2
3
54.38, 152.55, 144.16, 140.05, 132.50, 131.94, 129.44, 128.73,
28.28, 127.82, 126.94, 125.23, 120.40, 114.72, 113.74, 65.00,
13
s, 3H, OCH ), 1.77 (s, 3H, SCH ); C NMR (75 MHz, CDCl3):
3
3
δ 193.59, 162.94, 159.81, 153.09, 152.37, 144.33, 132.73,
1
1
+
3.19, 55.45, 15.80; HRMS [M+Na] calcd. For C H N O SNa
27
23
3
2
32.31, 131.24, 129.40, 128.37, 126.77, 125.23, 120.38, 115.02,
76.1403, found 476.1389.
13.76, 113.08, 64.86, 63.39, 55.53, 55.25, 15.83; HRMS
+
[
M+H] calcd. For C H N O S 484.1695, found 484.1713.
4
.2.3. 4-Amino-5-benzoyl-2-(4-fluorophenyl)-6-
28 26
3
3
methylthio-1-phenyl-1,2-dihydropyridine-3-
carbonitrile (4c).

6
Tetrahedron
4
.2.8. 4-Amino-2-(4-bromophenyl)-5-(4-
Ar), 5.91 (br, 2H, NH ), 5.52 (s, 1H, Chiral CH), 2.82-2.75 (m,
ACCEPTED MANUSCRIPT
2
methoxybenzoyl)-6-methylthio-1-phenyl-1,2-
dihydropyridine-3-carbonitrile (4h).
1H, SCH ), 2.37-2.31 (m, 1H, SCH ), 0.85 (t, J = 7.5 Hz, 3H,
2
2
13
CH3); C NMR (75 MHz, CDCl ): δ 181.24, 156.73, 153.63,
3
-
1
Yellow solid, mp 171-173 °C; FT IR (KBr, cm ): 3475, 3351,
152.16, 148.15, 145.80, 144.37, 143.60, 132.95, 129.92, 129.67,
1
2
7
6
939, 2152, 1674, 1432, 1064; H NMR (300 MHz, CDCl ): δ
.54-7.46 (m, 4H, Ar), 7.32-7.18 (m, 5H, Ar), 6.87 (br, 2H, Ar),
.56 (d, J = 8.7 Hz, 2H, Ar), 5.75 (br, 2H, NH ), 5.38 (s, 1H,
127.85, 125.75, 123.07, 120.48, 120.19, 117.17, 112.62, 112.50,
3
+
65.22,
63.17, 28.11, 13.71; HRMS [M+H] calcd. For
C H N O S 473.1283, found 473.1302.
25 21 4 4
2
13
Chiral CH), 3.73 (s, 3H, OCH ), 1.72 (s, 3H, SCH ); C NMR
3
3
4
2
.2.13. 4-Amino-6-ethylthio-5-(2-furoyl)-1-phenyl-
-(p-tolyl)-1,2-dihydropyridine-3- carbonitrile
(75 MHz, CDCl ): δ 193.35, 163.16, 153.01, 152.40, 144.06,
3
1
1
40.41, 131.84, 131.55, 131.11, 129.52, 128.96, 126.96, 125.08,
22.31, 120.12, 115.23, 113.22, 64.83, 62.82, 55.31, 15.83;
(
4m).
-1
+
Yellow solid, mp 165-166 °C; FT IR (KBr, cm ): 3456, 3342,
HRMS [M+Na] calcd. For C H BrN O SNa 554.0514, found
1
2
7
22
3
2
2
7
934, 2158, 1622, 1451, 1043; H NMR (300 MHz, CDCl ): δ
.50-7.20 (m, 10H, Ar), 6.29 (d, J = 1.8 Hz, 1H, Ar), 6.08 (br,
3
5
54.0552.
4
1
.2.9. 4-Amino-5-(4-methoxybenzoyl)-6-pentylthio-
,2-diphenyl-1,2-dihydropyridine-3- carbonitrile
1H, Ar), 5.76 (br, 2H, NH ), 5.41 (s, 1H, Chiral CH), 2.54-2.23
2
13
(m, 5H, SCH & tolyl CH ), 0.77 (t, J = 7.5 Hz, 3H, CH );
C
2
3
3
(
4i).
NMR (75 MHz, CDCl ): δ 181.51, 155.08, 153.63, 151.91,
3
-
1
Yellow solid, mp 69-71 °C; FT IR (KBr, cm ): 3486, 3342,
145.84, 144.58, 138.04, 137.69, 129.37, 129.08, 127.21, 126.88,
1
2
7
931, 2163, 1648, 1444, 1025; H NMR (300 MHz, CDCl ): δ
126.73, 125.84, 120.26, 117.67, 111.87, 65.56, 63.45, 27.88,
3
+
.66 (br, 2H, Ar), 7.45-7.40 (m, 7H, Ar), 7.25 (br, 1H, Ar), 6.95
21.06, 13.54; HRMS [M+Na] calcd. For C26
464.1403, found 464.1406.
H N O SNa
23 3 2
(br, 2H, Ar), 6.55 (d, J = 8.4 Hz, 2H, Ar), 5.82 (br, 2H, NH2),
5
2
.51 (s, 1H, Chiral CH), 3.76 (s, 3H, OCH ), 2.44-2.36 (m, 1H),
3
13
4.2.14. 4-Amino-2-(4-nitrophenyl)-1-phenyl-6-
propylthio-5-(2-thienoyl)-1,2- dihydropyridine-3-
.23-2.15 (m, 1H), 1.02-0.92 (m, 4H), 0.84-0.67 (m, 5H);
C
NMR (75 MHz, CDCl ): δ 193.96, 162.83, 153.35, 152.51,
3
carbonitrile (4n).
1
1
3
44.58, 141.02, 132.56, 131.18, 129.34, 128.42, 128.35, 127.10,
26.75, 125.46, 120.48, 115.22, 113.06, 65.33, 62.88, 55.24,
-1
Yellow solid, mp 163-165 °C; FT IR (KBr, cm ): 3478, 3351,
2924, 2172, 1654, 1463, 1032; H NMR (300 MHz, CDCl
1
+
3
): δ
3.17, 30.31, 28.02, 21.85, 13.63; HRMS [M+H] calcd. For
8
7
.33 (d, J = 8.4 Hz, 2H, Ar), 7.85 (d, J = 8.4 Hz, 2H, Ar), 7.47-
.35 (m, 6H, Ar), 6.81 (t, J = 4.2 Hz, 1H, Ar), 6.70 (d, J = 3.0
C H N O S 510.2210, found 510.2216.
31
32
3
2
4
1
.2.10. 4-Amino-6-butylthio-5-(3-methoxybenzoyl) -
-phenyl-2-(p-tolyl)-1,2-dihydropyridine-3-
Hz, 1H, Ar), 5.83 (br, 2H, NH ), 5.52 (s, 1H, Chiral CH), 2.54-
2
2.46 (m, 1H, SCH ), 2.36-2.28 (m, 1H, SCH ), 1.20-1.00 (m, 1H,
2
2
1
3
carbonitrile (4j).
CH ), 0.93-0.82 (m, 1H, CH ), 0.56 (t, J = 7.3 Hz, 3H, CH );
C
2
2
3
-
1
Yellow solid, mp 214-216 °C; FT IR (KBr, cm ): 3462, 3349,
NMR (75 MHz, CDCl ): δ 186.07, 172.42, 152.21, 148.54,
3
1
2
7
923, 2138, 1652, 1435, 1025; H NMR (300 MHz, CDCl ): δ
145.24, 144.28, 133.67, 132.62, 129.66, 127.93, 127.85, 127.62,
3
.54 (d, J = 7.5 Hz, 2H, Ar), 7.43-7.37 (m, 4H, Ar), 7.33-7.25
127.57, 125.77, 123.80, 123.69, 119.84, 114.76, 65.16, 62.15,
+
(m, 3H, Ar), 6.90-6.84 (m, 3H, Ar), 6.34 (s, 1H, Ar), 5.92 (br,
35.89, 21.56, 12.80; HRMS [M+H] calcd. For C26
503.1206, found 503.1214.
H N O S
23 4 3 2
2
H, NH ), 5.48 (s, 1H, Chiral CH), 3.66 (s, 3H, OCH ), 2.42-2.29
2
3
(
m, 4H), 2.21-2.10 (m, 1H), 0.98-0.82 (m, 4H), 0.60 (t, J = 6.4
13
4.2.15. 4-Amino-2-(3-chlorophenyl)-1-phenyl-6-
propylthio-5-(2-thienoyl)-1,2- dihydropyridine-3-
Hz, 3H, CH3); C NMR (75 MHz, CDCl ): δ 192.48, 159.40,
3
1
1
1
52.69, 144.68, 143.89, 141.92, 138.27, 137.64, 129.49, 129.40,
29.18, 128.63, 127.10, 127.00, 125.64, 121.71, 118.29, 114.86,
carbonitrile (4o).
-1
Yellow solid, mp 77-78 °C; FT IR (KBr, cm ): 3480, 3346,
12.90, 65.31, 62.86, 55.30, 33.05, 30.22, 21.32, 13.17, 12.94;
1
+
2933, 1641, 1434, 1048; H NMR (300 MHz, CDCl
H, Ar), 7.49 (d, J = 5.1 Hz, 1H, Ar), 7.39-7.25 (m, 8H, Ar), 6.82
t, J = 4.3 Hz, 1H, Ar), 6.57 (d, J = 3.0 Hz, 1H, Ar), 5.74 (br, 2H,
NH ), 5.45 (s, 1H, Chiral CH), 2.54-2.46 (m, 1H, SCH ), 2.31-
3
): δ 7.63 (br,
HRMS [M+H] calcd. For C H N O S 510.2215, found
5
31
32
3
2
1
(
10.2237.
4
5
.2.11. 4-Amino-2-(2,4-dichlorophenyl)-6-ethylthio-
-(2-furoyl)-1-phenyl-1,2-dihydropyridine-3-
2
2
2.22 (m, 1H, SCH ), 1.19-1.01 (m, 1H, CH ), 0.89-0.85 (m, 1H,
2
2
13
carbonitrile (4k).
CH ), 0.55 (t, J = 7.2 Hz, 3H, CH ); C NMR (75 MHz, CDCl ):
2
3
3
-
1
Yellow sticky solid; FT IR (KBr, cm ): 3481, 3350, 2916,
δ 186.56, 153.89, 151.94, 145.71, 144.30, 143.24, 134.59,
133.45, 132.91, 129.96, 129.49, 128.47, 127.43, 127.23, 126.93,
1
1
1
645, 1439, 1053; H NMR (300 MHz, CDCl ): δ 7.97-7.92 (m,
3
H, Ar), 7.51-7.18 (m, 8H, Ar), 7.06 (d, J = 3.6 Hz, 1H, Ar), 6.54
126.89, 125.62, 125.25, 120.09, 115.10, 65.19, 62.79, 35.54,
+
(t, J = 1.5 Hz, 1H, Ar), 5.89-5.79 (m, 3H, NH & Chiral CH),
21.67, 12.83; HRMS [M] calcd. For C26
found 491.0887.
H22ClN OS 491.0888,
3 2
2
2
7
1
1
1
.55-2.46 (m, 1H, SCH ), 2.23-2.14 (m, 1H, SCH ), 0.82 (t, J =
2
2
13
.5 Hz, 3H, CH3); C NMR (75 MHz, CDCl ): δ 181.15, 158.31,
3
4
.2.16. 4-Amino-5-benzoyl-2-cyclohexyl-6-
54.01, 152.34, 145.01, 144.50, 136.66, 134.74, 132.75, 130.30,
29.84, 129.34, 127.99, 127.30, 126.61, 119.57, 117.36, 112.80,
methylthio-1-phenyl-1,2-dihydropyridine-3-
carbonitrile (4p).
+
10.42, 63.15, 62.49, 28.81, 14.00; HRMS [M+H] calcd. For
-1
Yellow solid, mp 212-214 °C; FT IR (KBr, cm ): 3476, 3352,
C H Cl N O S 496.0653, found 496.0653.
1
25
20
2
3
2
2
938, 2147, 1664, 1442, 1066; H NMR (300 MHz, CDCl ): δ
3
4
.2.12. 4-Amino-6-ethylthio-5-(2-furoyl)-2-(3-
7.78 (d, J = 7.5 Hz, 2H, Ar), 7.50-7.22 (m, 8H, Ar), 5.90 (br, 2H,
nitrophenyl)-1-phenyl-1,2-dihydropyridine-3-
NH ), 3.88 (d, J = 10.2 Hz, 1H, Chiral CH), 2.17-2.05 (m, 5H),
2
13
carbonitrile (4l).
1.85-1.72 (m, 4H), 1.36-1.25 (m, 5H); C NMR (75 MHz,
CDCl ): δ 194.26, 156.53, 151.67, 145.20, 140.58, 132.03,
-
1
Yellow solid, mp 157-159 °C; FT IR (KBr, cm ): 3456, 3327,
3
1
2
8
1
923, 2181, 1643, 1416, 1059; H NMR (300 MHz, CDCl ): δ
129.24, 128.83, 128.18, 127.10, 126.35, 120.90, 113.46, 69.63,
3
+
.59 (s, 1H, Ar), 8.23 (d, J = 7.5 Hz, 1H, Ar), 7.91 (d, J = 7.5 Hz,
H, Ar), 7.60 (t, J = 8.1 Hz, 1H, Ar), 7.42-7.33 (m, 6H, Ar), 6.84
63.21, 41.33, 31.67, 29.85, 26.31, 26.00, 16.69; HRMS [M+H]
calcd. For C26H N OS 476.1948, found 476.1956.
28 3
(
d, J = 1.8 Hz, 1H, Ar), 6.43 (dd, J = 1.2 Hz, J = 3.0 Hz, 1H,
1 2

7
4
.2.17. 4-Amino-5-benzoyl-2-heptyl-6-methylthio-1-
3. (a) Tu, S.-J.; Jiang, B.; Jia, R.-H.; Zhang, J.-Y.; Zhang, Y.; Yao,
ACCEPTED MANUSCRIPT
C.-S.; Shi, F. Org. Biomol. Chem. 2006, 4, 3664-3668; (b) Tu, S.-
J.; Jiang, B.; Jia, R.-H.; Zhang, J.-Y.; Zhang, Y. Tetrahedron Lett.
007, 48, 1369-1374; (c) Wei, H.-L.; Yan, Z.-Y.; Niu, Y.-N.; Li,
G.-Q.; Liang, Y.-M. J. Org. Chem. 2007, 72, 8600-8603; (d) Cui,
S.-L.; Wang, J.; Wang, Y.-G. Org. Lett. 2008, 10, 1267-1269; (e)
Chen, X.-H.; Zhang, W.-Q.; Gong, L.-Z.; J. Am. Chem. Soc. 2008,
130, 5652-5653; (f) Li, N.; Chen, X.-H.; Song, J.; Luo, S.-W.;
Fan, W.; Gong, L.-Z. J. Am. Chem. Soc. 2009, 131, 15301-15310;
phenyl-1,2-dihydropyridine-3-carbonitrile (4q).
Yellow sticky solid; FT IR (KBr, cm ): 3482, 3349, 2912, 1665,
-
1
2
1
1
2
7
0
1
1
3
435, 1054; H NMR (300 MHz, CDCl ): δ 7.78 (d, J = 6.9 Hz,
3
H, Ar), 7.49-7.25 (m, 8H, Ar), 5.86 (br, 2H, NH ), 4.26 (t, J =
2
.3 Hz, 1H, Chiral CH), 1.70 (s, 3H, SCH ), 1.41-1.25 (m, 12H),
3
13
.89 (t, J = 5.1 Hz, 3H, CH3); C NMR (75 MHz, CDCl ): δ
3
94.73, 169.10, 151.77, 144.94, 140.84, 132.01, 129.30, 129.05,
28.77, 128.18, 127.84, 127.20, 125.92, 125.22, 63.78, 36.58,
(
1
g) Shen, Z.-L.; Xu, X.-P.; Ji, S.-J. J. Org. Chem. 2010, 75, 1162-
167; (h) guan, X.-Y.; Yang, L.-P.; Hu, W.-H. Angew. Chem. Int.
4.89, 31.83, 29.66, 29.25, 26.00, 25.86, 22.61, 14.05; HRMS
Ed. 2010, 49, 2190-2192.
+
[
M+H] calcd. For C H N OS 446.2266, found 446.2287.
4. (a) Sunderhaus, J. D.; Dockendorff, C.; Martin, S. F. Org. Lett.
27
32
3
2
007, 9, 4223-4226; (b) Armstrong, R. W.; Combs, A. P.;
4
.2.18. 4-Amino-1-(2-bromophenyl)-5-(2-
Tempest, P. A.; Brown, S. D.; Keating, T. A. Acc. Chem. Res.
1996, 29, 123-131; (c) Muller, F. L.; Constantieux, T.; Rodriguez,
J. J. Am. Chem. Soc. 2005, 127, 17176-17177; (d) Haurena, C.;
Gall, E. L.; Sengmany, S.; Martens, T.; Troupel, M. J. Org. Chem.
chlorobenzoyl)-2-(furan-2-yl)-6-methylthio-1,2-
dihydropyridine-3-carbonitrile (4r).
-
1
Yellow solid, mp 226-228 °C; FT IR (KBr, cm ): 3472, 3381,
2
010, 75, 2645-2650.
1
2
7
957, 2166, 1664, 1435, 1061; H NMR (300 MHz, CDCl ): δ
5. (a) Willy, B.; Muller, T. J. J. Eur. J. Org. Chem. 2008, 4157-4168;
(b) Adib, M.; Sheikhi, E.; Kavoosi, A.; Bijanzadeh, H. R.
Tetrahedron 2010, 66, 9263-9269; (c) Evdokimov, N. M.; Kireev,
A. S.; Yakovenko, A. A.; Antipin, M. Y.; Magedov, I. V.;
Kornienko, A. J. Org. Chem. 2007, 72, 3443-3453; (d) Chen, W.-
B.; Wu, Z.-J.; Pei, Q.-L.; Cun, L.-F.; Zhang, X.-M.; Yuan, W.-C.
Org. Lett. 2010, 12, 3132-3135.
3
.94 (d, J = 7.8 Hz, 1H, Ar), 7.61 (t, J = 7.9 Hz, 2H, Ar), 7.44 (t,
J = 7.5 Hz, 1H, Ar), 7.34-7.17 (m, 2H, Ar), 6.96 (t, J = 7.3 Hz,
H, Ar), 6.33 (dd, J = 1.2 Hz, J = 7.5 Hz, 1H, Ar), 6.50 (br, 2H,
1
1
2
13
NH ), 5.31 (s, 1H, Chiral CH), 1.53 (s, 3H, SCH ); C NMR (75
MHz, CDCl ): δ 193.14, 159.05, 154.90, 152.46, 147.64, 143.13,
2
3
3
1
1
1
41.27, 134.13, 133.28, 130.67, 130.57, 129.96, 129.83, 129.77,
29.65, 128.70, 125.61, 123.46, 119.36, 110.56, 61.30, 59.85,
6. (a) Tanaka, K. Solvent-Free Organic Synthesis, Wiley-VCH,
Weinheim, 2009; (b) Zhao, Y. N.; Li, J.; Li, C. J.; Yin, K.; Ye, D.
Y.; Jia, X. S. Green Chem. 2010, 12, 1370-1372; (c) Martins, M.
A. P.; Frizzo, C. P.; Moreira, D. N.; Buriol, L.; Machado, P.
Chem. Rev. 2009, 109, 4140-4182.
+
7.19; HRMS [M+H] calcd. For C H BrClN O S 525.9986,
24
18
3
2
found 525.9999.
7
.
(a) Singh, M. S.; Chowdhury, S. RSC Adv. 2012, 2, 4547-4592;
(b) Trost, B. M. Science 1991, 254, 1471-1477; (c) Corma, A.;
Garcia, H. Chem. Rev. 2003, 103, 4307-4365.
Acknowledgements
8
.
(a) Joule, J. A.; Mills, K. Heterocyclic Chemistry, Blackwell, 4th
Ed.; Oxford, UK, 2000; (b) Bull, J. A.; Mousseau, J. J.; Pelletier,
G.; Charette, A. B. Chem. Rev. 2012, 112, 2642-2713; (c)
Bergstorm, F. W. Chem. Rev. 1944, 35, 77-277; (d) Bergstorm, F.
W. Chem. Rev. 1945, 36, 143-144; (e) Rossi, R.; Bellina, F.
Tetrahedron 2006, 62, 7213-7256; (f) Walsh, C. T.; Garneau-
Tsodikova, S.; Howard-Jones, A. Nat. Prod. Rep. 2006, 23, 517-
We gratefully acknowledge the generous financial support
from the Science and Engineering Research Board (Grant No.
SB/S1/OC-30/2013), the Council of Scientific and Industrial
Research (Grant No. 02(0072)/12/EMR-II), and the UGC-
UKIERI Partnership-2013 (Grant No. 184-16/2013(IC), New
Delhi, India.
5
2
31; (g) McMurray, L.; O’Hara, F.; Gaunt, M. J. Chem. Soc. Rev.
011, 40, 1885-1898.
†
Dedication
9. Carey, J. S.; Laffan, D.; Thomson, C.; Williams, M. T. Org.
Biomol. Chem. 2006, 4, 2337-2347.
This paper is dedicated to Prof. Ganesh Pandey on the occasion
1
0. (a) Kaes, C.; Katz, A.; Hosseini, M. W. Chem. Rev. 2000, 100,
th
of his 60 birthday.
3
1
553-3590
995, 95, 2229-2260; (c) Mamula, O.; von Zelewsky, A. Coord.
(d) Sun, L.; Hammarström, L.;
; (b) Lawrence, D. S.; Jiang, T.; Levett, M. Chem. Rev.
References and notes
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Tetrahedron
Catal. 2006, 348, 2571-2574; (c) Wan, J.-P.; Gan, S.-F.; Sun,
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Supplementary Material
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H and C NMR spectra of all new compounds, experimental
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can be found in the online version, at
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4. The crystallographic coordinates have been deposited with the
Cambridge Crystallographic Data Centre; deposition no. CCDC
9
36654 (4b), 1024367 (4d), 1024825 (4j) and 1024366 (4m).
These data can be obtained free of charge from the Cambridge
Crystallographic Data Centre, 12 Union Rd., Cambridge CB2
1
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1
1297; (e) Kikkeri, R.; Traboulsi, H.; Humbert, N.; Gumienna-

ACCEPTED MANUSCRIPT
Lewis-acid mediated three-component one-flask regioselective
synthesis of densely functionalized 4-amino-1,2-dihydropyridines via
cascade Knoevenagel/Michael/cyclization sequence
a
a
a
a
b
Suvajit Koley, Sushobhan Chowdhury, Tanmoy Chanda, B. Janaki Ramulu, Subhasis Samai,
c
a,
Lerato Motisa, and Maya Shankar Singh *
a
Department of Chemistry, Faculty of Science, Banaras Hindu University, Varanasi-
221005, India
Fax: (+91) 542-2368127; E-mail: mssinghbhu@yahoo.co.in; Homepage:
http:\\drmssinghchembhu.com
b
School of Physics and Chemistry, University of Kwa-Zulu Natal, Durban-4000, South
Africa
c
School of Pharmacy and Pharmacology, University of Kwa-Zulu Natal, Durban-4000,
South Africa
Supporting Information
1
2
3
. Experimental Section
S2
. Characterization Data of the New Compounds
S3-S8
1
13
. Copies of the H and C NMR Spectra of the
Compounds 4a-r
S9-S45
4
. ORTEP Diagrams of 4d, 4j and 4m
S46-S48
S1

ACCEPTED MANUSCRIPT
1
. EXPERIMENTAL SECTION
General Methods: The commercially available starting materials were used as received without
further purification. α-Oxoketene-N,S-arylaminoacetals 1 were prepared following the known
procedure (Ref. 23a in main manuscript). Thin-layer chromatography (TLC) was performed
using silica gel 60 F254 precoated plates. Infrared (IR) spectra are measured in KBr, and
-1
1
13
wavenumber (ῡ) are reported in cm . H and C NMR spectra were recorded on NMR
spectrometer operating at 300 and 75 MHz, respectively. Chemical shifts (δ) are given in parts
per million (ppm) using the residue solvent peaks as reference relative to TMS. J values are
given in hertz. Electronic absorption spectra at 25 °C were acquired on a Shimadzu UV-1701
spectrophotometer, in CH CN-H O (9 : 1, v/v; c, 10 ꢀM). Mass spectra were recorded using
3
2
electrospray ionization (ESI) mass spectrometry. The melting points are uncorrected.
General Procedure for the Synthesis of the 1,2-Dihydropyridine (4a-r):
To a mixture of α-oxoketene-N,S-arylaminoacetals 1 (1.0 mmol), aldehyde (1.0 mmol) 2 and
malononitrile 3 (1.0 mmol), InCl (0.1 mmol) was added and the reaction mixture was heated at
3
o
8
0 C till the completion of the reaction (Table-2 of main manuscript). After completion of the
reaction (monitored by TLC), water (20 mL) was added to the reaction mixture followed by
extraction with ethyl acetate (2 X 10 mL). The combined organic layer was dried over anhydrous
Na SO and then evaporated in vacuo. The crude residue was purified by column
2
4
chromatography over silica gel using ethyl acetate/hexane as eluent to afford pure 1,2-
dihydropyridine 4.
UV-vis Study:
For electronic absorption study the stock solution of ligand was prepared in CH CN-H O (9 : 1,
3
2
+
+
3+
3+
3+
2+
2+
2+
2+
v/v; c, 10 ꢀM), while for various metal ions (Na , K , Fe , Al , Cr , Cu , Zn , Cd , Hg ,
2
+
and Pb ) by dissolving respective nitrates in triply distilled water (10 mM) containg phosphate
buffered saline (PBS).
S2

ACCEPTED MANUSCRIPT
2
. Characterization Data of New Compounds:
4
-Amino-5-benzoyl-6-methylthio-1,2-diphenyl-1,2-dihydropyridine-3-carbonitrile
(4a).
-1
O
NH
2
Yellow solid, mp 173-175 °C; FT IR (KBr, cm ): 3471, 3354, 2936, 2157,
CN
1
1
643, 1438, 1057; H NMR (300 MHz, CDCl
Ar), 7.42-7.24 (m, 9H, Ar), 7.04-6.99 (m, 2H, Ar), 6.88 (d, J = 7.2 Hz, 2H,
Ar), 5.89 (br, 2H, D O Exchangeable, NH ), 5.47 (s, 1H, Chiral CH), 2.10
s, 3H, SCH3); C NMR (75 MHz, CDCl ): δ 195.06, 154.54, 152.60,
3
): δ 7.62 (d, J = 6.3 Hz, 2H,
N
MeS
2
2
1
3
(
3
1
1
44.16, 140.86, 131.93, 129.47, 128.73, 128.65, 128.47, 128.32, 127.85, 126.97, 125.19, 120.41,
+
14.78, 65.33, 63.05, 15.74; HRMS [M+H] calcd. For C H N OS 424.1483, found 424.1490.
2
6
22
3
4
-Amino-5-benzoyl-2-(4-methoxyphenyl)-6-methylthio-1-phenyl-1,2-dihydropyridine-3-
-1
O
NH2
carbonitrile (4b). Yellow solid, mp 170-172 °C; FT IR (KBr, cm ):
CN
1
3
482, 3337, 2932, 2160, 1628, 1446, 1025; H NMR (300 MHz,
CDCl ): δ 7.58-7.31 (m, 8H, Ar), 7.17-6.98 (m, 6H, Ar), 5.92 (br, 2H,
N
3
MeS
NH
2 3
), 5.48 (s, 1H, Chiral CH), 3.86 (s, 3H, OCH ), 1.71 (s, 3H,
OMe
1
3
SCH ); C NMR (75 MHz, CDCl ): δ 195.02, 159.79, 154.38, 152.55,
3
3
1
1
4
44.16, 140.05, 132.50, 131.94, 129.44, 128.73, 128.28, 127.82, 126.94, 125.23, 120.40, 114.72,
+
13.74, 65.00, 63.19, 55.45, 15.80; HRMS [M+Na] calcd. For C H N O SNa 476.1403, found
2
7
23
3
2
76.1389.
4
-Amino-5-benzoyl-2-(4-fluorophenyl)-6-methylthio-1-phenyl-1,2-dihydropyridine-3-
-
1
O
NH2
carbonitrile (4c). Yellow solid, mp 145-147 °C; FT IR (KBr, cm ):
CN
1
3
463, 3348, 2922, 2139, 1651, 1436, 1021; H NMR (300 MHz, CDCl ):
3
δ 7.64 (t, J = 6.4 Hz, 2H, Ar), 7.40-7.33 (m, 6H, Ar), 7.20-7.10 (m, 4H,
N
MeS
Ar), 7.00 (d, J = 7.5 Hz, 2H, Ar), 5.95 (br, 2H, NH ), 5.48 (s, 1H, Chiral
F
2
1
3
CH), 1.73 (s, 3H, SCH ); C NMR (75 MHz, CDCl ): δ 194.89, 154.61,
3
3
1
1
52.58, 144.16, 139.87, 136.66, 132.17, 129.56, 128.85, 128.63, 127.94, 127.17, 125.25, 120.21,
15.36 (d, JCF = 22.9Hz), 114.80, 114.75, 65.03, 63.06, 15.95; HRMS [M+H] calcd. For
+
26 3
C H21FN OS 442.1389, found 442.1410.
4
-Amino-2-(2-bromophenyl)-5-(4-methylbenzoyl)-6-methylthio-1-phenyl-1,2-
O
NH
2
dihydropyridine-3-carbonitrile (4d). Yellow solid, mp 209-211 °C;
CN
Br
-1
1
FT IR (KBr, cm ): 3472, 3353, 2935, 2158, 1644, 1436, 1067; H
NMR (300 MHz, CDCl ): δ 7.68-7.63 (m, 2H, Ar), 7.51 (d, J = 8.1 Hz,
H, Ar), 7.30-7.23 (m, 7H, Ar), 7.12 (d, J = 7.8 Hz, 2H, Ar), 5.94 (br,
Me
N
3
MeS
2
2
H, NH
2
), 5.84 (s, 1H, Chiral CH), 2.37 (s, 3H, CH
3
), 1.82 (s, 3H,
S3

ACCEPTED MANUSCRIPT
1
3
SCH
3
); C NMR (75 MHz, CDCl
3
): δ 193.95, 158.55, 153.48, 144.31, 143.26, 138.59, 137.07,
1
6
5
34.03, 130.44, 130.21, 129.34, 129.11, 128.87, 127.68, 127.57, 127.15, 123.35, 119.87, 112.46,
+
4.75, 63.45, 21.55, 17.33; HRMS [M+Na] calcd. For C27
38.0563.
3
H22BrN OSNa 538.0559, found
4
-Amino-2-(4-methoxyphenyl)-5-(4-methylbenzoyl)-6-methylthio-1-phenyl-1,2-
O
NH
2
dihydropyridine-3-carbonitrile (4e). Yellow solid, mp 168-169
CN
-1
°
C; FT IR (KBr, cm ): 3438, 3328, 2925, 2180, 1623, 1413, 1058;
1
H NMR (300 MHz, CDCl ): δ 7.50 (d, J = 8.1 Hz, 2H, Ar), 7.34-
Me
N
3
MeS
7
.18 (m, 5H, Ar), 6.93-6.84 (m, 6H, Ar), 5.80 (br, 2H, NH ), 5.40
OMe
2
(
s, 1H, Chiral CH), 3.79 (s, 3H, OCH ), 2.22 (s, 3H, CH ), 1.18 (s,
3
3
1
3
3
1
6
4
H, SCH3); C NMR (75 MHz, CDCl ): δ 194.86, 174.92, 159.83, 152.50, 144.30, 137.21,
3
32.61, 129.66, 129.45, 129.31, 129.15, 129.02, 128.63, 128.30, 126.93, 126.89, 125.32, 113.80,
+
4.92, 63.24, 55.44, 21.50, 15.78; HRMS [M+H] calcd. For C H N O S 468.1745, found
2
8
26
3
2
68.1760.
4
-Amino-2-(4-chloro-3-fluorophenyl)-5-(4-methylbenzoyl)-6-methylthio-1-phenyl-1,2-
O
NH
2
dihydropyridine-3-carbonitrile (4f). Yellow solid, mp 161-163 °C;
CN
-1
1
FT IR (KBr, cm ): 3479, 3350, 2923, 2173, 1624, 1471, 1033; H
NMR (300 MHz, CDCl ): δ 7.53-7.31 (m, 9H, Ar), 6.95 (br, 3H,
F
Me
N
3
MeS
Ar), 5.92 (br, 2H, NH ), 5.45 (s, 1H, Chiral CH), 2.32 (s, 3H, CH ),
Cl
2
3
3
1
1
.79 (s, 3H, SCH
3
); C NMR (75 MHz, CDCl
3
): δ 194.32, 159.76,
1
1
56.44, 154.15, 152.53, 143.94, 143.35, 142.69, 136.79, 130.57, 129.57, 128.73, 127.20, 125.11,
23.36, 120.01, 115.33 (d, JCF = 22.9Hz), 114.78, 111.73, 64.74, 62.51, 21.53, 15.97; HRMS
+
[M+H] calcd. For C H ClFN OS 490.1156, found 490.1168.
2
7
22
3
4
-Amino-5-(4-methoxybenzoyl)-2-(4-methoxyphenyl)-6-methylthio-1-phenyl-1,2-
O
NH
2
dihydropyridine-3-carbonitrile (4g). Yellow sticky solid; FT IR
CN
-1
1
(
KBr, cm ): 3452, 3332, 2937, 2168, 1629, 1447, 1021; H NMR
(
300 MHz, CDCl ): δ 7.58 (d, J = 8.4 Hz, 2H, Ar), 7.41 (d, J =
MeO
N
3
MeS
4.5 Hz, 4H, Ar), 7.32-7.25 (m, 1H, Ar), 7.00-6.97 (m, 4H, Ar),
OMe
6
.60 (d, J = 8.7 Hz, 2H, Ar), 5.83 (br, 2H, NH ), 5.47 (s, 1H,
2
1
3
Chiral CH), 3.85 (s, 3H, OCH ), 3.78 (s, 3H, OCH ), 1.77 (s, 3H, SCH ); C NMR (75 MHz,
3
3
3
CDCl ): δ 193.59, 162.94, 159.81, 153.09, 152.37, 144.33, 132.73, 132.31, 131.24, 129.40,
3
1
28.37, 126.77, 125.23, 120.38, 115.02, 113.76, 113.08, 64.86, 63.39, 55.53, 55.25, 15.83;
+
HRMS [M+H] calcd. For C H N O S 484.1695, found 484.1713.
2
8
26
3
3
S4

ACCEPTED MANUSCRIPT
4
-Amino-2-(4-bromophenyl)-5-(4-methoxybenzoyl)-6-methylthio-1-phenyl-1,2-
O
NH
2
dihydropyridine-3-carbonitrile (4h). Yellow solid, mp 171-173
CN
-1
°
C; FT IR (KBr, cm ): 3475, 3351, 2939, 2152, 1674, 1432, 1064;
1
H NMR (300 MHz, CDCl ): δ 7.54-7.46 (m, 4H, Ar), 7.32-7.18
MeO
N
3
MeS
(m, 5H, Ar), 6.87 (br, 2H, Ar), 6.56 (d, J = 8.7 Hz, 2H, Ar), 5.75
Br
(
br, 2H, NH ), 5.38 (s, 1H, Chiral CH), 3.73 (s, 3H, OCH ), 1.72 (s,
2
3
1
3
3
1
6
H, SCH3); C NMR (75 MHz, CDCl ): δ 193.35, 163.16, 153.01, 152.40, 144.06, 140.41,
3
31.84, 131.55, 131.11, 129.52, 128.96, 126.96, 125.08, 122.31, 120.12, 115.23, 113.22, 64.83,
+
2.82, 55.31, 15.83; HRMS [M+Na] calcd. For C H BrN O SNa 554.0514, found 554.0552.
2
7
22
3
2
4
-Amino-5-(4-methoxybenzoyl)-6-pentylthio-1,2-diphenyl-1,2-dihydropyridine-3-
-1
O
NH2
carbonitrile (4i). Yellow solid, mp 69-71 °C; FT IR (KBr, cm ):
CN
1
3
486, 3342, 2931, 2163, 1648, 1444, 1025; H NMR (300 MHz,
CDCl ): δ 7.66 (br, 2H, Ar), 7.45-7.40 (m, 7H, Ar), 7.25 (br, 1H, Ar),
MeO
N
3
PentS
6
.95 (br, 2H, Ar), 6.55 (d, J = 8.4 Hz, 2H, Ar), 5.82 (br, 2H, NH
2
),
5
.51 (s, 1H, Chiral CH), 3.76 (s, 3H, OCH ), 2.44-2.36 (m, 1H), 2.23-
3
1
3
2
1
1
3
.15 (m, 1H), 1.02-0.92 (m, 4H), 0.84-0.67 (m, 5H); C NMR (75 MHz, CDCl ): δ 193.96,
62.83, 153.35, 152.51, 144.58, 141.02, 132.56, 131.18, 129.34, 128.42, 128.35, 127.10, 126.75,
25.46, 120.48, 115.22, 113.06, 65.33, 62.88, 55.24, 33.17, 30.31, 28.02, 21.85, 13.63; HRMS
+
[M+H] calcd. For C H N O S 510.2215, found 510.2216.
3
1
32
3
2
4
-Amino-6-butylthio-5-(3-methoxybenzoyl)-1-phenyl-2-(p-tolyl)-1,2-dihydropyridine-3-
-
O
NH2
carbonitrile (4j). Yellow solid, mp 214-216 °C; FT IR (KBr, cm
MeO
CN
1
1
): 3462, 3349, 2923, 2138, 1652, 1435, 1025; H NMR (300 MHz,
CDCl ): δ 7.54 (d, J = 7.5 Hz, 2H, Ar), 7.43-7.37 (m, 4H, Ar),
N
3
BuS
7
5
.33-7.25 (m, 3H, Ar), 6.90-6.84 (m, 3H, Ar), 6.34 (s, 1H, Ar),
.92 (br, 2H, NH ), 5.48 (s, 1H, Chiral CH), 3.66 (s, 3H, OCH ),
Me
2
3
3
1
2
.42-2.29 (m, 4H), 2.21-2.10 (m, 1H), 0.98-0.82 (m, 4H), 0.60 (t, J = 6.4 Hz, 3H, CH ); C
3
NMR (75 MHz, CDCl ): δ 192.48, 159.40, 152.69, 144.68, 143.89, 141.92, 138.27, 137.64,
3
1
6
5
29.49, 129.40, 129.18, 128.63, 127.10, 127.00, 125.64, 121.71, 118.29, 114.86, 112.90, 65.31,
+
2.86, 55.30, 33.05, 30.22, 21.32, 13.17, 12.94; HRMS [M+H] calcd. For C H N O S
3
1
32
3
2
10.2215, found 510.2237.
4
-Amino-2-(2,4-dichlorophenyl)-6-ethylthio-5-(2-furoyl)-1-phenyl-1,2-dihydropyridine-3-
-1
O
NH
2
carbonitrile (4k). Yellow sticky solid; FT IR (KBr, cm ): 3481, 3350,
CN
Cl
1
2
916, 1645, 1439, 1053; H NMR (300 MHz, CDCl ): δ 7.97-7.92 (m,
3
O
EtS
N
1H, Ar), 7.51-7.18 (m, 8H, Ar), 7.06 (d, J = 3.6 Hz, 1H, Ar), 6.54 (t, J =
Cl
S5

ACCEPTED MANUSCRIPT
1
1
1
1
.5 Hz, 1H, Ar), 5.89-5.79 (m, 3H, NH
2 2
& Chiral CH), 2.55-2.46 (m, 1H, SCH ), 2.23-2.14 (m,
1
3
H, SCH ), 0.82 (t, J = 7.5 Hz, 3H, CH ); C NMR (75 MHz, CDCl ): δ 181.15, 158.31, 154.01,
2
3
3
52.34, 145.01, 144.50, 136.66, 134.74, 132.75, 130.30, 129.84, 129.34, 127.99, 127.30, 126.61,
19.57, 117.36, 112.80, 110.42, 63.15, 62.49, 28.81, 14.00; HRMS [M+H] calcd. For
+
C H Cl N O S 496.0653, found 496.0653.
25
20
2
3
2
4
-Amino-6-ethylthio-5-(2-furoyl)-2-(3-nitrophenyl)-1-phenyl-1,2-dihydropyridine-3-
carbonitrile (4l). Yellow solid, mp 157-159 °C; FT IR (KBr, cm ):
-1
O
NH
2
CN
1
3
456, 3327, 2923, 2181, 1643, 1416, 1059; H NMR (300 MHz,
O
NO
2
CDCl ): δ 8.59 (s, 1H, Ar), 8.23 (d, J = 7.5 Hz, 1H, Ar), 7.91 (d, J =
N
3
EtS
7
6
.5 Hz, 1H, Ar), 7.60 (t, J = 8.1 Hz, 1H, Ar), 7.42-7.33 (m, 6H, Ar),
.84 (d, J = 1.8 Hz, 1H, Ar), 6.43 (dd, J = 1.2 Hz, J = 3.0 Hz, 1H,
1
2
Ar), 5.91 (br, 2H, NH
2
), 5.52 (s, 1H, Chiral CH), 2.82-2.75 (m, 1H, SCH
2
), 2.37-2.31 (m, 1H,
1
3
SCH ), 0.85 (t, J = 7.5 Hz, 3H, CH ); C NMR (75 MHz, CDCl ): δ 181.24, 156.73, 153.63,
2
3
3
1
1
52.16, 148.15, 145.80, 144.37, 143.60, 132.95, 129.92, 129.67, 127.85, 125.75, 123.07, 120.48,
20.19, 117.17, 112.62, 112.50, 65.22, 63.17, 28.11, 13.71; HRMS [M+H] calcd. For
+
25 21 4 4
C H N O S 473.1283, found 473.1302.
4
-Amino-6-ethylthio-5-(2-furoyl)-1-phenyl-2-(p-tolyl)-1,2-dihydropyridine-3- carbonitrile
-1
O
NH2
(4m). Yellow solid, mp 165-166 °C; FT IR (KBr, cm ): 3456, 3342,
CN
1
2
934, 2158, 1622, 1451, 1043; H NMR (300 MHz, CDCl ): δ 7.50-7.20
3
O
N
(m, 10H, Ar), 6.29 (d, J = 1.8 Hz, 1H, Ar), 6.08 (br, 1H, Ar), 5.76 (br,
EtS
2
CH
H, NH ), 5.41 (s, 1H, Chiral CH), 2.54-2.23 (m, 5H, SCH & tolyl
Me
2
2
1
3
3
3 3
), 0.77 (t, J = 7.5 Hz, 3H, CH ); C NMR (75 MHz, CDCl ): δ
1
1
81.51, 155.08, 153.63, 151.91, 145.84, 144.58, 138.04, 137.69, 129.37, 129.08, 127.21, 126.88,
26.73, 125.84, 120.26, 117.67, 111.87, 65.56, 63.45, 27.88, 21.06, 13.54; HRMS [M+Na]
+
calcd. For C H N O SNa 464.1403, found 464.1406.
2
6
23
3
2
4
-Amino-2-(4-nitrophenyl)-1-phenyl-6-propylthio-5-(2-thienoyl)-1,2-dihydropyridine-3-
-1
O
NH
2
carbonitrile (4n). Yellow solid, mp 163-165 °C; FT IR (KBr, cm ):
CN
1
3478, 3351, 2924, 2172, 1654, 1463, 1032; H NMR (300 MHz,
S
N
CDCl ): δ 8.33 (d, J = 8.4 Hz, 2H, Ar), 7.85 (d, J = 8.4 Hz, 2H, Ar),
3
PrS
7.47-7.35 (m, 6H, Ar), 6.81 (t, J = 4.2 Hz, 1H, Ar), 6.70 (d, J = 3.0 Hz,
NO
2
1
H, Ar), 5.83 (br, 2H, NH ), 5.52 (s, 1H, Chiral CH), 2.54-2.46 (m, 1H,
2
SCH ), 2.36-2.28 (m, 1H, SCH ), 1.20-1.00 (m, 1H, CH ), 0.93-0.82 (m, 1H, CH ), 0.56 (t, J =
2
2
2
2
1
3
7
1
.3 Hz, 3H, CH3); C NMR (75 MHz, CDCl ): δ 186.07, 172.42, 152.21, 148.54, 145.24,
3
44.28, 133.67, 132.62, 129.66, 127.93, 127.85, 127.62, 127.57, 125.77, 123.80, 123.69, 119.84,
S6

ACCEPTED MANUSCRIPT
+
1
14.76, 65.16, 62.15, 35.89, 21.56, 12.80; HRMS [M+H] calcd. For C26
H
23
N
4
O
3
S
2
503.1206,
found 503.1214.
4
-Amino-2-(3-chlorophenyl)-1-phenyl-6-propylthio-5-(2-thienoyl)-1,2-dihydropyridine-3-
-1
O
NH
2
carbonitrile (4o). Yellow solid, mp 77-78 °C; FT IR (KBr, cm ): 3480,
CN
1
3
1
4
1
346, 2933, 1641, 1434, 1048; H NMR (300 MHz, CDCl ): δ 7.63 (br,
H, Ar), 7.49 (d, J = 5.1 Hz, 1H, Ar), 7.39-7.25 (m, 8H, Ar), 6.82 (t, J =
3
S
Cl
N
PrS
.3 Hz, 1H, Ar), 6.57 (d, J = 3.0 Hz, 1H, Ar), 5.74 (br, 2H, NH ), 5.45 (s,
2
2 2
H, Chiral CH), 2.54-2.46 (m, 1H, SCH ), 2.31-2.22 (m, 1H, SCH ),
1
3
1
.19-1.01 (m, 1H, CH ), 0.89-0.85 (m, 1H, CH ), 0.55 (t, J = 7.2 Hz, 3H, CH ); C NMR (75
2 2 3
3
MHz, CDCl ): δ 186.56, 153.89, 151.94, 145.71, 144.30, 143.24, 134.59, 133.45, 132.91,
1
6
29.96, 129.49, 128.47, 127.43, 127.23, 126.93, 126.89, 125.62, 125.25, 120.09, 115.10, 65.19,
2.79, 35.54, 21.67, 12.83; HRMS [M] calcd. For C26H22ClN OS 491.0888, found 491.0887.
3 2
+
4
-Amino-5-benzoyl-2-cyclohexyl-6-methylthio-1-phenyl-1,2-dihydropyridine-3-carbonitrile
-1
O
NH
2
(4p). Yellow solid, mp 212-214 °C; FT IR (KBr, cm ): 3476, 3352, 2938,
CN
1
2
147, 1664, 1442, 1066; H NMR (300 MHz, CDCl ): δ 7.78 (d, J = 7.5
3
2
Hz, 2H, Ar), 7.50-7.22 (m, 8H, Ar), 5.90 (br, 2H, NH ), 3.88 (d, J = 10.2
N
MeS
Hz, 1H, Chiral CH), 2.17-2.05 (m, 5H), 1.85-1.72 (m, 4H), 1.36-1.25 (m,
1
3
5
H); C NMR (75 MHz, CDCl ): δ 194.26, 156.53, 151.67, 145.20,
3
1
3
4
40.58, 132.03, 129.24, 128.83, 128.18, 127.10, 126.35, 120.90, 113.46, 69.63, 63.21, 41.33,
+
1.67, 29.85, 26.31, 26.00, 16.69; HRMS [M+H] calcd. For C H N OS 476.1948, found
2
6
28
3
76.1956.
4
-Amino-5-benzoyl-2-heptyl-6-methylthio-1-phenyl-1,2-dihydropyridine-3-carbonitrile
-1
O
NH
2
(4q). Yellow sticky solid; FT IR (KBr, cm ): 3482, 3349, 2912, 1665,
CN
1
1
435, 1054; H NMR (300 MHz, CDCl ): δ 7.78 (d, J = 6.9 Hz, 2H, Ar),
3
Me
2
7.49-7.25 (m, 8H, Ar), 5.86 (br, 2H, NH ), 4.26 (t, J = 7.3 Hz, 1H, Chiral
N
CH2
MeS
6
CH), 1.70 (s, 3H, SCH ), 1.41-1.25 (m, 12H), 0.89 (t, J = 5.1 Hz, 3H,
3
13
CH
3 3
); C NMR (75 MHz, CDCl ): δ 194.73, 169.10, 151.77, 144.94,
1
3
4
40.84, 132.01, 129.30, 129.05, 128.77, 128.18, 127.84, 127.20, 125.92, 125.22, 63.78, 36.58,
+
4.89, 31.83, 29.66, 29.25, 26.00, 25.86, 22.61, 14.05; HRMS [M+H] calcd. For C27
46.2266, found 446.2287.
32 3
H N OS
4
-Amino-1-(2-bromophenyl)-5-(2-chlorobenzoyl)-2-(2-furyl)-6-methylthio-1,2-
Cl
O
NH2
dihydropyridine-3-carbonitrile (4r). Yellow solid, mp 226-228 °C; FT IR
CN
-1
1
(
KBr, cm ): 3472, 3381, 2957, 2166, 1664, 1435, 1061; H NMR (300
O
N
MeS
Br
S7

ACCEPTED MANUSCRIPT
MHz, CDCl
3
): δ 7.94 (d, J = 7.8 Hz, 1H, Ar), 7.61 (t, J = 7.9 Hz, 2H, Ar), 7.44 (t, J = 7.5 Hz,
1
1
H, Ar), 7.34-7.17 (m, 2H, Ar), 6.96 (t, J = 7.3 Hz, 1H, Ar), 6.33 (dd, J = 1.2 Hz, J = 7.5 Hz,
1 2
13
2 3
H, Ar), 6.50 (br, 2H, NH ), 5.31 (s, 1H, Chiral CH), 1.53 (s, 3H, SCH ); C NMR (75 MHz,
CDCl ): δ 193.14, 159.05, 154.90, 152.46, 147.64, 143.13, 141.27, 134.13, 133.28, 130.67,
3
1
1
30.57, 129.96, 129.83, 129.77, 129.65, 128.70, 125.61, 123.46, 119.36, 110.56, 61.30, 59.85,
+
7.19; HRMS [M+H] calcd. For C H BrClN O S 525.9986, found 525.9999.
2
4
18
3
2
S8

ACCEPTED MANUSCRIPT
1
13
3
. Copies of the H and C NMR Spectra of the Compounds 4a-r:
1
H NMR Spectrum of the Compound 4a:
S9

ACCEPTED MANUSCRIPT
1
2
D O Exchanged H NMR Spectrum of the Compound 4a:
S10

ACCEPTED MANUSCRIPT
1
3
C NMR Spectrum of the Compound 4a:
S11

ACCEPTED MANUSCRIPT
1
H NMR Spectrum of the Compound 4b:
S12

ACCEPTED MANUSCRIPT
1
3
C NMR Spectrum of the Compound 4b:
S13

ACCEPTED MANUSCRIPT
1
H NMR Spectrum of the Compound 4c:
S14

ACCEPTED MANUSCRIPT
1
3
C NMR Spectrum of the Compound 4c:
S15

ACCEPTED MANUSCRIPT
1
H NMR Spectrum of the Compound 4d:
S16

ACCEPTED MANUSCRIPT
1
3
C NMR Spectrum of the Compound 4d:
S17

ACCEPTED MANUSCRIPT
1
H NMR Spectrum of the Compound 4e:
S18

ACCEPTED MANUSCRIPT
1
3
C NMR Spectrum of the Compound 4e:
S19

ACCEPTED MANUSCRIPT
1
H NMR Spectrum of the Compound 4f:
S20