A facile four component protocol for the synthesis of dihydropyridine derivatives

Article abstract of DOI:10.1039/c2ob26074c

An efficient one pot synthesis of dihydropyridine derivatives employing the transient zwitterions generated from aniline and allenoates is described. The Royal Society of Chemistry 2012.

Full text of DOI:10.1039/c2ob26074c

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PAPER
A facile four component protocol for the synthesis of dihydropyridine
derivatives†
Vijay Nair,*a Anu Jose,a K. C. Seetha Lakshmi,a Rejithamol Rajana and Eringathodi Sureshb
Received 4th June 2012, Accepted 1st August 2012
DOI: 10.1039/c2ob26074c
An efficient one pot synthesis of dihydropyridine derivatives employing the transient zwitterions
generated from aniline and allenoates is described.
Introduction
Multicomponent reactions (MCRs) are well-known for their con-
vergence, atom economy and high stereoselectivity and they con-
stitute relatively simple and benign procedures which often lead
to biologically important and complex organic molecules in one
pot.1,2 The Strecker synthesis3 of α-amino acid from ammonia,
Scheme 1 Reaction of isoquinoline–allenoate zwitterion with p-fluoro-
phenylcyanoacrylate.
carbonyl compounds and hydrogen cyanide reported in 1850 is
generally considered as the first MCR. Undoubtedly, the isocya-
arylidenemalononitriles to form highly functionalized pyridoiso-
nide-based multicomponent reactions such as Passerini 3-com-
quinoline derivatives (Scheme 1).11
ponent reaction4 and Ugi 4-component reaction,5 invented
Success of the reaction described above encouraged us to
decades later, have provided a major thrust to this area. The
emergence of zwitterion chemistry6 has added a new dimension
explore this area further, especially to investigate the chemistry
of the zwitterion derived from electron deficient allene and a
to multicomponent reactions. Transient zwitterions are dipolar
species formed by the addition of nucleophiles such as phos-
phines, isocyanides, N-heterocycles and nucleophilic carbenes to
activated π systems such as alkenes, acetylenes, allenoates and
primary amine, viz., aniline. A recent report on the reaction of
zwitterions from acetylenic ester and aniline provided further
impetus to investigate the allenoate–aniline zwitterion.12 In the
event, we were able to intercept the zwitterion with arylidene
diazoesters. The chemistry of zwitterions dates back to 1932
malononitrile, generated in situ from the corresponding aldehyde
when Diels and Alder isolated a 1 : 2 adduct from the reaction of
pyridine and dimethylacetylene dicarboxylate.6a The structure of
and malononitrile, to afford dihydropyridine derivative. It may
this compound was independently established by Acheson,7
be mentioned that the reaction proceeds efficiently with premade
Winterfeldt8 and Huisgen9 three decades later.
dicyanostyrene and allenoate–aniline zwitterion in the presence
of triethylamine.
In a prototype experiment, a solution of 4-fluorobenzaldehyde,
malononitrile and triethylamine was stirred under argon atmos-
phere in ethanol. After 10 min, a solution of aniline and ethyl
Results and discussion
penta-2,3-dienoate in ethanol was added and the mixture was
stirred for 12 h. The crude product on purification by column
chromatography using silica gel and hexane : ethylacetate
(70 : 30) as the eluent afforded (E)-Ethyl 2-(6-amino-5-cyano-4-
(4-fluorophenyl)-3-methyl-1-phenyl-3,4-dihydropyridin-2(1H)-
ylidene)acetate 10a as colourless crystalline solid (M.P:
184–186 °C) in 62% yield (Scheme 2).
The structure of the product was established using usual spec-
troscopic analysis and elemental analysis. The IR spectrum
showed characteristic –NH2 and –CN absorptions at 3337 and
2179 cm−1, respectively. Absorption at 1702 cm−1 corresponds
to the ester carbonyl group. In the 1H NMR spectrum the
olefinic proton and the –NH2 protons were discernible as singlets
Recently, a novel three component reaction utilizing the transient
zwitterion generated from allenoate10 and isoquinoline was
reported by our group. The allenoate–isoquinoline zwitterion
was efficiently intercepted with cyanoacrylates and
aOrganic Chemistry Section, National Institute for Interdisciplinary
Science and Technology (CSIR), Trivandrum 695019, India.
E-mail: vijaynair_2001@yahoo.com; Fax: +91(471)2491712
bAnalytical Science Discipline, Central Salt and Marine Chemicals
Research Institute, Bhavnagar 364002, India
†Electronic supplementary information (ESI) available: general exper-
imental procedure, 1H and 13C spectra of compounds. CCDC 870088.
For ESI and crystallographic data in CIF or other electronic format see
DOI: 10.1039/c2ob26074c
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 7747–7752 | 7747

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Table 2 Substrate scope
Entry Ar
R1
R2
Product Yield (%)
Scheme 2
1
2
3
4
5
6
7
8
4-Fluorophenyl
4-Methylphenyl
4-Bromophenyl
4-Methoxyphenyl –CH3
2-Methylphenyl
Phenyl
4-Fluorophenyl
4-Chlorophenyl
4-Bromophenyl
–CH3
–CH3
–CH3
–Et
–Et
–Et
–Et
–Et
–Et
10a
10b
10c
10d
10e
10f
62
56
49
45
46
42
56
58
42
38
53
71
65
57
48
at δ 4.33 and 4.19 ppm respectively. In the 13C NMR spectrum
the ester carbonyl group displayed a resonance signal at δ
166.2 ppm. Final confirmation of the structure and stereo-
chemistry was derived from single crystal X-ray analysis of 10a
(Fig. 1).
With a view to optimise the reaction conditions, experiments
were conducted by varying solvent, base and temperature.
However, no improvement of the yield was observed (Table 1).
Analogous products were obtained when the reaction was
carried out using dialkyl penta-2,3-dienedioates under the same
conditions. The structure of the products was assigned using
–CH3
–CH3
–CO2Me –Me 10g
–CO2Me –Me 10h
–CO2Me –Me 10i
9
10
11
12
13
14
15
4-Methoxyphenyl –CO2Me –Me 10j
2-Methylphenyl
4-Fluorophenyl
4-Chlorophenyl
4-Bromophenyl
2-Methylphenyl
–CO2Me –Me 10k
–CO2Et
–CO2Et
–CO2Et
–CO2Et
–Et
–Et
–Et
–Et
10l
10m
10n
10o
Scheme 3
spectroscopic analysis and the stereochemistry was established
by nOe studies.
The reaction was found to be general with respect to different
types of allenoates and aldehydes and the results are summarized
in Table 2.
It appears that the reaction works well with substituted ani-
lines and an example using p-methyl aniline is shown in
Scheme 3.
Fig. 1 ORTEP diagram of 10a.
Table 1 Optimization of conditions
A mechanistic rationale for the formation of the dihydropyri-
dine derivative may be outlined as follows. Addition of aniline
to the allenoate affords a zwitterion which on proton transfer
delivers the enamine b. The latter then adds to the dicyanosty-
rene a, which is formed by the in situ Knoevenagel condensation
of aldehyde and malononitrile, to form c. This intermediate after
proton transfer yields e which then undergoes cyclization to an
imine followed by isomerization to afford the product. The anti
disposition of Ar1 and R1 is predicated by the Michael addition
of the enamine b to the acceptor a; Michael reactions of this
type are usually anti selective, presumably due to steric factors
(Scheme 4).
Entry
Base
Solvent
Temperature
Yield (%)
1
2
3
4
5
6
7
8
9
Et3N
Et3N
Et3N
Et3N
EtOH
THF
rt
rt
rt
62
—
—
32
56
—
—
—
—
DCM
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
0 °C–rt
80 °C
rt
rt
rt
rt
Et3N
DBU
DMAP
DABCO
NaH
Conclusions
In conclusion, we have developed a novel methodology for
the synthesis of dihydropyridine derivatives in one pot.
7748 | Org. Biomol. Chem., 2012, 10, 7747–7752
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IR (film) νmax: 3471, 3337, 2179, 1702, 1614, 1587, 1392,
1141 cm−1
.
1H NMR (500 MHz, CDCl3): δ 7.57–7.50 (m, 3H), 7.25–7.22
(m, 2H), 7.16 (d, 2H, J = 7.5 Hz), 7.00 (t, 2H, J = 8.5 Hz),
4.64–4.60 (m, 1H), 4.33 (s, 1H), 4.19 (s, 2H), 3.97–3.90 (m,
2H), 3.49 (s, 1H), 1.47 (d, 3H, J = 6.5 Hz), 1.10 (t, 3H, J =
7 Hz) ppm.
1
13C NMR (125 MHz, CDCl3): δ 166.2, 161.7 (d, JCF
=
4
243.8 Hz), 158.9, 151.2, 138.57 (d, JCF = 2.5 Hz), 136.9,
3
130.8, 130.0, 129.4, 128.3, (d, JCF = 7.5 Hz) 121.7, 115.5 (d,
2JCF = 21.3 Hz), 99.2, 59.4, 57.8, 42.4, 34.1, 19.9, 14.2 ppm.
LRMS (+FAB) m/z calcd for C23H22FN3O2 (M + H)+ 392.17;
Found: 392.69.
Anal. Calcd for C23H22FN3O2: C, 70.57; H, 5.66; N, 10.73.
Found: C, 70.71; H, 5.83; N, 10.94.
Scheme 4 Plausible mechanism.
(E)-Ethyl 2-(6-amino-5-cyano-3-methyl-1-phenyl-4-p-tolyl-3,4-
dihydropyridin-2(1H)-ylidene)acetate (10b). Yield: 217 mg
(0.56 mmol, 56%), colourless solid, M.P: 176–178 °C.
Dihydropyridine derivatives are biologically important com-
pounds; inter alia, they can act as calcium channel blockers and
hence useful in cardiovascular therapy.13 Some dihydropyridine
derivatives are effectively used against cystic fibrosis.14 It is also
noteworthy that the enamine moiety makes them versatile inter-
mediates for further synthetic transformations.
IR (film) νmax: 3470, 3336, 2178, 1702, 1613, 1588, 1393,
1138 cm−1
.
1H NMR (500 MHz, CDCl3): δ 7.57–7.54 (m, 2H), 7.52–7.50
(m, 1H), 7.18–7.16 (m, 3H) 7.14–7.10 (m, 3H), 4.62 (m, 1H),
4.32 (s, 1H), 4.10 (s, 2H), 3.97–3.91 (m, 2H), 3.47 (s, 1H), 2.32
(s, 3H), 1.47 (d, 3H, J = 7 Hz), 1.10 (t, 3H, J = 7 Hz) ppm.
13C NMR (125 MHz, CDCl3): δ 166.3, 159.3, 150.9, 139.7,
137.1, 136.2, 130.7, 129.9, 129.4, 126.6, 98.8, 59.3, 58.5, 42.6,
34.1, 21.1, 20.0, 14.2 ppm.
Experimental
General
Melting points were recorded on a Büchi melting point apparatus
and are uncorrected. NMR spectra were recorded at 300/500
(1H) and 75/125 (13C) MHz respectively on Bruker Avance
DPX-300/500S MHz NMR spectrometers. Chemical shifts (δ)
are reported relative to TMS (1H) and CDCl3 (13C) as the
internal standards. Coupling constant (J) is reported in Hertz
(Hz). Mass spectra were recorded under LRMS (FAB) using
JEOL JMS 600H mass spectrometer. Elemental analysis was
carried out on Perkin Elmer Series II CHNS Analyser 2400. IR
spectra were recorded on a Bruker Alpha-T FT-IR spectropho-
tometer. Allenoates were prepared using known literature pro-
cedures.15 Gravity column chromatography was performed using
silica gel and mixtures of petroleum ether–ethyl acetate were
used for elution.
LRMS (+FAB) m/z calcd for C24H25N2O3 (M + H)+ 388.19;
Found: 388.99.
Anal. Calcd for C24H25N2O3: C, 74.39; H, 6.50; N, 10.84.
Found: C, 73.83; H, 6.85; N, 10.78.
(E)-Ethyl 2-(6-amino-4-(4-bromophenyl)-5-cyano-3-methyl-1-
phenyl-3,4-dihydropyridin-2(1H)-ylidene)acetate (10c). Yield:
222 mg (0.49 mmol, 49%), colourless solid, M.P: 148–150 °C.
IR (film) νmax: 3463, 3333, 2178, 1699, 1615, 1586, 1389,
1139 cm−1
.
1H NMR (500 MHz, CDCl3): δ 7.58–7.51 (m, 3H), 7.45 (d,
2H, J = 8 Hz), 7.16 (d, 4H, J = 8.5 Hz), 4.64 (q, 1H, J = 7 Hz),
4.33 (s, 1H), 4.15 (s, 2H), 3.96–3.93 (m, 2H), 3.47 (s, 1H), 1.48
(d, 3H, J = 7 Hz), 1.11 (t, 3H, J = 7 Hz) ppm.
13C NMR (125 MHz, CDCl3): δ 166.2, 158.6, 151.1, 141.8,
131.7, 130.8, 130.7, 129.9, 129.3, 128.5, 120.7, 99.5, 59.5,
59.4, 42.8, 33.8, 19.8, 14.1 ppm.
General procedure for the synthesis of dihydropyridines
The aldehyde (1 mmol) and malononitrile (1 mmol) were taken
in a round bottom flask in ethanol (3 ml) under argon atmos-
phere. Triethylamine (1.2 mmol) was added and stirred for
10 min. To this reaction mass, mixture of aniline (1.2 mmol) and
allenoate (1.2 mmol) was added as a solution in ethanol (3 ml)
and stirred the reaction for 12 h at room temperature. After the
completion of the reaction as monitored by TLC, the reaction
mixture was concentrated and the crude product was purified by
column chromatography on silica gel (100–200 mesh) using
hexane : ethylacetate (70 : 30) as the eluent to afford the product
as a crystalline solid.
LRMS (+FAB) m/z calcd for C23H22BrN3O2 (M + H)+
453.09; Found: 452.89.
Anal. Calcd for C23H22BrN3O2: C, 61.07; H, 4.90; N, 9.29.
Found: C, 61.38; H, 5.07; N, 9.00.
(E)-Ethyl 2-(6-amino-5-cyano-4-(4-methoxyphenyl)-3-methyl-
1-phenyl-3,4-dihydropyridin-2(1H)-ylidene)acetate (10d). Yield:
182 mg (0.45 mmol, 45%), colourless solid, M.P: 210–214 °C.
IR (film) νmax: 3458, 3354, 2177, 1700, 1610, 1586, 1391,
1139 cm−1
.
1H NMR (500 MHz, CDCl3): δ 7.56–7.49 (m, 3H), 7.17 (d,
4H, J = 8 Hz), 6.83 (d, 2H, J = 8.5 Hz), 4.61 (q, 1H, J = 7 Hz),
4.30 (s, 1H), 4.11 (s, 2H), 3.98–3.89 (m, 2H), 3.78 (s, 3H), 3.45
(s, 1H), 1.46 (d, 3H, J = 6.5 Hz), 1.11 (t, 3H, J = 7 Hz) ppm.
(E)-Ethyl 2-(6-amino-5-cyano-4-(4-fluorophenyl)-3-methyl-1-
phenyl-3,4-dihydropyridin-2(1H)-ylidene)acetate (10a). Yield:
242 mg (0.62 mmol, 62%), colourless solid, M.P: 184–186 °C.
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 7747–7752 | 7749

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13C NMR (125 MHz, CDCl3): δ 166.3, 159.4, 158.4, 151.0,
137.1, 134.8, 130.7, 129.9, 129.44, 127.7, 121.8, 114.0, 98.8,
59.3, 58.5, 55.1, 42.3, 34.2, 19.9, 14.2 ppm.
(E)-Methyl 6-amino-4-(4-chlorophenyl)-5-cyano-2-(2-methoxy-2-
oxoethylidene)-1-phenyl-1,2,3,4-tetrahydropyridine-3-carboxy-
late (10h). Yield: 254 mg (0.58 mmol, 58%), colourless solid,
M.P: 184–186 °C.
LRMS (+FAB) m/z calcd for C24H25N3O3 (M + H)+ 404.19;
Found: 404.56.
IR (film) νmax: 3466, 3351, 2180, 1736, 1620, 1581, 1491,
1385, 1151 cm−1
.
Anal. Calcd for C24H25N3O3: C, 71.44; H, 6.25; N, 10.41.
Found: C, 71.40; H, 6.46; N, 10.46.
1H NMR (300 MHz, CDCl3): δ 7.57–7.54 (m, 4H), 7.34–7.26
(m, 5H), 5.66 (d, 1H, J = 2.1 Hz), 4.59 (s, 1H), 4.31 (s, 1H),
4.24 (s, 2H), 3.88 (s, 3H), 3.49 (s, 3H) ppm.
(E)-Ethyl 2-(6-amino-5-cyano-3-methyl-1-phenyl-4-o-tolyl-3,4-
dihydropyridin-2(1H)-ylidene)acetate (10e). Yield: 178 mg
(0.46 mmol, 46%), colourless solid, M.P: 218–220 °C.
13C NMR (75 MHz, CDCl3): δ 169.9, 166.7, 152.3, 151.2,
139.0, 136.7, 133.1, 131.0, 130.2, 129.3, 129.0, 128.3, 120.7,
102.1, 57.0, 53.0, 50.9, 45.6, 38.5 ppm.
IR (film) νmax: 3472, 3333, 2174, 1705, 1613, 1581, 1394,
1144 cm−1
.
LRMS (+FAB) m/z calcd for C23H20ClN3O4 (M + H)+
438.11; Found: 438.61.
1H NMR (500 MHz, CDCl3): δ 7.57–7.54 (m, 2H), 7.52–7.49
(m, 1H), 7.23 (s, 2H), 7.19–7.09 (m, 4H), 4.48 (q, 1H, J =
6 Hz), 4.30 (s, 1H), 4.22 (s, 2H), 3.93–3.84 (m, 2H), 3.67 (s,
1H), 2.43 (s, 3H), 1.49 (d, 3H, J = 6.5 Hz), 1.05 (t, 3H, J =
7.5 Hz) ppm.
Anal. Calcd for C23H20ClN3O4: C, 63.09; H, 4.60; N, 9.60.
Found: C, 62.73; H, 4.79; N, 9.76.
(E)-Methyl 6-amino-4-(4-bromophenyl)-5-cyano-2-(2-methoxy-
2-oxoethylidene)-1-phenyl-1,2,3,4-tetrahydropyridine-3-carboxy-
late (10i). Yield: 203 mg (0.42 mmol, 42%), colourless solid,
M.P: 177–179 °C.
13C NMR (125 MHz, CDCl3): δ 166.2, 158.9, 151.6, 140.2,
137.1, 135.4, 131.0, 130.8, 129.9, 129.4, 126.8, 126.0, 125.7,
99.3, 59.3, 57.8, 40.1, 32.8, 20.1, 19.2, 14.1 ppm.
LRMS (+FAB) m/z calcd for C24H25N3O2 (M + H)+ 388.19;
Found: 388.94.
IR (film) νmax: 3469, 3360, 2182, 1736, 1624, 1581, 1460,
1380, 1154 cm−1
.
1H NMR (500 MHz, CDCl3): δ 7.57–7.51 (m, 3H), 7.47
(d, 2H, J = 8.5 Hz), 7.21 (d, 3H, J = 8.5 Hz), 7.16 (s, 1H), 5.66
(d, 1H, J = 2 Hz), 4.58 (s, 1H), 4.29 (s, 1H), 4.22 (s, 2H), 3.88
(s, 3H), 3.49 (s, 3H) ppm.
Anal. Calcd for C24H25N3O2: C, 74.39; H, 6.50; N, 10.84.
Found: C, 74.58; H, 6.45; N, 10.64.
(E)-Ethyl 2-(6-amino-5-cyano-3-methyl-1,4-diphenyl-3,4-dihy-
dropyridin-2(1H)-ylidene)acetate
(0.42 mmol, 42%), colourless solid, M.P: 130–134 °C.
IR (film) νmax: 3469, 3335, 2178, 1701, 1614, 1587, 1392,
1139 cm−1
(10f). Yield:
157
mg
13C NMR (125 MHz, CDCl3): δ 169.8, 166.7, 152.5, 151.2,
139.6, 136.8, 131.9, 130.2, 129.3, 128.7, 121.3, 120.7, 102.1,
56.9, 53.0, 50.9, 45.6, 38.7 ppm.
.
LRMS (+FAB) m/z calcd for C23H20BrN3O4 (M + H)+
482.06; Found: 482.87.
1H NMR (500 MHz, CDCl3): δ 7.57–7.51 (m, 3H), 7.34–7.31
(m, 2H), 7.27 (d, 2H, J = 7.5 Hz) 7.23–7.18 (m, 3H), 4.66–4.61
(m, 1H), 4.34 (s, 1H), 4.15 (s, 2H), 3.96–3.90 (m, 2H), 3.51 (s,
1H), 1.49 (d, 3H, J = 6.5 Hz), 1.09 (t, 3H, J = 7 Hz) ppm.
13C NMR (125 MHz, CDCl3): δ 166.2, 159.2, 151.0, 142.7,
137.0, 130.8, 129.9, 128.6, 126.8, 126.7, 98.9, 59.3, 58.3, 43.0,
34.1, 20.0, 14.2 ppm.
Anal. Calcd for C23H20BrN3O4: C, 57.27; H, 4.18; N, 8.71.
Found: C, 57.53; H, 4.33; N, 8.92.
(E)-Methyl 6-amino-5-cyano-2-(2-methoxy-2-oxoethylidene)-4-
(4-methoxyphenyl)-1-phenyl-1,2,3,4-tetrahydropyridine-3-carbo-
xylate (10j). Yield: 165 mg (0.38 mmol, 38%), colourless solid,
M.P: 167–169 °C.
LRMS (+FAB) m/z calcd for C23H23N3O2 (M + H)+ 374.19;
Found: 374.34.
Anal. Calcd for C23H23N3O2: C, 73.97; H, 6.21; N, 11.25.
Found: C, 73.62; H, 6.54; N, 10.92.
IR (film) νmax: 3461, 3348, 2179, 1734, 1618, 1579, 1384,
1143 cm−1
.
1H NMR (500 MHz, CDCl3): δ 7.56–7.50 (m, 3H), 7.46
(s, 1H), 7.23 (d, 2H, J = 9 Hz), 7.19 (s, 1H), 6.86 (d, 2H, J =
8.5 Hz), 5.62 (d, 1H, J = 2.5 Hz), 4.57 (s, 1H), 4.27 (s, 1H),
4.17 (s, 2H), 3.88 (s, 3H), 3.80 (s, 3H), 3.48 (s, 3H) ppm.
13C NMR (75 MHz, CDCl3): δ 170.2, 166.8, 158.8, 152.0,
151.8, 137.0, 132.4, 130.0, 129.4, 127.9, 120.8, 114.2, 101.8,
58.3, 55.1, 52.8, 50.8, 46.1, 38.4 ppm.
(E)-Methyl 6-amino-5-cyano-4-(4-fluorophenyl)-2-(2-methoxy-
2-oxoethylidene)-1-phenyl-1,2,3,4-tetrahydropyridine-3-carboxy-
late (10g). Yield: 236 mg (0.56 mmol, 56%), colourless solid,
M.P: 178–180 °C.
IR (film) νmax: 3464, 3351, 2180, 1736, 1703, 1621, 1580,
1426, 1386, 1149 cm−1
.
1H NMR (300 MHz, CDCl3): δ 7.54 (s, 4H), 7.29–7.27 (m,
3H), 7.06–7.01 (m, 2H), 5.65 (s, 1H), 4.59 (s, 1H), 4.31 (s, 1H),
4.27 (s, 2H), 3.88 (s, 3H), 3.48 (s, 3H) ppm.
LRMS (+FAB) m/z calcd for C24H23N3O5 (M + H)+ 434.16;
Found: 435.04.
Anal. Calcd for C24H23N3O5: C, 66.50; H, 5.35; N, 9.69.
Found: C, 66.15; H, 5.35; N, 9.32.
13C NMR (125 MHz, CDCl3): δ 169.9, 166.7, 162.0 (d,
1JCF = 245 Hz), 152.2, 151.3, 136.8, 136.1, 130.2, 129.3, 128.4
3
2
(d, JCF = 8.8 Hz), 115.7 (d, JCF = 21.3 Hz), 102.1, 57.6,
53.0, 52.9, 50.9, 45.8, 38.4 ppm.
(E)-Methyl 6-amino-5-cyano-2-(2-methoxy-2-oxoethylidene)-1-
phenyl-4-o-tolyl-1,2,3,4-tetrahydropyridine-3-carboxylate (10k).
Yield: 221 mg (0.53 mmol, 53%), colourless solid, M.P:
210–214 °C.
LRMS (+FAB) m/z calcd for C23H20FN3O4 (M + H)+ 422.14;
Found: 422.96.
Anal. Calcd for C23H20FN3O4: C, 65.55; H, 4.78; N, 9.97.
Found: C, 65.47; H, 4.80; N, 10.05.
IR (film) νmax: 3466, 3355, 2180, 1735, 1620, 1585, 1386,
1148 cm−1
.
7750 | Org. Biomol. Chem., 2012, 10, 7747–7752
This journal is © The Royal Society of Chemistry 2012

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1H NMR (500 MHz, CDCl3): δ 7.59–7.56 (m, 2H), 7.53–7.50
(m, 1H), 7.47 (s, 1H), 7.29 (s, 1H), 7.19–7.14 (m, 4H), 5.54
(d, 1H, J = 2 Hz), 4.54 (s, 1H), 4.47 (s, 1H), 4.26 (s, 2H), 3.90
(s, 3H), 3.42 (s, 3H), 2.53 (s, 3H) ppm.
4.22 (s, 2H), 3.94 (q, 2H, J = 7 Hz), 1.39 (t, 3H, J = 7 Hz), 1.11
(t, 3H, J = 7 Hz) ppm.
13C NMR (75 MHz, CDCl3): δ 169.4, 166.3, 152.6, 151.1,
139.6, 136.8, 131.9, 130.4, 130.1, 129.3, 128.7, 121.2, 120.8,
102.5, 61.9, 59.7, 56.8, 45.7, 38.8, 14.3, 14.1 ppm.
LRMS (+FAB) m/z calcd for C25H24BrN3O4 (M + H)+
510.10; Found: 510.82.
13C NMR (125 MHz, CDCl3): δ 170.3, 166.7, 152.6, 151.4,
137.8, 137.0, 135.8, 131.2, 130.1, 129.4, 127.4, 126.1, 120.7,
102.0, 57.6, 53.0, 50.8, 44.2, 36.6, 19.0 ppm.
LRMS (+FAB) m/z calcd for C24H23N3O4 (M + H)+ 418.17;
Found: 419.03.
Anal. Calcd for C25H24BrN3O4: C, 58.83; H, 4.74; N, 8.23.
Found: C, 59.03; H, 4.88; N, 8.64.
Anal. Calcd for C24H23N3O4: C, 69.05; H, 5.55; N, 10.07.
Found: C, 68.68; H, 5.72; N, 10.36.
(E)-Ethyl
6-amino-5-cyano-2-(2-ethoxy-2-oxoethylidene)-1-
phenyl-4-o-tolyl-1,2,3,4-tetrahydropyridine-3-carboxylate
(10o). Yield: 214 mg (0.48 mmol, 48%), light yellow solid,
M.P: 138–140 °C.
(E)-Ethyl 6-amino-5-cyano-2-(2-ethoxy-2-oxoethylidene)-4-(4-
fluorophenyl)-1-phenyl-1,2,3,4-tetrahydropyridine-3-carboxylate
(10l). Yield: 319 mg (0.71 mmol, 71%), light yellow solid, M.P:
156–160 °C.
IR (film) νmax: 3467, 3366, 2180, 1733, 1623, 1590, 1394,
1148 cm−1
.
IR (film) νmax: 3463, 3385, 2180, 1732, 1623, 1578, 1382,
1H NMR (500 MHz, CDCl3): δ 7.60–7.57 (m, 2H), 7.54–7.49
(m, 2H), 7.30 (s, 1H), 7.20–7.13 (m, 4H), 5.51 (d, 1H, J =
2 Hz), 4.53 (s, 1H), 4.47 (d, 1H, J = 2 Hz), 4.37–4.30 (m, 2H),
4.22 (s, 2H), 3.93–3.82 (m, 2H), 2.53 (s, 3H), 1.40 (t, 3H, J =
7 Hz), 1.05 (t, 3H, J = 7 Hz) ppm.
1138 cm−1
.
1H NMR (500 MHz, CDCl3): δ 7.57–7.51 (m, 3H), 7.47 (s,
1H), 7.31–7.29 (m, 2H), 7.16 (s, 1H), 7.03 (t, 2H, J = 8.5 Hz),
5.64 (d, 1H, J = 2.5 Hz), 4.57 (s, 1H), 4.35–4.31 (m, 3H), 4.22
(s, 2H), 3.94 (q, 2H, J = 7 Hz), 1.39 (t, 3H, J = 7 Hz), 1.10
(t, 3H, J = 7 Hz) ppm.
13C NMR (125 MHz, CDCl3): δ 169.8, 166.3, 152.8, 151.3,
137.9, 137.0, 135.7, 131.1, 130.5, 130.0, 129.4, 127.3, 126.2,
126.1, 120.9, 102.4, 61.7, 59.6, 57.2, 44.4, 36.8, 18.9, 14.3,
14.1 ppm.
1
13C NMR (125 MHz, CDCl3): δ 169.4, 166.3, 161.9 (d, JCF
= 243.8 Hz), 152.4, 151.3, 136.9, 136.2, 130.4, 130.1, 129.3,
128.5 (d, JCF = 7.5 Hz), 120.8, 115.6 (d, JCF = 21.3 Hz),
102.4, 61.8, 59.7, 57.3, 45.9, 38.6, 14.3, 14.1 ppm.
LRMS (+FAB) m/z calcd for C25H24FN3O4 (M + H)+ 450.18;
Found: 451.05.
LRMS (+FAB) m/z calcd for C26H27N3O4 (M + H)+ 446.20;
Found: 446.85.
3
2
Anal. Calcd for C26H27N3O4: C, 70.09; H, 6.11; N, 9.43.
Found: C, 69.78; H, 6.17; N, 9.62.
Anal. Calcd for C25H24FN3O4: C, 66.80; H, 5.38; N, 9.35.
Found: C, 66.57; H, 5.77; N, 9.40.
(E)-Ethyl 2-(6-amino-5-cyano-4-(4-fluorophenyl)-3-methyl-1-
p-tolyl-3,4-dihydropyridin-2(1H)-ylidene)acetate
(12). Yield:
(E)-Ethyl 6-amino-4-(4-chlorophenyl)-5-cyano-2-(2-ethoxy-2-
oxoethylidene)-1-phenyl-1,2,3,4-tetrahydropyridine-3-carboxylate
(10m). Yield: 303 mg (0.65 mmol, 65%), colourless solid,
M.P: 168–170 °C.
227 mg (0.56 mmol, 56%), colourless solid, M.P: 150–152 °C.
IR (film) νmax: 3471, 3345, 2177, 1701, 1600, 1581, 1501,
1385, 1139 cm−1
.
1H NMR (500 MHz, CDCl3): δ 7.34 (d, 2H, J = 8 Hz),
7.24–7.21 (m, 2H), 7.04–6.98 (m, 4H), 4.61 (q, 1H, J = 6.5 Hz),
4.37 (s, 1H), 4.16 (s, 2H), 3.97–3.92 (m, 2H), 3.48 (s, 1H), 2.44
IR (film) νmax: 3460, 3358, 2180, 1731, 1618, 1588, 1385,
1143 cm−1
.
1H NMR (500 MHz, CDCl3): δ 7.56–7.50 (m, 3H), 7.47 (s,
1H), 7.32–7.26 (m, 4H), 7.15 (s, 1H), 5.65 (d, 1H, J = 2 Hz),
4.55 (s, 1H), 4.35–4.31 (m, 2H), 4.29 (s, 1H), 4.26 (s, 2H), 3.94
(q, 2H, J = 7 Hz), 1.39 (t, 3H, J = 7 Hz), 1.11 (t, 3H, J = 7 Hz)
ppm.
(s, 3H), 1.46 (d, 3H, J = 6.5 Hz), 1.11 (t, 3H, J = 7 Hz) ppm.
1
13C NMR (75 MHz, CDCl3): δ 166.3, 161.7 (d, JCF
=
4
243 Hz), 159.0, 151.6, 140.2, 138.7 (d, JCF = 3 Hz), 134.2,
3
2
131.4, 129.1, 128.3 (d, JCF = 7.5 Hz), 121.9, 115.4 (d, JCF
=
21 Hz), 99.0, 59.3, 57.3, 42.5, 34.1, 21.3, 19.9, 14.2 ppm.
13C NMR (125 MHz, CDCl3): δ 169.3, 166.3, 152.4, 151.1,
139.0, 136.9, 133.1, 130.1, 129.4, 128.9, 128.3, 120.6, 102.5,
61.8, 59.7, 57.1, 45.7, 38.7, 14.3, 14.1 ppm.
LRMS (+FAB) m/z calcd for C24H24FN3O2 (M + H)+ 406.19;
Found: 406.38.
Anal. Calcd for C24H24FN3O2: C, 71.09; H, 5.97; N, 10.36.
Found: C, 70.40; H, 5.83; N, 10.54.
LRMS (+FAB) m/z calcd for C25H24ClN3O4 (M + H)+
466.15; Found: 466.86.
Anal. Calcd for C25H24ClN3O4: C, 64.44; H, 5.19; N, 9.02.
Found: C, 64.71; H, 5.11; N, 9.32.
Acknowledgements
V. N. thanks the Department of Science and Technology (DST),
New Delhi for the Raja Ramanna Fellowship. We also thank
CSIR, New Delhi, for financial assistance.
(E)-Ethyl 6-amino-4-(4-bromophenyl)-5-cyano-2-(2-ethoxy-2-
oxoethylidene)-1-phenyl-1,2,3,4-tetrahydropyridine-3-carboxylate
(10n). Yield: 291 mg (0.57 mmol, 57%), light yellow solid,
M.P: 190–192 °C.
IR (film) νmax: 3463, 3347, 2180, 1731, 1621, 1587, 1384,
Notes and references
1143 cm−1
.
1H NMR (500 MHz, CDCl3): δ 7.57–7.51 (m, 3H), 7.47 (d,
3H, J = 8 Hz), 7.22 (d, 2H, J = 8.5 Hz), 7.15 (s, 1H), 5.66 (d,
1H, J = 2 Hz), 4.56 (s, 1H), 4.36–4.30 (m, 2H), 4.28 (s, 1H),
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