KF/Al2O3 mediated multicomponent reactions for the efficient synthesis of highly substituted dihydropyridines

Article abstract of DOI:10.1002/jhet.1914

KF/Al₂O₃ was found to be an efficient solid supported catalyst for the facile access of highly substituted dihydropyridine derivatives from the multicomponent reaction of aromatic aldehydes, amines, malononitrile, and alkylacetylened

Full text of DOI:10.1002/jhet.1914

Month 2014 KF/Al2O3 Mediated Multicomponent Reactions for the Efficient Synthesis
of Highly Substituted Dihydropyridines
*
Suman Pal, Md. Nasim Khan, and Lokman H. Choudhury
Department of Chemistry, Indian Institute of Technology Patna, Patliputra Colony, Patna 800 013, India
*
E-mail: lokman@iitp.ac.in
Received May 5, 2012
DOI 10.1002/jhet.1914
Published online 00 Month 2014 in Wiley Online Library (wileyonlinelibrary.com).
KF/Al2O3 was found to be an efficient solid supported catalyst for the facile access of highly substituted dihy-
dropyridine derivatives from the multicomponent reaction of aromatic aldehydes, amines, malononitrile, and
alkylacetylenedicarboxylates. The notable advantages of this protocol are reusable catalyst, good yields, applica-
ble to a wide range of substrates for the synthesis of pharmacologically interesting dihydropyridine derivatives.
J. Heterocyclic Chem., 00, 00 (2014).
INTRODUCTION
[19]. Yan et al. have demonstrated a four-component
reaction in presence of equivalent amount of Et3N as
base for the synthesis of poly substituted dihydropyridine
derivatives [20].
Multicomponent reactions (MCRs) are considered as a
powerful tool for generating molecular diversity needed for
the preparation of bioactive compounds [1,2]. MCRs have
some advantages over conventional linear syntheses, inclu-
ding lower costs, shorter reaction times, high degrees of atom
economy, structural variations, and environmental friendli-
ness. Considering these, multicomponent reactions have
gained substantial interest to both synthetic and medicinal
chemists in recent times [3]. The synthesis of N-heterocycles
is an important area of research because of their popularity in
the synthesis of natural products and drugs [4]. The Hantzsch
reaction discovered in 1881 is one of the most useful multi-
component reaction for the synthesis of wide range of bioac-
tive 1,4-dihydropyridines [5].
Substituted 1,4-dihydropyridines are considered as
‘privileged scaffold’ due to its various pharmaceutical
activities [6], for example, Clevidipine [7], Nicardipine
[8], Manidipine [9], and others are well-known in pharma-
cology as calcium channel blockers and used as cardiovas-
cular agents for the treatment of hypertension (Fig. 1).
Similarly, substituted dihydropyridines are also found
useful for other biological activities such as antioxidant
[10,11], antiviral [12], anticancer [13], and anti-tumor
activity [14].
From the recent literature, it is evident that the deve-
lopment of new methodology for the efficient synthesis of
substituted dihydropyridines has gained notable attention
[15,16]. Recently, Ohmura et al. have reported a palladium
catalyzed synthesis of silylated dihydropyridines from regio-
selective silaboration of pyridines [17]. Kirsch et al. have
developed a one-pot synthesis of 1,2-dihydropyridines by
expanding the diverse reactivity of propargyl vinyl ethers
[18]. Similarly, Rodriguez and his co workers have explored
the synthesis of 2,5-dihydropyridine derivatives by gold-
catalyzed reactions of b-ketoesters and propargylamines
As a part of our ongoing research in the field of multicom-
ponent reactions [21–23], we were interested to develop a
new methodology for the synthesis of highly functionalised
1,4-dihydropyridines employing a re-usable solid supported
catalyst. The use of solid-supported catalysts has gained
popularity in synthetic community because of their enhanced
reactivity as well as selectivity, easy workup procedure,
recyclability of the catalyst, and ecofriendly reaction condi-
tions. Among all other solid supported catalysts, alumina
supported potassium fluoride (KF) is one of the widely used
green catalyst [24]. KF/Al2O3 is an inexpensive, reusable,
and environmentally benign catalyst, which demonstrate
interesting catalytic behavior due to its unique surface prop-
erties in various two and multicomponent reactions. In recent
years, KF/Al2O3 has been proved to be a very useful
solid supported basic catalyst in carrying out various
organic reactions that include synthesis of fused pyri-
midine [25], synthesis of highly substituted pyrrolidines
[26], Hydrothiolation of butadiynes [27], acetylation of
amines, alcohols, and phenols [28], conversion of
aldehydes to nitriles [29], synthesis of carboacyclic
nucleosides [30] and synthesis of oxazolidinones [31].
Due to its strongly basic nature it replaces organic
bases in a number of reactions such as Sonogashira
couplings [32], Suzuki couplings [33], Knoevenagel
reactions [34] etc.
RESULTS AND DISCUSSION
Considering the merits of KF/Al2O3 and taking cue from
the work of Yan et al. [20], we were interested to explore
this cheap, readily available, and reusable heterogeneous
catalyst for the synthesis of highly substituted 1,4-DHPs.
© 2014 HeteroCorporation

S. Pal, Md. N. Khan, and L. H. Choudhury
Vol 000
Figure 1. Some pharmacologically important dihydropyridines.
In the preliminary stage of investigation, we focused on
systematic evaluation of different solid catalysts for the
model reaction of benzaldehyde (1.0 equiv.), aniline (1.0
equiv.) malononitrile (1.0 equiv.), and dimethylacetylene
dicarboxylate (1.0 equiv.) at room temperature in ethanol.
The reaction was unsuccessful in the absence of any cata-
lyst even after 24 h stirring. Moderate yields of 1a were
found in case of only KF or basic alumina alone. Interest-
ingly, the same reaction provided 80% yield in the pres-
ence of KF/Al2O3. The exact explanation for the better
efficacy of KF/Al2O3 in base catalyzed reactions is still a
subject of debate in the literature [35]. As per Ando
et al., the better catalytic activity of KF/Al2O3 may be
due to the presence of three basic species (i) co-ordinately
unsaturated active fluoride; (ii) the presence of [Al–O‾]
ion which generates OH‾ when water is added; and (iii)
the cooperation of F‾ and [Al–OH] [36] . A survey of
solvents revealed ethanol to be the best choice. Moderate
yields were obtained when acetonitrile, DMF and THF
was employed as the solvent (Table 1, entries 7, 8 and
10) whereas in water 1a was formed in poor yield (Table 1,
entry 11). When the reaction was performed in dichloro-
methane only a trace amount product was formed (Table 1,
entry 9). Some dependence was also observed on the
amount of KF/Al2O3 used. The optimum result was
obtained in the presence of 20 mol% KF/Al2O3 with no
significant improvement upon increasing the catalyst
loading (Table 1, entry 5).
The scope and limitations of this four-component reaction
under optimized reaction conditions were explored using a
variety of aldehydes, amines, malononitrile derivatives, and
alkylacetylene dicarboxylate, as summarized in Table 2.
The reaction proceeded smoothly with benzaldehyde and
substituted benzaldehydes tethered with both electron-
withdrawing and electron-releasing groups to generate the
corresponding products in good yields. In contrast, aliphatic
aldehydes such as heptaldehyde and cyclohexane carbo-
xaldehyde are not suitable for this methodology due to the
Table 1
Optimization of reaction conditions.
Entry
Catalyst (mol%)
Solvent
Time (h)
Yielda (%)
1
2
3
4
5
6
7
8
none
KF (20)
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
CH3CN
DMF
24
10
10
10
10
10
10
10
10
10
10
0
40
55
80
81
71
68
64
Trace
63
Basic Al2O3(20)
KF/Al2O3(20)
KF/Al2O3 (30)
KF/Al2O3 (10)
KF/Al2O3 (20)
KF/Al2O3 (20)
KF/Al2O3 (20)
KF/Al2O3(20)
KF/Al2O3 (20)
9
10
11
CH2Cl2
THF
H2O
20
Bold indicates the best optimized reaction condition.
aIsolated Yield
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2014
Multicomponent Reactions for the Synthesis of Substituted Dihydropyridines
Table 2
KF/Al2O3 mediated four component reactions for the synthesis of functionalized dihydropyridines (1a–1u).
Entry
R1
R2
R3
CN
CN
CN
CN
CN
CN
CN
CN
CN
CN
CN
R4
Product
Reaction time/h
Yielda (%)
1
2
3
4
5
6
7
8
C6H5
C6H5
Me
Me
Me
Me
Me
Me
Me
Me
Me
Et
Me
Me
Et
Me
Me
Me
Et
1a
1b
1c
1d
1e
1f
1g
1h
1i
1j
1k
1l
1m
1n
1o
1p
1q
1r
1s
10
10
10
10
8
80
82
83
78
84
86
81
83
87
81
62
79
83
81
84
56
51
52
65
63
64
4-Br-C6H4
4-Cl-C6H4
4-OMe-C6H4
3-NO2-C6H4
3-NO2-C6H4
4-Br-C6H4
4-Me-C6H4
4-Me-C6H4
4-OMe-C6H4
4-OMe-C6H4
4-Cl-C6H4
4-Cl-C6H4
4-OMe-C6H4
C6H5
4-CN-C6H4
C6H5-CH2
2-naph
4-Me-C6H4
C6H5
4-Cl-C6H4
4-OMe-C6H4
4-Me-C6H4
4-Cl-C6H4
4-Me-C6H4
C6H5
8
10
10
8
10
16
8
8
8
8
24
24
24
12
12
12
4-Br-C6H4
9
3-NO2-C6H4
4-OMe-C6H4
4-Cl-C6H4
10
11
12
13
14
15
16
17
18
19
20
21
4-Cl-C6H4
CN
3-NO2-C6H4
3-NO2-C6H4
3-NO2-C6H4
4-Cl-C6H4
4-Cl-C6H4
3-NO2 C6H4
4-Cl-C6H4
COOEt
COOEt
COOEt
CONH2
CONH2
CONH2
COPh
COPh
COPh
Et
Me
Me
Et
3-NO2-C6H4
3-NO2-C6H4
1t
1u
4-Cl-C6H4
aIsolated yield.
formation of mixture of inseparable compounds. This proto-
col was proved to be suitable both for aromatic amines bear-
ing electron-donating and withdrawing groups. Bulky amine
such as 2-napthyl amine reacted efficiently giving good yield
(Table 2, entry 12). Aliphatic amine such as benzylamine
gave the desired product with moderate yield (Table 2, entry
11).To expand the scope of malononitrile derivatives, ethyl
cyanoacetate, cyanoacetamide, and benzoyl acetonitrile were
applied to this methodology. In all these cases, the desired
reactions underwent successfully to afford the corresponding
dihydropyridines in moderate to good yields. Lastly, the
variability of alkylacetylene dicarboxylate was also tested.
Similar to dimethylacetylenedicarboxylate, diethylacetylene
dicarboxylate also underwent this reaction smoothly to
afford the desired products (Table 2, entries 10, 13, 17, 18
take place to produce intermediate B. Subsequently, the reac-
tion of intermediate A with intermediate B proceeds via
Michael type addition mediated by the basic species gener-
ated in situ from the KF/Al2O3 to provide intermediate C.
Then, intramolecular addition of the NH group to the C–N
triple bond gives the cyclic intermediate D that finally trans-
forms to the expected dihydropyridine tautomer E.
CONCLUSIONS
We have developed a facile and efficient four-component
reaction of aldehydes, malononitrile derivatives, amines, and
activated alkynes using a solid supported catalyst. A highly
substituted ring system containing dihydropyridine core
with -NH2 and -CN functional group can be generated from
simple and readily accessible starting materials via this meth-
odology. We believe that because of the presence of various
functional groups on these molecules, it might get impor-
tance to the synthetic as well as medicinal chemists.
1
and 21). The products were fully characterized by IR, H
NMR, 13C NMR spectra and by elemental analysis.
A proposed reaction mechanism for this four-component
reaction is outlined in Scheme 1. The active species gener-
ated from KF/Al2O3 act as basic catalyst for the Knoevenagel
condensation of aldehyde and malononitrile or its derivatives
to afford electron deficient alkene A. Next, aza-Michael
addition between arylamine and alkylacetylenedicarboxylate
EXPERIMENTAL
All reagents were purchased from commercial sources and used
without further purification. IR spectra were recorded in Shimadzu
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

S. Pal, Md. N. Khan, and L. H. Choudhury
Vol 000
Scheme 1. Proposed mechanism for the KF/Al2O3 mediated synthesis of functionalized dihydropyridines.
1
FTIR spectrophotometer (Shimadzu Corporation, Japan). HNMR
spectra and 13C NMR spectra were recorded on Jeol 500 (Jeol Ltd.,
Japan), Bruker 500 or 400 MHz spectrometer (Bruker BioSpin AG,
Switzerland) in CDCl3 using TMS as internal reference. Elemental
analyses were carried out in a Perkin Elmer 2400 automatic carbon,
hydrogen, nitrogen analyzer (Perkin Elmer, USA) or Elementar
Vario EL III (Elementar, Germany). All compounds were character-
ized by recording melting point, IR, 1H, and 13C NMR and elemen-
tal analysis.
(m, 6H), 7.25–7.27 (m, 1H), 4.65 (s, 1H), 4.11 (s, 2H), 3.58
(s, 3H), 3.42 (s, 3H); 13C NMR (CDCl3, 125 MHz): d = 165.9,
163.6, 149.7, 144.8, 141.9, 135.2, 130.6, 130.3, 130.0, 128.9,
127.3, 127.1, 120.6, 105.3, 62.9, 52.7, 52.1, 38.5; Anal. Calcd. for
C22H19N3O4 (389.40): C, 67.86; H, 4.92; N, 10.79. Found: C,
67.94; H, 4.97; N, 10.89.
Dimethyl 6-amino-4-(4-bromophenyl)-5-cyano-1-p-tolyl-1, 4-
dihydropyridine-2,3-dicarboxylate (1b). Light yellowish solid;
82%; mp: 185–187 ꢀC; IR (KBr): 3475, 3364, 3033, 2952, 2174,
1741, 1701, 1646, 1575, 1509, 1414, 1356, 1326, 1250, 1113,
Preparation of KF/Al2O3. The KF/Al2O3 was prepared by
dissolving 4 g of KF in 20 mL of water and 6 g of neutral Al2O3.
The mixture was stirred at 60 ꢀC for 1 h. The water was removed
under reduced pressure. The resulting free flowing powder was
dried at 120 ꢀC for 5 h to obtain KF/Al2O3 [37].
1
1071 cmÀ ; 1H NMR (CDCl3, 500 MHz)
:
d = 7.48
(d, J = 8.6 Hz, 2H), 7.27 (d, J = 8.0 Hz, 2H), 7.23 (d, J = 8.0 Hz,
2H), 7.19 (d, J = 8.0 Hz, 2H), 4.62 (s, 1H), 4.12 (s, 2H), 3.58
(s, 3H), 3.45 (s, 3H), 2.39 (s, 3H); 13C NMR (CDCl3,
125 MHz): 165.6, 163.4, 149.9, 143.9, 142.2, 141.1, 133.1,
132.2, 132.0, 131.8, 129.9, 129.6, 121.1, 120.4, 104.5, 62.1,
52.6, 52.1, 38.1, 21.3; Anal. Calcd. for C23H20BrN3O4 (482.33):
General procedure for the preparation of highly functionalized
dihydropyridines (1a). A solution of Benzaldehyde (1.0 mmol),
malononitrile (1.0mmol) and KF/Al2O3 (0.2 mmol, 32 mg) were
stirred in 3 mL of distilled ethanol at room temperature. Then, a
solution of aniline (1.0 mmol) and dimethyl acetylenedicarboxylate
(1.0 mmol) in 2 mL ethanol was added to it. The resulting mixture
was stirred until the reaction was completed as indicated by TLC
(ethyl acetate/hexane, 3:7). The resulting precipitates were collected
by filtration and dissolved in ethyl acetate. The catalyst was
recovered through filtration and the filtrate was evaporated under
reduced pressure to obtain crude product. The crude product was
purified by recrystalization method from hot ethanol/acetonitrile to
give pure products. After isolation of the product, the remaining KF/
Al2O3 was dried and reused for two times. The reaction proceeded
cleanly with consistent results, although yield was somewhat lesser
in the second and third recycles (73 and 68%, respectively).
C, 57.27; H, 4.18; N, 8.71. Found: C, 57.37; H, 4.24; N, 8.83.
Dimethyl6-amino-4-(4-chlorophenyl)-5-cyano-1-p-tolyl-1,4-
dihydropyridine-2,3-dicarboxylate (1c). Light yellowish solid;
83%; mp: 186–188 ꢀC; IR (KBr): 3472, 3360, 3221, 2950, 2175,
1742, 1699, 1646, 1574, 1508, 1413, 1355, 1301, 1248, 1216,
1
1176, 1016 cmÀ ; 1H NMR (CDCl3, 500MHz) : d = 7.33
(d, J = 8.5Hz, 2H), 7.29 (d, J = 7.9Hz, 2H), 7.27 (d, J = 7.6Hz,
2H), 7.20 (d, J = 7.9Hz, 2H), 4.65 (s, 1H), 4.09 (s, 2H), 3.58
(s, 3H), 3.46 (s, 3H), 2.40 (s, 3H); 13C NMR (CDCl3, 125MHz):
165.6, 163.4, 149.9, 143.5, 142.2, 141.1, 132.9, 132.2, 130.6,
129.9, 128.8, 128.5, 120.4, 104.6, 62.1, 52.6, 52.1, 38.1, 21.3;
Anal. Calcd. for C23H20ClN3O4 (437.87): C, 63.09; H, 4.60; N,
9.60. Found: C, 63.18; H, 4.67; N, 9.72.
Dimethyl 6-amino-5-cyano-1,4-bis(4-methoxy phenyl)-1,4-
Dimethyl 6-amino-5-cyano-1,4-diphenyl-1,4-dihydro pyridine-
dihydropyridine-2,3-dicarboxylate (1d). Yellow solid; 78%; mp:
159–161 ꢀC; IR (KBr): 3449, 3315, 3215, 2179, 1745, 1709,
2,3-dicarboxylate (1a).
Light yellowish solid; 80%; mp:161–
1
1647, 1568, 1510, 1416, 1318, 1256, 1221, 1119, 1028 cmÀ ; 1H
163 ꢀC; IR (KBr): 3465, 3376, 3336, 2950, 2175, 1746, 1707,
1650, 1568, 1492, 1413, 1353, 1247, 1212, 1109, 1076cm‾1; 1H
NMR (CDCl3, 500 MHz): d = 7.48–7.49 (m, 3H), 7.34–7.38
NMR (CDCl3, 400 MHz) : d = 7.29 (d, J = 6.8Hz, 2H), 7.26
(d, J = 7.2Hz, 2H), 6.96 (d, J = 8.8Hz, 2H), 6.90 (d, J = 8.4Hz,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2014
Multicomponent Reactions for the Synthesis of Substituted Dihydropyridines
2H), 4.61 (s, 1H), 4.05 (s, 2H), 3.88 (s, 3H), 3.81 (s, 3H), 3.59
(s, 3H), 3.48 (s, 3H); 13C NMR (CDCl3, 100MHz): d = 166.0,
163.8, 149.8, 142.0, 137.5, 137.4, 131.7, 131.5, 128.2, 127.4,
127.3, 120.8, 115.0, 105.3, 62.0, 55.4, 52.7, 52.1, 52.0, 37.7;
Anal. Calcd. for C24H23N3O6 (449.45): C, 64.13; H, 5.16; N,
9.35. Found: C, 64.23; H, 5.22; N, 9.48.
Dimethyl 6-amino-5-cyano-1-(4-methoxyphenyl)-4-(3-nitro-
phenyl)-1,4-dihydro pyridine-2,3-dicarboxylate (1e). Yellow
solid; 84%; mp: 184–186 ꢀC; IR (KBr): 3415, 3326, 3231,
3081, 2179, 1747, 1708, 1651, 1568, 1532, 1356, 1250, 1117,
1024 cm‾1; 1H NMR (CDCl3, 500 MHz) : d = 8.25 (s, 1H),
8.13 (d, J = 7.9 Hz, 1H), 7.70 (d, J = 7.6 Hz, 1H), 7.53
(t, J = 7.9 Hz, 1H), 7.30 (d, J = 8.5 Hz, 2H), 6.98 (d, J = 8.5 Hz,
2H), 4.77 (s, 1H), 4.23 (s, 2H), 3.85 (s, 3H), 3.60 (s, 3H), 3.48
(s, 3H); 13C NMR (CDCl3, 125 MHz): d = 165.3, 163.3, 161.0,
150.6, 148.9, 147.2, 142.8, 133.5, 131.5, 129.8, 126.7, 122.5,
122.3, 120.1, 115.3, 104.4, 61.5, 55.7, 52.9, 52.3, 38.7; Anal.
Calcd. for C23H20N4O7 (464.43): C, 59.48; H, 4.34; N, 12.06.
Found: C, 59.35; H, 4.39; N, 12.17.
(s, 1H), 3.20 (s, 3H), 3.01 (s, 3H); 13C NMR (CDCl3,
125 MHz): d = 165.0, 162.9, 150.6, 148.3, 147.3, 142.4, 134.7,
133.2, 130.4, 130.1, 129.7, 129.7, 121.9, 121.7, 120.4, 103.8,
59.7, 52.4, 51.9, 38.6; Anal. Calcd. for C22H18N4O6 (434.40):
C, 60.83; H, 4.18; N, 12.90. Found: C, 60.90; H, 4.24; N, 13.03.
Diethyl 6-amino-5-cyano-1-(4-cyanophenyl)-4-(4-methoxy-
phenyl)-1,4-dihydropyridine-2,3-dicar boxylate (1j). Yellow
solid; 81%; mp: 140–142 ꢀC; IR (KBr): 3460, 3369, 2983,
2234, 2192, 1726, 1706, 1655, 1589, 1515, 1412, 1373, 1306,
1
1228, 1178, 1107, 1032 cmÀ ; 1H NMR (CDCl3, 500 MHz) :
d = 7.79 (d, J = 8.0 Hz, 2H), 7.51 (d, J = 8.3 Hz, 2H), 7.23
(d, J = 7.7 Hz, 2H), 6.90 (d, J = 7.4Hz, 2H), 4.63 (s, 1H), 4.02–
4.06 (m, 1H), 3.95 (s, 2H), 3.89–3.93 (m, 3H), 3.80 (s, 3H),
1.11 (t, J = 7.1 Hz, 3H), 0.98 (t, J = 7.1 Hz, 3H);13C NMR
(CDCl3, 125 MHz):d = 165.0, 163.0, 158.9, 148.5, 140.2, 139.8,
136.7, 133.7, 131.6, 128.3, 119.9, 117.2, 114.7, 114.3, 107.2,
62.4, 61.2, 55.4, 37.9, 13.9, 13.5; Anal. Calcd. for C26H24N4O5
(472.49): C, 66.09; H, 5.12; N, 11.86. Found: C, 66.20; H,
5.18; N, 11.99.
Dimethyl 6-amino-1-(4-chlorophenyl)-5-cyano-4-(3-nitrophenyl) -
1,4-dihydro pyridine-2,3-dicarboxylate (1f). Yellow solid; 86%;
mp :195–197 ꢀC; IR (KBr): 3415, 3326, 3230, 3081, 2179, 1747,
Dimethyl 6-amino-1-benzyl-4-(4-chlorophenyl)-5-cyano-1,4-
dihydropyridine-2,3-dicarboxylate (1k). Yellow solid; 62%;
mp: 146–148 ꢀC; IR (KBr): 3466, 3346, 3038, 2955, 2188,
1
1706, 1651, 1570, 1532, 1427, 1356, 1250, 1117, 1024 cmÀ ; 1H
1743, 1705, 1645, 1569, 1493, 1434, 1343, 1290, 1215, 1116,
1
NMR (CDCl3, 500 MHz) : d = 8.23 (s, 1H), 8.14 (d, J = 8.2Hz,
1H), 7.69 (d, J = 7.6Hz, 1H), 7.54 (t, J = 7.9 Hz, 1H), 7.50
(d, J = 8.5Hz, 2H), 7.34 (d, J = 8.5 Hz, 2H), 4.77 (s, 1H), 4.20
(s, 2H), 3.61 (s, 3H), 3.49 (s, 3H); 13C NMR (CDCl3, 125MHz):
d = 165.1, 163.1, 149.9, 148.9, 146.8, 142.0, 137.3, 133.5, 133.2,
131.6, 130.6, 129.9, 122.6, 122.2, 119.7, 105.1, 62.4, 53.0, 52.4,
38.6; Anal. Calcd. for C22H17ClN4O6 (468.85): C, 56.36; H, 3.65;
N, 11.95. Found: C, 56.28; H, 3.60; N, 12.06.
1018 cmÀ ; 1H NMR (CDCl3, 400 MHz)
: d = 7.34–7.41
(m, 3H), 7.22–7.29 (m, 4H), 7.10 (d, J = 8.4 Hz, 2H), 4.78
(d, J = 17.2 Hz, 1H), 4.66 (d, J = 17.2 Hz, 1H), 4.57 (s, 1H),
4.15 (s, 2H), 3.77 (s, 3H), 3.63 (s, 3H); 13C NMR (CDCl3,
125 MHz): d = 165.6, 164.6, 151.3, 142.6, 142.2, 135.0, 132.9,
131.9, 130.1, 129.3, 128.8, 128.4, 126.7, 120.3, 106.9, 65.9,
53.3, 52.2, 50.8, 37.9; Anal. Calcd. for C23H20ClN3O4 (437.87):
C, 63.09; H, 4.60; N, 9.60. Found: C, 63.01; H, 4.67; N, 9.72.
Dimethyl 6-amino-4-(4-chlorophenyl)-5-cyano-1-(naphthalen-
2-yl)-1,4-dihydro pyridine-2,3-dicarboxylate (1l). Light yellowish
solid; 79%; mp: 171–173 ꢀC; IR (KBr): 3455, 3327, 3220, 2945,
2178, 1753, 1712, 1651, 1571, 1422, 1351, 1223, 1120,
Dimethyl 6-amino-4-(4-bromophenyl)-1-(4-chloro phenyl)-5-
cyano-1,4-dihydro pyridine-2,3-dicar boxylate (1g). Yellow
solid; 81%; mp: 163–165 ꢀC; IR (KBr): 3462, 3317, 3220,
2950, 2190, 1743, 1710, 1651, 1581, 1490, 1417, 1356, 1229,
1
1 1
1118, 1008 cmÀ ; 1H NMR (CDCl3, 500 MHz): d = 7.48
1009cmÀ ; H NMR (CDCl3, 400MHz): d = 7.95 (d, J = 8.4Hz,
2H), 7.89 (t, J = 6.8Hz, 2H), 7.83 (s, 1H), 7.58–7.64 (m, 2H),
7.31–7.36 (m, 4H), 4.68 (s, 1H), 4.12 (s, 2H), 3.58 (s, 3H), 3.33
(s, 3H); 13C NMR (CDCl3, 100MHz): d = 165.7, 163.5, 149.9,
143.4, 142.2, 133.5, 133.0, 132.3, 130.3, 129.8, 129.1, 128.5,
128.4, 128.0, 127.7, 126.5, 120.4, 104.9, 62.6, 52.8, 52.2, 38.2;
Anal. Calcd. for C26H20ClN3O4 (473.90): C, 65.89; H, 4.25; N,
8.87; Found: C, 65.96; H, 4.30; N, 8.96.
(d, J = 8.2 Hz, 2H), 7.45 (d, J = 8.5 Hz, 2H), 7.27 (d, J = 8.6 Hz,
2H), 7.21 (d, J = 8.5 Hz, 2H), 4.61 (s, 1H), 4.10 (s, 2H), 3.58
(s, 3H), 3.48 (s, 3H); 13C NMR (CDCl3, 125 MHz) : d = 165.5,
163.4, 149.5, 143.7, 141.7, 137.0, 133.5, 132.1, 131.7, 130.4,
128.8, 121.3, 120.1, 105.2, 62.9, 52.9, 52.3, 38.2; Anal. Calcd.
for C22H17BrClN3O4 (502.74): C, 52.56; H, 3.41; N, 8.36.
Found: C, 52.64; H, 3.47; N, 8.49.
Dimethyl 6-amino-4-(4-bromophenyl)-5-cyano-1-(4-methoxy-
phenyl)-1,4dihydro pyridine-2,3-dicarboxylate (1h). Yellow solid;
83%; mp: 165–167 ꢀC; IR (KBr): 3470, 3336, 3219, 2175, 1745,
Triethyl 6-amino-4-(3-nitrophenyl)-1-p-tolyl-1,4-dihydropy-
ridine-2,3,5-tricarboxylate (1m). Yellow solid; 83%; mp: 122–
124 ꢀC; IR (KBr): 3448, 3264, 3010, 2983, 1737, 1694, 1671,
1643, 1604, 1530, 1373, 1350, 1264, 1197, 1115, 1095,
1
1703, 1651, 1577, 1510, 1417, 1356, 1249, 1109, 1009 cmÀ ; 1H
1
NMR (CDCl3, 500MHz) : d = 7.48 (d, J = 8.2 Hz, 2H), 7.24
(d, J = 8.5Hz, 2H), 7.22 (d, J = 8.2Hz, 2H), 6.95 (d, J = 8.5Hz,
2H), 4.62 (s, 1H), 4.11 (s, 2H), 3.84 (s, 3H), 3.58 (s, 3H), 3.48
(s, 3H); 13C NMR (CDCl3, 125 MHz): d = 165.7, 163.5, 160.9,
150.1, 144.0, 142.5, 132.0, 131.5, 128.8, 127.0, 121.2, 120.4,
115.1, 104.5, 62.1, 55.7, 52.8, 52.2, 38.2; Anal. Calcd. for
C23H20BrN3O5 (498.33): C, 55.43; H, 4.05; N, 8.43. Found: C,
55.35; H, 4.11; N, 8.54.
1009 cmÀ ; 1H NMR (CDCl3, 500 MHz) : d = 8.32 (s, 1H),
8.04 (d, J = 8.0 Hz, 1H), 7.73 (d, J = 7.7Hz, 1H), 7.44
(t, J = 8.0 Hz, 1H), 7.29–7.33 (m, 4H), 6.30 (s, 2H), 5.09
(s, 1H), 4.02–4.10 (m, 4H), 3.90–3.96 (m, 1H), 3.79–3.86
(m, 1H), 2.40 (s, 3H), 1.14–1.20 (m, 6H), 0.93–0.96 (m, 3H);
13C NMR (CDCl3, 125 MHz) : d = 169.2, 165.3, 163.3, 151.7,
149.6, 148.3, 142.2, 140.9, 134.3, 132.3, 130.6, 130.5, 128.8,
123.3, 121.4, 106.5, 79.3, 61.9, 60.9, 59.6, 37.5, 21.4, 14.5,
14.1, 13.5; Anal. Calcd. for C27H29N3O8 (523.53): C, 61.94; H,
5.58; N, 8.03. Found: C, 61.85; H, 5.52; N, 8.15.
Dimethyl 6-amino-5-cyano-4-(3-nitrophenyl)-1-phenyl-1,4-
dihydropyridine-2,3-dicarboxylate (1i). Yellow solid; 87%; mp:
217–219 ꢀC; IR (KBr): 3446, 3336, 3229, 2951, 2178, 1755,
1704, 1651, 1577, 1521, 1421, 1349, 1250, 1213, 1112,
5-Ethyl 2,3-dimethyl 6-amino-4-(3-nitrophenyl)-1-phenyl-
1,4-dihydropyridine-2,3,5-tricarboxylate (1n). Yellow solid;
81%; mp: 172–173 ꢀC; IR (KBr): 3472, 3264, 2979, 2951,
1749, 1709, 1667, 1639, 1600, 1530, 1506, 1436, 1354, 1213,
1
1
926 cmÀ ; H NMR (CDCl3, 500 MHz) : d = 7.84 (s, 1H), 7.73
(d, J = 8.2 Hz, 1H), 7.34 (d, J = 7.9 Hz, 1H), 7.20 (t, J = 7.9 Hz,
1H), 7.12–7.14 (m, 3H), 6.96–6.98 (m, 2H), 4.75 (s, 2H), 4.36
1
1
1123, 1095, 1017 cmÀ ; H NMR (CDCl3, 500 MHz) : d = 8.54
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

S. Pal, Md. N. Khan, and L. H. Choudhury
Vol 000
(s, 1H), 8.25 (d, J = 8.0 Hz, 1H), 7.94 (d, J = 7.5 Hz, 1H), 7.70–
7.73 (m, 3H), 7.64–7.67 (m, 3H), 6.50 (s, 2H), 5.31 (s, 1H),
4.24–4.30 (m, 2H), 3.61 (s, 3H), 3.82 (s, 3H), 1.41–1.44
(m, 3H); 13C NMR (CDCl3, 125 MHz) : 169.1, 165.7, 163.6,
151.4, 149.3, 148.3, 142.2, 134.9, 134.0, 130.7, 130.5, 130.0,
128.8, 123.0, 121.5, 106.6, 79.4, 61.9, 59.6, 52.5, 52.0, 51.9,
37.3, 14.4, 13.5; Anal. Calcd. for C24H23N3O8 (481.45): C,
59.87; H, 4.82; N, 8.73. Found: C, 59.96; H, 4.90; N, 8.84.
5-Ethyl 2,3-dimethyl 6-amino-1-(4-chloro phenyl)-4-(3-
nitrophenyl)-1,4 dihydropyridine-2,3,5-tricarboxylate (1o). Yellow
solid; 84%; mp:186–188 ꢀC; IR (KBr): 3442, 3221, 3107, 2985,
2954, 1751, 1710, 1663, 1602, 1523, 1440, 1401, 1345, 1236,
Dimethyl 6-amino-5-benzoyl-4-(4-chlorophenyl)-1-p-tolyl-1,4-
dihydropyridine-2,3-dicarboxylate (1s). Yellow solid; 65%; mp:
184–186 ꢀC; IR (KBr): 3420, 3049, 2951, 1736, 1703, 1639,
1
1596, 1450, 1355, 1224, 1111, 1048cmÀ ; 1H NMR (CDCl3,
500 MHz) : d = 7.35–7.39 (m, 3H), 7.32 (d, J = 8.3Hz, 2H),7.22–
7.25 (m, 4H), 7.14 (d, J = 8.6 Hz, 2H), 6.84 (d, J = 8.6 Hz, 2H),
4.99 (s, 1H), 3.62 (s, 3H), 3.45 (s, 3H), 2.43 (s, 3H); 13C NMR
(CDCl3, 125 MHz): d = 194.5, 165.7, 163.7, 154.4, 144.7, 141.5,
141.2, 132.2, 131.8, 131.0, 130.2, 129.9, 129.5, 129.2, 128.6,
128.0, 126.8, 108.7, 89.5, 52.7, 52.2, 38.0, 21.4; Anal. Calcd. for
C29H25ClN2O5 (516.97): C, 67.38; H, 4.87; N, 5.42. Found: C,
67.46; H, 4.82; N, 5.53.
1
1095, 1042 cmÀ ; 1H NMR (CDCl3, 400MHz) : d = 8.31 (s, 1H),
Dimethyl 6-amino-5-benzoyl-4-(3-nitrophenyl)-1-phenyl-1,4-
dihydropyridine-2,3-dicarboxylate (1t). Yellow solid; 63%; mp:
156–157 ꢀC; IR (KBr): 3424, 3068, 2951, 2928, 2853, 1745,
8.06 (d, J = 7.6Hz, 1H), 7.71 (d, J = 7.6 Hz, 1H), 7.51
(d, J = 8.4Hz, 2H), 7.45 (t, J = 7.6Hz, 1H), 7.39 (d, J = 8.4Hz,
2H), 6.25 (s, 2H), 5.10 (s, 1H), 4.05–4.13 (m, 2H), 3.67 (s, 3H),
3.49 (s, 3H), 1.23 (t, J = 6.8Hz, 3H); 13C NMR (CDCl3,
125 MHz): 169.0, 165.6, 163.6, 151.1, 149.0, 148.4, 141.8, 136.9,
133.9, 133.4, 132.1, 130.3, 128.9, 122.9, 121.5, 107.1, 79.8, 62.2,
59.7, 52.7, 52.1, 37.2, 14.4; Anal. Calcd. for C24H22ClN3O8
(515.90): C, 55.87; H, 4.30; N, 8.15. Found: C, 55.94; H, 4.35;
N, 8.29.
1706, 1643, 1608, 1530, 1452, 1354, 1220, 1123, 1076, 1053,
1
1025 cmÀ ; 1H NMR (CDCl3, 500 MHz)
: d = 7.90–7.91
(m, 1H), 7.80–7.81 (m, 1H), 7.46–7.51 (m, 3H), 7.36–7.39
(m, 2H), 7.33–7.35 (m, 1H), 7.28–7.31 (m, 2H), 7.22
(t, J = 8.0 Hz, 1H), 7.13 (d, J = 8.5 Hz, 2H), 7.00 (d, J = 7.5 Hz,
1H), 5.02 (s, 1H), 3.40 (s, 3H), 3.37 (s, 3H); 13C NMR (CDCl3,
125 MHz) : d = 194.2, 165.3, 163.4, 154.2, 148.4, 148.3, 141.4,
141.2, 134.3, 133.3, 130.9, 130.4, 130.3, 129.4, 129.1, 128.5,
128.4, 126.5, 122.3, 121.7, 108.2, 89.2, 52.7, 52.2, 38.6; Anal.
Calcd. for C28H23N3O7 (513.50): C, 65.49; H, 4.51; N, 8.18.
Found: C, 65.57; H, 4.57; N, 8.30.
Dimethyl 6-amino-5-carbamoyl-4-(4-chloro phenyl)-1-(4-
methoxyphenyl)-1,4-dihydro pyridine-2,3-dicarboxylate (1p).
Light yellowish solid; 56%; mp: 221–223 ꢀC; IR (KBr): 3451,
3327, 3182, 2950, 2843, 1748, 1685, 1656, 1571, 1480, 1436,
1
1404, 1335, 1298, 1255, 1218, 1185, 1109, 1062 cmÀ ; 1H NMR
Diethyl 6-amino-5-benzoyl-1-(4-chlorophenyl)-4-(3-nitrophenyl)-
(CDCl3, 400 MHz): d = 7.38 (d, J = 8.4 Hz, 2H), 7.26–7.32
(m, 4H), 6.97 (d, J = 8.8 Hz, 2H), 6.74 (s, 2H), 4.95 (s, 2H), 4.74
(s, 1H), 3.85 (s, 3H), 3.68 (s, 3H), 3.42 (s, 3H); 13C NMR
(CDCl3, 125 MHz): 171.9, 165.9, 163.7, 160.6, 151.4, 144.2,
141.5, 132.8, 131.7, 129.1, 128.6, 127.2, 114.9, 105.9, 79.2, 55.6,
52.4, 51.9, 38.1; Anal. Calcd. for C23H22ClN3O6 (471.89): C,
58.54; H, 4.70; N, 8.90. Found: C, 58.43; H, 4.76; N, 8.78.
1, 4-dihydropyridine-2,3-dicarbo -xylate (1u).
64%; mp: 132–
134 ꢀC; IR (KBr): 3428, 3182, 3068, 2983, 1734, 1706, 1659, 1608,
1534, 1443, 1346, 1240, 1213, 1112, 1013 cmÀ ; 1H NMR
1
(CDCl3, 500MHz) : d =7.98–8.00 (d, J= 8.3 Hz, 1H), 7.86 (s, 1H),
7.54 (d, J= 8.6 Hz, 2H), 7.35–7.43 (m, 5H), 7.29 (t, J= 8.0 Hz, 1H),
7.21 (d, J= 8.3 Hz, 2H), 7.05 (d, J= 7.4 Hz, 1H), 5.14 (s, 1H), 4.01–
4.10 (m, 2H), 3.95–4.00 (m, 1H), 3.85–3.91 (m, 1H), 1.13 (t,
J= 7.1 Hz, 3H), 0.99 (t, J=7.1Hz, 3H); 13C NMR (CDCl3,
125 MHz) : d = 194.7, 164.7, 162.9, 154.0, 148.4, 148.2, 141.1,
141.0, 137.3, 133.5, 132.9, 132.0, 130.7, 129.5, 129.1, 128.5, 126.6,
122.4, 121.7, 108.7, 89.4, 62.4, 61.3, 38.6, 14.0, 13.6; Anal. Calcd.
for C30H26ClN3O7 (575.99): C, 62.56; H, 4.55; N, 7.30. Found: C,
62.64; H, 4.62; N, 7.34.
Diethyl 6-amino-5-carbamoyl-4-(4-chloro phenyl )-1-p-tolyl-
1,4-dihydropyridine-2,3-dicarboxylate (1q). Light yellowish
solid; 51%; mp: 147–149 ꢀC; IR (KBr): 3460, 3327, 3201, 2983,
1757, 1682, 1655, 1573, 1479, 1373, 1256, 1205, 1107,
1
1017cmÀ ; 1H NMR (CDCl3, 500 MHz) : d = 7.39 (d, J = 8.3Hz,
2H), 7.30 (d, J = 8.3 Hz, 2H), 7.27 (d, J = 8.3 Hz, 2H), 7.23
(d, J = 8.3 Hz, 2H), 6.72 (s, 2H), 4.95 (s, 2H), 4.74 (s, 1H), 4.06–
4.17 (m, 2H), 3.84–3.90 (m, 1H), 3.75–3.81 (m, 1H), 2.39
(s, 3H), 1.21 (t, J = 7.1 Hz, 3H), 0.92 (t, J = 7.1Hz, 3H); 13C NMR
(CDCl3, 125 MHz): d =172.0, 165.5, 163.3, 151.4, 144.3, 141.2,
140.7, 132.9, 132.5, 130.5, 130.4, 129.2, 128.9, 106.0, 79.2, 61.8,
60.9, 38.2, 21.4, 14.2, 13.5; Anal. Calcd. for C25H26ClN3O5
(483.94): C, 62.05; H, 5.42; N, 8.68. Found: C, 62.15; H, 5.48;
N, 8.80.
Acknowledgment. We gratefully acknowledge the financial support
from the Department of Science and Technology India, with
Sanction No. SR/FT/CS-042/2009. S.P and M.N.K are thankful
to UGC and CSIR for their research fellowship. Authors are
also grateful to SAIF, CDRI Lucknow and SAIF, IIT Madras
for providing NMR facilities for characterization of the
compounds.
Diethyl 6-amino-5-carbamoyl-1-(4-chlorophenyl )-4-(3-nitro-
phenyl)-1, 4-dihydropyridine-2,3 di- carboxylate (1r). Light
yellowish solid; 52%; mp: 171–173ꢀC; IR (KBr): 3452, 3335,
3186, 2983, 1745, 1686, 1663, 1530, 1491, 1378, 1350, 1260,
REFERENCES AND NOTES
1
1
1209, 1099, 1017 cmÀ ; H NMR (CDCl3, 500MHz) : d = 8.34
(s,1H), 8.10–8.12 (m, 1H), 7.77 (d, J = 7.7Hz, 1H), 7.51–7.52
(m, 1H), 7.49 (d, J = 7.8Hz, 2H), 7.37 (d, J = 8.6 Hz, 2H) 6.75
(s, 2H), 5.05 (s, 2H), 4.86 (s, 1H), 4.10–4.20 (m, 2H), 3.90–3.96
(m, 1H), 3.80–3.86 (m, 1H), 1.24 (t, J = 7.2Hz, 3H), 0.96
(t, J = 7.1 Hz, 3H); 13C NMR (CDCl3, 125MHz): d = 171.5,
165.0, 162.9, 151.2, 148.8, 147.6, 141.4, 136.9, 133.7, 133.5,
132.2, 130.4, 129.7, 122.8, 122.4, 106.1, 79.2, 62.2, 61.4, 38.6,
14.1, 13.5; Anal. Calcd. for C24H23ClN4O7 (514.91): C, 55.98; H,
4.50; N, 10.88. Found: C, 55.88; H, 4.57; N, 10.99.
[1] Ugi, I.; Domling, A.; Werner B. J Heterocycl Chem 2000, 37, 647.
[2] Bienayme, H.; Hulme, C.; Oddon, G.; Schmitt, P. Chem Eur J
2000, 6, 3321.
[3] Domling, A.; Ugi, I. Angew Chem Int Ed 2000, 39, 3168.
[4] Joule, J. A.; Mills, K. Heterocyclic Chemistry, 4th edn.; Black-
well: Oxford, UK, 2000.
[5] Hantzsch, A. Chem Ber 1881, 14, 1637.
[6] Triggle, D. J. Cell Mol Neurobiol 2003, 23, 293.
[7] Deeks, E. D.; Keating, G. M.; Keam, S. J. Am J Cardiovasc
Drugs 2009, 9, 117.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2014
Multicomponent Reactions for the Synthesis of Substituted Dihydropyridines
[8] Huang, R. I.; Patel, P.; Walinsky, P.; Fischman, D. L.; Ogilby, J. D.;
[24] Blass, B. E. Tetrahedron 2002, 58, 9301.
Awar, M.; Frankil, C.; Savage, M. P. Catheter Cardiovasc Interv 2006, 68, 671.
[9] Cheer, S. M.; McClellan, K. Drugs 2001, 61, 1777.
[10] Mason, R. P.; Mak, I. T.; Trumbore, M. W.; Mason, P. E. Am J
Cardiol 1999, 84, 16.
[11] Aruoma, O.; Smith, C.; Cecchini, R.; Evans, P.; Halliwell, B.
Biochem Pharmacol 1991, 42, 735.
[12] Hilgeroth, A. Mini Rev Med Chem 2002, 2, 235.
[13] Kawase, M.; Shah, A.; Gaveriya, H.; Motohashi, N.;
Sakagami, H.; Varga, A.; Molnar, J. Bioorg Med Chem 2002, 10, 1051.
[14] Safak, C.; Simsek, R. Mini Rev Med Chem 2006, 6, 747.
[15] Jiang, H.; Ji, X.; Li, H.; Chen, Z.; Wang, A. Org Biomol Chem
2011, 9, 5358.
[16] Tejedor, D.; Mendez-Abt, G.; Garcia-Tellado, F. Chem Eur J
2010, 16, 428.
[17] Oshima, K.; Ohmura, T.; Suginome, M. J Am Chem Soc 2011,
133, 7324.
[18] Harschneck, T.; Kirsch, S. F. J Org Chem 2011, 76, 2145.
[19] Fananas, F. J.; Arto, T.; Mendoza, A.; Rodriguez, F. Org Lett
2011, 13, 4184.
[25] Mizar, P.; Myrboh, B. Tetrahedron Lett 2008, 49, 5283.
[26] Boruah, M.; Konwar, D.; Sharma, S. D. Tetrahedron Lett
2007, 48, 4535.
[27] Alves, D.; Sachini, M.; Jacob, R. G.; Lenardão, E. J.; Contreira,
M. E.; Savegnago, L.; Perin, G. Tetrahedron Lett 2011, 52, 133.
[28] Yadav, V. K.; Babu, K. G.; Mittal, M. Tetrahedron 2001,
57, 7047.
[29] Movassagh, B.; Shokri, S. Tetrahedron Lett 2005, 46, 6923.
[30] Zare, A.; Hasaninejad, A.; Beyzavi, M. H.; Zare, A. R. M.;
Khalafi-Nezhad, A.; Asadi, F.; Baramaki, L.; Jomhori-Angali, S.; Ghaleh-
Golabi, R. Synth Commun 2009, 39, 139.
[31] Blass, B. E.; Drowns, M.; Harris, C. L.; Liu, S.; Portlock, D. E.
Tetrahedron Lett 1999, 40, 6545.
[32] Kabalka, G. W.; Wang, L.; Namboodiri, V.; Pagni, R. M.-
Tetrahedron Lett 2000, 41, 5151.
[33] Kabalka, G. W.; Pagni, R. M.; Hair, C. M. Org Lett 1999, 1,
1423.
[34] Nakano, Y.; Shi, W.; Nishii, Y.; Igarashi, M. J. J Heterocycl
Chem 1999, 36, 33.
[20] Sun, J.; Xia, E. Y.; Wu, Q.; Yan, C. G. Org Lett 2010, 12, 3678.
[21] Choudhury, L. H.; Parvin, T. Tetrahedron 2011, 67, 8213.
[22] Pal, S.; Choudhury, L. H.; Parvin, T. Mol Divers 2012, 16, 129.
[23] Pal, S.; Choudhury, L. H.; Parvin, T. Synth commun 2012.
doi: 10.1080/00397911.2011.618283
[35] Basu, B.; Das, P.; Das, S. Curr Org Chem 2008, 12, 141.
[36] Ando, T.; Clark, J. H.; Cork, D. G.; Hanafusa, T.; Ichihara, J.;
Kinura, T. Tetrahedron Lett 1987, 28, 1421.
[37] Wang, S. X.; Li, J. T.; Yang, W. Z.; Li, T. S. Ultrason
Sonochem 2002, 9, 159.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet