Synthesis of bis-1,4-dihydropyridine derivatives

Article abstract of DOI:10.1081/SCC-200054183

A series of bis-1,4-dihydropyridine derivatives were synthesized by the reaction of p-phenylenedialdehyde or m-phenylenedialdehyde and active methylene compounds. Copyright Taylor & Francis, Inc.

Full text of DOI:10.1081/SCC-200054183

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Synthesis of Bis‐1,4‐Dihydropyridine
Derivatives
Songlei Zhu a b , Shujang Tu a , Yuan Gao c , Chunbao Miao a , Tuanjie Li a ,
Xiaojing Zhang a , Fang Fang a & Daqing Shi a
a Department of Chemistry , Xuzhou Normal University, Key Laboratory of
Biotechnology on Medical Plant Jiangsu , Xuzhou, Jiangsu, China
b Department of Chemistry , Xuzhou Medical College , Xuzhou, Jiangsu,
China
c Department of Chemistry , Shenzhen University , Shenzhen, Guangdong,
China
Published online: 16 Aug 2006.
To cite this article: Songlei Zhu , Shujang Tu , Yuan Gao , Chunbao Miao , Tuanjie Li , Xiaojing Zhang ,
Fang Fang & Daqing Shi (2005) Synthesis of Bis‐1,4‐Dihydropyridine Derivatives, Synthetic Communications:
An International Journal for Rapid Communication of Synthetic Organic Chemistry, 35:8, 1011-1015, DOI:
10.1081/SCC-200054183
To link to this article: http://dx.doi.org/10.1081/SCC-200054183
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Synthetic Communicationsw, 35: 1011–1015, 2005
Copyright # Taylor & Francis, Inc.
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1081/SCC-200054183
Synthesis of Bis-1,4-Dihydropyridine
Derivatives
Songlei Zhu
Department of Chemistry, Xuzhou Normal University, Key Laboratory of
Biotechnology on Medical Plant Jiangsu, Xuzhou, Jiangsu, China and
Department of Chemistry, Xuzhou Medical College, Xuzhou, Jiangsu,
China
Shujang Tu
Department of Chemistry, Xuzhou Normal University, Key Laboratory of
Biotechnology on Medical Plant Jiangsu, Xuzhou, Jiangsu, China
Yuan Gao
Department of Chemistry, Shenzhen University, Shenzhen,
Guangdong, China
Chunbao Miao, Tuanjie Li, Xiaojing Zhang, Fang Fang, and Daqing Shi
Department of Chemistry, Xuzhou Normal University, Key Laboratory of
Biotechnology on Medical Plant Jiangsu, Xuzhou, Jiangsu, China
Abstract: A series of bis-1,4-dihydropyridine derivatives were synthesized by the
reaction of p-phenylenedialdehyde or m-phenylenedialdehyde and active methylene
compounds.
Keywords: Bis-1,4-dihydropyridine, synthesis
1,4-Dihydropyridines (1,4-DHPs) are well known as a consequence of
their pharmacological profile as the most important calcium channel
Received in Japan February 20, 2004
Address correspondence to Shujang Tu, Department of Chemistry, Xuzhou Normal
University, Key Laboratory of Biotechnology on Medical Plant Jiangsu, Xuzhou,
Jiangsu 221009, China. E-mail: laotu2001@263.net

1012
S. Zhu et al.
modulators.[1–7] Extensive efforts have been exerted to develop methodology
for the modification of the 1,4-DHP ring.[8] 4-Aryl-2,6-dimethyl-1,4-dihydro-
pyridine-3,5-dicarboxylate derivatives are widely used for the treatment of car-
diovascular diseases (such as hypertension, angina pectoris, and infarction).[9,10]
1,4-DHPs that have different ester groups on the 3 and 5 positions possess a
stereogenic carbon on the 4-position in the 1,4-DHP nucleus, and their two
enantiomers often show different biological activities.[11] It is well established
that slight structural modifications on the DHP ring may bring remarkable
changes of pharmacological effects. However, so far attention has mainly
been paid to the synthesis of monofunctional 1,4-DHP derivatives, and the
bisfunctional ones are seldom investigated. Here we would like to report the
synthesis of bis-1,4-dihydropyridine derivatives (Scheme 1).
Scheme 1.
The results are listed in Table 1.
Table 1. Synthesis of bis-1,4-DHP derivatives
Starting material
Yield
(%)
Entry
1
1
2
Ratio
1:4
Product
—
—
—
3a
75
2
3
1:4
1:4
3b
3c
78
70
4
5
6
1:2:2
1:2:2
1:2:2
4a
4b
4c
92
90
89

Bis-1,4-Dihydropyridine Derivatives
EXPERIMENTAL
1013
Melting points were determined in a capillary tube and are uncorrected. The
1H NMR spectra were recorded on a DPX 300 MHz Spectrometer with
TMS as internal standard. The IR spectra were obtained with an SE-1730
instrument as potassium bromide pellets.
General Procedure
A mixture of p-phenylenedialdehyde or m-phenylenedialdehyde 1 (2 mmol),
active methylene compounds 2 (in proper ratio), ammonium acetate
(4 mmol), and acetic acid (15 mL) was kept stirring for 4–6 h at 1008C
(TLC). Then the mixture was cooled and poured into 100 mL of water. The
solid products were filtered, dried, and recrystallized from ethanol.
1,4-bis(2,6-dimethyl-3,5-dimethoxylcarbonyl-1,4-dihydropyridine-4-
yl)benzene 3a: mp . 3008C; Y ¼ 75%; IR (KBr, n, cm21): 3354, 2954, 2864,
1
1652, 1483, 1220, 1122, 1017; H NMR (DMSO-d6) (d, ppm): 2.24 (6H, s,
2 Â CH3), 2.50 (6H, s, 2 Â CH3), 3.55 (12H, s, 4 Â CH3), 4.46 (2H, s,
2 Â CH), 6.97 (4H, s, ArH), 8.60 (2H, s, 2 Â NH); CHN analysis: %C
(calcd. 64.11, found 63.92); %H (calcd. 6.15, found 5.88); %N (calcd. 5.34,
found 5.10).
1,4-bis(2,6-dimethyl-3,5-diethoxylcarbonyl-1,4-dihydropyridine-4-yl)benzene
3b: mp . 3008C; Y ¼ 78%; IR (KBr, n, cm21): 3349, 2985, 1696, 1488,
1369, 1300, 1241, 1207, 1122, 1093, 1052, 1020, 859, 808, 739, 688;
1H NMR (DMSO-d6) (d, ppm): 1.09 (12H, t, J ¼ 6.8 Hz, 4 Â CH3), 2.23
(12H, s, 4 Â CH3), 3.97 (8H, q, J ¼ 6.8 Hz, 4 Â OCH2), 4.77 (2H, s,
2 Â CH), 6.96 (4H, s, ArH), 8.75 (2H, s, 2 Â NH); CHN analysis: %C
(calcd. 66.19, found 65.88); %H (calcd. 6.94, found 5.69); %N (calcd. 4.82,
found 4.63).
1,3-bis(2,6-dimethyl-3,5-diethoxylcarbonyl-1,4-dihydropyridine-4-yl)benzen
3c: mp . 3008C; Y ¼ 70%; IR (KBr, n, cm21): 3341, 2981, 2361, 1700,
1648, 1483, 1372, 1330, 1299, 1210, 1114, 1050, 1023, 780, 759, 686, 634;
1HNMR (DMSO-d6) d: 1.11 (12H, t, J ¼ 6.8 Hz, 4 Â CH3), 2.23 (12H, s,
4 Â CH3), 3.96 (8H, q, J ¼ 6.8 Hz, 4 Â OCH2), 4.79 (2H, s, 2 Â CH),
6.86–7.00 (4H, m, ArH), 8.74 (2H, s, 2 Â NH); CHN analysis: %C (calcd.
64.11, found 63.87); %H (calcd. 6.15, found 5.84); %N (calcd. 5.34, found
5.09).
1,4-bis(3-methoxylcarbonyl-1,4,5,6,7,8-hexahydro-5-oxo-2,7,7-trimethylqui-
noline-4-yl)benzene 4a: mp . 3008C; Y ¼ 92%; IR (KBr, n, cm21): 3291,
3082, 2955, 1698, 1604, 1488, 1381, 1310, 1281, 1213, 1187, 1168, 1142,
1
1110, 1078, 1016, 800, 739, 609, 592, 533; H NMR (DMSO-d6) (d, ppm):

1014
S. Zhu et al.
0.79 (6H, s, 2 Â CH3), 0.97 (6H, s, 2 Â CH3), 1.94–2.49 (8H, m, 4 Â CH2),
2.25 (6H, s, 2 Â CH3), 3.50 (6H, s, 2 Â CH3), 4.77 (2H, s, 2 Â CH), 6.90 (4H,
s, ArH), 9.00 (2H, s, 2 Â NH); CHN analysis: %C (calcd. 71.31, found 71.05);
%H (calcd. 7.04, found 6.79); %N (calcd. 4.89, found 4.62).
1,4-bis(3-ethoxylcarbonyl-1,4,5,6,7,8-hexahydro-5-oxo-2,7,7-trimethylqui-
noline-4-yl)benzene 4b: mp . 3008C; Y ¼ 90%; IR (KBr, n, cm21): 3291,
3082, 2955, 1698, 1605, 1488, 1381, 1311, 1281, 1214, 1187, 1168, 1142,
1
1111, 1078, 1016, 800, 739, 609, 592, 533; HNMR (DMSO-d6) d: 0.86
(6H, s, 2 Â CH3), 1.04 (6H, s, 2 Â CH3), 1.08 (6H, t, J ¼ 6.8 Hz, 2 Â CH3),
1.91–2.41 (8H, m, 4 Â CH2), 2.23 (6H, s, 2 Â CH3), 3.50 (4H, q,
J ¼ 6.8 Hz, 2 Â OCH2), 4.76 (2H, s, 2 Â CH), 6.83–6.94 (4H, m, ArH),
9.00 (2H, s, 2 Â NH); %C (calcd. 71.97, found 71.78); %H (calcd. 7.38,
found 7.15); %N (calcd. 4.66, found 4.37).
1,3-bis(3-methoxylcarbonyl-1,4,5,6,7,8-hexahydro-5-oxo-2,7,7-trimethylqui-
noline-4-yl)benzene 4c: mp . 3008C; Y ¼ 89%; IR (KBr, n, cm21): 3293,
3083, 2956, 2361, 1701, 1615, 1498, 1380, 1312, 1283, 1222, 1171, 1148,
1
1112, 1077, 1009, 788, 701, 527; H NMR (DMSO-d6) (d, ppm): 0.82 (6H,
s, 2 Â CH3), 0.99 (6H, s, 2 Â CH3), 1.90–2.43 (8H, m, 4 Â CH2), 2.23
(6H, s, 2 Â CH3), 3.50 (6H, s, 2 Â CH3), 4.76 (2H, s, 2 Â CH), 6.83–6.94
(4H, m, ArH), 9.00 (2H, s, 2 Â NH); %C (calcd. 71.31, found 71.03); %H
(calcd. 7.09, found 6.75); %N (calcd. 4.89, found 4.68).
ACKNOWLEDGMENTS
We thank the Nature Science Foundation of the China (No. 20372057),
Nature Science Foundation of the Jiangsu Province (No. BK2001142),
the Nature Science Foundation of Jiangsu Education Department (No.
01KJB150008), and the Key Laboratory of Chemical Engineering &
Technology of the Jiangsu Province Open Foundation (No. KJS02060) for
financial support.
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