Microwave-assisted synthesis of phenylenedi(4′,4′- tetrahydroquinoline) and di(4′,4′-tetrahydropyridine) derivatives

Article abstract of DOI:10.1002/jhet.5570420105

The synthesis of bifunctional pyridine and quinolione derivatives were investigated using terephthalic and isophthalic aldehydes as a precursor. The reaction proceeds under microwave irradiation with good yield (70-92%) and short reaction time (7-9 min.).

Full text of DOI:10.1002/jhet.5570420105

Jan-Feb 2005
Microwave-assisted Synthesis of Phenylenedi(4',4''-tetrahydro-
quinoline) and di(4',4''-tetrahydropyridine) Derivatives
29
Shujiang Tu,* Fang Fang, Songlei Zhu, Tuanjie Li, Xiaojing Zhang, Qiya Zhuang
Department of Chemistry, Xuzhou Normal University, Key Laboratory of Biotechnology on Medical
Plant, Xuzhou; Jiangsu, 221009, P. R. China
Shuijun Ji, Yong Zhang
College of Chemistry and Chemical Engineering, Key Lab. of Org. Synth. of Jiangsu Province, Suzhou
University, 215006 PR China
Received February 2, 2004
The synthesis of bifunctional pyridine and quinolione derivatives were investigated using terephthalic and
isophthalic aldehydes as a precursor. The reaction proceeds under microwave irradiation with good yield
70-92%) and short reaction time (7-9 min.). We provide a rapid and efficient method of synthesizing a range
of bifunctional monocyclic and bicyclic products related to 1,4-dihydropyridines (1,4-DHPs).
(
J. Heterocyclic Chem., 42, 29 (2005).
1
,4-Dihydropyridines (1,4-DHPs) are well-known com-
4-Aryl-2, 6-dimethyl-1,4-dihydropyridine-3, 5-dicar-
boxylate (1,4-DHP) derivatives are widely used for the
treatment of cardiovascular diseases (hypertension, angina
pectoris, infarction) [9]. 1,4-DHPs having different ester
groups at the 3- and 5-positions possess a stereogenic car-
bon at the 4-position in the 1,4-DHP nucleus, and their
enantiomers often show different biological activities [10].
Quinoline derivatives have also shown amoebicidal, bacteri-
cidal, fungicidal and antimalarial activity [11].
Dihyropyridone are potential calcium channel modulators
[12]. It is well established that slight structural modification
on the DHP ring may bring various pharmacological effect
[13]. Compounds which contain monofunctional groups
have shown significant biological and pharmacological
activities. In this paper we show that microwave irradiation
provides a convenient and efficient way to synthesize a
range of bifunctional monocyclic and bicyclic products
related to 1,4-DHPs with terephthalic and isophthalic alde-
hydes 1 as a precursor. When a mixture of terephthalic alde-
hydes or isophthalic aldehydes 1 and active methylene com-
pounds 2 (in proper ratio) was radiated with microwave
pounds because of their attractive pharmacological profile
as calcium channel modulators [1]. Extensive efforts have
been exerted on developing methodology for the modifica-
tion of the 1,4-DHP rings [2]. In addition, much attention
has been paid to the development of synthesis of mono-
functional 1,4-DHPs derivatives and the bifunctional 1,4-
DHPs are seldom investigated. Furthermore, introduction
of substituents to the pyridine ring often requires a long
time to achieve acceptable yields under conventional con-
ditions [3].
Recently, microwave heating was widely used in the
synthesis of heterocyclic compounds, for example hexahy-
droquinolines [4], octahydroquinolines [5] and dihydropy-
ridone [6], pyridopyrimidones [7], as well as decahy-
droacridines [8], with good yields and short reaction time.
The efficiency of microwave heating in promoting
organic synthesis and the success of their application in
these heterocyclic syntheses prompted us to extend those
procedures to the synthesis of compounds containing two
bifunctional compounds containing two 1,4-DHP nuclei.
Scheme 1

3
0
S. Tu, F. Fang, S. Zhu, T. Li, X. Zhang, Q. Zhuang, S. Ji, and Y. Zhang
Vol. 42
(
300 W) using a small amount glycol as energy transfer
reagent (Scheme 1), the reactions were almost completed in
-9 min. Then the reaction mixture was cooled and poured
to the proton on C-4 split by coupling with the protons on
C-3 (J3,4=1.1 and J3',4 =8.4 Hz). The two protons on C-6
appeared as an AB system, with a coupling constant ~15.6
Hz indicating that these two protons were nonequivalent.
7
into cold water, filtered and washed with a small volume of
ethanol. The crude products were purified by recrystalliza-
tion from 95% ethanol or acetone to afford products with
good yields (70-92%).
All the reactions were followed by TLC. The results for
the synthesis of these compounds are indicated in Table 1.
1
The IR, H NMR of compounds 4 and 6 are consistent
with the respective structures. And these compounds
showed good elemental analysis with their structures.
Mechanisms of the formation of 4, 5, 6 and 7 were similar
to that reported in other sources [3,14].
Table 1
Synthesis of Bifunctional 1,4-DHP Derivatives
Entry
Starting material
Ratio Time
Yield
(%)
(min)
1
2
3
4
4
4
a
b
c
-
-
-
NH OAc
1: 4: 3
1: 4: 3
1: 4: 3
7
8
7
75
78
70
4
NH OAc
4
NH OAc
4
5
6
6
6
7
NH OAc
1: 2: 2: 3
1: 2: 2: 3
1: 2: 2: 3
1: 2: 2: 3
1: 2: 2: 3
8
9
8
8
8
83
92
90
89
85
4
a
b
c
NH OAc
4
NH OAc
4
NH OAc
4
NH OAc
4
1
The IR and H NMR data of all compounds are consis-
tent with assigned structures. The IR spectra of compound
EXPERIMENTAL
showed the NH group at 3200 and 3100 cm–1 region.
The H NMR spectra of compound 5 showed the NH pro-
ton at 9.84 ppm. The two protons on C-3 appeared at 2.39-
.93 ppm and formed a part of an ABX system which was
confirmed by a doublet of doublets at 4.01-4.08 ppm cor-
responding to the proton on C-4 split by coupling with the
protons on C-3 (J3,4=1.9 and J3',4 =7.9 Hz). The H NMR
spectra of compound 7 showed the NH proton at 10.05
ppm. The two protons on C-3 appeared at 2.18-2.89 ppm
and formed a part of an ABX system which was confirmed
by a doublet of doublets at 4.06-4.08 ppm corresponding
Melting points were determined in a capillary tube and are
uncorrected. The H NMR spectra were recorded on a DPX 400
MHz spectrometer with TMS as internal standard. The IR spectra
were recorded for KBr discs with a SE-1730 instrument.
Elemental analyses were determined by using a Perkin-Elmer
240c elemental analysis instrument.
5
1
1
2
Microwave Assisted Syntheses.
1
A dry flask (25 mL) was charged with either terephthalic or
isophthalic aldehydes (2 mmol), corresponding 2 and 3 in a ratio
reported in Table 1, and glycol (2 mL) were refluxed for 7-9 min.
in a modifided commercial microwave oven (2450 MHz) set for
650 W. The reaction mixture was then cooled and poured into

Jan-Feb 2005
Microwave-assisted Synthesis of Phenylenedi(4',4''-tetrahydroquinoline)
31
cold water then filtered and washed with ethanol (3 mL). The
crude products were recrystallized from 95% ethanol or acetone.
(6H, t, J=6.8 Hz, CH ), 1.91-2.41 (8H, m, CH ), 2.23 (6H, s,
3 2
CH ), 3.50(4H, q, J=6.8 Hz, OCH ), 4.76(2H, s, CH), 6.83-6.94
3
2
(
4H, m, ArH), 9.00 (2H, s, NH).
1
,4-Bis(2,6-dimethyl-3,5-dimethoxylcarbonyl-1,4-dihydropyri-
Anal. Calcd. for C H N O : C, 71.97; H, 7.38; N, 4.66.
3
6 44 2 6
dine-4-yl)benzene (4a).
Found C, 71.78; H, 7.15; N, 4.37.
This compound was obtained as a yellow solid, 75% yield,
mp>300 °C; IR(KBr, ν, cm ): 3354(NH), 1692(CO); H NMR
1
,3-bis(3-methoxylcarbonyl-1,4,5,6,7,8-hexahydro -2,7,7-
-1
1
trimethylquinoline-5-one-4-yl)benzene (6c).
(
DMSO-d ) (δ, ppm): 2.24 (6H, s, CH ), 2.50 (6H, s, CH ), 3.55
6 3 3
(
12H, s, CH ), 4.46 (2H, s, CH), 6.97 (4H, s, ArH), 8.60 (2H, s,
This compound was obtained as a yellow solid, 89% yield,
3
-1
1
NH).
Anal. Calcd. for C H N O : C, 64.11; H, 6.15; N, 5.34.
mp>300 °C; IR(KBr, ν, cm ): 3293(NH), 1701(CO); H NMR
(DMSO-d ) (δ, ppm): 0.82 (6H, s, CH ), 0.99 (6H, s, CH ), 1.90-
2
8
32
2
8
6
3
3
Found C, 64.29; H, 5.88; N, 5.10.
2.43 (8H, m, CH ), 2.23 (6H, s, CH ), 3.50 (6H, s, OCH ), 4.76
2 3 3
(
2H, s, CH), 6.83-6.94 (4H, m, ArH), 9.00 (2H, s, NH).
1
,4-Bis(2,6-dimethyl-3,5-diethoxylcarbonyl-1,4-dihydropyri-
Anal. Calcd. for C H N O : C, 71.31; H, 7.04; N, 4.89.
3
4 40 2 6
dine-4-yl)benzene (4b).
Found C, 71.09; H, 6.75; N, 4.68.
This compound was obtained as a yellow solid, 78% yield,
1
,4-Bis(7,7-dimethyl-1,2,3,4,5,6,7,8-octahydroquinoline-2,5-
-1
1
mp>300 °C; IR(KBr, ν, cm ): 3349(NH), 1696(CO); H NMR
DMSO-d ) (δ, ppm): 1.09 (12H, t, J=6.8 Hz, CH ), 2.23 (12H, s,
dione-4-yl)benzene (7).
(
6
3
CH ), 3.97 (8H, q, J=6.8 Hz, OCH ), 4.77 (2H, s, CH), 6.96 (4H,
s, ArH), 8.75 (2H, s, NH).
This compound was obtained as a yellow solid, 85% yield,
3
2
-1
mp>300 °C; IR(KBr, ν, cm ): 3379(NH), 1713(CO), 1645(CO-
1
Anal. Calcd. for C H N O : C, 66.19; H, 6.94; N, 4.82;
N); H NMR (DMSO-d ) (δ, ppm): 0.98(6H, s, CH ), 1.04 (6H,
3
2
40
2
8
6
3
found C, 65.98; H, 6.69; N, 4.63.
s, CH ), 2.31 (2H, dd, J=15.6 Hz, C -H), 2.24 (2H, dd, J=15.6
3
6
Hz, C -H), 2.31(2H, dd, J=15.2 Hz, J=1.1 Hz, B part of ABX,
6
'
1
,3-Bis(2,6-dimethyl-3,5-diethoxylcarbonyl-1,4-dihydropyri-
C -H), 2.88 (2H, dd, J=8.4 Hz, J=15.2 Hz, A part of ABX, C -
3
3'
dine-4-yl)benzene (4c).
H), 4.07 (2H, dd, J=8.4 Hz, J=1.1 Hz, X part of ABX, C -H),
4
This compound was obtained as a yellow solid, 70% yield,
7.00 (4H, s, ArH), 10.05 (2H, s, NH).
-1
1
mp>300 °C; IR(KBr, ν, cm ): 3341(NH), 1700(CO); HNMR
DMSO-d ) ( δ, ppm): 1.11 (12H, t, J=6.8 Hz, CH ), 2.23 (12H,
Anal. Calcd. for C H N O : C, 73.02; H, 7.00; N, 6.08.
2
8 32 2 4
(
Found C, 72.93; H, 6.77; N, 5.87.
6
3
s, CH ), 3.96 (8H, q, J=6.8 Hz, OCH ), 4.79 (2H, s, CH), 6.86-
3
2
Acknowledgments.
7
.00 (4H, m, ArH), 8.74 (2H, s, NH).
Anal. Calcd. for C H N O : C, 66.19; H, 6.94; N, 4.82.
Found C, 66.33; H, 6.84; N, 5.01.
We wish to thank the National Natural Science Foundation of
China (No. 20372057), the Nature Science Foundation of the
Jiangsu Province (No. BK2001142) and the Nature Science
Foundation of Jiangsu Education Department (No.
3
2 40 2 8
1
4
,4-Bis(5-ethoxylcarbonyl-6-methyl-3,4-dihydropyridine-2-one-
-yl)benzene (5).
0
1KJB150008) and the Key Laboratory of Chemical Engineering
This compound was obtained as a yellow solid, 83% yield, mp
& Technology of the Jiangsu Province Open Foundation (No.
KJS02060) for financial support.
-1
2
1
65-266 °C; IR(KBr, ν, cm ): 3200(NH), 3100(NH), 1702(CO),
1
645(CO-N); H NMR (DMSO-d ) (δ, ppm): 1.09 (6H, t, J=7.0
6
Hz, CH ) , 2.29 (6H, s, CH ), 2.41 (2H, dd, J=16.3 Hz, J=1.9 Hz,
3
3
B part of ABX, C -H), 2.89 (2H, dd, J=16.3 Hz, J=7.9 Hz, A part
REFERENCE AND NOTES
3
of ABX, C -H), 3.96 (4H, q, J=6.9 Hz, OCH ), 4.06 (2H, dd,
3'
2
J=7.6 Hz, J=1.9 Hz, X part of ABX, C -H), 7.05 (4H, s, ArH),
[1a] F. Bossert, H. Meyers and E. Wehinger, Angew., 93, 755
(1981); [b] D. M. Stout and A. I. Meyers, Chem. Rev., 82, 223 (1982); [c]
R. A. Janis, P. J. Silver and D. J. Triggle, Adv. Drug Res., 16, 309 (1987);
4
9
.84 (2H, s, NH).
Anal. Calcd. for C H N O : C, 65.44; H, 6.41; N, 6.36.
2
4 28 2 6
[d] F. Bossert and W. Vater, Med. Res. Rev., 9, 291 (1989); [e] N. Martín
Found C, 65.58; H, 6.62; N, 6.14.
and C. Seoane, Quim. Ind., 36, 115 (1990); [f] S. Marchalin, M. Chudik,
V. Mastihuba and B. Decroix, Heterocycles., 48, 1943 (1998); [g] K.
Achiwa and T. Kato, Curr. Org. Chem., 3, 77 (1999).
1
,4-Bis(3-methoxylcarbonyl-1,4,5,6,7,8-hexahydro-2,7,7-
trimethylquinoline-5-one-4-yl)benzene (6a).
[2a] U. Eisner and J. Kuthan, Chem. Rev., 72, 1 (1972); [b] D. M.
This compound was obtained as a yellow solid, 92% yield,
Stout and A. I. Meyers, Chem. Rev., 82, 223 (1982); [c] Cherny Yie-Tia.
Tetrahedron, 58, 4931 (2002).
[3a] A. Loupy, N. Philippon, P. Pigeon and H. Gslond,
Heterocycles, 32, 1947 (1991); [b] K. Shuj, N. Minoru and T. Kazuichi, J.
Heterocyclic Chem., 24, 1243 (1984); [c] H. Rodrigues, M. Suares,
Rolando, Perez, Petit and A. Loupy, Tetrahedron Lett. 44, 3709 (2003).
-1
1
mp>300 °C; IR(KBr, ν, cm ): 3291(NH), 1698(CO); H NMR
(
DMSO-d ) (δ, ppm): 0.79(6H, s, CH ), 0.97(6H, s, CH ), 1.94-
6
3
3
2
.49 (8H, m, CH ), 2.25 (6H, s, CH ), 3.50 (6H, s, CH ), 4.77
2 3 3
(2H, s, CH), 6.90 (4H, s, ArH), 9.00 (2H, s, NH).
Anal. Calcd for C34H40N O : C, 71.31; H, 7.04; N, 4.89.
2
6
[4] S. J. Tu, Q. H. Wei, H. J. Ma, D. Q. Shi, Y. Gao and G. Y. Cui.
Found C, 71.05; H, 6.79; N, 4.62.
Synth.Commun., 17, 2675 (2001).
1
,4-Bis(3-ethoxylcarbonyl-1,4,5,6,7,8-hexahydro-2,7,7-
[5] S. J. Tu, X. D, D. Q. Shi, Y. G and J. C. Feng, Chin. J. Chem.,
19, 714 (2001).
trimethylquinoline-5-one-4-yl)benzene (6b).
[
6] T. Quiroga, C. Cisneros, B. Insuasty, R. Abonia, M. Nogueras
and A. Sanchez, Tetrahedron Lett., 42, 5625 (2001).
7] S. J. Tu, J. F. Zhou, P. J. Cai, H. W and J. Z. Feng,
Synth.Commun., 24, 3729 (2001).
This compound was obtained as a yellow solid, 90% yield,
-1
1
mp>300 °C; IR (KBr, ν, cm ): 3291(NH), 1698(CO); HNMR
DMSO-d ) ( δ, ppm): 0.86 (6H, s, CH ), 1.04 (6H, s, CH ), 1.08
[
(
6
3
3

32
S. Tu, F. Fang, S. Zhu, T. Li, X. Zhang, Q. Zhuang, S. Ji, and Y. Zhang
Vol. 42
[
8] S. J. Tu, Z. S. Lu, D. Q. Shi, C. S. Yao, Y. Gao and C. Guo, Synth.
Commun., 2002, 14, 2181.
9a] G. J. Dubur, M. M. Veveris, G. Weinheimer, E. A. Bisenieks,
[12] E. Ochoa, M. Suárez, Y. Verdecia, B. Pita, N. Martín, M.
Quinteiro, C. Seoane, J. L. Soto, J. Duque and R. Pomés, Tetrahedron, 54,
12409 (1998).
[
N. R. Makarova, A. A. Kimenis, J. R. Uldrikis, E. J. Lukevics, D. Dooley
and H, Osswald. Arzneim.-Forsch: Drug Res., 39, 1185 (1989); [b] V.
Klusa, Drugs Future, 20, 135 (1995).
[13a] R. J. Chorvat and K. J. Rorig, J. Org. Chem., 53, 5779 (1988);
[b] C. O. Kappe and W. M. F. Fabian, Tetrahedron, 53, 2803 (1997); [c]
C. O. Kappe, Tetrahedron, 49, 6937 (1993).
[
10] D. Vo, W. C. Matowe, M. Ramesh, N. Iqbal, M. W. Wolowyk,
S. E. Howlett and E. E. Knauss, J. Med. Chem., 38, 2851 (1995).
11a] J. H. Burkhaller and W. H. Edgerton, J. Am. Chem. Soc., 73,
837 (1951); [b] G. P. Bray, A. S. Ward, Pharmacology and
[14a] C. O. Kappe, J. Org. Chem., 62, 7201 (1997); [b] M. Suárez,
Y. Verdecia, E. Ochoa, E. Salfrán, L. Morán, N. Martín, R. Martínez, M.
Quinteiro, C. Seoane, J. L. Soto, H. Novoa, N. Blaton, O. M. Peeters and
C. D. J. Ranter, Eur. J. Org. Chem., 2079 (2000); [c] M. Suárez, E.
Ochoa, Y. Verdecia, M. Martin. C. Quinteiro, J. Seoane, J. L. Soto, N.
Novoa, N. O. M. Blaton, and Peeters, Tetrahedron, 55, 875 (1999); [d] V.
K. Ahluwalia, B. Goyal and U. Das, J. Chem. Research (S), 266 (1997).
[
4
Therapeutics, 77, 1 (1998); [c] S. D. Sharad, E. S. Robert and A Michael,
Toxicon., 35, 433 (1997); [d] G. Meilin, N. Tonglan, T. A. Laychoo, K.
Kunnika, and W. Prapon, Eur. J. Pharm Sci., 6, 19 (1998).