Enaminones in heterocyclic syntheses: Part 4. A new one-step synthetic route to pyrrolo[3,4-b]pyridine and convenient syntheses of 1,4-dihydropyridines and 1,1′-(1,4-phenylene)bis(1,4-dihydropyridine)

Article abstract of DOI:10.1002/jhet.1609

Reactions of cyano olefins with (i) enamino imides afforded novel pyrrolo[3,4-b]pyridines; (ii) enamino esters afforded new 1,4-dihydropyridines; and (iii) bisenamino ester afforded new 1,1′-(1,4-phenylene)bis(1,4- dihydropyridine). The new derivatives are planned as suggested drug candidates.

Full text of DOI:10.1002/jhet.1609

1078
Enaminones in Heterocyclic Syntheses: Part 4. A New One-Step Synthetic
Route to Pyrrolo[3,4-b]pyridine and Convenient Syntheses of
Vol 51
1,4-Dihydropyridines and 1,10-(1,4-Phenylene)bis(1,4-dihydropyridine)
a
a,b
M. M. Mashaly, S. R. El-Gogary, and T. R. Kosbara
*
aDepartment of Chemistry, Faculty of Science at (New) Damietta, Mansoura University (Damietta branch),
Mansoura, Egypt
bChemistry Department, Faculty of Science (Jazan), Jazan University, Kingdom of Saudi Arabia
*
E-mail: mashaly54321@mans.edu.eg
Received August 7, 2011
DOI 10.1002/jhet.1609
Published online 23 January 2014 in Wiley Online Library (wileyonlinelibrary.com).
Reactions of cyano olefins with (i) enamino imides afforded novel pyrrolo[3,4-b]pyridines; (ii) enamino
esters afforded new 1,4-dihydropyridines; and (iii) bisenamino ester afforded new 1,10-(1,4-phenylene)bis
(1,4-dihydropyridine). The new derivatives are planned as suggested drug candidates.
J. Heterocyclic Chem., 51, 1078 (2014).
INTRODUCTION
in reactions with activated cyano olefins 2a–c as a new, one-
step synthetic route to polyfunctionally substituted pyrrolo
[3,4-b]pyridines 5a–d (Scheme 1). We also present the first
reaction of the enamino esters (anilinofumarates) 9a–e
[14,15] with cyano olefins 2a–k to synthesize some new
1,4-dihydropyridines 10a–o (Scheme 2). Our interest is
extended to synthesize the new bis(enamino ester) 14 and
to involve it in a reaction with the cyano olefins 2a, g, l to
afford the novel bis(1,4-dihydropyridine) 15a–c (Scheme 3).
In the light of the aforementioned introduction [1–6], the
new derivatives 5a–d, 10a–o, and 15a–c are planned as a
source of valuable drug candidates.
There are few recent reports [1–4] on the synthesis and
biological activity of some pyrrolopyridines, and none of
them included the use of enamino imides in the synthesis of
pyrrolo[3,4-b]pyridine. Also, 1,4-dihydropyridine (1,4-DHP)
derivatives receive growing interest because of the variety
of the high biological activities of some of them,
especially their medicinal applications [5,6]. It has been
reported [7] that nifedipine [dimethyl 1,2,6-trimethyl-4-
(3-methyl-2-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate],
the first member of the calcium channel blocking medicinal
agents, was discovered in 1967 [8] and was launched into
the market in 1975 by Bayer [9]. Many structural analogs
to nifedipine with better pharmacokinetic profile were
developed and used for the treatment of mild and moderate
hypertension [7].
RESULTS AND DISCUSSION
In continuation of our work involving enaminones [10,11]
and enaminone-related compounds [12] in reactions with
activated cyano olefins aiming at the syntheses of polyfunc-
tionally substituted nitrogen heterocycles of potential biolog-
ical activity, we, herein, report on the first use of the enamino
imides 3-arlyamino-1-substituted-pyrrole-2,5-dions 1a, d [13]
Although the literature is rich with reactions of activated
cyano olefins, searching the available literature revealed
that the enamino imides 1a, d [13] were not reported
before to be involved in a Michael cycloaddition reaction
with activated cyano olefins. Thus, 1a was allowed to react
with 2a–c and 1d with 2a, in a molar ratio of 1:1, refluxed
© 2014 HeteroCorporation

July 2014
Enaminones in Heterocyclic Syntheses
1079
Scheme 1
Scheme 2
in absolute ethanol, in the presence of a catalytic amount of
piperidine for 4 h (Scheme 1). The reaction product that
was deposited on cooling to room temperature was
separated off by filtration and was recrystallized from
95% ethanol/water (2:1) mixture or from 95% ethanol to
afford 5a–c and 5d, respectively. Satisfactory elemental
The characteristic functional groups of 5a–c and 5d
showed IR stretching vibration bands in the following regions:
(~3471 to ~3448) and (~3367 to ~3309) cmꢀ1 (2 bands, NH2),
2187–2175 cmꢀ1 (CN band) and (~ 1770 and ~1708) cmꢀ1
(two bands, C═O of cyclic five-membered ring imide with
unsaturation, i.e., the pyrrole-2,5-dions moiety). The alcoho-
lic hydroxyl group of 5d showed a stretching band at
1
and spectral (IR, H NMR, 13C NMR, and MS) analyses
1
(cf. Experimental) have proved these products to be
2-amino-3-cyano-1,4-diaryl-5,7-dioxo-6-substituted-4,5,6,
7-tetrahydro-pyrrolo[3,4-b]pyridine derivatives 5a–c and
5d, respectively (Scheme 1).
3621 cmꢀ1. The H NMR spectrum of, for example, 5a
showed a singlet signal for the protons of each of the
N-CH3, CH-4, and NH2 groups at d values of 2.66, 4.61,
and 5.65 ppm, respectively. Its 13C NMR spectrum showed
Journal of Heterocyclic Chemistry
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1080
M. M. Mashaly, S. R. El-Gogary, and T. R. Kosbar
Vol 51
Scheme 3
signals at d 163.30 and 168.35 for two imidic-C, 120.9 ppm
for cyano-C, and 60.4 ppm for CH-4. The 1H NMR spectrum
of 5d showed each of the hydroxyl and (two) methylene,
moieties of the ethanolamine residue having the same J
coupling (6 Hz). Each of them showed a triplet signal. These
signals were at d 4.71 and (3.31 and 3.25) ppm, respectively.
A mass spectrum of 5d (mol. wt: 400.43) showed the molecular
ion (M+) as m/z (400, 10.4%).
Formation of 5 (Scheme 1) can be explained via initial
Michael addition of C-4 of 1 to the b-C of the cyano olefin
2 (procedure A), leading to the formation of an acyclic
intermediate 3, which cyclized into the cyclic intermediate
4 via a nucleophilic attack of the amino nitrogen on a
cyano carbon. The cyclic intermediate 4 underwent
tautomerization into the final product 5a–d 2-amino-3-cyano-
1,4-diaryl-5,7-dioxo-6-substituted-4,5,6,7-tetrahydro-pyrrolo
[3,4-b]pyridine. Further confirmation of structure 5 was
obtained, unambiguously, via a one-pot (1:1:1) reaction of
the aldehyde 7a, malononitrile 8, and 1a under the same
reaction conditions (procedure B). In this case, 7a condenses
with 8 with the elimination of a water molecule to afford
2a, which then reacts with 1a as suggested earlier to produce
5a whose structure (procedures A and B) was confirmed
through melting points, mixture melting points, TLC, and
IR analysis.
On the other hand, the possibility of forming the 2-oxo
derivative 6 (Scheme 1) was ruled out—as the reaction
product—on the same basis of approving 5.
The present new enamino imide-cyano olefin synthetic
route offers the advantage of obtaining the final pyrrolo
[3,4-b]pyridine product in as simple as the convenient
one-step Michael cycloaddition reaction.
In parallel to what is presented for 5a–d, the reaction of
the enamino ester 9a–e [14,15] with the cyano olefins 2a–k
had afforded the new 6-amino-1,4-diaryl-5-substituted-
2,3-diethoxycarbonyl-1,4-dihydropyridine derivatives 10a–o,
which were characterized through elemental and spectral
analyses (cf. Scheme 2, Table 1 and Experimental).
Formation of compounds 10a–o can be explained on the
same basis with what was suggested earlier for 5a–d.
To synthesize the bis(1,4-DHP) 15a–c (cf. Scheme 3
and Experimental), we have started with the synthesis of
the new bis(enamino ester) [tetraethyl 2,20-(1,4-phenylene)
bis(azanediyl) difumarate] 14. Compound 14 was next allowed
to react with either the cyano olefins 2a, g, l (procedure A) or
with the suitable aldehyde 7a, d and activated cyanomethy-
lene reagent 8, 16 (procedure B) to afford the novel 1,
10-(1,4-phenylene)bis(1,4-dihydropyridine) derivatives 15a–c
in 50–70% yield. Compounds 14 and 15a–c were character-
ized through elemental and spectral analyses.
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Enaminones in Heterocyclic Syntheses
1081
Table 1
Compounds 2, 9, and 10.
Reactant: cyano olefin 2
Reactant: enamino esters 9
Procedure
No.
Product 10 with Ar1, Ar2, and Z
No.
Z
Ar1
No.
Ar2
No.
A and B
A and B
A and B
10a
10b
10c
10d
10e
10f
10g
10h
10i
10j
10k
10l
10m
10n
10o
CN
CN
CN
CN
CN
CN
CN
CN
CN
C6H5
4-H3COC6H4
4-ClC6H4
2-ClC6H4
3-NO2C6H4
4-H3COC6H4
C6H5
C6H5
3-BrC6H4
C6H5
2a
2c
2d
2e
2f
2c
2a
2a
2b
2a
2 g
2 h
2i
C6H5
C6H5
C6H5
C6H5
C6H5
9a
9a
9a
9a
9a
9b
9c
9d
9d
9e
9a
9a
9d
9d
9a
A
A
A
A
A
A
A
A
A
A
A
A
4-H3COC6H4
4-H3CC6H4
4-BrC6H4
4-BrC6H4
4-ClC6H4
C6H5
CN
CO2Et
CO2Et
CO2Et
CO2Et
CONH2
C6H5
3-NO2C6H4
4-H3CCONHC6H4
2-BrC6H4
C6H5
C6H5
4-BrC6H4
4-BrC6H4
C6H5
2j
2 k
King Abd-Elaziz University, Jeddah, KSA, with the use of tetra-
methylsilane as an internal standard and DMSO or CDCl3 as sol-
vents. Chemical shifts were expressed as d ppm. The IR spectra
were performed on a Jasco 4100 FTIR spectrophotometer (KBr
pellet) at the Department of Chemistry, Faculty of Science at
(New) Damietta, Mansoura University, Damietta branch, Egypt.
The electron impact (EI) mass spectra were performed on a Shi-
madzu GCMS-QP 1000 EX mass spectrometer at 70eV, and the el-
emental analyses were performed on a Perkin-Elmer 2400 C, H, N
elemental analyzer at the Micro Analytical Unit, Cairo University.
Reported procedures were followed for the preparation of
3-arlyamino-2,5-dioxo-1-substituted-3-pyrroline 1a, b [13] and
anilinofumarates 9a–e [14,15].
Formation of compounds 15a–c can be explained on the
same basis with what was suggested earlier for 5a–d.
The structural symmetry of 14 and 15a–c was consistent
in their respective spectra (cf. Scheme 3 and Experimental).
For example, derivative 15a showed IR stretching bands in
the regions of 3468 and 3318 cmꢀ1 for two identical (NH2)
groups, 2189 cmꢀ1 for two identical (CN) groups, and
(1739) and (1700) cmꢀ1 for (C═O) moieties of identical
(two) and (two) of its four ethyl ester groups. The 1H
NMR spectrum of 15a showed each identical pair of ethyl
ester groups in the form of a triplet signal and a quartet
signal representing the identical pairs of methyl and methylene
moieties, respectively. The same trend was continued for the
other functional groups and through its 13C NMR spectrum.
Although the molecular ion peak could not be detected in
the MS spectrum of 15a, a suggested fragmentation pattern
assumes the formation of ions of H2NCꢁCCN (m/z66,
100%) and C6H5 (m/z77, 63.9%).
Synthesis
of
2-amino-3-cyano-1,4-diaryl-5,7-dioxo-6-
substituted-4,5,6,7-tetrahydro-pyrrolo[3,4-b]pyridine
derivatives (5a–d).
General procedure A. A mixture of enamino imide (1a or 1d)
(0.001mol), arylidenemalononitrile derivatives 2a–c (0.001 mol),
and two drops of piperidine in 10mL of absolute ethanol was
refluxed on a boiling water bath for 4 h and then allowed to cool
to room temperature. The solid product, so deposited, was
collected by filtration, washed with drops of cold 95% ethanol,
and recrystallized from the appropriate solvent.
The technique followed up throughout this work has the
advantages of (i) easy construction of the type and position
of the desired functional group through starting with
readily available and inexpensive raw materials and (ii)
application of a time-saving routine work that can be easily
handled by a beginner chemist.
General procedure B.
The procedure for a mixture of
enamino imide (1a) (0.001 mol), benzaldehyde 7a (0.001 mol),
malononitrile 8 (0.001 mol), and two drops of piperidine in
10 mL of absolute ethanol was the same as in procedure A.
2-Amino-3-cyano-5,7-dioxo-1,4-diphenyl-6-methyl-(3-
pyrrolino)[3,4-b](1,4-dihydro pyridine) (5a). mp 225–226 ꢂC
(95% ethanol), yield 88%, orange fine crystals; ir (KBr), υmax
,
EXPERIMENTAL
cmꢀ1 = 3463, 3309 (NH2), 2186 (CN), 1772, 1712 (two C═O),
1677 (C═C), 740, 694 (mono substituted benzene ring); 1H
NMR (600 MHz, DMSO), d, ppm = 7.53–7.27 (10H, m,
aromatic), 5.65 (2H, s, NH2), 4.61 (1H, s, CH-4), 2.66 (3H, s,
CH3); 13C NMR (150 MHz, DMSO), d, ppm = 23.05 (CH3),
60.4 (CH-4), 120.9 (CN), (110.6, 127.05, 127.61, 128.50,
129.42, 134.85, 137.60, 143.99, 151.52), 163.30 (C═O), 168.35
(C═O). Anal. Calcd for C211H6N4O2 (mol. wt: 356.38): C,
70.77; H, 4.53; N, 15.72. Found: C, 70.36; H, 4.92; N, 15.63.
The purchased diethyl oxalacetate sodium salt [Fluka, assay
≥95.0% (CH), may contain 1% NaOH]. Melting points were
obtained on a Gallenkamp melting point apparatus (open capillary
tubes) and were uncorrected. 1H NMR spectra were performed on
a Varian Mercury-VX-300 (300 MHz) at the Micro analytical
Unit, Cairo University, Giza, Egypt and a Bruker ultra shield
Avance III spectrometer (400 and 600 MHz for 1H NMR and
100 and 150 MHz for 13C NMR) at the Faculty of Science,
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M. M. Mashaly, S. R. El-Gogary, and T. R. Kosbar
Vol 51
2-Amino-4-(3-bromophenyl)-3-cyano-5,7-dioxo-6-methyl-1-
phenyl-(3-pyrrolino)[3,4-b](1,4-dihydropyridine) (5b). mp
Diethyl 6-amino-5-cyano-4-(4-methoxyphenyl)-1-phenyl-1,4-
dihydropyridine-2,3-dicarboxylate (10b).
mp 144–146 ꢂC
(95% ethanol), yield 78%, yellow fine crystals; ir (KBr), υmax
220–222 ꢂC (95% ethanol), yield 91%, orange fine crystals; ir
(KBr), υmax, cmꢀ1 = 3471, 3367 (NH2), 2175 (CN), 1770, 1708
(two C═O), 1670 (C═C), 744, 698 (mono substituted benzene
ring), 867, 798 (meta disubstituted benzene ring); 1H NMR
(300 MHz, CDCl3), d, ppm = 7.60–7.27 (9H, m, aromatic), 4.76
(1H, s, CH-4), 4.41 (2H, s, NH2), 2.83 (3H, s, CH3).
,
cmꢀ1 = 3459, 3324 (NH2), 2183 (CN), 1742, 1691 (two C═O),
1244, 1032 (OCH3), 831 (para disubstituted benzene ring), 748,
702 (mono substituted benzene ring); 1H NMR (400 MHz,
DMSO), d, ppm = 7.50 (3H, m, aromatic), 7.30 (2H, m,
aromatic), 7.24 (2H, d, J = 8.36, aromatic), 6.96 (2H, d, J = 8.36,
aromatic), 5.58 (2H, s, NH2), 4.43 (1H, s, CH-4), 3.96 (2H, q,
OCH2CH3), 3.76 (2H, m, OCH2CH3), 3.77 (3H, s, OCH3), 1.06
(3H, t, OCH2CH3), 0.814 (3H, t, OCH2CH3). Anal. Calcd for
C25H25N3O5 (mol. wt: 447.48): C, 67.10; H, 5.63; N, 9.39.
Found: C, 66.80; H, 5.20; N, 9.17.
2-Amino-3-cyano-5,7-dioxo-4-(4-methoxyphenyl)-6-methyl-1-
phenyl-(3-pyrrolino)[3,4-b](1,4-dihydropyridine) (5c).
mp
202–204 ꢂC (95% ethanol), yield 89%, orange fine crystals; ir
(KBr), υmax, cmꢀ1 = 3451, 3332 (NH2), 2175 (CN), 1770, 1716
(two C═O), 1677 (C═C), 1249, 1029 (OCH3), 836 (para
disubstituted benzene ring), 744, 690 (mono substituted benzene
Diethyl 6-amino-4-(4-chlorophenyl)-5-cyano-1-phenyl-1,4-
1
ring); H NMR (300 MHz, CDCl3), d, ppm = 7.58–7.56 (2H, m,
dihydropyridine-2,3-dicarboxylate (10c).
(95% ethanol), yield 78%, pale yellow fine crystals; ir (KBr),
max, cmꢀ1 = 3447, 3361 (NH2), 2186 (CN), 1722, 1704 (two
mp 188–189 ꢂC
aromatic), 7.37–7.27 (5H, m, aromatic), 6.95–6.92 (2H, m,
aromatic), 4.73 (1H, s, CH-4), 4.36 (2H, s, NH2), 3.81 (3H, s,
OCH3), 2.81 (3H, s, CH3).
υ
C═O), 1103 (C6H4Cl), 835 (para disubstituted benzene ring),
1
2-Amino-3-cyano-5,7-dioxo-6-(2-hydroxyethyl)-4-phenyl-1-
739, 698 (mono substituted benzene ring); H NMR (400 MHz,
(4-tolyl)-(3-pyrrolino)[3,4-b](1,4-dihydropyridine) (5d).
mp
DMSO), d, ppm = 7.46–7.52 (5H, m, aromatic), 7.33 (4H, d,
aromatic), 5.68 (2H, s, NH2), 4.51 (1H, s, CH-4), 3.96 (2H, q,
OCH2CH3), 3.76 (2H, m, OCH2CH3), 1.04 (3H, t, OCH2CH3),
0.815 (3H, t, OCH2CH3). Anal. Calcd for C24H22ClN3O4
(Cl = 35.45, mol. wt: 451.90): C, 63.79; H, 4.91; N, 9.30.
Found: C, 63.52; H, 4.52; N, 9.02.
190–192 ꢂC (95% ethanol/water, 2: 1), yield 70%, orange fine
crystals; ir (KBr), υmax, cmꢀ1 = 3621 (OH), 3448, 3320 (NH2),
2183 (CN), 1765, 1712 (two C═O), 1678 (C═C), 824 (para
disubstituted benzene ring), 744, 705 (mono substituted benzene
1
ring); H NMR (600 MHz, DMSO), d, ppm = 7.39–7.27 (9H, m,
aromatic), 5.62 (2H, s, NH2), 4.71 (1H, t, J = 6, OH), 4.60 (1H, s,
CH-4), 3.31 (2H, t, J = 6, CH2–N–), 3.25 (2H, t, J = 6, CH2–O),
2.39 (3H, s, CH3); 13C NMR (150 MHz, DMSO), d, ppm= 20.73
(CH3), 57.62 (CH2), 57.74 (CH2), 60.22 (CH-4), 120 (CN),
(110.4, 127.04, 128.5, 129.0, 129.96, 132.15, 137.41, 138.99,
144.03, 151.70), 163.21 (C═O), 168.28 (C═O); MS (EI): m/z
(ion, %): 400 (M+, 10.4), 91 ([C7H7]+, 100); 77 ([C6H5]+, 45).
Anal. Calcd for C23H20N4O3 (mol. wt: 400.43): C, 68.99; H, 5.03;
N, 13.99. Found: C, 68.75; H, 4.83; N, 13.86.
Diethyl 6-amino-4-(2-chlorophenyl)-5-cyano-1-phenyl-1,4-
dihydropyridine-2,3-dicarboxylate (10d).
(95% ethanol), yield 41%, pale yellow fine crystals; ir (KBr),
max, cmꢀ1 = 3465, 3333 (NH2), 2176 (CN), 1736, 1709 (two
mp 141–143 ꢂC
υ
C═O), 1111 (C6H4Cl), 760 (ortho disubstituted benzene ring);
1H NMR (400 MHz, DMSO), d, ppm = 7.52 (3H, m, aromatic),
7.45 (3H, m, aromatic), 7.37 (2H, m, aromatic), 7.26 (1H, m,
aromatic), 5.58 (2H, s, NH2), 5.11 (1H, s, CH-4), 3.90 (2H, q,
OCH2CH3), 3.79 (2H, m, OCH2CH3), 0.97 (3H, t, OCH2CH3),
0.833 (3H, t, OCH2CH3). Anal. Calcd for C24H22ClN3O4
(Cl = 35.45, mol. wt: 451.90): C, 63.79; H, 4.91; N, 9.30.
Found: C, 63.41; H, 4.23; N, 8.92.
Synthesis of 1,4-dihydropyridine derivatives (10a–o).
General procedure A.
A mixture of the appropriate
anilinofumarate 9a–e (0.01 mol), cinnamonitriles 2a–k (0.01 mol),
and two drops of piperidine in 10 mL of absolute ethanol was
refluxed on a boiling water bath for 6 h. The reaction mixture
was allowed to cool to the room temperature in air. The solid
product, so deposited, was collected by filtration and
recrystallized from the appropriate solvent. In the case of
derivatives 10 k, l, o and after cooling to room temperature, we
then stirred the reaction mixture for 30 min with 10 mL of 30%
ammonium hydroxide solution. The deposited product was
filtered off, washed with cold water, and dried in air before
crystallization.
Diethyl
dihydropyridine-2,3-dicarboxylate (10e).
(95% ethanol), yield 74%, yellow fine crystals; ir (KBr), υmax
6-amino-5-cyano-4-(3-nitrophenyl)-1-phenyl-1,4-
mp 187–188 ꢂC
,
cmꢀ1 = 3438, 3334 (NH2), 2183 (CN), 1741, 1687 (two C═O),
1527, 1347 (NO2), 888, 771, 700 (meta disubstituted benzene
ring); 1H NMR (400 MHz, DMSO), d, ppm = 8.16 (2H, m,
aromatic), 7.81–7.79 (2H, m, aromatic), 7.53 (3H, m, aromatic),
7.36 (2H, m, aromatic), 5.83 (2H, s, NH2), 4.72 (1H, s, CH-4),
3.97 (2H, q, OCH2CH3), 3.78 (2H, m, OCH2CH3), 1.05 (3H, t,
OCH2CH3), 0.80 (3H, t, OCH2CH3). Anal. Calcd for
C24H22N4O6 (mol. wt: 462.45): C, 62.33; H, 4.79; N, 12.12.
Found: C, 61.91; H, 4.90; N, 12.10.
General procedure B.
The procedure for a mixture of the
anilinofumarate 9a (0.01 mol), appropriate aldehyde 7a, c, d
(0.01 mol), malononitrile 8 (0.01 mol), and two drops of piperidine
in 10 mL of absolute ethanol was the same as in procedure A.
Diethyl 6-amino-5-cyano-1,4-diphenyl-1,4-dihydropyridine-2,3-
dicarboxylate (10a). mp 174–175 ꢂC (95% ethanol), yield 80%,
yellow fine crystals; ir (KBr), υmax, cmꢀ1 = 3471, 3324 (NH2),
2180 (CN), 1738, 1712 (two C═O), 760, 694 (mono substituted
Diethyl
6-amino-5-cyano-1,4-bis(4-methoxyphenyl)-1,4-
dihydropyridine-2,3-dicarboxylate (10f).
mp 178–179 ꢂC
(95% ethanol), yield 77%, yellow fine crystals; ir (KBr), υmax
,
cmꢀ1 = 3450, 3315 (NH2), 2181 (CN), 1743, 1692 (two C═O),
1
1238, 1020 (OCH3), 825 (para disubstituted benzene ring); H
NMR (400 MHz, DMSO), d, ppm = 7.22 [4H, dd, J = (8.48, 2),
aromatic], 7.03 (2H, d, J = 8.48, aromatic), 6.95 (2H, d,
J = 8.48, aromatic), 5.50 (2H, s, NH2), 4.40 (1H, s, CH-4),
3.97 (2H, q, OCH2CH3), 3.77 (2H, m, OCH2CH3), 3.80 (3H,
s, OCH3), 3.75 (3H, s, OCH3), 1.06 (3H, t, OCH2CH3), 0.87
(3H, t, OCH2CH3). Anal. Calcd for C26H27N3O6 (mol. wt:
477.51): C, 65.40; H, 5.70; N, 8.80. Found: C, 65.39; H, 5.35;
N, 8.57.
1
benzene ring); H NMR (400 MHz, DMSO), d, ppm= 7.52–7.28
(10H, m, aromatic), 5.64 (2H, s, NH2), 4.51 (1H, s, CH-4), 3.97
(2H, q, OCH2CH3), 3.80 (2H, m, OCH2CH3), 1.05 (3H, t,
OCH2CH3), 0.83 (3H, t, OCH2CH3); MS (EI): m/z (ion, %): 417
(M+, 4.6), 77 ([C6H5]+, 100). Anal. Calcd for C24H23N3O4 (mol.
wt: 417.46): C, 69.05; H, 5.55; N, 10.07. Found: C, 68.96; H,
5.20; N, 9.74.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

July 2014
Enaminones in Heterocyclic Syntheses
1083
Diethyl 6-amino-5-cyano-4-phenyl-1-p-tolyl-1,4-dihydropyridine-
58.52 (OCH2), 60.23 (OCH2), 61.16 (OCH2), 77.99 (CH-4),
(106.49, 126.12, 127.28, 128.04, 129.62, 129.95, 130.41,
135.08, 141.16, 147.02, 151.95), 162.50 (C═O), 164.70
(C═O), 168.37 (C═O). Anal. Calcd for C26H28N2O6 (mol. wt:
464.51): C, 67.23; H, 6.08; N, 6.03. Found: C, 67.02; H, 5.88;
N, 5.98.
2,3-dicarboxylate (10g). mp 188–190 ꢂC (95% ethanol/water, 3:1),
yield 67%, pale yellow fine crystals; ir (KBr), υmax, cmꢀ1 = 3472,
3313 (NH2), 2188 (CN), 1746, 1706 (two C═O), 827 (para
disubstituted benzene ring), 696, 749 (mono substituted benzene
1
ring); H NMR (400 MHz, DMSO), d, ppm = 7.40–7.20 (9H, m,
Triethyl 6-amino-4-(3-nitrophenyl)-1-phenyl-1,4-dihydropyridine-
2,3,5-tricarboxylate (10l). mp 139–140 ꢂC (95% ethanol), yield
75%, yellow fine crystals; ir (KBr), υmax, cmꢀ1 = 3465, 3272
(NH2), 1740, 1707, 1671 (three C═O), 1522, 1344 (NO2), 855,
aromatic), 5.59 (2H, s, NH2), 4.49 (1H, s, CH-4), 3.96 (2H, q,
OCH2CH3), 3.79 (2H, m, OCH2CH3), 2.35 (3H, s, CH3), 1.04
(3H, t, OCH2CH3), 0.86 (3H, t, OCH2CH3). Anal. Calcd for
C25H25N3O4 (mol. wt: 431.48): C, 69.59; H, 5.84; N, 9.74.
Found: C, 69.46; H, 5.66; N, 9.40.
1
785, 702 (meta disubstituted benzene ring); H NMR (600MHz,
Diethyl 6-amino-1-(4-bromophenyl)-5-cyano-4-phenyl-1,4-
DMSO), d, ppm = 8.17 (1H, m, aromatic), 8.16 (1H, m, aromatic),
7.80 (1H, m, aromatic), 7.686 (1H, t, J=7.8, aromatic), 7.591–7.419
(5H, m, aromatic), 7.00 (2H, s, br, NH2), 5.0 (1H, s, CH-4),
4.01–3.96 (4H, m, 2OCH2CH3), 3.80 (2H, m, OCH2CH3), 1.10
(3H, t, OCH2CH3), 1.06 (3H, t, OCH2CH3), 0.834 (3H, t,
OCH2CH3); 13C NMR (150 MHz, DMSO), d, ppm = 13.03
(CH3), 13.63 (CH3), 14.13 (CH3), 58.72 (OCH2), 60.47 (OCH2),
61.35 (OCH2), 77.23 (CH-4), (105.36, 121.32, 121.92, 129.71,
129.92, 130.18, 130.44, 134.02, 134.73, 141.96, 147.35, 149.25,
152.05), 162.17 (C═O), 164.33 (C═O), 167.99 (C═O). Anal.
Calcd for C26H27N3O8 (mol. wt: 509.51): C, 61.29; H, 5.34; N,
8.25. Found: C, 61.09; H, 5.64; N, 8.27.
dihydropyridine-2,3-dicarboxylate (10h).
(95% ethanol), yield 93%, white fine crystals; ir (KBr), υmax
mp 187–188 ꢂC
,
cmꢀ1 = 3456, 3323 (NH2), 2182 (CN), 1743, 1698 (two C═O),
831 (para disubstituted benzene ring); 1H NMR (600 MHz,
DMSO), d, ppm = 7.71 (2H, d, aromatic), 7.39 (2H, t, aromatic),
7.26 (5H, m, aromatic), 5.78 (2H, s, NH2), 4.48 (1H, s, CH-4),
3.96 (2H, q, OCH2CH3), 3.86 (2H, m, OCH2CH3), 1.03 (3H, t,
OCH2CH3), 0.88 (3H, t, OCH2CH3); 13C NMR (150 MHz,
DMSO), d, ppm = 13.01 (CH3), 13.59 (CH3), 59.43 (OCH2),
60.38 (OCH2), 61.45 (CH-4), 120.86 (CN), (104.58, 123.27,
126.78, 126.86, 128.61, 132.50, 132.54, 134.59, 141.20,
145.39, 150.55), 162.27 (C═O), 164.35 (C═O). Anal. Calcd for
C24H22BrN3O4 (Br = 79.9, mol. wt: 496.35): C, 58.07; H, 4.47;
N, 8.47. Found: C, 57.80; H, 4.87; N, 8.21.
Triethyl 4-(4-acetamidophenyl)-6-amino-1-(4-bromophenyl)-
1,4-dihydropyridine-2,3,5-tricarboxylate (10m). mp 195–196 ꢂC
(95% ethanol), yield 66%; yellow crystals; ir (KBr), υmax
,
Diethyl 6-amino-4-(3-bromophenyl)-1-(4-bromophenyl)-5-
cmꢀ1 = 3410, 3400, 3367, 3293 (NH2, NH), 1739, 1677,
1669 (three ester C═O and acetamido C═O), 825 (para
disubstituted benzene ring); 1H NMR (300 MHz, CDCl3), d,
ppm = 8.78 (1H, s, br, NH), 7.62–7.27 (8H, m, aromatic),
6.14 (2H, s, br, NH2), 4.98 (1H, s, CH-4), 4.11–3.95 (4H,
m, 2OCH2CH3), 3.90 (2H, m, OCH2CH3), 2.14 (3H, s,
COCH3), 1.20 (3H, t, OCH2CH3), 1.179 (3H, t, OCH2CH3),
0.99 (3H, t, OCH2CH3). Anal. Calcd for C28H30BrN3O7
(Br = 79.9, mol. wt: 600.46): C, 56.01; H, 5.04; N, 7.00.
Found: C, 55.86; H, 5.01; N, 6.85.
cyano-1,4-dihydropyridine-2,3-dicarboxylate
(10i).
mp
183–185 ꢂC (95% ethanol), yield 75%, white fine crystals; ir
(KBr), υmax, cmꢀ1 = 3389, 3325 (NH2), 2188 (CN), 1742, 1703
(two C═O), 828 (para disubstituted benzene ring), 862, 772, 690
(meta disubstituted benzene ring); MS (EI): m/z (ion, %): 575
([M + 2]+, 79Br and 81Br, 12.1), 157 ([C6H841Br]+, 44.7), 155
([C6H479Br]+, 40.7), 81 (81Br+, 14.1), 79 (79Br+, 13.6), 76
([C6H4]+, 100). Anal. Calcd for C24H21Br2N3O4 (Br = 79.9, mol.
wt: 575.25): C, 50.11; H, 3.68; N, 7.30. Found: C, 49.88; H,
3.77; N, 7.12.
Triethyl 6-amino-4-(2-bromophenyl)-1-(4-bromophenyl)-1,4-
dihydropyridine-2,3,5-tricarboxylate (10n).
(95% ethanol), yield 70%; yellow crystals; ir (KBr), υmax
mp 128–130 ꢂC
Diethyl 6-amino-1-(4-chlorophenyl)-5-cyano-4-phenyl-1,4-
dihydropyridine-2,3-dicarboxylate (10j).
(95% ethanol), yield 80%, pale yellow fine crystals; ir (KBr),
max, cmꢀ1 = 3457, 3325 (NH2), 2182 (CN), 1742, 1701 (two
mp 178–179 ꢂC
,
cmꢀ1 = 3451, 3251 (NH2), 1735, 1702, 1667 (three C═O), 829
(para disubstituted benzene ring), 755 (ortho disubstituted
benzene ring); MS (EI): m/z (ion, %): 622 ([M + 2]+, 79Br and
81Br, 9.7), 620 (M+, 79Br and 79Br, 6.9), 157 ([C6H841Br]+,
25.5), 155 ([C6H479Br]+, 22.1), 81 (81Br+, 8.3), 79 (79Br+, 8.3),
76 ([C6H4]+, 46.2). Anal. Calcd for C26H26Br2N2O6 (Br = 79.9,
mol. wt: 622.30): C, 50.18; H, 4.21; N, 4.50. Found: C, 50.27;
H, 4.02; N, 4.63.
υ
C═O), 1090 (C6H4Cl), 833 (para disubstituted benzene ring);
1H NMR (400 MHz, DMSO), d, ppm = 7.57 (2H, d, aromatic),
7.41–7.27 (7H, m, aromatic), 5.78 (2H, s, NH2), 4.48 (1H, s,
CH-4), 3.95 (2H, q, OCH2CH3), 3.80 (2H, m, OCH2CH3), 1.03
(3H, t, OCH2CH3), 0.88 (3H, t, OCH2CH3); 13C NMR
(100 MHz, DMSO), d, ppm = 13.6 (CH3), 14.17 (CH3), 60.03
(OCH2), 60.95 (OCH2), 62.02 (CH-4), 121.43 (CN), (105.17,
127.37, 127.44, 129.19, 130.12, 132.86, 134.72, 135.17,
141.83, 145.98, 151.18), 162.85 (C═O), 164.94 (C═O). Anal.
Calcd for C24H22ClN3O4 (Cl = 35.45, mol. wt: 451.90): C,
63.79; H, 4.91; N, 9.30. Found: C, 63.78; H, 4.48; N, 9.10.
Diethyl 6-amino-5-carbamoyl-1,4-diphenyl-1,4-dihydropyridine-
2,3-dicarboxylate (10o).
mp 202–203 ꢂC (95% ethanol), yield
79%, yellow fine crystals; ir (KBr), υmax, cmꢀ1 = 3444, 3369,
3142 (NH2), 1728, 1700 (two C═O, ester), 1661 (C═O, amide),
1
757, 694 (mono substituted benzene ring); H NMR (600MHz,
DMSO), d, ppm = 7.50–7.20 (10H, m, aromatic), 7.08 (2H, s, br,
CONH2), 6.48 (2H, s, NH2), 4.81 (1H, s, CH-4), 4.01 (2H, m,
OCH2CH3), 3.75 (2H, m, OCH2CH3), 1.13 (3H, t, OCH2CH3),
0.80 (3H, t, OCH2CH3); 13C NMR (150MHz, DMSO), d,
ppm = 13.03 (CH3), 13.73 (CH3), 60.08 (OCH2), 60.99 (OCH2),
79.94 (CH-4), (105.7, 126.18, 127.42, 128.02, 129.37, 129.6,
130.43, 135.58, 141.1, 146.67, 150.09), 162.69 (C═O), 164.89
(C═O), 171.23 (CONH2). Anal. Calcd for C24H25N3O5 (mol.
wt: 435.47): C, 66.19; H, 5.79; N, 9.65. Found: C, 65.90; H, 5.52;
N, 9.54.
Triethyl
tricarboxylate (10k).
6-amino-1,4-diphenyl-1,4-dihydropyridine-2,3,5-
mp 129–130 ꢂC (95% ethanol/water,
1:1), yield 50%, white needles; ir (KBr), υmax, cmꢀ1 = 3390,
3276 (NH2), 1736, 1709, 1700 (three C═O), 751, 696 (mono
substituted benzene ring); 1H NMR (600 MHz, DMSO), d,
ppm = 7.55–7.18 (10H, m, aromatic), 6.81 (2H, s, br, NH2),
4.89 (1H, s, CH-4), 4.01–3.98 (4H, m, 2OCH2CH3), 3.75 (2H,
m, OCH2CH3), 1.10 (3H, t, OCH2CH3), 1.07 (3H, t,
OCH2CH3), 0.821 (3H, t, OCH2CH3); 13C NMR (150 MHz,
DMSO), d, ppm = 13.04 (CH3), 13.70 (CH3), 14.23 (CH3),
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

1084
M. M. Mashaly, S. R. El-Gogary, and T. R. Kosbar
Vol 51
Synthesis of [tetraethyl 2,20-(1,4-phenylene)bis(azanediyl)]
difumarate (bis enamino ester) (14).
([H2NCꢁCCN]+, 100), 65 ([HNCꢁCCN]+, 44.4). Anal. Calcd for
C42H40N6O8 (mol. wt: 756.80): C, 66.66; H, 5.33; N, 11.10;
Found: C, 66.37; H, 4.99; N, 10.95.
General procedure AA.
A mixture of diethyl oxalacetate
Tetraethyl 1,10-(1,4-phenylene)bis(6-amino-4-(2-bromophenyl)-
sodium salt 12 (0.02 mol), p-phenylenediamine 11 (0.01 mol),
and 10 mL of glacial acetic acid was heated over a water bath at
40–50 ꢂC for 8 h, allowed to cool to room temperature, and then
poured into ice water, and the solution was adjusted to pH = 8
with 35% sodium hydroxide solution. The resulting mixture was
extracted with methylene chloride (3 ꢃ 20 mL). The combined
methylene chloride extracts were washed sequentially with
0.5 N HCl (4 ꢃ 20 mL) and 0.5 N NaOH (4 ꢃ 20 mL). The
separated organic phase was washed with water and dried with
anhydrous Na2SO4. The solvent was removed under reduced
pressure to give an oily product, which was solidified after
trituration with petroleum ether (40–60 ꢂC). Yield: 16%; orange
powder, mp 73–75 ꢂC (petroleum ether 40–60 ꢂC: diethyl ether,
3: 1); ir (KBr), υmax, cmꢀ1 = 3278 (two NH), 1736, 1672 (four
C═O), 813 (para disubstituted benzene ring); 1H NMR
(300 MHz, DMSO), d, ppm = 9.59 (2H, s, 2NH), 6.90 (4H, s,
aromatic), 5.21 (2H, s, 2CH, olefinic), 4.15–4.08 (8H, m,
4OCH2CH3), 1.21 (6H, t, 2OCH2CH3), 1.072 (6H, t, 2OCH2CH3).
Anal. Calcd for C22H28N2O8 (mol. wt: 448.47): C, 58.92; H, 6.29;
N, 6.25. Found: C, 58.51; H, 5.88; N, 5.98.
5-cyano-1,4-dihydro-pyridine-2,3-dicarboxylate) (15b).
mp
245–246 ꢂC (95% ethanol), yield 55%, pale yellow crystals; ir
(KBr), υmax, cmꢀ1 = 3432, 3333 (two NH2), 2173 (two CN),
1743, 1709 (four C═O), 818 (para disubstituted benzene ring),
739 (ortho disubstituted benzene ring); 1H NMR (300MHz,
CDCl3), d, ppm = 7.60–7.13 (12H, m, aromatic), 5.32 (2H, s,
2CH-4), 4.15 (4H, s, 2NH2), 4.03–3.96 (8H, q, 4OCH2CH3), 1.18
(6H, t, 2OCH2CH3), 1.07 (6H, t, 2OCH2CH3). Anal. Calcd for
C42H38Br2N6O8 (Br= 79.9, mol. wt: 914.59): C, 55.16; H, 4.19;
N, 9.19. Found: C, 54.88; H, 4.23; N, 9.24.
Hexaethyl
dihydropyridine-2,3,5-tricarboxylate) (15c).
1,10-(1,4-phenylene)bis(6-amino-4-phenyl-1,4-
mp 128–129 ꢂC
(95% ethanol/water 2:1), yield 60%, pale yellow crystals; ir
(KBr), υmax, cmꢀ1 = 3535, 3344 (two NH2); 1735, 1729, 1708 (six
C═O), 858 (para disubstituted benzene ring), 759, 697 (mono
substituted benzene ring); 1H NMR (600 MHz, DMSO), d,
ppm = 7.65 (2H, m, aromatic), 7.56 (4H, m, aromatic), 7.43 (2H,
m, aromatic), 7.34 (4H, m, aromatic), 7.20 (2H, m, aromatic),
6.78 (4H, s, 2NH2), 4.90 (2H, s, 2CH-4), 4.0 (8H, m,
4OCH2CH3), 3.84 (4H, m, 2OCH2CH3), 1.12 (6H, t,
2OCH2CH3), 1.04 (6H, t, 2OCH2CH3), 0.77 (6H, t, 2OCH2CH3);
13C NMR (150 MHz, DMSO), d, ppm = 13.27 (2CH3), 13.72
(2CH3), 14.31 (2CH3), 60.37 (2OCH2), 61.63 (2OCH2), 63.14
(2OCH2), 79.26 (2CH-4), (106.03, 107.32, 110.87, 127.14,
127.30, 128.13, 128.52, 129.81, 131.29, 134.96, 136.72, 137.11,
140.77, 146.62, 151.72, 157.98, 159.03, 159.82), 162.43 (2C═O),
163.17 (2C═O), 164.62 (2C═O). Anal. Calcd for C46H50N4O12
(mol. wt: 850.91): C, 64.93; H, 5.92; N, 6.58. Found: C, 64.82;
H, 5.77; N, 6.68.
General procedure BB. A mixture of diethyl oxalacetate 13
(0.02 mol) and p-phenylenediamine 11 (0.01 mol) in 20 mL of
absolute ethanol was refluxed over a boiling water bath for 6 h,
allowed to cool to room temperature, and then poured into ice
water. The resulting mixture was extracted with methylene
chloride (3 ꢃ 20 mL). The combined methylene chloride extracts
were washed with water (3 ꢃ 30 mL). The separated organic
phase was dried with anhydrous Na2SO4, and then the
procedure was the same as in procedure AA to give 14 (mp,
mixture mp, TLC, and IR), yield 44%.
Synthesis of 1,10-(1,4-phenylene)bis(1,4-dihydropyridine)
derivatives (15a–c).
General procedure A. A mixture of the bis enamino ester 14
(0.001mol), the appropriate cinnamonitrile 2a, g, l (0.002mol), and
two drops of piperidine in 10mL of absolute ethanol was heated
under reflux on a boiling water bath for 6 h. The reaction mixture
was allowed to cool overnight in the freezer. The solid product, so
deposited, was collected by filtration and recrystallized from the
appropriate solvent.
Acknowledgments. This work is dedicated to Prof. Dr M. Hammouda,
Professor of Organic Chemistry, Faculty of Science at Mansoura,
Mansoura University, Egypt. We are grateful to Prof. Dr S. N. Aiad,
Professor of Organic Chemistry, Faculty of Science, King Abd-Elaziz
University, Jeddah, KSA, for his help in performing the
spectral analyses.
General procedure B. The procedure for a mixture of the
bis enamino ester 14 (0.001 mol), the appropriate aldehyde 7a,
d (0.002 mol), malononitrile 8 (or ethyl cyanoacetate 16)
(0.002 mol), and two drops of piperidine in 10 mL of absolute
ethanol was the same as in procedure A.
REFERENCES AND NOTES
[1] Majumdar, K. C.; Samanta, S.; Chattopadhyay, B. Tetrahedron
Lett 2008, 49, 7213; and references cited therein.
Tetraethyl 1,10-(1,4-phenylene)bis(6-amino-5-cyano-4-phenyl-1,4-
mp 239–240 ꢂC (95%
[2] Kim, K. S.; Zhang, L.; Schmidt, R.; Cai, Z.; Wei, D.;
Williams, D. K.; Lombardo, L. J.; Trainor, G. L.; Xie, D. L.; Zhang, Y.;
An, Y.; Sack, J. S.; Tokarski, J. S.; Darienzo, C.; Kamath, A.; Marathe,
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Gullo-Brown, J.; Manne, V.; Hunt, J. T.; Fargn, J. J Med Chem 2008,
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[3] Palko, R.; Egyed, O.; Bombicz, P.; Riedl, Z.; Hajos, G.
Tetrahedron 2008, 64, 10375; and references cited therein.
[4] Paget, S. D.; Boggs, C. M.; Foleno, B. D.; Goldschmidt, R.
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K. B. M. J. Bioorg Med Chem Lett 2006, 16, 4537; and references cited
therein.
dihydropyridine-2,3-dicarboxylate) (15a).
ethanol/water, 2: 1), yield 70%, pale yellow crystals; ir (KBr),
max, cmꢀ1 = 3468, 3318 (two NH2), 2189 (two CN), 1738, 1700
υ
(four C═O), 823 (para disubstituted benzene ring), 760, 697
(mono substituted benzene ring); 1H NMR (600MHz, DMSO), d,
ppm = 7.50 (4H, m, aromatic), 7.39 (4H, m, aromatic), 7.31 (4H,
m, aromatic), 7.27 (2H, m, aromatic), 6.0 (4H, s, 2NH2), 4.51 (2H,
s, 2CH-4), 3.96 (4H, q, 2OCH2CH3), 3.84 (4H, q, 2OCH2CH3),
1.145 (6H, t, 2OCH2CH3), 1.027 (6H, t, 2OCH2CH3); 13C NMR
(150 MHz, DMSO), d, ppm = 13.28 (2CH3), 13.63 (2CH3), 58.09
(2OCH2), 60.35 (2OCH2), 61.53 (2CH-4), 121.11 (2CN), (104.1,
126.85, 126.92, 127.0, 128.58, 131.97, 136.29, 136.33, 140.97,
145.69, 145.75, 150.49, 150.72), 162.18 (2C═O), 164.46
(2C═O); MS (EI): m/z (ion, %): 77 (C6H+5, 63.9), 66
[5] Bandger, B. P.; More, P. E.; Kamble, V. T.; Totre, J. V.
Arkivoc 2008, xv, 1; and references cited therein.
[6] Kumar, S.; Sharma, P.; Kapoor, K. K.; Hundal, M. S.
Tetrahedron 2008, 64, 536; and references cited therein.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

July 2014
Enaminones in Heterocyclic Syntheses
1085
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet