Synthesis of some new unsymmetrically substituted 1,4-dihydropyridines

Article abstract of DOI:10.1515/znb-2006-0110

A series of some new 3,5-unsymmetrically substituted 1,4-dihydropyridines have been synthesized, which have ethoxycarbonyl and acetyl groups on 3- and 5-positions, respectively. A three-step procedure has been examined to increase the yield of the desired products, by suppressing the formation of the symmetrically substituted 3,5-diacetyl-1,4-dihydropyridines and 3,5-diethoxycarbonyl-1,4-dihydropyridines.

Full text of DOI:10.1515/znb-2006-0110

Synthesis of Some New Unsymmetrically Substituted
1,4-Dihydropyridines
Hamid R. Memariana, Masumeh Abdoli-Senejania, and Dietrich Do¨ppb
a University of Isfahan, Faculty of Science, Department of Chemistry, 81746-73441, Isfahan, Iran
b Universita¨t Duisburg-Essen, Organische Chemie, D-47057 Duisburg, Germany
Reprint requests to Prof. H. R. Memarian. Tel: +98-311-793 2707. Fax: +98-311-668 9732.
E-mail: memarian@sci.ui.ac.ir
Z. Naturforsch. 61b, 50 – 56 (2006); received August 23, 2005
A series of some new 3,5-unsymmetrically substituted 1,4-dihydropyridines have been synthe-
sized, which have ethoxycarbonyl and acetyl groups on 3- and 5-positions, respectively. A three-step
procedure has been examined to increase the yield of the desired products, by suppressing the for-
mation of the symmetrically substituted 3,5-diacetyl-1,4-dihydropyridines and 3,5-diethoxycarbonyl-
1,4-dihydropyridines.
Key words: 1,4-Dihydropyridines, Heterocycles, 2-Benzylidene-1,3-dicarbonyl Compounds
Introduction
devoted to the preparation of unsymmetrical 1,4-di-
hydropyridine-3,5-diesters, such as nitrendipine [10],
felodipine [11, 12] and others [13– 16]. Some studies
have also been devoted to the preparation of unsym-
metrical 1,4-dihydropyridines, in which an alkoxycar-
bonyl (ester) group and a alkanoyl (keto) group are
located on 3- and 5-positions, respectively [14, 17 –
21]. In the course of our studies on the chemistry
of 1,4-dihydropyridines, especially their photochemi-
cal reactions, we have prepared various 1,4-dihydro-
pyridine-3,5-diesters, known as Hantzsch dihydropy-
ridine and also 3,5-diacetyl-1,4-dihydropyridines and
investigated their photooxidation and oxidation to elu-
cidate the effect of nature and type of 4-substituent and
also the presence of ester or keto groups on 3- and 5-
position on the rate of reaction [22, 23]. In continua-
tion of these studies we were interested in the synthe-
sis of 5-acyl-1,4-dihydropyridine-3-carboxylates, with
the general structure 1. The aim of this work was to
find out the best procedure for the preparation of these
compounds by suppressing the formation of undesired
by-products.
The preparation of symmetrically substituted 1,4-di-
hydropyridines by classical Hantzsch synthesis [1], in-
volving the condensation of an aldehyde, ammonia and
acetoacetic ester or other 1,3-dicarbonyl compounds,
was modified by Beyer [2], Knoevenagel [3] to allow
the preparation of unsymmetrical 1,4-dihydropyridines
by condensation of an alkylidene or arylidene 1,3-
dicarbonyl compound with a β-amino-a,β-unsaturat-
ed carbonyl compound, which is known as Hantzsch-
Beyer synthesis. Symmetrically substituted 1,4-di-
hydropyridine drugs are achiral molecules, but when
the ester groups bear different alkoxy groups, a chiral
center is established in the 4-position of the dihydropy-
ridine ring. Chiral 1,4-dihydropyridines [4 – 6] have
been employed as synthetic intermediates for a wide
variety of compounds such as natural products [7],
calcium channel blockers [8], and NADH models [9].
Nifedipine, with symmetrical substituents on its dihy-
dropyridine ring, is achiral; while second generation
derivatives, such as felodipine, nitrendipine, nivadip-
ine, nimodipine, nicardipine, and amoldipine, with un-
symmetrical substitution (different ester groups on 3-
and 5-positions), are chiral. Because of the impor-
tance of C-4 chirality with respect to the pharmacolog-
ical activity of 4-aryl-1,4-dihydropyridines, the avail-
ability of asymmetric synthesis of this class of com-
pounds is highly desirable. Various studies have been
c
0932–0776 / 06 / 0100–0050 $ 06.00 ꢀ 2006 Verlag der Zeitschrift fu¨r Naturforschung, Tu¨bingen · http://znaturforsch.com
Unauthenticated
Download Date | 5/5/16 7:05 AM

H. R. Memarian et al. · Synthesis of Unsymmetrical 1,4-Dihydropyridines
51
Table 1. Isolated yields of 4a – e and 1a – e.
Results and Discussion
R-Substituent
4
1
The Hantzsch dihydropyridine synthesis provides
normally a convenient route to the preparation of all
symmetrical dihydropyridines. Although the mecha-
nism for the Hantzsch dihydropyridine synthesis has
been followed by NMR [24], the known mechanism
for this reaction consists of three reaction paths, which
occur simultaneously (Scheme 1): a) the Knoevenagel
condensation between aliphatic or aromatic aldehyde
with a 1,3-dicarbonyl compound yields an alkylidene-
or arylidene-1,3-dicarbonyl compound (path 1); b) the
condensation between ammonia and a 1,3-dicarbonyl
compound leading to the β-amino-a,β-unsaturated
carbonyl compound (path 2); c) the reaction between
both condensation products leading to the formation of
a 1,4-dihydropyridine (path 3).
Yield (%) Time (h) Yield (%) Time (h)
2-NO2-C6H4
3-NO2-C6H4
3,4-(CH3O)2-C6H3
5-methyl-2-furyl
3-(CH3O)-4-(OH)-C6H3
a
b
c
d
e
90
70
75
72
65
0.75
1.5
5
1.5
2
a
b
c
d
e
42
40
45
40
34
13
15
20
15
15
ter, therefore, this procedure has been chosen for the
preparation of all unsymmetrical dihydropyridines in
this work. The preparation of benzylidene intermedi-
ates was successful only in the cases of 4a – e, which
were isolated and fully characterized. But in the cases
of 4f – l, since the reaction in path 4 was not completed
and the yields were low, ethyl 3-aminocrotonate (5)
was added to the reaction mixture of path 4 after it had
been refluxed before for 4 h. Table 1 shows the yields
of 4a – e and 1a – e.
Formation of symmetrically substituted dihydropy-
ridines, namely 1,4-dihydropyridine-3,5-diester 6 and
3,5-diacetyl-1,4-dihydropyridine 7 has been observed
in some of our reactions (Table 2). These products can
be obtained by a retro Michael process of the reac-
tion intermediate followed by condensation of enam-
inoester 5 or enaminoketone 9 with the 2-benzylidene-
1,3-dicarbonyl compound 4 or 8 to the symmetrical di-
hydropyridines. Formation of symmetrical dihydropy-
ridine ester has been observed during the synthesis
of unsymmetrical dihydropyridine ester [16]. The au-
thors explain that the transformation of the benzylidene
alkyl ester (with bulky substituent) to the benzylidene
methyl ester according to the retro Michael process fa-
vors the formation of less hindered compound, which
leads to the formation of symmetrical dihydropyridine
methyl ester.
Scheme 1.
For the formation of 1,4-dihydropyridines unsym-
metrically substituted at 3- and 5-positions it is impor-
tant to select one of the two different 1,3-dicarbonyl
compounds for use in path 1 or path 2 to increase the
yields of both reaction paths and especially the yield of
dihydropyridine in path 3. Since the formation of sym-
1
IR, H NMR, MS and UV data gave useful infor-
metrical dihydropyridines has been observed during mation about the structural assignment of unsymmet-
the reaction path 3 [10, 16], we have tried to synthesise rical 1,4-dihydropyridines (1a – l). This was supported
some new and also some known 1,4-dihydropyridines by the following observations: a) A NH and two dif-
which have a carboethoxy group and an acetyl group ferent CO absorption bands are found in the IR spectra
in 3- and 5-positions, respectively. It should be noted corresponding to the acetyl and ester groups, respec-
that in many reports on the preparation of unsym- tively, and also the presence of dihydropyridine ring.
metrical 1,4-dihydropyridines, the formation of sym- b) The 1H NMR spectra show two different absorptions
metrical dihydropyridines was not mentioned [10– around δ = 2.4 ppm for the CH3CO group as singlet
21]. At first, as a test experiment, we have tried and also triplet around 1.3 ppm for the methyl group
the synthesise ethyl 5-acetyl-2,6-dimethyl-4-phenyl- of the CO2CH2CH3 moiety. The interesting point is
1,4-dihydropyridine-3-carboxylate (1f) in two differ- that due to presence of a chiral center at C-4, the CH2
ent ways (Scheme 2).
moiety of the CO2CH2CH3 group is diastereotopic and
The data shown in Scheme 2 indicated that the re- appears as two quartet of quartets and in most cases
sults obtained according to the procedure A are bet- as two partially overlapped quartet of quartets. c) The
Unauthenticated
Download Date | 5/5/16 7:05 AM

52
H. R. Memarian et al. · Synthesis of Unsymmetrical 1,4-Dihydropyridines
Scheme 2.
Unauthenticated
Download Date | 5/5/16 7:05 AM

H. R. Memarian et al. · Synthesis of Unsymmetrical 1,4-Dihydropyridines
53
Table 2. Isolated yields of
products obtained by prepa-
ration of unsymmetrical dihy-
dropyridines.
R
Unsymmetrical
DHP (%)
Symmetrical
DHP-Ester (%)
Symmetrical
DHP-Keto (%)
Time
(h)
13
15
20
15
15
14
13
12
16
15
14
17
2-NO2-C6H4
3-NO2-C6H4
3,4-(CH3O)2-C6H3
5-Methyl-2-furyl
3-(CH3O)-4-(OH)-C6H3 1e
1a
42
40
45
40
34
34
24
32
27
25
30
32
6a
trace
–
trace
5
5
trace
15
–
–
–
1b
1c
1d
6c
6d
6e
6f
7d
7
–
–
C6H5
1f
1g
1h
1i
4-Cl-C6H4
4-CH3-C6H4
3-Pyridyl
4-Pyridyl
2-Furyl
6g
7g
7h
4
23
–
6i
6j
6k
6l
22
14
trace
trace
–
–
–
–
1j
1k
1l
2-Thienyl
mass spectra show molecule ion peaks of each com- 1662 (CO), 1525 and 1351 (NO2) cm−1. – MS (EI,
70 eV): m/z (%) = 233(2) [M+], 191(5) [M+-COCH2],
pound and also several peaks due to characteristic frag-
mentation. d) The UV spectra show characteristic ab-
sorption above 300 nm for the dihydropyridine ring.
187(58) [M+-NO2], 173(44), 149(59), 148(43), 131(66),
103(79), 102(28).
3-(3-Nitrobenzylidene)pentane-2,4-dione (4b): Recrystal-
lized from petroleum ether/ethyl acetate (5 : 1) – M. p.
Experimental Section
95 – 97 ◦C. – UV/vis (MeOH): λmax(lgε) = 347 (3.28),
Melting points were determined using a Stuart Scientific
SMP2 capillary apparatus and are uncorrected. IR spectra
were recorded from KBr discs on Philips PU 9716. 1H NMR
spectra were recorded with a Bruker DRX 500 (500 MHz)
instrument. They are reported as follows: Chemical shifts δ,
[multiplicity, number of protons, coupling constants J (Hz),
and assignment]. Mass spectra were obtained on Sisonn,
TRIO 1000, EI-mode at 70 eV. Elemental analysis were run
on Euro EA-CHNS analyzer. UV spectra were measured on
a Shimadzu UV-160 spectrometer. Preparative layer chro-
matography (PLC) was carried out on 20 × 20 cm2 plates,
coated with a 1 mm layer of Merck silica gel PF254, prepared
by applying the silica as slurry and drying in air.
˜
230 nm (3.69) – IR (KBr): ν = 1708 and 1667 (CO),
1528 and 1359 (NO2) cm−1. – 1H NMR (500 MHz,
CDCl3): δ = 2.36 (s, 3H, CH3), 2.51 (s, 3H, CH3), 7.53 (s,
1H, vinylic H), 7.64 (m, 1H, 5’-H), 7.76 (d, 1H, J =
7.8 Hz, 6’-H), 8.30 (mc, 2H, 2’-H and 4’-H). – MS (EI,
70 eV): m/z (%) = 233(84) [M+], 218(88) [M+-Me],
216(96) [M+-OH], 191(66) [M+-COCH2], 190(64) [M+-
Ac], 187(16) [M+-NO2], 186(43), 176(100), 144(41),
131(84), 118(38), 101(88). – C12H11NO4 (233.23): calcd.
C 61.80, H 4.75, N 6.01, O 27.44; found C 61.91, H 4.71,
N 6.08.
3-(3,4-Dimethoxybenzylidene)pentane-2,4-dione (4c):
Recrystallized from petroleum ether/ethyl acetate (10 : 1)
– M. p. 101 – 102 ◦C. – UV/vis (MeOH): λmax(lgε) =
General procedure for the preparation of benzylidene inter-
mediates 4a – e [25]
˜
336 (4.40), 247(4.20), 226 nm (4.15). – IR (KBr): ν = 1714
and 1678 (CO) cm−1. – 1H NMR (500 MHz, CDCl3):
δ = 2.36 (s, 3H, CH3), 2.45 (s, 3H, CH3), 3.90 (s, 3H,
OCH3), 3.96 (s, 3H, OCH3), 6.91 (d, 1H, J = 8.3 Hz,
5’-H), 6.96 (d, 1H, J = 2.0 Hz, 2’-H), 7.07 (dd, 1H, J =
8.3 Hz and 2.0 Hz, 6’-H), 7.46 (s, 1H, vinylic H). –
MS (EI, 70 eV): m/z (%) = 248(92) [M+], 247(63) [M+-H],
233(89) [M+-Me], 217(83) [M+-OMe], 205(77) [M+-Ac],
191(100), 163(75), 148(58). – C14H16O4 (248.28): calcd.
C 67.73, H 6.50, O 25.78; found C 67.73, H 6.45.
A mixture of the appropriate benzaldehyde (1 mmol)
and acetylacetone (0.110 g, 1.1 mmol) was stirred for ap-
proximately 1 min at 65 C in a pre-heated oil bath un-
til a homogeneous viscous liquid has been obtained. After
that piperidine (0.015 g, 0.18 mmol) and glacial acetic acid
(0.011 g, 0.18 mmol) were added to the stirred mixture and
the progress of reaction was followed by TLC. After the re-
action was completed, the mixture was cooled to room tem-
perature, ether was added and the solid products were recrys-
tallized from an appropriate solvent.
◦
3-[(5-Methyl-2-furyl)methylene]pentane-2,4-dione (4d):
Recrystallized from petroleum ether/ethyl acetate (15 : 1). –
M. p. 90 – 91 ◦C. – UV/vis (MeOH): λmax(lgε) = 335(4.27),
˜
240(3.63), 214 nm(3.64). – IR (KBr): ν = 1706 and
Physical and spectroscopic data
1646 (CO) cm−1. – 1H NMR (500 MHz, CDCl3):
3-(2-Nitrobenzylidene)pentane-2,4-dione (4a): Recrystal- δ = 2.37 (br s, 3H, 5’-CH3), 2.39 (s, 3H, CH3), 2.49 (s, 3H,
lized from petroleum ether/ethyl acetate (12 : 1). – M. p. 74 – CH3), 6.18 (dd, 1H, J = 3.3 Hz and 0.8 Hz, 4’-H), 6.73 (d,
75 ◦C (lit. [14]: m. p. 63 – 63.5 ◦C). – UV/vis (MeOH): 1H, J = 3.3 Hz, 3’-H), 7.13 (s, 1H, vinylic H). – MS (EI,
˜
λ
max(lgε) = 242 nm (3.87). – IR (KBr): ν = 1697 and 70 eV): m/z (%) = 192(97) [M+], 177(95) [M+-Me],
Unauthenticated
Download Date | 5/5/16 7:05 AM

54
H. R. Memarian et al. · Synthesis of Unsymmetrical 1,4-Dihydropyridines
150(43) [M+-COCH2], 149(76) [M+-Ac], 135(100), tet of quartets, 2H, J = 7.1 Hz, CO2CH2CH3), 5.20 (s,
107(86), 79(76). – C11H12O3 (192.22): calcd. C 68.74, 1H, 4-H), 5.99 (s, 1H, NH), 7.44 (t, 1H, J = 7.9 Hz,
H 6.29, O 24.97; found C 68.84, H 6.29.
5’-H), 7.69 (br d, 1H, J = 7.7 Hz, 6’-H), 8.06 (dd,
1H, J = 8.1 Hz and 1.2 Hz, 4’-H), 8.15 (br s, 1H,
2’-H). – MS (EI, 70 eV): m/z (%) = 344(10) [M+],
327(11) [M+-OH], 315(12) [M+-Et], 301(15) [M+-Ac],
271(7) [M+-CO2Et], 222(100) [M+-Ar], 194(71), 106(7).
– C18H20N2O5 (344.37): calcd. C 62.78, H 5.85, N 8.13,
O 23.23; found C 62.7, H 5.8, N 7.5.
3-(4-Hydroxy-3-methoxybenzylidene)pentane-2,4-dione
(4e): Recrystallized from petroleum ether/ethyl acetate
(2 : 1). – M. p. 131 – 132 ◦C. – UV/vis (MeOH): λmax(lgε) =
˜
340(14.30), 249(4.00), 225 nm(3.95). – IR (KBr): ν =
3377 (OH), 1691 and 1643 (CO) cm−1. – 1H NMR
(500 MHz, CDCl3): δ = 2.36 (s, 3H, CH3), 2.44 (s, 3H,
CH3), 3.90 (s, 3H, OCH3), 6.20 (s, 1H, OH), 6.95 (mc,
2H, 2’-H and 6’-H), 7.01 (dd, 1H, J = 8.2 Hz and
1.8 Hz, 5’-H), 7.44 (s, 1H, vinylic H). – MS (EI,
70 eV): m/z (%) = 234(88) [M+], 219(83) [M+-Me],
217(60) [M+-OH], 203(47) [M+-OMe], 191(86) [M+-Ac],
177(97), 149(53), 145(100), 117(64), 105(58). – C13H14O4
(234.25): calcd. C 66.66, H 6.02, O 27.32; found C 66.62,
H 5.98.
Ethyl-5-acetyl-4-(3,4-dimethoxyphenyl)-2,6-dimethyl-
1,4-dihydropyridine-3-carboxylate (1c): Recrystallized from
ethyl acetate/methanol (20 : 1). – M. p. 162 – 163 ◦C. –
UV/vis (MeOH): λmax(lgε) = 369(3.88), 230 nm(4.26).
˜
– IR (KBr): ν = 3333 (NH), 1675 (CO2C2H5) and
1662 (COCH3) cm−1. – 1H NMR (500 MHz, CDCl3):
δ = 1.35 (t, 3H, J = 7.1 Hz, CO2CH2CH3), 2.21 (s, 3H,
2-CH3), 2.33 (s, 3H, 6-CH3), 2.42 (s, 3H, COCH3), 3.87 (s,
3H, OCH3), 3.88 (s, 3H, OCH3), 4.24 (two partially over-
lapped quartet of quartets, 2H, J = 7.1 Hz, CO2CH2CH3),
5.02 (s, 1H, 4-H), 5.71 (s, 1H, NH), 6.80 (mc, 2H, 5’-H
and 6’-H), 6.92 (d, 1H, J = 1.5 Hz, 2’-H). – MS (EI,
70 eV): m/z (%) = 359(55) [M+], 344(16) [M+-Me],
330(45) [M+-Et], 316(49) [M+-Ac], 314(19) [M+-OEt],
296(41), 286(26) [M+-CO2Et], 222(100) [M+-Ar], 194(93),
106(17). – C20H25NO5 (359.43): calcd. C 66.84, H 7.01,
N 3.90, O 22.26; found C 66.85, H 7.06, N 3.82.
General procedure for the preparation of unsymmetrical 1,4-
dihydropyridines 1a−l
A mixture of ethyl 3-aminocrotonate [26] (0.129 g,
1 mmol) and pure benzylidene 4a – e (1 mmol) or the reaction
mixture of not completed benzylidene reaction and glacial
acetic acid (0.009 g, 0.15 mmol) in methanol (5 ml) was re-
fluxed with stirring under protection from light for the time
given in Table 3. The solvent was evaporated, the residue was
dissolved in ethyl acetate and cooled in a refrigerator. The
precipitated products were purified either by recrystallization
or column chromatography.
Ethyl-5-acetyl-2,6-dimethyl-4-(5-methyl-2-furyl)-1,4-
dihydropyridine-3-carboxylate (1d): Column chromatogra-
phy with petroleum ether/ethyl acetate (4 : 1). – M. p.
142 – 143 ◦C. UV/vis (MeOH): λmax(lgε) = 362(3.80),
Ethyl-5-acetyl-2,6-dimethyl-4-(2-nitrophenyl)-1,4-di-
hydropyridine-3-carboxylate (1a): Recrystallized from
˜
239 nm(4.06). – IR (KBr): ν = 3307 (NH), 1691 (CO2C2H5)
1
and 1646 (COCH3) cm−1. – H NMR (500 MHz, CDCl3):
◦
petroleum ether/ethyl acetate (15 : 1). – M. p. 175 – 176 C
(lit. [14]: m. p. 175 – 175.4 ◦C).
– UV/vis (MeOH):
δ = 1.34 (t, 3H, J = 7.1 Hz, CO2CH2CH3), 2.24 (s,
3H, 2-CH3), 2.35 and 2.36 (6H, two singlets, 6-CH3,
5’-CH3), 2.37 (s, 3H, COCH3), 4.22 (qq, 1H, J = 7.1 Hz,
CO2CH2CH3), 4.29 (qq, 1H, J = 7.1 Hz, CO2CH2CH3),
5.14 (s, 1H, 4-H), 5.81 (mc, 2H, 3’-H and 4’-H), 5.86 (s,
1H, NH). – MS (EI, 70 eV): m/z (%) = 303(97) [M+],
288(12) [M+-Me], 274(47) [M+-Et], 260(68) [M+-Ac],
230(93) [M+-CO2Et], 222(16), 194(38), 188(45), 149(56),
106(14). – C17H21NO4 (303.36): calcd. C 67.31, H 6.98,
N 4.62, O 21.10; found C 67.44, H 7.05, N 4.57.
λ
max(lgε) = 366(3.72), 250 nm(4.22).
–
IR (KBr):
−1
˜
ν = 3333 (NH), 1675 (CO2C2H5) and 1655 (COCH3) cm
.
–
1H NMR (500 MHz, CDCl3): δ = 1.26 (t, 3H,
J = 7.1 Hz, CO2CH2CH3), 2.32 (s, 3H, 2-CH3), 2.36 (s, 3H,
6-CH3), 2.37 (s, 3H, COCH3), 4.04 (qq, 1H, J = 7.1 Hz,
CO2CH2CH3), 4.24 (qq, 1H, J = 7.1 Hz, CO2CH2CH3),
5.79 (br s, 1H, NH), 5.88 (s, 1H, 4-H), 7.33 (mc, 1H, 6’-H),
7.52 (mc, 2H, 4’- and 5’-H), 7.74 (d, 1H, J = 8.1 Hz, 3’-H). –
MS (EI, 70 eV): m/z (%) = 344(15) [M+], 328(50) [M+-O],
327(93) [M+-OH], 284(69) [M+-COCH2-H2O], 282(100),
268(71), 255(49), 254(70), 222(59), 194(49).
Ethyl-5-acetyl-4-(4-hydroxy-3-methoxyphenyl)-2,6-di-
methyl-1,4-dihydropyridine-3-carboxylate (1e): Recrys-
Ethyl 5-acetyl-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihy- tallized from ethyl acetate/methanol (10 : 1).
– M. p.
◦
dropyridine-3-carboxylate (1b): Recrystallized from◦petro- 192 – 193 C. – UV/vis (MeOH): λmax(lgε) = 370(3.88),
˜
leum ether/ethyl acetate (15 : 1). – M. p. 160 – 161 C (lit. 231 nm(4.18). – IR (KBr): ν = 3291 (NH), 1677 (CO2C2H5)
◦
1
[19]: m. p. 168 – 169 C). – UV/vis (MeOH): λmax(lgε) = and 1640 (COCH3) cm−1. – H NMR (500 MHz, CDCl3):
˜
369(3.49), 245 nm(4.04). – IR (KBr): ν = 3289 (NH), δ = 1.35 (t, 3H, J = 7.1 Hz, CO2CH2CH3), 2.20 (s,
1700 (CO2C2H5) and 1645 (COCH3) cm−1. – 1H NMR 1H, 2-CH3), 2.32 (s, 3H, 6-CH3), 2.41 (s, 3H, COCH3),
(500 MHz, CDCl3): δ = 1.33 (t, 3H, J = 7.1 Hz, 3.89 (s, 3H, 3’-OCH3), 4.22 (two partially overlapped
CO2CH2CH3), 2.24 (s, 3H, 2-CH3), 2.38 (s, 3H, 6-CH3), quartet of quartets, 2H, J = 7.1 Hz, CO2CH2CH3),
2.43 (s, 3H, COCH3), 4.21 (two partially overlapped quar- 4.99 (s, 1H, 4-H), 5.53 (s, 1H, 4’-OH), 5.70 (s, 1H, NH),
Unauthenticated
Download Date | 5/5/16 7:05 AM

H. R. Memarian et al. · Synthesis of Unsymmetrical 1,4-Dihydropyridines
55
6.76 (dd, 1H, J = 8.2 Hz and 1.75 Hz, 6’-H), 6.81 (d, 1H, (313.40): calcd. C 72.82, H 7.40, N 4.47, O 15.32; found
J = 8.1 Hz, 5’-H), 6.89 (d, 1H, J = 1.7 Hz, 2’-H). – MS (EI, C 72.98, H 7.47, N 4.45.
70 eV): m/z (%) = 345(24) [M+], 330(10) [M+-Me],
Ethyl-5-acetyl-2,6-dimethyl-4-(3-pyridyl)-1,4-dihydro-
316(23) [M+-Et], 302(29) [M+-Ac], 272(11) [M+-CO2Et],
pyridine-3-carboxylate (1i): Column chromatography with
◦
258(11), 222(100), 194(69), 106(8). – C19H23NO5 (345.40):
calcd. C 66.07, H 6.71, N 4.06, O 23.16; found C 66.13,
H 6.70, N 3.95.
petroleum ether/ethyl acetate (6 : 5). – M. p. 197 – 198 C,
(lit. [20]), m. p. 188 ◦C. – UV/vis (MeOH): λmax(lgε) =
˜
370(3.95), 243 nm(4.39). – IR (KBr): ν = 3033 (NH),
Ethyl-5-acetyl-2,6-dimethyl-4-phenyl-1,4-dihydropyr-
1691 (CO2C2H5) and 1662 (COCH3) cm−1. – 1H NMR
idine-3-carboxylate (1f): Recrystallized from petroleum (500 MHz, CDCl3): δ = 1.31 (t, 3H, J = 7.1 Hz,
◦
ether/ethyl acetate (10 : 1). – M. p. 163 – 164 C (lit. [14]: CO2CH2CH3), 2.23 (s, 3H, 2-CH3), 2.35 (s, 3H, 6-CH3),
m. p. 165 – 166 ◦C). – UV/vis (MeOH): λmax(lgε) = 2.39 (s, 3H, COCH3), 4.19 (two partially overlapped quar-
˜
370(3.63), 247 nm(3.91). – IR (KBr): ν = 3300 (NH), tet of quartets, 2H, J = 7.2 Hz, CO2CH2CH3), 5.08 (s,
1663 (CO2C2H5) and 1640 (COCH3) cm−1. – 1H NMR 1H, 4-H), 6.69 (s, 1H, NH), 7.24 (dd, 1H, J = 7.5 Hz and
(500 MHz, CDCl3): δ = 1.33 (t, 3H, J = 7.1 Hz, 4.9 Hz, 5’-H), 7.70 (d, 1H, J = 7.7 Hz, 4’-H), 8.43 (d,
CO2CH2CH3), 2.20 (s, 3H, 2-CH3), 2.32 (s, 3H, 6-CH3), 1H, J = 3.9 Hz, 6’-H), 8.57 (s, 1H, 2’-H). – MS (EI,
2.40 (s, 3H, COCH3), 4.21 (two partially overlapped quar- 70 eV): m/z (%) = 300(8) [M+], 299(12) [M+-H],
tet of quartets, 2H, J = 7.1 Hz, CO2CH2CH3), 5.05 (s, 1H, 285(3) [M+-Me], 271(13) [M+-Et], 257(9) [M+-Ac],
4-H), 5.87 (s, 1H, NH), 7.19 (mc, 1H, p-H), 7.28 (mc, 4H, 227(7) [M+-CO2Et], 222(100) [M+-Ar], 194(62), 106(9).
o and m-H). – MS (EI, 70 eV): m/z (%) = 299(5) [M+], – C17H20N2O3 (300.36): calcd. C 67.98, H 6.71, N 9.33,
298(7) [M+-H], 282 [M+-Me-H2] (15), 270(4) [M+-Et], O 15.98, found C 67.69, H 6.68, N 9.25.
254(11) [M+-Et], 236(50), 226(4) [M+-CO2Et], 222
Ethyl-5-acetyl-2,6-dimethyl-4-(4-pyridyl)-1,4-dihydro-
[M+-Ph](20), 194(20).
pyridine-3-carboxylate (1j): Column chromatography with
◦
Ethyl-5-acetyl-4-(4-chlorophenyl)-2,6-dimethyl-1,4-di-
petroleum ether/ethyl acetate (6 : 5). – M. p. 168 – 169 C.
hydropyridine-3-carboxylate (1g): Column chromatog- – UV/vis (MeOH): λmax(lgε) = 370(4.21), 242 nm(4.65).
˜
raphy with petroleum ether/ethyl acetate (4 : 1). – M. p. – IR (KBr): ν = 3162 (NH), 1643 (CO2C2H5) and
◦
174 – 175 C. – UV/vis (MeOH): λmax(lgε) = 369(3.82), 1632 (COCH3) cm−1. – 1H NMR (500 MHz, CDCl3):
˜
245 nm(4.20). – IR (KBr): ν = 3341 (NH), 1700 (CO2C2H5) δH = 1.33 (t, 3H, J = 7.0 Hz, CO2CH2CH3), 2.22 (s, 3H,
and 1654 (COCH3) cm−1. – H NMR (500 MHz, CDCl3): 2-CH3), 2.36 (s, 3H, 6-CH3), 2.42 (s, 3H, COCH3), 4.21 (two
1
δ = 1.33 (t, 3H, J = 7.1 CO2CH2CH3), 2.20 (s, 3H, 2-CH3), partially overlapped quartet of quartets, 2H, CO2CH2CH3),
2.33 (s, 3H, 6-CH3), 2.40 (s, 3H, COCH3), 4.20 (two 5.11 (s, 1H, 4-H), 6.06 (s, 1H, NH), 7.23 (d, 2H, J = 4.6 Hz,
partially overlapped quartet of quartets, 2H, J = 7.1 Hz, 3’-H and 5’-H), 8.50 (d, 2H, J = 4.6 Hz, 2’-H and 6’-H). –
CO2CH2CH3), 5.03 (s, 1H, 4-H), 5.84 (s, 1H, NH), 7.24 (mc, MS (EI, 70 eV): m/z (%) = 300(14) [M+], 271(9) [M+-Et],
4H, C6H4Cl). – MS (EI, 70 eV): m/z (%) = 333(17) [M+], 257(5) [M+-Ac], 222(100) [M+-Ar], 194(62), 149(5),
304(15) [M+-Et], 290(17) [M+-Ac], 260(12) [M+-CO2Et], 106(9). – C17H20N2O3 (300.36): calcd. C 67.98, H 6.71,
222(100) [M+-Ar], 194(64), 149(9), 106(5).
C18H20ClNO3 (333.82): calcd. 64.77, 6.04,
–
N 9.33, O 15.98; found C 67.21, H 7.08, N 9.03.
C
H
Ethyl-5-acetyl-4-(2-furyl)-2,6-dimethyl-1,4-dihydropyr-
N 4,20, Cl 10.62, O 14.38; found C 64.06, H 6.23,
N 4.02.
idine-3-carboxylate (1k): Recrystallized from petroleum
◦
ether/ethyl acetate (10 : 1). – M. p. 116 – 117 C (lit. [21]:
Ethyl-5-acetyl-2,6-dimethyl-4-(p-tolyl)-1,4-dihydropyr-
m. p. 118 – 120 ◦C). – UV/vis (MeOH): λmax(lgε) =
˜
idine-3-carboxylate (1h): Column chromatography with pe- 361(4.09), 244 nm(4.34). – IR (KBr): ν = 3231 (NH),
troleum ether/ethyl acetate (4 : 1). – M. p. 155 ◦C. – UV/vis 1676 (CO2C2H5) and 1660 (COCH3) cm−1. – 1H NMR
(MeOH): λmax(lgε) = 371(3.94), 249 nm(4.16).- IR (KBr): (500 MHz, CDCl3): δ = 1.33 (t, 3H, J = 7.1 Hz,
−1
˜
–
ν = 3290 (NH), 1692 (CO2C2H5) and 1648 (COCH3) cm
.
CO2CH2CH3), 2.34 (s, 3H, 2-CH3), 2.36 (s, 6H, 6-CH3
1H NMR (500 MHz, CDCl3): δ = 1.34 (t, 3H, J = and COCH3), 4.24 (two partially overlapped quartet of quar-
7.1 Hz, CO2CH2CH3), 2.20 (s, 3H, 2-CH3), 2.31 (s, 3H, tets, 2H, J = 7.1, CO2CH2CH3), 5.20 (s, 1H, 4-H), 5.96 (d,
6-CH3), 2.32 (s, 3H, 4’-CH3), 2.40 (s, 3H, COCH3), 1H, J = 2.7 Hz, 3’-H), 6.08 (s, 1H, NH), 6.26 (dd, 1H,
4.22 (two partially overlapped quartet of quartets, 2H, J = J = 2.8 Hz and 2.0 Hz, 4’-H), 7.28 (d, 1H, J = 1.7 Hz, 5’-H).
7.1 Hz, CO2CH2CH3), 5.02 (s, 1H, 4-H), 5.87 (s, 1H, – MS (EI, 70 eV): m/z (%) = 289(69) [M+], 288(3) [M+-H],
NH), 7.08 (d, 2H, J = 7.8 Hz, 3’-H and 5’-H), 7.20 (d, 274(7) [M+-Me], 260 [M+-Et] (85), 247(9) [M+-COCH2],
2H, J = 7.9 Hz, 2’-H and 6’-H). – MS (EI, 70 eV): 246(100) [M+-Ac], 244(28) [M+-OEt], 222(14) [M+-Ar],
m/z (%) = 313(18) [M+], 312(7) [M+-H], 298(4) [M+-Me], 218(38), 194(37), 174(48), 149(47). – C16H19NO4 (289.33):
284(15) [M+-Et], 270(19) [M+-Ac], 240(13) [M+-CO2Et], calcd. C 66.42, H 6.62, N 4.84, O 22.12; found C 66.26,
222(100) [M+-Ar], 194(64), 149(10), 106(6). – C19H23NO3 H 6.60, N 4.84.
Unauthenticated
Download Date | 5/5/16 7:05 AM

56
H. R. Memarian et al. · Synthesis of Unsymmetrical 1,4-Dihydropyridines
Ethyl-5-acetyl-2,6-dimethyl-4-(2-thienyl)-1,4-dihydro- 7.13 (dd, 1H, J = 5.6 and 1.1 Hz, 5’-H). – MS (EI,
pyridine-3-carboxylate (1l): Recrystallized from petroleum 70 eV): m/z (%) = 305(75) [M+], 304(9) [M+-H],
ether/ethyl acetate (10 : 1). – M. p. 134 – 135 C. – UV/vis 277(11) [M+-C2H4], 276(92) [M+-Et], 262(100) [M+-Ac],
◦
(MeOH): λmax(lgε) = 363(3.80), 238 nm(4.15). – IR (KBr): 232(38) [M+-CO2Et], 222(31) [M+-Ar], 218(45), 194(89),
−1
˜
ν = 3264 (NH), 1675 (CO2C2H5) and 1643 (COCH3) cm
.
149(23). – C16H19NO3S (305.40): calcd. C 62.93, H 6.27,
–
1H NMR (500 MHz, CDCl3): δ = 1.39 (t, 3H, J = N 4.59, O 23.37, S 10.50; found C 62.86, H 6.32, N 4.61,
7.1 Hz, CO2CH2CH3), 2.26 (s, 3H, 2-CH3), 2.34 (s, 3H, S 10.37.
6-CH3), 2.42 (s, 3H, COCH3), 4.28 (two partially over-
Acknowledgement
lapped quartet of quartets, 2H, J = 7.1, CO2CH2CH3),
5.35 (s, 1H, 4-H), 6.07 (s, 1H, NH), 6.84 (d, 1H, J =
3.4 Hz, 3’-H), 6.91 (dd, 1H, J = 5.0 and 3.5 Hz, 4’-H),
We are thankful to the Office of Graduate Studies of the Uni-
versity of Isfahan for their financial support.
[15] R. Alajarin, P. Jorda´n, J. J. Vaquero, J. Alvarez-Builla,
Synthesis 389 (1995).
[1] A. Hantzsch, Ber. Dtsch. Chem. Ges. 17, 1315 (1884);
ibid. 18, 1774 and 2379 (1885).
[16] R. Alajarin, J. J. Vaquero, J. Alvarez-Builla, M. Pas-
tor, C. Sunhel, M. F. de Gasa-Juana, J. Priego, P. R.
Statkow, J. Sanz-Aparicio, I. Fonseca, J. Med. Chem.
38, 2830 (1995).
[17] M. Mahendra, B. H. Doreswamy, M. A. Sridhar,
J. Shashidhara Prasad, G. R. Patel, J. A. Patel, A. Shah,
J. Chem. Crystallog. 34, 441 (2004).
[2] C. Beyer, Ber. Dtsch. Chem. Ges. 24, 1662 (1891).
[3] E. Knoevenagel, W. Ruschhaupt, Ber. Dtsch. Chem.
Ges. 31, 1025 (1898).
[4] U. Eisner, J. Kuthan, Chem. Rev. 72, 1 (1972).
[5] D. M. Stout, A. I. Meyers, Chem. Rev. 82, 223 (1982).
[6] J. Kuthan, A. Kurfu¨rst, Ind. Eng. Chem. Prod. Res. Dev.
21, 191 (1982).
[18] N. Tewari, N. Dwivedi, R. P. Tripathi, Tetrahedron Lett.
45, 9011 (2004).
[19] A. P. Philips, J. Am. Chem. Soc. 73, 2248 (1951).
[20] F. Bossert, W. Vater, Ger. Offen DE 2003146 (1971);
Chem. Abstr. 75, 98457 (1971).
[7] M. L. Bennasai, E. Zulaica, Y. Alonso, L. Mata,
E. Molins, J. Bosch, Chem. Commun. 1166 (2001), and
references cited therein
[8] S. Goldmann, J. Stoltefuss, Angew. Chem. Int. Ed.
Engl. 30, 1559 (1991).
[21] D. Ilavsky, V. Milata, Collect. Czech. Chem. Commun.
61, 1233(1996).
[9] M. Fujii, K. Nakamura, A. Ohno, Trends Heterocycl.
Chem. 5, 17 (1997).
[22] H. R. Memarian, M. Bagheri, D. Do¨pp, Monatsh.
Chem. 135, 833 (2004), and references cited therein.
[23] H. R. Memarian, I. Mohammadpoor-Baltork, M. Java-
heri, J. Chin. Chem. Soc., in press.
[24] A. R. Katritzky, D. L. Ostercamp, T. L. Yousaf, Tetra-
hedron 42, 5729 (1986).
[25] Benzylidene intermediates have been prepared by
adoption of the reported procedure: W. H. Correa, J. L.
Scott, Green Chem. 3, 296 (2001).
[26] Ethyl 3-aminocrotonate has been prepared according
to the known procedure: M. E. F. Braibante, H. S. B.
Braibante, L. Missio, A. Andricopulo, Synthesis 898
(1994).
[10] P. Naab, W. Lange, W. Teller, Eur. Pat. Appl. EP 319814
(1989); Chem. Abstr. 122, 7381 (1990).
[11] A. Gustavsson, A. Kallstrom, S. Palma, PCT Int.
App. WO 9725313 (1997); Chem. Abstr. 127, 149077
(1997).
[12] R. Desai, D. Aguilar, M. Aslam, N. Gallegos, PCT Int.
App. WO 9724326 (1997); Chem. Abstr. 127, 135726
(1997).
[13] W. Teller, W. Koebernick, A. Haaf, P. Naab, M. Preiss,
Ger. Offen DE 3312216 (1984); Chem. Abstr. 102,
95543 (1985).
[14] J. A. Berson, E. Brown, J. Am. Chem. Soc. 77, 444
(1955).
Unauthenticated
Download Date | 5/5/16 7:05 AM