Synthesis of polysubstituted 1,4-dihydropyridines via three-component reaction

Article abstract of DOI:10.1016/j.tet.2012.10.082

An efficient one-pot synthesis of novel N-substituted 1,4-dihydropyridine derivatives via a threecomponent reaction of primary amines, dialkyl acetylenedicarboxylates, and methyl (arylmethylidene) pyruvates has been reported. The reaction is performed using ZnCl₂ (40 mol %) in dichloroethane in good to high yields through a domino Michael/cyclization sequence. Notably, the ready availability of the starting materials, high bond-forming efficiency, good to high yields and the high level of practicability of the reaction and work up make this approach an attractive complementary method for access to Nsubstituted 1,4-dihydropyridines.

Full text of DOI:10.1016/j.tet.2012.10.082

Tetrahedron 69 (2013) 738e743
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis of polysubstituted 1,4-dihydropyridines via
three-component reaction
,
a
a
b
a
Saeed Balalaie a , Leila Baoosi , Fatemeh Tahoori , Frank Rominger , Hamid Reza Bijanzadeh
*
a Peptide Chemistry Research Center, K. N. Toosi University of Technology, P.O. Box 15875-4416, Tehran, Iran
Organisch-Chemisches Institut der Universitat Heidelberg, Im Neuenheimer Feld 270, D-69120 Heidelberg, Germany
b
€
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 25 May 2012
Received in revised form 16 October 2012
Accepted 29 October 2012
Available online 21 November 2012
An efficient one-pot synthesis of novel N-substituted 1,4-dihydropyridine derivatives via a three-
component reaction of primary amines, dialkyl acetylenedicarboxylates, and methyl (arylmethylidene)
pyruvates has been reported. The reaction is performed using ZnCl2 (40 mol %) in dichloroethane in good
to high yields through a domino Michael/cyclization sequence. Notably, the ready availability of the
starting materials, high bond-forming efficiency, good to high yields and the high level of practicability of
the reaction and work up make this approach an attractive complementary method for access to N-
substituted 1,4-dihydropyridines.
Dedicated to Professor Issa Yavari on the
occasion of his 65th birthday
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
N-Substituted 1,4-dihydropyridines
Methyl (arylmethylidene) pyruvate
Enaminone
Zinc chloride
Dialkyl acetylenedicarboxylate
Domino Michael/cyclization
1. Introduction
3 could reduce hyperplasia,7 and DHPs 4, and 5 have antimicrobial
activity8 and antitubercular activity,9 respectively (Fig. 1).
The design and efficient synthesis of bioactive compounds is one
of the main objectives of organic and medicinal chemistry. In recent
years, multicomponent reactions have become important tools in the
preparation of structurally diverse chemical libraries of drug-like
polyfunctional compounds.1 However, to ensure sufficient molecu-
lar diversity and complexity, there is a continuous need for novel
reactions with high efficiency and selectivity.2 Development of more
efficient synthetic methods in order to assemble diverse molecules
with minimal by-products, in a highly efficient and atom-economical
manner attracted a great deal of attention from chemists around the
world.2 To this day 4-aryl-1,4-dihydropyridine-3,5-dicarboxylic
esters of the nifedipine type (1) are one of the most widely used
and studied medications among calcium-channel blockers.3 Fur-
thermore, they are also used as cognition enhancers, neuro-
protectants, and platelet antiaggregatory agents.4 Additionally
a number of 1,4-DHP calcium antagonists have been introduced as
potential drugs for the treatment of congestive heart failure.5 For
example, 2 is suitable in treatment of multidrug resistance,6 SNAP5089
It is shown that the existence of ester groups in the structure of
DHP and their positions has an important role in its antihyper-
tensive activity.3def So far, many protocols for the synthesis of DHPs
have been reported.10 As a part of our current studies on the
development of new routes in heterocyclic synthesis via novel
one-pot MCRs,11 we report here for the first time a novel three-
component reaction of methyl (arylmethylidene) pyruvates 6,
primary amines 7, and dialkyl acetylenedicarboxylates 8 in the
presence of zinc chloride (40 mol %) for the synthesis of poly-
functionalized 1,4-dihydropyridines (Scheme 1).
2. Results and discussion
Recently, we have focused our research and development efforts
on the preparation of new compound libraries containing bi-
ologically active heterocyclic skeletons. In this way, methyl (aryl-
methylidene) pyruvates (6) have been used as suitable starting
materials. They play an important role as an attractive starting
material for the following reasons: (a) they have higher reactivities
in comparison to usual b,g-unsaturated a-ketones; (b) they contain
active functional groups, which can be used for further synthesis;
and (c) their preparation is easy, i.e., they can be synthesized
* Corresponding author. Fax: þ98 21 22853650; e-mail address: balalaie@
kntu.ac.ir (S. Balalaie).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.10.082

S. Balalaie et al. / Tetrahedron 69 (2013) 738e743
739
3
1
2
4
5
Fig. 1. Bioactive compounds with dihydropyridine core structure.
Scheme 1. Synthesis of N-substituted 1,4-dihydropyridines via three-component reaction in the presence of ZnCl2.
according to the known procedure by reaction of aromatic alde-
hydes and pyruvic acid in an aqueous MeOH solution of KOH.12
Typically, the addition of amines to dialkyl acetylenedicarbox-
ylate has been extensively studied and the desired DMAD-primary
amine adducts (enaminone) as a mixture of E and Z isomers have
been used as efficient starting materials for the synthesis of het-
erocyclic skeletons.13
Table 1
The effect of the amount of different Lewis acids on the synthesis of N-substituted
1,4-dihydropyridine 9a
Lewis acid
(mol %)
Yielda [%]
CuI
ZrO2
20
20
20
20
20
20
20
30
40
d
d
d
30
d
50
38
47
61
ZrCl4
CuBr2
Zn(OAc)2
FeCl3
ZnCl2
ZnCl2
ZnCl2
We began our investigation with methyl (phenylmethylidene)
pyruvate 6a, which was synthesized according to the reported
procedure.12 The reaction of 6a with benzylamine and dimethyl
acetylenedicarboxylate was selected as the model reaction. Heating
of the mixture in toluene for 72 h did not provide our goal and
a mixture of E and Z of enaminones was obtained. After this failure,
we tried various Lewis acids, such as ZrO2, ZrCl4, CuI, but the de-
sired product was not formed. We only got satisfactory results with
ZnCl2 and FeCl3. The best result was obtained with ZnCl2. According
to this result, ZnCl2 was selected as the best Lewis acid for the
synthesis of desired N-substituted 1,4-dihydropyridine 9a. Then the
amount of this Lewis acid was examined in the model reaction. The
reaction was checked without the presence of ZnCl2 and FeCl3 as
Lewis acids, and we did not get any product. In the presence of 20,
30, and 40% of ZnCl2, the yield of 9a was obtained 38, 47, and 61%,
respectively. This confirmed the important role of ZnCl2 in this
reaction. The optimum reaction condition used of 40% ZnCl2 and
boiling toluene as reaction medium (Table 1).
a
Yield of isolated product.
presence of 40% ZnCl2 were chosen for a model system, and this
reactionwas performed invarious solvents. A change in the solvent to
trifluoroethanol, ethanol, acetonitrile, toluene, 1,4-dioxane, THF, and
dichloroethane gave the desired N-substituted 1,4-dihydropyridine
9a in 8e68% yield. The results summarized in Table 2. The best yield
for reaction model was obtained in dichloroethane.
After finding suitable conditions, the three-component reaction
of methyl (arylmethylidene) pyruvates, dialkyl acetylenedicarbox-
ylates, and also different primary amines for the synthesis of 1,4-
dihydropyridines 9aen were studied. The results summarized in
Table 3. The scope of the reaction with regard to a substitution
pattern in primary amines was investigated. Some aniline de-
rivatives were used as primary amines and the best result was
obtained with 4-methoxyaniline (9e, 84%). Our investigation
showed that the existence of substituents on the aromatic ring in
The amount of reactants was further optimized and, finally, the
best ratio of 6a, 7a, and 8a (1.3:1.3:1) was selected. In an attempt to
investigate the range of solvents compatible with this reaction,
methyl (phenylmethylidene) pyruvate 6a and enaminone from
reaction of benzylamine and dimethyl acetylenedicarboxylate in the

740
S. Balalaie et al. / Tetrahedron 69 (2013) 738e743
Table 2
dimethyl acetylenedicarboxylate to form the desired enaminone (A),
then methyl (arylmethylidene) pyruvate could be activated by ZnCl2
and undergo the nucleophilic addition. The subsequent cyclization of
intermediate B followed by the nucleophilic addition of the amine
group leads to intermediate C. On the basis of the established chem-
istryofZn(II)chemistry, itisreasonabletoassumethatzinc(II)chloride
has an essential role in the addition of enaminone to methyl (aryl-
methylidene) pyruvate via coordination with oxygen lone pairs.15
Meanwhile, the presence of Zn(II) chloride could facilitate two steps
of reaction mechanism and also formation of 1,4-dihydropyridine
moiety. Meanwhile, Zn(II) has an essential role for the dehydration
process to obtain the final product 4aen. The reaction could proceed
via a domino Michael addition/cyclization reaction sequence.
Solvent effect on the synthesis of N-substituted 1,4-dihydropyridines 9a via three-
component tandem cyclization reaction
Solvent
Yield [%]a
Trifluoroethanol
Ethanol
Acetonitrile
Dichloroethane
Toluene
8
10
32
68
50
44
20
1,4-Dioxane
THF
a
Yield of isolated product.
Table 3
Synthesis of N-substituted 1,4-dihydropyridines 9aen via three-component re-
action in the presence of ZnCl2 (40%)
3. Conclusion
In conclusion, an efficient approach for the one-pot synthesis of
N-substituted 1,4-dihydropyridines by ZnCl2 has been developed.
Easy work-up, synthesis of polyfunctional compounds, which are
ready for further reactions, and an easily available and less
expensive Lewis acid, good to high yields are advantages of the
present method.
Entry
Product
R1
R2
Ar
Yield [%]a
1
2
3
4
5
6
7
8
9a
9b
9c
9d
9e
9f
9g
9h
9i
9j
9k
9l
9m
9n
PhCH2
PhCH2
C6H5
Allyl
p-CH3OeC6H4
p-BreC6H4
PhCH2
Me
Et
p-CH3C6H4
p-CH3C6H4
p-CH3C6H4
p-CH3C6H4
p-CH3C6H4
p-CH3C6H4
p-CH3OC6H4
p-CH3OC6H4
p-CH3OC6H4
p-CH3OC6H4
p-ClC6H4
68
52
71
42
84
61
61
52
76
59
74
77
87
67
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
C6H5
4. Experimental section
4.1. General
9
p-CH3OeC6H4
p-BreC6H4
PhCH2
C6H5
p-CH3OeC6H4
p-BreC6H4
10
11
12
13
14
p-ClC6H4
p-ClC6H4
p-ClC6H4
Commercially available materials were used without further
purification. Melting points were determined on an Electrothermal
9100 apparatus and were uncorrected. IR spectra were obtained on
an ABB FT-IR FTLA 2000 spectrometer. 1H NMR and 13C NMR
spectra were run on Bruker DRX-500 AVANCE spectrometer at
500 MHz and 300 MHz for 1H NMR, and 125 MHz and 75 MHz for
13C NMR. CDCl3 was used as solvent. HRMS was recorded on Mass-
ESI-POS (Apex Qe-FT-ICR instrument) spectrometer.
Reaction conditions: 1.3 mmol 8, 1.3 mmol primary amine,
(arylidene) pyruvate, 20 mL dichloroethane, 8e12 h.
1
mmol methyl
a
Yield of isolated product.
amine and methyl (arylmethylidene) pyruvates had a minor effect
on the reaction times of the products 9aen.
The structures of the products 9aen were deduced from their
HR-mass spectrometry and NMR spectroscopic data. The distin-
guished peak in the 1H NMR spectra of the products was indicated
4.2. General procedure for the synthesis of N-substituted-1,4-
dihydropyridines 9aen
by a signal at
d 4.46e4.69 ppm for the H-4 of 1,4-DHP proton, as
a doublet in 1H NMR and in 13C NMR a signal at 37.9e38.7 ppm for
C-4. Meanwhile, the structure of the products was confirmed
according to the X-ray crystallographic data.14 Fig. 2 shows the
ORTEP structure of the compound 9g.
A solution of primary amine (1.3 mmol) and dialkyl acetylene-
dicarboxylate (1.3 mmol) was stirred vigorously at room tempera-
ture for 10 min then methyl (arylmethylide) pyruvates (1 mmol)
and ZnCl2 (40%, 54 mg) in dichloroethane (20 mL) was added and
the mixture was heated under reflux for 8e12 h. The progress of
reaction was monitored by TLC (eluent hexane/ethyl acetate 3:1).
The solvent was removed under reduced pressure, and produced an
oil, which was purified by prep TLC plates (20ꢀ20 cm) (Eluent
hexane/ethyl acetate 3:1). Further purification was done by
recrystallization in mixture of methanol/water (9:1).
The possible mechanism of this conversion is shown in Scheme 2.
This conversion involves the initial reaction of primary amines with
4.2.1. Trimethyl 1-benzyl-4-p-tolyl-1,4-dihydropyridine-2,3,6-tri-
carboxylate (9a). Yield (0.274 g, 63%) as a yellow solid; mp
165.6e166.8 ꢁC; Rf (33% EtOAc/Hexane) 0.42; nmax (KBr) 1725 cmꢂ1
;
dH (500 MHz, CDCl3) 2.28 (3H, s, CH3), 3.59 (3H, s, OCH3), 3.72 (3H, s,
OCH3), 3.91 (3H, s, OCH3), 4.46 (1H, d, J 15.6 Hz, NeCH), 4.48 (1H, d, J
6.6 Hz, CH), 5.08 (1H, d, J 15.6 Hz, NeCH), 6.05 (1H, d, J 6.6 Hz, ]
CH), 6.84 (1H, d, J 7.9 Hz, Ar), 6.96 (1H, d, J 7.9 Hz, Ar), 7.24e7.33 (5H,
m, Ar); dC (125 MHz, CDCl3) 21.0, 38.4, 51.6, 52.0, 52.3, 53.0, 103.2,
122.3, 127.8, 128.1, 128.6, 128.7, 129.1, 130.5, 136.3, 136.4, 141.1, 145.8,
163.4, 165.6, 166.6; HRMS (ESI): [MþH]þ found 436.1756.
C25H26NO6 requires 436.1756, [MþNa]þ found 458.1574.
C25H25NNaO6 requires 458.1574, [MþK]þ found 474.1314.
C25H25KNO6 requires 474.1314.
4.2.2. 2,3-Diethyl 6-methyl 1-benzyl-4-p-tolyl-1,4-dihydropyridine-
Fig. 2. ORTEP structure of compound 9g.
2,3,6-tricarboxylate (9b). Yield (0.241 g, 52%) as an oil; Rf (33%

S. Balalaie et al. / Tetrahedron 69 (2013) 738e743
741
Scheme 2. Proposed mechanism for the synthesis N-substituted 1,4-dihydropyridines.
EtOAc/Hexane) 0.42; nmax (KBr) 1730 cmꢂ1
;
dH (500 MHz, CDCl3)
452.1702. C25H26NO7 requires 452.1702, [MþNa]þ found 474.1520.
C25H26NO7 requires 474.1520, [MþK]þ found 490.1260. C25H25KNO7
requires 490.1260.
1.15 (3H, t, J 7.1 Hz, CH3), 1.35 (3H, t, J 7.1 Hz, CH3), 2.28 (3H, s, CH3),
3.71 (3H, s, OCH3), 4.04 (2H, q, J 7.1 Hz, CH2), 4.29e4.44 (2H, m,
CH2), 4.50 (1H, d, J 15.6 Hz, NeCH), 4.51 (1H, d, J 6.5 Hz, CH), 5.10
(1H, d, J 15.6 Hz, NeCH), 6.04 (1H, d, J 6.5 Hz, ]CH), 6.84 (1H, d, J
8.0 Hz, Ar), 6.95 (1H, d, J 8.0 Hz, Ar), 7.27e7.34 (5H, m, Ar); dC
(125 MHz, CDCl3) 13.9, 14.0, 21.0, 38.6, 51.7, 52.3, 60.4, 62.2, 103.3,
122.2, 128.0, 128.6, 128.7, 129.0, 130.5, 136.3, 136.5, 141.3, 145.6,
163.5, 165.1, 166.1; HRMS (ESI): [MþH]þ found 464.2063.
C27H30NO6 requires 464.2064, [MþNa]þ found 486.1883.
C27H29NNaO6 requires 486.1884.
4.2.6. Trimethyl 1-(4-bromophenyl)-4-p-tolyl-1,4-dihydropyridine-
2,3,6-tricarboxylate (9f). Yield (0.305 g, 61%) as a yellow solid; mp
164.5e165.8 ꢁC; Rf (33% EtOAc/Hexane) 0.45; nmax (KBr)
1724.96 cmꢂ1
; dH (500 MHz, CDCl3) 2.36 (3H, s, CH3), 3.50 (3H, s,
OCH3), 3.57 (6H, s, OCH3), 4.65 (1H, d, J 6.0 Hz, CH), 6.16 (1H, d, J
6.0 Hz, ]CH), 7.16 (2H, d, J 8.0 Hz, Ar), 7.19 (2H, d, J 8.0 Hz, Ar), 7.25
(2H, d, J 8.5 Hz, Ar), 7.47 (2H, d, J 8.5 Hz, Ar); dC (125 MHz, CDCl3)
21.1, 38.6, 51.7, 52.1, 52.6, 102.6, 120.6, 122.3, 127.5, 129.6, 130.2,
130.8, 132.1, 136.9, 140.15, 141.8, 145.2, 162.6, 164.5, 166.4; HRMS
(ESI): [MþH]þ found 500.0700. C24H2379BrNO6 requires 500.0699,
[MþNa]þ found 522.0518. C24H2279BrNNaO6 requires 522.0517.
4.2.3. Trimethyl 1-phenyl-4-p-tolyl-1,4-dihydropyridine-2,3,6-tri-
carboxylate (9c). Yield (0.300 g, 71%) as a yellow solid; mp
149.8e150.9 ꢁC; Rf (33% EtOAc/Hexane) 0.44; nmax (KBr) 1725 cmꢂ1
;
dH (500 MHz, CDCl3) 2.35 (3H, s, CH3), 3.46 (3H, s, OCH3), 3.52 (3H, s,
OCH3), 3.56 (3H, s, OCH3), 4.66 (1H, d, J 6.0 Hz, CH), 6.11 (1H, d, J
6.0 Hz, ]CH), 7.3 (9H, m, Ar); dC (125 MHz, CDCl3) 21.1, 38.7, 51.6,
52.0, 52.4, 101.9, 119.8, 127.6, 128.3, 128.4, 128.9, 129.6, 131.3, 136.7,
141.0, 142.2, 145.6, 162.8, 164.6, 166.6; HRMS (ESI): [MþH]þ found
422.1596. C24H23NNaO6 requires 422.1596, [MþNa]þ found
444.1414. C24H23NNaO6 requires 444.1415.
4.2.7. Trimethyl 1-benzyl-4-(4-methoxyphenyl)-1,4-dihydropyridine-
2,3,6-tricarboxylate (9g). Yield (0.275 g, 61%) as a yellow crystalline;
mp 173.5e174.5 ꢁC; Rf (33% EtOAc/Hexane) 0.55; nmax (KBr)
1740 cmꢂ1
; dH (500 MHz, CDCl3) 3.60 (3H, s, OCH3), 3.73 (3H, s,
OCH3), 3.76 (3H, s, OCH3), 3.91 (3H, s, OCH3), 4.44 (1H, d, J 15.5 Hz,
NeCH), 4.46 (1H, d, J 6.6 Hz, CH), 5.10 (1H, d, J 15.5 Hz, NeCH), 6.06
(1H, d, J 6.6 Hz, ]CH), 6.67 (2H, d, J 8.4 Hz, Ar), 6.84 (2H, d, J 8.4 Hz,
Ar), 7.24e7.32 (5H, m, Ar); dC (125 MHz, CDCl3) 37.9, 51.63, 52.0, 52.4,
53.0, 55.2, 103.4, 113.8, 122.36, 128.0, 128.7, 128.7, 129.0, 130.5, 136.3,
136.4, 145.6, 158.5, 163.4, 165.6, 166.6; HRMS (ESI): [MþH]þ found
452.1704. C25H26NO7 requires 452.1705.
4.2.4. Trimethyl 1-allyl-4-p-tolyl-1,4-dihydropyridine-2,3,6-tri-
carboxylate (9d). Yield (0.162 g, 42%) as an oil; Rf (33% EtOAc/
Hexane) 0.33; nmax (KBr) 1735 cmꢂ1
; dH (500 MHz, CDCl3) 2.32 (3H,
s, CH3), 3.57 (3H, s, OCH3), 3.72 (3H, s, OCH3), 3.89 (3H, s, OCH3),
3.96e4.03 (1H, m, NeCH2), 4.39 (1H, dd, J 16.5, 7.5 Hz, NeCH2), 4.53
(1H, d, J 6.4 Hz, CH), 5.14 (1H, d, J 17.0 Hz, ]CH), 5.17 (1H, d, J
10.0 Hz, ]CH), 5.83e5.88 (1H, m, ]CH), 6.15 (1H, d, J 6.4 Hz, ]CH),
7.13 (2H, d, J 8.05 Hz, Ar), 7.17 (2H, d, J 8.05 Hz, Ar); dC (125 MHz,
CDCl3) 21.0, 38.4, 51.0, 51.6, 52.3, 52.8, 102.4, 118.9, 121.7, 127.6,
129.4, 130.5, 133.7, 136.6, 141.6, 145.8, 163.3, 165.4, 166.6; HRMS
(ESI): [MþH]þ found 386.4100. C21H24NO6 requires 386.4100.
Yellow crystal (polyhedron), dimensions 0.20ꢀ0.18ꢀ0.17 mm3,
ꢀ
crystal system triclinic, space group P1, Z¼2, a¼9.634(2) A,
b¼10.353(2) A, c¼12.449(3) A,
a
¼92.670(5)ꢁ,
b
¼103.161(5)ꢁ,
ꢀ
ꢀ
3
ꢀ
g
¼112.601(4)ꢁ, V¼1103.8(4) A ,
r
l
¼1.358 g/cm3, ꢁ T¼200(2) K,
Thetamax¼28.39ꢁ, radiation Mo K
a
,
¼0.71073 A, 0.3 omega-scans
ꢀ
with CCD area detector, covering a whole sphere in reciprocal
space, 11,762 reflections measured, 5427 unique (R(int)¼0.0472),
3724 observed (I>2s(I)), intensities were corrected for Lorentz and
polarization effects, an empirical absorption correction was applied
using SADABS14a based on the Laue symmetry of the reciprocal
4.2.5. Trimethyl 1-(4-methoxyphenyl)-4-p-tolyl-1,4-dihydropyrid-
ine-2,3,6-tricarboxylate (9e). Yield (0.380 g, 84%) as an orange
solid; mp146.4e147.5 ꢁC; Rf (33% EtOAc/Hexane) 0.42; nmax (KBr)
space,
m
¼0.10 mmꢂ1, Tmin¼0.98, Tmax¼0.98, structure solved by
1735 cmꢂ1
;
dH (500 MHz, CDCl3) 2.36 (3H, s, CH3), 3.49 (3H, s,
direct methods and refined against F2 with a Full-matrix least-
squares algorithm using the SHELXTL (Version 2008/4) software
package,14b 298 parameters refined, hydrogen atoms were treated
using appropriate riding models, goodness of fit 0.96 for observed
OCH3), 3.54 (3H, s, OCH3), 3.56 (3H, s, OCH3), 3.80 (3H, s, OCH3),
4.65 (1H, d, J 6.0 Hz, CH), 6.05 (1H, d, J 6.0 Hz, ]CH), 6.84 (2H, d, J
8.9 Hz, Ar), 7.19 (2H, d, J 7.9 Hz, Ar), 7.21 (2H, d, J 8.9 Hz, Ar), 7.28
(2H, d, J 7.9 Hz, Ar); dC (125 MHz, CDCl3) 21.1, 38.6, 51.6, 51.1, 52.4,
55.3, 101.6, 113.8, 119.2, 127.6, 129.6, 130.0, 131.5, 133.4, 136.7, 142.3,
146.0, 159.2, 162.9, 164.6, 166.6; HRMS (ESI): [MþH]þ found
reflections, final residual values R1(F)¼0.057, wR(F2)¼0.146 for
ꢀꢂ3
observed reflections, residual electron density ꢂ0.27e0.39 e A
.
CCDC 883084 contains the supplementary crystallographic data for

742
S. Balalaie et al. / Tetrahedron 69 (2013) 738e743
this paper. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
145.8, 162.7, 164.4, 166.3; HRMS (ESI): [MþH]þ found 442.1053.
C23H2135ClNO6 requires 442.1053, [MþH]þ found 444.1024.
C23H2137ClNO6 requires 444.1024, [MþNa]þ found 464.0872.
C23H2035ClNNaO6 requires 464.0872, [MþNa]þ found 466.0843.
C23H2037ClNNaO6 requires 466.0843, [MþK]þ found 480.0611.
C23H2035ClKNO6 requires 480.0611, [MþK]þ found 482.0584.
C23H2037ClKNO6 requires 482.0584.
4.2.8. Trimethyl4-(4-methoxyphenyl)-1-phenyl-1,4-dihydropyridine-
2,3,6-tricarboxylate (9h). Yield (0.227 g, 52%) as a yellow solid; mp
134.4e135.1 ꢁC; Rf (33% EtOAc/Hexane) 0.49; nmax (KBr) 1740 cmꢂ1
;
dH (500 MHz, CDCl3) 3.47 (3H, s, OCH3), 3.51 (3H, s, OCH3), 3.57 (3H,
s, OCH3), 3.82 (3H, s, OCH3), 4.65 (1H, d, J 6.0 Hz, CH), 6.10 (1H, d, J
6.0 Hz, ]CH), 6.92 (2H, d, J 7.0 Hz, Ar), 7.27e7.37 (7H, m, Ar); dC
(125 MHz, CDCl3) 38.2, 51.6, 52.0, 52.4, 55.3, 102.0, 114.3, 119.7,
128.3,128.4,128.8,128.9,131.2,137.5,141.1,145.4,158.7,162.9,164.6,
166.6; HRMS (ESI): [MþH]þ found 438.1546. C24H24NO7 requires
438.1546, [MþNa]þ found 460.1366. C24H23NNaO7 requires
460.1366, [MþK]þ found 476.1105. C24H23KNO7 requires 476.1105.
4.2.13. Trimethyl4-(4-chlorophenyl)-1-(4-methoxyphenyl)-1,4-
dihydropyridine-2,3,6-tricarboxylate (9m). Yield (0.410 g, 87%) as
a yellow crystalline; mp 164.4e165.4 ꢁC; Rf (33% EtOAc/Hexane)
0.52; nmax (KBr) 1740 cmꢂ1
; dH (300 MHz, CDCl3) 3.50 (3H, s, OCH3),
3.54 (3H, s, OCH3), 3.56 (3H, s, OCH3), 3.80 (3H, s, OCH3), 4.68 (1H, d,
J 5.8 Hz, CH), 6.00 (1H, d, J 5.8 Hz, ]CH), 6.84 (2H, d, J 8.8 Hz, Ar),
7.19 (2H, d, J 8.8 Hz, Ar), 7.26e7.37 (4H, m, Ar); dC (75 MHz, CDCl3)
38.5, 51.7, 52.2, 52.5, 55.4, 100.3, 113.9, 118.1, 128.1, 129.9, 132.9,
133.0, 143.7, 146.2, 159.3, 162.7, 164.4, 166.4; HRMS (ESI): [MþH]þ
found 472.1161. C24H2335ClNO7 requires 472.1161, [MþNa]þ found
494.0977. C24H2235ClNNaO7 requires 494.0977, [MþNa]þ found
496.0949. C24H2237ClNNaO7 requires 496.0949, [MþK]þ found
510.0717 C24H2235ClKNO7 requires 510.0718, [MþK]þ found
512.0691. C24H2237ClKNO7 requires 512.0691.
4.2.9. Trimethyl 1,4-bis(4-methoxyphenyl)-1,4-dihydropyridine-2,3,6-
tricarboxylate (9i). Yield (0.355 g, 76%) as a light-red solid; mp
117.4e118.4 ꢁC; Rf (33% EtOAc/Hexane) 0.45; nmax (KBr) 1735,
1704 cmꢂ1
; dH (300 MHz, CDCl3) 3.49 (3H, s, OCH3), 3.53 (3H, s,
OCH3), 3.56 (3H, s, OCH3), 3.80 (3H, s, OCH3), 3.81 (3H, s, OCH3),
4.63 (1H, d, J 6.0 Hz, CH), 6.04 (1H, d, J 6.0 Hz, ]CH), 6.84 (2H, d, J
8.8 Hz, Ar), 6.92 (2H, d, J 8.5 Hz, Ar), 7.21 (2H, d, J 8.8 Hz, Ar), 7.30
(2H, d, J 8.5 Hz, Ar); dC (75 MHz, CDCl3) 38.1, 51.6, 52.0, 52.4, 55.2,
55.3, 101.7, 113.8, 114.2, 119.2, 128.8, 129.9, 131.3, 133.3, 137.6, 145.8,
158.7, 159.2, 162.9, 164.6, 166.7; HRMS (ESI): [MþH]þ found
468.1657. C25H26NO8 requires 468.1658, [MþNa]þ found 490.1474.
C25H25NNaO8 requires 490.1475, [MþK]þ found 506.1215.
C25H25KNO8 requires 506.1215.
4.2.14. Trimethyl 1-(4-bromophenyl)-4-(4-chlorophenyl)-1,4-
dihydropyridine-2,3,6-tricarboxylate (9n). Yield (0.350 g, 67%) as
a yellow crystalline; mp 188.4e189.3 ꢁC; Rf (33% EtOAc/Hexane) 0.51;
nmax (KBr) 1730, 1709 cmꢂ1
; dH (500 MHz, CDCl3) 3.52 (3H, s, OCH3),
3.56 (3H, s, OCH3), 3.57 (3H, s, OCH3), 4.68 (1H, d, J 6.0 Hz, CH), 6.09
(1H, d, J 6.0 Hz, ]CH), 7.14 (2H, d, J 8.7 Hz, Ar), 7.29 (2H, d, J 8.4 Hz, Ar),
7.35 (2H, d, J 8.4 Hz, Ar), 7.48 (2H, d, J 8.7 Hz, Ar); dC (125 MHz, CDCl3)
38.5, 51.8, 52.2, 52.7,102.0,119.4,122.5,129.0,129.1,130.2,131.3,132.2,
133.1, 139.8, 143.2, 145.4, 162.4, 164.2, 166.1; HRMS (ESI): [MþH]þ
found 520.0158. C23H2079Br35ClNO6 requires 520.0158, [MþNa]þ
found 541.9974. C23H1979Br35ClNaNO6 requires 541.9974, [MþK]þ
found 557.9715. C23H1979Br35ClKNO6 requires 557.9715.
4.2.10. Trimethyl1-(4-bromophenyl)-4-(4-methoxyphenyl)-1,4-
dihydropyridine-2,3,6-tricarboxylate (9j). Yield (0.304 g, 59%) as
a yellow solid; mp 145.6e146.7 ꢁC; Rf (33% EtOAc/Hexane) 0.62; nmax
(KBr) 1776, 1730 cmꢂ1
; dH (300 MHz, CDCl3) 3.51 (3H, s, OCH3), 3.56
(3H, s, OCH3), 3.57 (3H, s,OCH3), 3.81 (3H, s, OCH3), 4.63(1H, d, J6.0 Hz,
CH), 6.15 (1H, d, J 6.0 Hz, ]CH), 6.91 (2H, d, J 8.7 Hz, Ar), 7.16 (2H, d, J
8.7Hz,Ar), 7.28(2H, d, J8.9 Hz, Ar), 7.48 (2H, d, J8.9 Hz, Ar); dC (75MHz,
CDCl3) 38.1, 51.8, 52.2, 52.6, 55.7, 102.6, 109.6,114.3, 120.5, 122.3, 128.7,
130.1, 130.7, 132.1, 137.0, 140.1, 158.8, 162.6, 164.5, 166.5; HRMS (ESI):
[MþNa]þ found 538.0476. C24H2279BrNNaO7 requires 538.0476,
[MþK]þ found 554.0217. C24H2279BrKNO7 requires 554.0218.
Acknowledgements
S.B. gratefully acknowledges Alexander von Humboldt founda-
tion for research fellowship. We are also thanking Ministry of
Health and medicinal education (Iran) and also presidential office
deputy of science and technology for financial support.
4.2.11. Trimethyl 1-benzyl-4-(4-chlorophenyl)-1,4-dihydropyridine-
2,3,6-tricarboxylate (9k). Yield (0.337 g, 74%) as a yellow crystal-
line; mp 217.3e218.5 ꢁC; Rf (33% EtOAc/Hexane) 0.31; nmax (KBr)
Supplementary data
1730, 1694 cmꢂ1
; dH (500 MHz, CDCl3) 3.60 (3H, s, OCH3), 3.75 (3H,
Supplementary data associated with this article can be found in
the online version, at http://dx.doi.org/10.1016/j.tet.2012.10.082.
These data include MOL files and InChiKeys of the most important
compounds described in this article.
s, OCH3), 3.93 (3H, s, OCH3), 4.42 (1H, d, J 15.5 Hz, NeCH2), 4.49 (1H,
d, J 6.6 Hz, CH), 5.11 (1H, d, J 15.5 Hz, NeCH2), 6.03 (1H, d, J 6.6 Hz, ]
CH), 6.83 (2H, d, J 8.4 Hz, Ar), 7.08 (2H, d, J 8.4 Hz, Ar), 7.21e7.33 (5H,
m, Ar); dC (125 MHz, CDCl3) 38.2, 51.7, 52.0, 52.5, 53.1, 102.9, 121.6,
128.3, 128.5, 128.7, 128.8, 129.2, 131.0, 132.6, 136.2, 142.3, 146.0,
163.2, 165.4, 166.3; HRMS (ESI): [MþH]þ found 456.1213.
C24H2335ClNO6 requires 456.1214, [MþH]þ found 458.1184.
C24H2337ClNO6 requires 458.1185, [MþNa]þ found 478.1030.
C24H2235ClNNaO6 requires 478.1031, [MþNa]þ found 480.1003.
C24H2237ClNNaO6 requires 480.1003, [MþK]þ found 494.0771.
C24H2235ClNKO6 requires 494.0772, [MþK]þ found 496.0744.
C24H2237ClNKO6 requires 496.0745.
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