J Chem Crystallogr
vasodilator, antitumor, antimutagenic, antihypertensive,
bronchodilator, geroprotective and antidiabetic agents [1]. In
recent years it was found that drugs such as nifedipine and
niguldipine undergo redox processes due to the catalysis of
cytochrome P-450 in the liver during their metabolism [2].
Also 1,4-DHPS are well-known compounds as a conse-
quence of their pharmacological profile as the most impor-
tant calcium channel modulators. For example, amlodepine
besylate, nifedepine and related dihydropyridines are cal-
cium channel blockers, and are rapidly emerging as one of
the most important classes of drugs for the treatment of
cardiovascular diseases including hypertension [3, 4].
Additionally, dihydropyridines are often produced in a
synthetic sequence, and have to be oxidized to pyridines [5].
The classical method for the synthesis of 1,4-DHPS is a one-
pot condensation of an aldehyde with 1,3-dicarbonyl com-
pounds, and ammonia either in acetic acid or refluxing in
alcohol [6].
methyl acetoacetate (20 mmol) and ammonium acetate
(10 mmol) was refluxed in ethanol for 3 h. After completion
of the reaction, the mixture was cooled to room temperature
and quenched into ice cold water. The yellow solid thus
obtainedwasfilteredandwashedwithwater andrecrystallised
from a mixture of acetone and diethyl ether. The molecular
formulae, compositions (calculated and found), melting
points and recrystallization solvents of each of the three
Hantzsch 1,4-DHPS are: dimethyl 4-(4-hydroxy-3-methox-
yphenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarbox-
ylate, (I): C18H21NO6, C: 62.19(62.24 %); H: 6.07(6.
09 %); N: 4.01(4.03 %); Found: C, 62.19; H, 6.07; N, 4.01;
M.P-505 K, methanol; dimethyl 4-(4-bromophenyl)-2,6-
dimethyl-1,4-dihydropyridine-3,5-dicarboxylate, (II): C17
H18BrNO4, C: 53.66 (53.70 %); H: 4.75(4.77 %); N:
3.65(3.68 %); Found: C, 53.66; H, 4.75; N, 3.65, M.P-
472 K, DMF; dimethyl 4-(3-bromo-4-methoxyphenyl)-
2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate, (III):
C18H20BrNO5, C: 52.71(52.70%); H:4.92 (4.91 %); N:
3.38(3.41 %); Found: C, 52.71; H, 4.92; N, 3.38, M.
P. 467 K, acetonitrile; dimethyl 2-(2,5-dimethoxyphenyl)-
4,6-dimethyl-1,2-dihydropyridine-3,5-dicarboxylate (IV)
C19H23NO6, Yield 62 %. C: 63.15; H, 6.41; N, 3.88; Found:
C, 63.11; H, 6.43; N, 3.82., M.P-410 K., acetone/diethyl
ether.
The crystal structures of some related 1,4-DHPS, viz.,
dimethyl 1,4-dihydro-4-(4-methoxyphenyl)-2,6-dimethylpyri-
dine-3,5-dicarboxylate [7], dimethyl 4-(4-ethoxyphenyl)-2,6-
dimethyl-1,4-dihydropyridine-3,5-dicarboxylate [8], dimethyl
4-(3,4-dimethoxyphenyl)-2,6-dimethyl-1,4-dihydropyridine-3,
5-dicarboxylate [9], diethyl 4-(4-bromophenyl)-2,6-dimethyl-
1,4-dihydropyridine-3,5-dicarboxylate [10], diethyl 4-(2,5-
dimethoxyphenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dic-
arboxylate [11], and three methoxy-substituted diethyl
4-phenyl-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarbox-
ylate compounds [12] have been reported. In view of the
importance of these derivatives, we report here the syn-
thesis, crystal structures and theoretical calculations for
four dihydropyridine derivatives namely, dimethyl 4-(4-
hydroxy-3-methoxyphenyl)-2,6-dimethyl-1,4-dihydropyri-
dine-3,5-dicarboxylate (I), dimethyl 4-(4-bromophenyl)-
2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate (II),
dimethyl 4-(3-bromo-4-methoxyphenyl)-2,6-dimethyl-1,4-
dihydropyridine-3,5-dicarboxylate (III) and dimethyl
2-(2,5-dimethoxyphenyl)-4,6-dimethyl-1,2-dihydropyridine-
3,5-dicarboxylate (IV) supported by DFT theoretical calcu-
lations Hirshfeld surface analysis and fingerprint plots ana-
lyzing intermolecular interactions.
Melting points were taken in open capillary tubes and
are uncorrected. The purity of the compounds were
confirmed by thin layer chromatography using Merck
silica gel 60 F254 coated aluminium plates. Elemental
analysis was carried out by using VARIO EL-III (Ele-
mentar Analysensysteme GmBH). All chemicals
were purchased from Sigma-Aldrich Co., USA. Absorp-
tion spectra were recorded on a Cary 300 UV–Vis
spectrophotometer.
X-Ray Structure Analysis and Refinement
X-ray data for was collected with an Agilent Gemini R
Eos CCD area detector using CrysAlisPro software [13]
˚
and graphite-monochromated Cu Ka (k = 1.54178 A) at
100(2) K. The structures were solved by direct methods
using SHELXS97 [14] and all of the non-hydrogen atoms
were refined anisotropically by full-matrix least-squares
on F2 using SHELXL97 [14]. In [II, III and IV] the
hydrogen atoms were placed in their calculated positions
and included in the refinement using the riding model. In
(I) the N–H hydrogen atom was located by a difference
map and refined isotropically. An absorption correction
was performed using CrysAlis RED [13] and all calcula-
tions were performed using SHELXTL [15]. Each struc-
ture was checked using PLATON [16]. Crystal and
experimental data for (I, II, II and IV) are listed in
Table 1. ORTEP and structural diagrams [17] of the
Experimental Procedures
Synthesis of compounds (I), (II), (III) and (IV) were carried
according to the Hantzschpyridine synthesis (Scheme 1). The
products (I), (II) and (III) are, therefore, Hantzsch 1,4-DHPS.
But inthe synthesis ofcompound (IV), instead ofa 1,4-DHPS,
a rearranged product 1,2-dihydropyridine, was obtained
(Scheme 2). The structures of the products were confirmed by
elemental analysis and single crystal XRD. In the synthesis
procedure, a mixture of substituted benzaldehyde (10 mmol),
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