Microwave assisted solid phase catalyst-free Biginelli synthesis of 3,4-dihydropyrimidin-2(1H)-one and 3,4-dihydropyrimidin-2(1H)-thione: A green approach, characterization and molecular crystal structures

Article abstract of DOI:10.1080/15421406.2016.1235928

Solid phase catalyst-free Biginelli synthesis of novel 5-carbethoxy-4-(3-bromo-4-hydroxy-5-methoxyphenyl)-6-methyl-3,4-dihydropyrimidin-2(1H)-one (C₁₅H₁₇BrN₂O₅) and 5-carbethoxy-4-(3-bromo-4-hydroxy-5-methoxyphe

Full text of DOI:10.1080/15421406.2016.1235928

Molecular Crystals and Liquid Crystals
ISSN: 1542-1406 (Print) 1563-5287 (Online) Journal homepage: http://www.tandfonline.com/loi/gmcl20
Microwave assisted solid phase catalyst-free
Biginelli synthesis of 3,4-dihydropyrimidin-2(1H)-
one and 3,4-dihydropyrimidin-2(1H)-thione: A
green approach, characterization and molecular
crystal structures
Minaxi S. Maru
To cite this article: Minaxi S. Maru (2016) Microwave assisted solid phase catalyst-free Biginelli
synthesis of 3,4-dihydropyrimidin-2(1H)-one and 3,4-dihydropyrimidin-2(1H)-thione: A green
approach, characterization and molecular crystal structures, Molecular Crystals and Liquid
Crystals, 641:1, 53-62, DOI: 10.1080/15421406.2016.1235928
To link to this article: http://dx.doi.org/10.1080/15421406.2016.1235928
Published online: 15 Dec 2016.
Article views: 4
View supplementary material
Submit your article to this journal
View related articles
View Crossmark data
Full Terms & Conditions of access and use can be found at
http://www.tandfonline.com/action/journalInformation?journalCode=gmcl20
Download by: [FU Berlin]
Date: 27 December 2016, At: 09:16

MOLECULAR CRYSTALS AND LIQUID CRYSTALS
, VOL. , –

http://dx.doi.org/./..
Microwave assisted solid phase catalyst-free Biginelli synthesis
of ,-dihydropyrimidin-(H)-one and

,-dihydropyrimidin-(H)-thione: A green approach,
characterization and molecular crystal structures
Minaxi S. Maru
Chemical Research Laboratory, Department of Chemistry, Saurashtra University, Rajkot, Gujarat, India
ABSTRACT
KEYWORDS
Solid phase catalyst-free Biginelli synthesis of novel 5-carbethoxy-4-(3-
bromo-4-hydroxy-5-methoxyphenyl)-6-methyl-3,4-dihydropyrimidin-2
,-Dihydropyrimidin-(H)-
one;

,-Dihydropyrimidin-(H)-
(
1H)-one (C H BrN O ) and 5-carbethoxy-4-(3-bromo-4-hydroxy-5-
15 17 2 5
thione; Microwave
irradiation; solid phase
catalyst-free biginelli
synthesis; single crystal
structure
methoxyphenyl)-6-methyl-3,4-dihydropyrimidin-2(1H)-thione
BrN O S) has been carried out under microwave irradiation at 400W.
(C H
15 17
2
4
1
13
The structures of both compounds were confirmed by H NMR,
C
NMR, Mass, FT-IR, Elemental analysis, and single crystal X-ray diffraction
method. The single crystals of both compounds were obtained by crys-
tallization in 0.35 × 0.30 × 0.25 mm dimension for (C H BrN O ) and
1
5
17
2
5
0
.35 × 0.32 × 0.30 mm dimension for (C H BrN O S). Both compounds,
1
5
17
2
4
(
C H BrN O ) and (C H BrN O S) crystallizes in the monoclinic P2 /c
15 17 2 5 15 17 2 4 1
space group and shows four and two intermolecular hydrogen bonds,
respectively.
Introduction
The Biginelli compounds, 4-substituted phenyl dihydropyrimidines (DHPMs) have set their
position as pharmacological important compounds since they deport themselves as neu-
ropeptide Y (NPY) antagonism, α -1a-antagonists, calcium channel blockers and antihyper-
1
tensive agents [1], also their use as an anticancer drug capable of inhibiting kinesin motor pro-
tein. In addition, DHPMs have been widely studied to develop their current Structure Activity
Relation (SAR) to get an extra vision into the molecular interactions at the receptor level [2–
4
]. Many DHPMs and their derivatives are very much familiar for their extensive variety of
biological properties, viz., antibacterial, antitumor, antiviral, anti-inflammatory, etc. [5] and
achieved a significant place in the empire of nature and synthetic organic chemistry. Many
alkaloids holding the DHPM motif as a core unit in their structure unveil exciting biologi-
cal belongings as well, which have been isolated from marine sources [6]. Precisely, batzel-
ladine alkaloids, found as a potent HIV gp-120-CD4 inhibitors [7]. Merely, thioxo deriva-
tive of DHPM “monastrol” can be considered as a lead molecule for the development of new
anticancer drugs because it is the only cell-permeable antagonist, which blocks normal bipolar
spindle assembly in mammalian cells resulting in halt of the cell cycle [8,9].
CONTACT Minaxi S. Maru
dr.maru@gmail.com
Saurashtra University, Rajkot, Gujarat, India.
Chemical Research Laboratory, Department of Chemistry,
Color versions of one or more of the figures in the article can be found online at www.tandfonline.com/gmcl.
Supplemental data for this article can be accessed on the publisher’s website.
©
 Taylor & Francis Group, LLC

5
4
M. S. MARU
Classically DHPM was first synthesized by Biginelli using one-pot condensation reaction
of benzaldehyde, ethyl acetoacetate, and urea under strong acidic conditions [5]. This con-
ventional DHPM synthetic method always struggles with long reaction time and low yields
throughout the entire reaction process with substituted aromatic and aliphatic aldehydes
[
10,11].
Moreover, various catalysts have been reported for the synthesis of DHPMs in past liter-
ature like triphenylphosphine [12], acidic ionic liquid [13], Tungstate Sulfuric Acid (TSA)
14], bioglycerol-based sulfonic acid functionalized carbon catalyst [15], hyderotalcite [16],
chiral organocatalyst [17], Fe O @ mesoporous SBA-15(mesoporous nanocatalyst) [18],
[
3
4
5
% perchloric acid doped silica (HClO /SiO ) [19], poly(1-vinyl-3-(3-sulfopropyl) imida-
4 2
zolium hydrogen sulfate) (poly(SIL)) [20], t-BuOK [21], SPINOL–phosphoric acid [22], 1-
methylimidazolium hydrogen sulfate in the presence of catalytic amount of chlorotrimethyl-
silane ([Hmim]HSO /TMSCl) [23], [Gmim]Cl-Cu(II) complex in neat condition [24] and
4
other general catalysts such as, triflates of lanthanide compounds [25], H BO [26], CAN
3
3
[
27], NaCl [28], [Al(H O) ](BF ) [29], SnCl .2H O [30], Fe(OTs) .6H O [31], etc. along
2 6 4 3 2 2 3 2
with microwave irradiation. All these catalytic approaches involves the use of organic solvents,
harsh reaction conditions, challenging and costly catalysts preparation, protracted reaction
time, inadequate and moderate yields and tiresome workup procedures.
That’s why, with a vision of the inclusive pharmacological and therapeutically impor-
tance, plus drawbacks of catalytic synthetic methods of 3,4-DHPMs, two novel compounds
5
-carbethoxy-4-(3-bromo-4-hydroxy-5-methoxyphenyl)-6-methyl-3,4-dihydropyrimidin-2
(1H)-one (C H BrN O ) and 5-carbethoxy-4-(3-bromo-4-hydroxy-5-methoxyphenyl)-
15
17
2
5
6
-methyl-3,4-dihydropyrimidin-2(1H)-thione (C H BrN O S) have been synthesized
15 17 2 4
without solvent and catalyst under microwave irradiation in 15 minutes and characterized
by single crystal X-ray diffraction crystallography and several spectroscopic methods. In
this paper, an efficient environment friendly procedure has been reported for the synthesis
of two new DHPM molecules in microwave irradiation system without using any solvent
and catalysts. There are very few reports on solvent- and catalyst-free synthesis of DHPMs
[
32,33].
Somehow, the crystal structure determination of the presented compounds is little bit dif-
ficult, because of very limited information on the DHPM crystal structures in their struc-
tural supports. The main approach of the present work is to discover these DHPMs under
microwave irradiated synthesis by means of green approach and development of their single
crystal structures because these compounds are extremely new and have not been reported in
past literature. This both compounds are mean to be important because of very limited tes-
timony on single crystal structures and very less medicinal accounts of the DHPMs as well.
This effort is a pintsize contribution in the world of DHPM structural chemistry through the
single crystal structure determination of innovative DHPM molecules.
The present research work is in prolongation of the previously published research involv-
ing two novel molecules of dihydropyridine (DHP) derivatives [34,35]. After successful solid
phase catalyst free synthesis and structural characterization of both new DHPMs, the single
crystal structure development of other DHPM and DHP derivatives is in progress.
Experimental
Materials and methods
All Reagents and solvents were commercially available from Spectrochem and Merck and was
used as received without further purification. Synthesis of both compounds was carried out

MOLECULAR CRYSTALS AND LIQUID CRYSTALS
55
in Whirlpool AKL260 microwave oven at 400 W. Analytical TLC was performed on silica
gel-G using chloroform:methanol as solvent system. Melting points were determined in open
capillaries on a melting point apparatus purchased from JSGW and is uncorrected. Both com-
pounds were micro analyzed satisfactorily for C, H and N in EURO EA Elemental Analyzer,
EA-3000, RS-232. The IR spectra were recorded on Shimadzu FT-IR 8400 spectrophotome-
ter using KBr discs. The ESI mass spectra were recorded on Micromass Q-Tof Micro having
1
13
mass Range of 4000 amu in quadruple and 20,000 amu in ToF. H and C NMR spectra were
recorded in DMSO-d on a Bruker Av 500 spectrophotometer using the TMS as an inter-
6
nal standard and the chemical shifts are reported in δ ppm scale. The single crystal X-Ray
Diffraction studies were acquired on Enraf Nonius CAD4-MV diffractometer.
31
Synthesis of 3-bromo-4-hydroxy-5-methoxybenzaldehyde
-Bromo-4-hydroxy-5-methoxybenzaldehyde has been synthesized according to the previ-
3
ously published method [36]. To the continuous stirring solution of vanillin (15 g, 100 mmol)
in glacial acetic acid (35 mL) at 0–5°C temperature, a solution of bromine (16 g, 100 mmol)
in glacial acetic acid (10 mL) was added dropwise. A white colored product was separated
immediately, which was treated with cold water and filtered through suction with 50 mL of
water wash. Crude product was then dried in vacuum and crystallized from alcohol as cubic
crystals. Yield 16 g (70.2%). M.p. 163–64°C. (Lit. m.p. 164°C) [37].
Synthesis of 5-carbethoxy-4-(3-bromo-4-hydroxy-5-methoxyphenyl)-6-methyl-3,4-
dihydropyrimidin-2(1H)-one/thione
A mixture of 3-bromo-4-hydroxy-5-methoxybenzaldehyde (2.301 g, 10 mmol), ethyl 3-
oxobutanoate (1.301 g, 10 mmol), and urea (0.630 g, 10.5 mmol)/thiourea (0.799 g,
1
0.5 mmol) in 50 mL beaker was placed in a domestic microwave oven and irradiated at 400 W
for 5 min. Reaction mixture was stirred with glass rod and again irradiated at 400W for 10 min
and was monitored by TLC using chloroform:methanol (8.5:1.5) solvent system. After com-
pletion of reaction the resulting reaction mixture was cooled to room temperature and 15 mL
methanol was added to soluble the solid which was then removed under reduced pressure to
desired product.
5-Carbethoxy-4-(3-bromo-4-hydroxy-5-methoxyphenyl)-6-methyl-3,4-
dihydro-pyrimidin-2(1H)-one (C H BrN O )
15
17
2
5
Yield 92% (3.55 g), m.p. 227°C, Elemental analysis: (C H BrN O ) Calcd. C, 46.77; H, 4.45;
15
17
2
5
N, 7.27; O, 20.77; Found C, 46.59; H, 4.32; N, 7.13; O, 20.61, Mass: m/z = 385, IR (KBr,
ν cm ): 3575–3291 (N-H stretching), 3104 and 3010 (C-H stretching of aromatic), 2975
C-H asymmetric stretching of –CH ), 2941 (C-H symmetric stretching of –CH ), 2848 (C-
−1
(
3
3
H asymmetric stretching of –CH ), 2745 (C-H symmetric stretching of –CH ), 1676 (C=O
2
2
stretching of NH-CO-NH), 1586 (C=O stretching of ester), 1285 and 1042 (C-O-C stretching
1
of –OCH ). H NMR (δ ppm, DMSO-d + 500 MHz): 1.11–1.14 (t, 3H, -CH ), 2.26 (s, 3H,
3
6
3
-
6
CH ), 3.79 (s, 3H, -OCH ), 3.98–4.05 (m, 2H, -CH ), 5.09 (s, 1H, -CH), 6.83 (s, 1H, Ar-H),
3 3 2
.87 (s, 1H, Ar-H), 7.72 (s, 1H –NH), 9.20 (s, 1H, -NH) and 9.44 (s, 1H, -OH). C NMR (δ
13
ppm, DMSO-d + 500 MHz): 14.56, 18.22, 53.70, 56.49, 59.69, 99.39, 109.41 & 109.91, 121.96,
6
1
37.22, 143.39, 148.67, & 148.91, 152.50, 165.75.

5
6
M. S. MARU
Figure . ORTEP diagram of -Carbethoxy--(-bromo--hydroxy--methoxyphenyl)--methyl-,-dihydr-
opyrimidin-(H)-one (C H BrN O ) using % probability level ellipsoids.


 
5-Carbethoxy-4-(3-bromo-4-hydroxy-5-methoxyphenyl)-6-methyl-3,4-
dihydropy-rimidin-2(1H)-thione (C H BrN O S)
15
17
2
4
Yield 87% (3.49 g), m.p. 210°C, Elemental analysis: (C H BrN O S) Calcd. C, 44.90; H,
15
17
2
4
4
.27; N, 6.98; O, 15.95; Found C, 44.77; H, 4.11; N, 6.83; O, 15.78, Mass: m/z = 401, IR (KBr,
−1
ν cm ): 3576–3363 (N-H stretching), 3108 (C-H stretching of aromatic), 2967 (C-H asym-
metric stretching of –CH ), 2933 (C-H symmetric stretching of –CH ), 2871 (C-H asymmet-
3
3
ric stretching of –CH ), 2733 (C-H symmetric stretching of –CH ), 1683 (C=O stretching of
2
2
NH-CO-NH), 1643 (C=O stretching of ester), 1228 and 1047 (C-O-C stretching of –OCH ).
3
1
H NMR (δ ppm, DMSO-d + 500 MHz): 1.12–1.14 (t, 3H, -CH ), 2.29 (s, 3H, -CH ), 3.78
6
3
3
(
s, 3H, -OCH ), 4.00–4.07 (m, 2H, -CH ), 3.98–4.01 (m, 2H, -CH ), 5.10 (s, 1H, -CH), 6.81–
3 2 2
6
.84 (dd, 2H, Ar-H, J = 15 Hz), 9.54 (s, 1H, -NH), 9.61 (s, 1H, -NH), and 10.35 (s, 1H, -OH).
1
3
C NMR (δ ppm, DMSO-d + 500 MHz): 14.03, 17.14, 53.24, 56.04, 59.62, 100.38, 109.06, &
6
1
09.47, 121.68, 135.35, 143.28, 145.12, 148.26, 156.06, 174.15.
Single crystal development method
In a 100 mL beaker 1 g quantity of dried pure product was taken along with sufficient amount
of methanol for compound (C H BrN O ) and binary mixture of methanol and acetonitrile
15
17
2
5
for compound (C H BrN O S), which were then heated on hot plate till solid product gets
15
17
2
4
dissolved, 1 g of activated charcoal was added and heated again then filtered the hot solution
through whatmann 42 filter paper in 50 mL stopper conical flask and loosely cover the stopper
for slow evaporation. The filtered solution was allowed to stand at room temperature for 2–
4
weeks to form colorless and light yellow colored crystals of compound (C H BrN O )
15 17 2 5
and (C H BrN O S), respectively. Obtained crystals were filtered and wash with very small
15
17
2
4
quantity of methanol and analyzed by single crystal X-ray diffraction method. Both structures
were successfully achieved by X-ray crystallographic analysis as displayed in Figures 1 and 2.

MOLECULAR CRYSTALS AND LIQUID CRYSTALS
57
Figure . ORTEP diagram of -Carbethoxy--(-bromo--hydroxy--methoxyphenyl)--methyl-,-dihydr-
opyrimidin-(H)-thione (C H BrN O S) using % probability level ellipsoids.


 
Results and discussions
Both pioneering, 5-carbethoxy-4-(3-bromo-4-hydroxy-5-methoxyphenyl)-6-methyl-3,4-
dihydropyrimidin-2(1H)-one (C H BrN O ) and 5-carbethoxy-4-(3-bromo-4-hydroxy-5-
15
17
2
5
methoxyphenyl)-6-methyl-3,4-dihydropyrimidin-2(1H)-thione (C H BrN O S) com-
15
17
2
4
pounds have been synthesized using Biginelli synthetic method under solvent- and
catalyst-free microwave irradiation in excellent yield and purity. The synthetic route used
for the synthesis of both compounds is given in Scheme 1. The reaction involves a one pot
multicomponent cyclocondensation reaction of ethyl 3-oxobutanoate, 3-bromo-4-hydroxy-
5
-methoxybenzaldehyde and urea/thiourea without solvent and catalyst.
Both compounds were screened for selected solvents under microwave irradiation by using
HCl as a catalyst to know the yield variation with and without use of solvents and catalyst, data
are given in Table S1 (Supplementary material). The data obviously shows the best results in
absence of solvent and catalyst under microwave irradiation at 400W for 15 min. Similarly,
Scheme . Reaction scheme for the synthesis of compounds (C H BrN O ) and (C H BrN O S).




 
 

5
8
M. S. MARU
both compounds were conventionally synthesized under optimized reaction condition too,
which takes 5 hours to give desired products with moderate yield formation when solvent
and catalyst were used, however without catalyst the reaction time was double and the yield
formations were very poor for both compounds.
The solid phase catalyst-free conventional Biginelly synthesis of both new compounds has
been completed in an open beaker under optimized reaction conditions by taking known
amounts of substrates and catalyst at 80°C temperature for 5 h with continuous stirring on oil
bath, which were then treated with sufficient amount of methanol to get the yield in 57% and
4
8% of desired products (C H BrN O ) and (C H BrN O S), respectively. While, without
15 17 2 5 15 17 2 4
catalyst under reflux condition for 10 h the yield formation was in the range of 65–41% and
2–40% of both compounds, respectively.
6
1
13
The elemental analysis, FT-IR, ESI mass, H and C NMR spectral data are in good agree-
ment with the crystal structures of the both newly synthesized DHPM compounds. Formation
1
of both compounds ((C H BrN O ) and (C H BrN O S)) was confirmed by the H NMR
15
17
2
5
15 17
2
4
spectra with a presence of two NH peak at δ 7.72, 9.20, and 9.54, 9.61 ppm, respectively, and
13
also by the C NMR spectra, which shows the carbonyl carbon peak of ester, methoxy and the
oxo groups at 156.75, 152.50, and 148.91 ppm, respectively in compound (C H BrN O ),
15
17
2
5
while in the compound (C H BrN O S) three characteristic carbon peak of ester, methoxy
15
17
2
4
and the thioxo groups observed at 174.15, 165.05, and 148.26 ppm, respectively. The ESI
mass spectra of both compounds show the molecular ion peaks at 389.28 m/z [M+4, 24%]
and 407.27 m/z [M+6, 100%], also shows the fragmented molecular ion peaks with respect
to their total molecular weight. The FT-IR spectrums of both compound displays a sharp
−1
band at 3291–3575 and 3327–3576 cm corresponds to the –NH groups present in DHPM
compounds.
Crystal structure determination
The crystal structures of both compounds were cracked by direct method SHELXS-97 [38]
2
and determined by full matrix least-squares on F with program system SHELXL-97 [39]. The
monoclinic single crystal system of the title compounds were obtained in 0.35 × 0.30 × 0.25
and 0.35 × 0.32 × 0.30 mm dimensional crystal size and analyzed at 296(2) K temperature
for the collection of crystal data of the compound (C H BrN O ) and (C H BrN O S)
15
17
2
5
15 17
2
4
respectively. The intensity data of the both crystals of the compound (C H BrN O ) and
15
17
2
5
(
C H BrN O S) having shelxl identification code were collected using graphite monochro-
15 17 2 4
˚
mated MoKα radiation is 0.71073 A in the ω-2θ scan mode. The compounds crystallizes in
˚
the monoclinic P2 /c space group with unit cell dimensions a = 11.2902(5) A, b = 8.7197(4)
1
˚
˚
A, c = 18.6642(7) A and α = 90°, β = 97.893(2)°, γ = 90° for (C H BrN O ) and a =
15
17
2
5
˚
˚
˚
1
0.7986(4) A, b = 8.1241(3) A, c = 18.9091(8) A, and α = 90°, β = 92.0810(10)°, γ = 90° for
(C H BrN O S). The crystal data and final refinement details of both DHPM compounds
15
17
2
4
are given in Table 1.
The crystal structure of the compound (C H BrN O ) shows the presence of methanol,
15
17
2
5
because this crystal has a tendency to behave as opaque without solvent. In contrary, com-
pound (C H BrN O S) doesn’t show any solvent molecule in its crystal structure as it is
15
17
2
4
translucent even without solvent (Figures 1 and 2). This difference may be because of the
substitution change of atom O(5) and S(1) in both compounds on the atom C(6) of DHPM
ring.
In both compound, (C H BrN O ) and (C H BrN O S) the DHPM ring having atoms
15
17
2
5
15 17
2
4
C(4), C(5), N(2), C(6), N(1), C(7), and C(4), C(5), N(1), C(6), N(2), C(7), respectively, are
not planar, as indicated by the atomic coordinates and equivalent isotropic displacement

MOLECULAR CRYSTALS AND LIQUID CRYSTALS
59
Table . Crystal data and structure refinement for (C H BrN O ) and (C H BrN O S).




 
 
Identification code
Shelxl
Shelxl
Empirical formula
Formula weight
Crystal colour
Temperature
C H BrN O
.
White
() K
C H BrN O S
   




.
Pale yellow
() K
. A˚
Wavelength
. A˚
Crystal system
space group
Unit cell dimensions
Monoclinic
Monoclinic
P /c
P /c


a = .() A˚ α = °
a = .() A˚ α = °
b = .() A˚ β = .()°
c = .() A˚ γ = °
b = .() A˚ β = .()°
c = .() A˚ γ = °
.() A

.() A


Volume
Z
Calculated density
Absorption coefficient
F()


. mg/m
. mg/m
−

−
. mm

. mm

Crystal size
Theta range for data collection
Limiting indices
. × . × . mm
. × . × . mm
.° to .°
− ࣘ h ࣘ 
− ࣘ k ࣘ 
− ࣘ l ࣘ 
. to .°
 ࣘ h ࣘ 


 ࣘ k ࣘ 
 ࣘ l ࣘ 
Reflections collected / unique
Completeness to theta = .
Absorption correction
Max. and min. transmission
Refinement method
 /  [R(int) = .]
 /  [R(int) = .]
.%
.%
Semi empirical from equivalents
. and .
Full matrix least squares on F
Semi empirical from equivalents
. and .
Full matrix least squares on F


Data / restraints / parameters
Goodness of fit on F
Final R indices [I > sigma(I)]
R indices (all data)
Largest diff. peak and hole
 /  / 
.
 /  / 
.
R = ., wR = .
R = ., wR = .




R = ., wR = .
R = ., wR = .




−

−
. and . e. A˚
. and . e.A
˚
parameters of atoms C(7) [x = 8207(3), y = 5497(3), z = 9649(2), U = 31(1) A] and C(5)
eq
˚
[
x = 2297(2), y = 5058(2), z = 2184(1), U = 28(1) A] and by the torsion angle 17.9(4)° of
eq
atoms C(4)-C(7)-N(1)-C(6) and 26.1(3)° of atoms C(4)-C(5)-N(1)-C(6).
Torsion angle obtained from the compound (C H BrN O ) is of the atoms C(7) and N(2)
15
17
2
5
(
1.8(5)°) and from the compound (C H BrN O S) is of the atoms C(5) and N(2) (4.6(3)°),
15 17 2 4
which gives a good agreement of displacement from the ring in the same direction. On the
other hand, opposite to those of pyrimidine ring, the substituted phenyl ring with methoxy,
hydroxy and bromo groups has an axial orientation. This axial orientated substituted phenyl
rings, C(9), C(10), C(11), C(12), C(13), C(14) being perpendicular to the DHPM ring in both
compounds (Figures 1 and 2). The distance observed between the C(7) and N(2) atoms of
compound (C H BrN O ) and C(5) and N(2) atoms of compound (C H BrN O S) and
15
17
2
5
15 17
2
4
the perpendicular orientation of phenyl ring on C(7) and C(5) atoms of both compounds
gives clear evidence about the flattened boat-type confirmation of the DHPM ring having
dihedral angles 110.1(2)° and 113.8(2)° of atoms N(1)-C(7)-C(9) and C(4)-C(7)-C(9) from
(
C H BrN O ), whereas, angles 110.92(16)° and 111.72(16)° of atoms N(1)-C(5)-C(9) and
15 17 2 5
C(4)-C(5)-C(9) from (C H BrN O S) with the substituted phenyl ring.
15
17
2
4
Hydrogen bonding determination
It is supposed to be for the DHPM compounds that hydrogen bonding existence in the crys-
tal structure could be the major role during the calcium channel antagonist effect. Accord-
ing to the H-pack diagram of compound (C H BrN O ), the carbonyl group substituted at
15
17
2
5

6
0
M. S. MARU
˚
Table . Hydrogen bonds for the compound (C H BrN O ) and (C H BrN O S) [A and°].




 


(
C H BrN O )
   
D-H···A
d(D-H)
d(H···A)
d(D···A)
<(DHA)
#
C()-H(C)···O()
.
.
.
.
.()
.()
.
.
.
.
.()
.()
.()
.()
.()
.()
.()
.()
.
.
.
.
()
()
#
N()-H(D)···O()
N()-H(D)···O()
#
#

N()-H(C)···O()
#

O()-H()···O()
O()-H(A)···O()
(
C H BrN O S)
   
D-H···A
d(D-H)
d(H···A)
d(D···A)
<(DHA)
#

C()-H(A)···S()
.
.
.
.
.
.
.
.
.
.
.()
.()
.()
.()
.()
.()
.()
.()
.
.
.
.
.
.
()
()
#

C()-H(B)···Br()
#

C()-H()···O()
C()-H(A)···O()
C()-H(B)···S()
#

#

O()-H()···O()
N()-H(C)···S()
.
.
#

.()
.()
.()
.()
#

N()-H(D)···O()
#

#
Symmetry transformations used to generate equivalent atoms for (C H BrN O ) -x + , −y + , −z + ; -x + , −y + , −z


 
#
#
#
#
#
+
; -x + , −y + , −z + ; x-, y, z and for (C H BrN O S) -x, y + /, −z + /; -x + , y + /, −z + /; -x + ,


 
#
y-/, −z + /; -x, −y + , −z.
C(4) in both compounds are involved in hydrogen bonding; thus, the structure of compound
C H BrN O ) exhibits four intermolecular hydrogen bonds involving;
(
1
5
17
2
5
(
a) An O(2) atom of C(4) substituted carbonyl group to the H(6A) hydrogen substituted
at O(6) atom of methanol molecule [O(6)-H(6A)···O(2) having (x-1, y, z) symmetry
˚
code with 1.85(6) A length and 153(6)° angle].
b) An O(6) atom substituted at C(16) atom of methanol to the H(4) hydrogen of hydroxyl
(
group substituted at C(12) atom [O(4)-H(4)···O(6) having (x-1, y, z) symmetry code
˚
with 1.85(6) A length and 153(6)° angle].
c) An O(3) atom of C(13) substituted methoxy group to the H(6) hydrogen of methanol.
(
(
d) Hydrogen bonding between DHPM rings, an O(5) atom substituted at C(6) to the
H(2C) hydrogen substituted at N(2) atom of DHPM ring [N(2)-H(2C)···O(5) hav-
˚
ing (−x + 2, −y + 2, −z + 2) symmetry code with 2.01 A length and 171.8° angle]
(Table 2, Figure 3).
Figure . The unit cell diagram of compound (C H BrN O ) showing hydrogen bonding interactions.


 

MOLECULAR CRYSTALS AND LIQUID CRYSTALS
61
Figure . The unit cell diagram of compound (C H BrN O S) showing hydrogen bonding interactions.


 
However, in the compound (C H BrN O S), the H-pack diagram only shows two inter-
15
17
2
4
molecular hydrogen bonds having same symmetry code (-x + 1, y-1/2, −z + 1/2);
(
a) An O(2) atom of C(2) substituted carbonyl group to the H(3) hydrogen of hydroxyl
˚
group substituted at C(12) [O(3)-H(3)···O(2) with 1.90 A length and 165.4° angle].
(b) An O(4) atom of methoxy group substituted at C(13) to the H(1D) hydrogen of N(1)
˚
atom at DHPM ring [N(1)-H(1D)···O(4) with 2.221(17) A length and 165(2)° angle]
(Table 2, Figure 4).
The rest of intermolecular hydrogen bonds of both compounds are summarized in Table 2
which are not displayed in H-pack diagrams, among them for the compound (C H BrN O )
15
17
2
5
are;
(
a) H(16C) hydrogen of C(16) atom of methanol to the oxo O(5) atom [C(16)-
˚
H(16C)···O(5) with 2.57 A length and 146.8° angle] and H(1D) hydrogen of N(1) atom
˚
to the O(6) atom of methanol [N(1)-H(1D)···O(6) with 2.62 A length and 153.9° angle]
having same symmetry code (-x + 2, −y + 1, −z + 2).
(b) H(1D) hydrogen of N(1) atom to the O(3) atom of methoxy group having (-x + 1,
˚
−
y + 1, −z + 2) symmetry code [N(1)-H(1D)···O(3) with 2.64 A length and 131.4°
angle].
And for the compound (C H BrN O S) are;
(
15
17
2
4
˚
a) H(2A) hydrogen of C(2) atom to the thioxo S(1) atom [C(2)-H(2A)···S(1) with 2.97 A
length and 136.8° angle] having (-x, y + 1/2, −z + 1/2) symmetry code.
(b) H(2B) hydrogen of C(2) atom to Br(1) atom substituted to the C(12) atom of phenyl
˚
ring [C(2)-H(2B)···Br(1) with 3.08 A length and 143.4° angle] and H(15B) hydrogen
˚
of C(15) atom to the thioxo S(1) atom [C(15)-H(15B)···S(1) with 3.00 A length and
1
42.4° angle] having (-x + 1, y + 1/2, −z + 1/2) symmetry code.
(
c) H(2C) hydrogen of N(2) atom to the thioxo S(1) atom having (-x, −y + 1, −z) sym-
˚
metry code [N(2)-H(2C)···S(1) with 2.571(16) A length and 172(2)° angle].
Crystallographic data information
Crystallographic data for the structures reported in this paper have been deposited in
the Cambridge Crystallographic Data Centre as supplementary information, which can
be accessed on an application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK (fax:
(
+44)1223–336–033; e-mail: deposit@ccdc.cam.ac.uk, www: http://www.ccdc.cam.ac.uk).
The structure deposition number for 5-Carbethoxy-4-(3-bromo-4-hydroxy-5

6
2
M. S. MARU
-
1
methoxyphenyl)-6-methyl-3,4-dihydropyrimidin-2(1H)-one (C H BrN O ) is CCDC-
001977 and for 5-Carbethoxy-4-(3-bromo-4-hydroxy-5-methoxyphenyl)-6-methyl-3,4-
15 17 2 5
dihydropyrimidin-2(1H)-thione (C H BrN O S) is CCDC-1001970.
15
17
2
4
References
[
1] (a) Atwal, K. S., Rovnyak, G. C., O’Reilly, B. C., & Schrartz, J. J. (1989). J. Org. Chem., 54, 5898–
5
907. (b) Atwal, K. S. et al. (1990). J. Med. Chem., 33, 2629–2635. (c) Rovnyak, G. C. et al. (1995).
J. Med. Chem., 38, 119–129.
2] Atwal, K. et al. (1990). J. Med. Chem., 33, 1510–1515.
3] Rovnyak, G. C. et al. (1992). J. Med. Chem., 35, 3254–3263.
4] (a) Kappe, C. O., (1993). Tetrahedron, 49, 6937–6963. (b) Kappe, C. O., Fabian, W. M. F., &
Semones, M. A. (1997). Tetrahedron, 53, 2803–2816.
5] Biginelli, P., (1893). Gazz. Chim. Ital., 23, 360–413.
6] Overman, L. E., Rabinowitz, M. H., & Renhowe, P. A. (1995). J. Am. Chem. Soc., 117, 2657–2658.
7] Patil, A. D. et al. (1995). J. Org. Chem., 60, 1182–1188.
8] Kappe, C. O., Shishkin, O. V., Uray, G., & Verdino, P. (2000). Tetrahedron, 56, 1859–1862.
9] Gartner, M. et al. (2005). ChemBioChem, 6, 1173–1177.
[
[
[
[
[
[
[
[
[
[
[
10] Folkers, K., & Johnson, T. B. (1934). J. Am. Chem. Soc., 56, 1180–1185.
11] Wipf, P., & Cunningham, A. (1995). Tetrahedron Lett., 36, 7819–7822.
12] Aswin, K., Sheik Mansoor, S., Logaiya, K., & Sudhan, S. P. N. (2014). J. King Saud Univ. Sci., 26,
1
41–148.
[
[
13] Heidarizadeha, F., Rezaee Nezhada, E., & Sajjadifar, S. (2013). Scientia Iranica C, 20, 561–565.
14] Karami, B., Haghighijou, Z., Farahi, M., & Khodabakhshi, S. (2012). Phosphorus, Sulfur Silicon
Relat. Elem., 187:6, 754–761.
[
[
15] Konkala, K. et al. (2012). Tetrahedron Lett., 53, 1968–1973.
16] Lal, J., Sharma, M., Gupta, S., Parashara, P., Sahua, P., & Agarwala, D. D. (2012) J. Mol. Catal. A.
Chem., 352, 31–37.
17] Saha, S., & Moorthy, J. N. (2011). J. Org. Chem. 76, 396–402.
[
[
[
18] Mondal, J., Sen, T., & Bhaumik, A. (2012). Dalton Trans., 41, 6173–6181.
19] Narahari, S. R., Reguri, B. R., Gudaparthi, O., & Mukkanti, K. (2012). Tetrahedron Lett., 53, 1543–
1
545.
[20] Pourjavadi, A., Hosseini, S. H., & Soleyman, R. (2012). J. Mol. Catal. A. Chem., 365, 55–59.
[21] Shen, Z. -L., Xu, X. -P., & Ji, S. -J. (2010). J. Org. Chem., 75, 1162–1167.
[22] Xu, F., Huang, D., Lin, X., & Wang, Y. (2012). Org. Biomol. Chem., 10, 4467–4470.
[23] Kefayati, H., Asghari, F., & Khanjanian, R. (2012). J. Mol. Liq., 172, 147–151.
[24] Parasuraman, K., Aswar, S. A., Muskawar, P. N., Bhagat, P. R., & Senthil Kumar, S. J. (2012). Organ-
met. Chem., 723, 154–162.
[
[
[
[
[
[
[
[
[
25] Huang, Y., Yang, F., & Zhu, C. (2005). J. Am. Chem. Soc., 127 (47), 16386–16387.
26] Ismaili, L. et al. (2008) Eur. J. Med. Chem., 43, 1270–1275.
27] Karade, H. N., Acharya, J., & Kaushik, M. P. (2012). Tetrahedron Lett., 53, 5541–5543.
28] Kolosov, M. A., Orlov, V. D., Beloborodov, D. A., & Dotsenko, V. V. (2009). Mol. Div., 13, 5–25.
29] Litvic, M. et al. (2010). Tetrahedron, 66, 3463–3471.
30] Ashok, M., Holla, B. S., & Kumari, N. S. (2007). Eur. J. Med. Chem., 42, 380–385.
31] Starcevich, J. T., Laughlin, T. J., & Mohan, R.S. (2013). Tetrahedron Lett., 54, 983–985.
32] Wang, R., & Liu, Z. -Q. (2012). J. Org. Chem., 77(8), 3952–3958.
33] Harikrishnan, P. S., Rajesh, S. M., Abdulrahman, S. P., & Almansour I. (2013). Tetrahedron Letters,
5
4, 1076–1079.
[
[
[
34] Minaxi, S. M., & Manish, K. S. (2013). Mol. Crys. Liq. Crys., 574(1), 117–128.
35] Minaxi S. M., & Manish K. S. (2015) Mol. Crys. Liq. Crys., 623(1), 217–225.
36] Ahluwalia, V. K., Bhagat, P., Aggarwal, R., & Chandra, R. (2005). Intermediates for organic synthe-
sis, I. K. international Pvt. Ltd., New Delhi, 44.
th
[
[
[
37] Dictionary of organic compounds by Chapman, & Hall, 5 Edition, B-02262.
38] Sheldrick, G. M. (1990). Acta Crystallogr., A46, 467–473.
39] Sheldrick, G. M. (1997). SHELXL-1997, Program for Refinement of Crystal Structures, University
of Göttingen: Germany.