Dimorphism in (2Z)-2-benzylidene-N,7-dimethyl-3-oxo-5-phenyl-2,3-dihydro- 5H-1,3-thiazolo[3,2-a]-pyrimidine-6-carboxamide

Article abstract of DOI:10.1107/S0108270106046567

The title compound, C₂₂H₁₉N₃O ₂S, crystallizes in two polymorphic forms having the same space group, viz. P1, with Z′ = 2 and Z′ = 1. In both polymorphs, the planar thiazole ring is fused cis with the dihydropyr

Full text of DOI:10.1107/S0108270106046567

organic compounds
Acta Crystallographica Section C
Crystal Structure
Communications
reported (Atwal et al., 1990) that the critical factor for the
biological activity of most DHPMs is the absolute stereo-
chemistry at the C5 sterocentre. The bond distances and
ISSN 0108-2701
Dimorphism in (2Z)-2-benzylidene-
N,7-dimethyl-3-oxo-5-phenyl-2,3-
dihydro-5H-1,3-thiazolo[3,2-a]-
pyrimidine-6-carboxamide
B. Sridhar,a* K. Ravikumara and Y. S. Sadanandamb
aLaboratory of X-ray Crystallography, Indian Institute of Chemical Technology,
Hyderabad 500 007, India, and bOrganic Division, Indian Institute of Chemical
Technology, Hyderabad 500 007, India
Correspondence e-mail: sshiya@yahoo.com
angles in (Ia) and (Ib) (Tables 1 and 3) are in normal ranges
(Allen et al., 1987) and are comparable with the corresponding
values observed in similar structures (Sulmon et al., 1989;
Chandra Mohan et al., 2003; Liang & Cao, 2004). The mol-
ecular geometries of the two independent molecules in (Ia)
Received 16 October 2006
Accepted 6 November 2006
Online 22 November 2006
The title compound, C22H19N3O2S, crystallizes in two poly-
morphic forms having the same space group, viz. P1, with Z0 =
2 and Z0 = 1. In both polymorphs, the planar thiazole ring is
fused cis with the dihydropyrimidine ring, the carbamoyl
group is in an extended conformation with an anticlinal
orientation with respect to the pyrimidine ring, and the phenyl
ring is attached to the pyrimidine ring approximately at a right
angle. The two polymorphs have different interplanar angles
between the phenyl and thiazole rings. The molecules are
linked by NÐHÁ Á ÁO and CÐHÁ Á ÁO hydrogen bonds.
Ê
are very similar; the largest differences are 0.012 (4) A for the
C24ÐC25 bond distance and 1.1 (2)ꢀ for the C2ÐC21ÐC22
angle. The bond distances involving the S atom, viz. C2Ð
Ê
S1 and C9ÐS1, are signi®cantly different [0.01 (2) A]. In
polymorph (Ib), the benzylidene C22±C27 phenyl ring is
disordered (all atoms except C22) over two sites of equal
occupancy (Fig. 2).
Comment
Dihydropyrimidines (DHPMs) are heterocyclic systems of
remarkable pharmacological potency with antiviral, anti-
tumour, antibacterial and anti-in¯ammatory activities, and
they are used as calcium channel modulators and anti-
hypertensive agents (Kappe, 2000; Rovnyak et al., 1995).
DHPMs exhibit a similar pharmacological pro®le to DHP
calcium channel modulators of the nifedipine type and much
activity has been observed in this area (Kappe, 1993; Atwal et
al., 1991). A DHPM analogue has recently been identi®ed as a
potential new anticancer lead that is involved in blocking
mitosis by inhibition of a kinesin motor protein (Mayer et al.,
1999). We have reported a series of DHPM crystal structures
(Ravikumar & Sridhar, 2005; Sridhar & Ravikumar, 2005a,b)
and now report the crystal structures of two triclinic poly-
morphs, (Ia) and (Ib), of the title compound.
The two polymorphs crystallize in the same space group,
viz. P1, but there are two independent but chemically identical
molecules (1 and 2) in the asymmetric unit of form (Ia) (Fig. 1),
whereas there is only one in form (Ib) (Fig. 2). The pyrimidine
rings in (Ia) and (Ib) have a chiral C atom at the point of
attachment of the phenyl group. Since both compounds crys-
tallize in a centrosymmetric space group, in the solid state a
racemic mixture was obtained from the synthesis. It has been
Figure 1
Perspective views of the two independent molecules of polymorph (Ia),
showing the atom-numbering scheme. Displacement ellipsoids are drawn
at the 30% probability level and H atoms are shown as small spheres of
arbitrary radii.
Acta Cryst. (2006). C62, o687±o690
DOI: 10.1107/S0108270106046567
# 2006 International Union of Crystallography o687

organic compounds
Each molecule consists of a fused thiazolo[3,2-a]pyrimidine
ring system with a carbamoyl group and two substituent
phenyl groups. It is interesting to note that the thiazole ring
cyclization, with respect to the central pyrimidine ring,
preferentially occurs with N4 (linear fusion) over N8 (angular
fusion), perhaps facilitated by the simultaneous formation of
conjugated double bonds. As observed in a similar thiazole±
pyrimidine structure (Liu et al., 2004), the thiazole and
pyrimidine rings are only approximately coplanar in both
atom N6 and carbonyl atom O6 of the carbamoyl side chain
for both polymorphs. The phenyl rings [e.g. C51±C56 in (Ia)]
are oriented approximately perpendicular to the pyrimidine
ring, as shown by the torsion angle C6ÐC5ÐC51ÐC52
(Tables 1 and 3). Speci®cally, the interplanar angles are
79.8 (1)ꢀ for molecule 1 of (Ia), 78.2 (2)ꢀ for molecule 2 of (Ia)
and 78.6 (1)ꢀ for (Ib).
A signi®cant difference is observed in the orientation of the
benzylidene C22±C27 phenyl ring with respect to the thiazole
ring between the two independent molecules of (Ia) and in
(Ib) (Fig. 3). The interplanar angles between the mean planes
of the phenyl and thiazole rings are 10.2 (2) and 23.4 (2)ꢀ,
respectively, for molecules 1 and 2 in (Ia), and 29.5 (2) and
15.4 (1)ꢀ for the two disordered components of (Ib). The
disposition of the C9 C10 double bond with respect to the
phenyl ring affords the possibility of E and Z isomers. Both
polymorphs contain Z isomers, as shown by the C2ÐC21Ð
C22ÐC23 torsion angle (Tables 1 and 3). The dihedral angles
between the two phenyl rings are 84.3 (1) and 64.3 (1)ꢀ,
respectively, for molecules 1 and 2 in (Ia), and 61.4 (2) and
85.2 (2)ꢀ for the two disordered components in (Ib).
Ê
polymorphs, with maximum deviations of 0.161 (2) A for atom
Ê
C5 of molecule 1 of (Ia), 0.042 (2) A for atom C7 of mol-
Ê
ecule 2 of (Ia) and 0.084 (3) A for atom C7 of (Ib) with
respect to the least-squares planes de®ned by atoms S1/C2/C3/
N4/C5±C7/N8/C9 of the ring system. The interplanar angles
between the pyrimidine and thiazole rings are 6.1 (2)ꢀ for
molecule 1 of (Ia), 2.8 (1)ꢀ for molecule 2 of (Ia) and 4.2 (1)ꢀ
for (Ib).
The carbamoyl side chain is in a fully extended conforma-
tion. The spatial arrangement of the carbonyl group at C6
adopts an anticlinal (ac) orientation about the C6ÐC61 bond
(Tables 1 and 3). This orientation can probably be attributed
to intermolecular NÐHÁ Á ÁO hydrogen bonding involving
In both polymorphs (Ia) and (Ib), the crystal structure is
stabilized by NÐHÁ Á ÁO, CÐHÁ Á ÁO and CÐHÁ Á ÁS hydrogen
bonds (Tables 2 and 4). A weak intramolecular CÐHÁ Á ÁS
hydrogen bond forms a pseudo-six-membered ring of an S(6)-
type motif (Bernstein et al., 1995) in both polymorphs. The
molecules of (Ia) are linked by a combination of NÐHÁ Á ÁO
Figure 2
A perspective view of the molecule of polymorph (Ib), showing the atom-
numbering scheme. Displacement ellipsoids are drawn at the 30%
probability level and H atoms are shown as small spheres of arbitrary
radii.
Figure 3
The least-squares ®t between molecule 1 of polymorph (Ia) (labelled 1),
Figure 4
A part of the crystal structure of polymorph (Ia), showing the in®nite
chain along the b axis. Dashed lines indicate NÐHÁ Á ÁO and CÐHÁ Á ÁO
hydrogen bonds. For the sake of clarity, H atoms not involved in hydrogen
bonding have been omitted. Only atoms involved in hydrogen bonding
are labelled. [Symmetry code: (i) x, y 1, z.]
Ê
molecule 2 of polymorph (Ia) (labelled 2) (r.m.s. deviation = 0.062 A) and
Ê
the molecule of polymorph (Ib) (labelled 3) (r.m.s. deviation = 0.031 A).
The disordered atoms of the minor component (C121±C161) and all H
atoms have been omitted for clarity.
ꢁ
o688 Sridhar et al. C22H19N3O2S and C22H19N3O2S
Acta Cryst. (2006). C62, o687±o690

organic compounds
mixture of (4) (5.2 g, 2 mmol), chloroacetic acid (2 g, 2 mmol),
benzaldehyde (2 g, 2 mmol), fused sodium acetate (4 g, 5 mmol),
acetic acid (20 ml) and acetic anhydride (8 ml) was re¯uxed for 1 h,
cooled and poured into cold water. The suspended solid was dissolved
in diethyl ether and then treated with petroleum ether (313±333 K) to
give a yellow solid, which was recrystallized from dimethylform-
amide. Crystals of polymorph (Ia) suitable for X-ray analysis were
obtained by slow evaporation of a dimethylformamide solution and
those of polymorph (Ib) were obtained from a methanol solution.
Polymorph (Ia)
Crystal data
3
Ê
C22H19N3O2S
Mr = 389.46
Triclinic, P1
a = 9.5353 (6) A
b = 10.2071 (6) A
c = 20.7901 (12) A
ꢀ = 79.198 (1)ꢀ
ꢁ = 79.645 (1)ꢀ
ꢂ = 78.257 (1)ꢀ
V = 1924.8 (2) A
Z = 4
3
Dx = 1.344 Mg m
Mo Kꢀ radiation
Ê
1
Ê
ꢃ = 0.19 mm
T = 293 (2) K
Ê
Needle, pale yellow
0.20 Â 0.11 Â 0.08 mm
Data collection
Bruker SMART APEX CCD area-
detector diffractometer
! scans
6733 independent re¯ections
5389 re¯ections with I > 2ꢄ(I)
Rint = 0.021
Figure 5
A part of the crystal structure of polymorph (Ib), showing the in®nite
chain along the a axis. Dashed lines indicate NÐHÁ Á ÁO and CÐHÁ Á ÁO
hydrogen bonds. For the sake of clarity, the disordered atoms of the minor
component (C121±C161) and all H atoms not involved in hydrogen
bonding have been omitted. Only atoms involved in hydrogen bonding
are labelled. [Symmetry code: (i) x 1, y, z.]
14058 measured re¯ections
ꢅmax = 25.0ꢀ
Re®nement
Re®nement on F2
R[F2 > 2ꢄ(F2)] = 0.053
wR(F2) = 0.141
w = 1/[ꢄ2(Fo2) + (0.0671P)2
+ 0.5641P]
2
where P = (Fo + 2Fc2)/3
S = 1.06
6733 re¯ections
517 parameters
H atoms treated by a mixture of
independent and constrained
re®nement
(Á/ꢄ)max = 0.001
3
Ê
Áꢆmax = 0.34 e A
3
Ê
0.15 e A
and CÐHÁ Á ÁO hydrogen bonds (Table 2). Within the asym-
metric unit, atom N6 acts as hydrogen-bond donor, via atom
H6N, to atom O60. In a similar manner, atom N60 at (x, y, z)
acts as donor, via atom H6N0, to atom O6 at (x, y 1, z). These
NÐHÁ Á ÁO hydrogen bonds lead to the formation of an in®nite
chain of C(4)-type motifs, running along the crystallographic b
axis (Fig. 4). In a similar fashion, CÐHÁ Á ÁO interactions
involving atom C52 of the phenyl ring and atom O3 of the
thiazole ring form an in®nite chain running along the b axis. In
(Ib), atoms N6 and C52 act as hydrogen-bond donors to atoms
O6 and O3 (Table 4) thereby generating a C(4)-type motif of
chains running along the crystallographic a axis (Fig. 5).
The hydrogen-bond networks thus formed facilitate alter-
nating hydrophobic and hydrophilic zones in both poly-
morphs. In polymorph (Ia), the hydrophobic layers around the
Áꢆmin
=
Table 1
Selected geometric parameters (A, ) for polymorph (Ia).
ꢀ
Ê
C2ÐS1
C9ÐS1
C24ÐC25
1.748 (2)
1.755 (2)
1.377 (4)
C20ÐS10
1.746 (2)
1.755 (2)
1.365 (4)
C90ÐS10
C240ÐC250
C2ÐC21ÐC22
131.1 (2)
C20ÐC210ÐC220
130.0 (2)
C2ÐC21ÐC22ÐC27
C2ÐC21ÐC22ÐC23
C6ÐC5ÐC51ÐC52
C7ÐC6ÐC61ÐO6
C6ÐC61ÐN6ÐC62
4.3 (4)
179.4 (2)
79.0 (2)
135.6 (2)
177.0 (2)
C20ÐC210ÐC220ÐC270
C20ÐC210ÐC220ÐC230
C60ÐC50ÐC510ÐC520
C70ÐC60ÐC610ÐO60
C60ÐC610ÐN60ÐC620
20.2 (4)
161.8 (3)
77.4 (2)
131.5 (2)
175.3 (2)
1
3
b = and b = axes are sandwiched between the hydrophilic
4
4
layers about b = 0 and b = 1, while in polymorph (Ib), the
hydrophobic layers around a = 12 are sandwiched between the
hydrophilic layers about a = 0 and a = 1.
Table 2
Hydrogen-bond geometry (A, ) for polymorph (Ia).
ꢀ
Ê
DÐHÁ Á ÁA
DÐH
HÁ Á ÁA
DÁ Á ÁA
DÐHÁ Á ÁA
Experimental
N6ÐH6NÁ Á ÁO60
N60ÐH6N0Á Á ÁO6i
C27ÐH27Á Á ÁS1
C270ÐH270Á Á ÁS10
C52ÐH52Á Á ÁO30
C520ÐH520Á Á ÁO3i
0.82 (2)
0.80 (2)
0.93
0.93
0.93
2.17 (2)
2.16 (2)
2.55
2.63
2.31
2.939 (3)
2.922 (3)
3.255 (3)
3.267 (3)
3.193 (3)
3.247 (3)
157 (2)
161 (2)
133
126
160
A mixture of N-methylacetoacetamide, (1) (100 mmol), thiourea, (2)
(100 mmol), benzaldehyde, (3) (100 mmol), absolute ethanol (50 ml)
and concentrated hydrochloric acid (2 ml) was stirred and warmed
slightly over a steam bath until the mixture become a clear solution. It
was allowed to stand overnight at room temperature. The
pyrimidinethione thus formed, (4), was ®ltered off and dried. A
0.93
2.32
173
Symmetry code: (i) x; y 1; z.
ꢁ
Acta Cryst. (2006). C62, o687±o690
Sridhar et al. C22H19N3O2S and C22H19N3O2S o689

organic compounds
methyl atoms and 1.2Ueq(C) for the other H atoms. In (Ib), atoms
C23±C27 of the C22±C27 phenyl ring were found to be disordered.
Re®ning the disordered model led to occupancy factors of 0.507 (4)
and 0.493 (4), not signi®cantly different from equal occupancy; in the
®nal cycles, the occupancies of the disordered atoms were ®xed at 0.5.
The displacement parameters of the disordered atoms C23/C231,
C24/C241, C25/C251, C26/C261 and C27/C271 were restrained to
isotropic behaviour. The geometries of the disordered atoms were
Polymorph (Ib)
Crystal data
3
Ê
C22H19N3O2S
Mr = 389.46
Triclinic, P1
a = 5.1109 (9) A
Ê
b = 9.5564 (16) A
V = 968.0 (3) A
Z = 2
3
Dx = 1.336 Mg m
Mo Kꢀ radiation
Ê
1
ꢃ = 0.19 mm
T = 293 (2) K
Ê
c = 20.503 (3) A
ꢀ = 97.594 (3)ꢀ
ꢁ = 93.371 (3)ꢀ
ꢂ = 101.755 (3)ꢀ
Block, pale yellow
0.20 Â 0.17 Â 0.12 mm
Ê
restrained, where distances were set to a target value of 1.39 A.
For both compounds, data collection: SMART (Bruker, 2001); cell
re®nement: SAINT (Bruker, 2001); data reduction: SAINT;
program(s) used to solve structure: SHELXS97 (Sheldrick, 1997);
program(s) used to re®ne structure: SHELXL97 (Sheldrick, 1997);
molecular graphics: SHELXTL/PC (Sheldrick, 1990); software used
to prepare material for publication: SHELXL97.
Data collection
Bruker SMART APEX CCD area-
detector diffractometer
! scans
3395 independent re¯ections
2656 re¯ections with I > 2ꢄ(I)
Rint = 0.037
9402 measured re¯ections
ꢅmax = 25.0ꢀ
Re®nement
The authors thank Dr M. Meera Shetty for providing the
compounds and Dr J. S. Yadav, Director, IICT, Hyderabad, for
his kind encouragement.
Re®nement on F2
R[F2 > 2ꢄ(F2)] = 0.067
wR(F2) = 0.161
S = 1.28
3395 re¯ections
254 parameters
H atoms treated by a mixture of
independent and constrained
re®nement
w = 1/[ꢄ2(Fo2) + (0.0565P)2
+ 0.3108P]
where P = (Fo2 + 2Fc2)/3
(Á/ꢄ)max < 0.001
3
Ê
Áꢆmax = 0.43 e A
Supplementary data for this paper are available from the IUCr electronic
archives (Reference: GA3031). Services for accessing these data are
described at the back of the journal.
3
Ê
0.30 e A
Áꢆmin
=
References
Table 3
Selected geometric parameters (A, ) for polymorph (Ib).
ꢀ
Ê
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132.4 (3)
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C2ÐC21ÐC22ÐC231
29.9 (7)
14.6 (7)
151.5 (5)
169.8 (5)
C6ÐC5ÐC51ÐC52
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Table 4
Hydrogen-bond geometry (A, ) for polymorph (Ib).
ꢀ
Ê
DÐHÁ Á ÁA
DÐH
HÁ Á ÁA
DÁ Á ÁA
DÐHÁ Á ÁA
N6ÐH6NÁ Á ÁO6i
C27ÐH27Á Á ÁS1
C52ÐH52Á Á ÁO3i
0.83 (3)
0.93
0.93
2.14 (3)
2.63
2.29
2.935 (3)
3.257 (6)
3.210 (4)
161 (3)
125
169
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Madison, Wisconsin, USA.
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È
Gottingen, Germany.
The N-bound H atoms were located in a difference density map
and re®ned isotropically. All other H atoms were positioned
geometrically and were treated as riding on their parent C atoms, with
Sridhar, B. & Ravikumar, K. (2005a). Acta Cryst. E61, o1414±o1416.
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54, 2587±2590.
Ê
CÐH distances of 0.93±0.98 A, and with Uiso(H) = 1.5Ueq(C) for
ꢁ
o690 Sridhar et al. C22H19N3O2S and C22H19N3O2S
Acta Cryst. (2006). C62, o687±o690