Synthesis and characterization via molecular quantum parameters of 2H-thiazolo[3,2-a]pyrimidine-3,5,7(6H)-trione

Article abstract of DOI:10.1002/jhet.746

2H-Thiazolo[3,2-a]pyrimidine-3,5,7(6H)-trione (2) was synthesized and characterized via molecular quantum parameters using the PM3-semiempirical MO method. This is considered the only route not previously reported in the literature to synthesize compound 2 from 2-imino-4-thiazolidinone (1).

Full text of DOI:10.1002/jhet.746

494
Synthesis and Characterization via Molecular Quantum
Vol 49
Parameters of 2H-Thiazolo[3,2-a]pyrimidine-3,5,7(6H)-trione
,*
Wafaa S. Hamama Mohamed A. Ismail, Mamdouh S. Soliman,
Saad Shaaban, and Hanafi H. Zoorob
Chemistry Department, Faculty of Science, Mansoura University, Egypt
*
E-mail: wshamama@yahoo.com
Received July 22, 2010
DOI 10.1002/jhet.746
View this article online at wileyonlinelibrary.com.
COOH
O
N
O
N
COOH
CH3COCl
S
O
O
2
HN
O
O
R
O
COOC2H5
NH
S
N
R
1
COOC2H5
S
N
R= H, n-butyl
2'
H3O+
O
HN
O
S
3
2H‐Thiazolo[3,2‐a]pyrimidine‐3,5,7(6H)‐trione (2) was synthesized and characterized via molecular quantum
parameters using the PM3‐semiempirical MO method. This is considered the only route not previously reported in
the literature to synthesize compound 2 from 2‐imino‐4‐thiazolidinone (1).
J. Heterocyclic Chem., 49, 494 (2012).
INTRODUCTION
RESULTS AND DISCUSSION
Biological activities of compounds containing uracil
moiety incorporated other heterocycles have been reported
[1,2]. Considering these reports, the development of new
and simple synthetic method for the efficient preparation
of heterocycles containing uracil ring fragment is therefore
an interesting challenge. The thiazolidinone ring system has
been widely used in the investigation of pharmacologically
active heterocyclic compounds [3–9], perhaps most notably
as a common structural motif in the Rosiglitazone class of
PPAR-8 agonists [10,11], anti-inflammatory Darbufelone
[12,13], and antiviral activities [14], have been found.
Few methods have been reported for the preparation of
thiazolo[3,2-a]pyrimidines, and the existed methodologies
required prolonged reaction times and strict reaction condi-
tions in organic solvents [15,16]. The preparation of thiazolo
[3,2-a]pyrimidines have been occurred by the reaction of
enones with 2-aminothiazole in ethanol [15], 2-thioxo-
1,2,3,4-tetrahydropyrimidines with phenacyl bromide in
glacial acetic acid [16], dihydropyrimidine-2-thiones with
α-bromophenylacetaldehyde in acetonitrile [17] and 4-
phenyl-3,4-dihydropyrimidine(1H)-2-thione with chloroa-
cetic acid in DMF [18] to afford thiazolo[3,2-a]pyrimidines
has also been reported.
The therapeutic importance of uracil nucleus condensed
with other heterocycles [1,2], enthused us to develop selec-
tive procedures to synthesize a number of condensed
heterocycles. Therefore, compound 1 as acetate salt was
reacted with an equimolar amount of the diesters namely;
diethyl malonate or diethyl n-butyl malonate in ethanol
containing few drops of H2O (least required amount to dis-
solve the salt) to give 2H-thiazolo[3,2-a]pyrimidine-3,5,7
(6H)-trione (20) was unsuccessful, but the thiazolidine-
2,4-dione (3) was obtained instead of the expected com-
pound 20. The structure of 3 was identical with that
reported in literature [19,20] (Scheme 1).
In addition, trials to obtain 2 by reaction of 1 with
diethylmalonate in the presence of the following media
(i) diphenyl ether, (ii) glacial acetic acid, (iii) triethyla-
mine/butanol, nitrobenzene or dry xylene, (iv) sodium
ethoxide/ethanol, or (v) diethylmalonate as solvent, were
failed. Accordingly, we used malonic acid catalyzed by
acetyl chloride at 60ꢀC whereby, 2H-thiazolo[3,2-a]-
pyrimidine-3,5,7(6H)-trione (2) was formed through bi-
functional attack of the reagent to the exo-cyclic imino
and endo-cyclicamido group of 1. The probable mecha-
nism for construction of 2 may be through the formation
© 2012 HeteroCorporation

May 2012
Synthesis and Characterization via Molecular Quantum Parameters of
2H‐Thiazolo[3,2‐a]pyrimidine‐3,5,7(6H)‐trione
495
Scheme 1
of protonated malonyl diacetate intermediate (A) followed
by its conversion to malonyl chloride via the chloride ion
attack to the intermediate (A), and subsequent condensation
with the thiazolidinone derivative 1. The condition of for-
mation of compound 2 was in line with the condition
reported in literature [21].
Figure 2. 3D-isosurface map at the total charge density contour value
0.02 of compound 1 with diethyl malonate.
process of this intermediate state did not lead to any addi-
tional interaction between hydrogen atom attached to N6
with the oxygen atom of (C1′¼ O), or any other kind of
bidentate interaction, which lead to ring nitrogen juncture
and the formation of compound 2 (Fig. 2).
The molecular quantum parameters and the electronic
structure of diethylmalonate and compound 1 when inter-
acted with each other were calculated. The resulted data
indicated that no bidentate addition is possible. Thus, we
used malonic acid in the presence of acetyl chloride
instead of diethyl malonate to produce the active malonyl
chloride reagent (Fig. 3). The MO calculations indicated
that, the bidentate addition of malonyl chloride to the
thiazolidinone ring is a possible process to be occurred
as the two molecules approach to each other as shown in
Table 1.
Once the two molecules approaching each other till a
certain distance, a strong interaction, raised between Cl
atoms of the malonyl chloride with H atoms of the
thiazolidinone ring. The 3D-isosurface was mapped at the
total charge density contour value of 0.02 and presented
in Figure 4. The molecular quantum parameters and the
electronic structure of malonyl chloride with compound 1
were calculated and the quantum parameters are shown in
Table 2.
The structure 2 was established on the basis of its analyt-
1
ical and spectral data. Thus, the H NMR spectrum of 2
displays two singlet signals at δ 4.38 and δ 4.69 ppm due
to (CH2CO) and (S-CH2) protons, respectively. Its mass
spectrum added further support to the assigned structure
and showed the molecular ion peak at m/z 184 (M+, 8%;
Fig. 1).
The reaction between thiazolidinone and diethyl malo-
nate showed that, the bidentate addition of diethyl
malonate to the thiazolidinone ring is not possible, and
the formation of compound 2 was unsuccessful. The elec-
tronic interaction behavior between the two molecules
was investigated using the PM3-semiempirical MO
method. Once, the two molecules approaching each other
till a certain distance, an interaction is generated between
H-atom attached to N3 with oxygen atom of carbonyl
(C3′¼ O) group. Consequently, geometry optimization
The distance between O— (C —03) and H— (Nꢁ3) was
calculated to be 1.878 Å. This value is lower than the
sum of the van der Waal’s radii of the two atoms (3.0 Å);
this indicates the strong H-bonding between the two atoms
prevent any interaction, that may occur between the carbon
atom of the carbonyl group of malonic acid with exo-cyclic
imino group. The same behavior was observed with the
Figure 1. Fragmentation pattern of 2H-thiazolo[3,2-a]pyrimidine-3,5,7
(6H)-trione (2).
0
endo-cyclic amido group H— (N−6) with O— (Cꢁ1 ).
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

496
W. S. Hamama, M. A. Ismail, M. S. Soliman, S. Shaaban, and H. H. Zoorob
Vol 49
Figure 4. 3D-isosurface map at the total charge density contour value
0.02 of compound 1 with malonic acid.
Figure 3. Mechanism of formation of 2H-thiazolo[3,2-a]pyrimidine-
3,5,7(6H)-trione (2).
(4) (Fig. 6). The two molecules were allowed to approach
each other and reorientate themselves according to their
electrostatic potential behavior.
However, in case of malonyl chloride, the distance between
the Cl— (C0–3) and H— (N−3) was calculated to be 2.58 Å,
which is lower than the sum of van der Waal’s radii of the
two atoms (3.0 Å). This indicates the strong interaction
This 3D-mapped isosurface of the molecule was calculated
for the optimized geometry of the two molecules (each under
the field-effect of the other) using the PM3-semiempirical MO
method. This display is a surface drawn with values of total
electron density and according to values of the electrostatic
potential. Accordingly, in Fedorova et al. reaction [22], there
is a possibility for interaction of the bromine atom with the
S-atom as shown in Figure 7. But there is no chance for the
additional interaction between the carbon atom of acetate
molecule with the nitrogen atom of the endo-cyclic amido
group of thiobarbituric acid molecule, which may lead to
cyclization. This is attributed to the steric hindrance as well
as the unsuitable charges and electrostatic potential at these
concerned sites. The important quantum chemical parameters
for the effective atoms and distances are depicted in Table 3.
0
between H (Nꢁ3) and Cl (Cꢁ3 ) and the possibility of the
elimination of HCl molecule, whereas, the bond between
0
H— (Nꢁ6) (of exo-cyclic imino group) and Cl— (C
)
ꢁ1
is stronger than the H —(Nꢁ3) (of endo-cyclic amido
0
group of thiazolidinone 1) and Cl (Cꢁ3 ) as indicated from
0
the shorter distance between H— (N−6)….Cl— (Cꢁ1 ).
These parameters give us an indication that the exo-cyclic
imino group of thiazolidinone 1 is more active for the
annulations process than that of endo-cyclic amido group.
The molecular quantum parameters and the electronic
structure of malonyl chloride with compound 1 were cal-
culated and illustrated in Table 2 and Figure 5.
This is the only route to synthesize compound 2 until
now from 2-imino-4-thiazolidinone (1) as Fedorova et al.
[22], tried to obtain compound 2 starting from thiobarbitu-
ric acid by alkylation with ethyl bromoacetate in ethanol
in the presence of alkali, she obtained undesired 5-
(2-oxo-2,5-dihydro-1,3-thiazol-4-y1)-2-thiobarbituric acid
EXPERIMENTAL
All melting points were determined on a Gallenkamp electric
melting point apparatus are uncorrected. Elemental microanalyses
were carried out at Microanalytical Unit (Faculty of Science,
Table 1
Important quantum chemical parameters for the effective atoms and bonds in compound 1 and diethyl malonate when interacted with each other (Fig. 2).
Atom
Charge
Bond
Bond length (Å)
Bond order
O¼ (C1′)
O¼ (C3′)
H— (N6′)
O— (C−3′
N6
(ꢁ0.270)
(ꢁ0.263)
(+0.089)
(+0.155)
(ꢁ0.095)
(ꢁ0.051)
O¼ C1′
O¼ C3′
N6— H
N3— H
N6 H…O¼ C1′
N3 H…O¼ C3′
N6 …C1′
1.213
1.219
0.988
0.998
4.03
1.841
1.76
0.993
0.004
—
)
N3
1.82
4.61
—
—
N3 …C3′
3.86
—
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

May 2012
Synthesis and Characterization via Molecular Quantum Parameters of
2H‐Thiazolo[3,2‐a]pyrimidine‐3,5,7(6H)‐trione
497
Table 2
Important quantum chemical parameters for the effective atoms and bonds
in compound 1 and malonyl chloride.
Bond
Bond
Atom
Charge
Bond
length (Å) order
Cl— (C1′)
Cl— (C3′)
H— (N6)
H— (N3)
C1
(ꢁ0.058) Cl— (C1′)
(ꢁ0.031) Cl— (C3′)
1.765
1.780
1.000
0.991
2.580
2.520
0.890
0.908
0.000
0.000
0.008
0.005
(0.109)
(0.079)
(0.260)
(0.270)
N6 H
N3 H
Cl….H— N6
Cl….H— N3
C3
Cairo University). IR spectra were recorded using KBr discs with
a Mattson 5000 FTIR spectrometer, Faculty of Science, Cairo
University. 1H NMR data were measured in CDCl3 or DMSO-d6
on a Varian XL 200, 300 MHz instruments using TMS as an inter-
nal standard. Chemical shifts were reported in ppm (δ) downfield
from that of TMS and coupling constants are expressed in hertz.
The mass spectra were recorded on GC-MS QP-1000 EX.
Shimadzu Instrument (Faculty of Science, Cairo University).
Reactions were monitored by thin layer chromatography (TLC)
using EM science silica gel coated plates with visualization by
irradiation with ultraviolet lamp. Molecular orbital calculations
and the quantum chemical parameters were determined using the
PM3-Semiempirical MO method using evaluation copy of
HyperChem.ver 7.5 (www.hyper.com). Package accommodated
on PIV-2.8-MHz computer system.
Figure 7. 3D-isosurface map at the total charge density contour value of
0.02 of thiobarbituric acid with ethyl bromoacetate.
2H-Thiazolo[3,2-a]pyrimidine-3,5,7(6H)-trione (2). To the
solution of 2-iminothiazolidin-4-one (1) (1 g, 8.6 mmol) in acetyl
chloride (10 mL), malonic acid (0.9 g, 8.6 mmol) was added, and
then the reaction mixture was heated for 3 h at 50–55ꢀC. The
reaction mixture poured onto ice temperature The precipitate
formed was collected by filtration and recrystallized from
Figure 5. 3D-isosurface map at the total charge density contour value 0.02 of compound 1 with malonylchloride.
Figure 6. Synthesis of 5-(2-oxo-2,5-dihydro-1,3-thiazol-4-y1)-2-thiobarbituric acid (4).
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

498
W. S. Hamama, M. A. Ismail, M. S. Soliman, S. Shaaban, and H. H. Zoorob
Vol 49
Table 3
REFERENCES AND NOTES
Important quantum chemical parameters for the effective atoms and bonds
in thiobarbituric acid and ethyl bromoacetate.
[1] Quiroga, J.; Cisneros, C.; Insuasty, B.; Abonia, R.; Nogueras
M.; Sanchez, A. Tetrahedron Lett 2001, 42, 5625.
[2] Girreser, U.; Heber, D.; Schutt, M. Tetrahedron 2004, 60, 11511.
[3] Rahman, V. P. M.; Mukhtar, S.; Ansari, W. H.; Lemiere, G.
Eur J Med Chem 2005, 40, 173.
Bond
length (Å)
Atom
Charge
Bond
[4] Rawal, R. K.; Prabhakar, Y. S.; Katti S. B.; De-Clercq, E.
Bioorg Med Chem 2005, 13, 6771.
S
Br
ꢁ0.208 Br-S
2.261
0.029
[5] Howard, M. H.; Cenizal, T.; Gutteridge, S.; Hanna, W. S.; Tao, Y.;
Totrov, M.; Wittenbach, V. A.; Zheng, Y. J. J Med Chem 2004, 47, 6669.
[6] Seebacher, W.; Brun, R.; Weis, R. Eur J Pharm Sci 2004, 21, 225.
[7] Kucukguzel, G.; Kocatepe, A.; De Clercq, E.; Sahin, F.;
Gulluce, M. Eur J Med Chem 2006, 41, 353.
[8] Bouzroura, S.; Bentarzi, Y.; Kaoua, R.; Nedjar-Kolli, B.;
Poulain-Martini, S.; Dunach, E. Org Commun 2010, 3, 8.
[9] Balzarini, J.; Orzeszko-Krzesinska, B.; Maurin, J. K.; Orzesko,
A, Eur J Med Chem 2009, 44, 303.
N(thiobarbituric
acid)
H— (N
thiobarbituric acid)
C(C¼ O acet)
0.057 NH(thiobarbituric
acid) —O¼ C (acet)
0.153
3.8374
2.7243
0.379 NH(thiobarbituric
acid)— O(acet)
O(C¼ O acet)
ꢁ0.379
ꢁ0.270
O(OC2H5 acet)
[10] Van Gaal, L.; Scheen, A. J. Diabetes Metab Res Rev 2002, 18, 51.
[11] Hulin, B.; Mc Carthy, P. A.; Gibbs, E. M. Cur Pharm Design
1996, 2, 85.
[12] Unangst, P. C.; Connor, D. T.; Cetenko, W. A.; Sorenson, R. J.;
Kostlan, C. R.; Sircar, J. C.; Wright, C. D.; Schrier D. J.; Dyer, R. D. J Med
Chem 1994, 37, 322.
[13] Johnson, A. R.; Marsletta M. A.; Dyer, R. D. Biochemistry
2001, 40, 7736.
[14] Harnden, M. R.; Bailey, S.; Boyd, M. R.; Taylor, D. R.;
Wright, N. D. J Med Chem 1978, 21, 82.
[15] Mishina, T.; Tsuda, N.; Inui, A.; Miura, Y. Jpn Kokai Tokkyo
Koho JP 62169793, 1987; Chem Abstr 1988, 108, 56120e.
[16] Balkan, A.; Uma, S.; Ertan, M.; Wiegrebe, W. Pharmazie
1992, 47, 687.
MeOH/DMF to afford (0.76 g, 48%) of 2; mp >300ꢀC; brown
crystals; Rf = 0.68 [pet. ether (40–60)/ethyl acetate, (1:4)]; IR
1
(KBr) ύ (cmꢁ1), 2936, 2862, 1674, 1562, 1266, 1188, 768; H
NMR (200 MHz, DMSO-d6): 4.38 (s, 2H, CH2), 4.69 (s, 2H,
CH2); MS: (m/z, %): 185 (M++1, 8), 184 (M+, 8), 168 (14), 169
(100), 111 (30), 71 (16), 69 (28). Anal. Calcd. for C6H4N2O3S
(184.17): C, 39.13; H, 2.19; N, 15.21. Found: C, 38.76; H,
2.07; N, 15.16.
Thiazolidine-2,4-dione (3).
Acetate salt of 2-imino-4-
thiazolidinone (1) (0.33 g, 2.8 mmol) was refluxed in aqueous/
ethanol (distilled water, 10 mL) for 2 h and left to cool. The
formed precipitate was collected by filtration and recrystallized
from ethanol to afford (0.14 g, 44%) of 3; mp 122-123ꢀC
[Lit [20] mp 123ꢀC]; Rf = 0.65 [pet. ether (40–60)/ethyl
acetate, (1:3)]; IR (KBr) ύ (cmꢁ1), 2936, 2862, 1674, 1562,
[17] Wichmann, J.; Adam, G.; Kolczewski, S.; Mutel, V.; Woltering,
T. Bioorg Med Chem Lett 1999, 9, 1573.
[18] Kurbanova, M. M. Zh Org Khim 2006, 42, 1871.
[19] Valls, N.; Segarra, V. M.; Alcalde, E.; Marin, A. J Prakt Chem
1985, 327, 251.
[20] Kochkanyan, R. O.; Israelyan, Yu. A.; Zaritovskii, A. N.
Chem Heterocycl Comp 1978, 14, 70.
[21] Singh, S.; Gupta, G. P.; Shanker, K. Indian J Chem 1985, 24B, 1094.
[22] Fedorova, E. V.; Meshcheryakov, M. P.; Ganina, M. B.;
Moskvin A.V.; Ivin, B. A. Russ J Gen Chem 2004, 74, 128.
1
1266, 1188, 768; H NMR (200 MHz, DMSO-d6): 3.98 (s, 2H,
CH2), 11.9 (s, 1H, NH exchangeable with D2O); ms: (m/z, %):
117 (M+, 95), 52 (100).
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet