Synthesis of thiazolo[3,2-a]pyrimidines based on 4-aryl-substituted 3,4-dihydro-pyrimidine(1H)-2-thiones and the crystal structure of ethyl 5-(2,4-dimethoxyphenyl)-7-methyl-3-oxo-3,5-dihydro-2H-thiazolo-[3,2-a] pyrimidine-6-carboxylate

Full text of DOI:10.1007/s10593-009-0346-z

Chemistry of Heterocyclic Compounds, Vol. 45, No. 7, 2009
SYNTHESIS OF THIAZOLO[3,2-a]PYRIMIDINES
BASED ON 4-ARYL-SUBSTITUTED 3,4-DIHYDRO-
PYRIMIDINE(1H)-2-THIONES AND THE CRYSTAL
STRUCTURE OF ETHYL 5-(2,4-DIMETHOXYPHENYL)-
7-METHYL-3-OXO-3,5-DIHYDRO-2H-THIAZOLO-
[3,2-a]PYRIMIDINE-6-CARBOXYLATE
I. V. Kulakov1*, O. A. Nurkenov1, D. M. Turdybekov2, G. M. Issabaeva1,
A. S. Mahmutova2, and K. M. Turdybekov2
Thiazolo[3,2-a]pyrimidines were obtained in good yield by the reaction of 4-aryl-substituted
3,4-dihydropyrimidine(1H)-2-thiones and methyl chloroacetate in boiling toluene. Their structures were
shown by 1H NMR spectroscopy and X-ray crystallography.
Keywords: 3,4-dihydropyrimidine(1H)-2-thiones, 3,5-dihydro-2H-thiazolo[3,2-a]pyrimidine, methyl
chloroacetate, intramolecular heterocyclization, X-ray crystallography, 1H NMR spectroscopy.
Recently there has been a considerable growth in the number of publications on the chemistry of 4-aryl-
3,4-dihydropyrimidin-2-ones and 4-aryl-3,4-dihydropyrimidine-2-thiones obtained by three-component
condensation in the Biginelli reaction is associated with the displaying by these readily available compounds a
wide range of pharmacological activities – analgesic, antibacterial, antihypertensive, etc. [1-3]. The attention of
synthetic chemists was drawn to the presence in 4-aryl-3,4-dihydropyrimidine-2-thiones of several reactive
nucleophilic centers allowing for a variety of mono- and dialkylation, acylation [4-6], and also the very
prospective cyclization reaction. For example, the conversion of 4-phenyl-3,4-dihydropyrimidine(1H)-2-thione
into 3,5-dihydro-2H-thiazolo[3,2-a]pyrimidine by boiling it in DMF with chloroacetic acid has been described
[7]. Attempts to carry out analogous cyclizations with 4-methoxy- and 2,4-dimethoxyphenyl-substituted
3,4-dihydropyrimidine(1H)-2-thiones gave rise to considerable amounts brightly colored by-products, difficult
to separate from the desired product.
_______
* To whom correspondence should be addressed, e-mail: kulakov_iv@mail.ru.
1Institute of Organic Synthesis and Coal Chemistry of the Republic of Kazakhstan, Karaganda 100008,
Kazakhstan.
2Research and Production Center "Phytochemistry", Ministry of Education and Science of the Republic of
Kazakhstan, Karaganda 100009, Kazakhstan.
__________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No.7, 1075-1079, July, 2009. Original article
submitted July 7, 2008.
856
0009-3122/09/4507-0856©2009 Springer Science+Business Media, Inc.

We have developed a new preparatively more simple method, based on 4-aryl-substituted
3,4-dihydropyrimidine(1H)-2-thiones 1a-d, to obtain 3,5-dihydro-2H-thiazolo[3,2-a]pyrimidines which involves
the boiling of solutions of compounds 1a-d in toluene with a slight excess of methyl chloroacetate in the
presence of triethylamine. The starting materials 1a-d were obtained by a three-component condensation of the
corresponding aldehydes, thiourea, and ethyl acetoacetate (compounds 1a and 1b) or acetylacetone (compounds
1c and 1d) by boiling in DMF as described elsewhere [5]. The structures of compounds 1a-d were confirmed by
1H NMR spectroscopy and other physical characteristics coincided with literature data [8, 9].
In each of the examples studied the formation of products of S- or N-alkylation was possible, but in all
cases only the desired products of cyclization 2a-d were isolated in 84-90% yield.
OMe
OMe
OMe
R
R
R
H
H
O
O
Et3N
– MeOH
H
O
3
O
6
ClCH2COOMe
HN
+
HN
R1
N
R1
4
R1
S
N
Me
MeOOCCH2S
N
Me
S
1
N 8 Me
2a–d
H
1a–d
1,2 a R = H, R1 = OEt; b R = OMe, R1 = OEt; c R = H, R1 = Me; d R = OMe, R1 = Me
The formation of compounds 2a-d was confirmed by the absence of amino group absorptions in the IR
1
spectra, and in the H NMR spectra absence of the signals of the COOMe and the N(3) proton which were
present in the spectra of the starting materials and in the products of their N(1) monoalkylation (doublet in the
9.2 ppm region). The signals of the protons of the CH2 unit in the thiazolidine ring appear as a doublet of
doublets with J = 17.7 Hz.
With the objective of determining the spatial structure of the synthesized bicyclic thiazolo-
[3,2-a]pyrimidines we carried out an X-ray crystallographic investigation of compound 2b.
2b2
2b1
Fig. 1. The Positions of the Independent Molecules 2b1 and 2b2 in the Unit Cell.
857

The unit cell contained two geometrically independent molecules 2b1 and 2b2 (Figure 1). The bond
lengths and valence angles were close to standard values [10]. The thiazolidine ring in each molecule is almost
planar (deviation ± 0.03Å) with the sulfur atoms 0.12 Å from the planes of the remaining atoms, in which atoms
O(1) and O(6) of the carbonyl groups also lie. The pyrimidine rings have a flattened sofa conformation
(∆C(1)s = 5.34 and ∆C(19)s = 5.48 Å) with atoms C(1) and C(19) out of their planes by 0.24 and 0.19 Å
respectively; this ring may take a distorted boat conformation as in 5-nitro-4-(2-nitrophenyl)-6-phenyl-
3,4-dihydro-(1H)-pyrimidin-2-one [11].
The dimethoxyphenyl substituents are oriented axially to the basic skeleton of the molecules (torsion
angles C(2)C(3)C(7)C(8) and C(20)C(19)C(25)C(26) are equal to -109.33° and 110.84° respectively). In both
molecules the methoxy groups lie in the planes of the benzene ring, probably because of repulsion of the oxygen
atom and the nitrogen atom of the pyrimidine ring (the distances between N(1) and O(2) and between N(3) and
O(7) are 3.02 and 2.98 Å respectively). The COOEt groups in both molecules are orientated equatorially
(torsional angles C(1)C(2)C(16)O(4) and C(19)C(20)C(34)O(10) 9.44° and -5.33° respectively).
EXPERIMENTAL
1H NMR spectra of DMSO-d6 solutions with TMS as internal standard were recorded with a Bruker
DRX500 (500 MHz) instrument and IR spectra of KBr tablets were recorded with an AVATAR-320 Fourier
spectrometer. Course of reactions and purity of products were monitored by TLC on Sorbfil plates.
X-ray Crystallography. Lattice parameters and intensities of 3712 independent reflexions for
compound 2b were measured at 20°C on a BrukerP4 automatic four-circle diffractometer with a graphite
monochromator and MoKα radiation (θ/2θ scanning, 2θ < 52°). Crystals were rhombic (ethanol), a = 9.495,
b = 10.330, c = 11.612, V = 926.1(8) Å3, dcalc = 1.350 g/cm3, Z = 1 (C36H40N4O10S2). Space group P-1.
In the calculation 3046 reflexions with I > 2σ(I) were used. The structure was solved by direct methods
using the program Sir-2002 [12] and refined by full matrix least squares analysis in the anisotropic
approximation for non-hydrogen atoms. H atoms were found geometrically and fixed by the riding
approximation. The final divergence factors were R = 0.0482 and wR2 = 0.1369. Refinement of the geometry
was carried out with the SHELXL-97 program [13]. Structural data for compound 2b have been deposited in the
Cambridge Structural Data Bank (CCDC 692504).
Ethyl 5-(4-Methoxyphenyl)-7-methyl-3-oxo-3,5-dihydro-2H-thiazolo[3,2-a]pyrimidine-6-carboxylate
(2). A mixture of 4-(4-methoxyphenyl)-3,4-dihydropyrimindine(1H)-2-thione (1a) (0.80 g, 2.6 mmol), methyl
chloroacetate (0.304 g, 2.8 mmol), and triethylamine (0.9 g, 9.0 mmol) was boiled for 4 h in absolute toluene
(10 ml). The crystals of triethylamine hydrochloride were filtered off and washed with a small amount of
benzene which was added to the filtrate which was then evaporated. The residue was crystallized from hexane to
give compound 2a (0.81 g, 90%), which, after recrystallization three times from ethanol, consisted of
light-orange transparent crystals; mp 126-127°C. IR spectrum, ν, cm-1: 1736 (C=O); 1700 (C=O); 1544 (C=N).
1H NMR spectrum, δ, ppm (J, Hz): 1.11 (3H, t, J = 7.1, CH2CH3); 2.33 (3H, s, CH3); 3.71 (3H, s, OCH3); 4.01
(2H, q, J = 7.1, CH2CH3); 4.10 (2H, dd, J1 = J2 = 17.7, SCH2); 5.83 (1H, s, H-5); 6.88 and 7.16 (4H, d, J = 8.6,
H arom). Found, %: C 59.17; H 5.56; N 8.32. C17H18N2O4S. Calculated, %: C 58.94; H 5.24; N 8.09.
Ethyl 5-(2,4-Dimethoxyphenyl)-7-methyl-3-oxo-3.5-dihydro-2H-thiazolo[3,2-a]pyrimidine-6-carboxy-
late (2b) was obtained analogously to ester 2a from 4-(2,4-dimethoxyphenyl)-3,4-dihydropyrimidine(1H)-
2-thione (1b) (2.02 g, 6.0 mmol), methyl chloroacetate (0.66 g, 6.1 mmol), and triethylamine (1.23 g,
12.0 mmol). Yield 89%, after three recrystallizations from ethanol, orange-clear crystals; mp 129-130°C. IR
spectrum, ν, cm-1: 1730 (C=O); 1697 (C=O); 1548 (C=N). 1H NMR spectrum, δ, ppm (J, Hz): 1.13 (3H, t, J = 7.1,
CH2CH3); 2.23 (3H, s, CH3); 3.71 (3H, s, OCH3); 3.73 (3H, s, OCH3); 3.98 (2H, q, J = 7.1, CH2CH3); 4.01 (2H, dd,
858

J1 = J2 = 17.6, SCH2); 5.95 (1H, s, H-5); 6.46 (1H, d, J = 8.4, H arom); 6.52 (1H, s, H arom); 7.09 (1H, d, J = 8.4,
H arom). Found, %: C 57.79; H 5.60; N 7.12. C18H20N2O5S. Calculated, %: C 57.43; H 5.36; N 7.44.
6-Acetyl-5-(4-methoxyphenyl)-7-methyl-2H-thiazolo[3,2-a]pyrimidin-3(5H)-one (2c) was obtained
analogously to ester 2a from 4-(2-methoxyphenyl)-3,4-dihydropyrimidine(1H)-2-thione (1c) (1.38 g, 5.0 mmol),
methyl chloroacetate (0.55 g, 5.1 mmol), and triethylamine (1.5 g, 15.0 mmol). Yield 86%, after three
recrystalizations from ethanol, dark-orange clear crystals; mp 121-122°C. IR spectrum, ν, cm-1: 1732 (C=O);
1
1695 (C=O); 1550 (C=N). H NMR spectrum, δ, ppm (J, Hz): 2.19 (3H, s, CH3); 2.32 (3H, s, C(O)CH3); 3.71
(3H, s, OCH3); 4.10 (2H, dd, J1 = J2 = 17.7, SCH2); 5.97 (1H, s, H-5); 6.88 and 7.18 (4H, d, J = 8.7, H arom).
Found, %: C 61.18; H 5.51; N 8.42. C16H16N2O3S. Calculated, %: C 60.74; H 5.10; N 8.85.
6-Acetyl-5-(4-methoxyphenyl)-7-methyl-2H-thiazolo[3,2-a]pyrimidin-3(5H)-one (2d) was made
analogously from 4-(2,4-dimethoxyphenyl)-3,4-dihydropyrimidine(1H)-2-thione (1d) (1.53 g, 5.0 mmol),
methyl chloroacetate (0.55 g, 5.1 mmol), and triethylamine (1.5 g, 15.0 mmol). Yield 84%, after three
recrystallizations from ethanol, dark-orange clear crystals; mp 131-133°C. IR spectrum, ν, cm-1: 1742 (C=O);
1
1656 (C=O); 1585 (C=N). H NMR spectrum, δ, ppm (J, Hz): 2.15 (3H, s, CH3); 2.17 (3H, s, C(O)CH3); 3.72
(3H, s, OCH3); 3.74 (3H, s, OCH3); 4.05 (2H, dd, J1 = J2 = 17.6, SCH2); 6.10 (1H, s, H-5); 6.48 (1H, d, J = 8.4,
H arom); 6.54 (1H, d, H arom); 7.06 (1H, d, J = 8.4, H arom). Found, %: C 59.31; H 5.56; N 8.37. C17H18N2O4S.
Calculated, %: C 58.94; H 5.24; N 8.09.
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