Synthesis of bicyclic pyrimido[2,1-b][1,3]thiazines based on 3,4-dihydropyrimidine-(1h)-2-thiones

Article abstract of DOI:10.1007/s10593-010-0510-5

Bicyclic pyrimido[2,1-b][1,3]thiazines were produced by the acylation of 4-aryl-substituted 3,4-di-hydropyrimidine(1H)-2-thiones with 3-bromopropionyl chloride, and their structures were proved by the data from X-ray crystallographic analysis. 2010 Spring

Full text of DOI:10.1007/s10593-010-0510-5

Chemistry of Heterocyclic Compounds, Vol. 46, No. 3, 2010
SYNTHESIS OF BICYCLIC PYRIMIDO[2,1-b][1,3]THIAZINES
BASED ON 3,4-DIHYDROPYRIMIDINE-(1H)-2-THIONES
I. V. Kulakov1* and D. M. Turdybekov2
Bicyclic pyrimido[2,1-b][1,3]thiazines were produced by the acylation of 4-aryl-substituted 3,4-di-
hydropyrimidine(1H)-2-thiones with 3-bromopropionyl chloride, and their structures were proved by
the data from X-ray crystallographic analysis.
Keywords: 3,4-dihydropyrimidine(1H)-2-thiones, pyrimidino[2,1-b][1,3]thiazines, 3-bromopropionyl
chloride, intramolecular heterocyclization, X-ray crystallographic analysis.
Today an enormous number of derivatives of 3,4-dihydropyrimidin-2-ones(2-thiones) with various
aromatic and heterocyclic functional substituents have been synthesized by the Biginelli reaction, numerous
methods including microwave and solvent-free methods have been developed for their production, and highly
effective catalysts leading to a significant increase in the yields and reduction of the time for the condensation
have been found [1-7]. Many researches on the synthesis and subsequent modification of derivatives of
3,4-dihydropyrimidin(1H)-2-ones have continued in many countries with developed pharmaceutical industry;
this is due to the fact that they display of a wide range of pharmacological activity – antihypertensive,
antibacterial, antiviral, antitumor, etc. [8-10], making further searches in the 3,4-dihydro-pyrimidin-2-one-
(2-thione) series extremely promising.
In [11] we proposed a convenient method for the synthesis of new derivatives of bicyclic 3,5-dihydro-
2H-thiazolo[3,2-a]pyrimidines from 3,4-dihydropyrimidine-2-thiones, established their stereochemical structure,
and studied the conditions for cyclization with various haloacetyl reagents [12]. In an attempt to produce
bicyclic thiazine derivatives based on 4-aryl-substituted 3,4-dihydropyrimidine-2-thiones the acylation of 4-aryl-
substituted 3,4-dihydropyrimidine-2-thiones 1a-c with 3-bromopropionyl chlorides according to the Scheme
was realized. (Compounds 1a-c are shown in a thiol tautomer form.)
Acylation was conducted in solution of anhydrous DMF in the presence of a twofold excess of
potassium carbonate with the reaction mixture heated from 25 to 120°C for 6-10 h. Here, as expected, the
heterocyclization products 2a-c in the form of slightly yellowish crystalline substances were isolated. The most
_______
* 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, Republic
of Kazakhstan.
2Scientific-Production Holding "Phytochemistry", Karaganda 100009, Republic of Kazakhstan.
__________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 3, pp. 435-439, March, 2010. Original
article submitted October 29, 2009.
342
0009-3122/10/4603-0342©2010 Springer Science+Business Media, Inc.

acceptable yields of compounds 2a-c were obtained when a 1.5-fold excess of 3-bromopropionyl chloride was
used. Realization of the reaction at a lower temperature (60-70°C) with an equimolar amount of the acid chloride
led to isolation not of the intermediate acylation products but mainly of the original 3,4-dihydro-
pyrimidine-2-thiones 1a-c.
R
R
R
O
O
O
O
O
5
O
7
120°C
– HBr
R1
3
2
DMF, K2CO3
25°C
R1
N
6
HN
HS
N
R1
+
Br
Cl
S
1
N
Me
N
Me
Br
HS
N
Me
2 a–c
1 a–c
a R = OMe, R1 = OEt; b R = OMe, R1 = Me; c R = F, R1 = OEt
In this case the pyrimido[2,1-b][1,3]thiazines 2a-c are formed, as described earlier in [12], according to
the general principles of the theory of hard and soft acids and bases, with initial acylation of the N(3) atom
followed by intramolecular alkylation of the thiol fragment and closure to a thiazine ring.
Fig. 1. The spatial structure of the molecule of 7-acetyl-6-(4-methoxyphenyl)-8-methyl-
2,3-dihydropyrimido[2,1-b][1,3]thiazin-4(6H)-one (2b).
The formation of the pyrimido[2,1-b][1,3]thiazines 2a-c was proved by the absence of the stretching
vibrations of the amino group in the IR spectra and also by the absence in the 1H NMR spectra of signals for the
N(3)–H protons, which appear in the initial compounds in the form of doublets at 9.2 ppm. The signals for the
methylene protons of the thiazine ring are complex multiplets centered in the region of 3.04 ppm.
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In order to establish the three-dimensional structure of the synthesized bicyclic pyrimido[2,1-b][1,3]thia-
zines and their possible differences from our previously synthesized structurally similar bicyclic 3,5-dihydro-
2H-thiazolo[3,2-a]pyrimidines we undertook an X-ray structural investigation of compound 2b (Fig. 1).
The bond lengths and valence angles in structure 2b are close to the standard values [13]. The thiazine
5,6
ring N(1)C(4)S(1)C(5)C(6)C(7) assumes a distorted 5,6-half-chair conformation with ΔC2 = 6.55 Å. In our
opinion the distortion occurs on account of the presence of the heavier sulfur atom in the ring, and the carbonyl
O(1) atom is in the equatorial position and lies in the С(4)N(1)C(7)C(6) plane. The pyrimidine ring assumes the
C(1)N(1)
conformation of a strongly distorted boat half-chair with ΔC2
= 19.57, as also in the structure of 5-nitro-
4-(2-nitrophenyl)-6-phenyl-3,4-dihydro(1H)-pyrimidin-2-one [14], although in our previously studied molecule
of ethyl 5-(2,4-dimethoxyphenyl)-7-methyl-3-oxo-3,5-dihydro-2H-thiazolo[3,2-a]pyrimidine-6-carboxylate [11]
the ring is in a flattened sofa conformation. Such a difference in our opinion depends on the presence and
position of the bulky substituent at the C(1) atom, which in the first case is turned through 24.3°, while the
rotation of the 2,4-dimethoxyphenyl substituent in the second case amounted to 68.6° in relation to the main
framework.
The 4-methoxyphenyl group is in the axial orientation to the main skeleton of the molecule (torsional
angle С(7)N(1)С(1)С(8) -106.31°). The methoxy group lies in the plane of the benzene ring. The methyl group
and aceto group are in the equatorial orientation in relation to the pyrimidine ring.
EXPERIMENTAL
1
The IR spectra (KBr) were recorded on an AVATAR-320 Fourier spectrometer. The H NMR spectra
were recorded in DMSO-d6 on a Bruker DRX500 instrument (500 MHz) with TMS as internal standard. The
mass spectra were obtained on a Finnigan MAT Incos 50 instrument with direct injection into the ion source and
ionization energy 70 eV. The reactions and the purity of the obtained compounds were monitored by TLC on
Sorbfil plates. The 3-bromopropionyl chloride was the commercial product from Aldrich and was used without
further purification. The initial 3,4-dihydropyrimidine(1H)-2-thiones 1a-c were prepared by the three-
component condensation of the respective aldehydes, acetoacetic ester (for compounds 1a,b), acetylacetone (for
compound 1c), and thiourea by boiling in DMF according to the procedure described in [15].
X-Ray Crystallographic Experiment. The cell parameters and the intensities of 3715 unique
reflections of compound 2b were measured at -100°C on a Bruker APEX-II CCD automatic four-circle
diffractometer with a graphite monochromator using MoKα radiation (θ/2θ scan, 2θ < 56°). Yellow crystals
(0.15×0.40×0.60 mm), monoclinic, а = 8.572(2), b = 9.919(3), с = 18.399(6), V = 1557.4(8) Å3, dcalc = 1.409 g/cm3,
Z = 4 (C17H18N203S). Space group P2(1)/n.
In the calculations we used 3283 reflections with intensity I > 2σ. The structure was interpreted by the
direct method with SHELXS-97 software [16] and was refined by full-matrix least-squares treatment in
anisotropic approximation for the non-hydrogen atoms. The H atoms were revealed from an electron density
difference synthesis. The final divergence factors were R = 0.0315, wR2 = 0.0829. The geometry was refined
with SHELXL-97 software [16]. The structural data have been deposited at the Cambridge structural data bank
(CCDC 752521).
Ethyl 6-(4-Methoxyphenyl)-8-methyl-4-oxo-2,3,4,6-tetrahydropyrimido[2,1-b][1,3]thiazine-7-carb-
oxylate (2a). To a solution of 4-(4-methoxyphenyl)-3,4-dihydropyrimidine(1H)-2-thione (1a) (1.53 g, 5.0 mmol)
in DMF (3 ml) we added K2CO3 (1.38 g, 10.0 mmol). With vigorous stirring at room temperature over 30 min
we added dropwise 3-bromopropionyl chloride (1.28 g, 7.5 mmol). The mixture was stirred for a further 6-8 h
while the temperature was gradually increased to 120°C. The mixture was cooled, 100 ml of iced water was
added to the suspension, and the light-pink precipitate was filtered off, washed several times with water, and
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dried. We obtained 1.26 g (70%) of compound 2a, which after threefold recrystallization from a 1:1 mixture of
2-propanol and hexane formed transparent light-yellow crystals, mp 147-148°C. IR spectrum, ν, cm−1: 1705
1
(С=O), 1612 (С=O), 1503 (C=N), 1240 (С–О). H NMR spectrum, δ, ppm (J, Hz): 1.15 (3Н, t, J = 7.1,
СН2СН3); 2.29 (ЗН, s, СН3); 3.72 (3Н, s, ОСН3); 3.05 (4Н, m, 2СН2); 4.09 (2Н, q, J = 7.1, СН2СН3); 6.56 (Н,
s, Н-6); 6.88 and 7.11 (4Н, two d, J = 8.7, Н arom). Found, %: С 60.39; Н 5.17; N 8.14. C18H20N2O4S.
Calculated, %: С 59.98; Н 5.59; N 7.77.
7-Acetyl-6-(4-methoxyphenyl)-8-methyl--2,3-dihydropyrimido[2,1-b][1,3]thiazin-4(6H)-one (2b).
This compound was obtained similarly to compound 2a from 4-(4-methoxyphenyl)-3,4-dihydropyrimi-
dine(1H)-2-thione (1b) (2.76 g, 10.0 mmol), K2CO3 (2.76 g, 20 mmol), and 3-bromopropionyl chloride (2.57 g,
15.0 mmol). The yield of compound 2b was 2.08 g (63%); after twofold recrystallization from a 5:1:1 mixture
of 2-propanol, benzene, and hexane it formed light-yellow rhombic crystals, mp 155-156°C. IR spectrum, ν,
cm−1: 1706 (С=0), 1632 (С=0), 1509 (C=N). 1H NMR spectrum, δ, ppm (J, Hz): 2.27 (3Н, s, СН3); 2.31 (3Н, s,
С(O)СН3); 3.04 (4Н, m, 2СН2); 3.71 (3Н, s, ОСН3); 6.67 (Н, s, Н-6); 6.88 and 7.10 (4Н, two d, J = 8.7,
Н arom.). Mass spectrum, m/z (Irel, %): 330 [М]+ (8.3), 287 (15.5), 233 (41.7), 169 (15.1), 55 (56), 43 (100).
Found, %: С 62.19; Н 5.17; N 8.83. C17H18N2O3S. Calculated, %: С 61.80; Н 5.49; N 8.48.
Ethyl 6-(4-Fluorophenyl)-8-methyl-4-oxo-2,3,4,6-tetrahydropyrimido[2,1-b][1,3]thiazine-7-carb-
oxylate (2c). This compound was obtained similarly to compound 2a from 4-(4-fluorophenyl)-3,4-dihydro-
pyrimidine(1H)-2-thione (1c) (1.47 g, 5.0 mmol), K2CO3 (1.38 g, 10.0 mmol), and 3-bromopropionyl chloride
(1.28 g, 7.5 mmol). The yield of compound 2c was 1.01 g (58%); after twofold recrystallization from a 1:1
mixture of 2-propanol and hexane it formed yellow-green crystals, mp 175-177°C. IR spectrum, ν, cm−1: 1703
1
(C=O), 1610 (C=O), 1512 (C=N), 1233 (C–O). H NMR spectrum, δ, ppm (J, Hz): 1.15 (3Н, t, J = 7.1,
СН2СН3); 2.30 (3Н, s, СН3); 3.06 (4Н, m, 2СН2); 4.10 (2Н, q, J = 7.1, СН2СН3); 6.60 (1Н, s, Н-6); 7.17 (2Н, t,
J = 8.8, Н arom.); 7.24 (2Н, q, J = 5.5, Н arom.). Mass spectrum, m/z (Irel, %): 348 [M]+ (2.1), 253 (15.2), 221
(17.5), 199 (30.6), 95 (17.4), 86 (18.1), 67 (42.4), 60 (17.6), 55 (100), 42 (19.3). Found, %: C 58.94; H 5.17;
N 8.37. C17H17FN2O3S. Calculated, %: C 58.61; H 4.92; N 8.04.
The work was carried out with financial support from the Public Fund “The Foundation of the First
President of the Republic of Kazakhstan” (Grant No. 112-09).
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