Synthesis of new thiazolopyrimidines proceeding from 4-aryl-substituted 3,4-dihydropyrimidine-2(1H)-thiones

Full text of DOI:10.1134/S1070428009080296

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2009, Vol. 45, No. 8, pp. 1262−1263. © Pleiades Publishing, Ltd., 2009.
Original Russian Text © I.V. Kulakov, 2009, published in Zhurnal Organicheskoi Khimii, 2009, Vol. 45, No. 8, pp. 1270−1271.
SHORT
COMMUNICATIONS
Synthesis of New Thiazolopyrimidines Proceeding
from 4-Aryl-Substituted 3,4-Dihydropyrimidine-2(1H)-thiones
I. V. Kulakov
Institute of Organic Synthesis and Coal Chemistry of Kazakhstan Republic, Karaganda,100008 Kazakhstan
e-mail: ivanku1@mail.ru
Received July 14, 2008
DOI: 10.1134/S1070428009080296
Recently a number of publications grew considerably
in the field of the chemistry of 4-aryl-3,4-dihydro-
pyrimidin-2-ones and 4-aryl-3,4-dihydropyrimidine-2-
thione obtained by the three-component Biginelli con-
densation. It is not only due to their preparative acces-
sibility but also to their wide range of pharmacological
action (analgesic, antibacterial, antihypertension etc.) [1–
in the boiling of toluene solutions of 4-aryl-substituted
3,4-dihydropyrimidine-2(1H)-thiones with a slight excess
of methyl chloroacetate in the presence of triethylamine.
It was expected that the reaction would stop at the
formation of one of intermediate products of S- or
N-alkylation whose formation depended on the solvents
and acceptors used affecting apparently the process of
thione-thiol transition [5]. However in 86–90% yield the
target cyclization products IIa–IId were isolated.
3
]. The presence of several reactive nucleophilic centers
also attracts attention to, e.g., 4-aryl-3,4-dihydro-
pyrimidine-2-thiones for it makes possible carry out both
versatile mono- and dialkylation and acetylation [4, 5]
and also very promising cyclizations. For instance,
a method was described of a cyclization of 4-phenyl-3,4-
dihydropyrimidine-2(1H)-thione into 3,5-dihydro-2H-
thiazolo[3,2-a]pyrimidine by boiling in DMF with
chloroacetic acid [6].
The formation of 3,5-dihydro-2H-thiazolo[3,2-a]-
pyrimidines IIa–IId was proved by the lack in the IR
spectra of the absorption bands of amino groups and also
1
the absence in the H NMR spectra of the signals of
3
ester methoxy group and of N H protons observed in the
initial compounds and in their monoalkylated products as
doublets in the region 9.2 ppm. The methylene protons
CH2 of the thiazole ring turned out to be nonequivalent
and thus appeared as a doublet of doublets with a coupling
constant of 17.7 Hz.
Aiming to preparation from 4-aryl-substituted 3,4-
dihydropyrimidine-2(1H)-thiones of new 3,5-dihydro-2H-
thiazolo[3,2-a]pyrimidines derivatives we developed
a new preparatively more accessible method consisting
OMe
OMe
OMe
R
S
O
C
R
O
C
R
S
O
C
O
Et N
3
+ ClCH2
C
_
O
OMe
R' _MeOH
_
+
HN
R'
Et NHCl
HN
N
3
OMe
O C
N
H
Me
H C S
N
Me
N
Me
2
_
_
Iа Id
IIа IId
R = H, R' = OEt (a); R = OMe, R' = OEt (b); R = H, R' = Me (c); R = OMe, R' = Me (d).
1262

SYNTHESIS OF NEW THIAZOLOPYRIMIDINES
1263
Ethyl 7-methyl-5-(4-methoxyphenyl)-3-oxo-3,5-
dihydro-2H-thiazolo[3,2-a]-pyrimidine-6-carb-
oxylate (IIa).Amixture of 0.80 g (2.6 mmol) of 2-thione
Ia, 0.304 g (2.8 mmol)of methyl chloroacetate, and 0.9 g
δ, ppm: 2.19 s (3H, CH ), 2.32 s [3H, C(O)CH ], 3.71 s
3
3
(3H, OCH ), 4.10 d.d (2H, SCH , J 17.72 Hz), 5.97 s
3
2
5
(1H, H ), 6.88 d, 7.18 d (4Harom, J 8.73 Hz). Found, %:
C 61.18; H 5.51; N 8.42. C H N O S. Calculated, %:
16
16
2
3
(
9 mmol) of triethylamine in 10 ml of anhydrous toluene
C 60.74; H 5.10; N 8.85.
was heated at reflux for 4 h. The precipitated crystals of
triethylamine hydrochloride were filtered off, washed with
a small quantity of benzene. On distilling off the solvent
the residue was crystallized by adding hexane. Yield 0.81g
6
-Acetyl-5-(2,4-dimethoxyphenyl)-7-methyl-2H-
thiazolo[3,2-a]pyrimidin-3(5H)-one (IId) was
similarly obtained from 1.53 g (5.0 mmol) of 2-thione Id,
.55 g (5.1mmol) of methyl chloroacetate, and 1.5 g
15.0mmol) of triethylamine. Yield 84%. After three
recrystallizations from ethanol dark brown transparent
0
(
(
90%). After three recrystallizations from ethanol light-
orange transparent crystals were obtained, mp 126–
–
1
1
27°C. IR spectrum, ν, cm : 1736, 1700, 1544, 1241, 1171.
crystals were obtained, mp 131–133°C. IR spectrum, ν,
1
H NMR spectrum, δ, ppm: 1.11 t (3H, CH , J 7.1 Hz),
–1
1
3
cm : 1742, 1656, 1585. H NMR spectrum, δ, ppm:
2
.33 s (3H, CH ), 3.71 s (3H, OCH ), 4.01 q (2H,
3 3
2.15 s (3H, CH ), 2.17 s [3H, C(O)CH ], 3.72 s
3
3
CH CH ), 4.10 d.d (2H, SCH , J 17.7 Hz), 5.83 s (1H,
2
3
2
(3H, OCH ), 3.74 s (3H, OCH , 4.05 d.d (2H, SCH ,
3 2 2
5
H ), 6.88 d, 7.16 d (4Harom, J 8.62 Hz). Found, %:
C 59.17; H 5.56; N 8.32. C H N O S. Calculated, %:
5
J 17.62 Hz), 6.10 s (1H, H ), 6.48 d, 6.54 s, 7.06 d (3Harom,
J 8.4 Hz). Found, %: C 59.31; H 5.56; N 8.37.
C H N O S. Calculated, %: C 58.94; H 5.24; N 8.09.
17
18
2
4
C 58.94; H 5.24; N 8.09.
1
7
18
2
4
Ethyl-5-(2,4-dimethoxyphenyl)-7-methyl-3-oxo-
,5-dihydro-2H-thiazolo[3,2-a]-pyrimidine-6-carb-
1H NMR spectra were registered on a spectrometer
Bruker DRX-500 at operating frequency 500 MHz in
3
oxylate (IIb) was similarly obtained from 2.02 g (6 mmol)
of 2-thione Ib, 0.66 g (6.1mmol) of methyl chloroacetate,
and 1.23 g (12mmol) of triethylamine. Yield 89%. After
three recrystallizations from ethanol orange transparent
crystals were obtained, mp 129–130°C. IR spectrum, ν,
DMSO-d , internal reference TMS. IR spectra were
6
recorded on a Fourier spectrophotometerAvatar-320 from
pellets with KBr. Monitoring the reaction progress and
checking the purity of compounds obtained was
performed by TLC on Sorbfil plates.
–1
1
cm : 1730, 1697, 1548, 1301, 1076. H NMR spectrum,
δ, ppm: 1.13 t (3H, CH CH , J 7.1 Hz), 2.23 s (3H, CH ),
2
3
3
REFERENCES
3
.71 s (3H, OCH ), 3.73 s (3H, OCH ), 3.98 q (2H,
3 3
CH CH ), 4.01 d.d (2H, SCH , J 17.6 Hz), 5.95 s (1H,
2
3
2
1. Wipf, P. and Cunningham, V., Tetrahedron Lett., 1995,
vol. 36, p. 7819.
2. Gupta, R., Gupta, A.K., Paul, S., and Kachroo, P.L., Ind. J.
Chem. B., 1995, vol. 34, p. 151.
5
H ), 6.46 d, 6.52 s, 7.09 d (3Harom, J 8.41 Hz). Found, %:
C 57.79; H 5.60; N 7.12. C H N O S. Calculated, %:
18
20
2
5
C 57.43; H 5.36; N 7.44.
6
-Acetyl-7-methyl-5-(4-methoxyphenyl)-2H-
3. Grover, G.J., Dzwonczyk, S., McMulltn, D.M., Normadi-
nam, C.S., and Moreland, S.J., J. Cardiovasc. Pharmacol.,
1995, vol. 26, p. 289.
thiazolo[3,2-a]pyrimidin-3(5H)-one (IIc) was
similarly obtained from 1.38 g (5 mmol) of 2-thione Ic,
0
.55 g (5.1mmol) of methyl chloroacetate, and 1.5 g
4. Kolosov, M.A. and Orlov, V.D., Vestn. Khar’kovskogo Nats.
Univ. Khimiya, 2005, vol. 669, p. 39.
(
15mmol) of triethylamine. Yield 86%. After three
recrystallizations from ethanol dark brown transparent
5. Kolosov, M.A., Orlov, V.D., and Vasil’eva, Yu.M., Vestn.
Khar’kovskogo, nats. univ. Khimiya, 2006, vol. 731, p. 69.
6. Kurbanova, M.M., Zh. Org. Khim., 2006, vol. 42, p. 1878.
crystals were obtained, mp 121–122°C. IR spectrum, ν,
–1
1
cm : 1732, 1695, 1550, 1300, 1084. H NMR spectrum,
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