Intramolecular cyclization of 4-aryl-3,4-dihydropyrimidine- (1H)-2-thiones to give bicyclic thiazolo[3,2-a]pyrimidines

Full text of DOI:10.1007/s10593-009-0374-8

Chemistry of Heterocyclic Compounds, Vol. 45, No. 8, 2009
INTRAMOLECULAR CYCLIZATION
OF 4-ARYL-3,4-DIHYDROPYRIMIDINE-
(1H)-2-THIONES TO GIVE BICYCLIC
THIAZOLO[3,2-a]PYRIMIDINES
1
I. V. Kulakov *
Keywords: 3,4-dihydropyrimidine(1H)-2-thiones, haloacetyl derivatives, 3,5-dihydro-2H-thiazolo-
[3,2-a]pyrimidines, intramolecular heterocyclization.
In previous work [1], we proposed a convenient method for the synthesis of new derivatives of bicyclic
3
,5-dihydro-2H-thiazolo[3,2-a]pyrimidines involving heating 4-aryl-3,4-dihydropyrimidine(1H)-2-thiones in
toluene at reflux with a slight excess of methyl chloroacetate in the presence of triethylamine.
Since many 3,4-dihydropyrimidine-2-thiones have analgesic, antibacterial, and antihypertensive activity
[2-4], we attempted to modify these compounds by alkylation using known pharmacoforming fragments,
namely, the β-chloroacetyl-β-phenylhydrazide of benzylic acid [5] and several nitro-substituted dihaloanilides of
bromoacetic acid [6].
OMe
OMe
OMe
O
Et N
R
3
R
R
S
C
H
Hal
+
O
3
O
O
Y
O
2
6
N
5
HN
1
HN
1
– YH
1
R
R
R
O
S1
N
Me
N
H
C
H
S
N
Me
Me
Y
2
2
a–d
1
a–d
1
1
1
1
a R = H, R = OEt; b R = OMe, R = OEt; c R = H, R = Me; d R = OMe, R = Me
Hal
OH
Ph
H
N
O
Y = Ph
;
Hal = Cl, Br
N N
H
NO2
Hal
Ph
_
*
______
To whom correspondence should be addressed, e-mail: kulakov-iv@mail.ru.
1
1
Institute of Organic Synthesis and Coal Chemistry of the Republic of Kazakhstan, Karaganda 100008,
Kazakhstan.
_
_________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 8, pp. 1274-1276, August, 2009.
Original article submitted June 8, 2009.
009-3122/09/4508-1019©2009 Springer Science+Business Media, Inc.
0
1019

The alkylation was carried out by a method similar to our previous procedure [1] heating equimolar
amounts of the reagents in toluene at reflux in the presence of triethylamine. However, the alkylation products
were not obtained. Instead, we obtained the products of the intramolecular cyclization of the expected alkylation
products to give the corresponding 3,5-dihydro-2H-thiazolo[3,2-a]pyrimidines through the already reported
reaction scheme [1].
The formation of thiazolopyrimidines 2a-d in this case proceeds through nucleophilic attack of the
carbonyl carbon atom of the intermediate alkylation product by the unshared electron pair of the nitrogen atom
with closure to give a thiazole ring and elimination of the bulky phenylhydrazide of benzylic acid, and
1
2
,6-dihalo-4-nitroaniline residues. IR, H NMR, and mass spectra showed that thiazolopyrimidines 2a-d were
identical to the compounds obtained upon cyclization by the action of methyl chloroacetate as described in our
previous work [1].
Thiazolopyrimidines 2a-d are also formed in the alkylation of 3,4-dihydro-2-pyrimidinethiones by the
acid bromide of bromoacetic acid in anhydrous DMF in the presence of a two-fold excess of potassium
carbonate although the initial nucleophilic attack of the electron-deficient carbonyl carbon atom presumably
leads to the intermediate S-acylation product followed by closure of the thiazole ring upon N-alkylation of the
remaining CH Br group to give isomeric thiazolo[3,2-a]pyrimidin-2-ones 3a-d. However, the reaction also
2
occurs by the apparently common scheme given above, which is in accord with the principle of hard and soft
acids and bases.
OMe
R
DMF,
O
H2
C
O
K CO
2 3
HN
HS
Br
1
2
a–d
δ+
+
R
Br
N
Me
OMe
OMe
R
R
DMF,
K CO3
O
O
2
6
O
3
5
HN
HS
N
1
Br
C
H
δ+
+
1
R
R
2
S1
Me
Br
O
N
N
Me
3
a–d
1
1
1
1
a R = H, R = OEt; b R = OMe, R = OEt; c R = H, R = Me; d R = OMe, R = Me
1
The H NMR spectra were taken on a Bruker DRX-500 spectrometer at 500 MHz in DMSO-d with
6
TMS as the internal standard. The IR spectra were taken on an Avatar-320 Fourier transform spectrometer for
KBr pellets. The mass spectra were taken on a Finnigan MAT Incos 50 mass spectrometer with direct inlet. The
ionization energy was 70 eV. The reaction course and purity of the products were monitored by thin-layer
chromatography on Sorbfil plates.
Ethyl Ester of 5-(4-Methoxyphenyl)-7-methyl-3-oxo-3,5-dihydro-2-thiazolo[2,3-a]pyrimidine-
6
2
-carboxylic Acid (2a). A solution of 4-(4-methoxyphenyl)-3,4-dihydropyrimidine(1H)-2-thione (1a) (0.61 g,
.0 mmol), β-chloroacetylphenylhydrazide of benzylic acid (0.79 g, 2.0 mmol), and triethylamine (0.4 g,
1
020

4
.0 mmol) in absolute toluene (10 ml) was heated at reflux for 3 h. Crystalline triethylamine hydrochloride was
filtered off and washed with a small amount of benzene, which was combined with the filtrate. The mixture was
evaporated. The oily residue was washed with ice water, dried, and crystallized from 1:1 2-propanol–hexane to
give 0.65 g (72%) ester 2a. Crystallization thrice from ethanol gave this product as light-orange transparent
crystals, mp 126-127°C.
Thiazolopyrimidines 2a-d were obtained by a similar method from 3,4-dihydropyrimidine-2-thi-
ones 1a-d and N-(2,6-dibromo-4-nitrophenyl)-2-bromoacetamide or N-(2,6-dichloro-4-nitrophenyl)-2-bromo-
1
acetamide. The IR and H NMR spectra of thiazolopyrimidine 2a-d were described in our previous work [1].
REFERENCES
1
.
I. V. Kulakov, O. A. Nurkenov, D. M. Turdybekov, G. M. Isabaeva, A. S. Makhmutova, and
K. M. Turdybekov, Khim. Geterotsikl. Soedin., 1075 (2009). [Chem. Heterocycl. Comp., 45, 856
(
2009)].
2
3
4
.
.
.
P. Wipf and V. Cunningham, Tetrahedron Lett., 36, 7819 (1995).
R. Gupta, A. K. Gupta, S. Paul, and P. L. Kachroo, Indian J. Chem., 34B, 151 (1995).
G. J. Grover, S. Dzwonczyk, D. M. McMultin, C. S. Normadinam, and S. J. Moreland, J. Cardiovasc.
Pharmacol., 26, 289 (1995).
5
6
.
.
I. S. Berdinskii and P. A. Petyunin, Zh. Obshch. Khim., 26, 2592 (1956).
I. V. Kulakov, Z. M. Zhambekov, S. D. Fazylov, and O. A. Nurkenov, Zh. Obshch. Khim., 78, 2028
(
2008).
1
021