Synthesis of some thioxopyrimidines, thiazolopyrimidines, thiazolodipyrimidines and pyrazolothiazolopyrimidines

Article abstract of DOI:10.1080/104265090885174

Thioxopyrimidines 4(a-c) were synthesized by using the Biginelli three-component cyclocondensation reaction of an appropriate β-diketone, arylaldehyde, and thiourea. Reaction of thioxopyrimidines 5 with bromomalononitrile under strong basic solution afforded thiazolopyrimidines 7(a-c). On condensation of thiazolopyrimidines 7 with hydroxylamine hydrochloride in acetic acid and in the presence of sodium acetate thiazolodipyrimidines 8(a-b) were obtained. However reaction of 7 with formic acid gave the corresponding pyrazolothiazolopyrimidine 9a. Copyright Taylor & Francis Inc.

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Synthesis of Some
Thioxopyrimidines,
Thiazolopyrimidines,
Thiazolodipyrimidines and
Pyrazolothiazolopyrimidines
A. Mobinikhaledi a , N. Foroughifar a & A. R.
Ghorbani a
a Department of Chemistry, Faculty of Science,
University of Arak, Arak, Iran
Published online: 01 Feb 2007.
To cite this article: A. Mobinikhaledi , N. Foroughifar & A. R. Ghorbani (2005):
Synthesis of Some Thioxopyrimidines, Thiazolopyrimidines, Thiazolodipyrimidines
and Pyrazolothiazolopyrimidines, Phosphorus, Sulfur, and Silicon and the Related
Elements, 180:7, 1713-1719
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Phosphorus, Sulfur, and Silicon, 180:1713–1719, 2005
Copyright © Taylor & Francis Inc.
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/104265090885174
Synthesis of Some Thioxopyrimidines,
Thiazolopyrimidines, Thiazolodipyrimidines
and Pyrazolothiazolopyrimidines
A. Mobinikhaledi
N. Foroughifar
A. R. Ghorbani
Department of Chemistry, Faculty of Science, University of Arak,
Arak, Iran
Thioxopyrimidines 4(a–c) were synthesized by using the Biginelli three-component
cyclocondensation reaction of an appropriate β-diketone, arylaldehyde, and
thiourea. Reaction of thioxopyrimidines 5 with bromomalononitrile under strong
basic solution afforded thiazolopyrimidines 7(a–c). On condensation of thiazolopy-
rimidines 7 with hydroxylamine hydrochloride in acetic acid and in the presence of
sodium acetate thiazolodipyrimidines 8(a–b) were obtained. However reaction of 7
with formic acid gave the corresponding pyrazolothiazolopyrimidine 9a.
Keywords Pyrazolothiazolopyrimidine; thiazolopyrimidines; thioxopyrimidines
INTRODUCTION
The pyrimidine nucleus, which is a useful structure for further molecu-
lar exploration and for the development of new derivatives with differ-
ent biological activities, has received much attention in recent years.1
Pyrimidine derivatives are of interest because of their pharmaco-
logical properties1−12 including antiviral,2 antitumor,5 antibacterial,6,10
and antihypertensive4 effects. Several synthetic strategies have been
reported for the preparation of pyrimidine derivatives.10,13−19 Most of
them are based on the modification of the classical one-pot Biginelli
reaction10,14−18 and in some cases based on the more complex multi
steps processes19,20 which may involve use of some expensive commer-
cially nonavailable materials. Owing to the versatility of pyrimidines
and as a continuation of our work, we have extended the convenient
Received July 15, 2004; accepted August 24, 2004.
Address correspondence to A. Mobinikhaledi, Department of Chemistry, Faculty of Sci-
ence, University of Arak, Dr. Beheshti Ave, Arak-Iran. E-mail: akbar mobini@yahoo.com
1713

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A. Mobinikhaledi et al.
Biginelli reaction for preparation of some different, fused pyrimidine
and dipyrimidine derivatives containing a thiazole or pyrazole ring.
RESULTS AND DISCUSSION
Different pyrimidine derivatives containing a thiazole or pyrazole ring
were synthesized under reflux temperature. Reaction of β-diketone
1, appropriate arylaldehyde 2, and thiourea under reflux condi-
tion afforded thioxopyrimidines 4(a–c). Also reaction thiazolopyrim-
idines 7 with hydroxylamine hydrochloride and formic acid gave
thiazolodipyrimidines 8(a–b) and pyrazolothiazolopyrimidine 9a re-
spectively as shown in Scheme 1.
On reaction of pyrimidine derivatives 5 with bromomalononitrile
two, isomeric products may be expected from an attack of the nucle-
ophile on N-1 and N-3 nitrogen. However, in this reaction we obtained
only thiazolopyrimidines 7(a–c) as a result of nucleophilic attack on
N-3 nitrogen. It is well established15,18,21,22 that the N-3 position in
pyrimidine 5 is more reactive towards electrophiles than the N-1 po-
sition, which is conjugated with the ester group in 5-position of the
pyrimidine ring.
1
Also on the basis of H NMR spectra the structures of 7(a–c) are
in support of nucleophilic attack on the N-3 nitrogen. Thus the chem-
ical shift of the pyrimidine H-4 proton in 7 compared to that of 4 or 5
appeared at lower shift.
Condensation of thiazolopyrimidine 7 with hydroxylamine hy-
drochloride in acetic acid and in the presence of sodium acetate gave
thiazolodipyrimidines 8(a–b) in a quantitative yield. However, conden-
sation of 7 with formic acid afforded the corresponding pyrazolothia-
zolopyrimidine 9a. The IR spectra of 8(a–b) display two absorption
bands at ca 1660 and 1710 cm−1, which are assigned to two carbonyl
groups, and are in support of the expected reactions. Also in the IR
spectra of 8(a–b) and 9a absence of the absorption around 2190 cm−1
,
the characteristic absorption of the CN group of the starting material,
is in support of the expected reaction.
EXPERIMENTAL
Pyrimidine derivatives were prepared using the procedure in our ear-
lier reports.23,24 Melting points were determined with an electrothermal
digital melting point apparatus. IR spectra were taken on a Galaxy se-
1
ries FT-IR 5000 spectrophotometer in potassium bromide pellets. H
NMR spectra were recorded at 25◦C on Bruker 400 and 500 MHz spec-
trometers with using Me4Si (TMS) as an internal standard. Reaction

Thiazolopyrimidines
1715
SCHEME 1
courses and product mixtures were monitored by thin layer chromatog-
raphy.
PREPARATION OF 4(a–c)
For the preparation of 4(a–c) a mixture of aryl aldehyde (0.1 mol),
thiourea (0.12 mol) and appropriate β-diketone (0.1 mol) in ethanol

1716
A. Mobinikhaledi et al.
(25 mL) containing a catalytic amount of concentrated hydrochloric acid
(37%, 4–5 drops) was refluxed for 6, 7, and 8 h, respectively. The reaction
mixture was kept at room temperature for overnight. The solid prod-
ucts was filtered, washed with a mixture of ethanol and water (1:1), and
recrystallized from ethanol.
PREPARATION OF 7(a–c)
To a warm solution of potassium hydroxide (0.01 mol) and pyrimi-
dine derivative 5 (0.01 mol) in ethanol (30 mL), bromomalononitrile
(0.011 mol) was added drop wise with stirring. The reaction mixture
was stirred for 2, 2, and 3 h, respectively. The solution was allowed
to stand overnight at room temperature and the solid product precip-
itated upon dilution with water. The precipitate was filtered off and
recrystallized from dilute DMF.
PREPARATION OF 8(a–b)
For the preparation of 8(a–b) a mixture of the appropriate thiazolopy-
rimidine derivative 7 (0.01 mol) and formic acid (3 mL) was heated un-
der reflux for 10 and 12 h, respectively. The solid product was filtered
off and recrystallized from ethanol.
PREPARATION OF 9a
A mixture of the thiazolopyrimidine 7a (0.01 mol), hydroxylamine
hydrochloride (0.012 mol), sodium acetate (0.01 mol) and acetic acid
(15 mL) was refluxed for 7 h, then left overnight at room temperature
and poured into cold water. The solid precipitate which formed was
filtered off and recrystallized from ethanol.
5-ACYL-4-(2,5-DIMETHOXYPHENYL)-6-METHYL-2-THIOXO-
1,2,3,4-TETRAHYDROPYRIMIDINE (4a)
Yield 87%, m.p. 190–192◦C
IR (KBr): ν = 3350, 3200, 3100, 1637, 1574, 1498 cm−1
HNMR (DMSO-d6): δ = 2.17 (s, 3H, CH3), 2.56 (s, 3H, CH3), 3.81, 4.18
(s, 6H, 2OCH3), 5.95 (s, 1H, H-4), 6.69–7.25 (m, 3Haromat), 7.81 (s, 1H,
NH), 8.71 (s, 1H, NH)

Thiazolopyrimidines
1717
5-ACYL-4-(4-METHOXYPHENYL)-6-METHYL-2-THIOXO-
1,2,3,4-TETRAHYDROPYRIMIDINE (4b)
Yield 78%, m.p. 183–184◦C
IR (KBr): ν = 3320, 3240, 3100, 2900, 1640, 1540 cm−1
HNMR (DMSO-d6): δ = 2.12 (s, 3H, CH3), 2.32 (s, 3H, CH3), 3.73 (s, 3H,
OCH3), 5.23 (s, 1H, H-4), 6.89–7.14 (m, 4Haromat), 9.69 (s, 1H, NH),
10.23 (s, 1H, NH)
ETHYL-4-(3-NITROPHENYL)-6-METHYL-2-THIOXO-1,2,3,4-
TETRAHYDROPYRIMIDINE-5-CARBOXYLATE (4c)
Yield 75%, m.p. 173–174◦C
IR (KBr): ν = 3380, 3200, 3160, 2940, 1730, 1600 cm−1
HNMR (DMSO-d6): δ = 1.12 (t, J = 7.2 Hz, 3H, CH3), 2.32 (s, 3H,
CH3), 4.02 (q, J = 7.2 Hz, 2H, CH2), 5.33 (d, 1H, H-4), 7.68–8.17 (m,
4Haromat), 9.77 (s, 1H, NH), 10.50 (s, 1H, NH)
ETHYL-3-AMINO-2-CYANO-5-(2,5-DIMETHOXYPHENYL)-
7-METHYL-5H-THIAZOLO[a-2,3]PYRIMIDINE-5-
CARBOXYLATE (7a)
Yield 88%, m.p. 228–229◦C
IR (KBr): ν = 3500, 3369, 3126, 2987, 2191, 1705, 1604 cm−1
HNMR (DMSO-d6): δ = 1.18 (t, J = 7.2 Hz, 3H, CH3), 2.25 (s, 3H, CH3),
3.47 (s, 6H, 2OCH3), 4.04 (q, j = 7.2 Hz, 2H, CH2), 6.38 (s, 1H, H-4),
7.29–7.37 (m, 3Haromat), 7.71 (s, 2H, NH2)
ETHYL-3-AMINO-5-(3-CHLOROPHENYL)-2-CYANO-7-METHYL-
5H-THIAZOLO[a-2,3]PYRIMIDINE-5-CARBOXYLATE (7b)
Yield 85%, m.p. 209–210◦C
IR (KBr): ν = 3472, 3371, 3063, 2976, 2191, 1710, 1650 cm−1
HNMR (DMSO-d6): δ = 1.19 (t, J = 7.2 Hz, 3H, CH3), (s, 3H, CH3), 4.03
(q, 2H, CH2), 6.34 (s, 1Hpyrimidine, H-4), 7.26–7.46 (m, 4Haromat), 7.68
(s, 2H, NH2)
ETHYL-3-AMINO-5-(3-NITROPHENYL)-2-CYANO-7-METHYL-
5H-THIAZOLO[a-2,3]PYRIMIDINE-5-CARBOXYLATE (7c)
Yield 85%, m.p. 259–260◦C
IR (KBr): ν = 3380, 3285, 3020, 2991, 2200, 1710, 1560 cm−1

1718
A. Mobinikhaledi et al.
HNMR (DMSO-d6): δ = 1.18 (t, J = 7.2 Hz, 3H, CH3), 2.25 (s, 3H, CH3),
4.02 (q, J = 7.2 Hz, 2H, CH2), 6.35 (s, 1Hpyrimidine, H-4), 7.29–7.34 (m,
4Haromat), 7.65 (s, 2H, NH2)
ETHYL-9-(2,5-DIMETHOXYPHENYL)-4-OXO-7-METHYL-
9H-3,4-DIHYDROTHIAZOLO[a-2,3:b-4,5]DIPYRIMIDINE-
8-CARBOXYLATE (8a)
Yield 70% m.p. 267–268◦C
IR (KBr): ν = 3440, 3160, 2940, 1720, 1670, 1530 cm−1
HNMR (DMSO-d6): δ = 1.18 (t, J = 7.2 Hz, 3H, CH3), 3.68 (s, 6H, OCH3),
4.05 (q, J = 7.2 Hz, 2H, CH2), 6.58 (s, 1Hpyrimidine, H-9), 6.88–7.48 (m,
3Haromat), 8.14 (s, 1H, NH), 8.29 (s, 1Hpyrimidine, H-2)
ETHYL-9-(3-CHLOROPHENYL)-4-OXO-7-METHYL-
9H-3,4-DIHYDROTHIAZOLO[a-2,3:b-4,5]DIPYRIMIDINE-
8-CARBOXYLATE (8b)
Yield 75%, m.p. 269–270◦C
IR (KBr): ν = 3300, 3180, 2980, 1710, 1660, 1580, 1500 cm−1
HNMR (DMSO-d6): δ = 1.12 (t, J = 7.2 Hz, 3H, CH3), 2.26 (s, 3H, CH3),
4.02 (q, 2H, J = 7.2 Hz, CH2), 6.36 (s, 1Hpyrimidine, H-9), 7.23–7.44 (m,
4Haromat), 8.27 (s, 1H, NH), 9.68 (s, 1Hpyrimidine, H-2)
ETHYL-3-AMINO-8-(3-CHLOROPHENYL)-6-METHYL-
1H,8H-PYRAZOLO[d-3,4]THIAZOLO[a-2,3]PYRIMIDINE-
7-CARBOXYLATE (9a)
Yield 70%, m.p. 199–200◦C
IR (KBr): ν = 3310, 3180, 2980, 1670, 1570 cm−1
HNMR (DMSO-d6): δ = 1.14 (t, J = 7.2 Hz, 3H, CH3), 2.09 (s, 3H, CH3),
4.03 (q, J = 7.2 Hz, 2H, CH2), 5.19 (s, 1Hpyrimidine, H-8), 7.17–7.42 (m,
4Haromat), 9.68 (s, 1H, NH-exchangeable), 10.41 (s, 1H, NH2)
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