Synthesis of some bicyclic thiazolo- and oxothiazolo-pyrimidines

Article abstract of DOI:10.1080/104265090508406

Oxothiazolopyrimidine compounds 2(a-e) were synthesized under reflux condition by a simple one-pot condensation reaction of the pyrimidine derivative 1 and chloroacetylchloride in the presence of silver acetate as a catalyst. In a similar way the thiazolo

Full text of DOI:10.1080/104265090508406

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Phosphorus, Sulfur, and Silicon
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Synthesis of Some Bicyclic
Thiazolo- and Oxothiazolo-
Pyrimidines
A. Mobinikhaledi a , N. Foroughifar a & B. Ahmadi a
a Department of Chemistry , University of Arak ,
Arak, Iran
Published online: 21 Dec 2010.
To cite this article: A. Mobinikhaledi , N. Foroughifar & B. Ahmadi (2005) Synthesis of
Some Bicyclic Thiazolo- and Oxothiazolo-Pyrimidines, Phosphorus, Sulfur, and Silicon
and the Related Elements, 180:2, 339-345, DOI: 10.1080/104265090508406
To link to this article: http://dx.doi.org/10.1080/104265090508406
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Phosphorus, Sulfur, and Silicon, 180:339–345, 2005
Copyright © Taylor & Francis Inc.
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/104265090508406
Synthesis of Some Bicyclic Thiazolo- and
Oxothiazolo-Pyrimidines
A. Mobinikhaledi
N. Foroughifar
B. Ahmadi
Department of Chemistry, University of Arak, Dr. Beheshti Ave,
Arak, Iran
Oxothiazolopyrimidine compounds 2(a–e) were synthesized under reflux condi-
tion by a simple one-pot condensation reaction of the pyrimidine derivative 1 and
chloroacetylchloride in the presence of silver acetate as a catalyst. In a similar way
the thiazolopyrimidine 3 and oxothiazolopyrimidine 4 were synthesized by reaction
of pyrimidine derivative 1 with 1,2-dibromoethane and 2-bromopropanoic acid re-
spectively. The yields of products following recrystallization from ethanol were of
the order of 55–89%.
Keywords 1,2-Dibromoethane; 2-bromopropanoic acid; chloroacetylchloride; oxothia-
zolo; pyrimidine; thiazolo
INTRODUCTION
Pyrimidine derivatives constitute an important chemical class of hete-
rocyclic compounds having a number of diverse biological activities.1–12
They show various interesting pharmacological properties including
antiviral,2 antibacterial,1,5 antitumor6 and antihypertensive4 effects.
Various synthetic approaches have been reported in the literature for
the synthesis of pyrimidines.1,13–19 Most of them based on the modifica-
tion of the classical one-pot Biginelli approach1,14–18 and in some cases
based on more complex multi steps processes,19 which may involve use
of some expensive or commercially nonavailable materials.
In continuation of our work on the synthesis and also pursuing our
continuous interest in synthesis of fused pyrimidine derivatives, we
wish to report synthesis of some novel bicyclic thiazolo- and oxothiazolo-
pyrimidines based on the general Biginelli reaction.
Received May 6, 2004; in final form July 6, 2004.
Address correspondence to A. Mobinikhaledi, Chemistry Department, Arak Univer-
sity, Dr. Beheshti Avenue, Arak, Iran. E-mail: akbor mobini@yahoo.com
339

340
A. Mobinikhaledi et al.
RESULTS AND DISCUSSION
Reaction of appropriate pyrimidine derivative 1 and chloroacetylchlo-
ride in dioxane as a solvent under reflux afforded 2(a–e). Also reac-
tion of starting pyrimidine derivative 1 with 1,2-dibromoethane and
2-bromopropanoic acid afforded 3 and 4 respectively as shown in
Scheme 1. In all reactions silver acetate was used as a catalyst to re-
move the NH proton of the pyrimidine ring.
SCHEME 1
Two isomeric products may be expected from an attack of nucleophile
on N-1 and N-3 position of 1. However it is well documented15,18,20,21
that N-3 in pyrimidine compound 1 is more reactive towards elec-
trophiles than the N-1 position, which is conjugated with the ester
group in 5-position of pyrimidine ring. Also the low field shift of the
pyrimidine proton in oxothiazolopyrimidine compounds compared to
that of the starting material is a good support of a nucleophilic attack
on N-3 position. The low field shift of the only pyrimidine proton in

Thiazolopyrimidines
341
these products is due to a deshielding effect of the neighboring carbonyl
group.
1
The H NMR spectra of 2(a–e) show a singlet signal at 2.74–2.60
ppm due to CH3 resonance of the pyrimidine ring. The multiplet signal
at 7.63–6.93 ppm and the sharp singlet signal at 6.59–6.11 ppm are
assigned to resonances of the aryl and pyrimidine ring protons, respec-
tively. Two protons of one CH2 group of the oxothiazolo ring resonate as
a singlet signal at 3.72–3.59 ppm. The CH3 of the ester group resonates
as a triplet at 1.10–1.25 ppm.
The 1H NMR spectra of 3 and 4 are very similar to those of 2(a–e). In
compound 3 the two CH2 groups of the thiazolo ring resonate as a triplet
at 3.98 ppm and 4.84 ppm respectively. In compound 4 the quartet signal
at 5.10 ppm and the doublet signal at 2.25 ppm are attributed to the
resonance of the CH3 group and the only CH group of the oxothiazolo
ring, respectively.
In the IR spectra of compounds 2(a–e), 3 and 4 absence of the ab-
sorption at 3200–3400 cm−1, the characteristic absorption of NH group
of starting material is in support of the expected reactions.
EXPERIMENTAL
Pyrimidine derivative 1 was prepared following a procedure in our
earlier reports.17,22,23 The melting points were determined using an
electrothermal digital melting point apparatus and are uncorrected.
1H NMR spectra were recorded on a Bruker (500 MHz) Spectrometer.
TMS was used as an internal standard. The IR spectra were recorded on
Glaxy FT-1R 500 Spectrometer. Reaction courses and product mixtures
were monitored by thin layer chromatography.
PREPARATION OF ETHYL-6-METHYL-4-(THIOPHEN-2-YL)-2-
THIO-1,2,3,4-TETRAHYDROPYRIMIDINE-5-CARBOXYLATE (1e)
A mixture of 2-thiophencarbaldehyde (0.02 mol), thiourea (0.022 mol)
and ethyl acetoacetate (0.02 mol) and 2–3 drops of HCl (37%) in ethanol
(4 ml) was refluxed for 3 h. The result was cooled at 0◦C for 3 days. The
precipitate was filtered off and then washed with ethanol. The crude
product was recrystallized from ethanol.
Yield: 75%, mp: 216–217◦C
IR (KBr): ν = 3310, 3190, 2990, 1670, 1640 cm−1
1H NMR (DMSO-d6): δ (ppm) = 1.22 (t, 3H, J = 7.2 Hz, CH3–ester), 2.43
(s, CH3), 4.21 (q, 2H, J = 7.2, CH2–ester), 5.71 (s, 1H, H–pyrimidine), 7.00
(m, 3H, H–thiophenyl), 7.80 (bs, 1H, NH), 9.09 (bs, 1H, NH)

342
A. Mobinikhaledi et al.
GENERAL PREPARATION FOR 2(a–e)
A mixture of appropriate thiazolopyrimidine derivative 1 (0.002 mol),
chloroacetylchloride (0.002 mol) and 10 mg silver acetate in dioxan
(7 ml) was refluxed for 30 min. The mixture was filtered and the fil-
trate cooled at room temperature for 2 h. The precipitate was filtered
off and washed with ethanol. The crude product was recrystallized from
ethanol.
5-(4-METHOXYPHENYL)-7-METHYL-3-OXO-2,3-
DIHYDRO-5H-THIAZOLO[3,2-a]PYRIMIDINE-6-CARBOXYLIC
ACID ETHYL ESTER (2a)
Yield: 81%, mp: 205–206◦C
IR (KBr): ν = 3100, 3000, 1725, 1660, 1610 cm−1
1H NMR (CDCl3): δ (ppm) = 1.21(t, 3H, J = 7.2 Hz, CH3-ester), 2.74 (s,
3H, CH3), 3.72 (s, 2H, CH2-thiazole), 3.81 (s, 3H, OCH3), 4.13 (q, 2H,
J = 7.2, CH2-ester), 6.11 (s, 1H, H–pyrimidine), 6.93 (m, 4H, H–arom
)
5-(2,5-DIMETHOXYPHENYL)-7-METHYL-3-OXO-2,3-DIHYDRO-
5H-THIAZOLO[3,2-a] PYRIMIDINE-6-CARBOXYLIC ACID ETHYL
ESTER (2b)
Yield: 89%, mp: 206–207◦C
IR (KBr): ν = 3200, 2990, 1710, 1675, 1615 cm−1
1H NMR (CDCl3): δ (ppm) = 1.25 (t, 3H, J = 7.2 Hz, CH3-ester), 2.60 (s,
3H, CH3), 3.59 (s, 2H, CH2-thiazole), 3.85, 3.88 (s, 6H, 2 OCH3−arom),
4.25 (q, 2H, J = 7.2, CH2-ester), 6.12 (s, 1H, H–pyrimidine), 7.01 (m, 3H,
H–arom
)
5-(3-NITROPHENYL)-7-METHYL-3-OXO-2,3-DIHYDRO-5H-
THIAZOLO[3,2-a] PYRIMIDINE-6-CARBOXYLIC ACID
ETHYL ESTER (2c)
Yield: 55%, mp: 185–186◦C
IR (KBr): ν = 3200, 2950, 1720, 1675, 1640 cm−1
1H NMR (CDCl3): δ (ppm = 1.22 (t, 3H, j = 7.2 Hz, CH3-ester), 2.64 (s, 3H,
CH3), 3.65 (s, 2H, CH2-thiazole), 4.17 (q, 2H, J = 7.2 Hz, CH2-ester), 6.24
(s, 1H, H–pyrimidine), 7.63 (m, 4H, H–arom
)

Thiazolopyrimidines
343
5-(4-METHYLPHENYL)-7-METHYL-3-OXO-2,3-DIHYDRO-
5H-THIAZOLO[3,2-a] PYRIMIDINE-6-CARBOXYLIC ACID ETHYL
ESTER (2d)
Yield: 85%, mp: 224–225◦C
IR (KBr): ν = 3130, 2950, 1750, 1720, 1670 cm−1
1H NMR (CDCl3): δ (ppm) = 1.10 (t, 3H, J = 7.2 Hz, CH3-ester), 2.41 (s,
3H, CH3-phenyl), 2.72 (s, 3H, CH3), 3.70 (s, 2H, CH2-thiazole), 4.21 (q, 2H,
J = 7.2 Hz, CH2-ester), 6.19 (s, 1H, H–pyrimidine), 7.17 (m, 4H, H–arom
)
7-METHYL-3-OXO-5-THIOPHEN-2-YL-2,3-DIHYDRO-5H-
THIAZOLO[3,2-a]PYRIMIDINE-6-CARBOXYLIC ACID
ETHYL ESTER (2e)
Yield: 62%, mp: 207–208◦C
IR (KBr): ν = 3150, 3075, 1770, 1720, 1680 cm−1
1H NMR (CDCl3): δ (ppm) = 1.23 (t, 3H, J = 7.2 Hz, CH3-ester), 2.72 (s,
3H, CH3), 3.71 (s, 2H, CH2-thiazole), 4.31 (q, 2H, J = 7.2 Hz, CH2-ester),
6.59 (s, 1H, H–pyrimidine), 7.09 (m, 3H, H–thiophenyl
)
5-(3-CHLOROPHENYL)-7-METHYL-2,3-DIHYDRO-5H-
THIAZOLO[3,2-a] PYRIMIDINE-6-CARBOXYLIC ACID
ETHYL ESTER (3)
A
mixture of ethyl-6-methyl-4-(3-chlorophenyl)-2-thioxo-1,2,3,4-
tetrahydropyrimidine-5-carboxylate (0.0011 mol), 1,2-dibromoethane
(0.003 mol), and a catalytic amount of silver acetate (10 mg) in
dimethylformamide (2 ml) was refluxed for 8 h. The mixture was
filtered and the filtrate was allowed to stand at −4◦C for overnight to
produce the oily product. The oily product was taken to water (5 ml)
and separated by separatory funnel. The aqueous layer was kept at
room temperature for one week. The resulting precipitate was then
filtered and washed with ethanol. The crude product was recrystallized
from ethanol.
Yield: 88%, mp: 205–207◦C
IR (KBr): ν = 3150, 2988, 1722, 1681 cm−1
1H NMR(DMSO-d6): δ (ppm) = 1.01 (t, 3H, J = 7.18Hz, CH3−ester), 2.26
(s, 3H, CH3), 3.55 (q, 2H, J = 7.18 Hz, CH2-ester), 3.98 (t, 2H, J = 7.0Hz,
N-CH2), 4.84 (t, 2H, J = 7.0Hz, S-CH2), 6.15 (s, 1H, H–pyrimidine), 7.13
(m, 4-H, H–arom
)

344
A. Mobinikhaledi et al.
5-(3-CHLOROPHENYL)-2,-7-DIMETHYL-3-OXO-2,3-DIHYDRO-
5H-THIAZOLO[3,2-a] PYRIMIDINE-6-CARBOXYLIC ACID
ETHYL ESTER (4)
A
mixture of ethyl-6-methyl-4-(3-chlorophenyl)-2-thioxo-1,2,3,4-
tetrahydropyrimidine-5-carboxylate (0.0011 mol), 2-bromopropanoic
acid (0.003 mol), and 10 mg silver acetate in dimethylformamide (2 ml)
was refluxed for 2 h. The mixture was filtered and the filtrate cooled at
0◦C to precipitate the desired compound. The precipitate was filtered
off and washed with ethanol. The crude product was recrystallized
from ethanol.
Yield: 80%, mp: 215–217◦C
IR (KBr): ν = 3150, 2988, 1725, 1719, 1699 cm−1
1H NMR (DMSO-d6): δ (ppm) = 1.10 (t, 3H, J = 7.20 Hz, CH3-ester), 2.25
(d, 3H, CH3−oxazole), 2.50 (s, 3H, CH3), 3.98 (q, 2H, J = 7.20 Hz,
CH2-ester), 5.10 (q, 1H, J = 7.20 Hz, H-2), 7.12 (s, 1H, H–pyrimidine),
7.79–8.04 (m, 4-H, H–arom
)
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