A facile synthesis and heteroannulation of thiazolopyrimidine and related heterocyclic systems

Article abstract of DOI:10.3184/030823407X248621

Reaction of pyrimidinylacetic acid 2 with different electrophilic and nucleophilic reagents gave annulated pyrimidine derivatives 3-11, respectively. Compound 3 ([7-(dibenzothien-2-yl)-5-phenyl-2,3-dihydro-5H-thiazolo[3,2-a]- pyrimidin-6-yl]acetic acid) w

Full text of DOI:10.3184/030823407X248621

552 RESEARCH PAPER
SEPTEMBER, 552–556
JOURNAL OF CHEMICAL RESEARCH 2007
A facile synthesis and heteroannulation of thiazolopyrimidine and related
heterocyclic systems
Aly A. Aly*
Chemistry Department, Faculty of Science, Benha University, Benha, Egypt
Reaction of pyrimidinylacetic acid 2 with different electrophilic and nucleophilic reagents gave annulated pyrimidine
derivatives 3–11, respectively. Compound
3
([7-(dibenzothien-2-yl)-5-phenyl-2,3-dihydro-5H-thiazolo[3,2-a]-
pyrimidin-6-yl]acetic acid) was transformed to pyrimidinylacetyl azide 12, which upon heterocyclisation with active
methylene compounds, acidic and basic reagents furnished functionally substituted heteroaromatic compounds 13–
21, respectively. The structures of the synthesised derivatives were elucidated by elemental and spectral analyses.
Keywords: polycyclic pyrimidines, triazolylpyrimidines, acid azide cyclisation
Pyrimidine derivatives and heterocyclic annulated pryimidine
are well known in medicinal chemistry for their pronounced
therapeutic applications1-5 such as inhibitors of HIV-1
integrase, CNS stimulants, protein kinase inhibitors and
anticancer drugs. Non-medicinal applications6-10 include
use as herbicides, agricultural fungicides, growth promoters
and UV absorbants. One possible reason for their activity is
the presence of a pyrimidine base in thymine, cytosine and
uracial which are essential building blocks of nucleic acids,
DNA and RNA. Our studies11-13 related to the synthesis of
annulated pyrimidines for testing as potential biodegradable
agrochemical and antimicrobial agents by the functionalisation
and cyclisation reactions of [4-(dibenzothien-2-yl)-2-
1H NMR (CDCl3) spectrum showed signals at d 2.95 ppm
for methylene protons, singlet at 4.63 for methine proton,
multiplet signals (12 H) for aromatic protons at (7.11–7.95)
ppm, two broad singlet at (8.40–8.60) ppm for two NH and
singlet at 10.61 ppm for OH, which disappeared upon addition
of D2O to the NMR sample. Also, the mass spectrum of 2
revealed a molecular ion peak at m/z = 430 which corresponds
to the molecular formula C24H18N2O2S2.
Pyrimidinylacetic acid 2 is used as a versatile intermediate for
the preparation of a variety of multifunctionalised polyhetero-
cycles, due to the presence of two adjacent reactive functional
groups. Thus, the reaction of 2 with 1,2-dibromoethane gave [7-
(dibenzothien-2-yl)-5-phenyl-2,3-dihydro-5H-thiazolo[3,2-a]
pyrimidin-6-yl]acetic acid (3). The condensation of 2 with
1,3-dibromopropane gave the corresponding pyrimido[2,1-
b][1,3]thiazine derivative 4 (Scheme 1).
The preparative use of pyrimidinylacetic acid 2 was
extended to prepare new annulated pyrimidine derivatives.
Thus, the alkylation of 2 with chloroacetic acid in a mixture
of glacial acetic acid/acetic anhydride containing anhydrous
sodium acetate gave [7-(dibenzothien-2-yl)-3-oxo-5-phenyl-
2,3-dihydro-5H-thiazolo[3,2-a]pyrimidin-6-yl]acetic acid 5,
which condensed with benzaldehyde to give the corresponding
benzylidene derivative 6 (Scheme 2).
mercapto-6-phenyl-1,6-dihydro-pyrimidin-5-yl]acetic
acid
(2) with different reagents.
Results and discussion
The required starting material, [4-(dibenzothien-2-yl)-2-
mercapto-6-phenyl-1,6-dihydropyrimidin-5-yl]acetic acid (2)
was prepared from readily available 3-[(dibenzothien-2-yl)
carbonyl]propanoic acid (1), thiourea and benzaldehyde in
ethanolic solution containing anhydrous potassium carbonate.
The structure of compound 2 was assigned on the basis of
elemental analysis and compatible spectroscopic data, thus,
its IR spectrum showed characteristic absorption bands at
3410–3260 due to n(OH,NH) and at 1695 cm-1 for nCO. The
Compound 6 underwent cyclisation into isoxazolothiazolo-
pyrimidine derivative 7 upon treatment with hydroxylamine
Ph
S
O
HO
EtOH
NH
ArCCH2CH2COOH + H2NCNH2 + PhCHO
O
1
Ar
N
H
S
Ph
HO
BrCH2CH2Br
N
O
Ar
N
S
Ph
N
3
HO
NH
SH
O
Ar
Ph
HO
2
Br(CH2)3Br
N
O
Ar
N
S
4
Ar =
S
Scheme 1
* Correspondent. E-mail: alymaboud@yahoo.com
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JOURNAL OF CHEMICAL RESEARCH 2007 553
Ph
Ph
N
HO
HO
N
NH
SH
CH2=CHCN
O
O
CN
Ar
SH
N
Ar
8
2
ClCH2CO2H
Cyclisation
Ph
Ph
HO
O
HO
N
N
O
O
Ar
N
5
S
O
Ar
N
9
S
PhCHO
PhCHO
Ph
Ph
HO
O
HO
N
CHPh
O
N
O
O
CHPh
Ar
N
6
S
Ar
N
S
10
H2NOH.HCl
H2NOH.HCl
Ph
Ph
O
HO
HO
N
NH
Ph
N
Ph
NH
O
O
Ar
N
S
Ar
N
S
O
7
11
Ar =
S
Scheme 2
hydrochloride in refluxing pyridine. Cyanoethylation of
compound 2 with an equimolar amount of acrylonitrile in
pyridine underwent a Michael-type addition to the activated
double bond of the nitrile to give the propionitrile derivative 8,
whichunderwent cyclisationtopyrimidothiazine9 by refluxing
in a mixture of glacial acetic acid and hydrochloric acid (3:1).
The condensation of compound 9 with benzaldehyde gave
[3-benzylidene-8-(dibenzothien-2-yl)-2-oxo-6-phenyl-3,4-
dihydro-2H,6H-pyrimido-[2,1-b][1,3]thiazin-7-yl]acetic acid
(10), which reacted with hydroxylamine hydrochloride to give
the cyclised tricyclic derivative 11 (Scheme 2).
In recent years, there has been increasing interest in the
synthesis of alkyl azide, this stems from its applicability for
synthesis of polyfunctionally substituted heterocycles.14-16
Thus, thiazolopyrimidinylacetyl azide 12 was synthesised
following the reported method17 by stirring equimolar
amounts of [7-(dibenzothien-2-yl)-5-phenyl-2,3-dihydro-5H-
thiazolo[3,2-b]pyrimidin-6-yl]acetyl chloride and aqueous
sodium azide in dry acetone at 0–5°C (Scheme 3).
5-phenyl-2,3-dihydro-5H-thiazolo[3,2-a]pyrimidin-6-yl]-
methyl}-3-phenyl-1,3,4-oxadiazol-2(3H)-one (17).
Additionally, the reaction of azide 12 with glycollic
acid and/or thioglycollic acid in boiling dry benzene gave
oxazolidine-2,4-dione and thiazolidine-2,4-dione 18a,b,
respectively, via Curtius rearrangement followed by 1,2-
dipolar addition and cyclisation to give the desired product.
Moreover, azide 12 decomposed through azido-displacement
pathway upon treatment with glycine in dry toluene containing
catalytic amount of piperidine to give 2-{[7-(dibenzothien-2-
yl)-5-phenyl-2,3-dihydro-5H-thiazolo[3,2-a]pyrimidin-6-yl]-
methyl}-oxazol-5(4H)-one (19).
Finally, the reaction of azide 12 with anthranilic acid gave
disubstituted urea 20, which was easily cyclised by boiling
in acetic anhydride to give the quinazoline derivative 21
(Scheme 3).
The structures of the synthesised compounds were
assigned on the basis of elemental analysis and spectral data
(see Experimental).
The azide 12 is a building blocks for the synthesis of
bioactive triazole,18 oxadiazole,19 quinazoline20 derivatives.
Accordingly, the cycloaddition reaction of alkyl azide 12
with active methylene compounds (viz malononitrile, ethyl
cyanoacetate, ethyl acetoacetate and diethyl malonate) gave
the triazole derivatives21 13–16, respectively (Scheme 3).
While, the cycloaddition addition reaction of 12 with phenyl
isocyanate in dry benzene gave 5-{[7-(dibenzothien-2-yl)-
Experimental
Melting points are uncorrected. IR spectra in KBr were recorded on
a Perkin-Elmer 298 spectrophotometer. Elemental analyses were
carried out at the Micro-analytical Centre of Cairo University, Egypt.
1H and 13C NMR spectra were obtained on an Varian Gemini 200
MHz and 50 MHz instrument using TMS as internal reference with
chemical shifts expressed as d ppm. Mass spectra were recorded on a
Shimadzu GCMS-QP 1000 instrument (70 eV El mode).
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554 JOURNAL OF CHEMICAL RESEARCH 2007
O
CH2(CN)2
Ar`CH
2C
N
N
N
H2N
CN
13
O
NCCH2COOEt
Ar`CH
N
N
N
2C
H2N
COOEt
14
O
CH3COCHCOOEt
Ar`CH2C
N
N
N
Ph
N
CH2COOH
Ar
H3C
15
N
COOEt
S
3
O
CH2(COOEt)2
N
N
N
Ar`CH2C
(i) SOCl2
(ii) NaN3
O
COOEt
16
Ph
O
CH2C N3
N
PhNCO
Ph
N
N
Ar
S
N
CH2Ar`
O
O
12
17
O
N-CH2Ar`
O
HXCH2CO2H
H2NCH2CO2H
X
18a,b
18a; X = O
18b; x = S
N
O
CH2Ar`
O
19
H2N
O
H
N
NHCNHCH2Ar`
O
HOOC
Ac2O
Ph
N
NCH2Ar`
COOH
N
O
Ar`=
20
S
21
S
Scheme 3
13C NMR values of phenyl and dibenzothiophene groups for
compounds 3–21 are the same as in compound 2 with d ± 0.1-0.5 ppm.
[4-(Dibenzothien-2-yl)-2-mercapto-6-phenyl-1,6-dihydro-pyrimidin-
5-yl]acetic acid (2): A mixture of 3-[(dibenzothien-2-yl)carbonyl]
propanoic acid (1), (5.7 g, 20 mmol), thiourea (1.6 g, 20 mmol),
benzaldehyde (2.1 ml, 20 mmol) and K2CO3 (2.8 g, 20 mmol) in
ethanol (60 ml) was refluxed for 10 h. The reaction mixture was cooled
and the solid obtained was dissolved in hot water. The filtrate was
neutralised with acetic acid to give solid product which recrystallised
from ethanol to give 2. Yield, 5.4 g (63%); m.p. 221–223°C; IR:
n = 3410–3260 (multiple bands OH, NH), 1695 (CO), 1265 cm-1
(CS); 1H NMR (CDCl3): d = 2.95 (s, 2H, CH2), 4.63 (s, 1H, methine),
7.11–7.95 (m, 12H, ArH), 8.40–8.60 (br s, 2H, 2NH, exchangeable),
10.61 (s, 1H, OH, exchangeable); 13C NMR: d = 26.8(CH2), 59.3
(C-6), 108.3(C-5), 136.3(C-4), 160.3(CO), 167.2(CS); 115.2, 115.8,
117.3, 118.2, 121.4, 126.3(C-of phenyl ring); 120.2, 120.8, 121.6,
122.2, 124.4, 124.9, 130.2, 130.9, 136.2, 137.1, 140.2, 141.3(C-of
dibenzothiophene ring); Anal. Calcd for C24H18N2O2S2 (430.54): C,
66.95; H, 4.21; N, 6.51%. Found: C, 66.80; H, 4.11; N, 6.71%.
[7-(Dibenzothien-2-yl)-5-phenyl-2,3-dihydro-5H-thiazolo[3,2-a]
pyrimidin-6-yl]acetic acid (3): 1,2-Dibromoethane (1.9 ml, 10 mmol)
in DMF (20 ml) was added dropwise to a stirred solution containing
compound 2 (4.3 g, 10 mmol) and sodium hydroxide (0.07 g in 10 ml
H2O). The reaction mixture was refluxed for 2 h, then stirred at room
temperature for an additional 2 h. The solid product which formed
was filtered off, washed with water and triturated with ethanol to
give colourless product which recrystallised from ethanol to give 3.
Yield, 3.4 g (74%); m.p. 163–165°C; IR: n = 3390–3170 (OH),
1695 cm-1 (CO); 1H NMR (CDCl3): d = 2.71–2.85 (m, 4H, 2CH2
of thiazole), 3.96 (s, 2H, CH2), 4.71 (s, 1H, methine), 7.51–8.21
(m, 12H, ArH), 10.80 (s, 1H, OH, exchangeable); 13C NMR:
d = 21.6(C-2), 28.1(CH2), 56.2(C-3), 62.7(C-5), 125.1(C-6), 138.2
(C-7), 163.4(CO), 176.2(C-8a); Anal. Calcd for C26H20N2O2S2
(456.58): C, 68.39; H, 4.42; N, 6.14%. Found: C, 68.53; H, 4.51; N,
6.26%.
[8-(Dibenzothien-2-yl)-6-phenyl-3,4-dihydro-2H,6H-pyrimido
[2,1-b][1,3]thiazin-7-yl]acetic acid (4): 1,3-Dibromopropane (1 ml,
5 mmol) in DMF (20 ml) was added dropwise to a stirred solution
containing compound 2 (2.2 g, 5 mmol) and sodium hydroxide (0.07 g
in H2O, 10 ml). The reaction mixture was refluxed for 3 h, then
stirred at room temperature for an additional 2 h. The solid product
which formed was filtered off, washed with water and triturated with
ethanol to give a colourless product which recrystallised from ethanol
to give 4. Yield 1.6 g (67%); m.p. 183–185°C. IR: n = 3385–3180
(OH), 1690 cm-1 (CO); 1H NMR (CDCl3): d = 2.65–2.93 (m, 6H,
3CH2 of thiazine), 3.93 (s, 2H, CH2), 4.13 (s, 1H, methine), 7.29–
8.11 (m, 12H, ArH), 10.71 (s, 1H, OH, exchangeable); Anal. Calcd
for C27H22N2O2S2 (470.61): C, 68.91; H, 4.71; N, 5.95%. Found: C,
68.80; H, 4.91; N, 5.83%.
[7-(Dibenzothien-2-yl)-3-oxo-5-phenyl-2,3-dihydro-5H-thiazolo
[3,2-a]pyrimidin-6-yl]acetic acid (5): A mixture of compound 2
(4.3 g, 10 mmol), chloroacetic acid (0.95 g, 10 mmol) and anhydrous
sodium acetate (2.0 g) was refluxed in a mixture of glacial acetic acid
(30 ml) and acetic anhydride (20 ml) for 4 h. The reaction mixture was
cooled and poured onto crushed ice (50 g). The solid which formed
was filtered off and recrystallised from benzene to give 5. Yield, 3.5 g
(75%); m.p. 201–203°C; IR: n = 3380–3210 (OH), 1690–1685 cm-1
(CO); 1H NMR (CDCl3); d = 2.85 (s, 2H, CH2 of thiazole), 3.11
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JOURNAL OF CHEMICAL RESEARCH 2007 555
(s, 2H, CH2), 4.12 (s, 1H, methine), 7.15–7.85 (m, 12H, ArH), 10.65
(s, 1H, OH, exchangeable); Anal. Calcd for C26H18N2O3S2 (470.56):
C, 66.36; H, 3.86; N, 5.95%. Found: C, 66.50; H, 3.97; N, 4.81%.
[2-Benzylidene-7-(dibenzothien-2-yl)-3-oxo-5-phenyl-2,3-dihydro-
5H-thiazolo[3,2-a]pyrimidin-6-yl]acetic acid (6): A mixture of
compound 5 (4.7, 10 mmol) and benzaldehyde (1.1 ml, 10 mmol) in
glacial acetic acid (25 ml) containing anhydrous sodium acetate (1 g)
was refluxed for 6 h. The reaction mixture left to cool, then poured
onto crushed ice (30 g) and the solid formed was recrystallised from
dioxane to give 6. Yield, 3.8 g (68%); m.p. 230–232°C; IR: n = 3405–
3190 (OH), 1690–1680 cm-1 (CO); MS: m/z = 558 (M+); Anal. Calcd
for C33H22N2O3S2 (558.67): C, 70.95; H, 3.97; N, 5.01%. Found: C,
70.81; H, 3.82; N, 5.15%.
solution of thiazolopyrimidinylacetyl chloride (5.79, 12 mmol) in dry
acetone (30 ml) at 0–5°C, then the mixture was stirred for further 1 h
at room temperature. The reaction mixture was added to crushed ice
(40 g) and the precipitated product was filtered off to give the acid
azide 12.Yield, 3.8 g (65%); m.p. 117–119°C (with decomposition);
IR: n = 2215 (CON3), 1680 cm-1 (CO).
General procedure for the preparation of triazole derivatives (13–16)
A cold solution of compound 12 (0.96 g, 2 mmol) in absolute ethanol
(25 ml) was added to a cold solution of active methylene compounds
(2 mmol) (viz malononitrile, ethyl cyanoacetate, ethyl acetoacetate
and diethyl malonate) in ethanolic sodium ethoxide solution (prepared
from sodium 1.66 g in absolute ethanol 20 ml). The reaction mixture
was stirred at room temperature overnight, then the solvent was
evaporated under vacuum. The concentrated ethanol solution was
poured onto crushed ice (50 g) and the solid obtained was filterated
off and recrystallised to give the compounds 13–16.
[6-(Dibenzothien-2-yl)-3,8-diphenyl-2,3-dihydro-8H-isoxazolo[5',4':
4,5]thiazolo[2,3-a]pyrimidin-7-yl]acetic acid (7): A mixture of
compound 6 (2.2 g, 4 mmol) and hydroxylamine hydrochloride (0.28 g,
4 mmol) was refluxed in pyridine (25 ml) for 6 h. The reaction
mixture was cooled, then poured onto ice–HCl (30 g, 10 ml) and
the solid formed was filtered off and recrystallised from dioxane
to give 7. Yield, 1.5 g (66%); m.p. 213–215°C; IR: n = 3395–3185
5-Amino-1-{2-[7-(dibenzothien-2-yl)-5-phenyl-2,3-dihydro-
5H-thiazolo[3,2-a]pyrimidin-6-yl]acetyl}-1H-1,2,3-triazole-4-
carbonitrile (13): Yield, 0.73 g (66%) (benzene); m.p. 195–197°C;
(multiple bands, OH, NH), 1685 cm-1 (CO); H NMR (DMSO-d6):
IR: n = 3350, 3280 (NH2), 2220 (CN), 1680 cm-1 (CO); H NMR
1
1
d = 2.76 (s, 2H, CH2), 4.11–4.30 (br s, 2H, 2CH, two methine), 7.35–
8.12 (m, 17H, ArH), 9.12 (s, 1H, NH, exchangeable), 10.90 (s, 1H,
OH, exchangeable); 13C NMR: d = 28.3(CH2), 59.6(C-4), 62.6(C-
9), 78.8(C-8a), 114.2(C-5), 137.3(C-6), 160.1(C-7a), 162.2(C-2a),
165.2(CO); 119.1, 119.9, 120.2, 120.9, 123.2, 125.1(C-of phenyl ring
of oxazole); Anal. Calcd for C33H23N3O3S2 (573.69): C, 69.09; H,
4.04; N, 7.32%. Found: C, 69.22; H, 4.21; N, 7.16%.
(CDCl3): d = 2.71–2.95 (m, 4H, 2CH2 of thiazole), 3.95 (s, 2H, CH2),
4.51 (s, 1H, methine), 5.85 (br s, 2H, NH2), 7.51–8.25 (m, 12H,
ArH); 13C NMR: d = 27.5(CH2), 29.4(C-2), 54.3(C-3), 56.8(C-5),
116.2(C-4 of triazole), 118.2(C-6), 124.2(C-7), 143.2(CN), 146.1
(C-5 of triazole), 170.2(C-8a), 180.2(CO); Anal. Calcd for
C29H21N7OS2 (547.66): C, 63.60; H, 3.86; N, 17.90%. Found: C,
63.72; H, 3.95; N, 17.79%.
[1-(2-Cyanoethyl)-4-(dibenzothien-2-yl)-2-mercapto-6-phenyl-
1,6-dihydropyrimidin-5-yl]acetic acid (8): A mixture of compound 2
(4.3 g, 10 mmol) and acrylonitrile (0.74 ml, 14 mmol) in pyridine
(30 ml) was refluxed for 6 h. The colourless solid which formed after
concentration and cooling was recrystallised from ethanol to give 8.
Yield 3.6 g (74%); m.p. 216–218°C; IR: n = 3375–3190 (OH), 2510
(SH), 2210 (CN), 1685 cm-1 (CO); 1H NMR (CDCl3): d = 2.22 (t, 2H,
CH2), 2.86 (s, 2H, CH2), 3.3 (t, 2H, CH2CN), 4.35 (s, 1H, methine),
7.14–7.95 (13H, ArH and SH), 10.76 (s, 1H, OH, exchangeable);
MS: m/z = 483 (M+); Anal. Calcd for C27H21N3O2S2 (483.61): C,
67.06; H, 4.38; N, 8.69%. Found: C, 67.18; H, 4.50; N, 8.73%.
[8-(Dibenzothien-2-yl)-2-oxo-6-phenyl-3,4-dihydro-2H,6H-
pyrimido[2,1-b][1,3]thiazin-7-yl]acetic acid (9): Compound 8 (2
g) in a mixture of glacial acetic acid (30 ml) and hydrochloric acid
(10 ml) was refluxed for 5 h. The reaction mixture was concentrated
by evaporation under reduced pressure, the solid formed was filtered
off, washed with water and recrsytallised from dioxane to give 9.
Yield 1.4 g (69%); m.p. 195–197°C; IR: n = 3390–3200 (OH), 1695–
1690 cm-1 (CO); 1H NMR (CDCl3): d = 2.81 (s, 2H, CH2), 2.90–3.1
(m, 4H, 2CH2 of thiazine), 4.13 (s, 1H, methine), 7.51–8.13 (m, 12H,
ArH), 10.76 (s, 1H, OH, exchangeable); MS: m/z = 484 (M+); Anal.
Calcd for C27H20N2O3S2 (484.59): C, 66.92; H, 4.16; N, 5.78%.
Found: C, 66.79; H, 4.01; N, 5.57%.
[3-Benzylidene-8-(dibenzothien-2-yl)-2-oxo-6-phenyl-3,4-dihydro-
2H,6H-pyrimido[2,1-b][1,3]thiazin-7-yl]acetic acid (10): A mixture
of compound 9 (4.8 g, 10 mmol) and benzaldehyde (1.1 ml, 10 mmol)
in glacial acetic acid (30 ml) containing anhydrous sodium acetate
(1.5 g) was refluxed for 6 h. The reaction mixture was cooled, poured
onto crushed ice (30 g) and the solid formed was recrystallised from
ethanol to give 10. Yield 3.8 g (66%); m.p. 230–232°C; IR: n = 3410–
3180 (OH), 1690–1680 cm-1 (CO); 1H NMR (CDCl3): d = 2.90
(s, 2H, CH2), 3.70 (s, 2H, CH2 of thiazine), 4.20 (s, 1H, methine),
7.13–8.11 (m, 18H, ArH and benzylic proton), 10.50 (s, 1H, OH,
exchangeable); MS: m/z = 572 (M+); Anal. Calcd for C34H24N2O3S2
(572.70): C, 71.31; H, 4.22; N, 4.89%. Found: C, 71.50; H, 4.32; N,
4.96%.
[8-(Dibenzothien-2-yl)-3,6-diphenyl-2,3-dihydro-4H,6H-
isoxazolo[4,5-e]pyrimido[2,1-b][1,3]thiazin-7-yl]acetic acid (11):
A mixture of compound 10 (2.3 g, 4 mmol) and hydroxylamine
hydrochloride (0.28 g, 4 mmol) in pyridine (30 ml) was refluxed for
6 h. The reaction mixture was cooled, then poured onto crushed ice
(40 g) and the solid product was filtered off and recrystallised from
DMF to give 11. Yield, 1.7 g (69%); m.p. 207–209°C; IR: n = 3390–
3180 (multiple bands, OH, NH), 1690 cm-1 (CO); 1H NMR (DMSO-
d6): d = 2.91 (s, 2H, CH2), 3.60 (s, 2H, CH2 of thiazine), 4.15–4.30
(br s, 2H, two methine), 9.55 (br s, 1H, NH, exchangeable); 10.75 (s,
1H, OH, exchangeable); Anal. Calcd for C34H25N3O3S2 (587.71): C,
69.48; H, 4.29; N, 7.15%. Found: C, 69.61; H, 4.40; N, 7.31%.
[7-(Dibenzothien-2-yl)-5-phenyl-2,3-dihydro-5H-thiazolo[3,2-a]
pyrimidin-6-yl]acetyl azide (12): A saturated solution of sodium azide
(0.78 g, 12 mmol) in H2O (2 ml) was added dropwise to a stirred
Ethyl 5-amino-1-{2-[7-(dibenzothien-2-yl)-5-phenyl-2,3-dihydro-
5H-thiazolo[3,2-a]pyrimidin-6-yl]acetyl}-1H-1,2,3-triazole-4-
carboxylate (14): Yield, 0.74 g (62%) (xylene); m.p. 226–228°C; IR:
1
n = 3340, 3270 (NH2), 1725, 1680 cm-1 (CO); H NMR (CDCl3):
d = 1.40 (t, 3H, CH3), 2.65–2.95 (m, 4H, 2CH2 of thiazole), 3.75 (s, 2H,
CH2), 4.12 (q, 2H, CH2), 4.65 (s, 1H, methine), 5.91 (br s, 2H, NH2),
7.61–8.23 (m, 12H, ArH); Anal. Calcd for C31H26N6O3S2 (594.71): C,
62.61; H, 4.41; N, 14.13%. Found: C, 62.49; H, 4.63; N, 14.25%.
Ethyl 1-{2-[7-(dibenzothien-2-yl)-5-phenyl-2,3-dihydro-5H-thiazolo
[3,2-a]pyrimidin-6-yl]acetyl}-5-methyl-1H-1,2,3-triazole-4-
carboxylate (15): Yield, 0.73 (61%) (xylene); m.p. 240–242°C; IR:
n = 1725, 1680 cm-1 (CO); 1H NMR (CDCl3): d = 1.40 (t, 3H, CH3),
2.50 (s, 3H, CH3), 2.85–2.95 (m, 4H, 2CH2 of thiazole), 3.50 (s, 2H,
CH2), 4.20 (q, 2H, CH2), 4.25 (s, 1H, methine), 7.23–8.31 (m, 12H,
ArH); MS: m/z = 593 (M+); Anal. Calcd for C32H27N5O3S2 (593.72):
C, 64.74; H, 4.58; N, 11.80%. Found: C, 64.85; H, 4.67; N, 11.96%.
Ethyl 1-{2-[7-(dibenzothien-2-yl)-5-phenyl-2,3-dihydro-5H-thiazolo
[3,2-a]pyrimidin-6-yl]acetyl}-5-oxo-4,5-dihydro-1H-1,2,3-triazole-
4-carboxylate (16): Yield, 0.68 g (57%) (toluene); m.p. 217–219°C;
IR: n = 1730 (CO of ester), 1685–1680 cm-1 (CO of amide);
1H NMR (CDCl3): d = 1.3 (t, 3H, CH3), 2.71–2.90 (m, 4H, 2CH2 of
thiazole), 3.62 (s, 2H, CH2), 4.11 (q, 2H, CH2), 4.35, 4.51 (2 s, 2H,
two methine), 7.15–8.11 (m, 12H, ArH); 13C NMR: d = 12.2(CH3),
22.1(CH2), 27.3(C-2), 50.1(CH of triazole), 56.7(C-3), 63.2
(C-5), 64.2(CH2CH3), 127.2(C-6), 129.2(C-7), 165.2(CO of ester),
168.1(COCH2), 173.1(CO of triazole); Anal. Calcd for C31H25N5O4S2
(595.69): C, 62.51; H, 4.23; N, 11.76%. Found: C, 62.65; H, 4.34; N,
11.85%.
5-{[7-(Dibenzothien-2-yl)-5-phenyl-2,3-dihydro-5H-thiazolo[3,2-
a]pyrimidin-6-yl]-methyl}-3-phenyl-1,3,4-oxadiazol-2(3H)-one (17):
A mixture of compound 12 (0.96 g, 2 mmol) and phenyl isocyanate
(3 ml) in dry benzene (40 ml) was heated under reflux for 5 h.
The solid that separated after concentration and cooling was
recrystallised from benzene to give 17. Yield, 0.76 g (69%);
m.p. 201–203°C; IR: n = 1725 cm-1 (CO); 1H NMR (CDCl3):
d = 2.63-2.85(m, 4H, 2CH2 of thiazole), 3.42 (s, 2H, CH2), 4.35 (s,
1H, methine), 7.37–8.13(m, 17H, ArH); 13C NMR: d = 22.1(CH2),
26.1(C-2), 53.1(C-3), 55.2(C-5), 117.2(C-6), 123.3(C-7), 143.2
(C-5, oxadiazole), 160.1(CO), 171.2(C-8a); 117.1, 118.2, 120.3,
121.4, 124.3, 126.2(phenyl ring of oxadiazole); Anal. Calcd for
C33H24N4O2S2 (572.70): C, 69.21; H, 4.22; N, 9.78%. Found: C,
69.11; H, 4.10; N, 9.86%.
3-{[7-(Dibenzothien-2-yl)-5-phenyl-2,3-dihydro-5H-thiazolo[3,2-a]
pyrimidin-6-yl]-methyl}oxazolidine-2,4(3H,5H)-dione (18a) and 3-
{[7-(dibenzothien-2-yl)-5-phenyl-2,3-dihydro-5H-thiazolo[3,2-a]
pyrimidin-6-yl]methyl}thiazolidine-2,4(3H,5H)-dione
(18b):
A
solution of 12 (0.96 g, 2 mmol) in dry benzene (30 ml), containing
piperidine (1 ml), glycolic acid and/or thioglycollic acid (3 mmol) was
heated under reflux temperature for 2 h. The solvent was evaporated
under reduced pressure and the residue was redissolved in ether
(40 ml). The solution was washed with 10% sodium carbonate
PAPER: 07/4758

556 JOURNAL OF CHEMICAL RESEARCH 2007
(3 ¥ 25 ml) and water (40 ml), dried over anhydrous Na2SO4.
Evaporation of the dried etheral layer under vacuum gave the
compounds 18a,b.
Received 19 July 2007; accepted 26 September 2007
Paper 07/4758 doi: 10.3184/030823407X248621
18a:Yield, 0.71 g (71%) (ethanol); m.p. 214–216°C; IR: n = 1710 cm-1
1
References
(CO); H NMR (CDCl3): d = 2.80–2.95 (m, 4H, 2CH2 of thiazole),
3.40, 3.60 (2 s, 4H, 2CH2), 4.31 (s, 1H, methine), 7.23–8.13 (m, 12H,
ArH); Anal. Calcd for C28H21N3O3S2 (511.62): C, 65.73; H, 4.14; N,
8.21%. Found: C, 65.52; H, 4.10; N, 8.09%.
18b: Yield, 0.84 g (76%) (ethanol); m.p. 230–232°C; IR:
n = 1705 cm-1 (CO); 1H NMR (CDCl3): d = 2.75–2.90 (m, 4H,
2CH2 of thiazole), 3.50, 3.65 (2 s, 4H, 2CH2), 4.35 (s, 1H, methine),
7.35–8.41 (m, 12H, ArH); MS: m/z = 527 (M+); Anal. Calcd for
C28H21N3O2S3 (527.68): C, 63.73; H, 4.01; N, 7.96%. Found: C,
63.84; H, 4.18; N, 7.83%.
2-{[7-(Dibenzothien-2-yl)-5-phenyl-2,3-dihydro-5H-thiazolo[3,2-a]
pyrimidin-6-yl]methyl}-oxazol-5(4H)-one (19): A mixture of 12
(0.96 g, 2 mmol) and glycine (0.15 g, 2 mmol) in dry toluene
(30 ml) containing piperidine (1 ml) was heated under reflux
for 7 h. The solid that separated after concentration and cooling
was recrystallised from toluene to give 19. Yield, 0.73 g (73%);
m.p. 223–225°C; IR: n = 1726 (CO), 1610 cm-1 (C=N); 1H NMR
(CDCl3): d = 2.70–2.81 (m, 4H, 2CH2 of thiazole), 3.71, 3.92 (2 s, 4H,
2CH2), 4.57 (s, 1H, methine), 7.63–8.25 (m, 12H, ArH); 13C NMR:
d = 24.2(CH2), 26.2(C-2), 49.2(C-4, oxazole), 53.2(C-3), 57.1(C-5),
118.2(C-6, oxazole), 128.3(C-7), 157.2(C-2, oxazole), 173.2(CO),
176.1(C-8a); Anal. Calcd for C28H21N3O2S2 (495.62): C, 67.85; H,
4.27; N, 8.48%. Found: C, 67.76; H, 4.10; N, 8.31%.
1
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4
5
6
7
1-{[7-(Dibenzothien-2-yl)-5-phenyl-2,3-dihydro-5H-thiazolo[3,2-a]
pyrimidin-6-yl]methyl}-3-o-tolylurea (20):Amixture of compound 12
(0.96 g, 2 mmol) and anthranilic acid (0.27 g, 2 mmol) in dry benzene
(30 ml) was refluxed for 30 min, the reaction mixture was allowed
to cool and the solid which precipitated after cooling, filtered off,
dried and recrystallised from benzene to give 20. Yield, 1.0 g (84%);
m.p. 242–244°C; IR: n = 3460–3260 (OH, NH), 1690–1680 cm-1
8
9
1
(CO); H NMR (CDCl3): d = 2.73–2.95 (m, 4H, 2CH2 of thiazole),
3.55 (s, 2H, CH2), 4.20 (s, 1H, methine), 7.12–8.25 (m, 16H, ArH),
9.21, 9.30, 10.10 (3 s, 3H, 2NH, OH, exchangeable); MS: m/z = 590
(M+); Anal. Calcd for C33H26N4O3S2 (590.72): C, 67.10; H, 4.44;
N, 9.48%. Found: C, 67.23; H, 4.53; N, 9.61%.
10 N. Kihara, I. Tomino, M. Takei, Jpn. Patent 61/76488 A2 [76488], 1986;
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42, 125.
3-{[7-(Dibenzothien-2-yl)-5-phenyl-2,3-dihydro-5H-thiazolo[3,2-
a]pyrimidin-6-yl]methyl}-quinazoline-2,4(1H, 3H)-dione (21):
A
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solution of 20 (1 g) in acetic anhydride (10 ml) was refluxed for 1 h.
The reaction mixture was cooled, poured onto crushed ice (50 g)
and the precipitated product was filtered off and recrystallised from
n-butanol to give 21. Yield, 0.61 g (63%); m.p. 196–198°C; IR:
n = 3210 (NH), 1680–1670 cm-1 (CO); 1H NMR (DMSO-d6):
d = 2.72–2.93 (m, 4H, 2CH2 of thiazole), 3.95 (s, 2H, CH2), 4.45
(s, 1H, methine), 7.61–8.13 (m, 16H, ArH), 9.22 (br s, 1H, NH,
exchangeable); 13C NMR: d = 25.1(CH2), 26.8(C-2), 54.1(C-3),
58.1(C-5), 119.1(C-6), 127.2(C-7), 176.7(C-8a); 149.2, 150.2(2 CO);
118.1, 119.3, 120.5, 126.2, 132.2, 134.3(C-of quinazolinedione);
Anal. Calcd for C33H24N4O2S2 (572.70): C, 69.21; H, 4.22; N, 9.78%.
Found: C, 69.35; H, 4.37; N, 9.86%.
PAPER: 07/4758