Synthesis and biological evaluation of some new coumarinyl thiazolopyrimidinones

Article abstract of DOI:10.1080/17415990903569544

Two new series of coumarin linked, linear and angularly fused thiazolo-[3,2-a]-pyrimidinones have been synthesized from 3-bromoacetyl coumarins by azole and azine approaches. Regioisomeric 5H and 7H thiazolo-[3,2-a]-pyrimidinones have been clearly distinguished by their IR and UV fluorescence spectral data. All the compounds have been characterized by analytical and spectroscopic methods. Rate and yield enhancements have been achieved using microwave irradiation. The results of in vivo diuretic activity indicate that substituents on coumarin do not enhance the activity. In vitro antimicrobial activities have shown that the compounds are specifically active against Gram-positive but are inactive against Gram-negative bacterial strains. Moderate fungal activity was observed against Candida albicans and Penicillium chrysogenum and all the compounds were found to be inactive against Aspergillus niger.

Full text of DOI:10.1080/17415990903569544

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Synthesis and biological evaluation
of some new coumarinyl
thiazolopyrimidinones
Naazneen B. Yaragatti a , Manohar V. Kulkarni a , Manjunath D.
Ghate b , Satyanarayan S. Hebbar c & Ganesh R. Hegde c
a Department of Chemistry, Karnatak University, Dharwad, 580
003, Karnataka, India
b Department of Pharmaceutical Chemistry, Kripanidhi College of
Pharmacy, Bangalore, 560 034, Karnataka, India
c Department of Botany, Karnatak University, Dharwad, 580 003,
Karnataka, India
Published online: 11 Feb 2010.
To cite this article: Naazneen B. Yaragatti , Manohar V. Kulkarni , Manjunath D. Ghate ,
Satyanarayan S. Hebbar & Ganesh R. Hegde (2010) Synthesis and biological evaluation of
some new coumarinyl thiazolopyrimidinones, Journal of Sulfur Chemistry, 31:2, 123-133, DOI:
10.1080/17415990903569544
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Journal of Sulfur Chemistry
Vol. 31, No. 2, April 2010, 123–133
Synthesis and biological evaluation of some new coumarinyl
thiazolopyrimidinones
Naazneen B.Yaragattia, Manohar V. Kulkarnia*, Manjunath D. Ghateb, Satyanarayan S. Hebbarc
and Ganesh R. Hegdec
aDepartment of Chemistry, Karnatak University, Dharwad 580 003, Karnataka, India; bDepartment
of Pharmaceutical Chemistry, Kripanidhi College of Pharmacy, Bangalore 560 034, Karnataka, India;
cDepartment of Botany, Karnatak University, Dharwad 580 003, Karnataka, India
(Received 12 September 2009; final version received 13 December 2009)
Two new series of coumarin linked, linear and angularly fused thiazolo-[3,2-a]-pyrimidinones have been
synthesized from 3-bromoacetyl coumarins by azole and azine approaches. Regioisomeric 5H and 7H
thiazolo-[3,2-a]-pyrimidinones have been clearly distinguished by their IR and UV fluorescence spectral
data. All the compounds have been characterized by analytical and spectroscopic methods. Rate and yield
enhancements have been achieved using microwave irradiation. The results of in vivo diuretic activity
indicate that substituents on coumarin do not enhance the activity. In vitro antimicrobial activities have
shown that the compounds are specifically active against Gram-positive but are inactive against Gram-
negative bacterial strains. Moderate fungal activity was observed against Candida albicans and Penicillium
chrysogenum and all the compounds were found to be inactive against Aspergillus niger.
Keywords: 3-bromoacetyl coumarins; 4-(3’-coumarinyl)-2-amino thiazole; 2-mercapto uracil; antimicro-
bial activity; diuretic activity
1. Introduction
Thiazole nucleus is an important component of vitamins, antibiotics and a variety of clinically
accepted drugs. Fused thiazolopyrimidines constitute a group of bicyclic heterocyclic systems
with the [5,4-d] isomer being isosteric with purines. The [3,2–a] isomers, possessing a bridge-
head nitrogen, have received a great deal of attention (1–3) in view of their interesting chemical
reactivityandwiderangeofbiologicalproperties.Auniquefeatureofthiazolo-[3,2-a]-pyrimidines
is their existence in 5H and 7H forms, which have been proposed in very few instances (4). Deriva-
tives of thiazolo-[3,2-a]-pyrimidines have been reported to exhibit antibacterial and antifungal (5),
anti-inflammatory (6), antitumor (7, 8), antihypertensive (9), acetyl cholinesterase inhibitory (10)
and diuretic activities (11). Thiazoles and benzimidazolo thiazoles linked to the C3 position of
coumarin have resulted in compounds with potent antimicrobial and anti-inflammatory activities
(12, 13). The interest in such compounds is due to the fact that biodegradation of coumarins would
*Corresponding author. Email: manohar274@gmail.com
ISSN 1741-5993 print/ISSN 1741-6000 online
© 2010 Taylor & Francis
DOI: 10.1080/17415990903569544
http://www.informaworld.com

124 N.B. Yaragatti et al.
OH
O
O
N
C2H5O
C2H5
Ph
N
N
N
N
S
S
R
O
O
S
N
OCH3
Anti-HIV-1 agent
Ar
Acetyl cholinesterase inhibitor
Anti-inflammatory agent
Figure 1. Structurally related bio-active compounds.
lead to in situ generation of thiazole-4-acetic acids, useful for the inflammation inhibition pro-
cess. Further, substituted 3-benzamido coumarins have been found to exhibit promising diuretic
activity (14). In the light of the above literature reports, it was thought of considerable interest
to synthesize 3’-coumarinyl thiazolopyrimidinones. Some of the structurally related compounds
are presented (Figure 1).
2. Results and discussion
Thiazolo-[3,2-a]-pyrimidines have been synthesized by the unambiguous azole (3 + 3) approach
involving the use of 2-amino thiazoles and β-keto esters leading to exclusive formation of
5H isomers (15). A second route involves the construction of a thiazole ring from 2-mercapto
uracils and α-halo ketones (16), termed as the azine approach, which has the potential of two
N-heterocyclizations possible at N3 and N1 leading to the 5H and 7H forms (Figure 2). Deriva-
tives of thiazolopyrimidines have also been synthesized from the retro Diels–Alder reaction (17)
and these cyclizations have also been achieved under microwave (MW) conditions (18).
The present paper demonstrates the azole and azine approaches to construct coumarinyl
thiazolo-[3,2-a]-pyrimidinones and the application of the MW irradiation to these reactions,
as well as the results of preliminary biological evaluation studies. The two synthetic routes
N
N
+
NH2
S
S
N
(3 + 3) azole approach
3
N
+
HN
+
S
N
S
N
1
2
H
(3 + 2) approach
Retro Diels–Alder approach
Figure 2. Synthetic routes to thiazolo-[3,2-a]-pyrimidines.

Journal of Sulfur Chemistry 125
O
N
N
R
S
O
O
CH3
(3)
Ethylaceto
-acetate
Polyphosphoric
O
N
-acid,150-165 oC
O
N
CH3
K2CO3, dry
xylene, reflux
S
Br
Thiourea
Ethanol, reflux
NH2
N
R
R
R
O
O
O
O
2-Mercapto-6
methyl uracil
O
O
S
(1)
(2)
(4)
2-Mercapto-6
phenyl uracil
MWI
125-130 oC
K2CO3, dry
xylene, reflux
Benzoyl-
acetoacetate
O
O
N
S
N
R
O
O
(5)
N
C6H5
N
O
C6H5
S
R
O
(6)
where R= H, 6-CH3, 6-Cl, 6-Br, 6-NO2, 5,6-benzo
Scheme 1. Synthesis of coumarinyl thiazolo-[3,2-a]-pyrimidines.
employed for the construction of thiazolopyrimidinones linked to the coumarin moiety are out-
lined in Scheme 1. Various 3-bromoacetyl coumarins (1) (19) required for both the routes were
obtained by the room temperature bromination of 3-acetyl coumarins in chloroform. The cor-
responding 4-3’-coumarinyl-2-amino thiazoles (2) (20) which are the precursors for the azole
(3 + 3) approach were in turn isolated as yellow solids by the reaction of (1) with thiourea in
refluxing ethanol. Reactions of aminothiazoles (2) with ethylacetoacetate in polyphosphoric acid
at high temperatures lead to thiazolo-[3,2-a]-pyrimidine-5-ones, which is in accordance with the
literature reports on the reactions of 2-amino thiazoles with β-keto esters (21). Compound 3a,
=
R H, exhibited the pyrimidinone carbonyl at 1685 cm−1 and the lactone carbonyl at 1716 cm−1
Its UV spectrum DMF showed two intense bands at 280 and 325 nm. The H NMR chemical
shifts and mass spectral data are consistent with the structure for all of the compounds (3a–3d).
In the azine approach, 3-bromoacetylcoumarins (1) were reacted with 2-mercapto-6-methyl
.
1
=
uracil in refluxing xylene with a view to compare with the azole approach. The product 4a, R H,
exhibited a band at 1658 cm−1 due to pyrimidinone carbonyl, which was significantly less than 3a.
The lactone carbonyl band in 4a was observed at 1726 cm−1, which is close to the value observed
in 3a. The lower carbonyl stretching frequency is consistent with the values observed in 2- and
4-quinolones and also 2- and 4-pyridones (22, 23). The UV spectrum of 4a in DMF showed two
1
bands at 258 and 290 nm, which is different from 3a. The H-NMR spectrum agrees with the

126 N.B. Yaragatti et al.
Table 1. UV–VIS and fluorescence of isomeric coumarinyl thiazolo-[3,2-a]-pyrimidinones (DMF).
5H isomer
7H isomer
Absorption
Emission
Absorption
Emission
Compound
λmax (nm)
λmax (nm)
Compound
λmax (nm)
λmax (nm)
3a
3b
3c
3d
325
352
416
434
368
409
477
492
4a
4b
4c
4d
280
309
375
382
328
352
422
438
Table 2. Preparation of the coumarinyl thiazolo [3,2-a]-pyrimidinones.
Melting point
Conventional
heating time
(h)/yield (%)
MW irradiation time
(min)/yield (%)
Entry
R
Rꢀ
Compound
(◦C)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
H
6-CH3
6-Cl
6-Br
5,6-Benzo
H
6-CH3
6-Cl
6-Br
5,6-Benzo
H
6-Cl
6-Br
6-NO2
H
6-Cl
6-Br
–CH3
–CH3
–CH3
–CH3
–CH3
–CH3
–CH3
–CH3
–CH3
–CH3
–C6H5
–C6H5
–C6H5
–C6H5
–C6H5
–C6H5
–C6H5
–C6H5
3a
3b
3c
3d
3e
4a
4b
4c
4d
4e
5a
5b
5c
5d
6a
6b
6c
6d
219–221
231–233
228–230
226–228
239–241
267–269
283–285
237–239
211–213
223–225
292–294
299–301
297–299
301–303
295–297
297–299
307–309
301–303
3.0/70
3.0/68
3.0/67
4.0/69
4.0/60
24/65
24/62
24/61
24/60
24/61
–
1.50/90
3.00/88
3.00/84
4.00/89
4.00/80
1.30/90
2.00/86
2.10/82
2.50/80
2.40/89
2.00/90
3.00/89
4.20/91
9.00/88
2.20/89
3.00/84
3.40/82
5.00/80
–
–
–
24/69
24/67
24/65
27/66
6-NO2
structure and expectedly did not show a significant difference with 3a. The mass spectral data are
consistent with the structures. The UV and fluorescence bands observed for these compounds are
listed in Table 1. It can be seen that the longest wavelength band for the angularly fused 7H-ones
(4a–4d) is less than the corresponding 5H-ones (3a–3d), which is also the case with the emission
bands.
Using these two approaches thiazolo-[3,2-a]-pyrimidine-5-ones (5a–5d) and thiazolo-[3,2-
a]-pyrimidine-7-ones (6a–6d) were obtained using benzoyl acetoacetate and 2-mercapto-6-
phenyluracil, respectively. In view of the longer reaction times required for both the approaches,
these reactions were also carried out in a Kenstar domestic MW oven at 125 ◦C (1200W). It was
found that the products were isolated in higher yields and the reaction was completed in a few
minutes (Table 2).
2.1. Pharmacology
2.1.1. Antimicrobial assay
The isomeric coumarinyl thiazolo-[3,2-a]-pyrimidinones were tested for their in vitro antibacterial
activity against a panel of Gram-positive and Gram-negative reference strains: all microbiolog-
ical products were purchased from Himedia. Chemicals were of analytical grade from Sigma.

Journal of Sulfur Chemistry 127
The microorganisms used in this study were Klebsiella pneumoniae MTCC109, Staphylococcus
aureus MTCC737, Pseudomonas aeruginosa MTCC1688 and Proteus vulgaris MTCC1771. The
fungal strains used in the study are Candida albicans MTCC183, Aspergillus niger and Peni-
cillium chrysogenum. DMF was used as a solvent control and the reference drugs used were
streptomycin for bacterial strains and nystatin for fungal strains. Antimicrobial activity tests were
conducted by using the cup plate method (24–26) at a concentration of 25, 50 and 100 μg/mL.
The bacteria were grown for 24 h on a nutritive agar medium at 37 ◦C. The fungal strains were
grown on potato dextrose agar medium at 30 ◦C for 24 h. The zone of inhibition was measured in
millimeters. The percentage inhibition of the test compounds was related to the standard, whose
zone of inhibition was taken as 100%.
The results of activity are tabulated in Table 3. Among the thiazolo-[3,2-a]-pyrimidinones,
compounds 5c and 5d showed moderate to good activity at 100 μg/mL concentration. The same
compounds were active even at 25 μg/mL concentration. Similarly, compounds 5c, 5d, 6a and
6b showed a good activity against P. vulgaris, whereas all the compounds (5a–5d and 6a–6d)
showed a very good activity against Staphylococcus aureus at all three concentrations. The
antibacterial activity demonstrated that all of the compounds were active only against the two
Gram-positive strains and had no effect on the Gram-negative strains. The results of antifungal
activity demonstrated that they were inactive against A. niger and they were more effective against
Table 3. Antimicrobial activity of the selected [3,2-a] pair of isomers.
Bacterial strain zone of inhibition
Gram positive Gram negative
P. vulgaris S. aureus K. pneumonia P. aureus C. albicans A. niger P. chrysogenum
Fungal strains zone of inhibition
Concentration
Compound
(μg/mL)
mm
%
mm
%
mm
%
mm
%
mm
%
mm
%
mm
%
5a
25
50
100
25
50
100
25
50
100
25
50
100
25
50
100
25
50
100
25
50
100
25
50
100
25
–
–
–
–
–
–
–
–
–
–
–
–
181 82
212 88
258 92
159 72
207 86
258 92
119 54
144 60
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
124
212
266
136
190
258
–
142
202
–
62
88
95
68
79
92
–
59
72
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
84
130
194
–
–
–
–
–
–
–
–
119
93
125
194
–
–
–
–
60
72
88
–
–
–
–
–
–
–
–
66
52
69
88
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
5b
5c
102 85
153 96
197 98.5 180 64
106 88.3 106 48
155 97
198 99
–
140 87.5 221 92
182 91 266 95
109 90.1 203 92
148 92.5 228 95
5d
135 56
182 65
198 90
–
–
185
124
183
247
132
171
230
–
101
152
–
–
174
66
62
76
88
66
71
82
–
42
54
–
–
62
6a
–
–
–
–
–
–
–
–
–
–
–
–
100
100
100
–
6b
194 97
271 97
150 68
190 79
238 85
137 62
178 74
247 88
220 100 80
240 100 120
280 100 160
6c
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
6d
–
–
Standard
120 100
160 100
200 100
100 100 200 100 100
140 100 240 100 140
180 100 280 100 180
140
180
220
20
100
100
100
–
50
100
Control
20
–
20
–
20
20
–
20
–
20
Notes: Standards used were streptomycin for bacteria and nystatin for fungal strains; control: DMF.

128 N.B. Yaragatti et al.
C. albicans and less active against P. chrysogenum. In this also, the best results were obtained
for compounds 5b and 6b, which were active against both C. albicans and P. chrysogenum at
25 μg/mL concentration. In the thiazolo-[3,2-a]-pyrimidinyl-5-ones, chloro, bromo and nitro sub-
stituted was found to be effective and compound 6b exhibited moderate antifungal activity against
P. chrysogenum.
2.1.2. Diuretic activity
The method of Lipschitz and Kavimani (27, 28) was employed for screening the diuretic activity.
Adult Wistar rats of either sex weighing 150–200 g were used for the experiment. The animals
were caged in standard metal cages provided with food and water ad libitum. The animals were
divided into six groups (six in each) and deprived of food and water for 18 h prior to the experiment.
The first two groups were administered with normal saline (control), furosemide (20 mg/kg, i.p.)
and compounds (1 mg/kg body weight, p.o.).
Immediately after administration, animals were placed in metabolic cages (two per cage) spe-
cially designed to separate urine and faecal matter and kept at room temperature (25 0.5 ◦C).
During the period of study, no food or water were available to the animals. The total volume of
urine was collected and measured from control, standard and compounds after 5 h of adminis-
tration. The parameters monitored for each individual rat were total urine volume (collected for
water intake during the rest period and measured after 24 h of treatment) and urine concentration
of Na+, K+ and Cl−. Na+ and K+ concentrations were measured by flame photometry and Cl−
concentration was estimated as NaCl by titration with silver nitrate solution (2.096 g/L) using one
drop of 5% potassium chromate solution as an indicator (Table 4). All the data are expressed as
mean SEM and analyzed by ANOVA followed by Dunnet’s t-test (n = 6).
The diuretic activity of the synthesized compounds showed significant activity, except 3d and
4d, which are substituted by -Br in the sixth position of the coumarin ring. The remaining tested
compounds, unsubstituted and substituted with chloro and methyl groups showed promising
activity. Compounds exhibit a high activity compared with standard Furosemide 20. The amount
of chlorine in the urine sample of the simple unsubstituted compound is very high (2600 μmol/kg),
which is significant compared with Furosemide 20.
Among all of the tested compounds, compounds 3a and 4a showed the highest activity in
the case of total sodium, potassium and chloride depletion compared with the standard. The
6-bromo-substituted compounds showed lower diuretic activity, and the sodium, potassium and
Table 4. The in vitro diuretic activity of selected [3,2-a] pair of isomers against Albino rats (μmol/kg).
Sl.
Total urine volume
Total Na+
Total K+
Total Cl−
no.
Compound R
(ml/24 h)
(μmol/kg)
(μmol/kg)
(μmol/kg)
1
2
3
4
5
6
7
8
3a
3b
3c
3d
4a
4b
4c
4d
32.44 0.4
25.72 0.2
28.23 0.5
20.55 0.3
32.34 0.4
27.72 0.1
28.62 0.2
20.62 0.1
18.2 0.3
142.5
119
123
115
146
120
123
118
85
4
7
4
2
4
3
5
2
3
3
150
125
145
116
148
120
149
118
82.2
120
6
5
3
7
6
5
3
9
2
9
2600
2048
2245
1658
2630
2022
2222
1652
685
Control
Furosemide 20 (standard)
24.18 0.7
113
1945
Notes: The values are expressed as mean SEM. The results are analyzed using ANOVA followed by Dunnet’s t-test
(n = 6).

Journal of Sulfur Chemistry 129
chloride depletion was also found to be very low. Thus, the synthesized coumarinyl thiazolo-[3,2-
a]-pyrimidinones proved to be promising diuretics that need further in-depth investigation.
3. Conclusion
3-Bromoacetyl coumarins have successfully been used as molecular handles to generate isomeric
thiazolo-[3,2-a]-pyrimidinones, and this method has the potential to be applied for other hetero-
cycles which would lead to a large number of biologically potent biheterocyclic compounds. To
the best of our knowledge, this is the first report in this direction.
4. Experimental
Melting points were determined in open capillaries and are uncorrected. IR spectra (KBr) were
run on a Nicolet impact 410 FT-IR spectrometer (υmax in cm−1). 1H NMR spectra were recorded
in DMSO-d6 with TMS as an internal standard (chemical shift δ in ppm and J values in Hz) on a
Bruker 300 MHz FTNMR spectrometer. Mass spectra were recorded on a Finnignan MAT (Model
MAT8200) spectrometer. The UV fluorescence spectrum was recorded on a U-3310 UV–VIS,
F-7000 spectrophotometer. Elemental analysis was carried out on a Heraus CHN rapid analyser.
Nomenclature was created using ChemDraw software. The purity of the compounds was checked
by thin layer chromatography on silica gel plates using ethyl acetate and a benzene solvent system.
All the reagents were of laboratory reagent quality and were used after purification.
4.1. General procedure for the synthesis of 7-methyl-3-[(3ꢀ-coumarinyl)]-5H-[1,3]-thiazolo-
[3,2-a]-pyrimidine-5-ones (3a–3e)
A mixture of substituted coumarinylaminothiazole (2) (0.0025 mol), ethylacetoacetate (0.0025
mol) and polyphosphoric acid (2.0 g) was heated to 150–165 ◦C for 3–4 h. The reaction mixture
was cooled and poured into ice-cold water, and the separated solid was filtered off. It was washed
severaltimeswithethanol, driedandrecrystallizedfromethanol/dioxane(1:1)toyieldacrystalline
solid.
4.1.1. 7-Methyl-3-[(3ꢀ-coumarinyl)]-5H-[1,3]-thiazolo-[3,2-a]-pyrimidine-5-one (3a)
IR (KBr) cm−1: 1685, 1716; 1H NMR (300 MHz, DMSO) δ: 2.29 (s, 3H, C6-H of pyrimidine),
7.36 (d, 1H, J = 7.4 Hz, C5H), 7.42 (t, 1H, J = 7.6 Hz, C6-H), 7.62 (s, 1H, C5-H of pyrimidine),
7.68 (t, 1H, J = 7.3 Hz, C7-H), 7.78 (d, 1H, J = 7.6 Hz, C8H), 8.15 (s, 1H, C5-H of thiazole),
8.50 (s, 1H, C4-H of coumarin); LC-MS 310.9 (M+, 100%). Anal. Calcd. for C16H10N2O3S: C,
61.93; H, 3.25; N, 9.03%. Found: C, 61.88; H, 3.27; N, 9.05.
4.1.2. 7-Methyl-3-[(6ꢀ-methyl-(3ꢀ-coumarinyl)]-5H-[1,3]-thiazolo-[3,2-a]-pyrimidine-5-one
(3b)
IR (KBr) cm−1: 1680, 1732; 1H NMR (300 MHz, DMSO) δ: 2.12 (s, 3H, C6-H of pyrimidine),
2.36 (s, 3H, C6-H of coumarin), 6.02 (s, 1H, C5-H of pyrimidine), 6.63 (s, 1H, C5-H of thiazole),
7.27–7.52 (m, 3H, Ar), 7.60 (s, 1H, C4-H of coumarin); LC–MS 326 (M+, 100%). Anal. Calcd.
for C17H12N2O3S: C, 62.95; H, 3.73; N, 8.64%. Found: C, 62.89; H, 3.70; N, 8.60.

130 N.B. Yaragatti et al.
4.1.3. 7-Methyl-3-[(6ꢀ-chloro-(3ꢀ-coumarinyl)]-5H-[1,3]-thiazolo-[3,2-a]-pyrimidine-5-one
(3c)
IR (KBr) cm−1: 1682, 1738; 1H NMR (300 MHz, DMSO) δ: 2.36 (s, 3H, C6-H of pyrimidine),
6.09 (s, 1H, C5-H of pyrimidine), 6.95 (s, 1H, C5-H of thiazole), 7.27–7.52 (m, 3H, Ar), 7.63 (s,
1H, C4-H of coumarin); LC–MS 345 (35Cl, M+1, 100%). Anal. Calcd. for C16H9ClN2O3S: C,
55.74; H, 2.63; N, 8.13%. Found: C, 55.52; H, 2.62; N, 8.10.
4.1.4. 7-Methyl-3-[(6ꢀ-bromo-(3ꢀ-coumarinyl)]-5H-[1,3]-thiazolo-[3,2-a]-pyrimidine-5-one
(3d)
IR (KBr) cm−1: 1636, 1727; 1H NMR (300 MHz, DMSO) δ: 2.37 (s, 3H, C6-H of pyrimidine),
6.11 (s, 1H, C5-H of pyrimidine), 6.95 (s, 1H, C5-H of thiazole), 7.28–7.67 (m, 3H, Ar), 7.82 (s,
1H, C4-H of coumarin); LC–MS 390.7 (79Br, M+2, 100%). Anal. Calcd. for C16H9BrN2O3S: C,
49.37; H, 2.33; N, 7.20%. Found: C, 49.22; H, 2.22; N, 7.10.
4.1.5. 7-Methyl-3-[(5,6-benzo-(3ꢀ-coumarinyl)]-5H-[1,3]-thiazolo-[3,2-a]-pyrimidine-5-one
(3e)
IR (KBr) cm−1: 1624, 1722; 1H NMR (300 MHz, DMSO) δ: 2.33 (s, 3H, C6-H of pyrimidine),
6.04 (s, 1H, C5-H of pyrimidine), 6.17 (s, 1H, C5-H of thiazole), 7.28–8.22 (m, 6H, Ar), 8.25 (s,
1H, C4-H of coumarin); LC–MS 360.9. Anal. Calcd. for C20H12N2O3S: C, 66.65; H, 3.36; N,
7.77%. Found: C, 66.68; H, 3.39; N, 7.66.
4.2. General procedure for the synthesis of 5-methyl-3-[(3ꢀ-coumarinyl)]-7H-[1,3]-thiazolo-
[3,2-a]-pyrimidine-7-ones (4a–4e)
A mixture of substituted 3-bromoacetyl coumarin (1) (0.0025 mol), 2-mercapto-6-methyl uracil
(0.0025 mol), K2CO3(0.0065 mol) was refluxed in 20 mL of dry xylene for 24 h. After completion
of reaction, the reaction mixture was filtered off and xylene concentrated on a rotary evaporator.
The solid separated was recrystallized from ethanol and dioxane mixture (1:1) to yield a crystalline
solid.
4.2.1. 5-Methyl-3-[(3ꢀ-coumarinyl)]-7H-[1,3]-thiazolo-[3,2-a]-pyrimidine-7-one-(4a)
IR (KBr) cm−1: 1658, 1726; 1H NMR (300 MHz, DMSO) δ: 2.15 (s, 3H, C6-H of pyrimidine),
7.42 (d, 1H, J = 7.5 Hz, C5-H), 7.45 (s, 1H, C5-H of pyrimidine), 7.65 (t, 1H, J = 7.1 Hz, C6-H),
7.78 (t, 1H, J = 7.1 Hz, C7-H), 7.90 (d, 1H, J = 7.6 Hz, C8H), 8.18 (s, 1H, C5-H of thiazole),
8.30 (s, 1H, C4-H of coumarin); LC–MS 310.9 (M+, 100%). Anal. Calcd. for C16H10N2O3S: C,
61.93; H, 3.25; N, 9.03. Found: C, 61.88; H, 3.38; N, 9.09.
4.2.2. 5-Methyl-3-[(6ꢀ-methyl-(3ꢀ-coumarinyl)]-7H-[1,3]-thiazolo-[3,2-a]-pyrimidine-7-one
(4b)
1
IR (KBr) cm−1: 1649, 1726; H NMR (300 MHz, DMSO) δ: 2.32 (s, 3H, C6-H of coumarin),
2.74 (s, 3H, C6-H of pyrimidine), 7.02 (s, IH, C5-H of pyrimidine), 7.62 (s, 1H, C5-H of thiazole),
7.37–8.02 (m, 3H, Ar), 8.49 (s, 1H, C4-H of coumarin); LC–MS 326 (M+, 100%). Anal. Calcd.
for C17H12N2O3S: C, 62.95; H, 3.73; N, 8.64. Found: C, 62.90; H, 3.75; N, 8.62.

Journal of Sulfur Chemistry 131
4.2.3. 5-Methyl-3-[(6ꢀ-chloro-(3ꢀ-coumarinyl)]-7H-[1,3]-thiazolo-[3,2-a]-pyrimidine-7-one
(4c)
IR (KBr) cm−1: 1642, 1719; 1H NMR (300 MHz, DMSO) δ: 2.74 (s, 3H, C6-H of pyrimidine),
7.02 (s, IH, C5-H of pyrimidine), 7.67 (s, 1H, C5-H of thiazole), 7.27–8.05 (m, 3H, Ar), 8.52 (s,
1H, C4-H of coumarin); LC–MS 345 (35Cl, M+1, 100%). Anal. Calcd. for C16H9ClN2O3S: C,
55.74; H, 2.63; N, 8.13%. Found: C, 55.72; H, 2.60; N, 8.10.
4.2.4. 5-Methyl-3-[(6ꢀ-bromo-(3ꢀ-coumarinyl)]-7H-[1,3]-thiazolo-[3,2-a]-pyrimidine-7-one
(4d)
IR (KBr) cm−1: 1643, 1728; 1H NMR (300 MHz, DMSO) δ: 2.73 (s, 3H, C6-H of pyrimidine),
7.06 (s, 1H, C5-H of pyrimidine), 7.80 (s, 1H, C5-H of thiazole), 7.27–7.79 (m, 3H, Ar), 8.42 (s,
1H, C4-H of coumarin); LC–MS 390.7 (79Br, M+2, 100%). Anal. Calcd. for C16H9BrN2O3S: C,
49.37; H, 2.33; N, 7.20. Found: C, 49.32; H, 2.22; N, 7.85.
4.2.5. 5-Methyl-3-[(5,6-benzo-(3ꢀ-coumarinyl)]-7H-[1,3]-thiazolo-[3,2-a]-pyrimidine-7-one
(4e)
IR (KBr) cm−1: 1644, 1726; 1H NMR (300 MHz, DMSO) δ: 2.18 (s, 3H, C6-H of pyrimidine),
6.27 (s, 1H, C5-H of pyrimidine), 6.56 (s, 1H, C5-H of thiazole), 7.45–8.05 (m, 6H, Ar), 8.65 (s,
1H, C4-H of coumarin); LC–MS 360.9. Anal. Calcd. for C20H12N2O3S: C, 66.65; H, 3.36; N,
7.77%. Found: C, 66.64; H, 3.17; N, 7.36.
4.3. General procedure for the MW-assisted synthesis of 7-phenyl-3-[(3ꢀ-coumarinyl)]-5H-
[1, 3]-thiazolo-[3,2-a]-pyrimidine 5-ones (5a–5d)
A mixture of substituted coumarinyl amino thiazole (2) (0.003 mol) and benzoylacetoacetate
(0.003 mol)washeatedat125–130 ◦CinaMWovenfor1–3 min.Thecrystallineproductseparated
out at room temperature was filtered and washed with water and ether to give a bright yellow-
colored solid.
4.3.1. 7-Phenyl-3-[(3ꢀ-coumarinyl)]-5H-[1,3]-thiazolo-[3,2-a]-pyrimidine-5-one (5a)
IR (KBr) cm−1: 1632, 1716; 1H NMR (300 MHz, DMSO) δ: 6.04 (s, 1H, C5-H of pyrimidine),
6.17 (s, 1H, C5-H of thiazole), 7.28–8.22 (m, 9H, Ar), 8.25 (s, 1H, C4-H of coumarin); LC–MS
372.9 (M+, 100%).Anal. Calcd. for C21H12N2O3S: C, 67.73; H, 3.25; N, 7.52%. Found: C, 67.52;
H, 3.45; N, 7.48.
4.3.2. 7-Phenyl-3-[(6ꢀ-chloro-(3ꢀ-coumarinyl)]-5H-[1,3]-thiazolo-[3,2-a]-pyrimidine-5-one
(5b)
IR (KBr) cm−1: 1666, 1732; 1 H NMR (300 MHz, DMSO) δ: 6.17 (s, 1H, C5-H of pyrimidine),
7.17 (s, 1H, C5-H of thiazole), 7.43–8.44 (m, 8H, Ar), 8.50 (s, 1H, C4-H of coumarin); LC–MS
407 (35Cl, M+1, 100%). Anal. Calcd. for C21H11ClN2O3S: C, 62.00; H, 2.73; N, 6.89%. Found:
C, 62.10; H, 2.05; N, 6.74.

132 N.B. Yaragatti et al.
4.3.3. 7-Phenyl-3-[6-bromo-(3ꢀ-coumarinyl)]-5H-[1,3]-thiazolo-[3,2-a]-pyrimidine-5-one
(5c)
IR (KBr) cm−1: 1658, 1740; 1H NMR (300 MHz, DMSO) δ: 6.27 (s, 1H, C5-H of pyrimidine),
7.10 (s, 1H, C5-H of thiazole), 7.53–8.44 (m, 8H, Ar), 8.40 (s, 1H, C4-H of coumarin); LC–MS
452.9 (79Br, M+2, 100%). Anal. Calcd. for C21H11BrN2O3S: C, 55.89; H, 2.46; N, 6.21. Found:
C, 55.74; H, 2.47; N, 6.30.
4.3.4. 7-Phenyl-3-[6-nitro-(3ꢀ-coumarinyl)]-5H-[1,3]-thiazolo-[3,2-a]-pyrimidine-5-one (5d)
IR (KBr) cm−1: 1642, 1736; 1H NMR (300 MHz, DMSO) δ: 6.27 (s, 1H, C5-H of pyrimidine),
7.10 (s, 1H, C5-H of thiazole), 7.53–8.44 (m, 8H, Ar), 8.40 (s, 1H, C4-H of coumarin; LC–MS
417.9 (M+, 100%). Anal. Calcd. for C21H11N3O5S: C, 60.43; H, 2.66; N, 10.07%. Found: C,
60.22; H, 2.62; N, 9.65.
4.4. General procedure for the synthesis of 5-phenyl-3-[(3ꢀ-coumarinyl)]-7H-[1,3]-thiazolo-
[3,2-a]-pyrimidine-7-ones (6a–6d)
A mixture of substituted 3-bromoacetyl coumarin (0.0026 mol), 2-mercapto 6-phenyl uracil
(0.0026 mol), K2CO3 (0.0065 mol) was refluxed in 20 mL of dry xylene for 24 h.After completion
of reaction, the reaction mixture was filtered off and xylene concentrated on a rotary evaporator.
The solid separated was washed with water and ethanol. The solid obtained was crystallized from
ethanol/dioxane (1:1).
4.4.1. 5-Phenyl-3-[(3ꢀ-coumarinyl)]-7H-[1,3]-thiazolo-[3,2-a]-pyrimidine-7-one (6a)
IR (KBr) cm−1: 1667, 1729; 1H NMR (300 MHz, DMSO) δ: 6.25 (s, 1H, C5-H of pyrimidine),
6.30 (s, 1H, C5-H of thiazole), 7.03–7.66 (m, 9H, Ar), 8.22 (s, 1H, C4-H of coumarin); LC–MS
372.9 (M+, 100%).Anal. Calcd. for C21H12N2O3S: C, 67.73; H, 3.25; N, 7.52%. Found: C, 67.53;
H, 3.55; N, 7.13.
4.4.2. 5-Phenyl-3-[(6ꢀ-chloro-(3ꢀ-coumarinyl)]-7H-[1,3]-thiazolo-[3,2-a]-pyrimidine-7-one
(6b)
IR (KBr) cm−1: 1650, 1730; 1H NMR (300 MHz, DMSO) δ: 6.07 (s, 1H, C5-H of pyrimidine),
6.50 (s, 1H, C5-H of thiazole), 8.76 (s, 1H, C4-H of coumarin), 7.45-8.05 (m, 8H, Ar); LC–MS
407 (35Cl, M+1, 100%). Anal. Calcd. for C21H11ClN2O3S: C, 62.00; H, 2.73; N, 6.89%. Found:
C, 62.12; H, 2.09; N, 6.76.
4.4.3. 5-Phenyl-3-[(6ꢀ-bromo-(3ꢀ-coumarinyl)]-7H-[1,3]-thiazolo-[3,2-a]-pyrimidine-7-one
(6c)
IR (KBr) cm−1: 1654, 1727; 1H NMR (300 MHz, DMSO) δ: 6.43 (s, 1H, C5-H of pyrimidine),
6.76 (s, 1H, C5-H of thiazole), 7.06–8.64 (m, 8H, Ar), 8.68 (s, 1H, C4-H of coumarin); LC–MS
452.9 (79Br, M+2, 100%). Anal. Calcd. for C21H11BrN2O3S: C, 55.89; H, 2.46; N, 6.21%. Found:
C, 55.80; H, 2.42; N, 6.33.

Journal of Sulfur Chemistry 133
4.4.4. 5-Phenyl-3-[(6ꢀ-nitro-(3ꢀ-coumarinyl)]-7H-[1,3]-thiazolo-[3,2-a]-pyrimidine-7-one
(6d)
IR (KBr) cm−1: 1660, 1743;1H NMR (300 MHz, DMSO) δ: 6.52 (s, 1H, C5-H of pyrimidine),
6.73 (s, 1H, C5-H of thiazole), 6.73–8.58 (m, 8H, Ar), 8.94 (s, 1H, C4-H of coumarin); LC–MS
417.9 (M+, 100%). Anal. Calcd. for C21H11N3O5S: C, 60.43; H, 2.66; N, 10.07%. Found: C,
60.22; H, 2.62; N, 9.65.
Acknowledgements
The authors are thankful to the University Scientific Instrumentation Centre (USIC), Karnatak University Dharwad, India,
for spectral and analytical data. N.B.Yaragatti is grateful to the University Grants Commission, New Delhi, for the financial
assistance in the form of a Research Fellowship in Science for Meritorious Students.
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