One-pot synthesis of novel 3-(2-Oxo-2H-chromen-3-yl)-[1,3,4] thiadiazino [2,3-b] quinazolin-6 (2H)-ones under microwave irradiation

Article abstract of DOI:10.1080/10426500600917094

An efficient one-pot synthesis of 3-(2-oxo-2H-chromen-3-yl)-[1,3,4] thiadiazino [2,3-b] quinazolin-6(2H)-ones in high yields has been developed by microwave-induced heterocyclization of 3-amino-2mercapto-3H-quinazolin-4-one when irradiated with 3-(2-bromo-acetyl)-chromen-2-one in ethanol and anhydrous potassium carbonate. A comparative study of conventional and MW methods is briefly discussed. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/10426500600917094

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Phosphorus, Sulfur, and Silicon
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One-Pot Synthesis of Novel
3-(2-Oxo-2H-chromen-3-yl)-
[1,3,4] Thiadiazino [2,3-b]
Quinazolin-6 (2H)-ones Under
Microwave Irradiation
V. Naveen Kumar a , E. De Clercq b & B. Rajitha a
a Department of Chemistry, National Institute of
Technology, Warangal, India
b Rega Institute of Medical Research, Belgium
Published online: 18 Feb 2007.
To cite this article: V. Naveen Kumar , E. De Clercq & B. Rajitha (2007) One-Pot
Synthesis of Novel 3-(2-Oxo-2H-chromen-3-yl)-[1,3,4] Thiadiazino [2,3-b] Quinazolin-6
(2H)-ones Under Microwave Irradiation, Phosphorus, Sulfur, and Silicon and the
Related Elements, 182:2, 273-279, DOI: 10.1080/10426500600917094
To link to this article: http://dx.doi.org/10.1080/10426500600917094
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Phosphorus, Sulfur, and Silicon, 182:273–279, 2007
Copyright © Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500600917094
One-Pot Synthesis of Novel
3-(2-Oxo-2H-chromen-3-yl)-[1,3,4] Thiadiazino [2,3-b]
Quinazolin-6 (2H)-ones Under Microwave Irradiation
V. Naveen Kumar
Department of Chemistry, National Institute of Technology,
Warangal, India
E. De Clercq
Rega Institute of Medical Research, Belgium
B. Rajitha
Department of Chemistry, National Institute of Technology,
Warangal, India
An efficient one-pot synthesis of 3-(2-oxo-2H-chromen-3-yl)-[1,3,4] thiadiazino [2,3-
b] quinazolin-6(2H)-ones in high yields has been developed by microwave-induced
heterocyclization of 3-amino-2mercapto-3H-quinazolin-4-one when irradiated with
3-(2-bromo-acetyl)-chromen-2-one in ethanol and anhydrous potassium carbonate.
A comparative study of conventional and MW methods is briefly discussed.
Keywords Chromen; microwave; one-pot synthesis; quinazolin
INTRODUCTION
Quinazolinones and coumarins constitute an important class of hetero-
cyclic molecules. Both moieties have been found to be of great interest
in view of their varied biological and pharmacological properties. Vari-
ous substituted quinazolinones are reported to possess a wide range of
biological activities, which include analgesic and antinflammatory,1−3
antibacterial,4−7 antiviral,8,9 antihistamine,10 antihypertensive,11,12
and anticancer13 activity. Coumarins are common in nature and
find their main applications as fragrances, pharmaceuticals, and
agrochemicals.14
Received May 22, 2006; accepted June 26, 2006.
The authors are thankful to the UGC for the sanction of a major project (F. 12-8/2003
(SR) Dt 30\3\2003).
Address correspondence to B. Rajitha, National Institute of Technology, Department
of Chemistry; Warangal, 506 004 India. E-mail: rajitabhargavi@yahoo.com
273

274
V. N. Kumar et al.
In the last few years there has been increased interest in the use
of microwave irradiation in organic synthesis. Some of the interest-
ing features of this method are milder reaction conditions, reduc-
tion of reaction times, enhanced selectivity, and associated ease of
manipulation.15 Earlier we reported the synthesis of desyl ethers,16
benzofurans,17 benzodifurans,18 quinolines,19 and xanthenes20 under
MW irradiation. Keeping in view the biological importance of quinozolin
and coumarin derivatives and in continuation of our work on coumarin
derivatives using microwave irradiation, we have desired to synthe-
size a rapid, convenient, and efficient microwave-assisted synthesis of
3-(2-oxo-2H-chromen-3-yl)-[1,3,4] thiadiazino [2,3-b] quinazolin-6(2H)-
ones that contain both quinazolinone and coumarin moieties in their
structures.
RESULTS AND DISCUSSION
A
mixture of 3-amino-2mercapto-3H-quinazolin-4-one and 3-(2-
bromoacetyl)-chromen-2-one in the presence of ethanol & K2CO3 was
refluxed for about 4–6 hours and furnished 3a–f. Alternatively, when
2a–f with 1, taken in a domestic MW oven at 400 W level, was irradi-
ated in an open vessel for 4–6 min in ethanol & K2CO3, they furnished
3a–f in good yields (Scheme 1).
EXPERIMENTAL SECTION
All melting points were determined in an open capillary in a liquid
paraffin bath and are uncorrected. The purity of the compounds was
1
checked by TLC. H NMR spectra on Varian Gemini 200 MHZ Spec-
trometer using TMS as an internal standard. The C, H, and N analysis
of the compounds was done on a Carlo Erba model EA1108. Mass spec-
tra was done on a jeol JMS D-300 spectrometer. For the microwave
irradiation experiments, BPL 800T was used.
Biological Results
All the newly synthesized compounds were tested for their cytotoxicity
and antiviral activity HFI HeLa, Vero, and murine-leukemia cells. The
results are summarized in Tables II–V. Other biological activities are
still in progress.
As shown in Tables II–V, some compounds (e.g., 3b and 3f) showed
significant cytotoxic and antiviral activities, while others (e.g., 3c and

3-(2-Oxo-2H-chromen-3-yl)-[1,3,4] Thiadiazino [2,3-b] Quinazolin-6 (2H)-Ones 275
SCHEME 1
3e) displayed medium cytotoxic and antiviral activities, and others
(e.g., 3a and 3d) only had marginal or no cytotoxic and antiviral
activities against HEL, Hela, Vero cell cultures, and murine leukemia
cells.
TABLE I Analytical Data of Title Compounds 3a–f
Calcd.
Method A
Method B
(Found) %
Mol formula
(Mol. Wt.)
Compound
Yield (%) Time (min) Yield (%) Time (h)
C
H N
3a
C19H11N3O3S
(361)
C19H10BrN3O3S
(440)
C19H9Br2N3O3S
(519)
C19H10N4O5S
(406)
C19H9N5O7S
(452)
C19H10CIN3O3S
(395)
90
89
72
75
78
74
4.15
4.00
4.30
5.30
5.30
6.00
82
79
66
70
70
69
4.00
4.00
4.00
5.00
6.00
6.00
63.15 3.07 11.63
(63.25 3.00 11.60)
1.83 2.29 18.15
(51.80 2.30 18.10)
3b
3c
3d
3e
3f
43.96 1.75
(43.90 1.79
8.09
8.01)
56.16 2.48 13.79
(56.16 2.48 13.79)
57.14 2.88 13.33
(57.15 2.85 13.40)
72.58 3.78
(72.56 3.76
2.92
2.90)

276
V. N. Kumar et al.
TABLE II Cytotoxicity and Antiviral Activity of Compounds (6a–f) in
HEL Cell Cultures
Minimum Inhibitory Concentrationb (ug/mL)
Minimum
Cytotoxic
Herpes
Simplex
Herpes
Simplex
Herpes
Vesicular
Concentration Virus-1
Simplex
Vesicular Stomatitis Virus-1 TK
Compound
(ug/mL)
(KOS) Virus-2(G)
Virus
Virus
KOS ACVr
3a
3b
3c
3d
3e
3f
>100
20
100
100
100
>100
>4 (20)
>20
>100
>20
>100
>4
>20
>100
>20
>4
>100
>4
>20
>100
>20
>4
>100
>4
>20
>100
>20
>4
>100
>4
>20
>100
>20
>4
20
>4
Brivudin
Ribavirin
Acyclovir
Ganciclovir
>400
>400
>400
>100
0.0768
9.6
0.128
0.0192
240
240
0.0768
0.0192
0.64
48
240
>400
240
>400
>100
>400
240
9.6
>100
0.16
aRequired to cause a microscopically detectable alteration of normal cell morphology.
bRequired to reduce virus-induced cytopathogenicity by 50%.
General Procedure: Synthesis of
3-(2-oxo-2H-chromen-3-yl)-[1,3,4] thiadiazino [2,3-b]
quinazolin-6 (2H)-ones
Method A (Microwave Irradiation Method)
A
mixture
of
3-amino-2mercapto-3H-quinazolin-4-one
la
(0.001 mole), 3-(2-bromo-acetyl)-chromene-2-one 2a (0.001 mole),
anhydrous K2CO3 (0.001 mole), and ethanol (2 ml) was irradiated
in microwave irradiation at 450W level for 4.15 min. Progress of the
reaction was monitored over TLC. After completion of the reaction, it
was poured over crushed ice, and the resulting solid was crystallized
from ethanol as shining needles.
Compounds 3b–f were prepared similarly.
Method B (Conventional Method)
3-amino-2mercapto-3H-quinazolin-4-one 1a (0.001 mole) was
treated with 3-(2-bromo-acetyl)-chromene-2-one 2a (0.001 mole) and
baked K2CO3 (0.001 mole), ethanol (5 mL) was added, and the reaction
mixture was refluxed for 10.30 h. Progress of the reaction was moni-
tored over TLC. After completion of the reaction, it was poured over
crushed ice, and the resulting solid was crystallized from ethanol as
shining needles.
Compounds 3b–f were prepared similarly.

3-(2-Oxo-2H-chromen-3-yl)-[1,3,4] Thiadiazino [2,3-b] Quinazolin-6 (2H)-Ones 277
TABLE III Cytotoxicity and Antiviral Activity of Compounds
(6a–f) in HeLa Cell Cultures
Minimum Inhibitory Concentrationb (ug/mL)
Minimum
Cytotoxic
Concentration
(ug/mL)
Vesicular
Stomatitis
Virus
Respiratory
Syncytical
Virus
Coxsackie
Virus B4
Compound
3a
3b
100
20
>20
>4
>20
>4
>20
>4
3c
3d
3e
3f
100
>100
100
>20
>100
>20
>4
>20
>100
>20
>4
>20
>100
>20
>4
20
Brivudin
(S)-DHPA
Ribavirin
>400
>400
>400
>400
>400
48
>400
>400
240
>400
>400
9.6
aRequired to cause a microscopically detectable alteration of normal cell
morphology.
bRequired to reduce virus-induced cytopathogenicity by 50%.
3a. 3-(2-oxo-2H-chromen-3-yl)-[1,3,4] thiadiazino [2,3-b]
quinazolin-6 (2H)-one. Colorless crystals, m.p. 230–232◦C. IR (KBr):
1720 (Coumarin C 0), 1640 (C 0), 1570 (C N), 1530 (C C), cm−1
.
1H NMR (DMSO-d6): δ 7.61–8.20 (m, 8H, Ar-H), 8.51 (s,1H, Coumarin
C-4), 2.84 (s, 2H, CH2). MS (FAB+): m/z: 362 (M + 1).
TABLE IV Cytotoxicity and Antiviral Activity of Compounds (6a–f)
in Vero Cell Cultures
Minimum Inhibitory Concentrationb (ug/mL)
Minimum
Cytotoxic
Concentration Influenza-3
Para
Punta
Toro
Sindbis Coxsackie
Compound
(ug/mL)
Virus
Reovirus-1
Virus
Virus B4
Virus
3a
3b
>100
20
>100
>4
>100
>4
>100
>4
>100
>4
>100
>4
3c
3d
3e
3f
100
100
100
20
>20
>20
>20
>4
>20
>20
>20
>4
>20
>20
>20
>4
>20
>20 (60)
>20
>20
>20
>20
>4
>4
Brivudin
(S)-DHPA
Ribavirin
>400
>400
>400
>400
>400
48
>400
>400
48
>400
>400
240
>400
>400
>400
>400
>400
48
aRequired to cause a microscopically detectable alteration of normal cell morphology.
bRequired to reduce virus-induced cytopathogenicity by 50%.

278
V. N. Kumar et al.
TABLE V Proliferation of Murine-Leukemia Cells
(L1210/0) and Human t-Lymphocyte Cells
(Molt4/C8,CEM/0)
IC50 (ug/mL)
Compound
L1210/0
Molt4/C8
CEM/0
3a
3b
3c
3d
3e
3f
161 40
2.4 0.1
>200
>200
1.3 0.2
5.5 0.6
>200
6.6 1.2
1.3 0.5
1.7 0.5
5.5 1.1
≥ 200
15
>200
15
2.4 0.1
2
1
1.6 0.6
1.7 0.6
50% inhibitory concentration.
3b. 3-(6-bromo-2-oxo-2H-chromen-3-yl)-[1,3,4] thiadiazino
[2,3-b] quinazolin-6 (2H)-one. Colorless crystals, m.p. 200–202◦C.
IR (KBr): 1720 (Coumarin C 0), 1640 (C 0), 1540 (C N), 1530 (C C)
cm−1 1H NMR (DMSO-d6): δ 7.10–7.82 (m, 7H, Ar-H), 8.21 (s, 1H,
.
Coumarin C-4), 2.91 (s, 2H, CH2). MS (FAB+): m/z: 441 (M + 1).
3c. 3-(6,8-dibromo-2-oxo-2H-chromen-3-yl)-[1,3,4] thiadiazino
[2,3-b] quinazolin-6 (2H)-one. Colorless crystals, m.p. 251–253◦C.
IR (KBr): 1720 (Coumarin C 0), 1640 (C 0), 1570 (C N), 1530 (C C)
cm−1 1H NMR (DMSO-d6): δ 6.91–7.80 (m, 6H, Ar-H), 8.25 (s, 1H,
.
Coumarin C-4), 2.85 (s, 2H, CH2). MS (FAB+): m/z: 520 (M + 1).
3d. 3-(6-nitro-2-oxo-2H-chromen-3-yl)-[1,3,4] thiadiazino [2,3-
b] quinazolin-6 (2H)-one. Colorless crystals, m.p. 190–192◦C. IR
(KBr): 1720 (Coumarin C 0), 1640 (C 0), 1570 (C N), 1530 (C C)cm−1
.
1H NMR (DMSO-d6): δ 7.21–8.30 (m, 7H, Ar-H), 8.50 (s, 1H, Coumarin
C-4), 2.90 (s, 2H, CH2). MS (FAB+): m/z: 406 (M+).
3e. 3-(6,8-dinitro-2-oxo-2H-chromen-3-yl)-[1,3,4] thiadiazino
[2,3-b] quinazolin-6 (2H)-one. Colorless crystals, m.p. >300. IR
(KBr): 1720 (Coumarin C 0), 1640 (C 0), 1570 (C N), 1530 (C C)cm−1
.
1H NMR (DMSO-d6): δ 7.21–7.80 (m, 6H, Ar-H), 8.20 (s, 1H, Coumarin
C-4), 2.85 (s, 2H, CH2). MS (FAB+): m/z: 453 (M + 1).
3f. 3-(6-chloro-2-oxo-2H-chromen-3-yl)-[1,3,4] thiadiazino [2,3-
b] quinazolin-6 (2H)-one. Colorless crystals, m.p. >300. IR (KBr):
1
1720 (Coumarin C 0), 1640 (C 0), 1570 (C N), 1530 (C C)cm−1. H
NMR (DMSO-d6): δ 7.10–7.80 (m, 7H, Ar-H), 8.20 (s, 1H, Coumarin C-4),
2.90 (s, 2H, CH2). MS (FAB+): m/z: 396 (M + 1).

3-(2-Oxo-2H-chromen-3-yl)-[1,3,4] Thiadiazino [2,3-b] Quinazolin-6 (2H)-Ones 279
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