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R. R. Kale et al.
LETTER
K.; Tiwari, V. K.; Chen, Xi. J. Am. Chem. Soc. 2009, 131,
18467. (c) Tewari, N.; Katiyar, D.; Tiwari, V. K.; Tripathi,
R. P. Tetrahedron Lett. 2002, 44, 6639. (d) Tewari, N.;
Mishra, R. C.; Tiwari, V. K.; Tripathi, R. P. Synlett 2002,
1779. (e) Tewari, N.; Tiwari, V. K.; Mishra, R. C.; Tripathi,
R. P.; Srivastava, A. K.; Ahmad, R.; Srivastava, R.;
Srivastava, B. S. Bioorg. Med. Chem. 2003, 11, 2911.
(f) Saxena, N.; Verma, S. S.; Tiwari, V. K.; Chaturvedi, V.;
Manju, Y. K.; Srivastva, A. K.; Gaikwad, A.; Sinha, S.;
Tripathi, R. P. Bioorg. Med. Chem. Lett. 2006, 14, 8186.
(10) Typical Experimental Procedure for the Synthesis of
Quinazolinone-Fused Azauracil Compounds 3a–h
Diverse 2-thioxo-2,3-dihydroquinazolin-4 (1H)-ones 2a–h
were obtained in good yield by the one-pot reaction of
anthranilic acid/esters, primary amines, and bis(benzo-
triazol-1-yl)methanethione in presence of the amidine base
as per ref. 7. Thioquinazolinone (2a, 0.5 g 1.96 mmol) was
added in anhyd MeCN (8 mL) and stirred for 10 min then
AgCNO (0.59 g, 3.93 mmol) was added in above solution.
Solid precipitated out within 5 min and reaction mixture was
further stirred for 30 min, where reaction mass turns into
greenish color. Progress of reaction was monitored by TLC
(25% EtOAc in n-hexane). After completion of reaction,
product was filtered, dried, and subjected to column
chromatography (25% EtOAc in n-hexane) to obtain pure
white solid (90–95% yield).
In conclusion, we have developed a simple and efficient
method for an easy access to diverse novel quinazolinone-
fused azauracil heterocycles through cyclodesulfurization
followed by intramolecular cyclization. To the best of our
knowledge the developed protocol is the first approach for
the synthesis of this type of quinazolinone-fused azauracil
heterocycles and offers numerous advantages such as (a)
mild reaction conditions (at ambient temperature without
any catalyst); (b) simple workup procedure, and (c) excel-
lent yields of the desired products. Methodology is highly
facile and may be extended for the synthesis of carbohy-
drate-based azauracil scaffolds of great medicinal values.
This investigation is under way in our laboratory.
Acknowledgment
We thank CISC, BHU and RSIC, CDRI for providing spectroscopic
and analytical data of synthesized compounds and Council of
Scientific & Industrial Research, New Delhi, India for funding.
References and Notes
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Freidinger, R. M.; Whitter, W. L.; Lundell, G. F.; Veber,
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893. (c) Kumar, A.; Maurya, R. A.; Ahmad, P. J. Comb.
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Compound 3a: yield 91%; mp 160–162 °C. IR (KBr): nmax
=
3429 (NH), 1676, 1591, 1568, 1508 cm–1. 1H NMR (300
MHz, CDCl3): d = 8.04 (d, J = 7.5 Hz, 1 H), 7.83 (t, J = 7.2
Hz, 1 H), 7.71 (d, J = 8.4 Hz, 1 H), 7.43 (m, 4 H), 6.77 (m,
2 H). 13C NMR (75 MHz, CDCl3): d = 166.10, 161.03,
145.95, 139.88, 134.52, 129.39, 129.16, 128.14, 128.04,
126.49, 124.01, 119.64 ppm. Anal. Calcd for C16H10N4O3: C,
62.74; H, 3.29; N, 18.29. Found: C, 62.51; H, 3.75; N, 18.88.
(2) Kale, R. R.; Prasad, V.; Mohapatra, P.; Tiwari, V. K.
Monatsh. Chemie 2010, 141, 1159.
Compound 3b: yield 91%; mp 178–180 °C. IR (KBr): nmax
=
3431 (NH), 1669, 1596, 1569, 1511 cm–1. 1H NMR (300
(3) Lawrence, R. N. Drug Discovery Today 2000, 5, 172.
(4) Molnar, A.; Boros, S.; Simon, K.; Hermecz, I.; Gonczi, C.
ARKIVOC 2010, (x), 199.
MHz, CDCl3): d = 11.02 (br s, 1 H, NH), 7.96 (d, J = 7.8 Hz,
2 H), 7.67 (t, J = 8.4 Hz, 2 H), 7.48 (d, J = 8.4 Hz, 1 H), 7.34
(t, J = 8.4 Hz, 1 H), 7.04 (t, J = 8.7 Hz, 2 H), 6.69 (s, 1 H).
13C NMR (75 MHz, CDCl3): d = 167.84, 162.0, 140.91,
134.79, 134.79, 133.17, 133.06, 130.66, 129.96, 126.84,
123.90, 123.41, 118.27 ppm. Anal. Calcd for C19H11N5O3S:
C, 58.61; H, 2.85; N, 17.99. Found: C, 58.22; H, 3.01; N,
18.45.
(5) (a) Kim, T. H.; Lee, N.; Lee, G.; Kim, J. N. Tetrahedron
2001, 57, 7137. (b) Gama, Y.; Shibuya, I.; Shimizu, M.
Chem. Pharm. Bull. 2002, 50, 1517. (c) Gama, Y.; Shibuya,
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459. (d) Alhede, B.; Clamen, F. P.; Christensen, J.;
McCluskey, K. K.; Preikschat, H. F. J. Org. Chem. 1991,
56, 2139. (e) Chern, J.; Groziak, M. P.; Townsend, L. B.
J. Heterocycl. Chem. 1986, 23, 153.
Compound 3c: yield 91%; mp 187–188 °C. IR (KBr): nmax
=
3430, 1677, 1593, 1577, 1507 cm–1. 1H NMR (300 MHz,
(6) Mhaske, S. B.; Argade, N. P. Tetrahedron 2006, 62, 9787.
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B.; Singh, A. Monatsh. Chemie 2008, 139, 43. (b) Tiwari,
V. K.; Hussain, H. A.; Mishra, B. B.; Singh, D. D.; Tripathi,
V. Med. Chem. Res. 2007, 15, 325. (c) Tiwari, V. K.; Kale,
R. R.; Mishra, B. B.; Singh, A. ARKIVOC 2008, (xiv), 27.
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2010, 51, 5740. (b) Kale, R. R.; Prasad, V.; Tiwari, V. K.
Lett. Org. Chem. 2010, 7, 136. (c) Tiwari, V. K.; Singh, A.;
Hussain, H. A.; Mishra, B. B.; Tripathi, V. Monatsh. Chem.
2007, 138, 1297. (d) Singh, A.; Kale, R. R.; Tiwari, V. K.
Trends Carbohydr. Res. 2009, 1, 80.
CDCl3): d = 9.82 (br s, NH, 1 H), 8.42 (d, J = 9.0 Hz, 2 H),
8.23 (m, 2 H), 7.77 (t, J = 7.8 Hz, 1 H), 7.48 (d, J = 8.7 Hz,
1 H), 7.38 (m, 1 H), 7.15 (d, J = 8.7 Hz, 1 H). 13C NMR (75
MHz, CDCl3): d = 165.5, 159.90, 145.33, 143.27, 137.98,
133.80, 129.00, 125.60, 124.35, 122.55, 122.42, 114.37,
114.17, 110.53 ppm.
Compound 3d: yield 91%; mp 171–173 °C. IR (KBr): nmax
=
3433 (NH), 1677 (O=CN), 1622, 1529 cm–1. 1H NMR (300
MHz, CDCl3): d = 8.35 (d, J = 8.7 Hz, 2 H), 7.99–7.89 (m,
merged with J = 7.2 Hz, 2 H), 7.75 (d, J = 8.4 Hz, 1 H), 7.49
(d, J = 8.1 Hz, 2 H), 7.33 (t, J = 7.5 Hz, 1 H). 13C NMR (75
MHz, CDCl3): d = 165.10, 159.07, 145.90, 139.54, 135.41,
130.72, 130.27, 130.17, 127.27, 126.27, 126.10, 124.39,
124.34 ppm. Anal. Calcd for C16H9FN4O3: C, 59.26; H, 2.80;
N, 17.28. Found: C, 59.93; H, 2.74; N, 17.97.
(9) (a) Pandey, J.; Sharma, A.; Tiwari, V. K.; Dube, D.;
Ramachandran, R.; Chaturvedi, V.; Sinha, S.; Mishra, N. N.;
Shulka, P. K.; Tripathi, R. P. J. Comb. Chem. 2009, 11, 422.
(b) Yu, H.; Cheng, J.; Ding, L.; Khedri, Z.; Chen, Y.; Lau,
Synlett 2011, No. 2, 195–198 © Thieme Stuttgart · New York