LETTER
2-Substituted Quinazolin-4(3H)-ones
825
Table 4 Synthesis of 2-Alkylquinazolinone Derivatives 8k–m Under the Optimized Conditions (continued)
Entrya
Amidoxime 7
Product
Time (h)
4.0
Yieldb (%)
O
N
O2N
OH
N
NO2
NH
3
89.0
NH2
7m
8m
a Reaction conditions: 6 (1 mmol), amidoxime 7 (1.1 mmol), FeCl3 (10 mol%), 1,4-dioxane (10 mL), 80 °C.
b Yield of isolated product.
(c) Deng, P.-Y.; Ye, F.; Cai, W.-J.; Tan, G.-S.; Hu, C.-P.;
Deng, H.-W.; Li, Y.-J. J. Hypertens. 2004, 22, 1819.
(7) (a) Hisano, T.; Ichikawa, M.; Nakagawa, A.; Tsuji, M.
Chem. Pharm. Bull. 1975, 23, 1910. (b) Mitobe, Y.; Ito, S.;
Mizutani, T.; Nagase, T.; Sato, N.; Tokita, S. Bioorg. Med.
Chem. Lett. 2009, 19, 4075. (c) Balakumar, C.; Lamba, P.;
Kishore, D. P.; Narayana, B. L.; Rao, K. V.; Rajwinder, K.;
Rao, A. R.; Shireesha, B.; Narsaiah, B. Eur. J. Med. Chem.
2010, 45, 4904. (d) Abdel-Jalil, R. J.; Aldoqum, H. M.;
Ayoub, M. T.; Voelter, W. Heterocycles 2005, 65, 2061.
(8) Zhou, J.; Fang, J. J. Org. Chem. 2011, 76, 7730.
(9) (a) Lingaiah, B. V.; Ezikiela, G.; Yakaiaha, T.; Reddy, G.
V.; Rao, P. S. Synlett 2006, 2507. (b) Chen, J.; Wu, D.; He,
F.; Liu, M.; Wu, H.; Ding, J.; Su, W. Tetrahedron Lett. 2008,
49, 3814. (c) Zeng, L.-Y.; Cai, C. J. Heterocycl. Chem.
2010, 47, 1035. (d) Wang, X.-S.; Yang, K.; Zhang, M.-M.;
Yao, C.-S. Synth. Commun. 2010, 40, 2633. (e) Salehi, P.;
Dabiri, M.; Zolfigolc, M. A.; Baghbanzadeh, M.
In conclusion, we have developed an efficient iron(III)
chloride catalyzed synthesis of 2-substituted quinazoli-
nones from isatoic anhydride (6) and various amidoximes
7 in good to excellent yields. The reaction proceeds under
mild conditions without needing an expensive catalyst,
and it provides the desired quinazolinones with high se-
lectivity. Extension of this method to the synthesis of var-
ious biologically active quinazolinone derivatives is in
progress and will be reported in due course.
Acknowledgment
The authors are grateful to Dr. Upadhya Timmanna and Dr. Vilas
H. Dahanukar for their constant encouragement, support, and useful
discussions. We also thank the analytical department of Dr. Reddy’s
Laboratories for providing timely support.
Tetrahedron Lett. 2005, 46, 7051.
(10) Draghici, B.; El-Gendy, B. El-D. M.; Katritzky, A. R.
Synthesis 2012, 44, 547.
Supporting Information for this article is available online at
m
o
ti
(11) (a) Agirbas, H.; Sumengen, D.; Durust, Y.; Durust, N. Synth.
Commun. 1992, 22, 209. (b) Durust, Y.; Akcan, M.;
Martiskainen, O.; Siirola, E.; Pihlaja, K. Polyhedron 2008,
27, 999. (c) Hussein, A. Q. Heterocycles 1987, 26, 163.
(d) Rai, N. P.; Narayanaswamy, V. K.; Govender, T.;
Manuprasad, B. K.; Shashikanth, S.; Arunachalam, P. N.
Eur. J. Med. Chem. 2010, 45, 2677.
References and Notes
(1) (a) Mhaske, S. B.; Argade, N. P. Tetrahedron 2006, 62,
9787. (b) Sharma, P. C.; Kaur, G.; Pahza, R.; Sharma, A.;
Rajak, H. Curr. Med. Chem. 2011, 18, 4786. (c) Arora, R.;
Kapoor, A.; Gill, N. S.; Rana, A. C. Int. Res. J. Pharm. 2011,
2, 22. (d) Reisch, J.; Kamal, G. M.; Gunaherath, G. J. Nat.
Prod. 1989, 52, 404. (e) Liu, J.-F.; Wilson, C. J.; Ye, P.;
Sprague, K.; Sargent, K.; Si, Y.; Beletsky, G.; Yohannes, D.;
Ng, S.-C. Bioorg. Med. Chem. Lett. 2006, 16, 686. (f) Liu, J.-
F.; Kaselj, M.; Isome, Y.; Ye, P.; Sargent, K.; Sprague, K.;
Cherrak, D.; Wilson, C. J.; Si, Y.; Yohannes, D.; Ng, S.-C.
J. Comb. Chem. 2006, 8, 7. (g) Ma, C.; Li, Y.; Niu, S.;
Zhang, H.; Liu, X.; Che, Y. J. Nat. Prod. 2011, 74, 32.
(h) Nett, M.; Hertweck, C. J. Nat. Prod. 2011, 74, 2265.
(2) Liu, J.-F.; Ye, P.; Sprague, K.; Sargent, K.; Yohannes, D.;
Baldino, C. M.; Wilson, C. J. Org. Lett. 2005, 7, 3363.
(3) (a) Chenard, B. L.; Menniti, F. S.; Pagnozzi, M. J.; Shenk, K.
D.; Ewing, F. E.; Welch, W. M. Bioorg. Med. Chem. Lett.
2000, 10, 1203. (b) Bhogal, N.; Balls, M. Curr. Drug
Discovery Technol. 2008, 5, 250.
(12) 2-Substituted Quinazolin-4(3H)-ones 8a–m; General
Procedure
The appropriate amidoxime 7 (1.1 mmol) and FeCl3 (10
mol%) were added sequentially to a solution of isatoic
anhydride (6; 1 mmol.) in 1,4-dioxane (10 mL), and the
mixture was stirred at 80 °C for 2–9 h until the reaction was
complete (TLC). The mixture was then diluted with EtOAc
(10 mL) and washed with H2O (2 × 5 mL). The organic layer
was dried (Na2SO4), filtered, and concentrated under
reduced pressure to give a crude product that was purified by
column chromatography (silica gel, 30% EtOAc–hexanes).
All new compounds gave satisfactory analytical and
spectroscopic results.
2-(4-Aminophenyl)quinazolin-4(3H)-one (8e)
Yellow solid; yield: 284 mg (78%); mp 250–254 °C; 1H
NMR (400 MHz, DMSO-d6): δ = 5.83 (s, 2 H, NH2), 6.62 (d,
J = 8.8 Hz, 2 H, ArH), 7.40 (t, J = 6.9 Hz, 1 H, ArH), 7.61
(d, J = 8.3 Hz, 1 H, ArH), 7.76 (t, J = 6.8 Hz, 1 H, ArH), 7.95
(d, J = 8.8 Hz, 2 H, ArH), 8.08 (dd, J = 6.9, 1 Hz, 1 H, ArH),
12.06 (br s, 1 H, NH); 13C NMR (100 MHz, DMSO-d6): δ =
113.0, 121.5, 125.3, 125.8, 126.9, 128.7, 129.1, 134.4,
149.6, 152.2, 152.4, 162.4; MS: m/z = 238.1 [M + H];
HRMS (ESI): m/z [M + H] calcd for C14H12 N3O: 238.0980;
found: 238.0969.
(4) (a) Ma, Z. Z.; Hano, Y.; Nomura, T.; Chen, Y. J.
Heterocycles 1997, 46, 541. (b) Cagir, A.; Jones, S. H.; Gao,
R.; Eisenhauer, B. M.; Hecht, S. M. J. Am. Chem. Soc. 2003,
125, 13628.
(5) Sun, H. H.; Barrow, C. J.; Sedlock, D. M.; Gillum, A. M.;
Copper, R. J. Antibiot. 1994, 47, 515.
(6) (a) Chen, A. L.; Chen, K. K. J. Am. Pharm. Assoc. 1933, 22,
716. (b) Hibino, S.; Choshi, T. Nat. Prod. Rep. 2001, 18, 66.
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