LETTER
Efficient Synthesis of 2-Phenylquinazolines
1095
Widely substituted 2-anilino ketones reacted well with
several benzylamine derivatives to give the corresponding
products in good to excellent yields. Substituents on the
aniline ring had a control over the reaction and these re-
sults are incorporated in Table 2. When C-5-H of 2-ami-
nobenzophenone was replaced with electron-withdrawing
groups such as chloro and bromo substituent the 2-phe-
nylquinazoline derivative was obtained in 90% yield
(Table 2, entries 1 and 11). 5-Substituted 2-aminoben-
zophenone on reaction with 4-methoxybenzylamine re-
sulted in lower yield (Table 2, entry 2). When 5-nitro-2-
aminobenzophenone was treated with simple benzyl-
amine the reaction gave the corresponding product in an
excellent yield (Table 2, entry 5), but on reaction with 4-
methoxybenzylamine, the product was obtained in a
slightly lower yield (Table 2, entry 6).
Acknowledgment
We thank the CSIR, New Delhi, India, for fellowships to K.K., J.S.
and S.N.M., and the UGC for a fellowship to K.R.
References and Notes
(1) (a) Chan, J. H.; Hong, J. S.; Kuyper, L. F.; Jones, M. L.;
Baccanari, D. P.; Tansik, R. L.; Boytos, C. M.; Rudolph,
S. K.; Brown, A. D. J. Heterocycl. Chem. 1997, 34, 145.
(b) Gackenheimer, S. L.; Schaus, J. M.; Gehlert, D. R.
J. Pharmacol. Exp. Ther. 1996, 732, 113. (c) Dempcy, R.
O.; Skibo, E. B. Biochemistry 1991, 30, 8480. (d) Nordisk-
Droge 18113; Patent, N. A., Ed.; Nordisk Drogeand Kemi-
Kalieforretning AIS: Netherlands, 1965.
(2) (a) Bogert, M. T.; Hand, W. F. J. Am. Chem. Soc. 1902, 24,
1031. (b) Bogert, M. T.; Hand, W. F. J. Am. Chem. Soc.
1903, 25, 935. (c) Taylor, E. C.; Knopf, R. J.; Borror, A. L.
J. Am. Chem. Soc. 1960, 82, 3152. (d) Irwin, W. J.;
Wibberly, D. G. J. Chem. Soc. 1965, 4240. (e) Witt, A.;
Bergman, J. Curr. Org. Chem. 2003, 7, 659. (f) Connolly,
D. J.; Cusack, D.; O’Sullivan, T. P.; Guiry, P. J. Tetrahedron
2005, 61, 10153. (g) Li, J. R.; Chen, X.; Shi, D. X.; Ma, S.
L.; Li, Q.; Zhang, Q.; Tang, J. H. Org. Lett. 2009, 11, 1193.
(h) Marsham, P. R.; Jackman, A. L.; Barker, A. J.; Boyle, F.
T.; Pegg, S. J.; Wardleworth, J. M.; Kimbell, R.; O’Connor,
B. M.; Calvert, A. H.; Hughes, L. R. J. Med. Chem. 1995, 38,
994.
To explore the scope of the developed protocol we have
reacted 2-aminoacetophenone with various benzylamines.
To our surprise all the benzylamines reacted well with 2-
aminoacetophenone and the corresponding results are tab-
ulated in Table 2. Here, the substituents on benzylamines
governed the reaction fate and gave good yields of the
product (Table 2, entries 18–20).
(3) Kotsuki, H.; Sakai, H.; Morimoto, H.; Suenaga, H. Synlett
1999, 1993.
(4) (a) Zhang, J.; Zhu, D.; Yu, C.; Wan, C.; Wang, Z. Org. Lett.
2010, 12, 2841. (b) Zhang, J.; Yu, C.; Wang, S.; Wan, C.;
Wang, Z. Chem. Commun. 2010, 46, 5244.
O
N
H2N
+
– H2O
(5) Truong, V. L.; Marrow, M. Tetrahedron Lett. 2010, 51, 758.
(6) (a) Ferrini, S.; Ponticelli, F.; Taddei, M. Org. Lett. 2007, 9,
69. (b) Yoon, D. S.; Han, Y.; Stark, T. M.; Haber, J. C.;
Gregg, B. T.; Stankovich, S. B. Org. Lett. 2004, 6, 4775.
(7) (a) Hioki, H.; Matsushita, K.; Nakamura, S.; Horiuchi, H.;
Kubo, M.; Harada, K.; Fukuyama, Y. J. Comb. Chem. 2008,
10, 620. (b) Coşkun, N.; Çetin, M. Tetrahedron 2007, 63,
2966. (c) Fekner, T.; Müuller-Bunz, H.; Guiry, P. J. Org.
Lett. 2006, 8, 5109. (d) Connolly, D. J.; Cusak, D.;
O’Sullivan, T. P.; Guiry, P. J. Tetrahedron 2005, 61, 10153.
(8) (a) Lewis, J. C.; Wiedemann, S. H.; Bergman, R. G.; Ellman,
J. A. Org. Lett. 2004, 6, 35. (b) Wiedemann, S. H.; Ellman,
J. A.; Bergman, R. G. J. Org. Chem. 2006, 71, 1969.
(9) For reviews on CAN-mediated reactions, see: (a) Ho, T. L.
Synthesis 1973, 347. (b) Ho, T. L. Organic Synthesis by
Oxidation with Metal Compounds; Plenum Press: New
York, 1986; and references therein. (c) Imamoto, T.
Lanthanide Reagents in Organic Synthesis; Academic Press:
London, 1994, 119. (d) Nair, V.; Mathew, J.; Prabhakaran,
J. Chem. Soc. Rev. 1997, 127. (e) Hwu, J. R.; King, K.-Y.
Curr. Sci. 2001, 8, 1043. (f) Encyclopedia of Reagents for
Organic Synthesis, 2nd ed., Vol. 3; Wiley: New York, 2009,
2132–2139.
NH2
NH2
[O]
Ce(IV)
Ce(III)
N
N
NH2
– H2O
N
Scheme 2 Proposed mechanism
The proposed mechanism for the formation of 2-phe-
nylquinazoline is shown in Scheme 2. In the first step of
the reaction, the amino group forms an imine with benzyl-
amine, which is further oxidized and cyclized intramolec-
ularly to the product by the actual oxidant cerium(IV) in
the presence of peroxide source.
In conclusion, the CAN–TBHP system has been devel-
oped as a novel, mild, and very efficient reagent for the
facile preparation of 2-phenylquinazoline derivatives in
good to excellent yields from the corresponding 2-anilino
ketones and benzylamines.
(10) All chemicals were purchased from Sigma-Aldrich with
purity not less than 99.9%. Analytical TLC was carried out
by using silica gel 60 F254 pre-coated plates. Visualization
was accomplished with UV lamp of I2 stain. All products
were characterized by their NMR and Mass spectra. 1H
NMR and 13C NMR were recorded at 200 MHz or 300 MHz,
in CDCl3 using TMS as the internal standard, chemical shifts
are reported in ppm (d) downfield from the TMS.
Supporting Information for this article is available online at
Typical Experimental Procedure for the Synthesis of
2-Phenylquinazolines: To a magnetically stirred 2-
aminobenzophenone/2-aminoacetophenone (1.0 mmol) in
Synlett 2011, No. 8, 1089–1096 © Thieme Stuttgart · New York