ORGANIC
LETTERS
1999
Vol. 1, No. 10
1619-1622
A Simple Synthesis of
2-Substituted-4H-3,1-benzoxazin-4-ones
by Palladium-Catalyzed
Cyclocarbonylation of o-Iodoanilines
with Acid Chlorides
Chitchamai Larksarp and Howard Alper*
Department of Chemistry, UniVersity of Ottawa, 10 Marie Curie,
Ottawa, Ontario, Canada K1N 6N5
Received August 30, 1999
ABSTRACT
One-pot reaction of o-iodoanilines with acid chlorides and carbon monoxide, in the presence of a palladium catalyst and diisopropylethylamine,
regioselectively affords 2-substituted-4H-3,1-benzoxazin-4-ones in good to excellent yields. The reaction is believed to proceed via in situ
amide formation from an o-iodoaniline and an acid chloride, followed by oxidative addition to Pd(0), CO insertion, and intramolecular cyclization
to form the 2-substituted-4H-3,1-benzoxazin-4-one derivatives.
4H-3,1-Benzoxazin-4-ones (acylanthranils) are a class of
fused heterocycles of considerable interest owing to their
biological activity.1 Indeed some of these compounds act as
chymotrypsin inactivators,1a inhibitors of human leukocyte
elastase,1b,c serine protease,1d and 2-aryl derivatives have the
ability to lower the concentration of plasma cholesterol and
triglyceride.1e Moreover, 2-substituted-4H-3,1-benzoxazin-
4-ones were reported to be used as precursors for the
preparation of pharmaceutically active compounds such as
antimicrobial agents (N-substituted-quinazolin-4-one deriva-
tives)2 and analgesics (4-hydroxy-3-quinoline-carbox-
amides).3 Several methods have been reported for the
preparation of 2-substituted-4H-3,1-benzoxazin-4-ones.4 The
most popular synthetic pathways involve the use of anthra-
nilic acid or its derivatives,5 N-acylanthranilic acids,6 or
isatonic anhydride.7 Other synthetic methods such as oxida-
tion of indoles,8 [4 + 2] cycloaddition of 1,2,3-benzotriazin-
(2) (a) Habib, O. M.; Moawad, E. B.; Girges, M. M.; El-Shafei, A. M.
Boll. Chim. Farm. 1995, 134, 503. (b) Errede, L. A.; Oien, H. T.; Yarian,
D. R. J. Org. Chem. 1977, 42, 12. (c) Ibrahim, S. S.; Abdel-Halim, A. M.;
Gabr, Y.; El-Edfawy, S.; Abdel-Rahman, R. J. Chem. Res., Synop. 1997,
154. (d) Shaban, M. A. E.; Taha, M. A. M.; Sharshira, E. M. AdVances in
Heterocyclic Chemistry; Academic Press: San Diego, 1991; Vol. 52.
(3) Cle´mence, F.; Le Martret, O.; Collard, J. J. Heterocycl. Chem. 1984,
21, 1345.
(4) For a recent review in the chemistry of 4H-3,1-benzoxazin-4-ones,
see: Coppola, G. M. J. Heterocycl. Chem. 1999, 36, 563 and references
therein.
(5) (a) Bain, D. I.; Smalley, R. K. J. Chem. Soc. C 1968, 1593. (b)
Johnson, J. L.; Pattison, I. J. Heterocycl. Chem. 1986, 23, 249. (c) Beck, J.
R.; Yahner, J. A. J. Org. Chem. 1973, 38, 2450.
(1) (a) Hedstrom, L.; Moorman, A. R.; Dobbs, J.; Abeles, R. H.
Biochemistry 1984, 23, 1753. (b) Krantz, A.; Spencer, R. W.; Tam, T. F.;
Liak, T. J.; Copp, L. J.; Thomas, E. M.; Rafferty, S. P. J. Med. Chem.
1990, 33, 464. (c) Stein, R. L., Strimpler, A. M., Viscarello, B. R.,
Wildonger, R. A., Mauger, R. C. Trainor, D. A. Biochemistry 1987, 26,
4126. (d) Hays, S. J.; Caprathe, B. W.; Gilmore, J. L.; Amin, N.; Emmerling,
M. R.; Michael, W.; Nadimpali, R.; Nath, R.; Raser, K. J.; Stafford, D.;
Watson, D.; Wang, K.; Jaen, J. C. J. Med. Chem. 1998, 41, 1060. (e) Fenton,
G., Newto, C. G., Wyman, B. M., Bagge, P., Dron, D. I. Riddell, D. Jones,
G. D. J. Med. Chem. 1989, 32, 265.
(6) (a) Zentmyer, D. T.; Wagner, E. C. J. Org. Chem. 1949, 14, 967. (b)
Balsubramaniyan, V.; Argade, N. P. Tetrahedron Lett. 1986, 27, 2487. (c)
Papadopoulos, E. P.; Torres, C. D. Heterocycles 1982, 19, 1039. (d)
Papadopoulos, E. P.; Torres, C. D. J. Heterocycl. Chem. 1982, 19, 269.
(7) Minami, T.; Ogata, M.; Hirao, I. Synthesis 1982, 231.
10.1021/ol990258y CCC: $18.00 © 1999 American Chemical Society
Published on Web 10/07/1999