ORGANIC
LETTERS
2005
Vol. 7, No. 7
1211-1214
One-Pot Multistep Synthesis of
4-Acetoxy-2-amino-3-arylbenzofurans
from 1-Aryl-2-nitroethylenes and
Cyclohexane-1,3-diones
Teruhiko Ishikawa,*,† Tadashi Miyahara,† Mami Asakura,‡ Shuichi Higuchi,†
Yayoi Miyauchi,† and Seiki Saito*,‡
School of Education and Department of Bioscience and Biotechnology, School of
Engineering, Okayama UniVersity, Tsushima, Okayama, 700-8530 (Japan)
Received December 1, 2004
ABSTRACT
A novel method for synthesizing 4-acetoxy-2-amino-3-arylbenzofurans (4) from 1-aryl-2-nitroethylenes (1) and cyclohexane-1,3-diones (2) is
described. The method features one-pot operation of a solution of 1 and 2 in THF with catalytic Et3N (rt, 12 h) followed with Ac2O, Et3N, and
DMAP (rt, 5 h), although the process consists of 13 elementary reactions.
The benzofuran framework is a core structure of many
heterocyclic compounds of synthetic or pharmaceutical
importance.1 Because benzofurans elicit a broad spectrum
of biological activities, a number of synthetic methods have
been reported. Many of these synthetic routes employ
substituted phenol derivatives as a starting material.2,3 During
the course of our studies on the synthetic potential of
cyclohexane-1,3-diones,4 we have discovered a novel domino
process5 consisting of 13 elementary reactions that com-
mences with a Michael addition reaction between 1-aryl-2-
nitroethylenes (1)6 and cyclohexane-1,3-diones (2) to even-
tually afford 4-acetoxy-2-amino-3-arylbenzofuran derivatives
(4) as outlined in Scheme 1.
Extremely simple reagents and conditions were used in
this two-component coupling reaction. A solution of 1 and
2 in THF containing a catalytic amount of triethylamine (10
mol %) was stirred at room temperature for 12 h, which was
expected to afford cyclic oxime intermediates (3).7 To this
mixture were added acetic anhydride (Ac2O), triethylamine
(Et3N), and 4-(N,N-dimethylamino)pyridine (DMAP) at room
‡ School of Engineering, Department of Bioscience and Biotechnology.
† School of Education.
(1) (a) Cagniant, P.; Cagniant, D. In AdVanced Heterocyclic Chemistry
Katritzky, A. R., Boulton, A. J., Eds.; Academic Press: New York, 1975;
pp 337-482. (b) Kleemann, A.; Engel, J.; Kutscher, B.; Reichert, D. In
Pharmaceutical Substances, 3rd ed.; Thieme: Stuttgart, 1999.
(2) For leading references, see: (a) Brady, W. T.; Giang, Y. F. J. Org.
Chem. 1986, 51, 2145-2147. (b) Nicolaou, K. C.; Snyder, S. A.; Bigot,
A.; Pfefferkon, J. A. Angew. Chem., Int. Ed. 2000, 39, 1093-1096; Angew.
Chem. 2000, 112, 1135-1138. (c) Meshram, H. M.; Sekhar, K. C. Ganesh,
Y. S. S. Yadav, J. S. Synlett 2000, 1273-1274. (d) Vedejs, E.; Wang, J.
Org. Lett. 2000, 2, 1031-1032. (e) Katritzky, A. R.; Ji, Y.; Fang, Y.;
Prakash, I. J. Org. Chem. 2001, 66, 5613-5615.
(3) For palladium-catalyzed synthesis of benzofurans from 2-alkynylphe-
nol derivatives, see: (a) Larock, R. C.; Yum. E. K.; Doty, M. J.; Sham, K.
K. C. J. Org. Chem. 1995, 60, 3270-3271 and references therein. (b) Arcadi,
A.; Cacchi, S.; Rosario, M. D.; Fabrizi, G.; Marinelli, F. J. Org. Chem.
1996, 61, 9280-9288. (c) Nan, Y.; Miao, H.; Yang, Z. Org. Lett. 2000, 2,
297-299. (d) Hu, Y.; Zhang, Y.; Yang, Z.; Fathi, R. J. Org. Chem. 2002,
67, 2365-2368.
(4) Ishikawa, T.; Kadoya, R.; Arai, M.; Takahashi, H.; Kaisi, Y.; Mizuta,
T.; Yoshikai, K.; Saito, S. J. Org. Chem. 2001, 66, 8000-8009.
(5) For reviews of domino reactions, see: (a) Tietze, L. F.; Beifuss, U.
Angew. Chem., Int. Ed. 1993, 32, 131-163. (b) Waldmann, H. In Organic
Synthesis Highlights II; Waldmann, H., Ed.; VCH: Weinheim, 1995; p 193.
(6) For the preparation of trans-1-aryl-2-nitroethylenes (1), see Supporting
Information.
(7) Formation of cyclic oximes of this class was fragmentally reported;
see: (a) Larson, H. O.; Oot, T.-C.; Siu, A. K. Q.; Hollenbeak, K. H.; Cue,
F. L. Tetrahedron 1969, 25, 4005-4010. (b) Ansell, G. B.; Moore, D. W.;
Nielsen, A. T. Chem. Commun. 1970, 1602-1603.
10.1021/ol047540b CCC: $30.25
© 2005 American Chemical Society
Published on Web 03/04/2005