ORGANIC
LETTERS
2011
Vol. 13, No. 23
6300–6303
A Divergent and Selective Synthesis
of Isomeric Benzoxazoles from a
Single NꢀCl Imine
Cheng-yi Chen,* Teresa Andreani, and Hongmei Li
Process Chemistry, Merck Research Laboratories, P.O. Box 2000, Rahway,
New Jersey 07065, United States
Received October 21, 2011
ABSTRACT
A divergent and regioselective synthesis of either 3-substituted benzisoxazoles or 2-substituted benzoxazoles from readily accessible ortho-
hydroxyaryl NꢀH ketimines is described. The reaction proceeds in two distinct pathways through a common NꢀCl imine intermediate: (a) NꢀO
bond formation to form benzisoxazole under anhydrous conditions and (b) NaOCl mediated Beckmann-type rearrangement to form benzoxazole,
respectively. The reaction path also depends on the electronic nature of the aromatic ring, with the electron-rich aromatic rings favoring the
rearrangement and the electron-deficient rings favoring the NꢀO bond formation. A Beckmann-type rearrangement mechanism via net [1,2]-aryl
migration for the formation of 2-substituted benzoxazole is proposed.
The isomeric benzisoxazole and benzoxazole hetero-
cycles are ubiquitous in the realms of pharmacologically
active agents and natural products (Figure 1). For exam-
ple, benzisoxazole serves as a starting material for the
synthesis of more elaborate structures with bioactive proper-
ties. Three important pharmaceutical drugs (the antipsycho-
tic risperidone1 and its hydroxyl analogue, paliperidone,2
and the anticonvulsant zonisamide) were discovered based
on the benzisoxazole core.3 Benoxaprofen and flunoxapro-
fen, both containing benzoxazole cores, are chiral nonsteroi-
dal anti-inflammatory drugs once approved for improving
the symptoms of osteoarthritis and rheumatoid arthritis.4
Additionally, the benzoxazole ring occurs in a number of
natural products such as salvianen and its regioisomer,
pseudosalvianen.5 Given the importance of this class of
heterocycles, the pursuit of a general and efficient synthesis
of both benzisoxazole and benzoxazole that controls the
formation of heterocycles in a regioselective fashion is of
great importance. Many existing approaches to either
benzisoxazole6 or benzoxazole7 have been reported. The
efficient synthesis of either benzisoxazoles or benzoxazoles
from the same substrate, however, remains elusive and
would have great advantages over existing protocols. Here-
in, we report a divergent and regioselective synthesis of either
(1) Risperidone was approved by the United States Food and Drug
Administration (FDA) in 1993 for the treatment of schizophrenia. For
reviews on risperidone, see: (a) Swainston, H. T.; Goa, K. L. CNS Drugs
2004, 18, 113. (b) Deeks, E. D. Drugs 2010, 70, 1001 and references cited
therein.
(2) Paliperidone was commercialized recently as an improved drug
compared to its parent, risperidone; see: (a) Yang, L. P. H.; Plosker,
G. L. CNS Drugs 2007, 21, 417. (b) Ivo, C. L.; Joris, B. In Bipolar
Psychopharmacotherapy: Caring for the Patient, 2nd ed.; Akiskal, H.,
Mauricio, T., Eds.; Wiley: 2011, p 153.
(3) Zonisamide, widely prescribed as an antiepileptic drug, was
developed by Dianippon of Japan. For reviews on zonisamide in the
treatment of epilepsy, see: (a) Andreas, S.-B. Expert Opin. Pharmaco.
2010, 11, 115. (b) Wroe, S. J. Zonisamide. Treatment of Epilepsy, 3rd ed.;
Wiley: 2009; p 713.
(4) (a) Dunwell, D. W.; Evans, D. J. Med. Chem. 1977, 20, 791.
(b) Hopkins, S. J. Drugs Today 1980, 16, 281. (c) Dong, J. Q.; Liu, J.;
Smith, P. C. Biochem. Pharmacol. 2005, 70, 937.
(5) (a) Don, M.-J.; Shen, C.-C.; Lin, Y.-L.; Syu, W., Jr.; Ding, Y.-H.;
Sun, C.-M. J. Nat. Prod. 2005, 68, 1066. (b) Viirre, R. D.; Evindar, G.;
Batey, R. A. J. Org. Chem. 2008, 73, 3452.
(6) For recent reviews of the synthesis of benzisoxazoles, see:
(a) Hartinger, S. Sci. Syn., Knowl. Upd. 2010, 1, 133. (b) Smalley,
R. K. Sci. Syn., Schaumann, E., Ed.; Thieme: Stuttgart, 2002, 11, 289.
(7) For recent reviews of the synthesis of benzoxazoles, see:
€
€
(a) Schnurch, M.; Hammerle, J.; Stanetty, P. Sci. Syn., Knowl. Upd.
2010, 1, 153. (b) Boyd, G. V. Sci. Syn. 2002, 11, 481.
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10.1021/ol202844c
Published on Web 11/08/2011
2011 American Chemical Society