[19788-37-5]  · C6H8ClNO  · 4-(Chloromethyl)-3,5-dimethylisoxazole  · (MW 145.59)

(annulation reagent used for the construction of cyclohexenones in the syntheses of steroids, terpenes, and alkaloids2)

Physical Data: bp 87-88 °C/8 mmHg; d 1.173 g cm-3.

Solubility: sol most common organic solvents.

Form Supplied in: liquid (97-98 + % pure).

Handling, Storage, and Precautions: light-sensitive lachrymator; refrigerate; handle and store under nitrogen.

The primary use for this reagent is in the isoxazole annulation.2a,b This procedure is related to the Robinson annulation.1b The method involves alkylation of a ketone, an a,b-unsaturated ketone, or an enamine with a latent 3-ketoalkyl synthon (eq 1).2b

In Stork's original procedure, catalytic hydrogenation of the isoxazole unmasks the appended b-amino enone, which then cyclizes to a vinylogous carbinolamide. Subsequent methanolysis and hydrolysis furnishes a 1,5-diketone which cyclizes to a cyclohexenone (eq 2).

A limitation of the original Stork procedure involves the instability of the intermediate vinylogous carbinolamides. These intermediates may undergo dehydration to the corresponding dihydropyridines. These are sensitive intermediates which readily air-oxidize to b-acylpyridines. Based on this potential side-reaction, Stork reported a method for the synthesis of b-acylpyridines from intermediate carbinolamides (eq 3).3

Scott, Banner, and Saucy have reported a modification of the original Stork procedure that moderately improves the overall yield of enone.2f The modification involves acetalization of the ketone prior to hydrogenation of the isoxazole, thus suppressing formation of the delicate vinylogous carbinolamides. Subsequent hydrogenation of the isoxazole provides a stable enamide which is directly converted to the corresponding 3-keto alkyl intermediate and cyclized to the desired enone in overall yields of about 65%.

An asymmetric isoxazole annulation for the formation of a chiral quaternary carbon has been reported.2e Alkylation of a diastereomeric pair of imines with 4-(chloromethyl)-3,5-dimethylisoxazole under appropriate conditions proceeded with diastereoselectivity, providing the corresponding isoxazolyl aldehyde in 70% ee. Unmasking of the keto functionality and subsequent cyclization provided the corresponding optically active cyclohexenone (eq 4).

An alternative method for the reductive cleavage of isoxazoles using Samarium(II) Iodide has been reported and applied to the Stork isoxazole annulation.4 Importantly, even delicate acetals survive the reduction, and subsequent cyclization efficiently furnishes the cyclohexenone in 78% overall yield (eq 5). The SmI2 modification significantly enhances the yields of the enone obtained.

The Stork isoxazole annulation has been applied to the synthesis of steroids such as (±)-D-homotestosterone, (±)-progesterone, and D9(11)-dehydrotestosterone.5,6 It has also been applied to the synthesis of substituted hydroazulenes, a ring system characteristic of the pseudoguaianolide family of sesquiterpenes.7

Recently, 4-(chloromethyl)-3,5-dimethylisoxazole has been transformed into a nucleophilic mercaptomethylisoxazole (eq 6). The mercaptomethylisoxazole has been used to open epoxides.8

1. (a) Jung, M. E. T 1976, 32, 3. (b) Gawley, R. E. S 1976, 777. (c) Kashima, C. H 1979, 12, 1343.
2. (a) Stork, G. PAC 1964, 9, 131. (b) Stork, G.; Danishefsky, S.; Ohashi, M. JACS 1967, 89, 5459. (c) Stork, G.; McMurry, J. E. JACS 1967, 89, 5461. (d) Stork, G.; McMurry, J. E. JACS 1967, 89, 5463. (e) Marron, B. E.; Schlicksupp, L.; Natale, N. R. JHC 1988, 25, 1067. (f) Scott, J. W.; Banner, B. L.; Saucy, G. JOC 1972, 37, 1664.
3. Ohashi, M.; Kamachi, H.; Kakisawa, H.; Stork, G. JACS 1967, 89, 5460.
4. Natale, N. R. TL 1982, 23, 5009.
5. Stork, G.; McMurry, J. E. JACS 1967, 89, 5464.
6. Scott, J. W.; Buchschacher, P.; Labler, L.; Meier, W.; Fürst, A. HCA 1974, 57, 1217.
7. Kretchmer, R. A.; Schafer, W. M. JOC 1973, 38, 95.
8. Moreno-Mañas, M.; Arredondo, Y.; Pleixats, R.; Teixidó, M.; Raga, M. M.; Palacín, C.; Castelló, J. M.; Ortiz, J. A. JHC 1992, 29, 1557.

Margaret E. Browne & Duane A. Burnett

Schering-Plough Research Institute, Kenilworth, NJ, USA

Copyright 1995-2000 by John Wiley & Sons, Ltd. All rights reserved.