A synthetic strategy to obtain a series of 3-heteroalkyl-4,5-dihydroisoxazoles, which is based on the cyclocondensation reaction of 5-heteroalkyl-1,1,1-trichloro-4-methoxy-3-penten[hexen]-2-ones 1a-g, 2a-g with hydroxylamine has been developed. The preparation of 1,1,1-trichloro-5-heteroalkyl-4-methoxy-3-penten[hexen]-2-ones in good yields is also described.Isoxazole derivatives possess very interesting pharmacological properties, especially some heteroalkylisoxazoles such as semi-synthetic penicillins and cephalosporins that were prepared from 2-(3-chloroisoxazole-5-il)acetic acid, 1 muscimol an analog of g-aminobutiric acid (GABA), 2 the 3-aminomethylisoxazole and the furtetronium (2-trimethylamonium methylfurane) a GABA A receptor. 3As part of our research program, we have developed general synthesis of 1,1,1-trihalo-4-methoxy-3-alken-2-ones 4,5 and demonstrated their usefulness in the preparation of heterocycles. 4,6-8 In general, the presence of a trihalomethyl group in the precursor is a determining factor to establish the regiochemistry of the heterocyclic ring 5-8 and increases its biological activity. 9-12 The transformation of the trichloromethyl group under mild conditions 8 into carboxylic groups prompted us to devote special attention to these substrates. Despite extensive studies on the applications of 1,1,1-trihalo-4-alkoxy-3-alken-2-ones in heterocyclic chemistry 4,6-8,13-16 , the strategy to synthesize 5-heteroalkyl substituted 1,1,1-trihalo-4-alkoxy-3-alken-2-ones and their usefulness in the synthesis of heterocycles has not yet been developed. These compounds are highly functionalized intermediates, which may be useful for further synthetic conversions.In this paper we report a new and efficient synthetic approach for the preparation of a series 5-heteroalkyl-1,1,1-trichloro-4-methoxy-3-penten[hexen]-2-one intermediates. 1-3 In a second step, we show a cyclocondensation reaction of 5-heteroalkyl-1,1,1-trichloro-4-methoxy-3-penten[hexen]-2-ones with hydroxylamine to obtain the related 3-heteroalkyl-4,5-dihydroisoxazoles (Scheme 1).The compounds 1a, 2a were obtained from the reaction of 1,1,1-trichloro-4-methoxy-3-penten[hexen]-2-ones with bromine in the presence of pyridine. The 1,1,1-trichloro-4-methoxy-3-penten[hexen]-2-ones were synthesized from the reaction of the enol ethers or acetals with trichloroacetyl chloride. 4,5The allyl nucleophilic substitution reaction for the synthesis of 1,1,1-trichloro-4-methoxy-3-penten[hexen]-2-ones 1b, 1f, 1g, 2b, 2f and 2g were carried out in acetone at 25°C for 2-96 h (Table 1). In the case of 1c and 2c, under the same conditions, we obtained only starting materials. To obtain compounds 1c and 2c it was necessary to use potassium carbonate (1 equiv) in acetone under reflux for 10-16 h.Compounds 1d, 1e, 2d and 2e were obtained by the reaction of 1a and 2a, respectively, with the appropriate nucleophile in benzene and triethylamine (1 equiv) at 25°C for 2 h. Table 1 shows the reaction conditions used for the synthesis of compounds 1b-g and 2b-g. Scheme 1 i)...
