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The preparation of steroidal heterocycles containing an isoxazole ring fused to the 2,3-positions of the steroid nucleus is described. These were prepared by the reaction of hydroxylamine with either a 2-hydroxymethylene-3-ketosteroid or a 2-acyl-3-ketosteroid. The factors which influence the ratio of androstano [2,3-d] isoxazole to androstano [3,2-c] isoxazole afforded by this reaction are discussed. Several of these novel steroidal heterocycles possess interesting, and often unpredictable, endocrinological activity. The cleavage of steroidal [2,3-d]isoxazoles by means of base leads to the corresponding 2-cyano-3-ketosteroids.In a previous publication2 we outlined attempts to alter the nucleophilic environment near position 3 of the steroid nucleus3 by the attachment of a pyrazóle ring at the 2,3-positions. This approach was based upon the rationalization that the cellular receptor sites would vary sufficiently to make the question of fit one of paramount importance.The success of our initial efforts in synthesizing steroidal [3,2-c [pyrazoles with very high anabolic/ androgenic ratios2 has led us to investigate the very closely related steroidal isoxazoles fused at the 2,3positions.4'5The reaction of hydroxylamine with a 2-hydroxymethylene-3-ketosteroid can conceivably afford both of the two isomeric derivatives,6 the steroidal [2,3-d]isoxazole (I) and the steroidal [3,2-c [isoxazole (II).I can be distinguished readily from II by its facile basecatalyzed conversion to the corresponding 2a-cyano-3ketosteroid. Under the same conditions II is recovered unchanged.7

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The forniylatiori of 3-ketosteroids of the il/B-cis series has been shown to yield predominantly 2-hydroxymethylene-3keto-5p-steroids rather than 4-hydroxymethylene derivatives. The structures of the formyl derivatives were proved by their conversion to the corresponding 5P-steroidal[3,2-c]pyrazoles and direct comparison of these with authentic samples prepared by catalytic hydrogenation of A4-steroidal [3,2-c]pyrazoles. Only in the 5p-stigmast-22-en-3-one series was evidence found for the formation of a 4-hydroxymethylene derivative as the mirlor product of formylation.The 2-hydroxymet8hy1enc-3-ketosteroids obtained by the condensation of A/B-transand A4-3-ketosteroids with ethyl formate in the presence of base have been employed extensively in recent years as intermediates in the preparation of a variety of substituted steroid^.^ On the other hand, the preparation and use of hydroxymethylene derivatives of A 'B-cis 3-ketosteroids have been reported in detail only by Tsuda and I n work concerned with the methylation of 3-ketosteroid^,^^ 5p-stigmast-22-en-3-one (I) was formylated with ethyl formate and sodium methoxide in benzene, the derivative was methylated, and the formyl group then cleaved with acid. The resulting product was assigned the 4p-methyl structure I1 on the basis of its non-identity with the 2pmethyl analog 111. The latter compound was prepared, in admixture with the da-isomer, by catalytic hydrogenation of 2a-methylstigmasta-4,22-dien-3one in the presence of base. Since both methyl (1) Paper

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