Pyridine ring synthesis from oximes

Axenrod and co-workers reported a synthesis of TNAZ (18) starting from 3-amino-l,2-propanediol (28). Treatment of (28) with two equivalents of p-toluenesulfonyl chloride in the presence of pyridine yields the ditosylate (29), which on further protection as a TBS derivative, followed by treatment with lithium hydride in THF, induces ring closure to the azetidine (31) in excellent yield. Removal of the TBS protecting group from (31) with acetic acid at elevated temperature is followed by oxidation of the alcohol (32) to the ketone (33). Treatment of the ketone (33) with hydroxylamine hydrochloride in aqueous sodium acetate yields the oxime (34). The synthesis of TNAZ (18) is completed on treatment of the oxime (34) with pure nitric acid in methylene chloride, a reaction leading to oxidation-nitration of the oxime group to em-dinitro functionality and nitrolysis of the A-tosyl bond. This synthesis provides TNAZ in yields of 17-21 % over the seven steps. 

Synthesis of isoxazolo[5,4- ]pyridines can be carried out from the corresponding chloronitrile intermediate 165 (Equation 64) <2002BML2925> or by deprotonation of an oxime with subsequent cyclization and expulsion of chloride (Equation 65) <1996JA10803>. Ring closure onto the nitrile in 166 by treatment with sodium hydroxide affords the isoxazolo[5,4- ]pyridine 167 in low yield (Equation 66) <1999JOC8479>. 

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