Azetidines - 1,3,3-trinitroazetidine TNAZ

Marchand and co-workers reported a synthetic route to TNAZ (18) involving a novel electrophilic addition of NO+ NO2 across the highly strained C(3)-N bond of 3-(bromomethyl)-l-azabicyclo[1.1.0]butane (21), the latter prepared as a nonisolatable intermediate from the reaction of the bromide salt of tris(bromomethyl)methylamine (20) with aqueous sodium hydroxide under reduced pressure. The product of this reaction, A-nitroso-3-bromomethyl-3-nitroazetidine (22), is formed in 10% yield but is also accompanied by A-nitroso-3-bromomethyl-3-hydroxyazetidine as a by-product. Isolation of (22) from this mixture, followed by treatment with a solution of nitric acid in trifluoroacetic anhydride, leads to nitrolysis of the ferf-butyl group and yields (23). Treatment of (23) with sodium bicarbonate and sodium iodide in DMSO leads to hydrolysis of the bromomethyl group and the formation of (24). The synthesis of TNAZ (18) is completed by deformylation of (24), followed by oxidative nitration, both processes achieved in one pot with an alkaline solution of sodium nitrite, potassium ferricyanide and sodium persulfate. This route to TNAZ gives a low overall yield and is not suitable for large scale manufacture. 

The synthesis of TNAZ (18) via the electrophilic addition of NO+NO2 across the C(3)-N bond of l-azabicyclo[1.1.0]butane (26) was found to be very low yielding ( 1 %) and impractical. Nagao and workers reported a similar synthesis of TNAZ via this route but the overall yield was low. 

O2N NO2 HNO3, CH2CI2 NOH A NH2OH.HC1, NaOAc (aq) 0 OH CrOa, AcOH  

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. 

Archibald, Coburn, and Hiskey at Los Alamos National Laboratory (LANL) have reported a synthesis of TNAZ (18) that gives an overall yield of 57 % and is suitable for large scale manufacture. Morton Thiokol in the US now manufactures TNAZ on a pilot plant scale via this route. This synthesis starts from readily available formaldehyde and nitromethane, which under base catalysis form tris(hydroxymethyl)nitromethane (35), and without isolation from 

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