2- Aminomethyl-1,3,4-oxadiazole

The polymer-supported 5-chloromethyl-l,2,4-oxadiazole 162 undergoes easy reaction with primary amines to give the 5-aminomethyl oxadiazoles 163, which serve as excellent substrates for the synthesis of amides or sulfonamides 164 (Scheme 21 - yields not reported) <1999TL8547>. 

The herbicide activity ascribed to the 1,2,4-oxadiazole derivative 67 (60) has prompted the search for other biologically active derivatives. This example was prepared from the corresponding 5-chloromethyl-1,2,4-oxadiazole 63 via conversion to the HHT 65 through the aminomethyl analog 64. Reaction of the HHT 65 with diethyl phosphite under neat conditions produced the desired diethyl ester intermediate 66, which was hydrolyzed to 67. 

Many other examples have been prepared (2) from the corresponding aminomethyl heterocycles using the very versatile reaction between HHTs and diaryl phosphites, as demonstrated specifically above for the 5-phenyl-l,3,4-oxadiazole system. Conversion of the 2-aminomethyl-l,3,4-oxadiazole 68 to the required HHT intermediate 69 was accomplished... 

However, with liquid ammonia or anhydrous methylamine 1,2,4-oxadiazines (88) are formed. 5-(Chloromethyl)-l,2,4-oxadiazoles (e.g., (86) react with urotropin to form salts, which are hydrolyzed with hydrochloric acid to 5-(aminomethyl) compounds (the Delepine reaction). Alternatively, 5-(aminomethyl)-l,2,4-oxadiazoles have been prepared by condensation of amidoximes with a-amino-acids <72JHC435>. 

A 3 2 mixture of coned. H2SO2 and HNO3 (d. 1.52) added slowly at —5 to 0° to a soln. of 3-phenyl-5-acetamidomethyl-l,2,4-oxadiazole in coned. H2SO4, and the mixture dil. with ice 3-(m-nitrophenyl)-5-acetamidomethyl-l,2,4-oxadia-zole. Y 90%.—Nitration of the free aminomethyl derivative gave a mixture of m- and p-nitrophenyl isomers, whereas only the m-nitrophenyl derivative was obtained, when the amino group was acetylated or further removed from the ring. F. e. s. G. Palazzo and G. Cor si, G. 93, 1196 (1963). 

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