A one-pot synthesis of 5-carbonylmethyl-1,2,4-oxadiazoles from amidoximes under solvent-free conditions

ORGN 571

Wu Du, wu_du@merck.com1, William K. Hagmann, william_hagmann@merck.com2, and Jeffrey J Hale1. (1) Department of Medicinal Chemistry, Merck Research Laboratories, RY123-1304, Rahway, NJ 07065, (2) Department of Basic Chemistry, Merck Research Laboratories, Rahway, NJ 07065
A practical one-pot synthesis of 5-carbonylmethyl-1,2,4-oxadiazoles from amidoximes under solvent-free conditions was developed. Reaction of amidoximes and malonic diesters under solvent-free conditions gave alpha-1,2,4-oxadiazolo esters. Reaction of amidoximes and alpha-keto esters under similar conditions gave 5-ketomethyl-1,2,4-oxadiazoles. The ester from a bulky alcohol is more reactive than those from less hindered alcohols. Thus a t-butyl ester reacted selectively in the presence of a methyl ester. It is likely that these reactions go through a ketene intermediate generated by elimination of a molecule of alcohol. Experimental details of this transformation and extension of this methodology to a broader scope of substrates will be presented.