On the methylation of 3-cyano-6-hydroxypyridine-2(1H)-ones

Article abstract of DOI:10.1016/S0040-4020(99)00755-3

In order to prepare new heterocyclic derivatives as building block for compounds with potential biological activities, we were led to study the O- methylation of 3-cyano-6-hydroxypyridine-2(1H)-ones such as 1. This enabled us to develop a new two steps method to prepare the corresponding 2,6- dimethoxy derivative 5 in 80 % yield. It consisted first in heating 1 in trimethylorthoformate, with or without an acidic catalyst, which gave a mixture of the two mono-methoxy isomers, then a classical methylation of the second hydroxy moiety led almost exclusively to 5. In this paper we present this 'methylation' method and various unexpected results recorded when we attempted to extend it to related derivatives or to other heterocycle containing lactim-lactam functions. An intramolecular transetherification mechanism requiring the simultaneous transfer of a hydrogen and a methyl is suggested.