Lithiation of Methoxypyridines Directed by α-Amino Alkoxides

Article abstract of DOI:10.1021/jo00288a014

The addition of methoxypyridinecarboxaldehydes to certain lithium dialkylamides gave α-amino alkoxides in situ that were ring-lithiated with alkyllithium bases.Alkylation and hydrolysis on workup provided ring-substituted methoxypyridinecarboxaldehydes via a one-pot reaction.The one-pot methylation of isomeric methoxypyridinecarboxaldehydes was examined.The regioselectivity of the lithiation-methylation was dependent on the aldehyde, the amine component of the α-amino alkoxide, and the metalation conditions.When lithiated N,N,N'-trimethylethylenediamine was used as the amine component of the α-amino alkoxide, methylation generally occured ortho to the aldehyde function.The analogous reactions using lithium N-methylpiperazide as the amine component gave substitution next to the methoxy group.Several new methylated methoxypyridinecarboxaldehydes were prepared in a regioselective manner by using this one-pot procedure.