A deconstruction-reconstruction strategy for pyrimidine diversification

Abstract

Structure-Activity Relationship (SAR) studies are fundamental to drug and agrochemical development, yet only a few synthetic strategies apply to the nitrogen heteroaromatics frequently encountered in small molecule candidates.^1-3 Here, we present an alternative approach where we convert pyrimidine-containing compounds various other nitrogen heteroaromatics. Transforming pyrmidines into their corresponding N-arylpyrimidinium salts enables cleavage into a three-carbon iminoenamine building block, used for various heterocycle-forming reactions. This deconstruction-reconstruction sequence diversifies the initial pyrimidine core and enables access to various heterocycles, such as azoles.⁴ In effect, this approach allows heterocycle formation on complex molecules, resulting in analogs that would be challenging to obtain by other methods. We anticipate this deconstruction-reconstruction strategy will extend to other heterocycle classes.