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 in which we convert pyrimidine-containing compounds into various other nitrogen heteroaromatics. Transforming pyrimidines 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 azoles⁴. In effect, this approach allows heterocycle formation on complex molecules, resulting in analogues that would be challenging to obtain by other methods. We anticipate that this deconstruction-reconstruction strategy will extend to other heterocycle classes.