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 candidates1–3. 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. We present a synthetic method that transforms complex pyrimidine-containing structures into iminoenamines and then uses de novo heterocycle synthesis to obtain substituted pyrimidine and 1,2-azole analogues.