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A deconstruction-reconstruction strategy for pyrimidine diversification

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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.

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Correspondence to Robert S. Paton or Andrew McNally.

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Supplementary Information, including 19 Supplementary Figures, 4 Supplementary Tables, and additional references.

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Uhlenbruck, B.J.H., Josephitis, C.M., de Lescure, L. et al. A deconstruction-reconstruction strategy for pyrimidine diversification. Nature (2024).

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