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 candidates1,2,3. 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.
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Acknowledgements
This work was supported by funds from the National Institutes of Health under award no. R01 GM144591 and from the Albert I. Meyers Foundation at Colorado State University. R.S.P. acknowledges support from the NSF (CHE-1955876) and computational resources from the Advanced Cyberinfrastructure Coordination Ecosystem: Services & Support (ACCESS) through allocation TG-CHE180056. This work also used the Alpine high performance computing resource at the University of Colorado Boulder, jointly funded by the University of Colorado Boulder, the University of Colorado Anschutz and Colorado State University.
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B.J.H.U. and C.M.J. performed the experimental work. A.M., B.J.H.U. and C.M.J. conceptualized the work. The computational studies were performed by R.S.P. and L.d.L. All authors contributed to the design of the experimental and computational work and to data analysis, discussed the results and commented on the manuscript. A.M. and R.S.P. wrote the manuscript.
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Extended data figures and tables
Extended Data Fig. 1 Additional examples of pyrimidine functionalization and pyrimidine to pyridine conversion.
a, Additional example of pyrimidine halogenation. b, Additional examples of pyrimidine to pyridine conversion using methyl ketones. Isolated yields are shown. Vinamidinium salt formation: Tf2O (1 equiv), 4-trifluoromethylaniline (1 equiv), collidine (1 equiv), EtOAc, –78 °C to room temperature, then pyrrolidine (6 equiv), EtOH, 60 °C. aIsolated yield of vinamidinium salt from pyrimidine.
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Supplementary Figs. 1–19, Tables 1–4 and 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 631, 87–93 (2024). https://doi.org/10.1038/s41586-024-07474-1
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DOI: https://doi.org/10.1038/s41586-024-07474-1
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