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Proton Donor Acidity Controls Selectivity in Nonaromatic Nitrogen Heterocycle Synthesis

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Science  08 Feb 2013:
Vol. 339, Issue 6120, pp. 678-682
DOI: 10.1126/science.1230704

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Acid-Derived Diversity

Compounds with nitrogen-bearing rings have proven rather promising in pharmaceutical research, spurring the need for improved synthetic methods to access structurally diverse variants of this motif. Duttwyler et al. (p. 678) show that applying acids of different strengths to a dihydropyridine intermediate leads to selective protonation at either of two sites, depending on whether the reaction proceeds under kinetic or thermodynamic (that is, equilibrated) control. The protonations in turn activate the rings for addition of various carbon nucleophiles to the periphery, thereby affording multiple different substitution patterns for use in screening studies.