tele-Substitution Reactions in the Synthesis of a Promising Class of 1,2,4-Triazolo[4,3‑a]pyrazine-Based Antimalarials

We have discovered and studied a tele-substitution reaction in a biologically important heterocyclic ring system. Conditions that favor the tele-substitution pathway were identified: the use of increased equivalents of the nucleophile or decreased equivalents of base or the use of softer nucleophile...

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Bibliographic Details
Published in:Journal of organic chemistry 2020-11, Vol.85 (21), p.13438-13452
Main Authors: Korsik, Marat, Tse, Edwin G, Smith, David G, Lewis, William, Rutledge, Peter J, Todd, Matthew H
Format: Article
Language:English
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Summary:We have discovered and studied a tele-substitution reaction in a biologically important heterocyclic ring system. Conditions that favor the tele-substitution pathway were identified: the use of increased equivalents of the nucleophile or decreased equivalents of base or the use of softer nucleophiles, less polar solvents, and larger halogens on the electrophile. Using results from X-ray crystallographic and isotope labeling experiments, a mechanism for this unusual transformation is proposed. We focused on this triazolopyrazine as it is the core structure of the in vivo active antiplasmodium compounds of Series 4 of the Open Source Malaria consortium.
ISSN:0022-3263
1520-6904
DOI:10.1021/acs.joc.0c01045