Cobalt-Catalyzed Alkylation of Drug-Like Molecules and Pharmaceuticals Using Heterocyclic Phosphonium Salts

Alkylated pyridines are common in pharmaceuticals, and metal catalysis is frequently used to prepare this motif via Csp2–Csp3 coupling processes. We present a cobalt-catalyzed coupling reaction between pyridine phosphonium salts and alkylzinc reagents that can be applied to complex drug-like fragmen...

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Bibliographic Details
Published inACS catalysis Vol. 9; no. 6; pp. 4862 - 4866
Main Authors Zhang, Xuan, McNally, Andrew
Format Journal Article
LanguageEnglish
Published American Chemical Society 07.06.2019
Subjects
pyridines
phosphonium salts
cross-coupling
alkylation
late-stage
cobalt-catalysis
alkyl Negishi
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Summary:Alkylated pyridines are common in pharmaceuticals, and metal catalysis is frequently used to prepare this motif via Csp2–Csp3 coupling processes. We present a cobalt-catalyzed coupling reaction between pyridine phosphonium salts and alkylzinc reagents that can be applied to complex drug-like fragments and for late-stage functionalization of pharmaceuticals. The reaction generally proceeds at room temperature, and 4-position pyridine C–H bonds are the precursors in this strategy. Given the challenges in selectively installing (pseudo)­halides in complex pyridines, this two-step process enables sets of molecules to be alkylated that would be challenging using traditional cross-coupling methods.
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ISSN:2155-5435
2155-5435
DOI:10.1021/acscatal.9b00851