Non-Directed Allylic C-H Acetoxylation in the Presence of Lewis Basic Heterocycles.

Malik, Hasnain A; Taylor, Buck L H; Kerrigan, John R; Grob, Jonathan E; Houk, K N; Du Bois, J; Hamann, Lawrence G; Patterson, Andrew W

Malik, Hasnain A; Taylor, Buck L H; Kerrigan, John R; Grob, Jonathan E; Houk, K N; Du Bois, J; Hamann, Lawrence G; Patterson, Andrew W.

Afiliación

Malik HA; Global Discovery Chemistry, Novartis Institutes for BioMedical Research, Inc., Cambridge, Massachusetts 02139.
Taylor BL; Department of Chemistry and Biochemistry, University of California, Los Angeles, California 90095.
Kerrigan JR; Global Discovery Chemistry, Novartis Institutes for BioMedical Research, Inc., Cambridge, Massachusetts 02139.
Grob JE; Global Discovery Chemistry, Novartis Institutes for BioMedical Research, Inc., Cambridge, Massachusetts 02139.
Houk KN; Department of Chemistry and Biochemistry, University of California, Los Angeles, California 90095.
Du Bois J; Department of Chemistry, Stanford University, Stanford, California 94305.
Hamann LG; Global Discovery Chemistry, Novartis Institutes for BioMedical Research, Inc., Cambridge, Massachusetts 02139.
Patterson AW; Global Discovery Chemistry, Novartis Institutes for BioMedical Research, Inc., Cambridge, Massachusetts 02139.

Chem Sci ; 5(6): 2352-2361, 2014 Jun 01.

Article en En | MEDLINE | ID: mdl-25685311

RESUMEN

We outline a strategy to enable non-directed Pd(II)-catalyzed C-H functionalization in the presence of Lewis basic heterocycles. In a high-throughput screen of two Pd-catalyzed C-H acetoxylation reactions, addition of a variety of N-containing heterocycles is found to cause low product conversion. A pyridine-containing test substrate is selected as representative of heterocyclic scaffolds that are hypothesized to cause catalyst arrest. We pursue two approaches in parallel that allow product conversion in this representative system: Lewis acids are found to be effective in situ blocking groups for the Lewis basic site, and a pre-formed pyridine N-oxide is shown to enable high yield of allylic C-H acetoxylation. Computational studies with density functional theory (M06) of binding affinities of selected heterocycles to Pd(OAc)2 provide an inverse correlation of the computed heterocycle-Pd(OAc)2 binding affinities with the experimental conversions to products. Additionally, 1H NMR binding studies provide experimental support for theoretical calculations.

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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: Chem Sci Año: 2014 Tipo del documento: Article Pais de publicación: Reino Unido

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