Non-directed allylic C–H acetoxylation in the presence of Lewis basic heterocycles

Abstract

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.

Direct Allylic Functionalization Through Pd‐Catalyzed C–H Activation

“…Accordingly, Malik et al tested two established Pd-catalyzed allylic acetoxylation protocols, either on a model terminal alkene in the presence of N-heterocycles, or on terminal alkenes incorporating a pyridine ring. [53] The study confirmed that both protocols are strongly affected by the presence of Lewis basic moieties. However, satisfactory conversion can be restored by two strategies: (a) addition of a Lewis acid such as BF 3 ·Et 2 O, and (b) prior conversion of the pyridine moiety into the corresponding pyridine N-oxide.…”

Diazafluorenone-Promoted Oxidation Catalysis: Insights into the Role of Bidentate Ligands in Pd-Catalyzed Aerobic Aza-Wacker Reactions

“…Subsequent studies have shown that DAF is uniquely effective in a number of other Pd-catalyzed aerobic oxidation reactions, including oxidative C–C and C–O coupling reactions with arenes, 18 α,β-dehydrogenation of cyclic ketones, 19 oxidative Heck reactions, 20 and also various non-aerobic oxidation reactions. 21 …”

CoIII‐Catalyzed Isonitrile Insertion/Acyl Group Migration Between C−H and N−H bonds of Arylamides

“…[4] Overcoming such strongc helation by heterocycles containing N, O, Pa nd Si sa nu phill task, and only few examples are known in the literature to surpass this issue (Scheme 1a). [6] Recently,Y ua nd co-workerse xemplified the remarkable yets elective synthesis of heterocyclesc atalyzed by Pd 0 using anionic NÀOMe as aw eakly chelating directing group in the presenceo fo ther heterocycles (Scheme 1b). [6] Recently,Y ua nd co-workerse xemplified the remarkable yets elective synthesis of heterocyclesc atalyzed by Pd 0 using anionic NÀOMe as aw eakly chelating directing group in the presenceo fo ther heterocycles (Scheme 1b).…”