Directed C−H Bond Oxidation of Bridged Cycloalkanes Catalyzed by Palladium(II) Acetate

Abstract

We have developed a synthesis of 1,2-substituted adamantane carboxylic acids and further bridged cycloalkanes (cage compounds) by palladium acetate-catalyzed C-H bond oxidation. Acetoxylation of cycloalkane framework was performed using picolylamide as a directing group. Modification of the substrate, ligand design and variation of reaction conditions enabled us to study the mechanism of acetoxylation of aliphatic compounds. Post-functionalization reactions and cleavage of the directing group were developed. For the first time the synthesis and characterization of a β-C -tri-substituted adamantane derivatives was achieved.

Directed C–H Functionalization of the Adamantane Framework

“…The oxidation of the palladacycle to the corresponding C-O bond is proposed to proceed via concerted demetalation-oxidation (CDO) or oxidation of Pd(II) complex to Pd(IV). 56 Scheme 39 Acetoxylation of a adamantanecarboxylic acid derivative to give the depicted stereoisomers formed in this reaction; stereoisomers with acetoxy groups facing each other are not formed A method for the alkynylation of aliphatic carboxylic acid derivatives and amino acid derivatives was developed using a perfluorinated aniline as the directing group (Scheme 40). 57 For the adamantane-1-carboxylic acid derivative 85, monoethynylation of the scaffold was observed in 53% yield.…”

Recent progress in catalytic acyloxylation of C(sp3)‐H bonds

“…Hrdina with coworkers developed Pd(II)-catalyzed acetoxylation of C(sp 3 )-H bonds adjacent to the amide moiety in bridged cage compounds such as adamantane derivatives 35. [40] Acetoxylation was performed using S C H E M E 4 γ-C-H acyloxylation of free amines using transient directing group (TDG) and bystanding oxidant and α-C(sp 3 )-H acetoxylation of Tröger's bases various bidentate DGs, with picolilamide providing the highest yields of desired products 36 (Scheme 7). The selectivity of mono-acetoxylation depended significantly on the reaction conditions and the nature of added base.…”

Towards an Effective Synthesis of Difunctionalized Heptacyclo [6.6.0.02,6.03,13.04,11.05,9.010,14]tetradecane: Ligand Effects on the Cage Assembly and Selective C−H Arylation Reactions

“…[5] Regioselective functionalization of two neighbouring carbons, a methine and a methylene units, are possible when a former substituent already present in the adamantane framework is able to assist the second CÀ H activation acting as directing group in typically a metal catalysed process (Figure 1B). [6] Despite this, the number of protocols already established to access 1,2-disubstituted adamantane derivatives is comparatively quite reduced. [7] Even more scarce are the examples in which the adjacent di-functionalization of heptacyclo [6.6.0.0 2,6 .0 3, 13 .0 4,11 .0 5,9 .0 10,14 ] tetradecane (HCTD, 10), the D 2d -symmetric isomer of 2 in which all carbons are part of five-membered rings, has been achieved.…”

“…[6] Despite this, the number of protocols already established to access 1,2-disubstituted adamantane derivatives is comparatively quite reduced. [7] Even more scarce are the examples in which the adjacent di-functionalization of heptacyclo [6.6.0.0 2,6 .0 3, 13 .0 4,11 .0 5,9 .0 10,14 ] tetradecane (HCTD, 10), the D 2d -symmetric isomer of 2 in which all carbons are part of five-membered rings, has been achieved. The routes available proceed through oxidative opening of the cage and without exception deliver product mixtures and marginal yields.…”