Ligand-Enabled γ-C(sp3 )-H Olefination of Free Carboxylic Acids

Abstract

We report the ligand-enabled C-H activation/olefination of free carboxylic acids in the γ-position. Through an intramolecular Michael addition, δ-lactones are obtained as products. Two distinct ligand classes are identified that enable the challenging palladium-catalyzed activation of free carboxylic acids in the γ-position. The developed protocol features a wide range of acid substrates and olefin reaction partners and is shown to be applicable on a preparatively useful scale. Insights into the underlying reaction mechanism obtained through kinetic studies are reported.

Keywords: C−H activation; carboxylic acids; ligand-enabled catalysis; palladium; δ-lactones.

Scheme 1

Key advances in the C(sp³)−H olefination of carboxylic acid derivatives.

Scheme 2

Identification of suitable ligands for the γ‐C(sp³)−H olefination of free carboxylic acids. Reactions were conducted on a 0.2 mmol scale. Yields were determined by ¹H NMR analysis of the crude reaction mixture with 1,3,5‐trimethoxy benzene as an internal standard.

Scheme 3

Acid scope of the ligand‐enabled γ‐C(sp³)−H olefination of free carboxylic acids. Reactions were conducted on a 0.2 mmol scale. a. 2 a (2.5 equiv) and Ag₂CO₃ (1.75 equiv) were used with 40 h reaction time. b. 2 a (7 equiv) and Ag₂CO₃ (2.5 equiv) were used with 72 h reaction time. c. The yield in parentheses was obtained on a 5 mmol scale.

Scheme 4

Olefin scope of the ligand‐enabled γ‐C(sp³)−H olefination of free carboxylic acids. Reactions were conducted on a 0.2 mmol scale. a. Diethyl vinylphosphate (7 equiv) was used with 72 h reaction time.

Scheme 5

Preliminary mechanistic studies. Experiments in (A) and (B) were conducted on a 0.2 mmol scale. The reversibility experiments were conducted on a 0.1 mmol scale.

Scheme 6

Proposed catalytic cycle and mechanism for side product formation.