Direct β- and γ-C(sp3 )-H Alkynylation of Free Carboxylic Acids*

Abstract

In this study we report the identification of a novel class of ligands for palladium-catalyzed C(sp³ )-H activation that enables the direct alkynylation of free carboxylic acid substrates. In contrast to previous synthetic methods, no introduction/removal of an exogenous directing group is required. A broad scope of acids including both α-quaternary and challenging α-non-quaternary can be used as substrates. Additionally, the alkynylation in the distal γ-position is reported. Finally, this study encompasses preliminary findings on an enantioselective variant of the title transformation as well as synthetic applications of the products obtained.

Keywords: Alkynylation; Carboxylic acids; C−H activation; Ligand-enabled catalysis; Palladium.

Scheme 1

Previous studies on the indirect C−H alkynylation of aliphatic acids (Path B) and direct C(sp³)−H alkynylation of free carboxylic acids developed in this study (Path A).

Scheme 2

Identification of suitable ligands for the β‐ and γ‐C(sp³)−H alkynylation 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 using 1,3,5‐trimethoxybenzene as an internal standard. The mass balance of the reactions is fully accounted for by the product formed and unreacted starting material. No di‐ or tri‐substituted product was observed in any case during the optimization studies.

Scheme 3

Reaction scope. Reactions were conducted on a 0.2 mmol scale. [a] L14 was used instead of L9, LiHFIP (1 equiv), H₂O (1.5 equiv), and HFIP (2.0 mL) were used at 60 °C for 24 h; [b] Pd(OAc)₂ (20 mol %), L14 (60 mol %), LiHFIP (2 equiv), Ag₂O (2 equiv), 1‐bromo‐2‐(triisopropylsilyl)acetylene (3 equiv), and HFIP (4 mL) were used at 60 °C for 24 h. The structures of the respective starting materials are shown for simplicity with the position that is C−H alkynylated highlighted.

Scheme 4

Initial findings on the enantioselective β‐C(sp³)−H alkynylation of carboxylic acids 1 c and 1 t.

Scheme 5

Synthetic utility of the β‐C(sp³)‐H alkynylation of aliphatic carboxylic acids.

Scheme 6

Preliminary mechanistic studies.