Ligand-Promoted Palladium-Catalyzed β-C(sp³)–H Arylation of Ketones Using Acetohydrazide as a Transient Directing Group

Abstract

A palladium-catalyzed β-C(sp³)–H arylation of aliphatic ketones by using acetohydrazide as a transient directing group has been developed. The reaction proceeds through a less-favored [5,5]-bicyclic palladacycle intermediate and is promoted by a pyridine ligand.

Key word

C–H arylation - transient directing group - acetohydrazides - ketones - palladium catalysis - pyridines

Publication History

Received: 05 April 2024

Accepted after revision: 20 April 2024

Accepted Manuscript online:
20 April 2024

Article published online:
29 April 2024

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• 12 4-(2-Ethyl-3-oxobutyl)benzonitrile (4h); Typical ProcedureA 15 mL reaction tube equipped with a magnetic stirrer bar was charged with 4-iodobenzonitrile (2h; 0.2 mmol, 2.0 equiv), AgTFA (0.25 mmol, 2.5 equiv), Pd(OAc)₂ (0.01 mmol, 10 mol%), and ligand L9 (0.08 mmol, 80 mol%). A solution of ketone 1a (0.1 mmol, 1.0 equiv) and TDG1 (0.05 mmol, 50 mol%) in HFIP (1.0 mL) was then added. The tube was sealed and the mixture was stirred at r.t. for 10 min, then heated at 110 °C for 24 h. When the reaction was complete, the mixture was cooled to r.t., filtered through a silica gel plug, and concentrated in vacuo. The crude reaction mixture was purified by column chromatography (silica gel, hexanes–EtOAc (10:1)] to give a colorless oil; yield: 46%. ¹H NMR [500 MHz, CDCl₃): δ = 7.56 (d, J = 7.7 Hz, 2 H), 7.25 (d, J = 7.5 Hz, 2 H), 2.97 (dd, J = 13.2, 8.2 Hz, 1 H), 2.73 (ddd, J = 19.2, 13.3, 6.4 Hz, 2 H), 2.03 (s, 3 H), 1.66 (dt, J = 21.7, 7.2 Hz, 1 H), 1.52 (dt, J = 17.2, 5.3 Hz, 1 H), 0.91 (t, J = 7.4 Hz, 3 H). ¹³C NMR (126 MHz, CDCl₃): δ = 211.0, 145.6, 132.2, 129.7, 118.8, 110.3, 55.5, 36.9, 30.1, 24.6, 11.3. HRMS (ESI-TOF): m/z calcd [M + H]⁺ for C₁₃H₁₆NO: 202.2768; found: 202.2765.§
• 13 Li Y.-H, Ouyang Y, Chekshin N, Yu J.-Q. ACS Catal. 2022; 12: 10581