Ligand-Promoted Palladium(II)-Catalyzed ortho-Hydroxylation of Masked Benzyl Alcohols

Abstract

A Pd^II-catalyzed ortho-C(sp²)–H hydroxylation of benzyl alcohols using an oxime ether as a monodentate directing group was developed. An N-acetylglycine ligand, in facilitating the cleavage of a C–H bond, is crucial to the reaction. The reaction might involve the formation of hydroxyl radicals generated from Oxone, and a six-membered exo-palladacycle intermediate is proposed. Various substituents on the phenyl ring were tolerated in the reaction. A gram-scale reaction and directing-group removal were also performed, demonstrating the applicability of the reaction in syntheses of salicyl alcohols.

Key words

C(sp²)–H hydroxylation - palladium-catalysis - benzylic alcohols - oxime ethers - phenolic compounds

Publication History

Received: 21 February 2025

Accepted after revision: 25 March 2025

Accepted Manuscript online:
25 March 2025

Article published online:
09 May 2025

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• 18 Acetone O-(2-Bromo-6-hydroxybenzyl)oxime (3c); Typical Procedure A 15 mL reaction tube equipped with a magnetic stirrer bar was charged with Oxone (0.5 mmol, 5.0 equiv), NaF (0.1 mmol, 1 equiv), Pd(OPiv)₂ (0.01 mmol, 10 mol %), and ligand L1 (0.02 mmol, 20 mol %). A solution of 1c (0.1 mmol, 1.0 equiv) in DCM (1.0 mL) was added and the tube was sealed and heated at 100 °C for 24 h. The mixture was then cooled to r.t., filtered through a silica gel plug, and concentrated in vacuo. The crude product was purified by chromatography [silica gel, hexanes–EtOAc (10:1)] to give a colorless oil; yield: 63%. ¹H NMR (500 MHz, CDCl₃): δ = 7.14 (dd, J = 8.1, 1.3 Hz, 1 H), 7.08 (t, J = 8.0 Hz, 1 H), 6.92 (dd, J = 8.0, 1.3 Hz, 1 H), 5.25 (s, 2 H), 1.91 (d, J = 9.4 Hz, 6 H). ¹³C NMR (126 MHz, CDCl₃): δ = 158.3, 156.9, 131.1, 125.8, 125.0, 124.6, 117.5, 71.3, 22.1, 15.8. HRMS (ESI-TOF): m/z [M + H]⁺ calcd for C₁₀H₁₃BrNO₂: 258.01293; found: 258.01296.