Palladium-Catalyzed C-O Cross-Coupling of Primary Alcohols

Abstract

Two catalyst systems are described, which together provide mild and general conditions for the Pd-catalyzed C-O cross-coupling of primary alcohols. For activated substrates, such as electron-deficient aryl halides, the commercially available ligand L2 promotes efficient coupling for a variety of alcohol nucleophiles. In the case of unactivated electrophiles, such as electron-rich aryl halides, the new ligand L8 was developed to improve these challenging C-O bond-forming reactions.

Figure 1

Examples of pharmaceutical molecules containing alkyl aryl ethers.

Figure 2

Biaryl phosphine ligands and their palladacycle precatalysts.

Scheme 1

General Catalytic Cycle for Pd-Catalyzed C–O Cross-Coupling of Aryl Halides and Primary Alcohols

Scheme 2

Pd-Catalyzed C–O Cross-Coupling of Activated Aryl Halides with Primary Alcohols^{a,b a}Reaction conditions: ArX (1.0 mmol), n-BuOH (2.0 mmol), NaOt-Bu (1.2 mmol), P2 (1.0–2.0 mol %), 1,4-dioxane (1.0 mL, 1.0 M), rt–60 °C, 6–15 h. ^bThe reported isolated yields are average results of two runs.

Scheme 3

Pd-Catalyzed C–O Cross-Coupling of Unactivated Substrates^{a,b,c,d a}Reaction conditions: ArX (1.0 mmol), n-BuOH (2.0 mmol), NaOt-Bu (1.2 mmol), P2/P8 (1.0–2.5 mol %), 1,4-dioxane (1.0 mL, 1.0 M), rt–80 °C, 2.5–18 h. ^bNMRY: yields determined by ¹H NMR spectroscopy using an internal standard. ^cC: conversions determined by GC using an internal standard. ^dIY: average isolated yields from two runs.