γ-Lactone Synthesis via Palladium(II)-Catalyzed Lactonization of Unactivated Methylene C(sp³)–H Bonds

Abstract

A palladium(II)-catalyzed intramolecular lactonization of unactivated methylene C(sp³)–H bonds using PIP bidentate auxiliary is described. This method provides an efficient and concise pathway to synthesize functionalized γ-lactones.

Key words

palladium - bidentate auxiliary - C(sp³)–H activation - lactonization - methylene - intramolecular

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• 15 General Procedure for the Lactonization To a 50 mL Schlenk tube was added substrate (0.2 mmol), Pd(OAc)₂ (4.5 mg, 0.02 mmol), PhI(OAc)₂ (128.8 mg, 0.4 mmol), NaI (30 mg, 0.1 mmol), AgOAc (16.7 mg, 0.1 mmol), and toluene (2 mL). This tube was charged with N₂, and the mixture was then heated at 100 °C for 24 h. The reaction mixture was cooled to room temperature, diluted with EtOAc, and quenched with water. The aqueous phase was extracted with EtOAc (3 × 10 mL). The combined organic phase was dried with anhydrous MgSO₄. After concentration, purification by flash chromatography gave target products.
• 16 2-(5-Oxotetrahydrofuran-2-yl)-N-[2-(pyridin-2-yl)propan-2-yl]acetamide (2a) The title compound 2a was prepared according to general procedure for the lactonization. Purification by flash chromatography in EtOAc gave the desired product as a white solid in 75% yield. ¹H NMR (400 MHz, CDCl₃): δ = 8.50 (d, J = 4.4 Hz, 1 H), 7.95 (s, 1 H), 7.72 (td, J = 7.8, 1.8 Hz, 1 H), 7.39 (d, J = 8.1 Hz, 1 H), 7.20 (ddd, J = 7.4, 4.9, 0.9 Hz, 1 H), 4.95 (m, 1 H), 2.75 (dd, J = 14.7, 6.5 Hz, 1 H), 2.63–2.52 (m, 3 H), 2.51–2.40 (m, 1 H), 2.12–1.99 (m, 1 H), 1.75 (s, 3 H), 1.74 (s, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 176.99, 167.87, 164.32, 147.84, 137.45, 122.23, 119.66, 57.02, 43.34, 29.94, 28.93, 27.92, 27.69, 27.66. HRMS (EI-TOF): m/z calcd for C₁₄H₁₈N₂O₃ [M⁺]: 262.1317; found: 262.1311