Synthesis of α-Hydroxy and α-Alkoxy Esters Enabled by a Visible-Light-Induced O–H Insertion Reaction of Diazo Compounds

Abstract

A visible-light-induced O–H insertion reaction of diazo compounds is reported. This synthetic method, unlike conventional pathways, does not rely on transition metals, Lewis acids, or Brønsted acids; does not use any catalyst; and produces valuable α-hydroxy and α-alkoxy esters in good yields of up to 98%. The protocol exhibits a broad substrate scope and good functional-group tolerance. Notably, a gram-scale synthesis has been performed in a photochemical continuous-flow mode.

Key words

photochemistry - diazo compounds - insertion reaction - flow reaction - hydroxy esters - alkoxy esters

Publication History

Received: 10 August 2022

Accepted after revision: 27 September 2022

Accepted Manuscript online:
27 September 2022

Article published online:
19 October 2022

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• 13 Photochemical Reaction of Diazoalkanes with Water; General Procedure 1 A solution of the appropriate diazoalkane (0.1 mmol, 1.0 equiv) and ultrapure H₂O (0.5 mmol, 5.0 equiv) in anhyd DMF (1 mL) was added to a reaction tube at r.t. The tube was filled with N₂, and the mixture was stirred at r.t. for 8 h with irradiation by a 1 W blue LED. The reaction was then quenched with H₂O (20 mL), and the mixture was extracted with EtOAc (2 × 10 mL). The combined organic layer was washed with sat. aq NaCl (10 mL), dried (MgSO₄, 0.5 h), and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel).Photochemical Reaction of Diazoalkanes with Alcohols; General Procedure 2 A solution of the appropriate diazoalkane (0.1 mmol, 1.0 equiv) and alcohol (0.5 mmol, 5.0 equiv) in anhyd DCE (1.0 mL) was added to a reaction tube at r.t. The tube was filled with N₂, and the mixture was stirred at r.t. for 8 h with irradiation by a 1 W blue LED. The solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (silica gel, PE–EtOAc). Methyl Hydroxy(phenyl)acetate (2a) Synthesized by the general procedure and purified by column chromatography [silica gel, pentane–EtOAc (30:1)] as a colorless oil; yield: 21 mg (95%). ¹H NMR (400 MHz, CDCl₃): δ = 7.48–7.36 (m, 5 H), 5.22 (s, 1 H), 3.80 (s, 3 H), 3.53 (s, 1 H). ¹³C NMR (101 MHz, CDCl₃): δ = 174.20, 138.29, 128.69, 128.59, 126.66, 72.95, 53.11. HRMS: m/z [M + H]⁺ calcd for C₉H₁₁O₃: 167.0703; found: 167.0709.
• 14 Gram-Scale Continuous-Flow Synthesis of Methyl Hydroxy(phenyl)acetate (2a) Methyl α-diazoacetate (1a; 4.0 g, 22.5 mmol) and H₂O (2.0 g, 112 mmol) were added to a 200 mL flask equipped with a rubber septum containing anhyd MeCN (22.5 mL), and the flask was sparged with N₂ for 20 min with mixing by a magnetic stirrer. The system was then connected to a flow reactor through a peristaltic pump (see the Supporting Information, Figure S2). The flow rate was set to 1 mL/min, and the mixture was passed through a microtube reactor (PFA; OD = 0.125 inches, ID = 0.625 inches, 10 m, volume = 18.8 mL) and irradiated by a 40 W blue LED. Fan ventilation was used to keep the device at r.t. The residence time in the reactor was controlled at 4 h. The reaction was then quenched and processed according to General Procedure 1 to give 3.4 g of 2a (91% yield).