A Mild Method for the Cleavage of the 4-Picolyloxy Group with Magnesium under Neutral Conditions

Abstract

A mild and efficient method for the selective hydrolysis of 4-picolyl esters with magnesium in methanol or water in the presence of other esters and sensitive protecting groups is described. 4-Picolyl aryl ethers and thioethers are also smoothly deprotected to give the corresponding phenols and thiophenols.

Key words

hydrolysis - 4-picolyloxy group - magnesium - protecting groups - phenols

References and Notes

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18

Typical Procedure A: Protection
A solution of N-Boc-l-alanine-l-valine (0.864 g, 3 mmol), 4-picolyl chloride hydrochloride (0.50 g, 3 mmol), and Et₃N (0.606 g, 6 mmol) in DMF (10 mL) was heated at 90 ˚C for 3 h, till TLC showed the absence of 4-picolyl chloride. The solvent was distilled off, and EtOAc (10 mL) was added to the residue. The solution was washed with sat. NaHCO₃ (3 × 10 mL), H₂O (2 × 10 mL), and brine (10 mL), and then dried over MgSO₄. After evaporation of the solvent, the dark brown solid was purified by column chromatography using EtOAc-PE (1:1). The filtrate was evaporated in vacuo, and the product was purified by column chromatography using EtOAc-PE (1:1). Yield 0.852 g (75%); [α]_D ^²0 -24.6 (c 1, DMF). ESI-MS: m/z = 380.2 [M + H]⁺, 402.2 [M + Na]⁺. ESI-HRMS: m/z calcd for [C₁₉H₂₉N₃O₅ + H]⁺: 380.2185; found: 380.2181; m/z calcd for [C₁₉H₂₉N₃O₅Na]⁺: 402.2005; found: 402.2002. ^¹H NMR (400 MHz, CDCl₃): δ = 0.90 (d, J = 7.0 Hz, 3 H), 0.95 (d, J = 7.0 Hz, 3 H), 1.35 (d, J = 6.9 Hz, 3 H), 1.44 (s, 9 H), 2.20-2.24 (m, 1 H), 4.23 (s, 1 H), 4.61 (t, J = 5.0, 9.0 Hz, 1 H), 5.18 (s, 2 H), 5.28 (d, J = 7.9 Hz, 1 H), 7.26-7.30 (m, 2 H), 8.61 (m, 2 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 17.5, 18.9, 28.1, 30.9, 49.8, 57.0, 64.7, 80.0, 121.8, 140.2, 149.9, 155.6, 171.3, 172.7.
Typical Procedure B: Deprotection
To a solution of picolyl N-Boc-l-alanine-l-valinate (0.76 g, 2 mmol) in MeOH (20 mL) magnesium turnings (288 mg, 12 mmol) were added. After stirring for 4 h at r.t. the reaction mixture was filtered. The filtrate was concentrated in vacuo, and the residue was diluted with 5% NaHCO₃ (10 mL) and EtOAc (10 mL), and the organic layer was extracted with 5% NaHCO₃ (2 × 10 mL). The aqueous extract was acidified to pH 2-3 with sat. KHSO₄ and extracted with EtOAc (2 × 10 mL). The organic layer was washed with brine (2 × 10 mL), dried with Na₂SO₄, and filtered. The residue was purified by silica gel column chromatography using EtOAc-PE. Yield 0.518 g (90%); [α]_D ^²0 8.7 (c 1, CHCl₃).