Chemo- and Regioselective Demethylation of 2-Bromo-α-resorcylic Acid Derivatives Using Alkylthiolate Salts

Abstract

We report here the chemo- and regioselective demethylation of 2-bromo-3,5-dimethoxy-α-resorcylic acid esters by a thiolate nucleophilic displacement reaction. Optimized conditions facilitate yields up to 93% for o-bromo-selective demethylation of diverse ester derivatives of dimethoxy 2-bromo-α-resorcylic acid. Our results highlight a new, efficient, and reliable demethylation reagent, as well as a useful steric bias directing strategy.

Key words

demethylation - thiolates - chemoselectivity - regioselectivity - α-resorcylic acid derivatives

Publication History

Received: 20 March 2024

Accepted after revision: 22 July 2024

Accepted Manuscript online:
22 July 2024

Article published online:
14 August 2024

• References and Notes

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• 30 General Demethylation Procedure for 1b–d Potassium hydride (361.0 mg, 9.0 mmol, 3.0 equiv.) was suspended in dry NMP (10 mL), in a two-neck round-bottom flask equipped with a stir bar and an addition funnel, under nitrogen atmosphere. The reaction flask was cooled down to 0 °C. A solution of t-BuSH (1.0 mL, 9.0 mmol, 3.0 equiv.) in NMP (5 mL) was added to the addition funnel. This solution was then added dropwise to the reaction mixture over 10 min. After the addition, the ice bath was removed, and the mixture was left to stir for 10 min. A solution of a 2-bromo-3,5-dimethoxy-α-resorcylic ester 1b–d (3.0 mmol, 1.0 equiv.) in NMP (5 mL) was then added in one portion, and the reaction mixture was left to stir for 3 h at 65 °C. The reaction mixture was cooled down before 50 mL of HCl 1 N were added. The crude reaction mixture was extracted three times with EtOAc (75 mL). The organic layers were combined, washed four times with HCl 1 N (100 mL), dried over MgSO₄, and concentrated in vacuo. The crude material was purified by silica gel chromatography. Ethyl 2-Bromo-3-hydroxy-5-methoxybenzoate (2b) Colorless oil; yield 67% (2.00 mmol, 549.0 mg); R_f = 0.49 (1:1 hexanes/EtOAc). ¹H NMR (500 MHz, CDCl₃): δ = 6.97 (1 H, d, J = 3.1 Hz), 6.73 (1 H, d, J = 2.9 Hz), 6.08 (1 H, s), 4.38 (2 H, q, J = 7.1 Hz), 3.79 (3 H, s), 1.39 (3 H, t, J = 7.2 Hz). ¹³C NMR (125 MHz, CDCl₃): δ = 165.9, 159.8, 154.0, 132.9, 109.9, 104.6, 100.7, 61.9, 55.8, 14.3. IR (ATR): ν_max = 3412, 2980, 2937, 2847, 1724, 1707, 1585, 1427, 1369, 1338, 1227, 1144, 1068, 1018, 1018 cm^–1. HRMS (ESI-TOF); m/z calcd for C₁₀H₁₁O₄Br [M + H]⁺: 274.9913; found: 274.9910. Isopropyl 2-Bromo-3-hydroxy-5-methoxybenzoate (2c) Colorless oil; yield 92% (2.76 mmol, 799.0 mg); R_f = 0.56 (1:1 hexanes/EtOAc). ¹H NMR (500 MHz, CDCl₃): δ = 6.90 (1 H, d, J = 2.9 Hz), 6.69 (1 H, d, J = 3.1 Hz), 6.20 (1 H, br), 5.24 (1 H, hept, J = 5.8 Hz), 3.77 (3 H, s), 1.36 (6 H, d, J = 6.4 Hz). ¹³C NMR (125 MHz, CDCl₃): δ = 165.6, 159.7, 154.0, 133.5, 109.6, 104.3, 100.4, 69.8, 55.7, 21.9. IR (ATR): ν_max = 3418, 2982, 2937, 2845, 1701, 1585, 1427, 1360, 1232, 1146, 1103, 997, 829 cm^–1. HRMS (ESI-TOF): m/z calcd for C₁₁H₁₃O₄Br [M + H]⁺: 289.0070; found: 289.0057 tert-Butyl 2-Bromo-3-hydroxy-5-methoxybenzoate (2d) Yellowish oil; yield 93% (2.79 mmol, 845.8 mg); R_f = 0.55 (1:1 hexanes/EtOAc). ¹H NMR (500 MHz, CDCl₃): δ = 6.88 (1 H, d, J = 2.9 Hz), 6.70 (1 H, d, J = 3.1 Hz), 3.79 (3 H, s), 1.60 (9 H, s). ¹³C NMR (125 MHz, CDCl₃): δ = 165.2, 159.6, 153.8, 134.7, 109.4, 103.8, 100.1, 82.9, 55.7, 28.1. IR (ATR): ν_max = 3398, 2980, 2937, 2845, 1724, 1703, 1585, 1367, 1348, 1242, 1142, 1020, 997, 841, 779 cm^–1. HRMS (ESI-TOF): m/z calcd for C₁₂H₁₅O₄Br [M + NH₄]⁺: 320.0492; found: 320.0482.