Facile In Situ Difluoromethylation of Phenols and Thiols Using Ethyl Bromodifluoroacetate and K₂CO₃

Abstract

Herein, we report an efficient method to access difluoromethyl ethers of thiols and phenols using ethyl bromodifluoroacetate and K₂CO₃. This method demonstrates chemoselective difluoromethylation of thiols and phenols in the presence of amines. The current method also discloses the synthesis of bis(aryloxy)fluoromethane compounds which are least reported in the literature. Mechanistic investigations revealed that the reaction proceeds through a nucleophilic substitution pathway. We strongly believe this protocol would offer an efficient alternative to earlier photocatalyzed or radical-mediated difluoromethylation methods and it has a great potential in the scale-up of pharmaceutical and agrochemical intermediates that possess difluoromethyl group.

Key words

difluoromethylation - aromatic thiols - phenols - ethyl bromodifluoroacetate - scalable process

Publication History

Received: 29 March 2023

Accepted after revision: 08 February 2024

Article published online:
26 February 2024

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• 34a General Procedure for Difluoromethylation To the stirred solution of aromatic, heteroaromatic, or heterocyclic thiol/phenol (1 mmol) in DMF (5 vol, 20% w/v.), anhydrous K₂CO₃ (1.2 mmol), and ethyl 2-bromo-2,2-difluoroacetate (1.05 mmol) were added. The resulting reaction mixture was heated to 60 °C/115 °C. Progress of the reaction was monitored by TLC and ESMS. After the completion of the reaction, insolubles were removed by filtration through a Hyflo bed, and the obtained filtrate was concentrated in vacuo. The mixture was purified by column chromatography on silica gel (60–120 mesh) using acetone and hexane mixture as the eluant to isolate the difluoromethylated compound (Table 2, entries 1–11) in 20–95% yield. Typical Procedure for the Synthesis of 2-[(Difluoromethyl)thio]-1H-benzo[d]imidazole To the stirred solution of 1H-benzo[d]imidazole-2-thiol (4a, 25 g, 0.166 mol) in DMF (125 mL), anhydrous K₂CO₃ (27.6 g, 0.199 mol) and ethyl 2-bromo-2,2-difluoroacetate (33.78 g, 0.166 mol) were added. The resulting reaction mixture was heated at 60 °C. Progress of the reaction was monitored by TLC and ESMS. After the completion of the reaction (2 h), insolubles were removed by filtration through a Hyflo bed, and the obtained filtrate was concentrated in vacuo. The crude compound was purified by column chromatography on silica gel (60–120 mesh) using acetone and hexane mixture as the eluant to afford 2-[(difluoromethyl)thio]-1H-benzo[d]imidazole (4b) as white solid; yield 31.97 g (95%). ¹H NMR (400 MHz, CDCl₃): δ = 13.10 (S, 1 H), 7.83 (t, J = 55.36 Hz, 1 H), 7.58 (br s, 2 H), 7.26–7.23 (m, 2 H). ¹³C NMR (100 MHz, DMSO-d₆): δ = 143.55, 140 (t, J = 4.6 Hz), 135.23, 123.06 (d, J = 98.87 Hz), 120.70 (t, J = 272.9 Hz), 118.61 (br), 111.37 (br). ¹⁹F NMR (376 MHz, CDCl₃): δ = –92.05, –92.20 (d, J = 56.4 Hz). ESMS: m/z calcd for C₈H₆F₂N₂S: 200.02; found: 198.8 [M – H] and 200.8 [M + H]. 2-[(Difluoromethyl)sulfanyl]-1H-imidazole (1b) Off-white solid (82% yield). ¹H NMR (500 MHz, DMSO-d₆): δ = 12.88 (S, 1 H), 7.39 (t, J = 55.75 Hz, 1 H), 7.24 (br s, 2 H). ¹³C NMR (126 MHz, DMSO-d₆): δ = 128.49 (t, J = 4.63 Hz), 120.40 (t, J = 272.5 Hz), 120.39. ¹⁹F NMR (470 MHz, DMSO-d₆, proton decoupled): δ = –92.14. ESMS: m/z calcd for C₄H₄F₂N₂S: 150.01; found: 149.0 [M – H] and 151.0 [M + H]. 2-[(Difluoromethyl)sulfanyl]-4,5-dihydro-1,3-thiazole (2b) Colourless oil (85% yield). ¹H NMR (400 MHz, CDCl₃): δ = 7.56 (t, J = 55.77 Hz, 1 H), 4.26 (t, J = 8.15 Hz, 2 H), 3.44 (t, J = 8.12 Hz, 2 H). ¹³C NMR (100 MHz, CDCl₃): δ = 159.81 (t, J = 4.0 Hz), 120.08 (t, 272 Hz), 64.18, 35.19; DEPT: confirmed all CH and CH₂. ¹⁹F NMR (376 MHz, CDCl₃): δ = –95.4 (d, 56.4 Hz). ESMS: m/z calcd for C₄H₅F₂NS₂: 168.98; product mass was not observed because it may not be ionizable in ESI. 6-(Difluoromethoxy)-2-[(difluoromethyl)thio]pyrimidin-4-amine (3b) Pale yellow solid (69% yield). ¹H NMR (400 MHz, DMSO-d₆): δ = 7.97 (t, J = 55.26 Hz, 1 H), 7.72 (t, J = 72.18 Hz, 1 H), 7.46 (s, 2 H), 5.76 (s, 1 H).¹³C NMR (125 MHz, DMSO-d₆): δ = 166.11, 164.81 (t, J = 6.25 Hz), 164.31 (t, J = 3.75 Hz), 121.46 (t, J = 266.25 Hz), 114.59 (t, J = 255 Hz), 85.02. DEPT: confirmed all CH. ESMS: m/z calcd for C₆H₅F₄N₃OS: 243.01; found: 241.8 [M – H] and 243.8 [M + H]. 4,4′-[(Fluoromethylene)bis(oxy)]dibenzaldehyde (7b) Brown oil (20% yield). ¹H NMR (500 MHz, CDCl₃): δ = 10.00 (s, 1 H), 7.94 (dd, J = 8.75 Hz, 2.0 Hz, 2 H), 7.30 (d, J = 8.65 Hz, 2 H), 6.81 (d, J = 72.9 Hz, 1 H). ¹³C NMR (125 MHz, CDCl₃): δ = 190.57 (2 C), 157.07 (2 C), 132.93 (2 C), 131.83 (2 C), 118.41 (2 C), 113.21 (d, J = 248.6 Hz). DEPT: confirmed all CH. ¹⁹F NMR (470 MHz, CDCl₃): δ = –84.29 (s). ESMS: m/z calcd for: C₁₅H₁₁FO₄: 274.06; product mass was not observed because it may not be ionizable in ESI. 1-(Difluoromethyl)-1H-tetrazole (11b) Yellow oil (82% yield). ¹H NMR (400 MHz, CDCl₃): δ = 9.12 (s, 1 H), 7.73 (t, J = 60 Hz). ¹³C NMR (100 MHz, CDCl₃): δ = 139.67, 108.30 (t, J = 257 Hz). ¹⁹F NMR (376 MHz, CDCl₃): δ = 95.58 (d, J = 56.4 Hz). ESMS: m/z calcd for C₂H₂F₂N₄: 120.02; found: 119.2 [M – H] and 120.8 [M + H].