Multigram-Scale Synthesis of a gem-Difluoro-Substituted 4,5,6,7-Tetrahydrobenzo[c]thiophen-4-one Heterocycle via Oxidative Chlorination and Radical Smiles Rearrangement

Abstract

We report an optimized synthetic route towards a functionalized 4,5,6,7-tetrahydrobenzo[c]thiophene heterocycle bearing a gem-difluoromethylene moiety in 4 steps with an overall yield of 43%. The CF₂ fragment was incorporated using a building block approach, by coupling an appropriate fluorinated alcohol with a C-3 sulfonyl chloride, synthesized via oxidative chlorination of an exocyclic benzyl thioether. Visible-light-mediated Smiles rearrangement of the resulting fluorosulfonate ester then furnishes the desired fluorinated thiophene scaffold.

Key words

gem-difluoromethylene - fluorinated building blocks - heterocycles - 4,5,6,7-tetrahydrobenzo[c]thiophen-4-one - radical Smiles rearrangement

Publication History

Received: 04 July 2023

Accepted after revision: 14 August 2023

Accepted Manuscript online:
14 August 2023

Article published online:
27 September 2023

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• 15 Ethyl 3-(Benzylthio)-4-oxo-4,5,6,7-tetrahydrobenzo[c]thiophene-1-carboxylate (3) A 500 mL round-bottomed flask was charged with 1,3-cyclohexanedione (1, 10.0 g, 89.2 mmol, 1 equiv.) and N,N-dimethylformamide (100 mL) was added under air. Potassium carbonate (30.8 g, 223.0 mmol, 2.5 equiv.) was added, and the resulting suspension was stirred at room temperature for 20 min. The reaction mixture was then treated with carbon disulfide (5.93 mL, 98.1 mmol, 1.1 equiv.), and the resulting mixture was stirred at room temperature for 35 min. Ethyl chloroacetate (8.59 mL, 86.3 mmol, 0.9 equiv.) in N,N-dimethylformamide (70 mL) was added dropwise over 40 min and then stirred at room temperature for a further 30 min. The reaction mixture was cooled to 0 °C, and benzyl bromide (10.6 mL, 89.2 mmol, 1 equiv.) in N,N-dimethylformamide (30 mL) was added dropwise over 30 min. The mixture was warmed to 50 °C and stirred for 4 h. After cooling to room temperature, water (100 mL) was added dropwise over 1 h and then the mixture was stirred at room temperature for 16 h. The resulting precipitate was collected, washed with water, and then triturated from hexane/ethyl acetate (9:1) to afford ethyl 3-(benzylthio)-4-oxo-4,5,6,7-tetrahydrobenzo[c]thiophene-1-carboxylate (3, 27.3 g, 88%) as a yellow solid. R_f = 0.18 (silica, petroleum ether/ethyl acetate = 4:1, stains red with vanillin). FT-IR: ν_max (neat) = 3391, 3258, 1697, 1676, 1533, 1393, 1267, 1234, 1207, 1182, 1136, 1070, 1022, 997 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 7.44–7.43 (m, 2 H), 7.36–7.29 (m, 3 H), 4.33 (q, J = 7.3 Hz, 2 H), 4.25 (s, 2 H), 3.19 (t, J = 6.4 Hz, 2 H), 2.55 (t, J = 6.4 Hz, 2 H), 2.08–2.03 (m, 2 H), 1.37 (t, J = 7.3 Hz, 3 H). ¹³C NMR (126 MHz, CDCl₃): δ = 194.3, 161.8, 157.4, 151.1, 134.7, 131.7, 129.4 (2 × CH), 128.9 (2 × CH), 128.2, 122.2, 61.2, 39.9, 38.8, 26.4, 23.1, 14.6. HRMS (ESI): m/z [M]⁺ calcd for C₁₈H₁₈O₃S₂: 346.0697; found: 346.0670.
• 16 Pu Y. -M, Christesen A, Ku Y.-Y. Tetrahedron Lett. 2010; 51: 418
• 17 Ethyl 3-(Chlorosulfonyl)-4-oxo-4,5,6,7-tetrahydrobenzo[c]thiophene-1-carboxylate (4) A stirred solution of ethyl 3-(benzylthio)-4-oxo-4,5,6,7-tetrahydrobenzo[c]thiophene-1-carboxylate (3, 10.0 g, 28.9 mmol, 1 equiv.) in acetonitrile/water (350 mL, 9:1) was cooled to 0 °C and glacial acetic acid (15 mL) was added. 1,3-Dichloro-5,5-dimethylhydantoin (14.2 g, 72.2 mmol, 2.5 equiv.) was added, and the reaction mixture was warmed to room temperature and stirred for 3 h. The reaction mixture was added dropwise into ice-cold water (1 L), and the resulting precipitate was collected by filtration and dried under high vacuum. This afforded ethyl 3-(chlorosulfonyl)-4-oxo-4,5,6,7-tetrahydrobenzo[c]thiophene-1-carboxylate (4, 8.77 g, 94%) as an off-white crystalline solid. R_f = 0.11 (silica, petroleum ether/ethyl acetate = 4:1, stains red with vanillin). FT-IR: ν_max (neat) = 3393, 3262, 2949, 2870, 1713, 1697, 1676, 1530, 1377, 1254, 1206, 1165, 1069 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 4.41 (q, J = 7.1 Hz, 2H), 3.29 (t, J = 6.3 Hz, 2 H), 2.70 (t, J = 6.5 Hz, 2 H), 2.20–2.14 (m, 2 H), 1.40 (t, J = 7.1 Hz, 3 H). ¹³C NMR (101 MHz, CDCl₃): δ = 190.8, 160.5, 151.6, 149.0, 137.2, 132.7, 62.6, 39.4, 26.2, 22.7, 14.3. HRMS (ESI): m/z [M + Na]⁺ calcd for C₁₁H₁₁ClNaO₅S₂: 344.9629; found: 344.9627.
• 18 2-Bromo-2,2-difluoroethanol (5) Sodium borohydride (2.41 g, 63.6 mmol, 1.1 equiv.) was suspended in a mixture of tetrahydrofuran (90 mL) and water (5 mL) at 0 °C. Ethyl bromodifluoroacetate (7.41 mL, 57.8 mmol, 1 equiv.) in tetrahydrofuran (40 mL) was added dropwise over 1 h, and the reaction mixture was warmed to room temperature and stirred for 2.5 h. After this time, the reaction was deemed complete via ¹⁹F NMR spectroscopic analysis. The mixture was acidified to pH 2 by the slow addition of 1 M aqueous hydrochloric acid (100 mL). Diethyl ether (100 mL) was added, the layers were separated, and the aqueous layer was extracted with a further portion of diethyl ether (100 mL). The combined organic extracts were washed with saturated aqueous sodium bicarbonate (100 mL) and brine (100 mL) then dried (MgSO₄), filtered, and concentrated at 45 °C/100 mbar to afford 2-bromo-2,2-difluoroethanol (5, 7.73 g; 64 w/w% in tetrahydrofuran) as a yellow oil which was used immediately in the next step without purification. Spectroscopic data were consistent with the literature.^{1 1}H NMR (400 MHz, CDCl₃): δ = 3.95 (t, J = 12.0 Hz, 2 H). ¹⁹F NMR (376 MHz, CDCl₃): δ = –58.5 (t, J = 12.0 Hz).
• 19 Ethyl 3-[(2-Bromo-2,2-difluoroethoxy)sulfonyl]-4-oxo-4,5,6,7-tetrahydrobenzo[c]thiophene-1-carboxylate (6) Ethyl 3-(chlorosulfonyl)-4-oxo-4,5,6,7-tetrahydrobenzo[c]thiophene-1-carboxylate (4, 6.26 g, 19.4 mmol, 1 equiv.) was dissolved in dichloromethane (100 mL) and 2-bromo-2,2-difluoroethanol (5, 7.73 g; 64 w/w% in tetrahydrofuran), 4-dimethylaminopyridine (0.474 g, 3.88 mmol, 0.2 equiv.), and triethylamine (4.05 mL, 29.09 mmol, 1.5 equiv.) were added. The resulting mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with dichloromethane (100 mL) and washed with water (100 mL). The aqueous layer was extracted with dichloromethane (100 mL). The combined organic extracts were washed with saturated aqueous sodium bicarbonate solution (200 mL), dried (MgSO₄), filtered, and concentrated in vacuo. Purification by column chromatography, eluting with 0–10% ethyl acetate in petroleum ether, afforded ethyl 3-[(2-bromo-2,2-difluoroethoxy)sulfonyl]-4-oxo-4,5,6,7-tetrahydrobenzo[c]thiophene-1-carboxylate (6, 5.97 g, 69%) as a pale yellow solid. R_f = 0.10 (silica, petroleum ether/ethyl acetate = 9:1, UV). FT-IR ν_max (neat): 2992, 1695, 1522, 1364, 1285, 1132, 987, 943, 806 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 5.04 (t, J = 11.8 Hz, 2 H), 4.41 (q, J = 7.3 Hz, 2 H), 3.28 (t, J = 6.4 Hz, 2 H), 2.65 (t, J = 6.4 Hz, 2 H), 2.17–2.12 (m, 2 H), 1.40 (t, J = 7.3 Hz, 3 H). ¹³C NMR (101 MHz, CDCl₃): δ = 191.7, 160.7, 151.8, 142.8, 137.4, 132.1, 116.8 (t, ¹ J _CF = 308.1 Hz), 73.9 (t, ² J _CF = 27.2 Hz), 62.4, 39.4, 26.2, 22.8, 14.4. ¹⁹F NMR (376 MHz, CDCl₃): δ = –57.8 Hz (t, J = 9.0 Hz). HRMS (ESI): m/z [M + H]⁺ calcd for C₁₃H₁₄ ⁷⁹BrF₂O₆S₂: 446.9378; found: 446.9377.
• 20 Optimization of Radical Smiles Rearrangement via a ¹⁹F NMR Assay – General Procedure Ethyl 3-[(2-bromo-2,2-difluoroethoxy)sulfonyl]-4- oxo-4,5,6,7-tetrahydrobenzo[c]thiophene-1-carboxylate (6, 44.7 mg, 0.100 mmol) was dissolved in the appropriate solvent (4 mL). To this solution was added the appropriate catalyst (0.1 mol%), formic acid (5.66 μL, 0.150 mmol), and base (0.150 mmol). The reaction was stirred for 16 h under a nitrogen atmosphere and blue light irradiation at 456 nm (where required) in a Hepatochem EvoluChem PhotoRedOx Box^TM (see the Supporting Information). The reaction mixture was spiked with benzotrifluoride (12.3 μL, 0.100 mmol) and a 100 μL aliquot was removed and diluted to 700 μL in deuterated chloroform and analyzed by ¹⁹F NMR spectroscopy. The longitudinal relaxation time constants (T1) were determined for sulfonate ester (6, T1 = 3.06 s), alcohol (7, T1 = 0.548 s), and the internal standard, benzotrifluoride (T1 = 2.28 s) using an inversion recovery experiment. A suitable relaxation time of 10 s (d1 ≥ 5 × T1) was used for all qNMR experiments to ensure >99% relaxation of all nuclei (see the Supporting Information for the inversion recovery graphs).
• 21 Cole KP, Douglas JJ, Hammerstad T, Stephenson CR. J. Org. Process. Res. Dev. 2023; 27: 399
• 22 Ethyl 3-(1,1-difluoro-2-hydroxyethyl)-4-oxo-4,5,6,7-tetrahydrobenzo[c]thiophene-1-carboxylate (7) In a 250 mL round-bottomed flask, ethyl 3-[(2-bromo-2,2-difluoroethoxy)sulfonyl]-4-oxo-4,5,6,7-tetrahydrobenzo[c]thiophene-1-carboxylate (5.97 g, 13.3 mmol) was suspended in dimethylsulfoxide (52 mL). Tris(bipyridine)ruthenium(II) chloride hexahydrate (9.96 mg, 0.0330 mmol) was added followed by tributylamine (4.74 mL, 20.0 mmol) and formic acid (0.750 mL, 20.0 mmol). The resulting solution was sparged with nitrogen with sonication for 0.5 h and then stirred under blue-light irradiation (456 nm) at 50 °C for 16 h. (The Kessil lamp was placed approximately 5 cm from the reaction vessel.) After 16 h, an aliquot was removed, and complete conversion of the starting material was observed by ¹⁹F NMR spectroscopy. The reaction mixture was diluted with ethyl acetate (150 mL) and washed with water (3 × 100 mL). The organic layer was dried (MgSO₄), filtered, and concentrated in vacuo. Purification by column chromatography, eluting with 10–30% ethyl acetate in petroleum ether, afforded ethyl 3-(1,1-difluoro-2-hydroxyethyl)-4-oxo-4,5,6,7-tetrahydrobenzo[c]thiophene-1-carboxylate (7, 3.07 g, 76%) as a beige solid. R_f = 0.20 (silica, petroleum ether/ethyl acetate = 7:3, stains purple with vanillin). FT-IR: ν_max (neat) = 3399, 3273, 1703, 1676, 1533, 1260, 1233, 1207, 1182, 1070, 1024 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 4.40–4.25 (m, 4 H), 3.25 (t, J = 6.4 Hz, 2 H), 2.93 (t, J = 7.1 Hz, 1 H), 2.60 (t, J = 6.4 Hz, 2 H), 2.13–2.08 (m, 2 H), 1.37 (t, J = 7.3 Hz, 3 H). ¹³C NMR (101 MHz, CDCl₃): δ = 194.1, 161.6, 151.8, 146.5 (t, ² J _CF = 30.6 Hz), 135.1, 127.4, 119.9 (t, ¹ J _CF = 245.6 Hz), 64.9 (t, ² J _CF = 30.9 Hz), 61.7, 40.0, 26.4, 22.8, 14.4. ¹⁹F NMR (376 MHz, CDCl₃): δ = –95.0. HRMS (ESI): m/z [M + Na]⁺ calcd for C₁₃H₁₄F₂NaO₄S₂ 327.0473; found: 327.0469.