Stereoselective Synthesis of (Z)-2-Bromo-2-CF₃-Vinyl Phenyl Sulfide and its Sonogashira Cross-Coupling Reaction

Abstract

A practical synthesis of (Z)-2-bromo-2-CF₃-vinyl phenyl sulfide from 2-CF₃-vinyl phenyl sulfide was achieved using bromine (Br₂) in the presence of LiBr and LiOAc in AcOH in one flask. This method affords a stereodefined product in high yield under mild conditions. The synthetic application of the product was briefly examined, providing a wide range of Sonogashira cross-coupling products using terminal acetylenes as a coupling partner.

Key words

organofluorine - trifluoromethyl group (CF₃) - bromoalkene - vinyl sulfide - stereoselective - Sonogashira cross-coupling

• References and Notes

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These reaction conditions were employed to transform 3-hexyne into the corresponding (E)-3,4-dibromo-3-hexene in 99% yield. Refer to the following original reports:
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• 6 Experimental Procedure for 2To a 100 mL round-bottom flask with a magnetic stir bar were successively added AcOH (27 mL), LiBr (53.8 mg, 0.62 mmol), and LiOAc (974.0 mg, 14.8 mmol) at ambient temperature. The mixture was stirred until these substances were dissolved into acetic acid. To this clear solution were added Br₂ (660 μL, 12.9 mmol) and sulfide 1 (2.0 mL, 12.3 mmol). After this dark orange solution was stirred at this temperature for 12 h, the solution was warmed to 40 °C for 3 h. After cooling to room temperature, to the mixture were successively added allyl alcohol (84 μ L, 1.23 mmol, due to removal of remaining Br₂), water (10 mL), and hexane (20 mL). After the organic layer was separated, an additional extraction with hexane was repeated two times. To the combined organic solution was added sat. aqueous NaHCO₃ (30 mL). The organic layer was separated, then dried over Na₂SO₄, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane) to give colorless oil (3.27 g, 94%). IR (ATR): 3047, 1715, 1593, 1580, 1479, 1442, 1276, 1234, 1167, 1126, 1025, 936, 838, 743, 705, 688, 617, 607 cm^–1. ¹H NMR (CDCl₃, 400 MHz): δ = 7.60 (s, 1 H), 7.53–7.46 (m, 2 H), 7.44–7.36 (m, 3 H). ¹³C NMR (CDCl₃, 101 MHz): δ = 140.3 (q, J = 4.7 Hz), 132.6, 132.5, 130.4, 129.7, 120.9 (q, J = 273.0 Hz), 104.4 (q, J = 39.7 Hz). ¹⁹F NMR (CDCl₃, 376 MHz): δ = 66.6 (s, 3 F). GC–MS (EI, 70 eV): m/z = 284 (59) [M⁺ (⁸¹Br)], 282 (59) [M⁺ (⁷⁹Br)], 183 (100), 134 (69), 109 (34), 69 (17). HRMS (ESI-TOF): m/z [M + Na]⁺ calcd for C₉H₆ ⁸¹BrF₃Na: 306.9197; found: 306.2657; calcd for C₉H₆ ⁷⁹BrF₃Ona: 304.9218; found: 304.2619 (the measured value of this compound did not agree with the calculated value).
• 7 The corresponding vinyl alkyl sulfide (2-CF₃-vinyl benzyl sulfide) was also employed for this bromination reaction, affording the desired 2-bromo-2-CF₃-vinyl benzyl sulfide in 82% yield under the optimized reaction conditions.
• 8 Experimental Procedure for 3A 50 mL two-neck round-bottom flask equipped with a stopcock, a magnetic stir bar, and a three-way stopcock, was charged with 5.0 mL of CH₂Cl₂ under argon. To this solution were added sulfide 2 (90.2 μL, 0.5 mmol) and mCPBA (75%, 322.2 mg, 1.4 mmol). After stirring for 24 h at room temperature, the reaction mixture was quenched with sat. aqueous Na₂S₂O₃ solution (5 mL) and sat. aqueous NaHCO₃solution (5 mL). After the organic layer was separated, the extraction was repeated twice. The combined organic layers were dried over Na₂SO₄ and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate = 3:1) to give a white solid (142.7 mg, 91%); mp 48.0–49.0 °C. IR (ATR): 3038, 1064, 1587, 1447, 1326, 1276, 1237, 1189, 1140, 1083, 931,824, 813, 750, 721, 678, 623, 575, 549, 526 cm^–1. ¹H NMR (CDCl₃, 400 MHz): δ = 8.02 (d, J = 8.0 Hz, 2 H), 7.75 (t, J = 8.0 Hz, 1 H), 7.66 (d, J = 8.0 Hz, 2 H), 7.59 (s, 1 H). ¹³C NMR (CDCl₃, 101 MHz): δ = 139.0, 137.8 (q, J = 3.9 Hz), 135.3, 129.9, 128.8, 123.0 (q, J = 39.2 Hz), 119.7 (q, J = 275.7 Hz). ¹⁹F NMR (CDCl₃, 376 MHz): δ = 69.4 (s, 3 F). GC–MS (EI, m/z, 70 eV): 316 (3) [M⁺ (⁸¹Br), 314 (3) [M⁺ (⁷⁹Br), 141 (10), 125 (100), 97 (11), 77 (63), 51 (24). HRMS (ESI-TOF): m/z [M + Na]⁺ calcd. for C₉H₆ ⁸¹BrF₃O₂Na: 338.9095; found: 338.9052; calcd for C₉H₆ ⁷⁹BrF₃O₂Na: 336.9116; found: 336.9067.
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• 12 Experimental Procedure for 6aA 50 mL two-neck round-bottom flask equipped with a stopcock, a magnetic stir bar, and a three-way stopcock, was charged with 1.6 mL of THF under argon. After the solution was degassed with argon for 20 min, to this solution were added Pd(OAc)₂ (5.4 mg, 0.024 mmol) and PPh₃ (12.6 mg, 0.048 mmol). After the reaction mixture was stirred for 1.5 h at room temperature, to the reaction mixture were added CuI (9.1 mg, 0.048 mmol), DMEA (130 μL, 1.20 mmol), sulfide 2 (72 μL, 0.40 mmol), and ethynylbenzene (48 μL, 0.44 mmol). After being stirred for 2 h, the mixture was quenched with sat. aqueous NH₄Cl solution (5 mL). After the organic layer was separated, the extraction was repeated twice. The combined organic layers were washed with brine, then dried over Na₂SO₄, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane) to give pale yellow oil as an E/Z = 95:5 mixture (88.6 mg, 73%). IR (ATR): 3060, 2197, 1567, 1488, 1442, 1369, 1256, 1227, 1169, 1121, 1069, 1040, 1025, 839, 753, 709, 868 cm^–1. ¹H NMR (CDCl₃, 400 MHz): δ = 7.60–7.54 (m, 2 H), 7.54–7.47 (m, 2 H), 7.46–7.30 (m, 7 H). ¹³C NMR (CDCl₃, 101 MHz): δ = 144.2 (q, J = 6.9 Hz), 132.7, 131.7, 131.4, 129.6, 129.2, 128.8, 128.4, 122.1, 121.6 (q, J = 273.3 Hz), 109.0 (q, J = 35.8 Hz), 100.8, 80.0 (d, J = 42.2 Hz). ¹⁹F NMR (CDCl₃, 376 MHz): δ = –65.8 (s, 3 F). GC–MS (EI, 70 eV): m/z = 304 (100) [M⁺], 289 (44), 251 (18), 234 (68), 202 (32), 121 (16). HRMS (ESI-TOF): m/z [M + Na]⁺ calcd for C₁₇H₁₁F₃SNa: 327.0426; found: no corresponding peak.