Synthesis of Internal Alkynes through an Effective Tandem ­Elimination–Hydrodebromination–Cross-Coupling of gem-­Dibromoalkenes with Halobenzenes

Abstract

Carbon–carbon couplings are among the most important strategies for constructing functional molecules in organic synthetic chemistry, and cheap, diverse, and readily available coupling partners are crucial to these diverse reactions. In this contribution, we report the first palladium-catalyzed C–C cross-coupling reaction of two kinds of organic halide, a gem-dibromoalkene and a halobenzene, as the starting materials. Terminal alkynes were generated in situ through a tandem elimination–hydrodebromination process, and the internal alkyne final products were synthesized in one pot. The reaction proceeded under simple, facile, and classic copper-free Sonogashira coupling reaction conditions in good to excellent yields.

Key words

alkynes - dibromoalkenes - halobenzenes - Sonogashira reaction - palladium catalysis - C–C coupling

• References and Notes

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• 22 Cross-Coupling of gem-Dibromoalkenes with Iodobenzene; General Procedure A mixture of the appropriate gem-dibromoalkene 1 (0.68 mmol), Cs₂CO₃ (2.4 mmol), and DMSO (2 mL) was stirred at 115 °C for 15 h. When 1 was completely consumed, PhI (0.4 mmol) and Pd/C (5 mol%) were added and the mixture was deaerated with N₂ and stirred at 80 °C for 25 h. The mixture was then cooled to r.t., diluted with EtOAc (30 mL), and washed with H₂O (3 × 10 mL). The organic phases were combined, dried (MgSO₄), and concentrated, and the residue was purified by column chromatography (silica gel, hexane). 1,2-Dichloro-4-(phenylethynyl)benzene (3m) White solid; yield: 47.4 mg (48%). ¹H NMR (400 MHz, CDCl₃): δ = 7.60 (t, J = 5.6 Hz, 1 H), 7.54–7.48 (m, 2 H), 7.43–7.27 (m, 5 H). ¹³C NMR (101 MHz, CDCl₃): δ = 133.1, 132.5, 132.5, 131.6, 130.6, 130.3, 128.7, 128.3, 123.2, 122.4, 91.2, 86.9. HRMS (EI): m/z [M]⁺ calcd for C₁₄H₈Cl₂: 246.0003; found: 246.0012.
• 23 Palladium-Catalyzed Cross-Coupling of gem-Dibromoalkenes 1 with Bromobenzene or 1-Chloro-4-nitrobenzene; General Procedure A mixture of the appropriate gem-dibromoalkene 1 (0.68 mmol), Cs₂CO₃ (2.4 mmol), and DMSO (2 mL) was stirred at 115 °C for 15 h. When the alkene 1 was completely consumed, bromobenzene (4) or 1-chloro-4-nitrobenzene (5) (0.4 mmol), Pd(OAc)₂ (5 mol%), and PPh₃ (10 mol%) were added and the mixture was deaerated with N₂ gas and stirred at 60 °C or 80 °C for 25 h. When the reaction was complete, the product was isolated and purified as described above. 1-Chloro-4-[(4-methoxyphenyl)ethynyl]benzene (3x) Brown solid; yield: 81.5 mg (84%). ¹H NMR (400 MHz, CDCl₃): δ = 7.50–7.36 (m, 4 H), 7.32–7.25 (m, 2 H), 6.92–6.77 (m, 2 H), 3.83–3.69 (m, 3 H). ¹³C NMR (101 MHz, CDCl₃): δ = 160.0, 133.2, 132.8, 131.8, 128.8, 128.5, 122.3, 114.2, 90.5, 87.2, 55.5. HRMS (EI): m/z [M]⁺ calcd for C₁₅H₁₁ClO: 242.0498; found: 242.0506. Methyl 4-[(4-Chlorophenyl)ethynyl]benzoate (3y) Brown solid; yield: 88.1 mg (82%). ¹H NMR (400 MHz, CDCl₃): δ = 8.10–7.96 (m, 2 H), 7.61–7.50 (m, 2 H), 7.44 (t, J = 13.1 Hz, 2 H), 7.36–7.27 (m, 2 H), 3.98–3.83 (m, 3 H). ¹³C NMR (101 MHz, CDCl₃): δ = 166.6, 134.9, 133.0, 131.6, 129.8, 129.7, 128.9, 127.7, 121.3, 91.2, 89.6, 52.3. HRMS (EI): m/z [M]⁺ calcd for C₁₆H₁₁ClO₂ [M]⁺ 270.0448; found: 270.0459. 1-Fluoro-4-[(4-methoxyphenyl)ethynyl]benzene (3z) Brown solid; yield: 76.8 mg (85%). ¹H NMR (400 MHz, CDCl₃): δ = 7.53–7.35 (m, 4 H), 7.06–6.95 (m, 2 H), 6.85 (d, J = 8.5 Hz, 2 H), 3.81 (d, J = 14.4 Hz, 3 H). ¹³C NMR (101 MHz, CDCl₃): δ = 162.3 (J _CF = 249.2 Hz), 159.7, 133.3 (J _CF = 7.6 Hz), 133.0, 119.7 (J _CF = 3.0 Hz), 115.7, 115.4 (J _CF = 22.7 Hz), 114.1, 89.1, 87.0, 55.3.HRMS (EI): m/z [M]⁺ calcd for C₁₅H₁₁FO: 226.0794; found: 226.0800. Methyl 4-[(4-Fluorophenyl)ethynyl]benzoate (3za) Brown solid; yield: 60.0 mg (59%). ¹H NMR (400 MHz, CDCl₃): δ = 8.01 (d, J = 8.2 Hz, 2 H), 7.64–7.41 (m, 4 H), 7.05 (t, J = 8.6 Hz, 2 H), 3.90 (d, J = 12.0 Hz, 3 H). ¹³C NMR (101 MHz, CDCl₃): δ = 166.5, 162.8 (J _CF = 250.7 Hz), 133.7 (J _CF = 9.01 Hz), 131.5, 129.6, 128.4, 127.8, 118.8 (J _CF = 3.0 Hz), 115.8 (J _CF = 22.7 Hz), 91.3, 88.4, 52.2. HRMS (EI): m/z [M]⁺ calcd for C₁₆H₁₁FO₂: 254.0743; found: 254.0750.