Asymmetric Sonogashira Coupling with a Chiral Palladium Imidazoindole Phosphine Complex

Abstract

The asymmetric Sonogashira coupling of 1-(2,6-di­bromophenyl)naphthalene or 4,16-dibromo[2,2]paracyclophane with various terminal alkynes was carried out with a palladium complex of a homochiral imidazoindole phosphine, a derivative of a (3R,9aS)-2-aryl-[3-(2-dialkylphosphanyl)phenyl]tetrahydro-1H-imidazo[1,5a]indol-1-one, to give the corresponding axially chiral monoalkynylated biaryl products with up to 72% enantiomeric ­excess.

Key words

asymmetric catalysis - coupling - alkynes - chirality - ­catalysis - palladium

• References

• 1 Present address: China Three Gorges University (CTGU); [e-mail].

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• 10 The starting material 1, dialkynylated product 4, and homocoupling product of 2a were also detected by GC/MS, but were inseparable by column chromatography
• 11 The amount of dialkynylated product 4 was assessed on the basis of the peak area determined by GC/MS analysis.
• 12 General Procedure: [PdCl(π-allyl)]₂ (0.005 mmol), chiral imidazoindole phosphine ligand L₃ (0.012 mmol), and toluene (0.5 mL, degassed) were charged into a Schlenk tube under N₂, and the mixture was stirred at room temperature for 15 min. After removal of the solvent, 1-(2,6-dibromophenyl)naphthalene (1; 0.1 mmol), CuI (0.01 mmol), acetonitrile (2 mL, degassed), alkyne (2; 0.3 mmol) and Et₃N (0.35 mmol) were charged into the Schlenk tube. The mixture was stirred at 80 °C under a nitrogen atmosphere for 24 h. After cooling to room temperature, the reaction mixture was passed through a short pad of silica gel to remove the catalyst, and the filtrate was concentrated under reduced pressure. The residue was purified by chromatography with silica gel to give the mono- and dialkynylated products 3 and 4. The enantiomeric excess of 3 was determined by HPLC analysis with a chiral stationary phase column (Chiralcel AD-H, Chiralpak OD-H).
• 13 Analytical Data of Selected Compounds1-[2-Bromo-6-(phenylethynyl)phenyl]naphthalene (3a): [α]²⁵ _D −78.6 (c 1.0, CHCl₃); 63% ee (HPLC conditions: Chiralpac AD-H column; hexane–i-PrOH, 200:1; flow rate = 0.5 mL/min; wavelength = 254 nm; t_R = 13.68 (major isomer), 14.93 (minor isomer) min; ¹H NMR (500 MHz, CDCl₃): δ = 7.95 (t, J = 7.5 Hz, 2 H), 7.73–7.72 (m, 1 H), 7.64–7.57 (m, 2 H), 7.50–7.39 (m, 4 H), 7.30 (t, J = 7.5 Hz, 1 H), 7.16–7.07 (m, 3 H), 6.70–6.69 (m, 2 H); ¹³C NMR (125 MHz, CDCl₃): δ = 143.4, 138.1, 133.5, 132.5, 131.4, 131.2, 130.7, 128.8, 128.3, 128.2, 128.0, 127.3, 126.2, 125.8, 125.5, 125.2, 124.7, 122.5, 93.9, 88.1; HRMS (EI-TOF): m/z calcd for C₂₄H₁₅Br: 382.0357; found: 382.0348.1-[2-Bromo-6-(p-tolylethynyl)phenyl]naphthalene (3b): [α]²⁵ _D −69.6 (c 0.9, CHCl₃); 39% ee (HPLC conditions: Chiralpac AD-H column; hexane–i-PrOH, 200:1; flow rate = 0.5 mL/min; wavelength = 254 nm; t_R = 12.84 (major isomer), 14.16 (minor isomer) min; ¹H NMR (500 MHz, CDCl₃): δ = 7.94 (t, J = 7.5 Hz, 2 H), 7.71 (d, J = 8.0 Hz, 1 H), 7.62–7.57 (m, 2 H), 7.49–7.38 (m, 4 H), 7.29 (t, J = 8.0 Hz, 1 H), 6.90 (d, J = 8.0 Hz, 2 H), 6.58 (d, J = 8.0 Hz, 2 H), 2.23 (s, 3 H); ¹³C NMR (125 MHz, CDCl₃): δ 143.3, 138.4, 138.1, 133.5, 132.4, 131.5, 131.3, 131.1, 130.5, 129.2, 128.9, 128.8, 128.2, 127.4, 126.4, 126.2, 125.8, 125.6, 125.2, 124.7, 119.5, 94.2, 87.5, 21.4; HRMS (EI-TOF): m/z calcd for C₂₅H₁₇Br: 396.0514; found: 396.0506.1-{2-Bromo-6-[(4-methoxyphenyl)ethynyl]phenyl}-naphthalene (3c): [α]²⁵ _D = −62.4 (c 0.5, CHCl₃); 36% ee (HPLC conditions: Chiralpac AD-H column; hexane–i-PrOH, 200:1; flow rate = 0.8 mL/min; wavelength = 254 nm; t_R = 13.05 (major isomer), 14.00 (minor isomer) min; ¹H NMR (500 MHz, CDCl₃): δ = 7.94 (t, J = 7.0 Hz, 2 H), 7.70–7.69 (m, 1 H), 7.61–7.57 (m, 2 H), 7.50–7.39 (m, 4 H), 7.28 (t, J = 8.0 Hz, 1 H), 6.62 (s, 4 H), 3.71 (s, 3 H); ¹³C NMR (125 MHz, CDCl₃): δ = 159.5, 143.1, 138.2, 133.4, 132.7, 132.2, 131.5, 130.4, 128.8, 128.2, 127.4, 126.5, 126.1, 125.8, 125.6, 125.2, 124.7, 114.7, 113.7, 94.1, 86.9, 55.2; HRMS (EI-TOF): m/z calcd for C₂₅H₁₇BrO: 412.0463; found: 412.0477.1-(2-Bromo-6-{[2-(trifluoromethyl)phenyl]ethynyl}-phenyl)naphthalene (3d): [α]²⁵ _D = −47.7 (c 0.9, CHCl₃); 31% ee (HPLC conditions: Chiralpac OD-H column; hexane–i-PrOH, 200:1; flow rate = 0.5 mL/min; wavelength = 254 nm; t_R = 12.18 (major isomer), 14.48 (minor isomer) min; ¹H NMR (500 MHz, CDCl₃): δ = 7.87 (t, J = 8.5 Hz, 2 H), 7.69–7.67 (m, 1 H), 7.60 (dd, J = 7.5, 1.5 Hz, 1 H), 7.53–7.50 (m, 1 H), 7.43–7.32 (m, 5 H), 7.24 (t, J = 8.0 Hz, 1 H), 7.18–7.12 (m, 2 H), 6.47–6.45 (m, 1 H); ¹³C NMR (125 MHz, CDCl₃): δ = 143.3, 137.7, 133.9, 133.5, 133.1, 131.4, 131.0, 130.7, 128.9, 128.3, 128.2, 127.8, 127.4, 126.2, 125.8, 125.6, 125.5, 125.4, 125.2, 124.9, 122.0, 120.8, 93.2, 89.3; HRMS (EI-TOF): m/z calcd for C₂₅H₁₄BrF₃: 450.0231; found: 450.0235.1-{2-Bromo-6-[(2-fluorophenyl)ethynyl]phenyl}-naphthalene (3e): [α]²⁵ _D −84.4 (c 0.5, CHCl₃); 3% ee (HPLC conditions: Chiralpac AD-H column; hexane–i-PrOH, 200:1; flow rate = 0.5 mL/min; wavelength = 254 nm; t_R = 12.21 (major isomer), 13.21 (minor isomer) min; ¹H NMR (500 MHz, CDCl₃): δ = 7.94 (t, J = 8.0 Hz, 2 H), 7.74 (dd, J ₁= 8.0 Hz, J ₂ = 1.5 Hz, 1 H), 7.68–7.67 (m, 1 H), 7.60 7.57 (m, 1 H), 7.50–7.40 (m, 4 H), 7.31 (t, J = 8.0 Hz, 1 H), 7.13–7.11 (m, 1 H), 6.88–6.83 (m, 2 H), 6.53–6.50 (m, 1 H); ¹³C NMR (125 MHz, CDCl₃): δ = 163.1, 143.4, 137.8, 133.5, 133.3, 132.9, 131.4, 131.0, 129.9, 128.8, 128.3, 128.2, 127.3, 126.2, 125.8, 125.5, 124.8, 123.6, 115.3, 115.1, 92.8, 87.0; HRMS (EI-TOF): m/z calcd for C₂₄H₁₄BrF: 400.0263; found: 400.0251.1-{2-Bromo-6-[(3-fluorophenyl)ethynyl]phenyl}-naphthalene (3f): [α]²⁵ _D −77.6 (c 0.5, CHCl₃); 43% ee (HPLC conditions: Chiralpac AD-H column; hexane–i-PrOH, 200:1; flow rate = 0.5 mL/min; wavelength = 254 nm; t_R = 15.07 (major isomer), 17.13 (minor isomer) min; ¹H NMR (500 MHz, CDCl₃): δ = 7.96 (t, J = 8.0 Hz, 2 H), 7.74 (d, J = 7.0 Hz, 1 H), 7.63–7.58 (m, 2 H), 7.51–7.39 (m, 4 H), 7.30 (t, J = 8.0 Hz, 1 H), 7.06–7.02 (m, 1 H), 6.86–6.82 (m, 1 H), 6.47 (d, J = 7.5 Hz, 1 H), 6.35–6.32 (m, 1 H); ¹³C NMR (125 MHz, CDCl₃): δ = 163.0, 143.6, 137.9, 133.5, 132.9, 131.4, 130.7, 129.6, 128.9, 128.4, 127.3, 127.0, 126.2, 125.9, 125.7, 125.2, 124.8, 124.4, 118.0, 117.9, 115.6, 115.4, 92.5, 88.9; HRMS (EI-TOF): m/z calcd for C₂₄H₁₄BrF: 400.0263; found: 400.0241.1-{2-Bromo-6-[(4-fluorophenyl)ethynyl]phenyl}-naphthalene (3g): [α]²⁵ _D −71.3 (c 0.9, CHCl₃); 50% ee (HPLC conditions: Chiralpac AD-H column; hexane–i-PrOH, 200:1; flow rate = 0.5 mL/min; wavelength = 254 nm; t_R = 10.84 (major isomer), 12.27 (minor isomer) min; ¹H NMR (500 MHz, CDCl₃): δ = 7.87 (t, J = 7.5 Hz, 2 H), 7.65 (dd, J ₁ = 8.0, J ₂ = 1.0 Hz, 1 H), 7.54–7.49 (m, 2 H), 7.43–7.31 (m, 4 H), 7.21 (t, J = 8.0 Hz, 1 H), 6.72–6.68 (m, 2 H), 6.59–6.55 (m, 2 H); ¹³C NMR (125 MHz, CDCl₃): δ = 161.3, 143.4, 138.0, 133.4, 133.1, 133.0, 132.6, 131.4, 130.5, 128.8, 128.2, 127.3, 126.2, 126.0, 125.8, 125.5, 125.2, 124.7, 118.6, 115.4, 115.2, 92.8, 87.8; HRMS (EI-TOF): m/zcalcd for C₂₄H₁₄BrF: 400.0263; found: 400.0241.1-{2-Bromo-6-[(2,4-difluorophenyl)ethynyl]phenyl}-naphthalene (3h): [α]²⁵ _D −74.0 (c 0.7, CHCl₃); 45% ee (HPLC conditions: Chiralpac AD-H column; hexane–i-PrOH, 200:1; flow rate = 0.5 mL/min; wavelength = 254 nm; t_R = 12.22 (major isomer), 13.01 (minor isomer) min; ¹H NMR (500 MHz, CDCl₃): δ = 7.94 (t, J = 7.5 Hz, 2 H), 7.74 (d, J = 8.0 Hz, 1 H), 7.65 (d, J = 7.5 Hz, 1 H), 7.58 (t, J = 7.5 Hz, 1 H), 7.50–7.39 (m, 4 H), 7.31 (t, J = 8.0 Hz, 1 H), 6.65–6.58 (m, 2 H), 6.47 (q, J = 7.5 Hz, 1 H); ¹³C NMR (125 MHz, CDCl₃): δ = 163.5, 161.4, 143.4, 137.8, 134.2, 133.5, 132.9, 131.4, 130.8, 128.8, 128.3, 127.3, 126.2, 125.8, 125.6, 125.4, 125.2, 124.8, 111.3, 111.1, 107.6, 103.9, 92.6, 86.0; HRMS (EI-TOF): m/z calcd for C₂₄H₁₃BrF₂: 418.0169; found: 418.0157.1-[2-Bromo-6-(pent-1-ynyl)phenyl]naphthalene (3i): [α]²⁵ _D −10.2 (c 0.8, CHCl₃); 42% ee (HPLC conditions: Chiralpac OD-H column; hexane–i-PrOH, 200:1; flow rate = 0.3 mL/min; wavelength = 254 nm; t_R = 14.70 (major isomer), 16.08 (minor isomer) min; ¹H NMR (500 MHz, CDCl₃): δ = 7.88 (d, J = 8.0 Hz, 2 H), 7.66–7.64 (m, 1 H), 7.55–7.45 (m, 3 H), 7.39–7.34 (m, 3 H), 7.22 (t, J = 8.0 Hz, 1 H), 1.92–1.89 (m, 2 H), 1.32–1.25 (m, 2 H), 1.14–1.06 (m, 2 H), 0.96–0.70 (m, 7 H); ¹³C NMR (125 MHz, CDCl₃): δ = 143.3, 138.4, 133.4, 131.8, 131.5, 130.8, 128.6, 128.1, 128.0, 127.1, 126.9, 126.0, 125.6, 125.5, 125.2, 124.7, 95.3, 79.1, 31.2, 27.9, 27.8, 22.3, 19.0, 14.1; HRMS (EI-TOF): m/z calcd for C₂₄H₂₃Br: 390.0983; found: 390.0994