Chemicals
All chemicals were purchased from Sigma-Aldrich and used without further purification. Immobilized form of Candida antarctica Lipase B (iCAL-B) was purchased from c-LEcta GmbH (trade name CALB-immo).
DES preparation
The components were mixed in the desired molar ratio and stirred at 60°C until a clear solution was obtained. After cooling down to room temperature, the DES was directly used. DESs were stored for maximum 1 month in a closed vessel.
Analytics
All NMR spectra were measured on a 400 MHz (1H-NMR: 400 MHz, 13C-NMR: 101 MHz), and 300 MHz (1H-NMR: 300 MHz, 13C-NMR: 75 MHz) Bruker device from BioSpin GmbH at 20°C. Chemical shifts are relative to the used solvents (CDCl3: 1H: δ = 7.26 ppm, 13C: δ = 77.16 ppm), indicated in ppm. Following abbreviations were used for the signal patterns: s = singlet, bs = broad signal, d = doublet, t = triplet, q = quartet, m = multiplet, dd = doublet of doublets etc. for the 1H-spectra.
Cat2 synthesis
(2S,4R)-4-hydroxy-2-(methoxycarbonyl)pyrrolidin-1-ium chloride
Freshly distilled methanol (125 mL) was added to a round bottom flask and trans-4-hydroxy-l-proline (5.00 g, 38.13 mmol) was suspended. The slurry was cooled down to 0°C. After drop wise addition of thionyl chloride (2.78 mL, 38.2 mmol, 1.00 equiv.) the reaction mixture was stirred for 4 h at RT. Removal of the solvent under reduced pressure gave the product (6.80 g, 37.4 mmol, 98% yield) as a white solid. 1H-NMR (CDCl3, 300 MHz): δ = 2.08–2.18 (2H, m), 3.06 (1H, d, J = 12.0 Hz), 3.36 (1H, dd, J = 12.0, 4.4 Hz), 3.75 (3H, s), 4.41–4.48 (2H, m), 5.62 (1H, br-s), 9.91 (2H, br-s) ppm. 13C-NMR (CDCl3, 75 MHz): δ = 37.0, 53.0, 57.3, 68.4, 68.5, 169.0 ppm. Data are fully consistent with previous literature [16].
Methyl (2S,4R)-1-benzyl-4-hydroxypyrrolidine-2-carboxylate
Toluene (30 mL) was added to a round bottom flask and (2S,4R)-4-hydroxy-2-(methoxycarbonyl)pyrrolidin-1-ium chloride (5.30 g, 29.2 mmol) was suspended. The mixture was cooled down to 0°C. Firstly N,N-Diisopropylethylamine (DIPEA, 12.60 mL, 72.34 mmol, 2.48 equiv.) was added drop wise and then followed by benzyl bromide (3.80 mL, 31.92 mmol, 1.09 equiv.). The reaction mixture was refluxed for 6 h and quenched with saturated aqueous ammonium chloride solution (30 mL). The aqueous solution was extracted with ethyl acetate (3 × 150 mL). The combined organic layers were washed with brine (150 mL) and dried over sodium sulfate. Filtering of the drying agent and solvent removal under reduced pressure gave the product (6.74 g, 28.7 mmol, 98% yield) as yellowish oil. 1H-NMR (CDCl3, 300 MHz): δ = 1.75 (1H, br-s), 2.02–2,13 (1H, m), 2.18–2.33 (1H, m), 2.48 (1H, dd, J = 10.2, 3.7 Hz), 3.33 (1H, dd, J = 10.2, 5.6 Hz), 3.58–3.70 (2H, m), 3.66 (3H, s), 3.90 (1H, d, 12.9 Hz), 4.45 (1H, br-s), 7.20–7.38 (5H, m) ppm. 13C-NMR (CDCl3, 75 MHz): δ = 39.6, 51.9, 58.2, 61.3, 63.7, 70.4, 127.36, 128.4, 129.2, 138.2, 174.1 ppm. Analytic data agree with literature [17].
(3R,5S)-1-benzyl-5-(bis(3,5-bis(trifluoromethyl)phenyl)(hydroxy) methyl)pyrrolidin-3-ol
Dry THF (20 mL) was added to a round bottom flask under argon atmosphere and magnesium turnings (1.70 g, 70.00 mmol, 5.00 equiv.) were suspended. A solution of 1-bromo-3,5-bis(trifluoromethyl) benzene (7.97 mL, 46.20 mmol, 3.30 equiv.) in dry THF (180 mL) was added drop wise at 0°C. The reaction mixture was refluxed for 2 h, transferred into a dropping funnel and added drop wise to a solution of methyl (2S,4R)-1-benzyl-4-hydroxypyrrolidine-2-carboxylate (3.29 g, 14.00 mmol) in dry THF (60 mL) at 0°C over 30 min. The mixture was stirred 4 h at RT, before it was quenched by the addition of saturated aqueous ammonium chloride solution (100 mL) and subsequently neutralized with aqueous 10% HCl solution. The aqueous layer was extracted with ethyl acetate (3 × 100 mL). The combined organic layers were washed with brine (100 mL) and dried over sodium sulfate. Filtering of the drying agent and solvent removal under reduced pressure gave the crude product, which was purified via flash column chromatography (eluent: EtOAc/PE 1:6; Rf = 0.22). The final product (5.29 g, 8.37 mmol, 60% yield) was obtained as yellowish oil. 1H-NMR (CDCl3, 400 MHz): δ = 1.67–1.75 (1H, m), 1.76–1.85 (1H, m), 2.68–2.76 (1H, m), 3.12–3.26 (2H, m), 3.52 (1H, d, J = 13.0 Hz), 3.49–3.55 (1H, m), 4.53 (1H, dd, J = 8.7, 7.5 Hz), 5.55 (1H, br-s), 6.97–7.00 (2H, m), 7.19–7.29 (3H, m), 7.75 (2H, d, J = 11.6 Hz) 8.06 (2H, s), 8.24 (2H, s) ppm. 13C-NMR (CDCl3, 101 MHz): δ = 38.9, 61.8, 62.7, 70.8, 71.1, 76.2, 121.5, 121.7, 121.9, 124.6, 125.7, 126.1, 127.7, 128.3, 128.7, 132.2, 138.5, 147.2, 149.4 ppm. Analytic data agree with literature results [18].
(3R,5S)-5-(bis(3,5-bis(trifluoromethyl)phenyl)(hydroxy)methyl) pyrrolidin-3-ol
To a suspension of acetic acid (106 µL, 1.86 mmol, 1.20 equiv.) and palladium on carbon (10 wt% Pd/C, 100 mg), and dry methanol (3.0 mL) (3R,5S)-1-benzyl-5-(bis(3,5-bis(trifluoromethyl)phenyl)(hydroxy) methyl)pyrrolidin-3-ol (1.00 g, 1.55 mmol) was added. The reaction was stirred in a hydrogen atmosphere (18 bar) for 18 h at RT. Filtering over Celite and removal of the solvent under reduced pressure gave an oil which was solubilized in ethyl acetate (15 mL). Saturated aqueous NaHCO3 solution (15 mL) was added and neutralized to pH 7. The aqueous layer was extracted with ethyl acetate (3 × 15 mL). The combined organic layers were washed with brine (15 mL) and dried over sodium sulfate. Filtering of the drying agent and solvent removal under reduced pressure gave the product (748 mg, 1.38 mmol, 89% yield) as yellowish solid. 1H-NMR (CDCl3, 300 MHz): δ = 1.40–1.52 (1H, m), 1.67–1.77 (1H, m), 3.05-3.22 (2H, m), 4.41–4.47 (1H, m), 4.72 (1H, dd, J = 10.1, 6.3 Hz), 7.76 (1H, s), 7.79 (1H, s), 7.94 (1H, s), 8.06 (1H, s) ppm. 13C-NMR (CDCl3, 75 MHz): δ = 36.5, 55.6, 63.3, 72.6, 76.5, 125.7, 126.3, 132.2, 146.1, 149.2 ppm. Analytic data agree with previous literature [19].
DES screening
4-Nitrobenzaldehyde (1.00 mmol) was added with (S)-α,α-Bis[3,5-bis(trifluoromethyl)phenyl]-2-pyrrolidinemethanol (cat 1, 0.20 mmol), vinyl acetate (276 μL, 3.00 mmol, 3.00 equiv.), iso-propanol (230 μL, 3.00 mmol, 3.00 equiv.) and iCALB (3 mg) to 1 mL of 1:2 ChCl/glycerol DES in a G15 vial, equipped with a 15 mm × 4 mm magnetic stirring bar. The vessel was closed with a cap and gasket. After stirring (300 rpm) for 24 h at RT, methanol (2.00 mL) was added and the reaction mixture was transferred into a round bottom flask and cooled down to 0°C. After slow addition of sodium borohydride (226 mg, 6.00 mmol over 30 min), the reaction was allowed to stir another hour at 0°C. Quenching was conducted by the addition of aqueous saturated ammonium chloride solution (15 mL) followed by the addition of ethyl acetate (15 mL). The phases were separated and the aqueous phase was extracted with ethyl acetate (2 × 15 mL). After washing of the combined organic layers with brine (15 mL), drying was proceed over sodium sulfate. Filtration of drying agent and solvent removal under reduced pressure led to the crude product which was purified via flash chromatography (eluent: 4:1 EtOAc/PE; Rf = 0.33) to give a colorless oil. 1H-NMR (CDCl3, 300 MHz): δ = 1.97 (q, J = 5.8 Hz, 2H), 2.18 (br-s, 1H), 3.50 (d, J = 2.9 Hz, 1H), 3.90–3.95 (m, 2H), 5.10 (t, J = 6.00 Hz, 1H), 7.55 (d, J = 8.8 Hz, 2H), 8.21 (d, J = 8.8 Hz, 2H) ppm. 13C-NMR (CDCl3, 75 MHz): δ = 40.6, 61.7, 73.7, 124.1, 126.8, 147.6, 152.1 ppm.
Recycling system
4-Nitrobenzaldehyde (1.00 mmol) was added with organocatalyst (0.20 mmol), vinyl acetate (276 μL, 3.00 mmol, 3.00 equiv.), iso-propanol (230 μL) and iCALB (3.00 mg) to 1 mL of 1:2 ChCl/glycerol DES in a G15 vial, equipped with a 15 mm × 4 mm stirring bar. The vessel was closed with a cap and gasket. After stirring for the 48 h at 300 rpm, the DES phase was extracted with the 2-MTHF (3 × 2 mL). The combined organic layers were separated and methanol was added, while the mixture was cooled down to 0°C. After slow addition of sodium borohydride (6.00 mmol over 30 min), the reaction was allowed to stir another hour at 0°C. Quenching was conducted by the addition of aqueous saturated ammonium chloride solution (15 mL) followed by the addition of ethyl acetate (15 mL). The phases were separated and the aqueous phase was extracted with ethyl acetate (2 × 15 mL). After washing of the combined organic layers with brine (15 mL), drying was proceed over sodium sulfate. Removal of drying agent and solvent under reduced pressure led to the crude product which was purified via flash chromatography (eluent: 4:1 EtOAc/PE; Rf = 0.33) to give a colorless oil. The extracted DES was directly used in the next cycle.