Supporting Information
General and Practical Conversion of Aldehydes to Homologated Carboxylic Acids
Lauren R. Cafiero and Timothy S. Snowden*
Department of Chemistry, The University of Alabama, Tuscaloosa, Alabama, 35487, USA
[email protected] General Experimental Section Preparation of Aliphatic, Alkenyl, and Aromatic Trichloromethyl Carbinols Preparation of One-Carbon Homologated Carboxylic Acids References 1 H/13C Spectra of Reported Major Products
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General Information. The 1H and 13C NMR spectra were recorded at 500 MHz and 125 MHz respectively. All melting points are uncorrected. High-resolution mass spectra for the trichloromethyl carbinols were recorded on an AutoSpec-UltimaTM NT mass spectrometer using electron ionization (EI) at 70 eV. High resolution mass spectra for the carboxylic acids were recorded on a Micromass Q-TOF Ultima instrument with an electrospray probe and a Zspray source. Optical rotation was determined on a Perkin-Elmer 241 digital polarimeter; concentration c is reported as g/100 mL. All reagents were used directly as obtained from commercial sources unless otherwise noted. All melting points are uncorrected. TLC visualization was achieved by UV light (254nm) and KMnO4 staining. Synthesis of Aliphatic, Alkenyl, and Aromatic Trichloromethyl Carbinols. Trichloromethyl carbinols in entries 2a-e and 2l-n were prepared by the method of Corey and Link1 from the respective aldehydes. Yields and reaction times are unoptimized. The following serves as a general procedure: To a solution of aldehyde (1 mmol) in 1.35mL of anhydrous DMF was added trichloroacetic acid (1.5 mmol) then sodium trichloroacetate (1.5 mmol) with stirring at room temperature. Initially rapid evolution of CO2 was observed. After 6-8 h, the mixture was monitored by TLC. If starting material remained, one equivalent of sodium trichloroacetate and trichloroacetic acid was added. After an additional 4-8 h, the mixture was diluted with 5 mL of diethyl ether and washed with saturated aqueous sodium bicarbonate. Precipitated solids were filtered and washed three times with diethyl ether. The filtrate was washed two more times with sodium bicarbonate solution and once with brine. The organic phase was dried with sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was eluted through a plug of silica gel with indicated ratios of hexane/ethyl acetate to afford the corresponding trichloromethyl carbinol. Trichloromethyl carbinols in entries 2f-k were prepared by the method of Wyvratt2 from the respective aldehydes, without modification. 1,1,1-Trichlorononan-2-ol (2a) The crude material was purified by flash chromatography through a plug of silica gel, using 95:5 hexane/EtOAc as the eluant. The indicated compound was obtained as a yellow oil in 93% yield. IR (film): 3578 (b), 2959 (s), 2929 (s), 1265 (s), 748 (s) cm-1; 1 H NMR (CDCl3, 500 MHz) ppm: 3.99 (d, 1H, J = 8.9 Hz), 2.77 (s, 1H), 2.04 (m, 1H), 1.63 (ddd, 2H, J = 4.7 Hz, J = 12.0 Hz, J = 14.0 Hz), 1.33 (m, 9H), 0.89 (t, 3H, J = 6.9 Hz); 13C NMR (CDCl3, 125 MHz) ppm: 104.4, 83.0, 31.8, 31.5, 29.2, 29.1, 26.1, 22.6, 14.1; HRMS m/z calcd. for C8H17O [M-CCl3]+, 129.1279; found 129.1280. 5-(tert-Butyldimethylsilyloxy)-1,1,1-trichloropentan-2-ol (2b) The crude material was purified by flash chromatography through a plug of silica gel, using 95:5 hexane/EtOAc as the eluant. The indicated compound was obtained as a colorless oil in 93% yield. IR (film): 3580 (b), 3053 (m), 2956 (m), 1265 (s), 739 (s) cm-
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; 1H NMR (CDCl3, 500 MHz) ppm: 4.01 (ddd, 1H, J = 1.8 Hz, J = 5.6 Hz, J = 9.4 Hz), 3.66 (m, 2H), 2.87 (m, 1H), 2.08 (m, 1H), 1.64 (m, 5H), 0.90 (s, 9H), 0.06 (s, 6H); 13 C NMR (CDCl3, 125 MHz) ppm: 104.3, 83.1, 63.0, 32.2, 31.2, 26.0, 22.8, 18.4, -5.3; HRMS m/z calcd. for C8H16Cl3SiO2 [M-C4H9]+, 276.9985; found 276.9977. 1,1,1-Trichloro-4-phenylbutan-2-ol (2c) The crude material was purified by flash chromatography through a plug of silica gel, using 9:1 hexane/EtOAc as the eluant. The indicated compound was obtained as a colorless oil in 89% yield. IR (film): 3439 (b), 3028 (m), 2936 (m), 1265 (m), 746 (s) cm1 1 ; H NMR (CDCl3, 500 MHz) ppm: 7.28 (td, 5H, J = 7.4Hz, J = 14.4Hz), 3.99 (ddd, 1H, J = 1.9Hz, J = 5.4Hz, J = 10.0Hz), 3.01 (ddd, 1H, J = 4.8 Hz, J = 9.1 Hz, J = 13.9 Hz), 2.77 (m, 2H), 2.39 (m, 1H), 2.00 (dddd, 1H, J = 4.8 Hz, J = 8.8 Hz, J = 10.0 Hz, J = 13.8 Hz); 13C NMR (CDCl3, 125 MHz) ppm: 140.7, 128.6, 128.5, 126.3, 104.1, 82.0, 32.9, 32.0; HRMS m/z calcd. for C10H11Cl3O, 251.9875; found 251.9885. 2,2,2-Trichloro-1-cyclohexylethanol (2d) The crude material was purified by flash chromatography through a plug of silica gel, using 95:5 hexane/EtOAc as the eluant. The indicated compound was obtained as a colorless oil in 87% yield. IR (film): 3577 (b), 3053 (m), 2986 (m), 1266 (s), 747 (s) cm1 1 ; H NMR (CDCl3, 500 MHz) ppm: 3.83 (dd, 1H, J = 6.50, 2.51 Hz), 2.73 (m, 1H), 2.04 (m, 2H), 1.70 (m, 4H), 1.32 (m, 4H); 13C NMR (CDCl3, 125 MHz) ppm: 104.2, 86.4, 39.9, 32.9, 26.7, 26.5, 26.0, 25.9; HRMS m/z was calcd. for C7H13O [M-CCl3]+, 113.0966; found 113.0965. 1,1,1-Trichloro-3-phenylbutan-2-ol (2e) The crude material was purified by flash chromatography through a plug of silica gel, using 9:1 hexane/EtOAc as the eluant. The indicated compound was obtained as a colorless oil in 90% yield. IR (film): 3577 (b), 3054 (s), 2986 (s), 1265 (s), 748 (s) cm-1; 1 H NMR (CDCl3, 500 MHz) ppm: 7.33 (m, 1H), 7.25 (dd, 1H, J = 2.2 Hz, J = 4.8 Hz), 4.29 (dd, 1H, J = 2.6 Hz, J = 5.8 Hz), 4.21 (dd, 1H, J = 3.3 Hz, J = 8.3 Hz), 3.62 (dd, 1H, J = 3.3 Hz, J = 7.3 Hz), 3.54 (dd, 1H, J = 2.6 Hz, J = 7.1 Hz), 2.94 (d, 1H, J = 5.8 Hz), 2.56 (d, 1H, J = 8.3 Hz), 1.52 (d, 1H, J = 7.3 Hz), 1.48 (d, 1H, J = 7.1 Hz); 13C NMR (CDCl3, 125 MHz) ppm: 145.7, 140.3, 129.5, 128.7, 128.4, 127.4, 126.8, 104.0, 85.8, 41.7, 41.1, 21.7, 15.9; HRMS m/z calcd. for C10H11Cl3O, 251.9875; found 251.9872. 1,1,1-Trichloro-1-phenylethanol (2f) The crude material was purified by flash chromatography through a plug of silica gel, using 9:1 hexane/EtOAc as the eluant. The indicated compound was obtained as a colorless oil in 96% yield. IR (film): 3446 (b), 3055 (m), 2984 (w), 2901 (w), 1265 (s), 697 (s) cm-1; 1H NMR (CDCl3, 500 MHz) ppm: 7.45 (m, 5H), 5.22 (d, 1H, J = 4.0 Hz), 3.27 (d, 1H, J = 4.0 Hz); 13C NMR (CDCl3, 125 MHz) ppm: 134.8, 129.5, 129.2, 127.8, 103.1, 84.5; HRMS m/z calcd. for C8H7Cl3O, 223.9562; found 223.9563. 2,2,2-Trichloro-1-(4-methoxyphenyl)ethanol (2g)
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The crude material was purified by flash chromatography through a plug of silica gel, using 9:1 hexane/EtOAc as the eluant. The indicated compound was obtained as a white solid in 97% yield; m.p. 44-45°C. IR (solid): 3511 (b), 3019 (w), 2840 (w), 1253 (s), 1175 (s), 740 (s) cm-1; 1H NMR (CDCl3, 500 MHz) ppm: 7.52 (d, 2H, J = 8.6 Hz), 6.90 (d, 2H, J = 8.9 Hz), 5.16 (d, 1H, J = 3.9 Hz), 3.81 (s, 3H), 3.26 (d, 1H, J = 4.0 Hz); 13C NMR (CDCl3, 125 MHz) ppm: 160.4, 130.4, 126.9, 113.2, 103.5, 84.2, 55.3; HRMS m/z was calcd. for C9H9OCl3, 253.9668; found 253.9665. 2,2,2-Trichloro-1-(4-nitrophenyl)-ethanol (2h) The crude material was purified by flash chromatography through a plug of silica gel, using 8:2 hexane/EtOAc as the eluant. The indicated compound was obtained as a white solid in 95% yield; m.p. 107-108 °C. IR (film): 3568 (b), 3054 (s), 2986 (m), 1525 (s), 1350 (s), 1265 (s), 747 (s) cm-1; 1H NMR (CDCl3, 500 MHz) ppm: 8.25 (d, 2H, J = 8.9 Hz), 7.83 (d, 2H, J = 8.7 Hz), 5.34 (d, 1H, J = 3.6 Hz), 3.44 (d, 1H, J = 3.6 Hz); 13C NMR (CDCl3, 125 MHz) ppm: 148.5, 141.3, 130.4, 122.8, 102.0, 83.5; HRMS m/z calcd. for C8H6Cl3NO, 268.9413; found 268.9406. 2,2,2-Trichloro-1-napthalen-2-yl-ethanol (2i) The crude material was purified by flash chromatography through a plug of silica gel, using 9:1 hexane/EtOAc as the eluant. The indicated compound was obtained as a white solid in 93% yield; m.p. 93-94 °C. IR (solid): 3486 (b), 3049 (m), 1240 (m), 745 (s) cm-1; 1 H NMR (CDCl3, 500 MHz) ppm: 8.09 (s, 1H), 7.88 (m, 3H), 7.74 (dd, 1H, J = 1.7 Hz, J = 8.6 Hz), 7.53 (m, 2H), 5.40 (d, 1H, J = 3.9 Hz), 3.37 (d, 1H, J = 4.0 Hz); 13C NMR (CDCl3, 125 MHz) ppm: 133.7, 132.5, 132.2, 129.2, 128.4, 127.7, 127.4, 126.8, 126.3, 126.1, 103.2, 84.7; HRMS m/z was calcd. for C12H9OCl3, 273.9712; found 273.9713 2,2,2-Trichloro-1-furan-2-yl-ethanol (2j) The crude material was purified by flash chromatography through a plug of silica gel, using 95:5 hexane/EtOAc as the eluant. The indicated compound was obtained as a white solid in 95% yield; m.p. 34-35 °C. IR (film): 3431 (b), 2922 (w), 1263 (w), 707 (s) cm-1; 1H NMR (CDCl3, 500 MHz) ppm: 7.47 (dd, 1H, J = 0.8 Hz, J = 1.8 Hz), 6.61 (d, 1H, J = 3.4 Hz), 6.44 (dd, 1H, J = 1.8 Hz, J = 3.3 Hz), 5.24 (s, 1H), 3.33 (s, 1H); 13C NMR (CDCl3, 125 MHz) ppm: 148.4, 143.1, 110.9, 110.7, 101.2, 79.3; HRMS m/z was calcd. for C6H5Cl3O2, 213.9355; found 213.9352. 2,2,2-Trichloro-1-thiophen-2-ylethanol (2k) The crude material was purified by flash chromatography through a plug of silica gel, using 95:5 hexane/EtOAc as the eluant. The indicated compound was obtained as a yellow oil in 93% yield. IR (film): 3422 (b), 3060 (w), 2912 (w), 1265 (m), 742 (s) cm-1; 1 H NMR (CDCl3, 500 MHz) ppm: 7.40 (dd, 1H, J = 5.09, 1.20 Hz), 7.31 (ddd, 1H, J = 3.59, 1.05, 0.59 Hz), 7.05 (dd, 1H, J = 5.08, 3.62 Hz), 5.47 (d, 1H, J = 4.76 Hz), 3.51 (d, 1H, J = 4.83 Hz); 13C NMR (CDCl3, 125 MHz) ppm: 137.3, 129.1, 127.1, 126.2, 102.4, 81.4; HRMS m/z was calcd. for C6H5Cl3SO, 229.9127; found 229.9122. 1,1,1-Trichloro-4-methylpent-3-en-2-ol (2l)
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The crude material was purified by flash chromatography through a plug of silica gel, using 95:5 hexane/EtOAc as eluant. The indicated compound was obtained as a white solid in 87% yield; m.p. 85-86 oC. 1H NMR (CDCl3, 360 MHz) ppm: 5.35 (d, 1H, J = 1.08 Hz), 4.79 (t, 1H), 2.59 (d, 1H, J = 5.76 Hz), 1.83 (s, 6H); 13C NMR (CDCl3, 90 MHz) ppm: 142.5, 119.5, 103.6, 79.5, 26.1, 19.2; HRMS m/z calcd. for C5H9Cl3O, 201.9719; found 85.0652 which corresponds to [M-CCl3]+. 1,1,1-Trichlorohex-3-en-2-ol (2m) The crude material was purified by flash chromatography through a plug of silica, using 95:5 hexane/EtOAc as eluant. The indicated compound was obtained as a yellow oil in 90% yield. 1H NMR (CDCl3, 500 MHz) ppm: 6.07 (m, 1H), 5.65 (ddd, 1H, J = 1.6 Hz, J = 6.5 Hz, J = 15.4 Hz), 4.53 (t, 1H, J = 6.1 Hz), 2.73 (t, 1H, J = 6.1 Hz), 2.16 (dd, 2H, J = 7.1 Hz, J = 13.9 Hz), 1.05 (dt, 3H, J = 1.3 Hz, J = 7.5 Hz); 13C NMR (CDCl3, 90 MHz) ppm: 140.9, 122.8, 103.1, 83.5, 25.5, 12.9; HRMS m/z calcd. for C5H9O, 85.0653 [M-CCl3]+; found 85.0650. 1,1,1-Trichloro-3-methylhex-3-en-2-ol (2n) The crude material was purified by flash chromatography through a plug of silica, using 95:5 hexane/EtOAc as eluant. The indicated compound was obtained as a colorless oil in 86% yield. 1H NMR (CDCl3, 500 MHz) ppm: 5.74 (t, 1H, J = 7.0 Hz), 4.55 (d, 1H, J = 2.7 Hz), 2.89 (d, 1H, J = 4.1 Hz), 2.12 ( m, 2H, J = 7.6 Hz), 1.82 (s, 3H), 1.01 (t, 3H, J = 7.6 Hz); 13C NMR (CDCl3, 90 MHz) ppm: 137.7, 129.1, 87.7, 21.2, 13.4, 13.0; HRMS m/z calcd. for C7H11Cl3O, 215.9875; found 214.9803 which corresponds to [M-1]+.
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General Procedure for the Preparation of One-Carbon Homologated Carboxylic Acids from Trichloromethyl Carbinols Method A: To a solution of trichloromethyl carbinol (1 mmol) in tert-BuOH (10mL) was added freshly powdered NaOH (3.3 mmol) at 30 °C. The mixture was stirred rapidly for 10 min, then NaBH4 (1.5 mmol) was added and the heterogeneous mixture was warmed to 35 °C or 55 °C with vigorous stirring. The reaction was monitored by TLC after 12 h (stain plate with KMnO4 if necessary), and an additional 0.5 mmol of NaBH4 was added if starting material remained. Once the reaction was completed, (12-48 h in total, depending on temperature and substrate), the tert-BuOH was removed by rotary evaporation and the amorphous solids were dissolved in 5 mL diethyl ether and 5 mL H2O. The resulting solution was cooled to 0 °C and adjusted to pH 1 with 1 N HCl (or to pH 4 with KH2PO4 for entry 2j). The product was extracted with diethyl ether (5 × 10 mL), dried with anhydrous magnesium sulfate, and then concentrated by rotary evaporation. The crude material was purified by flash chromatography through a small plug of silica using specified eluants, affording the carboxylic acid. Method B: Diphenyl diselenide (1.05 mmol, 328 mg) was added to dry round-bottom flask equipped with stir bar under a blanket of argon. Deoxygenated absolute ethanol (4 mL) (purged for 30 minutes with argon) was then added, followed by the rapid addition of NaBH4 (2.1 mmol, 80 mg) under argon. After the addition of NaBH4, the yellow solution turned clear and colorless, and then the reaction stirred at room temperature for 30 minutes. Neat alkenyl or aryl trichloromethyl carbinol (1 mmol) was quickly added, followed by the addition of NaOH (6 mmols, 240 mg) under argon. The reaction was heated to 40°C and then allowed to react at this temperature for 24-36 hours while monitoring by TLC for consumption of starting material. After completion, ethanol was removed by rotary evaporation and the amorphous solids were dissolved in 5 mL ethyl acetate and 5mL H2O. The resulting solution was cooled to 0 °C and adjusted to pH 1 with 1 N HCl. The product was extracted with ethyl acetate (5 × 10 mL), dried with anhydrous magnesium sulfate, and then concentrated by rotary evaporation. The crude material was purified by flash chromatography through a small plug of silica using specified eluants, affording the carboxylic acid. Nonoic acid (5a) After preparing using Method A, the crude material was purified by flash chromatography through a plug of silica gel, using 9:1 hexane/EtOAc as the eluant. The indicated compound was obtained as a yellow oil in 94% yield. 1H NMR (CDCl3, 500 MHz) ppm: 9.98 (s, 1H), 2.34 (t, 2H, J = 7.52, 7.52 Hz), 1.62 (td, 2H, J = 14.87, 7.44, 7.44 Hz), 1.28 (m, 10H), 0.87 (t, 3H, J = 6.81, 6.81 Hz); 13C NMR (CDCl3, 125 MHz) ppm: 180.2, 34.1, 31.8, 29.2, 29.1, 29.1, 24.7, 22.6, 14.1; HRMS m/z was calcd. for C9H18O2, 158.1312; found 158.1307. 6-(tert-Butyldimethylsilyloxy)hexanoic acid (5b)
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After preparing using Method A, the crude material was purified by flash chromatography through a plug of silica gel, using 9:1 hexane/EtOAc as the eluant. The indicated compound was obtained as a colorless oil in 89% yield. 1H NMR (CDCl3, 500 MHz) ppm: 3.61 (t, 2H, J = 6.62, 6.31 Hz), 2.36 (t, 2H, J = 7.57, 7.57 Hz), 1.66 (m, 2H), 1.53 (m, 2H), 1.39 (m, 2H), 0.89 (s, 9H), 0.04 (s, 6H); 13C NMR (CDCl3, 125 MHz) ppm: 178.8, 62.9, 33.8, 32.4, 26.0, 24.5, 18.3, -5.3; HRMS m/z was calcd. for C8H17SiO3 [M-C4H9]+, 189.0950; found 189.0949. 4-Phenylbutanoic acid (5c) After preparing using Method A, the crude material was purified by flash chromatography through a plug of silica gel, using 85:15 hexane/EtOAc as the eluant. The indicated compound was obtained as colorless crystals in 93% yield; m.p. 50-51 °C. 1 H NMR (CDCl3, 500 MHz) ppm: 10.70 (s, 1H), 7.29 (t, 2H, J = 7.44, 7.44 Hz), 7.20 (t, 3H, J = 8.37, 8.37 Hz), 2.68 (t, 2H, J = 7.60, 7.60 Hz), 2.39 (t, 2H, J = 7.44, 7.44 Hz), 1.98 (m, 2H); 13C NMR (CDCl3, 125 MHz) ppm: 179.5, 141.2, 128.5, 128.4, 126.0, 35.0, 33.3, 26.2; HRMS m/z was calcd. for C10H12O2, 164.0842; found 164.0837. Cyclohexylacetic acid (5d) After preparing using Method A, the crude material was purified by flash chromatography through a plug of silica gel, using 9:1 hexane/EtOAc as the eluant. The indicated compound was obtained as a colorless oil in 85% yield. 1H NMR (CDCl3, 500 MHz) ppm: 11.06 (s, 1H), 2.23 (d, 2H, J = 6.21Hz), 1.77 (m, 6H), 1.26 (m, 4H), 0.98 (m, 1H); 13C NMR (CDCl3, 125 MHz) ppm: 178.7, 41.7, 34.7, 33.0, 26.1, 26.0; HRMS m/z was calcd. for C8H14O2, 142.0990; found 142.0994. 3-Phenylbutyric acid (5e) After preparing using Method A, the crude material was purified by flash chromatography through a plug of silica gel, using 85:15 hexane/EtOAc as the eluant. The indicated compound was obtained as a colorless oil in 85% yield. 1H NMR (CDCl3, 500 MHz) ppm: 7.31 (m, 2H), 7.23 (dd, 3H, J = 7.78, 3.25 Hz), 3.28 (dd, 2H, J = 14.73, 7.12 Hz), 2.64 (ddd, 1H, J = 23.74, 15.52, 7.51 Hz), 1.33 (d, 3H, J = 6.98 Hz); 13C NMR (CDCl3, 125 MHz) ppm: 177.9, 145.5, 128.6, 126.7, 42.5, 36.2, 21.8; HRMS m/z was calcd. for C10H12O2, 164.0830; found 164.0837. Phenylacetic acid (5f) After preparing using Method A, the crude material was purified by flash chromatography through a plug of silica gel, using hexane to remove diphenyldiselenide then 85:15 hexane/EtOAc as the eluant. The indicated compound was obtained as colorless crystals in 92% yield; m.p. 77-78 °C. 1H NMR (CDCl3, 500 MHz) ppm: 11.78 (s, 1H), 7.32 (m, 5H), 3.66 (s, 2H); 13C NMR (CDCl3, 125 MHz) ppm: 178.1, 133.2, 129.3, 128.6, 127.3, 41.1; HRMS m/z was calcd. for C8H8O2, 136.0527; found 136.0524. (4-Methoxyphenyl)acetic acid (5g) After preparing using Method B, the crude material was purified by flash chromatography through a plug of silica gel, using hexane to remove diphenyldiselenide
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then 8:2 hexane/EtOAc as the eluant. The indicated compound was obtained as a white solid in 92% yield; m.p. 85-86 °C. 1H NMR (CDCl3, 360 MHz) ppm: 7.20 (d, 2H, J = 8.7 Hz), 6.87 (d, 2H, J = 8.7 Hz), 3.59 (s, 3H), 3.80 (s, 2H); 13C NMR (CDCl3, 125 MHz) ppm: 177.3, 158.9, 130.4, 125.3, 114.1, 55.3, 40.0; HRMS m/z calcd. for C9H10O3, 166.0630; found 166.0634. 4-Nitrophenyl acetic acid (5h) After preparing using Method B, the crude material was purified by flash chromatography through a plug of silica gel, using hexane to remove diphenyldiselenide then 1:1 hexane/EtOAc with 1% AcOH as the eluant. The indicated compound was obtained as a white solid in 85% yield; m.p. 154-155 °C. 1H NMR (CD3COCD3, 500 MHz) ppm: 8.19 (d, 2H, J = 8.6 Hz) ppm 7.58 (d, 2H, J = 8.5 Hz) ppm 3.77 (s, 2H); 13C NMR (CD3COCD3, 125 MHz) ppm: 171.672, 148.261, 143.537, 131.766, 124.456, 41.351; HRMS m/z was calcd. for C8H7NO4, 181.0377; found 181.0375. Naphthalen-2-ylacetic acid (5i) After preparing using Method B, the crude material was purified by flash chromatography through a plug of silica gel, using hexane to remove diphenyldiselenide then 8:2 hexane/EtOAc as the eluant. The indicated compound was obtained as a white solid in 94% yield; m.p. 142-143 °C. 1H NMR (CDCl3, 500 MHz) ppm: 11.00 (s, 1H), 7.81 (t, 3H, J = 9.1 Hz), 7.74 (s, 1H), 7.47 (m, 2H), 7.41 (dd, 1H, J = 1.8 Hz, J = 8.4 Hz), 3.82 (s, 2H); 13C NMR (CDCl3, 125 MHz) ppm: 177.4, 133.4, 132.6, 130.7, 128.3, 128.2, 127.7, 127.7, 127.3, 126.2, 125.9, 41.1; HRMS m/z calcd. for C12H10O2, 186.0681; found 186.0683. 2-(Furan-2-yl)acetic acid (5j) After preparing using Method B, the crude material was purified by flash chromatography through a plug of silica gel, using hexane to remove diphenyldiselenide then 85:15 hexane/EtOAc as the eluant. The indicated compound was obtained as a white solid in 92% yield; m.p. 60-61°C . 1H NMR (CDCl3, 500 MHz) ppm: 10.96 (s, 1H), 7.40 (dd, 1H, J = 1.79, 0.72 Hz), 6.37 (dd, 1H, J = 3.15, 1.90 Hz), 6.28 (dd, 1H, J = 3.21, 0.64 Hz), 3.77 (s, 2H); 13C NMR (CDCl3, 125 MHz) ppm: 173.7, 146.9, 142.3, 110.6, 108.4, 33.5; HRMS m/z was calcd. for C6H6O3, 126.0321; found 126.0317. 2-(Thiophen-2-yl)acetic acid (5k) After preparing using Method B, the crude material was purified by flash chromatography through a plug of silica gel, using hexane to remove diphenyldiselenide then 85:15 hexane/EtOAc as the eluant. The indicated compound was obtained as a gray solid in 94% yield; m.p. 64-65 °C. 1H NMR (CDCl3, 500 MHz) ppm: 11.16 (s, 1H), 7.24 (dd, 1H, J = 4.52, 1.87 Hz), 6.98 (dd, 1H, J = 5.47, 2.55 Hz), 3.89 (s, 1H); 13C NMR (CDCl3, 125 MHz) ppm: 176.4, 134.0, 127.3, 126.9, 125.3, 35.0; HRMS m/z was calcd. for C6H6SO2, 142.0092; found 142.0089. 4-Methylpent-3-enoic acid (5l) After preparing using Method B, the crude material was purified by flash chromatography through a plug of silica gel, using hexane to remove diphenyldiselenide
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then 9:1 hexane/EtOAc as the eluant. The indicated product was obtained as a yellow oil in 95% yield. 1H NMR (CDCl3, 360 MHz) ppm: 5.30 (tddd, 1H, J = 1.4 Hz, J = 2.8 Hz, J = 5.7 Hz, J = 8.5 Hz), 3.07 (d, 2H, J = 7.2 Hz), 1.75 (d, 3H, J = 1.1 Hz), 1.64 (s, 3H); 13C NMR (CDCl3, 360 MHz) ppm: 178.7, 136.3, 115.0, 33.5, 25.6, 17.9; HRMS m/z calcd. for C6H10O2, 114.0681; found 114.0681. (E)-Hex-3-enoic acid (5m) After preparing using Method B, the crude material was purified by flash chromatography through a plug of silica gel, using hexane to remove diphenyldiselenide then 9:1 hexane/EtOAc as the eluant. The indicated compound was obtained as a yellow oil in 95% yield. 1H NMR (CDCl3, 360 MHz) ppm: 5.64 (ddd, 1H, J = 6.1 Hz, J = 11.8 Hz, J = 12.3 Hz), 5.51 (ddd, 1H, J = 6.1 Hz, J = 11.8 Hz, J = 12.3 Hz), 3.07 (dd, 2H, J = 1.1 Hz, J = 6.8 Hz), 2.07 (ddd, 2H, J = 3.8 Hz, J = 6.9 Hz, J = 7.4 Hz), 0.98 (d, 3H, J = 7.5 Hz); 13C NMR (CDCl3, 360 MHz) ppm: 178.5, 137.0, 119.8, 37.7, 25.5, 13.4; HRMS m/z calcd. for C6H10O2, 114.0681; found 114.0676. (E)-3-Methylhex-3-enoic acid (5n) After preparing using Method B, the crude material was purified by flash chromatography through a plug of silica gel, using hexane to remove diphenyldiselenide then 9:1 hexane/EtOAc as the eluant. The indicated product was obtained as a yellow oil in 87% yield. 1H NMR (CDCl3, 360 MHz) ppm: 5.31 (dd, 1H, J = 7.0 Hz, J = 8.1 Hz), 3.02 (s, 2H), 2.04 ( p, 2H, J = 7.2 Hz), 1.70 (s, 3H), 0.96 (t, 3H, J = 7.6 Hz); 13C NMR (CDCl3, 360 MHz) ppm: 178.7, 131.9, 127.0, 44.7, 21.3, 16.0, 13.9; HRMS m/z calcd. for C7H12O2, 128.0837; found 128.0838. Preparation of (S)-2-tert-Butoxycarbonylamino-3-phenylpropanaldehyde (20). Protected (S)-amino aldehyde 20 was prepared by the method of Myers and co-workers.3 The indicated crude product was obtained as a white solid in quantitative yield after work-up. Sensitive aldehyde 20 was used in the next step without purification. Preparation of tert-Butyl (2S)-4,4,4-trichloro-3-hydroxy-1-phenylbutan-2-yl carbamate. To a solution of sodium trichloroacetate (245 mg, 1.5 mmol) and trichloroacetic acid (278 mg, 1.5 mmol) in 2 mL of DMF was added 20 (249 mg, 1 mmol) in 1 mL DMF with stirring at 0°C. After 15 min., warm the reaction mixture to room temperature. After 12 h, the mixture was diluted with 5 mL of diethyl ether and washed with saturated aqueous sodium bicarbonate solution. Precipitated solids were filtered and washed three times with diethyl ether. The filtrate was washed two more times with the sodium bicarbonate solution and once with brine. The organic phase was dried with sodium sulfate and the diethyl ether was evaporated under reduced pressure. The crude material was purified by flash chromatography through a plug of silica gel, using 8:2 hexane/EtOAc as eluant. The indicated compound was obtained as a white solid in 91% yield (335 mg, 0.91 mmol); m.p. 147-148°C. IR (film): 3579 (w), 3439 (b), 3054 (m), 2985 (m), 1709 (m), 1265 (s), 1166 (m), 739 (s) cm-1; 1H NMR (CDCl3, 500 MHz) ppm: 7.30 (m, 3H), 7.27 (m, 2H), 5.04 (m, 2H), 4.38 (m, 1H), 4.03 (d, 1H, J = 7.0 Hz), 3.18 (m, 1H), 2.94 (m, 1H), 1.41 (s, 9H); 13C NMR (CDCl3, 90 MHz) ppm: 156.2,
S8
137.3, 129.4, 128.6, 126.8, 102.2, 81.3, 80.2, 52.6, 39.7, 28.3; HRMS m/z calcd. for C15H20Cl3NO3 [M-C4H9]+, 310.9878; found 310.9878. Preparation of (S)-3-tert-Butoxycarbonylamino-4-phenylbutyric acid methyl ester (21) by Method A. To a solution of (2S)-4,4,4-trichloro-3-hydroxy-1-phenylbutan-2-yl carbamate (170 mg, 0.46 mmol) in tert-BuOH (4.6 mL) was added freshly powdered NaOH (61 mg, 1.52 mmol) at 30 °C. The mixture was stirred rapidly for 10 min, then NaBH4 (26 mg, 0.69 mmol) was added and the heterogeneous mixture was warmed to 55 °C with vigorous stirring. The reaction was monitored by TLC after 12 h, and an additional 0.5 mmol of NaBH4 was added to achieve full conversion. Once the reaction was completed (24 h in total) the tert-BuOH was removed by rotary evaporation and the amorphous solids were dissolved in 3 mL of THF. Dimethyl sulfate (0.87 mL, 9.2 mmol) was added and the reaction was stirred at room temperature for 24 h. The THF was removed by rotary evaporation and the amorphous solids were dissolved in 5 mL of ethyl acetate. The resulting solution was cooled to 0°C and 5 mL of a 50% aqueous solution of ammonium hydroxide was added. After 1 hour of stirring at 0°C, the solution was allowed to warm to room temperature. The product was extracted with ethyl acetate (5 × 10 mL), dried with anhydrous magnesium sulfate, and then concentrated by rotary evaporation. The crude material was purified by flash chromatography through a plug of silica gel, using hexane to remove diphenyldiselenide then 97:3 hexane/EtOAc as the eluant. The -amino ester 21 was obtained as a colorless amorphous solid in 70% yield (90 mg, 0.32 mmol). Preparation of (S)-3-tert-Butoxycarbonylamino-4-phenylbutyric acid methyl ester (21) by Method B. Diphenyl diselenide (0.96 mmol, 300 mg) was added to dry roundbottom flask equipped with stir bar under a blanket of argon. Deoxygenated absolute ethanol (3.7 mL, purged for 30 minutes with argon) was then added, followed by the rapid addition of NaBH4 (1.9 mmol, 73 mg) under argon. After the addition of NaBH4, the yellow solution turned clear and colorless, and then the reaction was stirred at room temperature for an additional 30 minutes. Neat (2S)-4,4,4-trichloro-3-hydroxy-1phenylbutan-2-yl carbamate (0.91 mmol, 335 mg) was added, followed by the addition of NaOH (5.46 mmols, 218 mg). The reaction was heated to 40°C and then allowed to react at this temperature for 33 hours while monitoring by TLC for complete conversion. After completion, ethanol was removed by rotary evaporation and the amorphous solids were dissolved in 5 mL of THF. Dimethyl sulfate (18.2 mmol, 1.73 mL) was added and the reaction was stirred at room temperature for 24 hours. The THF was removed by rotary evaporation and the amorphous solids were dissolved in 5 mL of ethyl acetate. The resulting solution was cooled to 0°C and 5 mL of a 50% aqueous solution of ammonium hydroxide was added. After 1 hour of stirring at 0°C, the solution was allowed to warm to room temperature. The product was extracted with ethyl acetate (5 × 10 mL), dried with anhydrous magnesium sulfate, and then concentrated by rotary evaporation. The crude material was purified by flash chromatography through a plug of silica gel, using hexane to remove diphenyldiselenide then 97:3 hexane/EtOAc as the eluant. The -amino ester 21 was obtained as a colorless amorphous solid in 83% yield (243 mg, 0.83 mmol). [ ]24D -19.8 (c 1.11, MeOH)4; IR (film): 3582 (w), 3054 (m), 2983 (m), 1774 (s), 1669 (m), 1111 (s); 1H NMR (CDCl3, 500 MHz) ppm: 7.28 (m, 5H), 5.06 (m, 1H), 4.19 (m, 1H),
S9
3.71 (s, 3H), 2.85 (m, 2H), 2.52 (dd, 2H, J = 5.4 Hz, J = 19.5 Hz), 1.43 (s, 9H); 13C NMR (CDCl3, 360 MHz) ppm: 172.1, 155.1, 137.7, 129.4, 128.5, 126.6, 79.3, 51.6, 48.8, 40.4, 40.3, 37.6, 28.3; HRMS m/z calcd. for C16H23NO4, 293.1636; found 293.1632. Preparation of (S)-4-Phenyl-3-((R)-3,3,3-trifluoro-2-methoxy-2phenylpropionylamino)butyric acid methyl ester. (S)-4-Phenyl-3-((R)-3,3,3-trifluoro-2-methoxy-2-phenylpropionylamino)butyric acid methyl ester was prepared by the method of Mazaleyrat and co-workers and then analyzed by 1H, 13C, and 19F NMR spectroscopy.5 1H NMR (CDCl3, 500 MHz) ppm: 7.39 (m, 8H), 7.206 (m, 3H), 4.52 (m, 1H), 3.62 (s, 3H), 3.27 (d, 3H, J = 1.26 Hz), 2.95 (dd, 2H, J = 7.57 Hz, J = 5.99 Hz), 2.54 (m, 2H); 13C NMR (CDCl3, 500 MHz) ppm: 171.7, 165.8, 137.1, 132.6, 129.4, 129.3, 128.7, 128.5, 127.6, 126.8, 124.9, 54.8, 51.7, 47.8, 39.7, 36.9; 19F NMR (CDCl3, 360 MHz) ppm: -68.9. Preparation of 4-Phenyl-2-deuterobutyric acid (22). To a solution of trichloromethyl carbinol (2c) (252 mg, 1 mmol) in tert-BuOH (10mL) was added freshly powdered NaOH (132 mg, 3.3 mmol) at 30 °C. The mixture was stirred rapidly for 10 min, then NaBD4 (63 mg, 1.5 mmol) was added and the heterogeneous mixture was warmed to 55 °C with vigorous stirring. The reaction was monitored by TLC after 12 h (stain plate with KMnO4 if necessary), and an additional 0.5 mmol of NaBD4 (21mg, 0.5 mmol) was added. Once the reaction was completed, (24 h in total), the tert-BuOH was removed by rotary evaporation and the amorphous solids were dissolved in 5 mL diethyl ether and 5 mL H2O. The resulting solution was cooled to 0 °C and adjusted to pH 1 with 1 N HCl. The product was extracted with diethyl ether (5 × 10 mL), dried with anhydrous magnesium sulfate, and then concentrated by rotary evaporation. The crude material was purified by flash chromatography through a plug of silica gel, using 97:3 hexane/EtOAc as the eluant. The indicated product was obtained as a colorless oil in 87 % yield (144 mg, 0.87 mmol). 1H NMR (CDCl3, 500 MHz) ppm: 11.16 (s, 1H), 7.29 (m, 1H), 7.20 (m, 1H), 2.69 (m, 1H), 2.37 (m, 1H), 1.98 (dd, 1H, J = 7.5 Hz, J = 15.1 Hz); 13C NMR (CDCl3, 360 MHz) ppm: 179.1, 141.2, 128.5, 128.4, 126.1, 77.3, 77.0, 76.7, 35.0, 33.1, 33.0, 32.8, 26.1; HRMS m/z calcd. for C10H11DO2, 165.0900; found 165.0899.
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References 1) Corey, E. J.; Link, J. O.; Shao, Y. Tetrahedron Lett. 1992, 33, 3435. 2) Wyvratt, J. M.; Hazen, G. G.; Weinstock, L. M. J. Org. Chem. 1987, 52, 944. 3) Myers, A. G.; Zhong, B.; Movassaghi, M.; Kung, D. W.; Lanman, B. A.; Kwon, S. Tetrahedron Lett. 2000, 41, 1359. 4) Gordon, E. M.; Godfrey, J. D.; Delaney, N. G.; Asaad, M. M.; Von Langen, D.; Cushman, D. W. J. Med. Chem. 1988, 31, 2199. 5) Mazaleyrat, J. –P.; Gaucher, A.; Dutot, L.; Barbeau, O.; Hamchaoui, W.; Wakselman, M. Tetrahedron: Asymmetry 2005, 16, 857.
S11
OH
CCl3 2a
S12
OH
CCl3 2a
S13
Si
O
CCl3 OH 2b
S14
Si
O
CCl3 OH 2b
S15
OH CCl3 2c
S16
OH CCl3 2c
S17
OH CCl3 2d
S18
OH CCl3 2d
S19
CCl3 OH 2e
S20
CCl3 OH 2e
S21
OH
CCl3 2f
S22
OH
CCl3 2f
S23
OH CCl3 H3CO
2g
S24
OH CCl3 H3CO
2g
S25
OH CCl3 O2N
2h
S26
OH CCl3 O2N
2h
S27
OH CCl3
2i
S28
OH CCl3
2i
S29
OH
O
CCl3 2j
S30
OH
O
CCl3 2j
S31
OH
S
CCl3
2k
S32
OH
S
CCl3
2k
S33
OH CCl3 2l
S34
OH CCl3 2l
S35
OH CCl3 2m
S36
OH CCl3 2m
S37
OH CCl3 2n
S38
OH CCl3 2n
S39
O OH
5a
S40
O OH
5a
S41
O TBSO
OH 5b
S42
O TBSO
OH 5b
S43
OH O 5c
S44
OH O 5c
S45
OH
O 5d
S46
OH
O 5d
S47
O OH 5e
S48
O OH 5e
S49
O OH 5f
S50
O OH 5f
S51
OH
H3CO
O 5g
S52
OH
H3CO
O 5g
S53
O2N
O OH 5h
S54
O2N
O OH 5h
S55
OH
O 5i
S56
OH
O 5i
S57
O
O
OH 5j
S58
O
O
OH 5j
S59
O
S
OH 5k
S60
O
S
OH 5k
S61
OH
5l
O
S62
OH
5l
O
S63
O OH 5m
S64
O OH 5m
S65
O OH 5n
S66
O OH 5n
S67
D
OH O 22
S68
D
OH O 22
S69
O HN
O CCl3 OH
S70
O HN
O CCl3 OH
S71
O HN
O
O
O
21
S72
O HN
O
O
O
21
S73
O O O F3C
HN O
S74
O O O F3C
HN O
S75
O O O F3C
HN O
S76
