Chapter Chapter Experimental 87 Experimental 5.1 General Information 5.1.1 General procedures and methods H and 13 C NMR spectra were recorded on a Bruker ACF300 (300MHz), Bruker DPX300 (300MHz) or AMX500 (500MHz) spectrometer. Chemical shifts are reported in parts per million (ppm). The residual solvent peak was used as an internal reference. Low resolution mass spectra were obtained on a Finnigan/MAT LCQ spectrometer in ESI mode and a Finnigan/MAT 95XL-T mass spectrometer in FAB mode. All high resolution mass spectra were obtained on a Finnigan/MAT 95XL-T spectrometer. Infrared spectra were recorded on a BIO-RAD FTS 165 FTIR spectrometer. Enantiomeric excess values were determined by chiral HPLC analysis on two sets: Jasco HPLC units, including a Jasco DG-980-50 Degasser, a LG-980-02 Ternary Gradient Unit, a PU-980 Intelligient HPLC Pump, UV-975 Intelligient UV/VIS Detectors, and an AS-950 Intelligient Sampler; Dionex Ultimate 3000 HPLC units, including a Ultimate 3000 Pump, Ultimate 3000 variable Detectors. Optical rotations were recorded on Jasco DIP-1000 polarimeter. Melting points were determined on a BÜCHI B-540 melting point apparatus. Analytical thin layer chromatography (TLC) was performed with Merck pre-coated TLC plates, silica gel 60F-254, layer thickness 0.25 mm. Flash chromatography separations were performed on Merck 60 (0.040 - 0.063mm) mesh silica gel. Toluene was distilled from sodium/benzophenone and stored under N2 atmosphere. Dichloromethane was distilled from CaH2 and stored under 88 Chapter N2 atmosphere. Other reagents and solvents were commercial grade and were used as supplied without further purification, unless otherwise stated. 5.1.2 Materials All commercial reagents were purchased from Sigma-Aldrich, Fluka, Alfa Aesar, Merck, TCI, and Acros of the highest purity grade. They were used without further purification unless specified. All solvents used, mainly hexane (Hex) and ethyl acetate (EtOAc), were distilled. Anhydrous DCM was freshly distilled from CaH2. Anhydrous THF was freshly distilled from Na/benzophenone. MeCN and CHCl3 were distilled from CaH2. MeOH was distilled from Mg. 5.2 Preparation and Characterization of Substrates and catalysts 5.2.1 Preparation and characterization of -fluorinated aromatic ketones The -tetralone derivatives 81c and 81g were synthesized according to the modified reported procedure.1 To a 100 mL round bottom flask was added 4-(4-chlorophenyl)-4-oxobutanoic acid 83a (5 mol, 1.1 g), H2O (10 mL), concn. HCl (8 mL) and Zn (40 mol, 2.6 g). After stirring at room temperature for half an hour, the suspension was heated to reflux. The reaction was monitored by TLC. Then, the resulting mixture was extracted by EtOAc for three times. The crude 89 Experimental intermediates 84a was obtained and used directly for next step after removing the solvents. The crude 84a and PPA (3.2 g) were placed in 50 mL round bottom flask. After stirring at 80 oC for 20 min, the mixture was heated to 110 oC for overnight. Then water (15 mL) was added and the solution was exacted by EA for three times. After removed the solvent, the pure product 81c was obtained by flash chromatography (gradient elution with hexane and EtOAc mixtures: 50/1 to 10/1). Yield of 81c was 42%; 81g was prepared by the same procedure as 81c, yield of 81g was 50%. Their spectral properties were in agreement with literature values.1 General procedure: The -fluorinated aromatic ketones 82a-82m were prepared according to the previously reported method.2 To a 50 mL clean round bottom flask was added aromatic cyclic ketone (3.5 mmol, 1.0 equiv.), Selectfluor (1.490 g, 4.2 mmol, 1.2 equiv.) and MeOH (30 mL). The suspension was stirred under reflux condition for 2-12 hours, monitored by TLC. The white insoluble material was filtered off. Then the reaction solvent was removed in vacuo and the crude product was directly loaded onto a silica gel column, followed by gradient elution with hexane/EtOAc mixtures (50/1 ~ 10/1 ratio). After removing the solvents, pure -fluorinated aromatic cyclic ketone was obtained. O F 90 Chapter Following general procedure, 2-fluoro-3,4-dihydronaphthalen-1(2H)-one (82d) 81% yield. Yellow oil; Its spectral properties were in agreement with literature values.2 O Br F 7-Bromo-2-fluoro-3,4-dihydronaphthalen-1(2H)-one (82a) The title compound was prepared according to the general procedure. Yield: 61%; yellow solid. 1H NMR (500 MHz, CDCl3, ppm): δ = 8.2 (s, 1H), 7.63 (d, J = 8.2 Hz, 1H), 7.16 (d, J = 8.2 Hz, 1H), 5.14 (ddd, J = 5.0, 12.0 49.1 Hz,1H), 3.12-3.02 (m, 2H), 2.61-2.54 (m, 1H), 2.40-2.31 (m, 1H) 13 C NMR (75.5 MHz, CDCl3, ppm): δ = 192.0 (d, J = 15.0 Hz), 141.7, 136.9, 132.7, 130.5, 121.2, 90.8 (d, J = 188.7 Hz), 29.8 (d, J = 19.3 Hz), 26.5 (d, J = 11.5 Hz); 19 F NMR (282.4 MHz, CDCl3, ppm): -114.7~-114.9 (m); LRMS (FAB) m/z 243.0 (M + H+). O F TsO 6-Fluoro-5-oxo-5,6,7,8-tetrahydronaphthalen-2-yl-4-methylbenzenesulfonate (82b) The title compound was prepared according to the general procedure. Yield: 71%; white solid. 1H NMR (500 MHz, CDCl3, ppm): δ = 7.97 (d, J = 8.6 Hz, 1H), 7.73 (d, J = 8.3 Hz, 1H), 7.34(d, J = 8.1 Hz, 2H), 6.86-6.84 (m, 1H), 5.11 (ddd, J 91 Experimental = 5.0, 12.0, 48.0 Hz, 1H), 3.10-3.08 (m, 2H), 2.59-2.34 (m, 5H); 13C NMR (75.5 MHz, CDCl3, ppm): δ = 192.0 (d, J =14.8 Hz), 153.5, 145.9, 145.1, 132.0, 130.0, 130.0, 130.0, 128.4, 122.3, 121.0, 90.7 (d, J = 188.3 Hz), 29.8 (d, J = 19.8 Hz), 26.8 (d, J = 16.5 Hz); 19 F NMR (282.4 MHz, CDCl3, ppm): -114.8~-115.0 (m); LRMS (FAB) m/z 335.1 (M + H+). O Cl F 7-Chloro-2-fluoro-3,4-dihydronaphthalen-1(2H)-one (82c) The title compound was prepared according to the general procedure. Yield: 65%; yellow solid. 1H NMR (500 MHz, CDCl3, ppm): δ = 8.0 (s, 1H), 7.47 (dd, J = 1.8, 8.2 Hz, 1H), 7.22 (d, J = 8.2 Hz, 1H), 5.13 (ddd, J = 5.0, 12.0, 47.6 Hz, 1H), 3.14-3.04 (m, 2H), 2.60-2.53 (m, 1H), 2.39-2.30 (m, 1H); 13 C NMR (75.5 MHz, CDCl3, ppm): δ = 192.1 (d, J = 14.8 Hz), 141.2, 134.0, 133.4, 132.4, 130.2, 127.4, 127.4, 90.8 (d, J = 188.7 Hz), 29.8 (d, J = 19.3 Hz), 26.4 (d, J = 11.4 Hz); NMR (282.4 MHz, CDCl3, ppm): -114.7~-114.9 (m); 19 F LRMS (ESI) m/z 197.1 (M - H+). O F 2-Fluoro-5,7-dimethyl-3,4-dihydronaphthalen-1(2H)-one (82e) The title compound was prepared according to the general procedure. Yield: 76%; colorless liquid. 1H NMR (500 MHz, CDCl3, ppm): δ = 7.74 (s, 1H), 7.22 (s, 1H), 92 Chapter 5.14 (ddd, J = 5.0, 13.0 48.5 Hz, 1H), 3.10-3.04 (m, 1H), 2.90-2.83 (m, 1H), 2.62-2.55 (m, 1H), 2.34-2.26 (m, 7H); 13 C NMR (75.5 MHz, CDCl3, ppm): δ = 194.0 (d, J =14.5 Hz), 138.3, 136.6, 136.3, 131.2, 125.6, 91.0 (d, J = 187.7 Hz), 29.3 (d, J = 18.9 Hz), 24.1 (d, J = 17.8 Hz); 19F NMR (282.4 MHz, CDCl3, ppm): -114.9~-115.1 (m); LRMS (FAB) m/z 193.1 (M + H+). O O2 N F 2-Fluoro-7-nitro-3,4-dihydronaphthalen-1(2H)-one (82f) The title compound was prepared according to the general procedure. Yield: 35%; brown solid. 1H NMR (500 MHz, CDCl3, ppm): δ = 8.87 (d, J = 2.4, 1H), 8.35 (dd, J = 2.4, 8.6 Hz, 1H), 7.49(d, J = 8.5, 1H), 5.20 (ddd, J = 5.0, 13.0 48.0 Hz, 1H), 3.12-3.18 (m, 2H), 2.67-2.60 (m, 1H), 2.48-2.40 (m, 1H) 13 C NMR (75.5 MHz, CDCl3, ppm): δ = 191.2 (d, J =15.2 Hz), 149.4, 147.2, 132.1, 130.3, 127.8, 123.0, 123.0, 90.5 (d, J = 189.2 Hz), 29.3 (d, J = 19.7 Hz), 26.9 (d, J = 11.2 Hz) 19 F NMR (282.4 MHz, CDCl3, ppm): -115.1~-115.4 (m); LRMS (ESI) m/z 208.1 (M - H+). O F F 7-Fluoro-2-fluoro-3,4-dihydronaphthalen-1(2H)-one (82g) The title compound was prepared according to the general procedure. Yield: 54%; white solid. 1H NMR (500 MHz, CDCl3, ppm): δ = 7.74 (dd, J = 2.5, 8.8 Hz, 93 Experimental 1H), 7.30-7.24 (m, 2H), 5.14 (ddd, J = 5.0, 13.0 47.6 Hz 1H), 3.17-3.07 (m, 2H), 2.64-2.56 (m, 1H), 2.43-2.33 (m, 1H); 13 C NMR (75.5 MHz, CDCl3, ppm): δ = 192.3 (d, J = 14.0 Hz), 161.7 (d, J = 247.3 Hz), 138.8, 132.9, 130.7, 130.6; 121.8, 121.5, 113.6 (d, J = 22.3 Hz), 90.9 (d, J = 188.5 Hz), 30.0 (d, J = 19.0 Hz), 26.3 (d, J = 16.7 Hz); 19 F NMR (282.4 MHz, CDCl3, ppm): -38.1~-38.2 (m), -114.9~-115.2 (m); LRMS (ESI) m/z 181.1 (M - H+). O F O 3-Fluorochroman-4-one (82h) The title compound was prepared according to the general procedure. After the reaction solvent was removed in vacuo, then crude product was dissolved in MeCN (3 mL), hydrolysis with 10% aqueous HCl (9 mL) for hours. The product was extracted with ethyl acetate, washed by brine and dried with anhydrous Na2SO4. The solvent was evaporated under vacuum. The residue was purified by column chromatography; using 20:1 ethyl acetate-hexanes gave the pure product. Yield: 64%; white solid. 1H NMR (300 MHz, CDCl3, ppm): δ = 7.93 (dd, J =8, Hz, 1H), 7.57-7.51 (m, 1H), 7.26-7.00 (m, 1H), 5.14 (ddd, J = 5, 8, 48 Hz, 1H), 4.69-4.50 (m, 1H). Its spectral properties were in agreement with literature values.2 94 Chapter O F O 3-Fluoro-6-methylchroman-4-one (82i) The title compound was prepared according to the general procedure as 82h. Yield: 58%; white solid. 1H NMR (500 MHz, CDCl3, ppm): δ = 7.71 (d, J = 1.2 Hz, 1H), 7.34 (dd, J = 2.2, 8.5 Hz, 1H), 6.91 (d, J = 8.5, 1H), 5.14 (ddd, J = 4.0, 9.0, 46.9 Hz, 1H), 4.60-4.56 (m, 1H), 4.53-4.50 (m, 1H), 2.32 (s, 3H); 13C NMR (75.5 MHz, CDCl3, ppm): δ = 187.1 (d, J =15.6 Hz), 159.3, 137.8, 131.8, 127.0, 118.9, 117.6, 85.6 (d, J = 187.7 Hz), 68.6 (d, J = 25.9 Hz), 20.3; 19F NMR (282.4 MHz, CDCl3, ppm): -127.9~-128.2 (m); LRMS (FAB) m/z 181.0 (M + H+). O Cl F O 6-Chloro-3-fluorochroman-4-one (82j) The title compound was prepared according to the general procedure as 82h. Yield: 79%; white solid. 1H NMR (500 MHz, CDCl3, ppm): δ = 7.87 (d, J = 2.6 Hz, 1H), 7.47 (dd, J = 2.6, 8.9 Hz, 1H), 6.98 (d, J = 8.9, 1H), 5.14 (ddd, J = 6.0, 9.0, 46.8 Hz, 1H), 4.66-4.53 (m, 2H); 13 C NMR (75.5 MHz, CDCl3, ppm): δ = 185.8 (d, J =16.2 Hz), 159.6, 136.6, 127.9, 126.8, 120.1 119.6, 85.2 (d, J = 188.5 Hz), 68.8 (d, J = 25.8 Hz); 19 F NMR (282.4 MHz, CDCl3, ppm): -127.5~-127.8 (m); LRMS (ESI) m/z 199.1 (M - H+). 95 Experimental O F F O 6-Fluoro-3-fluorochroman-4-one (82k) The title compound was prepared according to the general procedure as 82h. Yield: 65%; white solid. 1H NMR (500 MHz, CDCl3, ppm): δ = 7.55 (dd, J = 3.0, 8.0 Hz, 1H), 7.28-7.24 (m, H), 7.02-6.99 (m, 1H), 5.19 (ddd, J = 4.4, 9.0, 46.7 Hz, 1H), 4.64-4.52 (m, 2H); 13C NMR (75.5 MHz, CDCl3, ppm): δ = 186.1 (d, J =17.3 Hz), 157.6 (d, J = 243.5 Hz), 157.5, 128.7, 124.4 (d, J = 25.1 Hz), 119.7 (d, J = 7.2Hz), 112.4 (d, J = 23.4 Hz), 85.2 (d, J = 187.7 Hz), 69.0 (d, J = 25.6 Hz); 19 F NMR (282.4 MHz, CDCl3, ppm): -44.0~ -44.1 (m); -127.7~-128.0 (m); LRMS (ESI) m/z 183.1 (M - H+). O F 2-Fluoro-6-methyl-2,3-dihydro-1H-inden-1-one (82l) The title compound was prepared according to the general procedure. Yield: 80%; white solid. 1H NMR (300 MHz, CDCl3, ppm): δ = 7.53-7.48 (m, H), 7.24-7.15 (m, 2H), 5.20 (ddd, J = 4.4, 9.0, 46.7 Hz, 1H), 4.64-4.52 (m, 2H), 3.61-3.51 (m, 1H), 3.25-3.10 (m, 1H), 2.60 (s, 3H); 19F NMR (282.4 MHz, CDCl3, ppm): -116.8~ -117.1. 96 Chapter mm); Hexane/2-propanol = 90/10; flow rate 0.1 ml/min; 25 °C; 254 nm; retention time: major isomer (syn-product): 22.2 min; minor isomer (syn-product): 41.1 min; minor isomer (anti-product): 32.1 min, major isomer (anti-product): 36.1 O F NHMs TsO Cl (R)-6-((S)-(4-Chlorophenyl)(methylsulfonamido)methyl)-6-fluoro-5-oxo-5,6,7, 8-tetrahydronaphthalen-2-yl 4-methylbenzenesulfonate (165b) Colorless oil. yield: 92% (syn and anti); dr = 3.4/1, 95% ee, [α]29 D = +32.5 (c 1.6, CHCl3); 1H NMR (300 MHz, CDCl3, ppm): δ = 7.79-7.74 (m, 3H),7.42-7.25 (m, 4H), 7.12-7.03 (m, 2H), 7.02-6.94 (m, 1H), 6.92 (dd, J = 2.3, 8.7 Hz, 1H), 5.96 (d, J = 10.2, 1H), 4.84 (dd, J = 10.2, 21.5 Hz, 1H), 3.20-3.12 (m, 2H), 2.62 (s, 3H), 2.60-2.37 (m, 2+3 H); 13C NMR (75.5 MHz, CDCl3, ppm): δ = 190.8(d, J = 18.1 Hz), 153.9, 145.9, 144.6, 135.0, 133.9, 133.8, 132.1, 130.2, 129.9, 129.5, 129.2, 129.1, 128.3, 122.3, 121.3, 96.1(d, J = 192.2 Hz), 58.8 (d, J = 21.4 Hz), 41.9, 30.7 (d, J = 22.0 Hz), 25.2(d, J = 9.9 Hz), 21.7; 19F NMR (282.4 MHz, CDCl3, ppm): -91.9~-92.0(m); LRMS (ESI) m/z 549.9 (M-H+), HRMS (ESI) m/z 574.0548 (M + Na+), calc. for C25H23Cl1F1N123Na1O6S2 574.0532 O F NHMs TsO Cl 125 Experimental (R)-6-((R)-(4-chlorophenyl)(methylsulfonamido)methyl)-6-fluoro-5-oxo-5,6,7, 8-tetrahydronaphthalen-2-yl 4-methylbenzenesulfonate (165b’) White solid; Mp: 170-172 oC. 6% ee. 1H NMR (500 MHz, CDCl3, ppm): δ = 7.97 (d, J = 8.8, 1H),7.75-7.74 (m, 2H), 7.44-7.35 (m, 6H), 7.11 (s, 1H), 6.84 (dd, J = 1.9, 8.8 Hz, 1H), 5.78-5.77 (m, 1H), 4.84 (dd, J = 7.6, 24.6 Hz, 1H), 3.08-2.98 (m, 2H), 2.53 (s, 3H), 2.47 (s, H), 2.36-2.28 (m, 1H), 2.01-1.94 (m, 1H); 13C NMR (75.5 MHz, CDCl3, ppm): δ = 191.2(d, J = 18.4 Hz), 154.0, 146.0, 143.9, 135.2, 134.1, 132.1, 130.8, 130.0, 129.9, 129.3, 129.2, 128.4, 122.5, 121.5, 95.9(d, J = 193.9 Hz), 58.1 (d, J = 20.0 Hz), 42.1, 30.5 (d, J = 20.7 Hz), 25.5(d, J = 11.6 Hz), 20.7; 19F NMR (282.4 MHz, CDCl3, ppm): -95.1~-95.3(m) The ee was determined by HPLC analysis. CHIRALCEL IA (4.6 mm i.d. x 250 mm); Hexane/2-propanol = 90/10; flow rate 0.1 ml/min; 25 °C; 254 nm; retention time: major isomer (syn-product): 65.0 min; minor isomer (syn-product): 72.6 min; minor isomer (anti-product): 75.6 min, major isomer (anti-product): 81.9 O Cl F NHMs Cl N-((S,R)-7-Chloro-2-fluoro-1-oxo-1,2,3,4-tetrahydronaphthalen-2-yl)(4-chlor ophenyl)methyl)methanesulfonamide (165c) White solid. Mp: 186-187 oC. yield: 90% (syn and anti); dr = 3.0/1, 95% ee, [α]29 D = -9.1 (c 1.5, CHCl3); 1H NMR (500 MHz, CDCl3, ppm): δ = 7.79 (d, J = 1.8, 1H), 126 Chapter 7.53 (d, J = 1.9, 1H), 7.51-7.51 (m, 2H), 7.32-7.24 (m, 2H), 7.12-7.10 (m, 1H), 5.75 (d, J = 10.0, 1H), 4.85 (dd, J = 10.1, 22.7Hz, 1H), 3.30-3.20 (m, 1H), 3.18-3.13 (m, 1H), 2.69-2.61 (m, 1+3H), 2.46-2.40 (m, 1H); 13C NMR (75.5 MHz, CDCl3, ppm): δ = 191.0 (d, J = 18.0 Hz), 140.6, 135.2, 134.7, 133.8, 132.3, 130.7, 129.3, 129.2, 127.6, 96.5(d, J = 192.8 Hz), 58.7(d, J = 20.6 Hz), 42.0, 30.8 (d, J = 21.7 Hz), 25.8(d, J = 10.0 Hz); 19 F NMR (282.4 MHz, CDCl3, ppm): -92.8~-93.0(m); LRMS (ESI) m/z 413.9 (M-H+), HRMS (ESI) m/z 438.0107 (M + Na+), calc. for C18H16Cl2F1N123Na1O3S1 438.0104; O Cl F NHMs Cl N-((R,R)-7-Chloro-2-fluoro-1-oxo-1,2,3,4-tetrahydronaphthalen-2-yl)(4-chlor ophenyl)ethyl)methanesulfonamide (165c’) White solid. Mp: 222-224 oC. 9% ee. 1H NMR (500 MHz, CDCl3, ppm): δ = 8.03 (s, 1H), 7.53 (d, J = 8.2, 1H),7.42 (s, 4H), 7.26-7.22 (m, 2H), 5.63 (s, 1H), 4.86 (d, J = 24.6 Hz, 1H), 3.03-3.01 (m, 2H), 2.57 (s, 3H), 2.33-2.30 (m, 1H), 2.02-1.97 (m, 1H); 13C NMR (75.5 MHz, CDCl3, ppm): δ = 191.4 (d, J = 18.4 Hz), 139.8, 135.3, 134.8, 134.2, 134.0, 131.8, 130.4, 129.9, 129.4, 128.2, 96.0(d, J = 193.3 Hz), 58.1(d, J = 20.1 Hz), 42.2, 30.6 (d, J = 21.7 Hz), 25.1 (d, J = 10.6 Hz); 19F NMR (282.4 MHz, CDCl3, ppm): -95.4~-95.6(m); The ee was determined by HPLC analysis. CHIRALCEL ADH (4.6 mm i.d. x 250 127 Experimental mm); Hexane/2-propanol = 90/10; flow rate 0.1 ml/min; 25 °C; 254 nm; retention time: major isomer (syn-product): 21.9 min; minor isomer (syn-product): 44.6 min; minor isomer (anti-product): 36.5 min, major isomer (anti-product): 57.8 O F NHMs Cl N-((S)-(4-chlorophenyl)-(R)-2-fluoro-1-oxo-1,2,3,4-tetrahydronaphthalen-2-yl )methyl)methanesulfonamide (165d) Colorless oil. yield: 86% (syn and anti); dr = 3.0/1, 95% ee (syn); 5% ee (anti), [α]29 D , NA; H NMR (300 MHz, CDCl3, ppm): δ = 8.08 (d, J = 7.9, 0.4H, anti), 7.82 (d, J = 7.9, 1H, syn),7.61-7.56 (m, 1.4H, anti and syn), 7.42-7.25 (m, 7H, anti and syn), 7.12 (d, J = 7.9, 2H, anti and syn), 5.92 (d, J = 9.9 Hz, 1H, syn), 5.90-5.77 (m, 0.4H), 4.93-4.82 (m, 1.5H, anti and syn), 3.35-3.06 (m, 3.2H, anti and syn), 2.73-2.60 (m, 4.2H, syn and anti), 2.53-2.36 (m, 2.5H, syn and anti) 2.02-1.94 (m, 0.5H, anti); 13C NMR (75.5 MHz, CDCl3, ppm): δ = 192.6 (d, J = 18.7 Hz, anti), 192.1 (d, J = 15.9 Hz, syn), 142.3, 141.6, 135.1, 134.9, 134.8, 134.6, 134.4, 134.0, 134.0, 131.0, 130.5, 129.9, 129.8, 129.2, 129.1, 129.0, 128.8, 128.6, 128.1, 127.7, 127.3, 96.6 (d, J = 188.4 Hz syn), 96.3 (d, J = 195.5 Hz anti), 58.7 (d, J = 22.5 Hz syn), 58.1 (d, J = 20.9 Hz anti), 42.0 (anti), 41.9 (syn), 30.9 (d, J = 21.5 Hz, syn), 30.7 (d, J = 20.9 Hz, anti), 25.5 (d, J = 10.9 Hz, anti), 25.2 (d, J = 9.9 Hz, syn); 19F NMR (282.4 MHz, CDCl3, ppm): - 92.5~-92.7 (m, syn), 128 Chapter -95.2~-95.4(m, anti); LRMS (ESI) m/z 379.9 (M-H+), HRMS (ESI) m/z 404.0494 (M + Na+), calc. for C18H17Cl1F1N1O523Na1O3S1 404.0494; The ee was determined by HPLC analysis. CHIRALCEL IA (4.6 mm i.d. x 250 mm); Hexane/2-propanol = 90/10; flow rate 0.1 ml/min; 25 °C; 254 nm; retention time: major isomer (syn-product): 24.5 min; minor isomer (syn-product): 30.2 min; minor isomer (anti-product): 44.8 min, major isomer (anti-product): 76.8 O F NHMs Cl N-((S)-(4-Chlorophenyl)-(R)-2-fluoro-5,7-dimethyl-1-oxo-1,2,3,4-tetrahydron aphthalen-2-yl)methyl)methanesulfonamide (165e) Colorless oil. yield: 70% (syn and anti); dr = 3.3/1, 96% ee, [α]29 D = +11.2 (c 0.8, CHCl3); 1H NMR (500 MHz, CDCl3, ppm): δ = 7.47 (s, 1H),7.29-7.27 (m, 3H), 7.09-7.07 (m, 2H), 5.72 (d, J = 10.1, 1H), 4.84 (dd, J = 10.1, 24.0 Hz, 1H), 3.13-3.08 (m, 1H), 3.07-2.99 (m, 1H), 2.76-2.69 (m, 1H), 2.60 (s, 3H), 2.44-2.36 (m, 1H), 2.32 (s, H), 2.29 (s, 3H); 13 C NMR (75.5 MHz, CDCl3, ppm): δ = 192.6 (d, J = 20.0 Hz), 137.7, 137.2, 136.9, 136.9, 134.9, 134.1, 131.2, 129.2, 129.0, 125.8, 97.0 (d, J = 192.2 Hz), 58.4 (d, J = 20.6 Hz), 42.0, 30.4 (d, J = 21.2 Hz), 22.9 (d, J = 10.6 Hz), 20.7, 19.1; 19 F NMR (282.4 MHz, CDCl3, ppm): -94.1~-94.2(m); LRMS (ESI) m/z 408.0 (M-H+), HRMS (ESI) m/z 432.0815 (M + Na+), calc. for C20H21Cl1F1N123Na1O3S1 432.0807; 129 Experimental O F NHMs Cl N-((R)-(4-Chlorophenyl)-(R)-2-fluoro-5,7-dimethyl-1-oxo-1,2,3,4-tetrahydron aphthalen-2-yl)methyl)methanesulfonamide (165e’) White solid. Mp: 198-200oC. 14% ee; 1H NMR (500 MHz, CDCl3, ppm): δ = 7.75 (s, 1H),7.45-7.40 (m, 4H), 7.28 (s, 1H), 5.68 (m, 1H), 4.81 (dd, J = 7.6, 25.8 Hz, 1H), 2.93-2.90 (m, 1H),2.83-2.77 (m, 1H), 2.53 (s, 3H), 2.39 (s, H), 2.36-2.28 (m, 1+3H), 2.01-1.97 (m, 1H); 13C NMR (75.5 MHz, CDCl3, ppm): δ = 193.2 (d, J = 17.3 Hz), 137.4, 137.3, 137.0, 136.6, 135.0, 134.6, 130.6, 129.9, 129.9, 129.2, 126.4, 96.2 (d, J = 193.3 Hz), 58.2 (d, J = 19.5 Hz), 42.0, 30.2 (d, J = 20.6 Hz), 23.1 (d, J = 11.1 Hz), 20.8, 19.1; 19 F NMR (282.4 MHz, CDCl3, ppm): -96.0~-96.1(m); The ee was determined by HPLC analysis. CHIRALCEL IA (4.6 mm i.d. x 250 mm); Hexane/2-propanol = 90/10; flow rate 0.1 ml/min; 25 °C; 254 nm; retention time: major isomer (syn-product): 15.9 min; minor isomer (syn-product): 25.0 min; minor isomer (anti-product): 31.8 min, major isomer (anti-product): 38.7 O F NHMs O Cl N-((S)-(4-Chlorophenyl)-(S)-3-fluoro-4-oxochroman-3-yl)methyl)methanesulf 130 Chapter onamide (165f) White solid. Mp: 177-179 oC. yield: 88% (syn and anti); dr = 3.0/1, 98% ee, [α]29 D = -21.5 (c 1.9, CHCl3); 1H NMR (500 MHz, CDCl3, ppm): δ = 7.77-7.75 (m, 1H),7.56-7.55 (m, 1H), 7.31-7.30 (m, 2H), 7.16-7.11 (m, 1H), 7.10-7.03 (m, 1H), 5.75 (d, J = 10.1Hz, 1H), 5.00 (dd, J = 10.1, 20.8Hz, 1H), 4.67 (dd, J = 10.1, 12.0Hz, 1H), 4.45 (dd, J = 7.0, 12.0 Hz, 1H), 2.73 (s, H); 13C NMR (75.5 MHz, CDCl3, ppm): δ = 187.0(d, J = 17.3 Hz), 160.5, 137.4, 135.3, 133.3,129.3, 129.0, 127.6, 122.8, 119.5, 118.2, 91.8 (d, J = 195.4 Hz), 69.2 (d, J = 29.8 Hz), 57.7 (d, J = 20.6 Hz), 42.0; 19F NMR (282.4 MHz, CDCl3, ppm): -103.5~-103.6(m); LRMS (ESI) m/z 381.8 (M-H+), HRMS (ESI) m/z 406.0296 (M+Na+), calc. for C17H15Cl1F1N123Na1O4S 406.0287; O F NHMs O Cl N-((R)-(4-Chlorophenyl)-(S)-3-fluoro-4-oxochroman-3-yl)methyl)methanesulf onamide (165f’) White solid. Mp: 190-192 oC. 14% ee; 1H NMR (500 MHz, CDCl3, ppm): δ = 7.97 (d, J = 7.6, 1H),7.61-7.59 (m, 1H), 7.40 (s, 4H), 7.18-7,15 (m, 1H), 7.06-7.04 (m, 1H), 6.06-6.05 (m, 1H), 5.02 (dd, J = 7.6, 27.1Hz, 1H), 4.28-4.25 (m, 1H), 4.05-4.02 (m, 1H), 2.60 (s, H); 13C NMR (75.5 MHz, CDCl3, ppm): δ = 180.0 (d, J = 17.3 Hz), 160.5, 137.3, 135.3, 133.1, 129.9, 129.3, 128.2, 123.1, 131 Experimental 119.0, 117.9, 91.8 (d, J = 197.8 Hz), 68.8 (d, J = 30.6 Hz), 57.2 (d, J = 19.5 Hz), 42.0; 19F NMR (282.4 MHz, CDCl3, ppm): -113.4(d, J = 27.8); The ee was determined by HPLC analysis. CHIRALCEL IA (4.6 mm i.d. x 250 mm); Hexane/2-propanol = 90/10; flow rate 0.1 ml/min; 25 °C; 254 nm; retention time: major isomer (syn-product): 22.6 min; minor isomer (syn-product): 21.2 min; minor isomer (anti-product): 29.6 min, major isomer (anti-product): 72.3 O F NHMs O Cl N-((S)-(4-Chlorophenyl)-(S)-3-fluoro-6-methyl-4-oxochroman-3-yl)methyl)me thanesulfonamide (165g) Colorless oil. yield: 94% (syn and anti); dr = 4.6/1, 97% ee, [α]29 D = -34.6 (c 1.0, CHCl3); 1H NMR (500 MHz, CDCl3, ppm): δ = 7.54 (s, 1H),7.38-7.36 (m, 1H), 7.31-7.29 (m, 2H), 7.17-7.16 (m, 2H), 6.93 (d, J = 8.8, 1H), 5.93 (d, J = 10.1, 1H), 5.01 (dd, J = 10.1, 22.0 Hz, 1H), 4.65 (dd, J = 9.5, 12.0 Hz, 1H), 4.39 (dd, J = 6.9, 12.0 Hz, 1H), 2.72 (s, H), 2.30 (s, 3H); 13C NMR (75.5 MHz, CDCl3, ppm): δ = 187.1 (d, J = 17.8 Hz), 158.6, 138.5, 135.2, 133.4, 132.5, 129.2, 129.1, 127.0, 119.2, 118.0, 91.9 (d, J = 195.0 Hz), 69.2 (d, J = 30.1 Hz), 57.6 (d, J = 21.2 Hz), 41.9, 20.3; 19F NMR (282.4 MHz, CDCl3, ppm): -103.4~-103.4(m); LRMS (ESI) m/z 395.8 (M-H+), HRMS (ESI) m/z 420.0453 C18H17Cl1F1N123Na1O4S 420.0443; 132 (M + Na+), calc. for Chapter O F NHMs O Cl N-((R)-(4-Chlorophenyl)-(S)-3-fluoro-6-methyl-4-oxochroman-3-yl)methyl)m ethanesulfonamide (165g’) White solid. Mp: 188-190 oC. 8% ee; 1H NMR (500 MHz, CDCl3, ppm): δ = 7.75 (s, 1H),7.44-7.39 (m, 5H), 6.95 (d, J = 8.2, 1H),7.40 (s, 4H), 5.85 (d, J = 8.2, 1H), 5.00 (dd, J = 8.2, 27.7Hz, 1H), 4.22 (dd, J = 4.4, 12.0 Hz, 1H), 3.98 (dd, J = 1.9, 12.0 Hz, 1H), 2.59 (s, H), 2.35 (s, 3H); 13C NMR (75.5 MHz, CDCl3, ppm): δ = 188.1 (d, J = 17.3 Hz), 158.7, 138.6, 135.3, 133.2, 132.8, 129.9, 129.3, 127.5, 91.8 (d, J = 197.8 Hz), 68.8 (d, J = 31.2 Hz), 57.2 (d, J = 18.9 Hz), 42.0, 20.4; 19F NMR (282.4 MHz, CDCl3, ppm): -114.1(d, J = 27.8); The ee was determined by HPLC analysis. CHIRALCEL ADH (4.6 mm i.d. x 250 mm); Hexane/2-propanol = 90/10; flow rate 0.1 ml/min; 25 °C; 254 nm; retention time: major isomer (syn-product): 21.9 min; minor isomer (syn-product): 25.8 min; minor isomer (anti-product): 31.2 min, major isomer (anti-product): 45.8 O F NHMs Cl O Cl N-(S,S)-6-Chloro-3-fluoro-4-oxochroman-3-yl-4-chlorophenyl)methyl)methan esulfonam ide (165h) 133 Experimental White solid. Mp: 150-152 oC. yield: 88% (syn and anti); dr = 3.0/1, 97% ee, [α]29 D = -49.6 (c 0.8, CHCl3); 1H NMR (500 MHz, CDCl3, ppm): δ = 7.71 (d, J = 2.6 Hz, 1H),7.52-7.49 (m, 1H), 7.33-7.31 (m, H), 7.16-7.15 (m, 1H), 7.01 (d, J = 8.8, 1H), 5.89 (d, J = 10.1Hz, 1H), 5.00 (dd, J = 10.1,22.0 Hz, 1H), 4.69 (dd, J = 10.1, 12.0 Hz, 1H), 4.44 (dd, J = 6.9, 12.0 Hz, 1H), 2.72 (s, H); 13C NMR (75.5 MHz, CDCl3, ppm): δ = 185.9 (d, J = 17.8 Hz), 159.0, 137.2, 135.5, 133.0, 129.4, 129.0, 128.5, 126.7, 120.2, 119.9, 91.7 (d, J = 195.6 Hz), 69.4 (d, J = 30.1 Hz), 57.6 (d, J = 21.2 Hz), 42.0; 19F NMR (282.4 MHz, CDCl3, ppm): -103.6~-103.6(m); LRMS (ESI) m/z 415.8 (M-H+), HRMS (ESI) m/z 439.9904 (M + Na+), calc. for C17H14Cl2F1N123Na1O4S 439.9897; O F NHMs Cl O Cl N-(R,S)-6-Chloro-3-fluoro-4-oxochroman-3-yl-4-chlorophenyl)methyl)metha nesulfonamide (165h’) White solid. Mp: 190-192 oC. 8% ee; 1H NMR (500 MHz, CDCl3, ppm): δ = 7.92 (d, J = 3.2Hz, 1H), 7.55-7.52 (m, 1H), 7.46-7.41 (m, H), 7.02 (d, J = 8.9, 1H), 5.85 (s, 1H), 5.01 (d, J = 27.2Hz, 1H), 4.26 (dd, J = 4.4, 12.0Hz, 1H), 4.04 (dd, J = 3.2, 12.0Hz, 1H), 2.61 (s, H); 13C NMR (75.5 MHz, CDCl3, ppm): δ = 186.8 (d, J = 17.8 Hz), 158.9, 137.2, 135.5, 132.8, 129.8, 129.4, 128.9, 127.3, 119.9, 119.7, 91.6 (d, J = 198.3 Hz), 69.0 (d, J = 30.6 Hz), 57.1 (d, J = 19.5 Hz), 42.1; 134 Chapter 19 F NMR (282.4 MHz, CDCl3, ppm): -114.1 (d, J = 27.8); The ee was determined by HPLC analysis. CHIRALCEL ADH (4.6 mm i.d. x 250 mm); Hexane/2-propanol = 90/10; flow rate 0.1 ml/min; 25 °C; 254 nm; retention time: major isomer (syn-product): 19.4 min; minor isomer (syn-product): 23.9 min; minor isomer (anti-product): 28.1 min, major isomer (anti-product): 37.8 O F NHMs F O Cl N-((S)-(4-chlorophenyl)-(S)-3,6-difluoro-4-oxochroman-3-yl)methyl)methanes ulfonamide (165i) White solid. Mp: 155-157 oC. yield: 90% (syn and anti); dr = 2.4/1, 95% ee, [α]29 D = -30.4 (c 0.7, CHCl3); 1H NMR (500 MHz, CDCl3, ppm): δ = 7.43-7.41 (m, 1H), 7.46-7.41 (m, 4H), 7.34-7.30 (m, H), 7.35-7.29 (m, 3H), 7.20-7.18 (m, 2H), 7.07-7.05 (m, 1H), 6.00 (d, J = 10.1Hz, 1H), 5.04 (dd, J = 10.1, 21.4Hz, 1H), 4.71 (J = 9.4, 12.0Hz, 1H), 4.46 (dd, J = 7.0, 12.0 Hz, 1H), 2.74 (s, H); 13 C NMR (75.5 MHz, CDCl3, ppm): δ = 186.3 (d, J = 18.4 Hz), 159.5, 156.6 (d, J = 45.1 Hz), 135.4, 133.1, 129.3, 129.0, 125.3, 125.0, 120.1, 120.0, 119.9 112.4 (d, J = 23.4 Hz), 91.8 (d, J = 196.1 Hz), 69.4 (d, J = 30.1 Hz), 57.5 (d, J = 20.6 Hz), 42.0; 19 F NMR (282.4 MHz, CDCl3, ppm): -43.1~-43.2(m); -104.2 (d, J = 10.9); LRMS (ESI) m/z 399.9 (M-H+), HRMS (ESI) m/z 424.0182 (M + Na+), calc. for C17H14Cl1F2N123Na1O4S 424.0192; 135 Experimental O F NHMs F O Cl N-((R)-(4-chlorophenyl)-(S)-3,6-difluoro-4-oxochroman-3-yl)methyl)methane sulfonamide (165i’) White solid. Mp: 218-220 oC. 8% ee; 1H NMR (500 MHz, CDCl3, ppm): δ = 7.62 (dd, J = 3.2, 7.6 Hz, 1H),7.46-7.41 (m, 4H), 7.34-7.30 (m, H), 7.06-7.04 (m, 1H), 5.79 (s, 1H), 5.01 (d, J = 26.5 Hz, 1H), 4.27-4.24 (m, 1H), 4.02 (dd, J = 2.5, 12.0 Hz, 1H), 2.60 (s, H); 13C NMR (75.5 MHz, CDCl3, ppm): δ = 187.0 (d, J = 20.0 Hz), 159.7, 156.6 (d, J = 21.7 Hz), 135.5, 132.8, 129.8, 129.4, 125.2, 124.9, 119.8, 119.7, 119.6, 113.1 (d, J = 23.9 Hz), 91.8 (d, J = 197.8 Hz), 69.1 (d, J = 31.2 Hz), 57.1 (d, J = 19.5 Hz), 42.1; 19 F NMR (282.4 MHz, CDCl3, ppm): -42.6~-42.7(m); -114.0 (d, J = 28.0); The ee was determined by HPLC analysis. PHENOMENEX Lux 5u Cellulose-1 (4.6 mm. x 250 mm); Hexane/2-propanol = 90/10; flow rate 0.1 ml/min; 25 °C; 254 nm; retention time: major isomer (syn-product): 25.5 min; minor isomer (syn-product): 30.8 min; minor isomer (anti-product): 18.0 min, major isomer (anti-product): 20.5 O F NHMs Cl 136 Chapter N-((S)-(4-Chlorophenyl)((R)-2,6-difluoro-1-oxo-2,3-dihydro-1H-inden-2-yl)m ethyl)methanesulfonamide (165j) Colorless oil. yield: 87% (syn and anti); dr = 3.4/1, >99% ee; 25% ee (for anti-product); [α]29 D = NA; H NMR (500 MHz, CDCl3, ppm): δ = 7.62-7.58 (m, 1.3H, syn and anti), 7.43-7.40 (m, 1.3H, syn and anti), 7.38-7.30 (m, 4H, syn and anti), 7.22 (s, 4.2H), 6.29-6.21 (m, 1.3H, syn and anti), 5.02 (dd, J = 7.6, 12.6Hz, 1H, syn), 4.80 (d, J = 22.0Hz, 1H, anti), 3.47-3.41 (m,1H, syn), 3.35-3.26 (m, 1.3H, syn and anti), 3.18-2.79 (s, 3H, syn), 2.69 (s, 0.9H, anti); 13 C NMR (75.5 MHz, CDCl3, ppm): δ = 199.6 (d, J = 20.0 Hz, syn), 198.6 (d, J = 20.0 Hz, anti),150.2, 150.2, 149.4, 149.4, 137.0, 135.0, 134.8, 134.2, 134.0, 133.4, 130.1, 129.3, 129.0, 128.8, 128.6, 126.6, 126.5, 125.4, 124.9, 95.6 (d, J = 197.6 Hz, anti), 94.2 (d, J = 200.3 Hz, syn), 60.8 (d, J = 25.4 Hz, syn), 59.8 (d, J = 21.6 Hz, anti), 42.0 (anti), 41.8 (syn), 36.7 (d, J = 23.8Hz, syn), 36.2 (d, J = 4.8Hz, anti); 19 F NMR (282.4 MHz, CDCl3, ppm): -80.6~-80.8(m, syn); -90.4~-90.4 (m, anti); LRMS (ESI) m/z 365.8 (M-H+), HRMS (ESI) m/z 390.0354 (M + Na+), calc. for C17H15Cl1F1N123Na1O3S 390.0337 The ee was determined by HPLC analysis. CHIRALCEL ADH (4.6 mm i.d. x 250 mm); Hexane/2-propanol = 90/10; flow rate 0.1 ml/min; 25 °C; 254 nm; retention time: major isomer (syn-product): 34.5 min; minor isomer (syn-product): 24.0 min; minor isomer (anti-product):30.3 min, major isomer (anti-product): 38.5 137 Experimental O F NHMs OCH N-((S)-((R)-2-Fluoro-1-oxo-1,2,3,4-tetrahydronaphthalen-2-yl)(4-methoxyphe nyl)methyl)methanesulfonamide (165k) The reaction was carried out at -5 oC with 20% chiral guanidine catalyst. Colorless oil. yield: 79% (syn and anti); dr = 1.8/1, 96% ee; 33% ee (for anti-product); [α]29 D = NA; H NMR (300 MHz, CDCl3, ppm): δ = 8.12 (dd, J = 1.0, 7.9 Hz, 1H, syn), 7.84 (dd, J = 0.9, 7.8 Hz, 0.6 H, anti), 7.63-7.55 (m, 1.6H, syn and anti), 7.47-7.29 (m, 5.6H, syn and anti), 7.14-7.12 (m, 1H), 7.00-6.96 (m, 2H), 6.88-6.83 (m, 1H), 6.04 (d, J = 10.2 Hz, 0.5H, anti), 5.81 (d, J = 7.9Hz, 1H, syn), 4.76-4.63 (m, 1.6 H, syn and anti), 3.86 (s, H, syn), 3.81 (s, 1.7H, anti), 3.44-3.32 (m,0.6H, anti), 3.24-2.99 (m, 2.7H, syn and anti), 2.62 (s, 1.7H, anti), 2.51 (s, 3.0H, syn), 2.47-2.29 (m, 1.6H, syn and anti), 2.01-1.99 (m, 1H); 13 C NMR (75.5 MHz, CDCl3, ppm): δ = 193.1 (d, J = 17.5 Hz, syn), 192.6 (d, J = 17.2 Hz, anti), 160.0, 159.8, 142.4, 141.2, 134.6, 134.4, 131.4, 130.7, 129.8, 129.8, 129.1, 129.1, 128.8, 128.6, 128.0, 127.7, 127.5, 127.4, 127.2, 114.4, 114.2, 97.3 (d, J = 192.8 Hz, syn), 96.9 (d, J = 193.3 Hz, anti), 58.5 (d, J = 20.8 Hz, anti), 58.2 (d, J = 19.3 Hz, syn), 41.9 (syn), 41.8 (anti), 30.9(d, J = 21.7Hz, anti), 30.8 (d, J = 21.2Hz, syn), 25.7 (d, J = 11.3Hz, syn), 25.4; 19 F NMR (282.4 MHz, CDCl3, ppm): -93.0~-93.2(m, syn); -95.8~-96.0 (m, anti); LRMS (ESI) m/z 376.0 138 Chapter (M-H+), HRMS (ESI) m/z 400.1005 (M + Na+), calc. for C19H20F1N123Na1O4S 400.0989 The ee was determined by HPLC analysis. CHIRALCEL IA (4.6 mm i.d. x 250 mm); Hexane/2-propanol = 90/10; flow rate 0.1 ml/min; 25 °C; 254 nm; retention time: major isomer (syn-product): 58.3 min; minor isomer (syn-product): 50.8 min; minor isomer (anti-product): 85.5 min, major isomer (anti-product): 129.3 min; 139 Experimental References: 1. Owton, W. M.; Brunavs, M. Synth. Commun. 1991, 21, 981. 2. Stavber, S.; Jereb, M.; Zupan, M. Synthesis, 2002, 17, 2609. 3. (a) Aldous, D. L.; Riebsomer, J. L.; Castle, R. N. J. Org. Chem. 1960, 25, 1151. (b) Tanner, D. D.; Chen, J. J. J. Org. Chem. 1989, 54, 3842 4. (a) Little, R. D.; Venegas, R. G. Org. Syn., 61, 1983, 17. (b) Carpino, L. A.; Carpino, B. A.; Giza, C. A.; Terry, P. H. Org. Syn., 44, 1964, 15. (c) Carpino, L. A.; Crowley, P. J. Org. Syn., 44, 1964, 18. 5. Ye, W.; Leow, D.; Goh, S. L. M.; Tan, C.-T.; Chian, C.-H.; Tan, C.-H. Tetrahedron Lett. 2006, 47, 1007 6. (a) Allen, C. F. H.; Edens, C. O.; Vanallan, J. Org. Syn., 26, 1946, 34. (b) Ryoda, A.; Yajima, N.; Haga, T.; Kumamoto, T.; Nakanishi, W.; Kawahata, M.; Yamaguchi, K.; Ishikawa, T. J. Org. Chem. 2003. 73, 133. (c) 7. Yamanaka, M.; Nishida, A.; Nakagawa, M. J. Org. Chem. 2003. 68. 3112. 140 [...]... Chen).6 102 Chapter 5 Ar CS2 Ar EtOH/H2O Ar H 2N NH2 concd HCl reflux 155 a: Ar = Ph HN H 2N Ar Ar NH2 DMF, RT Ar RHN S 161 MeOH, 0oC N Ar Ar HN NH NH 2 NaOH (5 M) HI NH THF, RT SMe 158 157 Ar Lawessen' reagent CH2Cl2 RHN NHR o-xylene 145oC O 160 159 Ar Ar NHR MeI 1 NH3 (g) MeOH 3 days triphosgene/Et 3N NHR (COCl)2 RHN Ar Ar RBr K2CO3 155 a: Ar = Ph 155 b: Ar = p-CH3OC6H4 Ar NH Ar S 156 155 b: Ar = p-CH3OC6H4... Di-tert-butyl1-(7-bromo-2-fluoro-1-oxo-1,2,3,4-tetrahydronaphthalen-2-yl)-2butylhydrazine-1,2-dicarboxylate (136) 121 Experimental Colorless oil LRMS (ESI) m/z 55 1.3 (M+Na+); 5. 5 Protocol for bicyclic guanidine catalyzed asymmetric C- C bond formation reactions and characterization of products Procedures for the preparation of N- Mesyl (Ms) imines 15 4c- 154 g NMs O O S NH 2 O R' Si(OEt)4 160oC R' 15 4c: R' = Cl, yield: 80% 154 g: R' = CH3O, yield: 82% N- Mesyl... 1463, 1267, 1130, 1045cm-1; LRMS (ESI) m/z 52 1.0 (M-H+), HRMS (ESI) m/z 52 1.2 451 (M + Na+), calc for C2 5H3 6N2 F2O623Na1 52 1.2434 The ee was determined by HPLC analysis CHIRALCEL IC (4.6 mm i.d x 250 mm); Hexane/2-propanol = 90/10; flow rate 1.0 ml/min; 25 C; 254 nm; retention time: major isomer: 13 .5 min; minor isomer: 5. 4 min Modification of amination products To a 50 mL RBF containing 108h (107 mg,... nm; retention time: major isomer: 124.3 min; minor isomer: 132.8 min 5. 4 Protocol for bicyclic guanidine catalyzed asymmetric C- N bond formation reaction and characterization of products 2-Fluoro-3,4-dihydronaphthalen-1(2H)-one 82d (33.0 mg, 0.2 mmol, 4.0 equiv.) and 25 (1.12 mg, 0.0 05 mmol, 0.1 equiv) were dissolved in THF (0.4 ml) and stirred at 0 oC for 20 min, then di-3-ethylpentan-3-yl azodicarboxylate... 2974, 29 45, 2884, 1732, 1613, 153 0, 1 458 , 14 25, 1384, 13 45, 1290, 1133 cm-1; LRMS (ESI) m/z 54 6.9 (M+Na+), HRMS (ESI) m/z 54 6. 259 4 (M + Na+), calc for C2 6H3 8N3 F1O723Na1 54 6. 258 6 The ee was determined by HPLC analysis CHIRALCEL IC (4.6 mm i.d x 250 mm); Hexane/2-propanol = 92/8; flow rate 0.8 ml/min; 25 C; 254 nm; retention time: major isomer: 26.4 min; minor isomer: 16.2 min O F Eoc F NH N Eoc 1 15 Experimental... for overnight (A clear solution was formed one hour later) The reaction solvent was removed in vacuo The residue was dissolved in DCM, and the organic layer was washed with brine three times and dried over Na2SO4 The crude product was obtained after removing the solvent Flash chromagraphy over silica gel using 20:1 EtOAc-hexane gave 3-ethylpentan-3-yl 1H-imidazole-1-carboxylate 102 ( 5. 1 g, 82%) as a... (ESI) m/z 50 3. 255 3 (M + Na+), calc for C2 5H3 7N2 F1O623Na1 50 3. 252 8 The ee was determined by HPLC analysis CHIRALCEL AD-H (4.6 mm i.d x 250 mm); Hexane/2-propanol = 97/3; flow rate 0 .5 ml/min; 25 C; 254 nm; retention time: major isomer: 103.2 min; minor isomer: 81.3 min O O Eoc F NH N Eoc (S)-Bis(3-ethylpentan-3-yl)1-(3-fluoro-6-methyl-4-oxochroman-3-yl)hydrazine -1,2-dicarboxylate (108i) Colorless oil... mmol) and o-xylene (6 mL) 104 Chapter 5 was added Lawessen’s reagent (1.0 g, 2 equiv.) The resulting mixture was heated to 1 45 oC for 12 hours And the reaction was monitored by TLC and quenched by MeOH After removing the solvent, the crude product was loaded on the colomn and flashed by gradient elution with hexane/EA mixtures (50 /1 ~ 8/1 ratio) Pure product 161b (R = Bn) was obtained with 79% yield Under... products tBu O Br F N tBu N N H 25 (30 mol%) O F D Br D2O ( 150 equiv.) 82a ClCH2CH2Cl, 0oC 15h 82a-d 1 To a solution of 30 mol% chiral guanidine 25 (2.7 mg, 0.012 mmol) in 0.8 mL of ClCH2CH2Cl (DCE), D2O (0.12 mL, 6 mmol) was added Then, the reaction mixture was cooled to 0 oC After stirring at 0 oC for 20 min, 82a (9.7 mg, 0.04 mmol) was added in two batches This resulting solution was stirred for 15. .. stirred for 15 hours at 0 oC The reaction mixture was purified by flash chromatography on silica gel eluting with hexane/EtOAc (30/1 to 5/ 1) to give 82a-d1 (13 mg) as an off-white solid with 96% yield The deuteration incorporation was determined by 1H NMR spectroscopy by comparing the relative intensity to a non-exchangeable proton in the molecule The product 82a-d1 was obtained as an off-white solid Yield: . sets: Jasco HPLC units, including a Jasco DG-980 -50 Degasser, a LG-980-02 Ternary Gradient Unit, a PU-980 Intelligient HPLC Pump, UV-9 75 Intelligient UV/VIS Detectors, and an AS- 950 Intelligient. reference. Low resolution mass spectra were obtained on a Finnigan/MAT LCQ spectrometer in ESI mode and a Finnigan/MAT 95XL-T mass spectrometer in FAB mode. All high resolution mass spectra. NHR triphosgene/Et 3 N CH 2 Cl 2 NN Ar Ar R R Cl Cl N N N N H N Ar ArAr Ar R R HCl imidazoline salt Lawessen' reagent o-xylene 1 45 o C 155 a: Ar = Ph 155 b: Ar = p-CH 3 OC 6 H 4 159 160 Ar Ar RHN NHR O Ar Ar RHN NHR S 2.