benzyl N-ethenylcarbamate

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A one liter, four neck flask under nitrogen atmosphere was charged with N-vinyl-carbamic acid benzyl ester (27.66 g, 156 mmol, 1.0 equiv) and dry toluene (500 mL). (1-Benzotriazol-1-yl-propyl)-(4-trifluoromethyl-phenyl)-amine (50.0 g, 156 mmol, 1.0 equiv) and p-toluenesulfonic acid monohydrate (297 mg, 1.56 mmol, 0.01 equiv) were added, and the mixture heated to 70° C. After 2 h, the mixture was cooled to room temperature and transferred to a separatory funnel. Ethyl acetate (500 mL) was added. The mixture was washed 1×200 mL 1 N NaOH, 1×200 mL H2O, 1×200 mL brine, and dried (MgSO4). The mixture was filtered and the solids washed 1×50 mL ethyl acetate. The filtrate was concentrated to approximately 250 mL. 500 mL toluene were added, and the mixture concentrated to approximately 500 mL. 500 mL n-heptane were added, the slurry was stirred 1 h, filtered through a Buchner funnel, and dried. cis-(2-Ethyl-6-trifluoromethyl-1,2,3,4-tetrahydro-quinolin4-yl)-carbamic acid benzyl ester was isolated as a white powder (45.04 g, 76%): mp 155-157° C.; 1H NMR (DMSO-d6, 400 MHz) δ0.92 (t, 3H, J=7.5 Hz), 1.5 (m, 3H), 2.00 (m, 1H), 3.35 (m, 1H), 4.77 (m, 1H), 5.07 (d, 1H, J=12.5 Hz), 5.15 (d, 1H, J=12.5 Hz), 6.35 (s, 1H), 6.61 (d, 1H, J=8.5 Hz), 7.12 (s, 1H), 7.18 (dd, 1H, J=1.9, 8.5 Hz), 7.4 (m, 5H), 7.70 (d, 1H, J=9.1 Hz); 13C NMR (DMSO-d6, 100 MHz) δ157.03, 149.02, 137.79, 128.82, 128.23, 128.03, 125.9 (q, J=270 Hz), 125.06, 123.50, 121.73, 115.2 (q, J=31.7 Hz), 113.33, 65.85, 52.09, 47.83, 34.02, 28.68, 9.93; DEPT spectrum: quaternary carbons δ157.03, 149.02, 137.79, 125.9, 121.73, 115.2; CH carbons δ128.82, 128.23, 128.03, 125.06, 123.50, 113.33, 52.09, 47.83; CH2 carbons δ65.85, 34.02, 28.68; CH3 carbon δ9.93; IR (drifts) 3430 (m), 3303 (s), 2951 (m), 1686 (vs), 1542 (vs), 1088 (vs); MS (APCI+) m/z (rel. intensity) 379 (M+H+, 53), 228 (100); Anal. Calcd for C20H21N2O2F3: C, 63.48; H, 5.59; N, 7.40; Found: C, 63.69; H, 6.06, N, 7.36. the mixture was cooled to room temperature transferred to a separatory funnel The mixture was washed 1×200 mL 1 N NaOH, 1×200 mL H2O, 1×200 mL brine dried (MgSO4) The mixture was filtered the solids washed 1×50 mL ethyl acetate The filtrate was concentrated to approximately 250 mL 500 mL toluene were added the mixture concentrated to approximately 500 mL 500 mL n-heptane were added filtered through a Buchner funnel dried

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Scheme Va, step A: 2-(4-iodophenyl) propyl isopropylsulfonamide (1.5 g, 4.1 mmol), (phenylmethoxy)-N-vinylcarboxamide (0.87 g, 4.9 mmol, prepared in example 6), 9-BBN dimer (1.3 g, 5.3 mmol), [1,1′bis(diphenylphosphino)-ferrocene] dichloropalladium (II), PdCl2(dppf) (0.17 g, 0.2 mmol), 3N sodium hydroxide (3 mL), and pH=7 buffer: hydrogen peroxide (2:1, 15 mL) were combined in a manner analogous to the procedure described in example 6 to provide the intermediate title compound, N{2-[4-(1-methyl-2-{[(methylethyl)sulfonyl]amino}ethyl)phenyl]ethyl}(phenylmethoxy)carboxamide, (0.6 g, 35%). Electron spray M.S. 417 (M*−H).

Conditions: temp:-10.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Into a 100 mL single neck flask was placed (phenylmethoxy)-N-vinylcarboxamide (5.54 g, 31.25 mmol) in THF (15 mL). The mixture was cooled down to −10° C. while treated dropwise with a solution of 9-BBN dimer (3.81 g, 15.62 mmol) in THF (20 mL). The reaction mixture was warmed up to RT while stirring for additional 2 hours. The reaction mixture was quenched with 3N NaOH (2mL) and the mixture was stirred for 10 minutes before its addition to a solution of 4-bromo-2-fluorobenzonitrile (5 g, 25 mmol) and [1,1′bis(diphenylphosphino)-ferrocene] dichloropalladium (II), PdCl2(dppf), (0.4 g, 0.5 mmol) in THF (10 mL). The mixture was stirred at RT for 12 hour and then was quenched with a 2:1 mixture of pH=7 buffer hydrogen peroxide (10 mL). The product was extracted with EtOAc and the organic layer was separated and washed twice with H2O, dried over anhydrous Na2SO4, filtered, and concentrated under reduced vacuum. The resulting semi-solid was further purified via flash chromatography (Silica gel, isocratic) and eluting with a solvent of Hexanes/EtOAc 50% to provide the intermediate title compound, N-[2-(4-cyano-3-fluorophenyl)ethyl](phenylmethoxy)carboxamide, (6.4 g, 86%) as a white solid. Electron spray M.S. 299 (M*+H). Into a 100 mL single neck flask was placed The reaction mixture was warmed up to RT The reaction mixture was quenched with 3N NaOH (2mL) The mixture was stirred at RT for 12 hour was quenched with a 2:1 mixture of pH=7 buffer hydrogen peroxide (10 mL) The product was extracted with EtOAc the organic layer was separated washed twice with H2O dried over anhydrous Na2SO4 filtered concentrated under reduced vacuum The resulting semi-solid was further purified via flash chromatography (Silica gel, isocratic) eluting with a solvent of Hexanes/EtOAc 50%

Conditions: temp:110.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Into a 500 mL single neck flask were placed benzyl alcohol (76.5 mL, 792 mmol), hydroquinone (3.05 g, 27.7 mmol), pyridine (3 mL, 27.7 mmol) and the mixture was stirred at 100° C. while treated with the toluene solution of 1-aza-1-diazobuta-1,3-dien-2-one (200 mL) dropwise. The mixture was stirred at 110° C. for 30 minutes and at RT for 12 hours. The reaction mixture was concentrated and the resulting crude oil was distilled under reduced pressure (0.4 mm Hg) to provide the intermediate title compound, (phenylmethoxy)-N-vinylcarboxamide, (43.1 g, 45%) as a pure oil (came out at 110-115° C.) which solidified upon sitting at RT. Electron spray M.S. 178 (M*+H) Analysis for C10H11NO2: Into a 500 mL single neck flask were placed The reaction mixture was concentrated the resulting crude oil was distilled under reduced pressure (0.4 mm Hg)

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Scheme Va, step A: 2-(4-iodophenyl) propyl isopropylsulfonamide (1.5 g, 4.1 mmol), (phenylmethoxy)-N-vinylcarboxamide (0.87 g, 4.9 mmol, prepared in example 6), 9-BBN dimer (1.3 g, 5.3 mmol), [1,1′bis(diphenylphosphino)-ferrocene] dichloropalladium (II), PdCl2(dppf) (0.17 g, 0.2 mmol), 3N sodium hydroxide (3 mL), and pH=7 buffer: hydrogen peroxide (2:1, 15 mL) were combined in a manner analogous to the procedure described in example 6 to provide the intermediate title compound, N{2-[4-(1-methyl-2-{[(methylethyl)sulfonyl]amino}ethyl)phenyl]ethyl}(phenylmethoxy)carboxamide, (0.6 g, 35%). Electron spray M.S. 417 (M*−H).

Conditions: temp:-10.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Into a 100 mL single neck flask was placed (phenylmethoxy)-N-vinylcarboxamide (5.54 g, 31.25 mmol) in THF (15 mL). The mixture was cooled down to −10° C. while treated dropwise with a solution of 9-BBN dimer (3.81 g, 15.62 mmol) in THF (20 mL). The reaction mixture was warmed up to RT while stirring for additional 2 hours. The reaction mixture was quenched with 3N NaOH (2mL) and the mixture was stirred for 10 minutes before its addition to a solution of 4-bromo-2-fluorobenzonitrile (5 g, 25 mmol) and [1,1′bis(diphenylphosphino)-ferrocene] dichloropalladium (II), PdCl2(dppf), (0.4 g, 0.5 mmol) in THF (10 mL). The mixture was stirred at RT for 12 hour and then was quenched with a 2:1 mixture of pH=7 buffer hydrogen peroxide (10 mL). The product was extracted with EtOAc and the organic layer was separated and washed twice with H2O, dried over anhydrous Na2SO4, filtered, and concentrated under reduced vacuum. The resulting semi-solid was further purified via flash chromatography (Silica gel, isocratic) and eluting with a solvent of Hexanes/EtOAc 50% to provide the intermediate title compound, N-[2-(4-cyano-3-fluorophenyl)ethyl](phenylmethoxy)carboxamide, (6.4 g, 86%) as a white solid. Electron spray M.S. 299 (M*+H). Into a 100 mL single neck flask was placed The reaction mixture was warmed up to RT The reaction mixture was quenched with 3N NaOH (2mL) The mixture was stirred at RT for 12 hour was quenched with a 2:1 mixture of pH=7 buffer hydrogen peroxide (10 mL) The product was extracted with EtOAc the organic layer was separated washed twice with H2O dried over anhydrous Na2SO4 filtered concentrated under reduced vacuum The resulting semi-solid was further purified via flash chromatography (Silica gel, isocratic) eluting with a solvent of Hexanes/EtOAc 50%

Conditions: temp:110.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Into a 500 mL single neck flask were placed benzyl alcohol (76.5 mL, 792 mmol), hydroquinone (3.05 g, 27.7 mmol), pyridine (3 mL, 27.7 mmol) and the mixture was stirred at 100° C. while treated with the toluene solution of 1-aza-1-diazobuta-1,3-dien-2-one (200 mL) dropwise. The mixture was stirred at 110° C. for 30 minutes and at RT for 12 hours. The reaction mixture was concentrated and the resulting crude oil was distilled under reduced pressure (0.4 mm Hg) to provide the intermediate title compound, (phenylmethoxy)-N-vinylcarboxamide, (43.1 g, 45%) as a pure oil (came out at 110-115° C.) which solidified upon sitting at RT. Electron spray M.S. 178 (M*+H) Analysis for C10H11NO2: Into a 500 mL single neck flask were placed The reaction mixture was concentrated the resulting crude oil was distilled under reduced pressure (0.4 mm Hg)

Conditions: temp:-25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Aniline (3.64 mL, 39.97 mmol, 1.0 equ) was dissolved in methylene chloride (100 mL) and Na2SO4 (2 g) was added and cooled to −25° C. Acetaldehyde (2.23 mL, 39.97 mmol, 1.0 equ.) was added to the solution and stirred for 1 h at −25° C. Sodium sulfate was filtered off and N-vinyl-carbamic acid benzyl ester (7.07 g, 39.97 mmol, 1.0 equiv) was added to the filtrate at −25° C., followed by boron triflouride diethyl etherate (0.50 mL, 3.9 mmol, 0.1 equ). The reaction was allowed to stir at −25° C. for 1 h and then warmed to room temperature and stirred for 10 h. The reaction was evaporated in vacuo and the residue was purified by Biotage flash system (20% ethyl acetate/80% hexane) to yield 4.0 g, 33% of (±)-cis-(2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl)-carbamic acid benzyl ester as a white solid. Sodium sulfate was filtered off to stir at −25° C. for 1 h warmed to room temperature stirred for 10 h The reaction was evaporated in vacuo the residue was purified by Biotage flash system (20% ethyl acetate/80% hexane)

Conditions: temp:-25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Aniline (3.64 mL, 39.97 mmol, 1.0 equ) was dissolved in methylene chloride (100 mL) and Na2SO4 (2 g) was added and cooled to −25° C. Acetaldehyde (2.23 mL, 39.97 mmol, 1.0 equ.) was added to the solution and stirred for 1 h at −25° C. Sodium sulfate was filtered off and N-vinyl-carbamic acid benzyl ester (7.07 g, 39.97 mmol, 1.0 equiv) was added to the filtrate at −25° C., followed by boron triflouride diethyl etherate (0.50 mL, 3.9 mmol, 0.1 equ). The reaction was allowed to stir at −25° C. for 1 h and then warmed to room temperature and stirred for 10 h. The reaction was evaporated in vacuo and the residue was purified by Biotage flash system (20% ethyl acetate/80% hexane) to yield 4.0 g, 33% of (±)-cis-(2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl)-carbamic acid benzyl ester as a white solid. Sodium sulfate was filtered off to stir at −25° C. for 1 h warmed to room temperature stirred for 10 h The reaction was evaporated in vacuo the residue was purified by Biotage flash system (20% ethyl acetate/80% hexane)

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A one liter, four neck flask under nitrogen atmosphere was charged with N-vinyl-carbamic acid benzyl ester (27.66 g, 156 mmol, 1.0 equiv) and dry toluene (500 mL). (1-Benzotriazol-1-yl-propyl)-(4-trifluoromethyl-phenyl)-amine (50.0 g, 156 mmol, 1.0 equiv) and p-toluenesulfonic acid monohydrate (297 mg, 1.56 mmol, 0.01 equiv) were added, and the mixture heated to 70° C. After 2 h, the mixture was cooled to room temperature and transferred to a separatory funnel. Ethyl acetate (500 mL) was added. The mixture was washed 1×200 mL 1 N NaOH, 1×200 mL H2O, 1×200 mL brine, and dried (MgSO4). The mixture was filtered and the solids washed 1×50 mL ethyl acetate. The filtrate was concentrated to approximately 250 mL. 500 mL toluene were added, and the mixture concentrated to approximately 500 mL. 500 mL n-heptane were added, the slurry was stirred 1 h, filtered through a Buchner funnel, and dried. cis-(2-Ethyl-6-trifluoromethyl-1,2,3,4-tetrahydro-quinolin4-yl)-carbamic acid benzyl ester was isolated as a white powder (45.04 g, 76%): mp 155-157° C.; 1H NMR (DMSO-d6, 400 MHz) δ0.92 (t, 3H, J=7.5 Hz), 1.5 (m, 3H), 2.00 (m, 1H), 3.35 (m, 1H), 4.77 (m, 1H), 5.07 (d, 1H, J=12.5 Hz), 5.15 (d, 1H, J=12.5 Hz), 6.35 (s, 1H), 6.61 (d, 1H, J=8.5 Hz), 7.12 (s, 1H), 7.18 (dd, 1H, J=1.9, 8.5 Hz), 7.4 (m, 5H), 7.70 (d, 1H, J=9.1 Hz); 13C NMR (DMSO-d6, 100 MHz) δ157.03, 149.02, 137.79, 128.82, 128.23, 128.03, 125.9 (q, J=270 Hz), 125.06, 123.50, 121.73, 115.2 (q, J=31.7 Hz), 113.33, 65.85, 52.09, 47.83, 34.02, 28.68, 9.93; DEPT spectrum: quaternary carbons δ157.03, 149.02, 137.79, 125.9, 121.73, 115.2; CH carbons δ128.82, 128.23, 128.03, 125.06, 123.50, 113.33, 52.09, 47.83; CH2 carbons δ65.85, 34.02, 28.68; CH3 carbon δ9.93; IR (drifts) 3430 (m), 3303 (s), 2951 (m), 1686 (vs), 1542 (vs), 1088 (vs); MS (APCI+) m/z (rel. intensity) 379 (M+H+, 53), 228 (100); Anal. Calcd for C20H21N2O2F3: C, 63.48; H, 5.59; N, 7.40; Found: C, 63.69; H, 6.06, N, 7.36. the mixture was cooled to room temperature transferred to a separatory funnel The mixture was washed 1×200 mL 1 N NaOH, 1×200 mL H2O, 1×200 mL brine dried (MgSO4) The mixture was filtered the solids washed 1×50 mL ethyl acetate The filtrate was concentrated to approximately 250 mL 500 mL toluene were added the mixture concentrated to approximately 500 mL 500 mL n-heptane were added filtered through a Buchner funnel dried