(2-OXO-2-PHENYL-ETHYL)-CARBAMIC ACID TERT-BUTYL ESTER

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 2-(tert-Butoxycarbonylamino)acetophenone (3.00 g) was dissolved in methanol (21.0 mL). To the solution was added an aqueous solution (water: 9.0 mL) of thiosemicarbazide hydrochloride (3.11 g, 24.4 mmol) at room temperature. After the mixture was stirred at the same temperature for 30 minutes, water (12.0 mL) was added, and the mixture was stirred at room temperature for 20 minutes and then at 0° C. for 1 hour. The deposited solid was collected by filtration and washed with cooled 50% aqueous methanol (20 mL). The resulting solid was dried at 40° C. under reduced pressure to give seed crystals of 2-(tert-butoxycarbonylamino)acetophenone thiosemicarbazone (3.56 g, yield: 95.1%) as a white solid. the mixture was stirred at room temperature for 20 minutes at 0° C. for 1 hour The deposited solid was collected by filtration washed with cooled 50% aqueous methanol (20 mL) The resulting solid was dried at 40° C. under reduced pressure

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: tert-butyl 1-oxo-1-phenylethan-2-ylcarbamate (18) (2.4 g, 10.0 mmol, 1.0 equiv.) was added to a 100 mL RBF followed by EtOH (41 mL, 200 proof). Next, a 0.5 M solution of NaHCO3 (420 mg, 5.0 mmol, 0.5 equiv.) was added followed by a 37% solution of formaldehyde (1.2 mL, 15.0 mmol, 1.5 equiv.). The solution was stirred at rt. for 6 days and transferred to a separatory funnel with a 1.0 M solution of NaCl (5.0 g, 85.5 mmol). The solution was extracted with CH2Cl2 (5×50 mL). The organic layer was dried over Na2SO4, concentrated on a rotary evaporator, and dried under vacuum to give a crude light yellow oil. The residue was purified by flash column chromatography (30% EtOAc/hexanes) to give 2.3 g (88%) of 19 as a colorless oil which crystallized to a white solid. (Note: It is essential to use a 100 mL RBF for full vortex stirring over the entire reaction period) Rf=0.16 (30% EtOAc/Hexanes); mp=69-71° C.; IR (film) 3420, 2976, 2931, 1683, 1503, 1366, 1165, 1061 cm−1; 1H NMR (500 MHz, CDCl3) δ 8.00 (d, J=7.0 Hz, 2H, Ph-H), 7.60 (t, J=7.0 Hz, 1H, Ph-H), 7.48 (t, J=7.0 Hz, 2H, Ph-H), 5.96 (d, J=6.0 Hz, 1H, carbamate-NH), 5.36 (br s, 1H, Boc-NH—CH), 4.00 (m, 1H, CH—CH2), 3.86 (m, 1H, CH—CH2), 3.29 (br s, 1H, CH2—OH), 1.45 (s, 9H, t-butyl-CH3); 13C (125 MHz, CDCl3) δ 197.4, 156.3, 134.6, 134.1, 129.0, 128.9, 80.5, 64.7, 58.1, 28.4; LRMS (ESI-MS m/z): Mass calcd for C14H19NNaO4 [M+Na]+, 288.29. Found 288. Anal. calcd for C14H19NO4: C, 63.38; H, 7.22; N, 5.28 Found: C, 63.22; H, 7.25; N, 5.28. The solution was extracted with CH2Cl2 (5×50 mL) The organic layer was dried over Na2SO4 concentrated on a rotary evaporator dried under vacuum to give a crude light yellow oil The residue was purified by flash column chromatography (30% EtOAc/hexanes)

反应条件: temp:35.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: tert-butyl 1-oxo-1-phenylethan-2-ylcarbamate (18) (1.4 g, 6.0 mmol, 1.0 equiv.) was added to a 100 mL RBF followed by EtOH (21 mL). Next, a 37% solution of formaldehyde (14.5 mL, 180 mmol, 30.0 equiv.) was added to the reaction mixture and the solution heated to 35° C. Finally, a 3.0 M solution of K2CO3 (410 mg, 3.0 mmol, 1.0 mL dH2O, 0.5 equiv.) was added to the reaction flask and the solution stirred vigorously for 30 min. The solution was neutralized with 1% HCl, transferred to a separatory funnel with a 2.3 M solution of NaCl (12.0 g, 205 mmol, 90.0 mL H2O), and extracted with CH2Cl2 (5×60 mL). The organic layers were combined and dried over Na2SO4. The resulting solution was concentrated on a rotary evaporator and dried under vacuum to give 2.9 g of crude oil. The residue was purified by flash column chromatography (4% MeOH/CH2Cl2) to give 720 mg (41%) of 1 as a white solid. Rf=0.20 (4% MeOH/CH2Cl2); mp=127-130° C.; IR (KBr) 3437, 3372, 2980, 2967, 1701, 1671, 1504, 1282, 1026 cm−1; 1H NMR (500 MHz, CDCl3) δ Major Rotamer: 8.03 (m, 2H, Ph-H), 7.43 (br s, 3H, Ph-H), 5.87 (br s, 1H, carbamate-NH), 5.35 (br s, 1H, Boc-NH—CH), 4.25 (d, J=11.0 Hz, 2H, CH—CH2), 4.02 (d, J=11.0 Hz, 2H, CH—CH2), 3.31 (br s, 2H, (CH2—OH2), 1.28 (s, 9H, t-butyl-CH3). Minor Rotamer: 8.19 (br s, 2H, Ph-H), 7.52 (br s, 3H, Ph-H), 1.07 (s, 9H, t-butyl-CH3); 13C NMR (125 MHz, CDCl3) δ 202.2, 201.1, 155.4, 154.9, 136.3, 135.1, 133.4, 132.7, 129.1, 128.7, 128.4, 82.2, 80.7, 68.2, 67.4, 64.6, 64.2, 28.2, 27.7; LRMS (ESI-MS m/z): Mass calcd for C15H21NO5 [M]+, 295.33. Found 296. Anal. calcd for C15H21NO5: C, 61.00; H, 7.17; N, 4.74 Found: C, 60.90; H, 7.17; N, 4.74. extracted with CH2Cl2 (5×60 mL) dried over Na2SO4 The resulting solution was concentrated on a rotary evaporator dried under vacuum to give 2.9 g of crude oil The residue was purified by flash column chromatography (4% MeOH/CH2Cl2)

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: tert-butyl 1-oxo-1-phenylethan-2-ylcarbamate (18) (2.4 g, 10.0 mmol, 1.0 equiv.) was added to a 100 mL RBF followed by EtOH (41 mL, 200 proof). Next, a 0.5 M solution of NaHCO3 (420 mg, 5.0 mmol, 0.5 equiv.) was added followed by a 37% solution of formaldehyde (1.2 mL, 15.0 mmol, 1.5 equiv.). The solution was stirred at rt. for 6 days and transferred to a separatory funnel with a 1.0 M solution of NaCl (5.0 g, 85.5 mmol). The solution was extracted with CH2Cl2 (5×50 mL). The organic layer was dried over Na2SO4, concentrated on a rotary evaporator, and dried under vacuum to give a crude light yellow oil. The residue was purified by flash column chromatography (30% EtOAc/hexanes) to give 2.3 g (88%) of 19 as a colorless oil which crystallized to a white solid. (Note: It is essential to use a 100 mL RBF for full vortex stirring over the entire reaction period) Rf=0.16 (30% EtOAc/Hexanes); mp=69-71° C.; IR (film) 3420, 2976, 2931, 1683, 1503, 1366, 1165, 1061 cm−1; 1H NMR (500 MHz, CDCl3) δ 8.00 (d, J=7.0 Hz, 2H, Ph-H), 7.60 (t, J=7.0 Hz, 1H, Ph-H), 7.48 (t, J=7.0 Hz, 2H, Ph-H), 5.96 (d, J=6.0 Hz, 1H, carbamate-NH), 5.36 (br s, 1H, Boc-NH—CH), 4.00 (m, 1H, CH—CH2), 3.86 (m, 1H, CH—CH2), 3.29 (br s, 1H, CH2—OH), 1.45 (s, 9H, t-butyl-CH3); 13C (125 MHz, CDCl3) δ 197.4, 156.3, 134.6, 134.1, 129.0, 128.9, 80.5, 64.7, 58.1, 28.4; LRMS (ESI-MS m/z): Mass calcd for C14H19NNaO4 [M+Na]+, 288.29. Found 288. Anal. calcd for C14H19NO4: C, 63.38; H, 7.22; N, 5.28. Found: C, 63.22; H, 7.25; N, 5.28. The solution was extracted with CH2Cl2 (5×50 mL) The organic layer was dried over Na2SO4 concentrated on a rotary evaporator dried under vacuum to give a crude light yellow oil The residue was purified by flash column chromatography (30% EtOAc/hexanes)

反应条件: temp:35.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: tert-butyl 1-oxo-1-phenylethan-2-ylcarbamate (18) (1.4 g, 6.0 mmol, 1.0 equiv.) was added to a 100 mL RBF followed by EtOH (21 mL). Next, a 37% solution of formaldehyde (14.5 mL, 180 mmol, 30.0 equiv.) was added to the reaction mixture and the solution heated to 35° C. Finally, a 3.0 M solution of K2CO3 (410 mg, 3.0 mmol, 1.0 mL dH2O, 0.5 equiv.) was added to the reaction flask and the solution stirred vigorously for 30 min. The solution was neutralized with 1% HCl, transferred to a separatory funnel with a 2.3 M solution of NaCl (12.0 g, 205 mmol, 90.0 mL H2O), and extracted with CH2Cl2 (5×60 mL). The organic layers were combined and dried over Na2SO4. The resulting solution was concentrated on a rotary evaporator and dried under vacuum to give 2.9 g of crude oil. The residue was purified by flash column chromatography (4% MeOH/CH2Cl2) to give 720 mg (41%) of 1 as a white solid. Rf=0.20 (4% MeOH/CH2Cl2); mp=127-130° C.; IR (KBr) 3437, 3372, 2980, 2967, 1701, 1671, 1504, 1282, 1026 cm−1; 1H NMR (500 MHz, CDCl3) δ Major Rotamer: 8.03 (m, 2H, Ph-H), 7.43 (br s, 3H, Ph-H), 5.87 (br s, 1H, carbamate-NH), 5.35 (br s, 1H, Boc-NH—CH), 4.25 (d, J=11.0 Hz, 2H, CH—CH2), 4.02 (d, J=11.0 Hz, 2H, CH—CH2), 3.31 (br s, 2H, (CH2—OH)2), 1.28 (s, 9H, t-butyl-CH3). Minor Rotamer: 8.19 (br s, 2H, Ph-H), 7.52 (br s, 3H, Ph-H), 1.07 (s, 9H, t-butyl-CH3); 13C NMR (125 MHz, CDCl3) δ 202.2, 201.1, 155.4, 154.9, 136.3, 135.1, 133.4, 132.7, 129.1, 128.7, 128.4, 82.2, 80.7, 68.2, 67.4, 64.6, 64.2, 28.2, 27.7; LRMS (ESI-MS m/z): Mass calcd for C15H21NO5 [M]+, 295.33. Found 296. Anal. calcd for C15H21NO5: C, 61.00; H, 7.17; N, 4.74. Found: C, 60.90; H, 7.17; N, 4.74. extracted with CH2Cl2 (5×60 mL) dried over Na2SO4 The resulting solution was concentrated on a rotary evaporator dried under vacuum to give 2.9 g of crude oil The residue was purified by flash column chromatography (4% MeOH/CH2Cl2)

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 2-(tert-Butoxycarbonylamino)acetophenone (3.00 g) was dissolved in methanol (21.0 mL). To the solution was added an aqueous solution (water: 9.0 mL) of thiosemicarbazide hydrochloride (3.11 g, 24.4 mmol) at room temperature. After the mixture was stirred at the same temperature for 30 minutes, water (12.0 mL) was added, and the mixture was stirred at room temperature for 20 minutes and then at 0° C. for 1 hour. The deposited solid was collected by filtration and washed with cooled 50% aqueous methanol (20 mL). The resulting solid was dried at 40° C. under reduced pressure to give seed crystals of 2-(tert-butoxycarbonylamino)acetophenone thiosemicarbazone (3.56 g, yield: 95.1%) as a white solid. the mixture was stirred at room temperature for 20 minutes at 0° C. for 1 hour The deposited solid was collected by filtration washed with cooled 50% aqueous methanol (20 mL) The resulting solid was dried at 40° C. under reduced pressure