6-methoxy-1-methyl-4,5-dihydro-3H-1-benzazepin-2-one

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

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

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

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

Procedure: To a solution of 6-Methoxy-1-methyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (INT-1) (538 mg, 2.62 mmol) in acetonitrile brought to 0° C. in an ice bath was added 1.8 mL TFAA (2.7 g, 13.1 mmol), followed by KNO3 (320 mg, 3.14 mmol). After approximately 5 minutes, the reaction was allowed to warm to room temperature. Conversion of starting material to product was monitored by LC/MS. Upon completion, the reaction was cooled to 0° C. in an ice bath and quenched with sat. NaHCO3 (aq), 1N NaOH (aq), and ice until pH ˜9-10 was achieved. The aqueous mixture was extracted 3× with EtOAc and the organic layers were washed with brine, dried with MgSO4, and concentrated to give 6-Methoxy-1-methyl-7-nitro-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (INT-2) as an orange solid (530 mg, 82%). By NMR, the product showed a 4:1 mixture of nitration products, 80% of which was the desired product. By TLC, the products appeared inseparable, so the material was taken on for reduction crude. Data for Major Isomer: 1H-NMR (CDCl3) δ 7.83 (d, J=8.8 Hz, 1H), 7.04 (d, J=8.8 Hz, 1H), 3.94 (s, 3H), 3.37 (s, 3H), 2.87 (br m, 2H), 2.36 (t, J=7.1 Hz, 2H), 2.24 (m, 2H); LC/MS (ESI-pos) m/z 251.03 (M+H). Upon completion, the reaction was cooled to 0° C. in an ice bath quenched with sat. NaHCO3 (aq), 1N NaOH (aq), and ice until pH ˜9-10 The aqueous mixture was extracted 3× with EtOAc the organic layers were washed with brine dried with MgSO4 concentrated

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 6-Methoxy-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (prepared according to: Hassner, A.; Amit, B.; Marks, V.; Gottlieb, Hugo E., J. Org. Chem. 2003, 68(18), 6853-6858.) (300 mg, 1.57 mmol) in 15 mL of DMF was cooled to 0° C. in an ice bath, and to the solution was added NaH (60% in mineral oil) (70 mg, 1.73 mmol). After 10 minutes of stirring at 0° C., Iodomethane (270 mg, 1.88 mmol) was added to the solution. The reaction was allowed to warm to room temperature and upon completion (after 30 minutes) was quenched with ice and water. The aqueous solution was extracted 3× with diethyl ether, and the organic layers were washed with water and brine, dried with MgSO4, and concentrated to give 6-Methoxy-1-methyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one as a yellow oil (quantitative yield). 1H-NMR (CDCl3) δ 7.22 (t, J=8.2 Hz, 1H), 6.80 (d, J=8.1 Hz, 1H), 6.75 (d, J=8.3 Hz, 1H), 3.84 (s, 3H), 3.33 (s, 3H), 2.52-3.09 (br pk, 2H), 2.29 (t, J=7.1 Hz, 2H), 2.12 (br s, 2H); LC/MS (ESI-pos) m/z 205.98 (M+H). to warm to room temperature and upon completion (after 30 minutes) was quenched with ice and water The aqueous solution was extracted 3× with diethyl ether the organic layers were washed with water and brine dried with MgSO4 concentrated

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 6-Methoxy-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (prepared according to: Hassner, A.; Amit, B.; Marks, V.; Gottlieb, Hugo E., J. Org. Chem. 2003, 68(18), 6853-6858.) (300 mg, 1.57 mmol) in 15 mL of DMF was cooled to 0° C. in an ice bath, and to the solution was added NaH (60% in mineral oil) (70 mg, 1.73 mmol). After 10 minutes of stirring at 0° C., Iodomethane (270 mg, 1.88 mmol) was added to the solution. The reaction was allowed to warm to room temperature and upon completion (after 30 minutes) was quenched with ice and water. The aqueous solution was extracted 3× with diethyl ether, and the organic layers were washed with water and brine, dried with MgSO4, and concentrated to give 6-Methoxy-1-methyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one as a yellow oil (quantitative yield). 1H-NMR (CDCl3) δ 7.22 (t, J=8.2 Hz, 1H), 6.80 (d, J=8.1 Hz, 1H), 6.75 (d, J=8.3 Hz, 1H), 3.84 (s, 3H), 3.33 (s, 3H), 2.52-3.09 (br pk, 2H), 2.29 (t, J=7.1 Hz, 2H), 2.12 (br s, 2H); LC/MS (ESI-pos) m/z 205.98 (M+H). to warm to room temperature and upon completion (after 30 minutes) was quenched with ice and water The aqueous solution was extracted 3× with diethyl ether the organic layers were washed with water and brine dried with MgSO4 concentrated

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

Procedure: To a solution of 6-Methoxy-1-methyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (INT-1) (538 mg, 2.62 mmol) in acetonitrile brought to 0° C. in an ice bath was added 1.8 mL TFAA (2.7 g, 13.1 mmol), followed by KNO3 (320 mg, 3.14 mmol). After approximately 5 minutes, the reaction was allowed to warm to room temperature. Conversion of starting material to product was monitored by LC/MS. Upon completion, the reaction was cooled to 0° C. in an ice bath and quenched with sat. NaHCO3 (aq), 1N NaOH (aq), and ice until pH ˜9-10 was achieved. The aqueous mixture was extracted 3× with EtOAc and the organic layers were washed with brine, dried with MgSO4, and concentrated to give 6-Methoxy-1-methyl-7-nitro-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (INT-2) as an orange solid (530 mg, 82%). By NMR, the product showed a 4:1 mixture of nitration products, 80% of which was the desired product. By TLC, the products appeared inseparable, so the material was taken on for reduction crude. Data for Major Isomer: 1H-NMR (CDCl3) δ 7.83 (d, J=8.8 Hz, 1H), 7.04 (d, J=8.8 Hz, 1H), 3.94 (s, 3H), 3.37 (s, 3H), 2.87 (br m, 2H), 2.36 (t, J=7.1 Hz, 2H), 2.24 (m, 2H); LC/MS (ESI-pos) m/z 251.03 (M+H). Upon completion, the reaction was cooled to 0° C. in an ice bath quenched with sat. NaHCO3 (aq), 1N NaOH (aq), and ice until pH ˜9-10 The aqueous mixture was extracted 3× with EtOAc the organic layers were washed with brine dried with MgSO4 concentrated

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 6-Methoxy-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (prepared according to: Hassner, A.; Amit, B.; Marks, V.; Gottlieb, Hugo E., J. Org. Chem. 2003, 68(18), 6853-6858.) (300 mg, 1.57 mmol) in 15 mL of DMF was cooled to 0° C. in an ice bath, and to the solution was added NaH (60% in mineral oil) (70 mg, 1.73 mmol). After 10 minutes of stirring at 0° C., Iodomethane (270 mg, 1.88 mmol) was added to the solution. The reaction was allowed to warm to room temperature and upon completion (after 30 minutes) was quenched with ice and water. The aqueous solution was extracted 3× with diethyl ether, and the organic layers were washed with water and brine, dried with MgSO4, and concentrated to give 6-Methoxy-1-methyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one as a yellow oil (quantitative yield). 1H-NMR (CDCl3) δ 7.22 (t, J=8.2 Hz, 1H), 6.80 (d, J=8.1 Hz, 1H), 6.75 (d, J=8.3 Hz, 1H), 3.84 (s, 3H), 3.33 (s, 3H), 2.52-3.09 (br pk, 2H), 2.29 (t, J=7.1 Hz, 2H), 2.12 (br s, 2H); LC/MS (ESI-pos) m/z 205.98 (M+H). to warm to room temperature and upon completion (after 30 minutes) was quenched with ice and water The aqueous solution was extracted 3× with diethyl ether the organic layers were washed with water and brine dried with MgSO4 concentrated

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

Procedure: To a solution of 6-Methoxy-1-methyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (INT-1) (538 mg, 2.62 mmol) in acetonitrile brought to 0° C. in an ice bath was added 1.8 mL TFAA (2.7 g, 13.1 mmol), followed by KNO3 (320 mg, 3.14 mmol). After approximately 5 minutes, the reaction was allowed to warm to room temperature. Conversion of starting material to product was monitored by LC/MS. Upon completion, the reaction was cooled to 0° C. in an ice bath and quenched with sat. NaHCO3 (aq), 1N NaOH (aq), and ice until pH ˜9-10 was achieved. The aqueous mixture was extracted 3× with EtOAc and the organic layers were washed with brine, dried with MgSO4, and concentrated to give 6-Methoxy-1-methyl-7-nitro-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (INT-2) as an orange solid (530 mg, 82%). By NMR, the product showed a 4:1 mixture of nitration products, 80% of which was the desired product. By TLC, the products appeared inseparable, so the material was taken on for reduction crude. Data for Major Isomer: 1H-NMR (CDCl3) δ 7.83 (d, J=8.8 Hz, 1H), 7.04 (d, J=8.8 Hz, 1H), 3.94 (s, 3H), 3.37 (s, 3H), 2.87 (br m, 2H), 2.36 (t, J=7.1 Hz, 2H), 2.24 (m, 2H); LC/MS (ESI-pos) m/z 251.03 (M+H). Upon completion, the reaction was cooled to 0° C. in an ice bath quenched with sat. NaHCO3 (aq), 1N NaOH (aq), and ice until pH ˜9-10 The aqueous mixture was extracted 3× with EtOAc the organic layers were washed with brine dried with MgSO4 concentrated

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 6-Methoxy-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (prepared according to: Hassner, A.; Amit, B.; Marks, V.; Gottlieb, Hugo E., J. Org. Chem. 2003, 68(18), 6853-6858.) (300 mg, 1.57 mmol) in 15 mL of DMF was cooled to 0° C. in an ice bath, and to the solution was added NaH (60% in mineral oil) (70 mg, 1.73 mmol). After 10 minutes of stirring at 0° C., Iodomethane (270 mg, 1.88 mmol) was added to the solution. The reaction was allowed to warm to room temperature and upon completion (after 30 minutes) was quenched with ice and water. The aqueous solution was extracted 3× with diethyl ether, and the organic layers were washed with water and brine, dried with MgSO4, and concentrated to give 6-Methoxy-1-methyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one as a yellow oil (quantitative yield). 1H-NMR (CDCl3) δ 7.22 (t, J=8.2 Hz, 1H), 6.80 (d, J=8.1 Hz, 1H), 6.75 (d, J=8.3 Hz, 1H), 3.84 (s, 3H), 3.33 (s, 3H), 2.52-3.09 (br pk, 2H), 2.29 (t, J=7.1 Hz, 2H), 2.12 (br s, 2H); LC/MS (ESI-pos) m/z 205.98 (M+H). to warm to room temperature and upon completion (after 30 minutes) was quenched with ice and water The aqueous solution was extracted 3× with diethyl ether the organic layers were washed with water and brine dried with MgSO4 concentrated