tert-butyl N-(2-methoxyphenyl)carbamate

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

Conditions: temp:-20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To tert-butyl 2-methoxyphenylcarbamate (24.1 g, 108 mmol) in dry Et2O (100 mL) at −20° C. was added dropwise tert-butyllithium (140 ml, 237 mmol). The clear solution turned cloudy at the end of the addition. The reaction was stirred for 3 hours at −20° C., then cooled to −100° C. with a liquid N2/Et2O bath. Iodine (27.4 g, 108 mmol) in Et2O (250 mL) was added to the solution. Following addition of I2, the reaction was slowly warmed to ambient temperature over night. Na2S2O3 (saturated, 200 mL) was then added to the reaction mix and phases were separated. The aqueous was extracted with Et2O, and the combined organic layers were dried (MgSO4), filtered and concentrated. DCM (50 mL) was added, followed by hexanes (200 mL). The solution was concentrated to remove DCM. The product crashed out, and was collected by filtration and washed with hexanes (100 mL) to give the crude product (58%). The clear solution turned cloudy at the end of the addition cooled to −100° C. with a liquid N2/Et2O bath the reaction was slowly warmed to ambient temperature over night mix phases were separated The aqueous was extracted with Et2O the combined organic layers were dried (MgSO4) filtered concentrated DCM (50 mL) was added The solution was concentrated to remove DCM was collected by filtration washed with hexanes (100 mL)

Conditions: temp:-20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To tert-butyl 2-methoxyphenylcarbamate (24.1 g, 108 mmol) in dry Et2O (100 mL) at −20° C. was added dropwise tert-butyllithium (140 ml, 237 mmol). The clear solution turned cloudy at the end of the addition. The reaction was stirred for 3 hours at −20° C., then cooled to −100° C. with a liquid N2/Et2O bath. Iodine (27.4 g, 108 mmol) in Et2O (250 mL) was added to the solution. Following addition of I2, the reaction was slowly warmed to ambient temperature over night. Na2S2O3 (saturated, 200 mL) was then added to the reaction mix and phases were separated. The aqueous was extracted with Et2O, and the combined organic layers were dried (MgSO4), filtered and concentrated. DCM (50 mL) was added, followed by hexanes (200 mL). The solution was concentrated to remove DCM. The product crashed out, and was collected by filtration and washed with hexanes (100 mL) to give the crude product (58%). The clear solution turned cloudy at the end of the addition cooled to −100° C. with a liquid N2/Et2O bath the reaction was slowly warmed to ambient temperature over night mix phases were separated The aqueous was extracted with Et2O the combined organic layers were dried (MgSO4) filtered concentrated DCM (50 mL) was added The solution was concentrated to remove DCM was collected by filtration washed with hexanes (100 mL)

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a cold (−23° C.), stirred solution of tert-butyl 2-methoxyphenylcarbamate (548 mg, 2.454 mmol) in ether (6 mL) under N2 was added t-BuLi (3.2 mL, 5.44 mmol). After stirring for 2.5 h, the reaction mixture was cooled to −78° C. To the reaction mixture was added a solution of ethyl 5-chloropicolinate (564.5 mg, 3.04 mmol) in ether (12 mL) dropwise via cannula over 5 min. The reaction mixture was stirred for 60 min, and then warmed to room temperature. After 1.5 h, to the reaction mixture was added H2O with vigorous stirring. The reaction mixture was diluted with EtOAc, and the organic phase was separated, washed with sat NaCl then dried (Na2SO4), filtered and concentrated to yield the product Intermediate A-29A (511.5 mg, 57.4% yield)) as a yellow solid: 1H NMR (400 MHz, chloroform-d) δ ppm 8.55 (1H, dd, J=2.3, 0.6 Hz), 8.08 (1H, dd, J=8.4, 0.7 Hz), 7.80 (1H, dd, J=8.4, 2.4 Hz), 7.16-7.25 (2H, m), 7.06 (1H, dd, J=7.5, 2.2 Hz), 6.90 (1H, s), 3.92 (3H, s), 1.28 (9H, s). The reaction mixture was stirred for 60 min warmed to room temperature After 1.5 h the organic phase was separated washed with sat NaCl then dried (Na2SO4) filtered concentrated to yield the product Intermediate A-29A (511.5 mg, 57.4% yield)) as a yellow solid

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a cold (−23° C.), stirred solution of tert-butyl 2-methoxyphenylcarbamate (548 mg, 2.454 mmol) in ether (6 mL) under N2 was added t-BuLi (3.2 mL, 5.44 mmol). After stirring for 2.5 h, the reaction mixture was cooled to −78° C. To the reaction mixture was added a solution of ethyl 5-chloropicolinate (564.5 mg, 3.04 mmol) in ether (12 mL) dropwise via cannula over 5 min. The reaction mixture was stirred for 60 min, and then warmed to room temperature. After 1.5 h, to the reaction mixture was added H2O with vigorous stirring. The reaction mixture was diluted with EtOAc, and the organic phase was separated, washed with sat NaCl then dried (Na2SO4), filtered and concentrated to yield the product Intermediate A-29A (511.5 mg, 57.4% yield)) as a yellow solid: 1H NMR (400 MHz, chloroform-d) δ ppm 8.55 (1H, dd, J=2.3, 0.6 Hz), 8.08 (1H, dd, J=8.4, 0.7 Hz), 7.80 (1H, dd, J=8.4, 2.4 Hz), 7.16-7.25 (2H, m), 7.06 (1H, dd, J=7.5, 2.2 Hz), 6.90 (1H, s), 3.92 (3H, s), 1.28 (9H, s). The reaction mixture was stirred for 60 min warmed to room temperature After 1.5 h the organic phase was separated washed with sat NaCl then dried (Na2SO4) filtered concentrated to yield the product Intermediate A-29A (511.5 mg, 57.4% yield)) as a yellow solid

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a cold (−23° C.), stirred solution of tert-butyl 2-methoxyphenylcarbamate (443.3 mg, 1.986 mmol) in ether (5 mL) under N2 was added t-BuLi (2.6 mL, 4.42 mmol). The reaction mixture was stirred for 2 h, and then cooled to −78° C. To the reaction mixture was added a solution of methyl 5-(trifluoromethyl)picolinate (501.3 mg, 2.44 mmol) in ether (10 mL) dropwise via cannula over 5 min. After 2 h, the reaction mixture was warmed to room temperature, stirred for an additional hour, and then the reaction was quenched by the addition of water with vigorous stirring. The reaction mixture was diluted with EtOAc, the organic phase was separated, washed with sat NaCl then dried (Na2SO4), filtered and concentrated to yield a yellow solid. The residue was purified by flash chromatography (Teledyne ISCO CombiFlash Rf, 0% to 100% solvent A/B=hexane/EtOAc, REDISEP® SiO2 40 g) to obtained Intermediate A-28A (546.8 mg, 69.5% yield)) as a yellow solid: 1H NMR (400 MHz, chloroform-d) δ ppm 8.83-8.88 (1H, m), 8.24 (1H, d, J=8.4 Hz), 8.07 (1H, dd, J=8.4, 1.8 Hz), 7.25 (1H, d, J=1.5 Hz), 7.18-7.24 (1H, m), 7.09 (1H, dd, J=8.0, 1.7 Hz), 6.95 (1H, s), 3.93 (3H, s), 1.25 (9H, s). After 2 h the reaction mixture was warmed to room temperature stirred for an additional hour the reaction was quenched by the addition of water with vigorous stirring The reaction mixture was diluted with EtOAc the organic phase was separated washed with sat NaCl then dried (Na2SO4) filtered concentrated to yield a yellow solid The residue was purified by flash chromatography (Teledyne ISCO CombiFlash Rf, 0% to 100% solvent A/B=hexane/EtOAc, REDISEP® SiO2 40 g) to obtained Intermediate A-28A (546.8 mg, 69.5% yield)) as a yellow solid

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

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a cold (−23° C.), stirred solution of tert-butyl 2-methoxyphenylcarbamate (548 mg, 2.454 mmol) in ether (6 mL) under N2 was added t-BuLi (3.2 mL, 5.44 mmol). After stirring for 2.5 h, the reaction mixture was cooled to −78° C. To the reaction mixture was added a solution of ethyl 5-chloropicolinate (564.5 mg, 3.04 mmol) in ether (12 mL) dropwise via cannula over 5 min. The reaction mixture was stirred for 60 min, and then warmed to room temperature. After 1.5 h, to the reaction mixture was added H2O with vigorous stirring. The reaction mixture was diluted with EtOAc, and the organic phase was separated, washed with sat NaCl then dried (Na2SO4), filtered and concentrated to yield the product Intermediate A-29A (511.5 mg, 57.4% yield)) as a yellow solid: 1H NMR (400 MHz, chloroform-d) δ ppm 8.55 (1 H, dd, J=2.3, 0.6 Hz), 8.08 (1 H, dd, J=8.4, 0.7 Hz), 7.80 (1 H, dd, J=8.4, 2.4Hz), 7.16-7.25 (2 H, m), 7.06 (1 H, dd, J=7.5, 2.2Hz), 6.90 (1 H, s), 3.92 (3 H, s), 1.28 (9 H, s). The reaction mixture was stirred for 60 min warmed to room temperature After 1.5 h the organic phase was separated washed with sat NaCl then dried (Na2SO4) filtered concentrated to yield the product Intermediate A-29A (511.5 mg, 57.4% yield)) as a yellow solid

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a cold (−23° C.), stirred solution of tert-butyl 2-methoxyphenylcarbamate (443.3 mg, 1.986 mmol) in ether (5 mL) under N2 was added t-BuLi (2.6 mL, 4.42 mmol). The reaction mixture was stirred for 2 h, and then cooled to −78° C. To the reaction mixture was added a solution of methyl 5-(trifluoromethyl)picolinate (501.3 mg, 2.44 mmol) in ether (10 mL) dropwise via cannula over 5 min. After 2 h, the reaction mixture was warmed to room temperature, stirred for an additional hour, and then the reaction was quenched by the addition of water with vigorous stirring. The reaction mixture was diluted with EtOAc, the organic phase was separated, washed with sat NaCl then dried (Na2SO4), filtered and concentrated to yield a yellow solid. The residue was purified by flash chromatography (Teledyne ISCO CombiFlash Rf, 0% to 100% solvent A/B=hexane/EtOAc, REDISEP® SiO2 40 g) to obtained Intermediate A-28A (546.8 mg, 69.5% yield)) as a yellow solid: 1H NMR (400 MHz, chloroform-d) δ ppm 8.83-8.88 (1 H, m), 8.24 (1 H, d, J=8.4Hz), 8.07 (1 H, dd, J=8.4, 1.8 Hz), 7.25 (1 H, d, J=1.5 Hz), 7.18-7.24 (1 H, m), 7.09 (1 H, dd, J=8.0, 1.7 Hz), 6.95 (1 H, s), 3.93 (3 H, s), 1.25 (9 H, s). After 2 h the reaction mixture was warmed to room temperature stirred for an additional hour the reaction was quenched by the addition of water with vigorous stirring The reaction mixture was diluted with EtOAc the organic phase was separated washed with sat NaCl then dried (Na2SO4) filtered concentrated to yield a yellow solid The residue was purified by flash chromatography (Teledyne ISCO CombiFlash Rf, 0% to 100% solvent A/B=hexane/EtOAc, REDISEP® SiO2 40 g) to obtained Intermediate A-28A (546.8 mg, 69.5% yield)) as a yellow solid

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

Procedure: 0.35 g of tert-butyl-N-(2-methoxyphenyl)carbamate (theoretically 2 mmol/g) bonded on solid support 8 is reacted with 0.5 ml (7 mmol, 10 eq) of a 20% solution of TFA/CH2Cl2 at room temperature for 1 hour. The resin is filtered on a scintered filter and rinsed with CH2Cl2 and MeOH. Then, the filtrate is concentrated under vacuum, taken up in CH2Cl2, washed with a saturated aqueous NaHCO3 solution. After drying on MgSO4 and evaporation of the solvent, 31.1 mg of 2-methoxyaniline is obtained and characterized by the 1H NMR spectrum and compared with the commercial product (yield: 36%). An IR control of the resin showed that the cleavage was not complete (presence of a carbonyl band at 1729 cm−1). The resin was then reacted again with 10 equivalents of a 20% solution of TFA/CH2Cl2 for 15 hours at room temperature. After an identical treatment, 13.8 g of pure 2-methoxyaniline were obtained (overall yield: 52%). The resin is filtered on a scintered filter rinsed with CH2Cl2 and MeOH Then, the filtrate is concentrated under vacuum washed with a saturated aqueous NaHCO3 solution After drying on MgSO4 and evaporation of the solvent

Conditions: temp:-20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To tert-butyl 2-methoxyphenylcarbamate (24.1 g, 108 mmol) in dry Et2O (100 mL) at −20° C. was added dropwise tert-butyllithium (140 ml, 237 mmol). The clear solution turned cloudy at the end of the addition. The reaction was stirred for 3 hours at −20° C., then cooled to −100° C. with a liquid N2/Et2O bath. Iodine (27.4 g, 108 mmol) in Et2O (250 mL) was added to the solution. Following addition of I2, the reaction was slowly warmed to ambient temperature over night. Na2S2O3 (saturated, 200 mL) was then added to the reaction mix and phases were separated. The aqueous was extracted with Et2O, and the combined organic layers were dried (MgSO4), filtered and concentrated. DCM (50 mL) was added, followed by hexanes (200 mL). The solution was concentrated to remove DCM. The product crashed out, and was collected by filtration and washed with hexanes (100 mL) to give the crude product (58%). The clear solution turned cloudy at the end of the addition cooled to −100° C. with a liquid N2/Et2O bath the reaction was slowly warmed to ambient temperature over night mix phases were separated The aqueous was extracted with Et2O the combined organic layers were dried (MgSO4) filtered concentrated DCM (50 mL) was added The solution was concentrated to remove DCM was collected by filtration washed with hexanes (100 mL)

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a cold (−23° C.), stirred solution of tert-butyl 2-methoxyphenylcarbamate (548 mg, 2.454 mmol) in ether (6 mL) under N2 was added t-BuLi (3.2 mL, 5.44 mmol). After stirring for 2.5 h, the reaction mixture was cooled to −78° C. To the reaction mixture was added a solution of ethyl 5-chloropicolinate (564.5 mg, 3.04 mmol) in ether (12 mL) dropwise via cannula over 5 min. The reaction mixture was stirred for 60 min, and then warmed to room temperature. After 1.5 h, to the reaction mixture was added H2O with vigorous stirring. The reaction mixture was diluted with EtOAc, and the organic phase was separated, washed with sat NaCl then dried (Na2SO4), filtered and concentrated to yield the product Intermediate A-29A (511.5 mg, 57.4% yield)) as a yellow solid: 1H NMR (400 MHz, chloroform-d) δ ppm 8.55 (1H, dd, J=2.3, 0.6 Hz), 8.08 (1H, dd, J=8.4, 0.7 Hz), 7.80 (1H, dd, J=8.4, 2.4 Hz), 7.16-7.25 (2H, m), 7.06 (1H, dd, J=7.5, 2.2 Hz), 6.90 (1H, s), 3.92 (3H, s), 1.28 (9H, s). The reaction mixture was stirred for 60 min warmed to room temperature After 1.5 h the organic phase was separated washed with sat NaCl then dried (Na2SO4) filtered concentrated to yield the product Intermediate A-29A (511.5 mg, 57.4% yield)) as a yellow solid