Diethyl 2-((4-bromophenylamino)methylene)malonate

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

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

Procedure: 2-[(4-Bromophenylamino)methylene]malonic acid diethyl ester (5 g) was heated with POCl3 (phosphoryl chloride, 31.5 mL) at 150° C. in a sealed tube for about 6 h. The excess POCl3 was removed by rotavapor and the crude mixture was diluted with dichloromethane. The dichloromethane extract was washed with 10% NaOH solution, dried over sodium sulphate and purified by column chromatography (Silica gel, hexane/ethyl acetate 80:20) to give 2.3 g (50%) of 6-bromo-4-chloroquinoline-3-carboxylic acid ethyl ester. 1H NMR (300 MHz, CDCl3) δ 9.22 (s, 1H, aromatic), 8.60 (d, 1H, J=2.1 Hz, aromatic), 8.04 (d, 1H, J=9 Hz, aromatic), 7.95-7.85 (m, 1H, aromatic), 4.53 (q, 2H, J=7 Hz, —CH2—), 1.50 (t, 3H, J=7 Hz, —CH3); LC-MS (m/z) 315.8 (M+1). The excess POCl3 was removed by rotavapor the crude mixture was diluted with dichloromethane The dichloromethane extract was washed with 10% NaOH solution dried over sodium sulphate purified by column chromatography (Silica gel, hexane/ethyl acetate 80:20)

Conditions: temp:180.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A 20 mL microwave vial was charged with 2-[(4-bromo-phenylamino)methylene]malonic acid diethyl ester (1.711 g, 5.0 mmol) and POCl3 (phosphoryl chloride, 10.0 mL, 16.8 g, 109 mmol). The vial was capped and the mixture was microwave heated stepwise up to 180° C. (watching the pressure) over 5 min and then kept at 180° C. for 30 min Excess POCl3 was evaporated and the residue partitioned between CH2Cl2 (40 mL) and 2 N NaOH (aq) (40 mL). The aqueous layer was extracted with CH2Cl2 (2×40 mL). The organic layers were combined, dried with Na2CO3 and evaporated. The residue was purified on column (silica gel, CH2Cl2 as eluent). Pure fractions were pooled, evaporated and the residue dried under vacuum to give 0.821 g (52%) of 6-bromo-4-chloroquinoline-3-carboxylic acid ethyl ester. MS (ESI+) m/z 314, 316 (MH+). The vial was capped over 5 min Excess POCl3 was evaporated the residue partitioned between CH2Cl2 (40 mL) and 2 N NaOH (aq) (40 mL) The aqueous layer was extracted with CH2Cl2 (2×40 mL) dried with Na2CO3 evaporated The residue was purified on column (silica gel, CH2Cl2 as eluent) evaporated the residue dried under vacuum

Conditions: temp:150.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A 20 mL microwave vial was charged with 4-bromoaniline (6.881 g, 40.0 mmol), diethyl ethoxymethylenemalonate (8.650 g, 40.0 mmol) and toluene (5 mL). The vial was capped and the mixture was microwave heated at 150° C. for 30 min. After cooling, the solution was poured onto 50 mL of vigorously stirred iso-hexane. A thick, white precipitate formed and the suspension was stirred for another 15 min. The suspension was filtered and the product washed with 20 mL of iso-hexane. The product was dried under vacuum to give 11.678 g (85%) of 2-[(4-bromo-phenylamino)methylene]malonic acid diethyl ester. MS (ESI+) m/z 342, 344 (MH+). The vial was capped After cooling A thick, white precipitate formed The suspension was filtered the product washed with 20 mL of iso-hexane The product was dried under vacuum

Conditions: temp:150.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A 20 mL microwave vial was charged with 4-bromoaniline (6.881 g, 40.0 mmol), diethyl ethoxymethylenemalonate (8.650 g, 40.0 mmol) and toluene (5 mL). The vial was capped and the mixture was microwave heated at 150° C. for 30 min. After cooling, the solution was poured onto 50 mL of vigorously stirred iso-hexane. A thick, white precipitate formed and the suspension was stirred for another 15 min. The suspension was filtered and the product washed with 20 mL of iso-hexane. The product was dried under vacuum to give 11.678 g (85%) of 2-[(4-bromo-phenylamino)methylene]malonic acid diethyl ester. MS (ESI+) m/z 342, 344 (MH+). The vial was capped After cooling A thick, white precipitate formed The suspension was filtered the product washed with 20 mL of iso-hexane The product was dried under vacuum

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The solid 2-[(4-bromo-phenylamino)-methylene]-malonic acid diethyl ester (157 g, 458.8 mmol) was added to a hot diphenyl ether (260 g) and the mixture was heated to reflux for 5 h to afford a brown suspension. Then, the mixture was cooled to 100° C. and diluted with ethanol (˜200 mL). This suspension was refluxed for 10 min and then cooled to room temperature. The solids were collected by filtration and washed with diethyl ether. After drying in air, 132.59 g (97.6% yield) of 6-bromo-4-hydroxy-quinoline-3-carboxylic acid ethyl ester was isolated as a white solid: EI-HRMS m/e calcd for C8H6N2O (M+) 146.0480, found 146.0478. the mixture was heated to reflux for 5 h to afford a brown suspension This suspension was refluxed for 10 min cooled to room temperature The solids were collected by filtration washed with diethyl ether After drying in air

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The solid 2-[(4-bromo-phenylamino)-methylene]-malonic acid diethyl ester (157 g, 458.8 mmol) was added to a hot diphenyl ether (260 g) and the mixture was heated to reflux for 5 h to afford a brown suspension. Then, the mixture was cooled to 100° C. and diluted with ethanol (˜200 mL). This suspension was refluxed for 10 min and then cooled to room temperature. The solids were collected by filtration and washed with diethyl ether. After drying in air, 132.59 g (97.6% yield) of 6-bromo-4-hydroxy-quinoline-3-carboxylic acid ethyl ester was isolated as a white solid: EI-HRMS m/e calcd for C8H6N2O (M+) 146.0480, found 146.0478. the mixture was heated to reflux for 5 h to afford a brown suspension This suspension was refluxed for 10 min cooled to room temperature The solids were collected by filtration washed with diethyl ether After drying in air

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 4-bromoaniline (100 g, 563.9 mmol) and 2-ethoxymethylene-malonic acid diethyl ester (126.9 g, 575 mmol) was heated to 90° C. Then, the resulting brown mixture was stirred for 5 h. After cooling to room temperature, the reaction mixture was diluted with ethanol (˜200 mL) and cooled down in an ice-water bath to afford a hard solid. This mixture was then heated to break down the hard solid and also to remove most of the impurities. After cooling the suspension in the refrigerator, the solids were collected by filtration and washed with cold ethanol. After drying in air, 168 g (87% yield) of 2-[(4-bromo-phenylamino)-methylene]-malonic acid diethyl ester was isolated as a white solid: mp 100-102° C. (lit. 100-101° C.). After cooling to room temperature cooled down in an ice-water bath to afford a hard solid This mixture was then heated also to remove most of the impurities After cooling the suspension in the refrigerator the solids were collected by filtration washed with cold ethanol After drying in air

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

Procedure: 2-[(4-Bromophenylamino)methylene]malonic acid diethyl ester (5 g) was heated with POCl3 (phosphoryl chloride, 31.5 mL) at 150° C. in a sealed tube for about 6 h. The excess POCl3 was removed by rotavapor and the crude mixture was diluted with dichloromethane. The dichloromethane extract was washed with 10% NaOH solution, dried over sodium sulphate and purified by column chromatography (Silica gel, hexane/ethyl acetate 80:20) to give 2.3 g (50%) of 6-bromo-4-chloroquinoline-3-carboxylic acid ethyl ester. 1H NMR (300 MHz, CDCl3) δ 9.22 (s, 1H, aromatic), 8.60 (d, 1H, J=2.1 Hz, aromatic), 8.04 (d, 1H, J=9 Hz, aromatic), 7.95-7.85 (m, 1H, aromatic), 4.53 (q, 2H, J=7 Hz, —CH2—), 1.50 (t, 3H, J=7 Hz, —CH3); LC-MS (m/z) 315.8 (M+1). The excess POCl3 was removed by rotavapor the crude mixture was diluted with dichloromethane The dichloromethane extract was washed with 10% NaOH solution dried over sodium sulphate purified by column chromatography (Silica gel, hexane/ethyl acetate 80:20)

Conditions: temp:180.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A 20 mL microwave vial was charged with 2-[(4-bromo-phenylamino)methylene]malonic acid diethyl ester (1.711 g, 5.0 mmol) and POCl3 (phosphoryl chloride, 10.0 mL, 16.8 g, 109 mmol). The vial was capped and the mixture was microwave heated stepwise up to 180° C. (watching the pressure) over 5 min and then kept at 180° C. for 30 min. Excess POCl3 was evaporated and the residue partitioned between CH2Cl2 (40 mL) and 2 N NaOH (aq) (40 mL). The aqueous layer was extracted with CH2Cl2 (2×40 mL). The organic layers were combined, dried with Na2CO3 and evaporated. The residue was purified on column (silica gel, CH2Cl2 as eluent). Pure fractions were pooled, evaporated and the residue dried under vacuum to give 0.821 g (52%) of 6-bromo-4-chloroquinoline-3-carboxylic acid ethyl ester. MS (ESI+) m/z 314, 316 (MH+). The vial was capped over 5 min Excess POCl3 was evaporated the residue partitioned between CH2Cl2 (40 mL) and 2 N NaOH (aq) (40 mL) The aqueous layer was extracted with CH2Cl2 (2×40 mL) dried with Na2CO3 evaporated The residue was purified on column (silica gel, CH2Cl2 as eluent) evaporated the residue dried under vacuum

Conditions: temp:150.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A 20 mL microwave vial was charged with 4-bromoaniline (6.881 g, 40.0 mmol), diethyl ethoxymethylenemalonate (8.650 g, 40.0 mmol) and toluene (5 mL). The vial was capped and the mixture was microwave heated at 150° C. for 30 min. After cooling, the solution was poured onto 50 mL of vigorously stirred iso-hexane. A thick, white precipitate formed and the suspension was stirred for another 15 min. The suspension was filtered and the product washed with 20 mL of iso-hexane. The product was dried under vacuum to give 11.678 g (85%) of 2-[(4-bromo-phenylamino)methylene]malonic acid diethyl ester. MS (EST+) m/z 342, 344 (MH+). The vial was capped After cooling A thick, white precipitate formed The suspension was filtered the product washed with 20 mL of iso-hexane The product was dried under vacuum

Conditions: temp:240.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Diphenyl ether (870 mL) was heated to 240° C. then diethyl 2-[[(4-bromophenyl)amino]methylidene]propanedioate (75 g, 219.18 mmol) added portionwise. The mixture was stirred at 240° C. for 60 minutes in a flask fitted with clean-stark apparatus. After cooling (25° C.) a crystallized solid was formed. The mixture was diluted with Et2O and the solid was collected by filtration, washed with Et2O and dried to afford the desired material (59.9 g) as a beige crystallized solid, which was used without purification or characterisation. fitted with clean-stark apparatus After cooling (25° C.) a crystallized solid was formed the solid was collected by filtration washed with Et2O dried