4-Iodo-3-methylaniline

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

Conditions: temp:95.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Chloral hyrdate (17.40 g) is dissolved in water (256 mL) with sodium sulfate (108.75 g). The solution is warmed to 60° C. whereupon hydroxylamine hydrochloride (19.95 g) in water (124 mL) was added. In a separate flask a slurry of 2-iodo 5-aminotoluene (commercially available, Buttpark Ltd, U.K.) in water (139 mL) and CHCl (7.87 mL) was prepared at 80° C. The mixtures were combined and the reaction temperature increased to 95° C. for 20 min. then cooled to room temperature and then at 0° C. for 5 min. The solids were collected by filtration and washed with water (250 mL) and dried under vacuum to afford isonitrosoacetanilide 2.1 as a tan solid. Conc. H2SO4 (75 mL) was warmed to 50° C. and isonitrosoacetanilide 2.1 was added portionwise so that the temperature did not go above 70° C. After the addition the temperature was raised to 80° C. for 10 min. and then the mixture was allowed to cool to ambient temperature and poured onto ice water (10–12× volume). The isatin was filtered and washed with cold water (4×500 mL). The 1:1 isomeric mixture was taken up in 2N NaOH solution (316 mL) and stirred for 2 h then filtered. The filtrate was acidified to approx. pH 6 with acetic acid and refiltered to remove the undesired isatin isomer. The filtrate was acidifed to pH 1 with conc. HCl and filtered and the precipitate (desired isomer 2.7 g) was washed with water and dried by suction. Isatin 2 was converted to the corresponding aldehyde (3.1) as for isatin 1.1 above. was added then cooled to room temperature The solids were collected by filtration washed with water (250 mL) dried under vacuum

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

Procedure: To a solution of 4-iodo-3-methylaniline (commercially available) (1 eq), NaHCO3 (2.5 eq), and iodomethane (2.5 eq), in DMF ((0.2M) was stirred at ambient temperature overnight. The reaction mixture was then diluted with ethyl acetate and water. The two phases were separated, and the aqueous phase was extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated en vacuo. The crude material was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 0-80% ethyl acetate in hexane and 4-iodo-N,N,3-trimethylaniline was isolated as a yellow solid. The two phases were separated the aqueous phase was extracted twice with ethyl acetate The combined organic layers were washed with brine dried over sodium sulfate concentrated en vacuo The crude material was purified by flash chromatography on a COMBIFLASH® system (ISCO) was isolated as a yellow solid

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

Procedure: To a solution of 4-iodo-3-methylaniline (200 mg, 0.86 mmol) in benzene (5 mL) in a sealable tube was added 1-isocyanato-3-(trifluoromethyl)benzene (0.133 mL, 0.94 mL; “E” is an electrophilic group discussed in scheme 3, and here is an isocyanate). The tube was sealed and heated at 90° C. for 4 h. The mixture was allowed to cool to room temperature before filtering. The off white solid was washed with additional benzene (10 mL) and used without further purification. The tube was sealed to cool to room temperature before filtering The off white solid was washed with additional benzene (10 mL) used without further purification

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

Procedure: To a solution of 4-iodo-3-methyl aniline (200 mg, 0.86 mmol) and iPr2NEt (0.19 mL, 0.95 mmol) in CH2Cl2 (10 mL) was added 3-(trifluoromethyl)benzoyl chloride (0.133 mL, 0.90 mmol). The mixture was allowed to stir at room temperature for 0.5 h at which time it was diluted with CH2Cl2 (20 mL). The organic layer was washed with aq. HCl (10 mL, 1 M), 9% aq. Na2CO3 (10 mL), brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting oil was used without further purification. The organic layer was washed with aq. HCl (10 mL, 1 M), 9% aq. Na2CO3 (10 mL), brine dried over anhydrous sodium sulfate filtered concentrated under reduced pressure The resulting oil was used without further purification

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

Procedure: 2-Chloroisonicotinic acid (3.3 g, 21 mmol), HATU (8.75 g, 23 mmol), diisopropylethyl amine (10.9 ml, 63 mmol) and 4-iodo-3-methylaniline (5.00 g, 21 mmol) in dimethylformamide (50 ml) were heated under nitrogen for 16 hours. The reaction was cooled, solvent removed in vacuo and the residue taken up in dichloromethane (150 ml). The organic solution was washed with water (3×100 ml) and brine (100 ml), dried over magnesium sulfate, filtered and solvent removed in vacuo. The residue was purified by column chromatography (40:60 ethyl acetate: cyclohexane) to give 2-chloro-N-(3-iodo-4-methylphenyl)-isonicotinamide as a white solid (7.00 g, 18.8 mmol). LCMS: retention time 3.59 min MH− 373. NMR: δH [2H6]-DMSO 10.52 (1H, s), 8.62 (1H, d), 8.29 (1H, d), 7.99 (1H, b), 7.87 (1H, dd), 7.70 (1H, dd), 7.34 (1H, d), 2.36 (3H, s). The reaction was cooled solvent removed in vacuo The organic solution was washed with water (3×100 ml) and brine (100 ml) dried over magnesium sulfate filtered solvent removed in vacuo The residue was purified by column chromatography (40:60 ethyl acetate: cyclohexane)

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

Procedure: A solution of 4-iodo-3-methylaniline (4.37 g, 18.75 mmol) in CH2Cl2 (25 ml) was treated with pyridine (6.07 ml, 75 mmol) followed by drop wise addition of methanesulfonyl chloride (1.607 ml, 20.63 mmol) to give a reddish/orange mixture. The mixture was stirred for 2 h, concentrated and diluted with EtOAc. The EtOAc layer was washed with 1M HCl, water, saturated NaCl, dried (Na2SO4) and filtered. The EtOAc filtrate was treated with activated charcoal for 30 min at 50° C. and filtered through a 10 g silica plug and concentrated to give the title compound as a light yellow solid (5.5 g, 94%). to give a reddish/orange mixture concentrated diluted with EtOAc The EtOAc layer was washed with 1M HCl, water, saturated NaCl dried (Na2SO4) filtered The EtOAc filtrate was treated with activated charcoal for 30 min at 50° C. filtered through a 10 g silica plug concentrated

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

Procedure: To a solution of 4-iodo-3-methylaniline (200 mg, 0.86 mmol) in benzene (5 mL) in a sealable tube was added 1-isocyanato-3-(trifluoromethyl)benzene (0.133 mL, 0.94 mL; “E” is an electrophilic group disussed in scheme 3, and here is an isocyanate). The tube was sealed and heated at 90° C. for 4 h. The mixture was allowed to cool to room temperature before filtering. The off white solid was washed with additional benzene (10 mL) and used without further purification. The tube was sealed to cool to room temperature before filtering The off white solid was washed with additional benzene (10 mL) used without further purification

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

Procedure: To a solution of 4-iodo-3-methylaniline (200 mg, 0.86 mmol) in benzene (5 mL) in a sealable tube was added 1-isocyanato-3-(trifluoromethyl)benzene (0.133 mL, 0.94 mL; “E” is an electrophilic group disussed in scheme 3, and here is an isocyanate). The tube was sealed and heated at 90° C. for 4 h. The mixture was allowed to cool to room temperature before filtering. The off white solid was washed with additional benzene (10 mL) and used without further purification. The tube was sealed to cool to room temperature before filtering The off white solid was washed with additional benzene (10 mL) used without further purification

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

Procedure: To a solution of 4-iodo-3-methyl aniline (200 mg, 0.86 mmol) and iPr2NEt (0.19 mL, 0.95 mmol) in CH2Cl2 (10 mL) was added 3-(trifluoromethyl)benzoyl chloride (0.133 mL, 0.90 mmol). The mixture was allowed to stir at room temperature for 0.5 h at which time it was diluted with CH2Cl2 (20 mL). The organic layer was washed with aq. HCl (10 mL, 1 M), 9% aq. Na2CO3 (10 mL), brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting oil was used without further purification. The organic layer was washed with aq. HCl (10 mL, 1 M), 9% aq. Na2CO3 (10 mL), brine dried over anhydrous sodium sulfate filtered concentrated under reduced pressure The resulting oil was used without further purification

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

Procedure: To a solution of 4-iodo-3-methyl aniline (200 mg, 0.86 mmol) and iPr2NEt (0.19 mL, 0.95 mmol) in CH2Cl2 (10 mL) was added 3-(trifluoromethyl)benzoyl chloride (0.133 mL, 0.90 mmol). The mixture was allowed to stir at room temperature for 0.5 h at which time it was diluted with CH2Cl2 (20 mL). The organic layer was washed with aq. HCl (10 mL, 1 M), 9% aq. Na2CO3 (10 mL), brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting oil was used without further purification. The organic layer was washed with aq. HCl (10 mL, 1 M), 9% aq. Na2CO3 (10 mL), brine dried over anhydrous sodium sulfate filtered concentrated under reduced pressure The resulting oil was used without further purification

Conditions: temp:95.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Chloral hyrdate (17.40 g) is dissolved in water (256 mL) with sodium sulfate (108.75 g). The solution is warmed to 60° C. whereupon hydroxylamine hydrochloride (19.95 g) in water (124 mL) was added. In a separate flask a slurry of 2-iodo 5-aminotoluene (commercially available, Buttpark Ltd, U.K.) in water (139 mL) and CHCl (7.87 mL) was prepared at 80° C. The mixtures were combined and the reaction temperature increased to 95° C. for 20 min. then cooled to room temperature and then at 0° C. for 5 min. The solids were collected by filtration and washed with water (250 mL) and dried under vacuum to afford isonitrosoacetanilide 2.1 as a tan solid. Conc. H2SO4 (75 mL) was warmed to 50° C. and isonitrosoacetanilide 2.1 was added portionwise so that the temperature did not go above 70° C. After the addition the temperature was raised to 80° C. for 10 min. and then the mixture was allowed to cool to ambient temperature and poured onto ice water (10–12× volume). The isatin was filtered and washed with cold water (4×500 mL). The 1:1 isomeric mixture was taken up in 2N NaOH solution (316 mL) and stirred for 2 h then filtered. The filtrate was acidified to approx. pH 6 with acetic acid and refiltered to remove the undesired isatin isomer. The filtrate was acidifed to pH 1 with conc. HCl and filtered and the precipitate (desired isomer 2.7 g) was washed with water and dried by suction. Isatin 2 was converted to the corresponding aldehyde (3.1) as for isatin 1.1 above. was added then cooled to room temperature The solids were collected by filtration washed with water (250 mL) dried under vacuum