3-chloro-2-methylaniline

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:

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:

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

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

Procedure: 3-Chloro-2-methylaniline was treated with t-butylnitrite in excess thiophene as described in J. Chem. Soc., 4257 (1963) to produce 2-(3-chloro-2-methylphenyl)thiophene as an oil. Reaction of the oil with N-bromosuccinimide as described in J. Am. Chem. Soc., 89, 2348 (1967) yielded 2-(2-bromomethyl-3-chlorophenyl)thiophene as an oil, which was reacted without further purification, as described in J. Chem. Soc., 2708 (1955), with diethyl malonate in the presence of tetrabutyl ammonium bromide and potassium hydroxide in dry tetrahydrofuran, producing ethyl [2-carboethoxy-3-[2-chloro-6-(thien-2-yl)phenyl]]propionate. Hydrolysis of the latter with hydrochloric acid in glacial acetic acid provided 3-[2-chloro-6-(thien-2-yl)phenyl]propionic acid; mp 83°-86°.

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

Procedure: To a stirred solution of 3-chloro-2-methylaniline (21.6 g, 0.15 mol) in n-butanol (200 ml) was added bis(2-chloroethyl)amine hydrochloride (30 g, 0.17 mol) at room temperature and allowed to refluxed temperature for 2 days. After cooled to room temperature Na2CO3 (9 g, 0.08 mol) was added and then reaction mixture was refluxed 30 min. The resulting mixture was filtered with n-butanol (100 ml) and collected solid was dried under reduced pressure to be obtained title compound (24.8 g, 81%) as white solid. to refluxed temperature for 2 days was added reaction mixture was refluxed 30 min The resulting mixture was filtered with n-butanol (100 ml) collected solid was dried under reduced pressure

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

Procedure: To a 250 ml flask with stir bar was added 2-methyl-3-chloroaniline (8.4 ml, 9.95 g, 70.6 mmol), potassium acetate (8.3 g, 84.7 mmol) and chloroform (120 ml). This mixture was cooled to 0° C. with stirring. To the cooled mixture was added acetic anhydride (20.0 ml, 212 mmol) drop wise over 2 minutes. The reaction mixture was warmed to 25° C. and stirred for 1 hour. At this point, the reaction was heated to 60° C. Isoamyl nitrite (18.9 ml, 141 mmol) was added and the reaction was stirred overnight at 60° C. Once complete, water (75 ml) and THF (150 ml) were added and the reaction was cooled to 0° C. LiOH (20.7 g, 494 mmol) was added and the reaction was stirred at 0° C. for 3 hours. Water (200 ml) was added and the product was extracted with EtOAc (300 ml, 100 ml). The organic layers were combined, dried with MgSO4 and concentrated in vacuo to yield 4-chloro-1H-indazole 11.07 g (100%) as an orange solid. 1H NMR (400 MHz, CDCl3) δ 8.18 (d, J=1 Hz, 1H), 7.33 (d, J=8 Hz 1H), 7.31 (t, J=7 Hz, 1H), 7.17 (dd, J=7 Hz, 1 Hz 1H). LCMS (ESI pos) m/e 153 (M+1). with stirring The reaction mixture was warmed to 25° C. stirred for 1 hour At this point, the reaction was heated to 60° C the reaction was stirred overnight at 60° C the reaction was cooled to 0° C the reaction was stirred at 0° C. for 3 hours the product was extracted with EtOAc (300 ml, 100 ml) dried with MgSO4 concentrated in vacuo