7-chloro-1H-indole-2,3-dione

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: A Grignard reagent prepared from 62 g. magnesium, 400 g. bromobenzene in two liters tetrahydrofuran (THF) is added to 181 g. (1.0 mole) 7-chloroisatin (1a) in two liters THF at a rate to keep a gentle reflux. After three hours of reflux, the reaction is cooled and decomposed with 350 ml. saturated ammonium chloride, filtered, and the THF stripped to give a dark oil. The oil is dissolved in aqueous sodium hydroxide and precipitated with hydrochloric acid. Recrystallization from aqueous ethanol gives 7-chloro-3-hydroxy-3-phenyl-2-indolinone, m.p. 154°-156°. After three hours of reflux the reaction is cooled saturated ammonium chloride, filtered to give a dark oil precipitated with hydrochloric acid Recrystallization from aqueous ethanol

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

Procedure: In a 100 mL round-bottomed flask, a solution of 7-chloroindoline-2,3-dione (1 g, 5.51 mmol) in THF (10 mL) was cooled in an ice/water bath. A solution of o-tolylmagnesium bromide (2M, 5.51 mL, 11.01 mmol) was added, and the reaction mixture was removed from the cooling bath and warmed to room temperature. After 1 hour, the reaction mixture was quenched with saturated aqueous NH4Cl and extracted with EtOAc. The organic layer was dried over MgSO4, filtered and concentrated to give Intermediate A-20A. MS(ES): m/z=272 [M−H−]; HPLC: RT=2.478 min (H2O/MeOH with TFA, CHROMOLITH® ODS S5 4.6×50 mm, gradient=4 min, wavelength=220 nm). the reaction mixture was removed from the cooling bath the reaction mixture was quenched with saturated aqueous NH4Cl extracted with EtOAc The organic layer was dried over MgSO4 filtered concentrated to give Intermediate A-20A

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

Procedure: A Grignard reagent prepared from 62 g. magnesium, 400 g. bromobenzene in two liters tetrahydrofuran (THF) is added to 181 g. (1.0 mole) 7-chloroisatin (1a) in two liters THF at a rate to keep a gentle reflux. After three hours of reflux, the reaction is cooled and decomposed with 350 ml. saturated ammonium chloride, filtered, and the THF stripped to give a dark oil. The oil is dissolved in aqueous sodium hydroxide and precipitated with hydrochloric acid. Recrystallization from aqueous ethanol gives 7-chloro-3-hydroxy-3-phenyl-2-indolinone, m.p. 154°-156°. After three hours of reflux the reaction is cooled saturated ammonium chloride, filtered to give a dark oil precipitated with hydrochloric acid Recrystallization from aqueous ethanol

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

Procedure: A Grignard reagent prepared from 62 g. magnesium, 400 g. bromobenzene in two liters tetrahydrofuran (THF) is added to 181 g. (1.0 mole) 7-chloroisatin (1a) in two liters THF at a rate to keep a gentle reflux. After three hours of reflux, the reaction is cooled and decomposed with 350 ml. saturated ammonium chloride, filtered, and the THF stripped to give a dark oil. The oil is dissolved in aqueous sodium hydroxide and precipitated with hydrochloric acid. Recrystallization from aqueous ethanol gives 7-chloro-3-hydroxy-3-phenyl-2-indolinone, m.p. 154°-156°. After three hours of reflux the reaction is cooled saturated ammonium chloride, filtered to give a dark oil precipitated with hydrochloric acid Recrystallization from aqueous ethanol

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

Procedure: A suspension of 7-chloroindoline-2,3-dione (15 g.) and potassium carbonate (15 g.) in N,N-dimethylformamide (100 ml.) was stirred and treated with a solution of 4-bromo-2-fluorobenzyl bromide (24.7 g.) in chlorobenzene (100 ml.). The mixture was stirred at 90° C. for five hours, cooled to ambient temperature, and diluted with a mixture of water (500 ml.) and petrol ether (b.p 60°-80° C.) (500 ml.) The aqueous phase was adjusted to pH3 with 10M hydrochloric acid. The mixture obtained was separated by filtration. The solid obtained was washed with further petrol ether, then with water, and recrystallised from ethanol to give 1-(4-bromo-2-fluorobenzyl)-7-chloro-indoline-2,3-dione (15.5 g.), m.p. 164°-166° C. The mixture was stirred at 90° C. for five hours The mixture obtained was separated by filtration The solid obtained was washed with further petrol ether with water, and recrystallised from ethanol

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: A suspension of 7-chloroindoline-2,3-dione (15 g.) and potassium carbonate (15 g.) in N,N-dimethylformamide (100 ml.) was stirred and treated with a solution of 4-bromo-2-fluorobenzyl bromide (24.7 g.) in chlorobenzene (100 ml.). The mixture was stirred at 90° C. for five hours, cooled to ambient temperature, and diluted with a mixture of water (500 ml.) and petrol ether (b.p 60°-80° C.) (500 ml.) The aqueous phase was adjusted to pH3 with 10M hydrochloric acid. The mixture obtained was separated by filtration. The solid obtained was washed with further petrol ether, then with water, and recrystallised from ethanol to give 1-(4-bromo-2-fluorobenzyl)-7-chloro-indoline-2,3-dione (15.5 g.), m.p. 164°-166° C. The mixture was stirred at 90° C. for five hours The mixture obtained was separated by filtration The solid obtained was washed with further petrol ether with water, and recrystallised from ethanol

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

Procedure: Following the procedure as described in PREPARATION 4A, and making non-critical variations using 7-chloro-1H-indole-2,3-dione to replace 4-chloro-1H-indole-2,3-dione, 7-chloro-1-(diphenylmethyl)-1H-indole-2,3-dione was obtained (38%) as an orange solid: mp 172-173° C. (hexanes/ethyl acetate); 1H NMR (300 MHz, DMSO-d6) δ 7.71-7.60 (m, 2H), 7.36-7.27 (m, 11H), 7.22-7.17 (m, 1H).

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

Procedure: Following the procedure as described in PREPARATION 4A, and making non-critical variations using 7-chloro-1H-indole-2,3-dione to replace 4-chloro-1H-indole-2,3-dione, 7-chloro-1-(diphenylmethyl)-1H-indole-2,3-dione was obtained (38%) as an orange solid: mp 172-173° C. (hexanes/ethyl acetate); 1H NMR (300 MHz, DMSO-d6) δ 7.71-7.60 (m, 2H), 7.36-7.27 (m, 11H), 7.22-7.17 (m, 1H).