6-iodo-1,3-dihydroindol-2-one

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

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

Procedure: To a jacketed reactor, N,N-dimethylacetamide (DMAc) (120 mL) and sodium ethylate (NaOEt) powder (12.1 g) is charged at 20° C. Diethylmalonate (28.8 g) is added dropwise into the above mixture while keeping internal temperature at around 10° C. After finishing addition, warm up the mixture to 20° C., and continue to stir for another 10 minutes. Then, 2-chloro-5-iodonitrobenzene (17 g) is added in one portion, and heat the mixture to 78° C. and stir for usually at least 2.5 hours until process monitor shows almost complete conversion. The resulting mixture is cooled down to 20° C., and it is quenched by 2 N cold aq. HCl solution (180 mL). The bottom yellow oil was transferred to a jacket reactor with ethanol (92 mL) in it. Then, to the above solution the first portion of SnCl2.2H2O (30 g) powder is added, and the resulting mixture is heated to 70° C. and stirred for 1 hour. The second portion of SnCl2.2H2O (30 g) is added, the mixture is stirred usually at least 0.5 hour until process monitor shows almost complete conversion. Then, heat the resulting mixture to 80° C. and add 36% aq. HCl solution (60 mL) during 0.5 hour. The mixture is stirred for at least 2.5 hours until process monitor shows almost complete conversion. Then, to the mixture water (90 mL) is added and the resulting mixture is cooled down to 20° C. Collect the solid by filtration and wash the solid with water (250 mL) to afford the crude 6-iodo-2-oxindole. Then, it is purified by crystallization with acetic acid (HOAc) (110 mL), and followed by washing with 3 N aq. HCl solution (80 mL) to afford the 6-iodo-2-oxindole in 53% yield and 99% HPLC purity (Rt=7.45 min). at around 10° C addition heat the mixture to 78° C. stir for usually at least 2.5 hours until process monitor The resulting mixture is cooled down to 20° C. it is quenched by 2 N cold aq. HCl solution (180 mL) The bottom yellow oil was transferred to a jacket reactor with ethanol (92 mL) in it Then, to the above solution the first portion of SnCl2.2H2O (30 g) powder is added the resulting mixture is heated to 70° C. stirred for 1 hour The second portion of SnCl2.2H2O (30 g) is added the mixture is stirred usually at least 0.5 hour until process monitor Then, heat the resulting mixture to 80° C. add 36% aq. HCl solution (60 mL) during 0.5 hour The mixture is stirred for at least 2.5 hours until process monitor Then, to the mixture water (90 mL) is added the resulting mixture is cooled down to 20° C Collect the solid by filtration wash the solid with water (250 mL) to afford the crude 6-iodo-2-oxindole Then, it is purified by crystallization with acetic acid (HOAc) (110 mL) by washing with 3 N aq. HCl solution (80 mL)

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

Procedure: To a jacketed reactor, N,N-dimethylacetamide (DMAc) (120 mL) and sodium ethylate (NaOEt) powder (12.1 g) is charged at 20° C. Diethylmalonate (28.8 g) is added dropwise into the above mixture while keeping internal temperature at around 10° C. After finishing addition, warm up the mixture to 20° C., and continue to stir for another 10 minutes. Then, 2-chloro-5-iodonitrobenzene (17 g) is added in one portion, and heat the mixture to 78° C. and stir for usually at least 2.5 hours until process monitor shows almost complete conversion. The resulting mixture is cooled down to 20° C., and it is quenched by 2 N cold aq. HCl solution (180 mL). The bottom yellow oil was transferred to a jacket reactor with ethanol (92 mL) in it. Then, to the above solution the first portion of SnCl2.2H2O (30 g) powder is added, and the resulting mixture is heated to 70° C. and stirred for 1 hour. The second portion of SnCl2.2H2O (30 g) is added, the mixture is stirred usually at least 0.5 hour until process monitor shows almost complete conversion. Then, heat the resulting mixture to 80° C. and add 36% aq. HCl solution (60 mL) during 0.5 hour. The mixture is stirred for at least 2.5 hours until process monitor shows almost complete conversion. Then, to the mixture water (90 mL) is added and the resulting mixture is cooled down to 20° C. Collect the solid by filtration and wash the solid with water (250 mL) to afford the crude 6-iodo-2-oxindole. Then, it is purified by crystallization with acetic acid (HOAc) (110 mL), and followed by washing with 3 N aq. HCl solution (80 mL) to afford the 6-iodo-2-oxindole in 53% yield and 99% HPLC purity (Rt=7.45 min). at around 10° C addition heat the mixture to 78° C. stir for usually at least 2.5 hours until process monitor The resulting mixture is cooled down to 20° C. it is quenched by 2 N cold aq. HCl solution (180 mL) The bottom yellow oil was transferred to a jacket reactor with ethanol (92 mL) in it Then, to the above solution the first portion of SnCl2.2H2O (30 g) powder is added the resulting mixture is heated to 70° C. stirred for 1 hour The second portion of SnCl2.2H2O (30 g) is added the mixture is stirred usually at least 0.5 hour until process monitor Then, heat the resulting mixture to 80° C. add 36% aq. HCl solution (60 mL) during 0.5 hour The mixture is stirred for at least 2.5 hours until process monitor Then, to the mixture water (90 mL) is added the resulting mixture is cooled down to 20° C Collect the solid by filtration wash the solid with water (250 mL) to afford the crude 6-iodo-2-oxindole Then, it is purified by crystallization with acetic acid (HOAc) (110 mL) by washing with 3 N aq. HCl solution (80 mL)

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

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: CuI (40 mg, 0.05 mmol), potassium carbonate (1.66 g, 12 mmol), 6-iodooxindole (as prepared in Preparation 1; 0.5 g, 1.93 mmol) and N-(2,5-Dimethyl-2H-pyrazol-3-yl)-2-mercapto-benzamide (as prepared in step 3 above; 0.477 g, 1.93 mmol) were added to a dry schlenk tube. The tube was evacuated and refilled with Ar(g) (3 times). Isopropanol (3.0 mL) and ethylene glycol (0.250 mL) were injected into the schlenk tube. The schlenk tube was sealed with a teflon valve and was heated to 80° C. and stirred for over 24 hours. Subsequently the reaction mixture was allowed to reach room temperature then diluted with EtOAc (˜20 mL) and water (˜10 mL). The mixture was acidified with 1 M HCl(aq) and the organics were separated and set aside. The aqueous phase was washed with EtOAc (2×20 mL). The organic layers were combined, dried over silica gel, filtered and concentrated in vacuo affording a yellow solid. The solid was then purified via flash silica gel chromatography (gradient eluant 10 to 40% EtOAc in Hexanes) affording the title compound as a pale yellow solid (0.379 g, 1.01 mmol, 52% yield). The tube was evacuated refilled with Ar(g) (3 times) The schlenk tube was sealed with a teflon valve to reach room temperature then diluted with EtOAc (˜20 mL) and water (˜10 mL) the organics were separated The aqueous phase was washed with EtOAc (2×20 mL) dried over silica gel filtered concentrated in vacuo affording a yellow solid The solid was then purified via flash silica gel chromatography (gradient eluant 10 to 40% EtOAc in Hexanes)

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: CuI (40 mg, 0.05 mmol), potassium carbonate (1.66 g, 12 mmol), 6-iodooxindole (as prepared in Preparation 1; 1.0 g, 4.0 mmol) and 2-mercapto-benzoic acid (0.62 g, 4.0 mmol) were added to a dry schlenk tube. The tube was evacuated and refilled with Ar(g) (3 times). 2-Propanol (5.0 mL) and ethylene glycol (0.5 mL, 8.0 mmol) were injected into the schlenk tube. The schlenk tube was sealed with a teflon valve and was heated to 80° C. and stirred for over 24 hours. Subsequently the reaction mixture was allowed to reach room temperature then diluted with EtOAc (10 mL) and water (10 mL). The mixture was acidified of to a pH=3-4 with the addition of 1 M HCl(aq) and the organics were separated and set aside. The aqueous phase was washed with additional EtOAc (10 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo affording a yellow solid. The solid was then purified via flash silica gel chromatography (gradient eluant starting with 5% MeOH in CHCl3 increasing to 10% MeOH in CHCl3) affording the title compound as a pale yellow solid (0.228 g, 0.77 mmol, 20% yield). The tube was evacuated refilled with Ar(g) (3 times) The schlenk tube was sealed with a teflon valve to reach room temperature the organics were separated The aqueous phase was washed with additional EtOAc (10 mL) The combined organic layers were dried over Na2SO4 filtered concentrated in vacuo affording a yellow solid The solid was then purified via flash silica gel chromatography (gradient eluant starting with 5% MeOH in CHCl3 increasing to 10% MeOH in CHCl3)

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

Procedure: A schlenk tube and stir bar were dried in an oven overnight and then were evacuated, filled with Ar(g) and cooled. The schlenk tube was charged with CuI (45 mg, 0.236 mmol, 5 mol %), 6-bromoxindole (1.0 g, 4.72 mmol), and NaI (1.42 g, 9.44 mmol). The schlenk tube was evacuated and backfilled with Ar(g) (3 times). Racemic trans-N,N′-dimethyl-1,2-cyclohexanediamine (74 μL, 0.472 mmol, 10 mol %) and anhydrous dioxane (4.72 mL) were added via syringe under Ar(g). The schlenk tube was sealed with a teflon valve and the suspension was stirred at 110° C. for 24 h. The reaction was then cooled to room temperature and 15% NH4OH(aq) (˜50 mL) was added to the reaction mixture while stirring. The suspension was allowed to stir for about 30 min after which the tan solid was vacuum filtered and dried affording 6-Iodooxindole in 84% yield (1.027 g, 3.96 mmol). were dried in an oven overnight were evacuated filled with Ar(g) cooled The schlenk tube was evacuated The schlenk tube was sealed with a teflon valve the suspension was stirred at 110° C. for 24 h while stirring to stir for about 30 min after which the tan solid filtered dried

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

Procedure: To a jacketed reactor, N,N-dimethylacetamide (DMAc) (120 mL) and sodium ethylate (NaOEt) powder (12.1 g) is charged at 20° C. Diethylmalonate (28.8 g) is added dropwise into the above mixture while keeping internal temperature at around 10° C. After finishing addition, warm up the mixture to 20° C., and continue to stir for another 10 minutes. Then, 2-chloro-5-iodonitrobenzene (17 g) is added in one portion, and heat the mixture to 78° C. and stir for usually at least 2.5 hours until process monitor shows almost complete conversion. The resulting mixture is cooled down to 20° C., and it is quenched by 2 N cold aq. HCl solution (180 mL). The bottom yellow oil was transferred to a jacket reactor with ethanol (92 mL) in it. Then, to the above solution the first portion of SnCl2.2H2O (30 g) powder is added, and the resulting mixture is heated to 70° C. and stirred for 1 hour. The second portion of SnCl2.2H2O (30 g) is added, the mixture is stirred usually at least 0.5 hour until process monitor shows almost complete conversion. Then, heat the resulting mixture to 80° C. and add 36% aq. HCl solution (60 mL) during 0.5 hour. The mixture is stirred for at least 2.5 hours until process monitor shows almost complete conversion. Then, to the mixture water (90 mL) is added and the resulting mixture is cooled down to 20° C. Collect the solid by filtration and wash the solid with water (250 mL) to afford the crude 6-iodo-2-oxindole. Then, it is purified by crystallization with acetic acid (HOAc) (110 mL), and followed by washing with 3 N aq. HCl solution (80 mL) to afford the 6-iodo-2-oxindole in 53% yield and 99% HPLC purity (Rt=7.45 min). at around 10° C addition heat the mixture to 78° C. stir for usually at least 2.5 hours until process monitor The resulting mixture is cooled down to 20° C. it is quenched by 2 N cold aq. HCl solution (180 mL) The bottom yellow oil was transferred to a jacket reactor with ethanol (92 mL) in it Then, to the above solution the first portion of SnCl2.2H2O (30 g) powder is added the resulting mixture is heated to 70° C. stirred for 1 hour The second portion of SnCl2.2H2O (30 g) is added the mixture is stirred usually at least 0.5 hour until process monitor Then, heat the resulting mixture to 80° C. add 36% aq. HCl solution (60 mL) during 0.5 hour The mixture is stirred for at least 2.5 hours until process monitor Then, to the mixture water (90 mL) is added the resulting mixture is cooled down to 20° C Collect the solid by filtration wash the solid with water (250 mL) to afford the crude 6-iodo-2-oxindole Then, it is purified by crystallization with acetic acid (HOAc) (110 mL) by washing with 3 N aq. HCl solution (80 mL)

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