4-(trifluoromethyl)-1H-indole

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

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

Procedure: To a solution of 4-(trifluoromethyl)-1H-indole (0.535 g, 2.89 mmol; step A above), tetrabutylammonium bromide (0.097 g, 0.30 mmol) and benzenesulfonyl chloride (0.44 mL, 3.5 mmol) in PhMe (5 mL) at rt was added 50 wt % NaOH (3 mL) and H2O (2 mL). The mixture was stirred 30 min, partitioned between Et2O/H2O and the layers were separated. The organic layer was washed (H2O, brine), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography (EtOAc/hexanes), affording 0.771 g of the title compound as a thick, pale yellow oil: 1H NMR (300 MHz, methanol-d4) δ 8.25 (d, J=8.3 Hz, 1H), 8.00-7.94 (m, 2H), 7.88 (d, J=3.8 Hz, 1H), 7.65-7.58 (m, 1H), 7.57-7.41 (m, 4H), 6.87 (br. s, 1H). partitioned between Et2O/H2O the layers were separated The organic layer was washed (H2O, brine) dried over Na2SO4 filtered concentrated in vacuo The residue was purified by flash chromatography (EtOAc/hexanes)

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 2-methyl-1-nitro-3-(trifluoromethyl)benzene (10.00 g, 48.8 mmol), pyrrolidine (4.44 mL, 53.7 mmol) and dimethylformamide dimethylacetal (19.8 mL, 146 mmol) in DMF (100 mL) was heated at 100° C. for 4 h, cooled and concentrated in vacuo. The residue was partitioned between Et2O/H2O, the layers were separated and the aqueous layer was extracted with Et2O (×3). Combined organics were washed (H2O, brine), dried over Na2SO4, filtered and concentrated in vacuo. The residue was dissolved in THF/MeOH (1:1, 200 mL), and transferred to a 3-necked flask equipped with an overhead stirrer, reflux condenser, and dropping addition funnel. Raney-Ni (Raney® 2800 slurry in water, 10 g) was added in one portion and the entire apparatus was thoroughly flushed with N2. The mixture was heated to 60° C., under N2, and a solution of hydrazine monohydrate (8 mL) in THF/MeOH (1:1, 20 mL) was added dropwise over 1 h. The mixture was heated at 60° C. for 1 h, cooled, and filtered through a pad of Celite®. The filtrate was concentrated in vacuo, the residue was partitioned between Et2O/H2O, the layers were separated and the aqueous layer was extracted with Et2O (×3). Combined organics were washed (10% HCl, H2O, brine), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography (EtOAc/hexanes), affording 5.17 g of the title compound as a light brown liquid: 1H NMR (300 MHz, methanol-d4) δ 7.61 (d, J=8.2 Hz, 1H), 7.39 (d, J=3.2 Hz, 1H), 7.32 (d, J=7.4 Hz, 1H), 7.19 (partially resolved dd, J≈8.4, 7.5 Hz, 1H), 6.59 (br. s, 1H). cooled concentrated in vacuo The residue was partitioned between Et2O/H2O the layers were separated the aqueous layer was extracted with Et2O (×3) Combined organics were washed (H2O, brine) dried over Na2SO4 filtered concentrated in vacuo The residue was dissolved in THF/MeOH (1:1, 200 mL) transferred to a 3-necked flask equipped with an overhead stirrer reflux condenser addition funnel Raney-Ni (Raney® 2800 slurry in water, 10 g) was added in one portion the entire apparatus was thoroughly flushed with N2 a solution of hydrazine monohydrate (8 mL) in THF/MeOH (1:1, 20 mL) was added dropwise over 1 h The mixture was heated at 60° C. for 1 h cooled filtered through a pad of Celite® The filtrate was concentrated in vacuo the residue was partitioned between Et2O/H2O the layers were separated the aqueous layer was extracted with Et2O (×3) Combined organics were washed (10% HCl, H2O, brine) dried over Na2SO4 filtered concentrated in vacuo The residue was purified by flash chromatography (EtOAc/hexanes)

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

Procedure: 4.4 mmol of 4-trifluoromethyl-1H-indole were dissolved in 8 ml acetic acid. 8.8 mmol of sodium cyanoborohydride were added at once and the reaction mixture stirred at room temperature for 3.5 hours. 20 ml of water were added. The reaction mixture is treated with aqueous sodium hydroxide 40% until basic. Extraction with ethyl acetate yields the crude title compound as a yellowish waxy solid. Yield=76%. MS (m/e): 188.4 ([M+H]+, 97%). Extraction with ethyl acetate

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

Procedure: 7.7 mmol Dimethyl-[(E)-2-(2-nitro-6-trifluoromethyl-phenyl)-vinyl]-amine was dissolved in 20 ml methanol. 200 mg of palladium 5% on charcoal was added and the reaction mixture hydrogenated at room temperature and atmospheric pressure. When no further hydrogen is absorbed (ca. 3 hours), the reaction mixture is filtered, concentrated and dissolved in diethyl ether. The organic phase is washed with 2 M hydrochloric acid and brine and concentrated to yield the title compound as a yellowish solid. Yield=58%. MS (m/e): 184.9 ([M+H]+, 100%). hydrogenated at room temperature When no further hydrogen is absorbed (ca. 3 hours) the reaction mixture is filtered concentrated dissolved in diethyl ether The organic phase is washed with 2 M hydrochloric acid and brine concentrated

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

Procedure: 4.4 mmol of 4-trifluoromethyl-1H-indole were dissolved in 8 ml acetic acid. 8.8 mmol of sodium cyanoborohydride were added at once and the reaction mixture stirred at room temperature for 3.5 hours. 20 ml of water were added. The reaction mixture is treated with aqueous sodium hydroxide 40% until basic. Extraction with ethyl acetate yields the crude title compound as a yellowish waxy solid. Yield=76%. MS (m/e): 188.4 ([M+H]+, 97%). Extraction with ethyl acetate

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

Procedure: 7.7 mmol Dimethyl-[(E)-2-(2-nitro-6-trifluoromethyl-phenyl)-vinyl]-amine was dissolved in 20 ml methanol. 200 mg of palladium 5% on charcoal was added and the reaction mixture hydrogenated at room temperature and atmospheric pressure. When no further hydrogen is absorbed (ca. 3 hours), the reaction mixture is filtered, concentrated and dissolved in diethyl ether. The organic phase is washed with 2 M hydrochloric acid and brine and concentrated to yield the title compound as a yellowish solid. Yield=58%. MS (m/e): 184.9 ([M+H]+, 100%). hydrogenated at room temperature When no further hydrogen is absorbed (ca. 3 hours) the reaction mixture is filtered concentrated dissolved in diethyl ether The organic phase is washed with 2 M hydrochloric acid and brine concentrated

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

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

Procedure: 370 mg of NaH at 60% in oil are added to a solution of 0.85 g of 4-trifluoromethyl-1H-indole in 15 ml of tetrahydrofuran, under an inert atmosphere. The reaction mixture is stirred at ambient temperature for one hour and then 0.88 ml of benzenesulfonyl chloride is added dropwise and the stirring is continued for 16 hours. The reaction mixture is then poured into a 10% ammonium chloride solution, extracted with ethyl acetate and dried over magnesium sulfate. After filtration and concentration under reduced pressure, the residue is purified by silica column chromatography, elution being carried out with a mixture of heptane and diisopropyl ether (98/2, then 95/5: v/v), so as to give 1.08 g of 1-benzenesulfonyl-4-trifluoromethyl-1H-indole in the form of a pale yellow oil which is used as it is in the next step. the stirring is continued for 16 hours extracted with ethyl acetate dried over magnesium sulfate After filtration and concentration under reduced pressure the residue is purified by silica column chromatography, elution being carried out with a mixture of heptane and diisopropyl ether (98/2

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

Procedure: 370 mg of NaH at 60% in oil are added to a solution of 0.85 g of 4-trifluoromethyl-1H-indole in 15 ml of tetrahydrofuran, under an inert atmosphere. The reaction mixture is stirred at ambient temperature for one hour and then 0.88 ml of benzenesulfonyl chloride is added dropwise and the stirring is continued for 16 hours. The reaction mixture is then poured into a 10% ammonium chloride solution, extracted with ethyl acetate and dried over magnesium sulfate. After filtration and concentration under reduced pressure, the residue is purified by silica column chromatography, elution being carried out with a mixture of heptane and diisopropyl ether (98/2, then 95/5: v/v), so as to give 1.08 g of 1-benzenesulfonyl-4-trifluoromethyl-1H-indole in the form of a pale yellow oil which is used as it is in the next step. the stirring is continued for 16 hours extracted with ethyl acetate dried over magnesium sulfate After filtration and concentration under reduced pressure the residue is purified by silica column chromatography, elution being carried out with a mixture of heptane and diisopropyl ether (98/2

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

Procedure: 370 mg of NaH at 60% in oil are added to a solution of 0.85 g of 4-trifluoromethyl-1H-indole in 15 ml of tetrahydrofuran, under an inert atmosphere. The reaction mixture is stirred at ambient temperature for one hour and then 0.88 ml of benzenesulfonyl chloride is added dropwise and the stirring is continued for 16 hours. The reaction mixture is then poured into a 10% ammonium chloride solution, extracted with ethyl acetate and dried over magnesium sulfate. After filtration and concentration under reduced pressure, the residue is purified by silica column chromatography, elution being carried out with a mixture of heptane and diisopropyl ether (98/2, then 95/5: v/v), so as to give 1.08 g of 1-benzenesulfonyl-4-trifluoromethyl-1H-indole in the form of a pale yellow oil which is used as it is in the next step. the stirring is continued for 16 hours extracted with ethyl acetate dried over magnesium sulfate After filtration and concentration under reduced pressure the residue is purified by silica column chromatography, elution being carried out with a mixture of heptane and diisopropyl ether (98/2

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

Procedure: 850 mg of powdered iron are added to a solution of 1.2 g of dimethyl[(E)-2-(2-nitro-6-trifluoromethylphenyl)vinyl]amine in 30 ml of acetic acid. The reaction mixture is refluxed for 16 hours and then poured into a solution of hydrochloric acid (HCl, 2N), and extracted with ethyl acetate. The organic phases are washed with a 10% sodium carbonate solution and then with a saturated NaCl solution, dried over magnesium sulfate, filtered, and concentrated under reduced pressure so as to give 959 mg of 4-trifluoromethyl-1H-indole which is used in the next step. The reaction mixture is refluxed for 16 hours extracted with ethyl acetate The organic phases are washed with a 10% sodium carbonate solution with a saturated NaCl solution, dried over magnesium sulfate filtered concentrated under reduced pressure so as