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Stage #1: With 1,10-Phenanthroline; platinum on carbon; hydrogen In ethanol at 20℃; Flow reactor; Green chemistry Stage #2: With acetic acid In ethanol at 20℃; Green chemistry
General procedure: Ethanol (30 mL) wasadded to 2-nitrophenylacetic acid (300 mg, 1.66 mmol) and 1,10-phenanthroline (33 mg, 0.23 mmol) in a reaction flask. The resultant solutionwas pumped through the H-Cube Mini (5percent Pt/C, 20 C, flowrate 1.5 mL min1,H2 inlet pressure 610 bar) to near dryness. Then the reaction flask was rinsedwith ethanol (3 5 mL). The product eluant from the H-Cube was collected andconcentrated in vacuo to 1 mL, then diluted to 6 mL with ethanol. Glacialacetic acid (0.21 mL, 36.7 mmol) was added and the reaction mixture stirredovernight at room temperature. The reaction mixture was concentrated invacuo. The residue was dissolved in CH2Cl2 (10 mL) and washed with saturatedaqueous NaHCO3 (5 5 mL). The combined aqueous extracts were treated withconc. H2SO4 to pH 1 to precipitate the hydroxamic acid, which was filteredand washed with cold deionized water (10 mL).
With hydrogen;palladium 10% on activated carbon; In acetic acid; for 4h;
To prepare 6-trifluoromethyloxindole, first a 2L flask with a stir bar was charged with 45.8 ml (400 mmol) of dimethylmalonate and 500 ml of anhydrous DMSO. Next, 15.6 grams (391 mmol) of NaH was added in portions over 10 minutes to the vigorously stiring solution under an atmosphere of N2. That solution was heated to 1000C and stirred for lhour and then allowed to cool to ambient temperature. Next, 26 ml (186 mmol) of 4-fluoro-3-nitrobenzotrifluoride (CASNo. 367-86-2) was added using a syringe in one portion, which resulted in the previously colorless solution becoming dark brown/red. That colored solution was again heated to 1000C5 stirred for 1 hour and allowed to cool to ambient temperature. The solution was then poured into 1.3 L of saturated NH4Cl solution. The resulting mixture was Extracted with ethyl acetate followed by drying (using MgSO4) and concentration in vacuo, resulting in a red/orange oil that crystallized on standing overnight. Some of the excess dimethylmalonate was <n="51"/>removed by decanting from the crystallized solid product. The crystallized solid product was then pulverized using a mortar and pestle, suspended in hexanes and filtered to remove the remaining dimethylmalonate.[0138] The resulting 2-(2-Nitro-4-trifluoromethyl-phenyl)-malonic acid dimethyl ester (56.1 g) was suspended in 200 ml of 6N HCl and stirred at reflux overnight. That solution was cooled, diluted with 500 ml of water, and filtered. The filtered solids were pulverized using mortar and pestil and suspended in water and filtered again, washing with copious water to remove traces of HCl. After drying in vacuo, the resuting solid (2-Nitro-4-trifluoromethyl-phenyl)-acetic acid was dissolved in 200 ml of AcOH to which was then added 5.4 grams of Palladium (10%) on Carbon. The resulting suspension was placed under one atmosphere of hydrogen (60 psi, Parr apparatus) for 4 hours. The suspenson was filtered through celite, washed with MeOH and CH2CI2, and concentrated in vacuo. Recrystallization from ethyl acetate/hexanes gave 27.19 g from the first crop, and 1.1 g from a second crop for a total yield of 28.29 g (76%, 3 steps) of 6-trifluoromethyloxindole (CASNo. 1735-89-3) as white prisms.