Reaction #479952

Reaction equation

diethyl oxalate

potassium ethoxide

3-methyl-2-nitroanisole

→

3-(3-Methoxy-2-nitro-phenyl)-2-oxo-propionic acid ethyl ester

Solvents

ethyl ether

Conditions

Workup

1. 1
   OtherThe lumpy, deep purple potassium salt was separated by filtration
2. 2
   Washwashed with anhydrous ether until the filtrate
3. 3
   workup.DISSOLUTIONThis salt was dissolved in aqueous ammonium chloride
4. 4
   Extractionthe solution was extracted with dichloromethane
5. 5
   WashThe combined organic extracts were washed with brine
6. 6
   Dryingdried over sodium sulfate
7. 7
   Filtrationfiltered
8. 8
   Otherthe solvent was evaporated
9. 9
   OtherThe residue was purified via silica gel chromatography (5-30% ethyl acetate/hexanes)

Procedure

At room temperature, diethyl oxalate (13.6 mL) was added to a solution of potassium ethoxide (8.4 g) in anhydrous ethyl ether (200 mL). After 10 min, 3-methyl-2-nitroanisole (16.7 g) was added and stirred at ambient temperature for 24 h. The lumpy, deep purple potassium salt was separated by filtration and washed with anhydrous ether until the filtrate remained colorless. This salt was dissolved in aqueous ammonium chloride, and the solution was extracted with dichloromethane. The combined organic extracts were washed with brine, dried over sodium sulfate and filtered, and the solvent was evaporated. The residue was purified via silica gel chromatography (5-30% ethyl acetate/hexanes) to give 3-(3-Methoxy-2-nitro-phenyl)-2-oxo-propionic acid ethyl ester (14.0 g). This material (14.0 g) was dissolved in ethanol (200 mL) containing 5 wt. % palladium on activated carbon (1.4 g) and placed on a Parr hydrogenator at 60 psi H2. After 2 h, the mixture was filtered through Celite, and concentrated to give a clear liquid. The liquid was purified by silica gel chromatography (5%-30% EtOAc/Hexanes) to obtain (7-Methoxy-1H-indol-2-yl)-(4-methyl-6-Methoxy-1H-indole-2-carboxylic acid ethyl ester (11.7 g). This ethyl ester (4.0 g) was treated with lithium hydroxide (1.75 g) in THF (100 mL) followed by water (30 mL) and stirred at ambient temperature for 16 h. The solution was acidified with 10% hydrochloric acid, diluted with water and extracted with ethyl acetate. The organic extracts were washed with brine, dried over sodium sulfate, filtered, and concentrated to afford 6-Methoxy-1H-indole-2-carboxylic acid (3.50 g). This material (3.50 g) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (5.26 g) in dichloromethane (100 mL) were treated with N-methylpiperazine (3.05 mL) and stirred at ambient temperature for 16 h. The reaction mixture was poured into dichloromethane (200 mL), washed with water, saturated sodium hydrogencarbonate solution and then brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified via silica gel chromatography (0-10% methanol/dichloromethane) to give (7-Methoxy-1H-indol-2-yl)-(4-methyl-piperazin-1-yl)-methanone (4.50 g). This material (3.5 g) was dissolved in dichloromethane (85 mL). At room temperature, 1 M Boron tribromide (2.42 mL) was added dropwise. The reaction mixture was heated to reflux for 2 h, cooled, and then quenched with saturated sodium hydrogencarbonate solution. The suspension was filtered. The filtrate was washed with saturated sodium hydrogencarbonate solution and then brine, dried over sodium sulfate and filtered, and solvent was evaporated. The residue was purified via silica gel chromatography (0-10% methanol/dichloromethane) to give the title compound (1.95 g). 1H NMR (400 MHz, CDCl3/CD3OD): δ 7.52 (s, 1H), 7.16 (dd, J=0.78, 7.24 Hz, 1H), 6.96 (t, J=7.63 Hz, 1H), 6.77 (s, 1H), 6.70 (dd, J=0.98, 6.65 Hz, 1H), 3.93 (br s, 4H), 2.55 (t, J=5.09 Hz, 4H), 2.38 (s, 3H). MS (electrospray): exact mass calculated for C14H17N3O2, 259.13; m/z found, 260.1 [M+H]+.

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