December 2010

 Substituted indoles

Substituted indoles are popular component of fragrances and the precursor to many pharmaceuticals. Notably, the indolic amino acid tryptophan is the precursor of the neurotransmitter serotonin. Other indolic compounds include the plant hormone Auxin (indolyl-3-acetic acid, IAA), the anti-inflammatory drug indomethacin, the betablocker pindolol, and the naturally occurring hallucinogen dimethyltryptamine (N,N-DMT).

 Synthesis of Substituted indoles.


A solution of Methyl 2-methyl-3-nitrobenzoate (20 g, 0.1 mol), N,N-dimethylformamide dimethylacetal (40 ml, 0.3 mol) in DMF (50 ml) was stirred at 120°C under nitrogen for 12 h. The solution became deep red. The excess amount of N,N-dimethylformamide dimethylacetal and DMF was distilled under reduced pressure to give crude enamine that was directly used in the next step without purification.

The crude enamine was dissolved in anhydrous benzene (250 ml). To this solution was added Pd–C (10%, 2.8 g). The resulting mixture was hydrogenated at 55 psi. Warming was observed at the start of the reaction. The deep red mixture became dark gray after 12 h at room temperature. Pd–C was filtered off over Celite and the filtrate was concentrated under reduced pressure. Chomatography on silica gel (ethyl acetate:hexanes: 30:70 v/v, Rf=0.55) afforded indole (11.8 g, 67%) as a light yellow solid: mp 67.5–69.0°C.


To a mixture of potassium (6.24 g, 159 mmol) in Et2O (60 mL) was added mixture of EtOH (40 mL) and Et2O (100 mL), followed by a solution of diethyl oxalate (27.8 g, 190 mmol) in Et2O (60 mL), and finally, a solution of 4-chloro-2-nitrotoluene (27.4 g, 160 mmol) in Et2O (40 mL). The reaction mixture was stirred for 15 h and then sonicated for 7 h. The mixture was poured into 1 N HCl at 0 ºC. The mixture was neutralized and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried and concentrated to afford the ketoester intermediate which was used directly in the next step. To crude ethyl 3-(4-chloro-2-nitrophenyl)-2-oxopropanoate (ca 150 mmol) in EtOH (280 mL) and glacial AcOH (280 mL) was added iron powder (74.4 g, 1.33 mol)6 and the reaction mixture was heated to reflux for 4 h. The mixture was filtered and evaporated. The residue was partitioned between DCM and 1 N HCl. The organic layer was washed with 1 N HCl, sat. NaHCO3, and brine and dried. Evaporation followed by crystallization from DCM gave indole as a pale yellow solid (16.8 g, 50% over 2 steps).


The nitro–compound (5 mmol) was placed in a two–necked round–bottomed flask fitted with a gas inlet (argon) and rubber septum. The flask was purged several times with argon before adding THF (35–40 ml) and cooling to between –40 and –45 °C. The Grignard reagent (3 eq.) was then added rapidly in one portion to the THF solution and stirring continued for a further 30 mins to 1 hour (exact length of time had little effect on yield). Saturated ammonium chloride solution was added to the reaction mixture (at ca. –40 °C) before allowing the mixture to warm to room temperature. The mixture was thoroughly extracted with diethyl ether (2 x 200 ml), the ether extracts combined and thoroughly washed with further ammonium chloride (300 ml), water (300 ml) and brine (300 ml) before drying (Mg2SO4) and concentrating in vacuo to give a dark brown gum, which was purified by flash column chromatography (hexane:ethyl acetate 9:1) to give the title compound. Compounds were in good agreement with literature data; new compounds gave satisfactory spectroscopic and analytical data, as illustrated by the following representative compounds.

 The application of Indole Compounds:




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