Tetrahydrofuran → 7-Chloro-2-methyl-1H-indene

Participants

Reaction Conditions

Reaction Steps

A 5 L round-bottom flask is equipped with a mechanical stirrer, thermometer and reflux condenser, and swept thoroughly with nitrogen. 2 L tetrahydrofuran (THF) is added to the flask and then 116 g NaH, 60% dispersion in mineral oil (2.9 mol). An ice bath is applied to the flask and moderate stirring begun. 506 g methyl diethyl malonate (2.9 mol) is added slowly from an addition funnel maintaining the temperature below 10° C. Hydrogen evolution is monitored and vented through a mineral oil bubbler and controlled by the rate of addition of the methyl dimethyl malonate. Once the addition is complete, the cooling bath is removed, and the reaction stirred for 2 hours. The flask is again cooled to 5° C. and 367 mL 2-chlorobenzylchloride (2.9 mol) added over 1 hour, then stirred for 12 hours at ambient temperature. Reflux condenser is changed to short path distillation. 520 mL 50% W/v NaOH(aq) and 1500 mL H2O is added, then heating begun to distill the THF. Distillation was continued to 100° C. with additional water to keep the reaction clear and fluid. Distillation was continued to remove ethanol and water at 100° C. for 15-30 minutes. Once cooled, the reaction mixture is poured into 1.5 L H2O and 1 L 12N HCl with vigorous stirring. White solids, which formed immediately, were collected by filtration and dried on the Buchner funnel by aspiration for 15 minutes, then returned to the 5 L flask equipped for short path distillation. Heating was applied slowly to melt the solids, and then increased to 135° C. for at least 1 hour. CO2 evolution was monitored by venting through a mineral oil bubbler. The melt was cooled to 50° C. and 2 L heptane added, then warmed to 45° C., and addition of 265 mL SOCl2 (3.63 mol) was begun. Adequate venting was provided. After all the SOCl2 was added, the reaction was stirred for 1.5 hours at 60° C., then heated to 120° C. to distill the excess SOCl2 and all the heptane. The reaction flask was allowed to cool to ambient temperature and 1.5 L CH2Cl2 is added. Cooling was applied to −5°−0° C., and 465 g AlCl3 (3.5 mol) added in portions. The reaction was stirred at ambient temperature for 2 hours, then quenched by pouring onto 2 Kg ice. The layers were separated, and the organic layer was washed with 500 mL H2O, and then 250 mL 5% w/v NaHCO3(aq). All the solvent was distilled to a temperature of 70° C. 1 L methanol was added to the oil, the flask cooled with an ice bath, and a slurry of 56 g NaBH4 (1.5 mol) in 500 mL methanol containing 1 g NaOCH3 was slowly added. Hydrogen evolution was monitored by venting through a mineral oil bubbler and controlled by the rate of addition. The reaction was quenched by adding 1.5 L H2O and 500 mL CH2Cl2 to separate the product. Solvent was distilled from the separated organic layer up to 70° C. 1.5 L toluene was added to the oil and the 5 L flask equipped with a Dean-Stark trap. Heating was begun and p-toluene sulfonic acid was added in 1-3 g portions. The reaction was followed by GC until the dehydration was complete. 1.5 L 5% w/v NaHCO3(aq) was added to the reaction, the layers separated, and the organic layer dried over anhydrous Na2SO4. Toluene was distilled under reduced pressure to 90° C. and the product, 2-methyl-7-chloroindene, obtained by distillation thorough a 30 cm packed column at 93-5° C. at 1-3 mm Hg. Yield was 310 g (1.89 mol), 65%, of a clear, colorless oil b.p. 229° C. FIG. 2 was the NMR spectrum of the product.

Provenance & Evidence