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

Temperature

5 °C

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.

1. customA 5 L round-bottom flask is equipped with a mechanical stirrer
2. temperaturethermometer and reflux condenser
3. customAn ice bath is applied to the flask
4. temperaturemaintaining the temperature below 10° C
5. additionOnce the addition
6. customthe cooling bath is removed
7. stirringthe reaction stirred for 2 hours
8. stirringstirred for 12 hours at ambient temperature
9. temperatureReflux condenser
10. distillationis changed to short path distillation
11. addition520 mL 50% W/v NaOH(aq) and 1500 mL H2O is added
12. temperatureheating
13. distillationto distill the THF
14. distillationDistillation
15. customwas continued to 100° C. with additional water
16. distillationDistillation
17. customto remove ethanol and water at 100° C. for 15-30 minutes
18. temperatureOnce cooled
19. additionthe reaction mixture is poured into 1.5 L H2O and 1 L 12N HCl with vigorous stirring
20. customWhite solids, which formed immediately
21. filtrationwere collected by filtration
22. customdried on the Buchner funnel by aspiration for 15 minutes
23. customequipped for short path distillation
24. temperatureHeating
25. temperatureincreased to 135° C. for at least 1 hour
26. temperatureThe melt was cooled to 50° C.
27. addition2 L heptane added
28. temperaturewarmed to 45° C.
29. customAdequate venting was provided
30. stirringthe reaction was stirred for 1.5 hours at 60° C.
31. temperatureheated to 120° C.
32. distillationto distill the excess SOCl2 and all the heptane
33. temperatureto cool to ambient temperature
34. addition1.5 L CH2Cl2 is added
35. temperatureCooling
36. customwas applied to −5°−0° C.
37. stirringThe reaction was stirred at ambient temperature for 2 hours
38. customquenched
39. additionby pouring onto 2 Kg ice
40. customThe layers were separated
41. washthe organic layer was washed with 500 mL H2O
42. distillationAll the solvent was distilled to a temperature of 70° C
43. addition1 L methanol was added to the oil
44. temperaturethe flask cooled with an ice bath
45. additioncontrolled by the rate of addition
46. customThe reaction was quenched
47. additionby adding 1.5 L H2O and 500 mL CH2Cl2
48. customto separate the product
49. distillationSolvent was distilled from the separated organic layer up to 70° C
50. addition1.5 L toluene was added to the oil
51. customthe 5 L flask equipped with a Dean-Stark trap
52. temperatureHeating
53. additionp-toluene sulfonic acid was added in 1-3 g portions
54. additionwas added to the reaction
55. customthe layers separated
56. dry with materialthe organic layer dried over anhydrous Na2SO4
57. distillationToluene was distilled under reduced pressure to 90° C.

ORD record

ord-4948dfed2cd44e9992bc284aaaddb446

Source dataset

uspto-grants-2002_10

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US06465700B1