Hydrochloric Acid → Ethyl (2R)-2-methyl-5-(propan-2-ylidene)cyclopentane-1-carboxylate

(R)-(+)-Pulegone (76.12 g, 0.5 mmol), anhydrous NaHCO3 (12.5 g) and anhydrous ether (500 mL) were added to a 1 L round-bottom flask. The reaction mixture was cooled with an ice-bath under nitrogen. Bromine (25.62 mL, 0.5 mmol) was added dropwise over 30 minutes. The mixture was filtered and carefully added to NaOEt (21%, 412 mL, 1.11 mmol) in an ice-cooled bath. The mixture was stirred at room temperature overnight, and then 5% HCl (1 L) and ether (300 mL) were added. The aqueous phase was extracted with ether (2×300 mL). The combined organic phase was washed with water, dried and concentrated. The residue was added to a warmed solution of semicarbazide hydrochloride (37.5 g) and NaOAc (37.5 g) in water (300 mL). Then boiling ethanol (300 mL) was added to give a clear solution. The mixture was refluxed for 2.5 hours and then stirred at room temperature overnight. The mixture was treated with water (1 L) and ether (300 mL). The aqueous phase was extracted with ether (2×300 mL). The combined organic phase was washed with water, dried and concentrated. The residue was purified by vacuum distillation (73-76° C. at 0.8 mm Hg) to give (2R)-ethyl 2-methyl-5-(propan-2-ylidene)cyclopentanecarboxylate (63 g, 64%). 1H NMR (CDCl3, 400 MHz) δ 4.13 (m, 2H), 3.38 (d, J=16 Hz, 0.5H), 2.93 (m, 0.5H), 2.50-2.17 (m, 2H), 1.98 (m, 1H), 1.76 (m, 1H), 1.23 (m, 6H), 1.05 (m, 6H).

1. temperatureThe reaction mixture was cooled with an ice-bath under nitrogen
2. filtrationThe mixture was filtered
3. temperaturecooled bath
4. extractionThe aqueous phase was extracted with ether (2×300 mL)
5. washThe combined organic phase was washed with water
6. customdried
7. concentrationconcentrated
8. additionThe residue was added to a warmed solution of semicarbazide hydrochloride (37.5 g) and NaOAc (37.5 g) in water (300 mL)
9. additionThen boiling ethanol (300 mL) was added
10. customto give a clear solution
11. temperatureThe mixture was refluxed for 2.5 hours
12. stirringstirred at room temperature overnight
13. extractionThe aqueous phase was extracted with ether (2×300 mL)
14. washThe combined organic phase was washed with water
15. customdried
16. concentrationconcentrated
17. distillationThe residue was purified by vacuum distillation (73-76° C. at 0.8 mm Hg)

ORD record

ord-b639c16762084560a2dcb3b77a95a28a

Source dataset

uspto-grants-2014_11

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08895566B2