2- Benzoyloxycyclohexanone

An intriguing rearrangement was reported by Yates (72) during an attempt to carry out the Stobbe condensation. It resulted in the formation of a cyclopropane derivative from 4-benzoyloxycyclohexanone by the (proposed) mechanism shown. 

A 250-ml three-necked flask is fitted with a condenser (drying tube). The system is flushed with dry nitrogen, and a dry nitrogen atmosphere is maintained. In the flask is placed a solution of potassium /-butoxide (2.8 g, 0.025 mole) in dry /-butyl alcohol (100 ml). 4-Benzoyloxycyclohexanone (5 g, 0.022 mole, Chapter 7, Section X) is added to the solution, the transfer being assisted by the use of 10-15 ml of dry /-butyl alcohol. The mixture is cautiously brought to reflux, and refluxing is continued for 45 minutes. The mixture is then cooled rapidly to room temperature and carefully acidified by the addition of 10 ml of 6 A hydrochloric acid (potassium chloride will precipitate). The mixture is placed on a rotary evaporator and the bulk of the solvent is removed. The residue is diluted with sufficient water to dissolve the potassium chloride and extracted three times with 50-ml portions of ether. The ether extracts are combined and extracted four times with 100-ml portions of aqueous 5% sodium bicarbonate solution. The bicarbonate extracts are combined and the solution is acidified by the addition of concentrated hydrochloric acid to pH 4. The mixture is now extracted three times with 100-ml portions of ether, the combined ethereal extracts are washed with water, then dried, and the solvent is removed. The residual product may be recrystallized from benzene-hexane. The acid has mp 65-68°. 

Scheme 24. Synthesis of optically pure frovatriptan ((/ )-6) utilizing 4-benzoyloxycyclohexanone in the Fischer indole cyclization.

Reaction of 4-cyanophenylhydrazine hydrochloride (70) with 4-benzoyloxycyclohexanone in refluxing acetic acid furnished the Fischer indole product... 

---