Preparation of 7(R)-Isopropyl-4(R)-methyl- 4,5,6,7 -tetrahedron- 2H-indazole (menthylpyrazol)

A solution of 2-(hydroxymethylene)-6-isopropyl-3-methylcyclohexanone (90 g, 0.5 mol) dissolved in MeOH (400 cm3) was prepared in a three necked round-bottomed fitted with dropping funnel and condenser. Hydrazine monohydrate (25.1 cm3, 0.52 mol) was added dropwise whilst stirring with a magnetic stirrer over 0.3 h. The reaction was exothermic and was refluxed for 2 h. Solvent was removed under reduced pressure and the resulting orange oil was dissolved in CH2Cl2 (200 cm3). This solution was treated with concentrated HCl (200 cm3) at room temperature and after rapid stirring for 0.2 h, the organic layer was separated and the aqueous layer was extracted with 3 x 100 cm3 of CH2Cl2. The combined organic extracts were dried with MgSO4 and solvent was removed under reduced pressure to leave a light orange solid. The solid was washed with copious amounts of Et2O to leave a tan solid (80 g, 76% yield).

Recrystallisation from CHCl3 / di n-Butyl ether afforded a 1:1 mixture of the hydrochloride salts of cis and trans menthylpyrazole by 1H NMR. Further recrystallisations yielded the pure cis menthylpyrazole hydrochloride as a white solid (21.6 g, 20% yield): 1H NMR (CDCl3, 270 MHz) d 7.61 (s, 1H), 2.77 (m, 2H), 2.42 (m, 1H), 1.75 (m, 3H), 1.52 (m, 1H), 1.15 (d, J = 6.84 Hz, 3H), 1.02 (d, J = 6.84 Hz, 3H), 0.77 (d, J = 6.84 Hz, 3H) ppm. The free menthylpyrazole was obtained from its hydrochloride salt by adding a solution of menthylpyrazole.HCl (21.6 g, 0.10 mol) in CH2Cl2 (150 cm3) to a solution of NaHCO3 (23.4 g, 0.28 mol) in water (160 cm3). The mixture was vigorously stirred for 0.3 h. and a colourless gas was evolved. The organic and aqueous layers were separated and the aqueous layer was extracted with 3 x 100 cm3 of CH2Cl2. The organic layers were combined and dried with Na2CO3 and the solvent was removed under reduced pressure to leave menthylpyrazole (18.2 g, 10.2% yield from menthol):

G.C.[50 oC / inc.temp.2 oC / min / 200 oC (10 min)] RT = 66.29 min (single peak).

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