A. 3-Ethyl-4-hydroxymethyl-5-methylisoxazole. A slurry of lithium aluminum hydride (21.0 g., 0.553 mole) in anhydrous diethyl ether is prepared by cautiously adding the powdered reagent (Note 1) to 2.5 l. of freshly prepared anhydrous ether in a 5-l., three-necked flask fitted with a reflux condenser, a 500-ml. pressure-equalizing addition funnel, and a strong mechanical stirrer. The contents of the flask are then placed under a nitrogen atmosphere via a gas-inlet tube attached to the top of the condenser. Ethyl 3-ethyl-5-methyl-4-isoxazolecarboxylate (124 g., 0.678 mole) (Note 2), dissolved in 300 ml. of dry ether, is placed in the addition funnel and added dropwise over 4 hours to the lithium aluminum hydride slurry (Note 3). The reaction is refluxed gently for 4 hours, then placed in an ice bath. Quenching of excess reagent and hydrolysis of aluminate salts is effected by cautious, slow addition of 20 ml. of water, followed by 30 ml. of aqueous 10% sodium hydroxide and another 30 ml. of water (Note 4). The ether layer is filtered from granular aluminum salts, poured into a 2-l. separatory funnel, and washed with 250 ml. of saturated brine. The organic extract is dried over anhydrous magnesium sulfate and filtered, and the solvent is removed with a rotary evaporator. The residual oil is distilled, yielding 76–82 g. (80–86%) of 3-ethyl-4-hydroxymethyl-5-methylisoxazole, b.p. 99–101° (0.15 mm.); n_D23 1.4835; IR: 3450, 1640 cm.⁻¹; ¹H NMR (CCl₄): δ 1.2 (t, 3H, CH₂CH₃), 2.2 (s, 3H, C=CCH₃), 2.6 (q, 2H, CH₂CH₃), 4.2 (s, 2H, CH₂O).

B. 4-Chloromethyl-3-ethyl-5-methylisoxazole. Caution! The following reaction should be carried out in a fume hood to avoid thionyl chloride vapors.

3-Ethyl-4-hydroxymethyl-5-methylisoxazole (54 g., 0.38 mole) is dissolved in 70 ml. of dichloromethane and placed in a 500-ml., one-necked flask fitted with a 100-ml., pressure-equalizing addition funnel and a magnetic stirrer. The flask is placed in an ice bath, and its contents are stirred while a solution of 53 g. of thionyl chloride (32 ml., 0.45 mole) in 50 ml. of dichloromethane is added dropwise. Addition is complete in 1 hour, and the reaction is allowed to warm to room temperature and stirred for an additional hour. The solvent is removed with a rotary evaporator and the dark residual liquid is distilled, yielding 47–49 g. (78–81%) of 4-chloromethyl-3-ethyl-5-methylisoxazole, b.p. 77–78° (1.5 mm.); n_D23 1.4845; IR: 1620, 680 cm.⁻¹; ¹H NMR (CCl₄): δ 1.3 (t, 3H, CH₂CH₃), 2.3 (s, 3H, C=CCH₃), 2.6 (q, 2H, CH₂CH₃), 4.3 (s, 2H, CH₂Cl).

C. 2-(3-Ethyl-5-methyl-4-isoxazolylmethyl)cyclohexanone. Sodium hydride (10.0 g. of a 60% slurry in mineral oil, 0.25 mole) is degreased in a flame-dried, 1-l., three-necked flask fitted with a 250-ml., pressure-equalizing addition funnel and a condenser through which a stream of nitrogen is blown. The sodium hydride is washed by adding 20 ml. of dry benzene, stirring magnetically, allowing it to settle, and drawing off the supernatant benzene wash with a syringe. The washing process is repeated four more times before 100 ml. of dry benzene is added, followed with 100 ml. of dry N,N-dimethylformamide (Note 5). The contents of the flask are covered with a nitrogen atmosphere and a solution of ethyl 2-cyclohexanonecarboxylate (41.0 g., 0.241 mole) (Note 6) in 100 ml. of 1:1 benzene–dimethylformamide is added slowly over 45 minutes, with cooling, keeping the reaction mixture near room temperature (Note 7). A solution of 4-chloromethyl-3-ethyl-5-methylisoxazole (32 g., 0.20 mole) in 100 ml. of 1:1 benzene–dimethylformamide is then added over 30 minutes, and the reaction is stirred for 2 days at room temperature. The reaction is diluted with 300 ml. of ether, poured into a 1-l. separatory funnel, washed three times with 100-ml. portions of water and once with brine, dried over anhydrous magnesium sulfate and filtered. The solvents are removed with a rotary evaporator, and the residual oil is dissolved in 150 ml. of glacial acetic acid and placed in a 500-ml., one-necked flask fitted with a magnetic stirrer and a reflux condenser. Hydrochloric acid (150 ml., 6 N) is added. The mixture is refluxed for 36 hours (Note 8), then concentrated with a rotary evaporator. The residue is taken up in 500 ml. of ether, poured into a 1-l. separatory funnel, and washed twice with 100-ml. portions of water, once with 5% aqueous sodium hydroxide, and once with brine. After drying over anhydrous magnesium sulfate and filtration, the organic extracts are concentrated with a rotary evaporator and distilled (Note 9), yielding 33–35 g. (75–80%) of 2-(3-ethyl-5-methyl-4-isoxazolylmethyl)cyclohexanone, b.p. 130° (0.001 mm.); n_D23 1.4970; IR: 1710, 1630 cm.⁻¹; ¹H NMR (CCl₄): δ 1.2 (t, 3H, CH₂CH₃). 1.5–2.2 (m, 11H, 5CH₂ and CH), 2.3 (s, 3H, C=CCH₃), 2.5 (q. 2H, CH₂CH₃).

D. 1-Methyl-4,4a,5,6,7,8-hexahydronaphthalen-2(3H)-one. Caution! Sodium ethoxide formation should be carried out in a hood since a large volume of hydrogen gas is evolved.

2-(3-Ethyl-5-methyl-4-isoxazolylmethyl)cyclohexanone (27.6 g., 0.125 mole) is dissolved in 250 ml. of ethanol in a Parr hydrogenation bottle, and 20 g. of freshly prepared W-4 Raney nickel catalyst (Note 10) is added. Hydrogenation is started at an initial hydrogen pressure of 25 p.s.i. Cleavage of the isoxazole ring is complete after 6 hours, after which time the reaction is stopped and the solution is filtered free of catalyst (Note 11). The catalyst is washed with ether and absolute ethanol, and the combined organic filtrates are concentrated with a rotary evaporator (Note 12).

The viscous, residual liquid is dissolved in 25 ml. of absolute ethanol and a stream of nitrogen is bubbled through the solution for 15 minutes, removing dissolved oxygen (Note 13). A solution of sodium ethoxide is then prepared by cautiously dissolving freshly cut sodium (11.5 g., 0.500 mole) in 150 ml. of absolute ethanol, under a nitrogen atmosphere, in a 500-ml., three-necked flask fitted with a reflux condenser topped with a gas-inlet, a magnetic stirrer, and a rubber serum cap on one of the sidearms. When ethoxide formation is complete, the deoxygenated solution of the hydrogenated isoxazole is injected into the stirred reaction mixture through the rubber serum cap with a syringe. The solution is refluxed until the UV spectrum of a small aliquot withdrawn with a syringe through the serum cap shows the absence of absorption at 345 nm. (Note 14). This requires about 30 hours.

A solution of 15 ml. of glacial acetic acid and 30 ml. of water is deoxygenated as described above and slowly injected with a syringe into the reaction. Refluxing is continued for 6 hours, the flask is cooled, and its contents are poured into a 1-l. separatory funnel along with 200 ml. of water. The solution is extracted four times with 100-ml. portions of ether, and the combined ether extracts are washed successively with 100 ml. of 6 N hydrochloric acid, 100 ml. of water, and 100 ml. of brine. The organic extracts are dried over anhydrous magnesium sulfate, filtered, concentrated with a rotary evaporator, and distilled, yielding 13.2–13.8 g. (65–67%) of 1-methyl-4,4a,5,6,7,8-hexahydronaphthalen-2(3H)-one, b.p. 85–90° (0.5 mm.); n_D23 1.5120; IR: 1670, 1605 cm.⁻¹; ¹H NMR (CCl₄): δ 1.0–2.5 (m, 13H, 6CH₂ and CH), 1.7 (s, 3H, C=CCH₃).