SYNTHESIS OF CIS- AND TRANS-4-t-BUTYLCYCLOHEXANOL

Method A: cis-4-t-Butylcyclohexanol.⁵³

• An oven-dried 250-ml two-necked flask, equipped with a Teflon stopcock, a magnetic stirrer bar, and a reflux condenser connected to a mercury bubbler, is cooled to room temperature under a dry stream of nitrogen. 

• Lithium trisiamylborohydride solution in tetrahydrofuran (LS-Selectride, 67 ml, 28 mmol) is introduced into the reac­tion flask and cooled to — 78 °C (dry ice—acetone). 

• Then 3.7 g (24 mmol) of 4- t-butylcyclohexanone dissolved in 25 ml of tetrahydrofuran (maintained at 0 °C) is added. 

• The resulting mixture is stirred vigorously for 2 hours at 78 °C and then allowed to equilibrate to room temperature (1 hour). 

• The reaction mixture is hydrolysed with 4 ml of water and 15 ml of ethanol is added; the organoborane is oxidised with 10 ml of 6 M sodium hydroxide and 15 ml of 30 per cent hydrogen peroxide. 

• The aqueous phase is saturated with anhydrous potassium carbonate, the organic phase separ­ated, and the aqueous phase extracted with two 20-ml portions of ether. 

• The combined extracts are dried (MgSO₄). Gas—liquid chromatography analysis indicates the presence of the cis-alcohol in > 99.5 per cent isomeric purity. 

• The volatile solvents and the isoamyl alcohol were removed under reduced pressure to give 3.65 g (98%) of essentially pure cis-4-t-butylcyclohexanol as a snow-white solid, m.p. 80 °C (lit. m.p. 82 °C).

Method B: trans-4-t-Butylcyclobutylcyclohexanol.⁵⁴

• Preparation of lithium n-but ylborohydride in tetrahydrofuran—hexane. 

• In a 100-ml flask with a mag­netic stirrer bar and a rubber septum under a dry nitrogen atmosphere is placed borane—dimethyl sulphide complex (1.0 ml, 10.0 mmol). 

• Tetrahydro­furan (32.5 ml) is added and the flask immersed in an ice bath. 

• Butyllithium in hexane (1.5 M, 6.6 ml, 9.9 mmol) is slowly added to the flask with vigorous stirring, and the resulting solution is stirred for an additional 30 minutes to give a solution of lithium n-butylborohydride (0.25 M) in tetrahydrofuran­hexane. 

• The hydride concentration is determined by hydrolysing a known ali­quot of the solution with a mixture of tetrahydrofuran and 0.5 M sulphuric acid at room temperature and measuring the volume of hydrogen evolved.

• In a 25-m1 flask with a magnetic stirrer and a rubber septum under a dry nitrogen atmosphere 4-t-butylcyclohexanone (72 mg, 0.47 mmol) is placed, and tetrahydrofuran (2.7 ml) is added. 

• To the resulting solution in a dry-ice­acetone bath under a dry nitrogen atmosphere is added dropwise a solution of lithium n-butylborohydride (1.8 ml of a 0.25 M solution, 0.45 mmol) in tetrahydrofuran—hexane. 

• After 2 hours of being stirred at — 78 °C, the reac­tion mixture is hydrolysed with water (0.5 ml), allowed to warm to room tem­perature, and oxidised with 10 per cent sodium hydroxide solution (3 ml) and 30 per cent hydrogen peroxide (2 ml) (1) by stirring overnight at room temperature. 

• After diethyl ether (10 ml) is introduced, the aqueous layer is separated and extracted three times with ether. 

• The combined organic layers are washed with sodium hydrogen sulphite solution and saturated sodium chloride solution, dried over anhydrous magnesium sulphate, and evaporated to dryness to give the corresponding alcohol (72 mg, 98%). 

• The product is subjected to g.l.c. analysis (2.1 m x 3.7 mm, 10% Carbowax 20 M column at 125 °C) which shows 98 per cent of the trans alcohol and 2 per cent of the cis alcohol.

Notes to keep in mind:

1. For the precautions that must be taken before evaporating extracts arising from reactions involving the use of hydrogen peroxide in the presence of tetrahydrofuran.