SYNTHESIS OF ERYTHRO- AND THREO-2-(1' -HYDROXYBENZYL) CYCLOHEXANONES

1-TrimethyIsiIyIoxycycIohexene:

• To a well-stirred suspension of lithium sulphide (1.5g, 30mmol) (1) in dry acetonitrile (25 ml) in a 100-ml round- bottomed flask, fitted with a water condenser and a nitrogen inlet, is added chlorotrimethylsilane (6.3 ml, 50 mmol). 

• To this mixture are added cyclohexanone (1.96g, 20 mmol) and triethylamine (3 ml, 20 mmol) in succession, and the solution is allowed to stir at room temperature (25 °C). 

• The progress of the reaction is monitored by removing aliquots periodically and analysing them after work-up by t.l.c. (silica gel plates with hexane as an eluant). 

• Soon after the completion of the reaction (c. 16 hours), the mixture is taken up in ether (50 ml) and washed thoroughly with ice-cold aqueous 5 per cent hydrochloric acid solution (4 x 50 ml) to remove all basic and water-soluble materials. 

• The ethereal extract is washed with ice-cold aqueous 5 per cent sodium hydrogen carbonate solution (50 ml), water (50 ml), and brine (25 ml). 

• It is dried over anhydrous sodium sulphate and subjected to distillation under reduced pressure to obtain the crude enol silyl ether. 

• The product is further purified by distillation (b.p. 70-71 °C/12mmHg) to obtain spectrally (p.m.r. and i.r.) pure 1-trimethylsilyloxyclohexene (95%).

Erythro- and Threo-2-(1'-Hydroxybenzyl)cycIohexanones:

• A dichloro-methane (10 ml) solution of 1-trimethylsilyloxycyclohexene (0.426g, 2.5mmol) is added dropwise into a mixture of benzaldehyde (0.292g, 2.75 mmol) and titanium(IV) chloride (0.55g, 2.75 mmol) (2) in dry dichloro-methane (20 ml) under an argon atmosphere at — 78 °C, and the reaction mixture is stirred for 1 hour. 

• After hydrolysis (with water) at that temperature, the resulting organic layer is extracted with ether, and the extract is washed with water and dried over anhydrous sodium sulphate. 

• The extract is evaporated under reduced pressure, and the residue is purified by column chromatography (silica gel). 

• Elution with dichoromethane affords 115mg (23%) of erythro-2-(1'-hydroxybenzyl)-cyclohexanone, m.p. 103 °C (recrystallised from propan-2-ol, m.p. 103.5-104.5 °C); i.r. 3530 (OH), 1700 (C=0) cm⁻¹ ; p.m.r. (CDCl₃ , TMS) 1.1-2.7 (broad, 9H, aliphatic CH), 3.05 (s, 1H, OH, exchangeable with D₂O), 5.40 (d, 1H, J = 2.5 Hz, O— CH), and 7.27 (s, 5H, aryl CH).

• From the last fraction, 346 mg (69%) of threo-2-(1'-hydroxybenzyl)cyclohexanone are obtained, m.p. 74 °C (recrystallised from hexane-ether, m.p. 75 °C); i.r. 3495 (OH), 1695 (C=0) cm⁻¹; p.m.r. (CCl₄, TMS) 1.1-2.9 (broad, 9H, aliphatic CH), 3.77 (s, 1H, OH, exchangeable with D₂O), 4.83 (d, 1H, J = 9.0 Hz, O— CH), 7.29 (s, 5H, aryl CH).

Notes to keep in mind:

1.  Lithium sulphide is obtained from Alfa Ventron. Acetonitrile is purified and stored over molecular sieves.

2. Titanium(iv) chloride is distilled under an argon atmosphere before use.