Organic Syntheses, CV 6, 719
(−)-ISOPINOCAMPHEOL
[Bicyclo[3.1.1]heptan-3-ol, 2,6,6-trimethyl-, [1R-(1α,2β,3α,5α)]-]
Submitted by C. F. Lane and J. J. Daniels1.
Checked by D. M. Ryckman and R. V. Stevens.
1. Procedure
A 300-ml., three-necked flask (Note 1), equipped with a magnetic stirring bar, thermometer, pressure-equalizing dropping funnel fitted with septum inlet adapter (Note 2), and reflux condenser fitted with a hose adapter leading to a mineral oil bubbler (Note 3), is charged with 10.0 ml. (0.100 mole) of boranemethyl sulfide complex (Note 4) and 30 ml. of tetrahydrofuran (Note 5) and (Note 6). The flask is immersed in an ice-water bath as 27.2 g. (31.7 ml., 0.200 mole) of (+)-α-pinene (Note 7) is added dropwise at 0–3° to the well-stirred reaction mixture over a period of 15 minutes. The (−)-diisopinocampheylborane [(−)-di-3-pinanylborane] precipitates as a white solid as the reaction proceeds. Following addition, the reaction mixture is stirred for 3.5 hours at 0°. Under a slow stream of nitrogen, the outlet hose adapter on the reflux condenser is connected with rubber vacuum hose to a vacuum trap which is then cooled in an acetone–dry ice bath. The dimethyl sulfide and tetrahydrofuran are bulb-to-bulb vacuum-distilled (0.1 mm.) with the reaction flask in a room temperature water bath. When only a dry, white solid residue remains, the vacuum is released with nitrogen. The flask is again placed under a slight positive pressure of nitrogen. The solid is slurried in 36 ml. of tetrahydrofuran (Note 5) at room temperature. An additional 4.08 g. (4.76 ml., 0.030 mole) of (+)-α-pinene (Note 7) is added. The resulting slurry is stirred at room temperature for 5 minutes and then stored under nitrogen in a closed system in a cold room at 4° for 3 days (Note 8). The flask is then removed from the cold room and immersed in an ice-water bath. Under a slow stream of nitrogen, the outlet adapter on the reflux condenser is again connected to the mineral oil bubbler. The excess hydride is destroyed by the slow, dropwise addition of 8 ml. of methanol (Note 9), followed by the addition in one portion of 36.6 ml. of 3 M aqueous sodium hydroxide. The borinic acid intermediate is now oxidized by the dropwise addition of 24 ml. of 30% aqueous hydrogen peroxide (Note 10) to the well-stirred reaction mixture at 35° ± 3° (Note 11). After the hydrogen peroxide addition is complete, the ice-water bath is replaced with a warm-water bath and the reaction mixture is stirred for one hour at 50–55° (Note 12) and then cooled to room temperature. The aqueous layer is saturated with sodium chloride and 50 ml. of diethyl ether is added. The upper organic layer is removed, and the aqueous layer is extracted with two 100-ml. portions of ether. The organic layer and extracts are combined, dried over anhydrous potassium carbonate, filtered, and concentrated to an oil on a rotary evaporator at 60° (15 mm.) (Note 13). The crude product is fractionally distilled using a 30-cm. column packed with glass helices, giving 24.7 g. (80%) of (−)-isopinocampheol, b.p. 60–65° (0.1 mm.) (Note 14). The distillate crystallizes completely in the receiver, m.p. 49–55°, 97.5% purity by GC, [α]19D −34.3° (C, 20 in ethanol) (Note 15). Slurrying 4.7 g. in 2.3 ml. of pentane at room temperature, cooling to −78°, collecting on a filter, and air drying gives 3.8 g. of crystalline (−)-isopinocampheol, m.p. 52–55°, purity 99.2% by GC, [α]19D −34.9° (C, 20 in ethanol).
2. Notes
1. The apparatus is dried in an oven and assembled hot while being flushed with nitrogen. A slow stream of nitrogen is continued until the apparatus is cool. Alternatively, the apparatus can be assembled and then flame-dried while flushing with nitrogen.
2. A suitable septum inlet adapter is available from Aldrich Chemical Company (product number Z10, 130-3).
3. A suitable bubbler is available from Aldrich (product number Z10, 121-4) and used to maintain a slight positive pressure of nitrogen in the reaction vessel.
4. Boranemethyl sulfide complex was obtained from Aldrich and used as received.
5. An anhydrous grade of tetrahydrofuran was obtained from Aldrich and used as received.
6. Boranemethyl sulfide and anhydrous tetrahydrofuran are extremely moisture-sensitive. All transfers must be done under a nitrogen atmosphere, with syringe techniques being the most convenient.2
7. (+)-α-Pinene ([α]21D +47.1°) was obtained from Aldrich and was short-path vacuum-distilled under nitrogen from a small amount of lithium aluminum hydride.
8. The equilibrated (−)-diisopinocampheylborane obtained at this point can be utilized directly for asymmetric hydroboration.3
9. Since the pinene is hydroborated only to the dialkylborane stage (R2BH), methanolysis liberates a large amount of hydrogen. The rate of evolution is controlled by the slow addition of methanol, and some foaming is observed. The hydrogen must be vented to an efficient hood. Water can be used to destroy the hydride, but methanol addition is easier to control and the final mixture is homogenous once methanolysis is complete.
10. Thirty percent aqueous hydrogen peroxide was obtained from Aldrich and used as received.
11. The oxidation is exothermic and can be quite vigorous. It should be controlled by the slow, dropwise addition of hydrogen peroxide. Cooling in an ice-water bath is necessary. However, a reaction temperature of around 35° must be maintained.
12. The additional one hour of heating is necessary to destroy excess hydrogen peroxide. Oxygen is evolved and some foaming occurs.
13. The oil solidifies upon cooling but can be easily remelted in a warm-water bath for transfer to a small distillation flask.
14. An air-cooled condenser is used for the distillation of isopinocampheol.
15. The enantiomeric excess of (−)-isopinocampheol was determined to be greater than 95% by 200 MHz 1H NMR using the chiral shift reagent, tris[3-heptafluoropropylhydroxymethylene)-d-camphorato], europium(III). Addition of the lanthanide reagent (40 mg., 0.034 mmol.) to the chiral alcohol (30 mg., 0.21 mmol.) produced a shift of 7.5 p.p.m. in the peak centered around δ 4.05. Only one broad peak was observed.
Treatment of (±)-isopinocampheol in a similar manner gave two broad singlets of equal intensity centered around δ 10.75 (separated by 0.15 p.p.m.), attributable to the diastereomeric protons.
3. Discussion
Isopinocampheol has been prepared by hydroboration of α-pinene using in situ generated diborane with diglyme as the solvent.4
The present procedure employs a recently developed method which provides a product of greatly improved enantiomeric purity (>99%).5 Also, this preparation utilizes commercially available boranemethyl sulfide and α-pinene of 92% enantiomeric purity. An equilibration is used to improve the optical purity of the intermediate dialkylborane.
Isopinocampheol is only of limited interest. More importantly this procedure provides optically pure (−)-diisopinocampheylborane, a very versatile reagent which has been used widely for the synthesis of many chiral products.3
This preparation is referenced from:
References and Notes
  1. Aldrich-Boranes, Inc., Sheboygan Falls, Wisconsin 53085.
  2. C. F. Lane, Aldrichimica Acta, 10, 11 (1977).
  3. For a review of asymmetric syntheses using chiral organoboranes, see H. C. Brown, P. K. Jadhav, and A. K. Mandal, Tetrahedron, 37, 3547 (1981).
  4. G. Zweifel and H. C. Brown, Org. Synth., 52, 59 (1972).
  5. H. C. Brown, M. C. Desai, and P. K. Jadhav, J. Org. Chem., 47, 5065 (1982).

Appendix
Compounds Referenced (Chemical Abstracts Registry Number)

diborane

(−)-ISOPINOCAMPHEOL

(−)-diisopinocampheylborane

(−)-di-3-pinanylborane

tris[3-heptafluoropropylhydroxymethylene)-d-camphorato], europium(III)

ethanol (64-17-5)

potassium carbonate (584-08-7)

methanol (67-56-1)

ether, diethyl ether (60-29-7)

hydrogen (1333-74-0)

sodium hydroxide (1310-73-2)

sodium chloride (7647-14-5)

oxygen (7782-44-7)

nitrogen (7727-37-9)

hydrogen peroxide (7722-84-1)

Pentane (109-66-0)

borane (7440-42-8)

methyl sulfide, dimethyl sulfide (75-18-3)

Tetrahydrofuran (109-99-9)

lithium aluminum hydride (16853-85-3)

diglyme (111-96-6)

Isopinocampheol (27779-29-9)

(+)-α-pinene, α-pinene

pinene (18172-67-3)

Bicyclo[3.1.1]heptan-3-ol, 2,6,6-trimethyl-, [1R-(1α,2β,3α,5α)]- (1196-00-5)