Organic Syntheses, Coll. Vol. 9, p.745 (1998); Vol. 72, p.57 (1995).
(1R)-(+)-α-Pinene (25.0 g, 0.183 mol
, [α]D20 +50.9°
(neat), 98.6% ee) (Note 1)
and 350 mL of dry benzene (Note 2)
are placed in a base-washed, 1000-mL Morton flask fitted with a mechanical stirrer, condenser, internal thermometer, and gas inlet
. The flask is set in a heating mantle
and warmed to 65°C, at which point lead tetraacetate (77.8 g, 0.175 mol)
is added via Gooch tubing
over 20 min (Note 3)
. The reaction mixture becomes bright yellow, this color slowly changing to tan after heating at 65°C with stirring for 1 hr. The solution is cooled to room temperature and filtered through a 1-in pad of Celite. The Celite is washed with several 50-mL portions of benzene
. To the filtrate is added 300 mL of water, at which point brown-black lead oxide
precipitates (Note 4)
. The two-phase system is swirled vigorously at 10-min intervals for an hour and then filtered through a 1-in pad of Celite. The layers of the filtrate are separated and the aqueous phase is extracted with three 150-mL portions of ether
. The combined organic fractions are dried over magnesium sulfate
, filtered, and concentrated by rotary evaporation at room temperature to give a mixture of acetates
as a colorless liquid (Note 5)
Without purification, the mixture of acetates is placed in a 250-mL, round-bottomed flask
and 150 mL of a 10% potassium hydroxide
solution in aqueous methanol
is introduced at room temperature. After 24 hr of stirring, the brown mixture is poured into a separatory funnel
, diluted with 200 mL of water, and extracted with four 150-mL portions of ether
. The combined ethereal fractions are dried over anhydrous magnesium sulfate
, filtered, and concentrated to give a mixture of alcohols (Note 6)
as a light yellow oil.
The mixture of alcohols is placed in a 1000-mL round-bottomed flask
, dissolved in 300 mL of ether
, and cooled to 0°C. To this solution is added via an addition funnel
over a 30-min period a mixture of sodium dichromate dihydrate (27.5 g, 0.092 mol)
, 100 mL of water, and 10.2 mL of concd sulfuric acid
. The mixture is stirred at 0°C for 1 hr, warmed to room temperature where stirring is maintained overnight, diluted with 200 mL of water, and poured into a separatory funnel. The layers are separated and the aqueous phase is extracted with ether (3 × 200 mL)
. The combined organic layers are washed with saturated sodium bicarbonate solution (200 mL)
and brine (200 mL)
, dried over anhydrous magnesium sulfate
, filtered, and concentrated by rotary evaporation to give 16.8–17.8 g
) of verbenone (Note 7)
. Final purification is achieved by distillation of the oil through a 5-in Vigreux column
at reduced pressure (dry ice-acetone cooled receiver
); 13.1 g
), bp 108–110°C (5 mm) (Note 8)
(1R)-(+)-α-Pinene was purchased from the Aldrich Chemical Company, Inc.
The optical purity of the starting material is based on the maximum reported rotation for the dextrorotatory enantiomer: [α]D20 +51.6°
The levoratory form is also available from the same vender in high optical purity.
Benzene is reagent grade
quality and distilled from sodium/benzophenone ketyl
. This solvent is a suspect carcinogen and should be handled in a well-ventilated hood.
Lead tetraacetate was purchased from the Sigma Chemical Company
. This reagent is highly toxic and should be handled in a well-ventilated hood with gloves.
The checkers did not observe a precipitate on this scale, but it was observed on smaller-scale runs.
The tertiary acetate is formed initially3,4
and constitutes the major component of the mixture that may also contain residual amounts of benzene
. Failure to remove all the lead oxide
can induce further isomerization to the secondary acetate. To avoid this, a second filtration may be necessary. Although further purification is unnecessary, results in lower yields, and is not recommended, distillation at this point will give 26.8 g
) of a colorless oily acetate mixture.
Decomposition and lower yields result if this mixture is distilled, since the tertiary isomer loses water on attempted purification.5
Both alcohols yield the same ketone in the oxidation step.
The undistilled product is sufficiently pure for most purposes.
is clear on distillation but yellows slightly on exposure to air. This does not affect its quality. Radial chromatography (4-mm plate, 10% ethyl acetate/hexane
) of a 1-g sample yielded 900 mg
of pure verbenone
, [α]D 222.0°
2.00). Column chromatography (200 g of m, 10% ethyl acetate/hexane
) was used to purify verbenone
from the small scale preparation. A 43%
overall yield was obtained, [α]D 202.5°
(EtOH). The optical rotation of high quality verbenone
has been reported by several groups as neat samples.6,7,8
The percent of enantiomeric excess in the present example is correlated directly to the optical purity of the starting α-pinene
Waste Disposal Information
All toxic materials were disposed of in accordance with "Prudent Practices in the Laboratory"; National Academy Press; Washington, DC, 1995. Particular care must be taken in the disposal of waste materials containing lead and chromium
In recent years, verbenone
has been used with increasing frequency as a convenient "chiral pool" starting material for enantiospecific natural product synthesis9
and for the preparation of chiral ligands for transition metals.10
However, a serious deterrent to the use of verbenone
in this capacity is the rather low enantiomeric purity of commercially available material (customarily 55–60% ee). The short sequence outlined here provides a ready and convenient means for obtaining (1R, 5R)-(+)-verbenone
in high optical purity. Since several firms offer both enantiomers of the α-pinene
precursor in high quality (> 98% ee), the present procedure is a direct method for obtaining either essentially pure verbenone
enantiomer in reasonable quantities. The possibility of upgrading the optical purity of lower grade α-pinene
in advance of its oxidation also exists.2
The reaction sequence is based on the readiness with which α-pinene
undergoes oxidation predominantly to the tertiary acetate with Pb(OAc)4
Dichromate oxidation of the derived alcohol proceeds by way of a second allylic rearrangement to give verbenone
without affecting the neighboring stereogenic centers.
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