Checked by Timothy J. Watson and Leo A. Paquette.
1. Procedure
A.
(−)-(1R,3R,4S,8R)-p-Menthane-3,9-diol. To a dry,
2-L, three-necked flask equipped with a gas outlet, an
overhead stirrer, and a
500-mL pressure-equalizing dropping funnel with a gas inlet, is added a solution of
31 g (0.20 mol) of isopulegol (Note
1) in
550 mL of tetrahydrofuran (THF) (Note
2) under
nitrogen. From the funnel,
230 mL of a 1.0 M diborane solution (Note
3) is added dropwise with stirring at room temperature at such a rate to insure that gas evolution is not violent. When the addition is complete, the clear solution is stirred for 3 hr at room temperature. The dropping funnel is removed and
100 mL of aqueous 3 N sodium hydroxide is added slowly; the solution is then warmed to 60°C on the
steam bath for 2 hr. The gas outlet is replaced by a
thermometer and the septum is replaced by another dropping funnel charged with
120 mL of aqueous 30% hydrogen peroxide and the reaction flask is placed in an
ice bath.
Hydrogen peroxide is then added and the reaction temperature is maintained between 30–50°C by carefully controlling the rate of addition (the reaction is strongly exothermic at the beginning). When the addition is complete, the ice bath is removed and the reaction mixture is stirred at 50°C for 2 hr. The bulk of the
THF is removed under reduced pressure and the residue is diluted with
200 mL of ether and washed with
brine. The aqueous layer is extracted with two
50-mL portions of ether; the resulting extracts are combined and dried over anhydrous
sodium sulfate for several hours and filtered. The filtrate is concentrated using a
rotary evaporator. The resulting oil is dissolved in
100 mL of hot hexane, allowed to cool slowly, and stored at 0°C for 2 days. The supernatant mother liquor is decanted,
100 mL of fresh hexane is added, the crystalline mass is swirled for 2–3 min and the product is separated by filtration. After vacuum drying,
17.6 g (
51%) of
(−)-(1R,3R,4S,8R)-p-menthane-3,9-diol is obtained as colorless crystals, mp
105–107°C (Note
4).
B.
(+)-(3aS,7aR)-Hexahydro-(3S,6R)-dimethyl-2(3H)-benzofuranone. To a
1-L round-bottomed flask equipped with an
efficient magnetic stirrer is added
10 g (58 mmol) of (−)-(1R,3R,4S,8R)-p-menthane-3,9-diol and
400 mL of dichloromethane. The resulting suspension is stirred until all the solid dissolves at which time a mixture of powdered
potassium permanganate and
copper sulfate (CuSO4·5H2O) (Note
5) is added in one portion. The reaction mixture is then stirred at 25°C between 6 and 8 hr depending upon the quality of the oxidant (Note
6),
400 mL of ether is added, and stirring is continued for an additional 20 min. The suspension is transferred with the aid of a small amount of
ether onto a
fritted-disk Büchner funnel containing
50 g of silica gel and a little
ether. The spent manganese salt is mixed with some of the silica gel, using a
spatula, to insure that all the solution is absorbed. The resulting filter-cake is washed with
500 mL of ether (Note
7). Upon removal of the solvent, the crude product is obtained as a clear, colorless oil. More product is recovered by taking the filter-cake from the funnel and placing it in a
2-L beaker containing
100 mL of ether and a solution of
270 g of sodium metabisulfite in 1 L of water that is cooled in an ice bath (Note
8). The cake is broken up with a glass rod and stirred. To the resulting slurry,
150 mL of aqueous 10% hydrochloric acid is added in portions with stirring until the color turns from dark gray to pale yellow and all the solid material, except the silica, is dissolved. The resulting mixture is filtered and the filtrate is extracted with three
150-mL portions of ether. The
ether extracts are combined and washed twice with water and once with
brine. The ethereal solution is dried by shaking with
30 g of anhydrous sodium sulfate and filtered. The filtrate is concentrated to about 150 mL and stirred with 10 g of Amberlyst-15 for 3 hr (Note
9). After another filtration, the solvent is evaporated and the residual oil is combined with that previously obtained. Purification by vacuum distillation gives
4.8–5.0 g (
49–51% yield) of
3aS,7aR-hexahydro-3S,6R-dimethyl-2(3H)-benzofuranone as a colorless oil, bp
110°C (0.05 mm) (Note
10).
2. Notes
1.
Isopulegol (Tech. as obtained from Aldrich-Chemie GmbH & Company KG, D-7924 Steinheim, Federal Republic of Germany) contains about 65–70% (−)-isopulegol according to its NMR spectrum. It has an optical rotation of
[α]D20 −4.6° (neat), while
[α]D20 −22° is reported
2 for the pure material. The technical grade product was used without further purification. Pure
(−)-isopulegol can be prepared in a highly stereoselective manner from
(+)-citronellal.
3
3.
Diborane was obtained as a 1.0 M THF solution from Aldrich Chemical Company, Inc.
4. The NMR spectrum of the diol obtained was identical to that already reported:
2 1H NMR (360 MHz, CDCl
3) δ: 0.86–0.99 (m, 2 H), 0.92 (d, 3 H, J = 6.6), 0.96 (d, 3 H, J = 7.5), 1.17–1.29 (m, 1 H), 1.32–1.49 (m, 2 H), 1.57 (m, 1 H), 1.64 (m, 1 H), 1.85 (m, 1 H), 1.96 (m, 1 H), 3.29 (br, s, 2 H), 3.47 (t, d, 1 H, J = 10.4, 4.2), 3.60 (dd, 1 H, J = 10.6, 3.5), 3.66 (dd, 1 H, J = 10.6, 5.4). Its optical rotation (
[α]D20 −18.7° (CHCl
3,
c 10)) was identical to that reported.
2 The checkers recorded an
[α]D20 of −20.7° (CHCl
3,
c 10).
5. The oxidant was prepared from
130 g of crystalline potassium permanganate (KMnO4) and
25 g of CuSO4·5H2O by grinding them together in a
mortar until a fine powder was obtained.
6. The progress of the oxidation can be monitored by the disappearance of the diol using TLC (eluent,
hexane:
ethyl acetate, 2:7).
7. It is essential to mix thoroughly the spent oxidant and the silica gel with a spatula while washing. This process does not cause any manganese salt to pass into the filtrate.
8. The quality of the
KMnO4 and
CuSO4·5H2O varies with the supplier and affects the yield. Consequently, some hydroxy acid, instead of the lactone, may be formed. In such a case, treatment with
sodium metabisulfite solution followed by acidification converts any free acid retained on the filter cake into lactone.
9. Amberlyst-15, a cation exchange resin, was supplied by Fluka Chemical Corporation.
10. The lactone is identical to that previously reported
4 and has the following spectral data: IR (neat) cm
−1: 1770, 1453, 1375, 1290, 1190, 1096, 847;
1H NMR (360 MHz, CDCl
3) δ: 0.99–1.38 (m, 3 H), 1.02 (d, 3 H, J = 6.5), 1.15 (d, 3 H, J = 7.6), 1.59 (m, 1 H), 1.78 (m, 2 H), 1.92 (m, 1 H), 2.25 (m, 1 H), 2.64 (quint., 1 H, J = 7.6), 4.00 (dt, 1 H, J = 11, 4);
13C NMR (360 MHz, CDCl
3) δ: 9.57, 21.99, 23.77, 31.25, 34.15, 38.72 (2 carbons), 47.09, 81.38, 180.27. It has
[α]D20 +106.2° (CHCl
3,
c 0.6). The checkers recorded
[α]D25 of +72 to +88° (CHCl
3,
c 0.6). If the temperature of the distillation exceeds 110°C, a decrease in [α]
D might be observed because of epimerization α to the lactone carbonyl. If the pure diastereomer is required, it is recommended that purification be effected by column chromatography over silica gel (eluent,
pentane:ethyl acetate 20:1). Typically, the lactone is obtained in a yield of
55% with an
[α]D20 +149° (CHCl
3,
c 1.1).
All toxic materials were disposed of in accordance with "Prudent Practices in the Laboratory"; National Academy Press; Washington, DC, 1995.
3. Discussion
There are few oxidants that oxidize primary alcohols faster than secondary ones. We have demonstrated that a solid mixture of
KMnO4 and
CuSO4·5H2O treated with base can bring about such selectivity.
4 The present procedure illustrates a general and convenient method for the oxidation of α,ω-diols to give lactones, that is typified by procedure B, where base is not necessary since ideally no acid is produced. When conducted on a 1-g scale and using pure
(−)-isopulegol, overall yields were as high as 89%. In the present instance, starting with pure diol in 10-g lots, maximum yields of only 55% were attained. The reason for the lower yield on larger scale is unclear, although the formation of hydroxy acid rather than lactone may account for some loss. Nonetheless, the procedure has undeniable advantages, including, the formation of a single lactone retaining the initial stereochemistry at C(3). Although Jones oxidation of the diol
5 is reported to give the product lactone in
89% yield, repetition of the experiment reveals that only
38% is found in practice, the balance of material being two other related, but different products.
4 Other routes
6,7 to this lactone, because of the conditions, give most probably the 3R epimer as evidenced by the NMR spectral data.
Appendix
Compounds Referenced (Chemical Abstracts Registry Number)
sodium metabisulfite
brine
diborane
(−)-(1R,3R,4S,8R)-p-Menthane-3,9-diol
(−)-isopulegol
KMnO4
CuSO4·5H2O
hydrochloric acid (7647-01-0)
ethyl acetate (141-78-6)
ether (60-29-7)
sodium hydroxide (1310-73-2)
potassium permanganate (7722-64-7)
sodium sulfate (7757-82-6)
nitrogen (7727-37-9)
copper sulfate,
cupric sulfate (7758-98-7)
Benzophenone (119-61-9)
sodium (13966-32-0)
hydrogen peroxide (7722-84-1)
Pentane (109-66-0)
dichloromethane (75-09-2)
Tetrahydrofuran,
THF (109-99-9)
hexane (110-54-3)
(+)-citronellal (106-23-0)
(3aS,7aR)-HEXAHYDRO-(3S,6R)-DIMETHYL-2(3H)-BENZOFURANONE,
3aS,7aR-hexahydro-3S,6R-dimethyl-2(3H)-benzofuranone,
(+)-(3aS,7aR)-Hexahydro-(3S,6R)-dimethyl-2(3H)-benzofuranone (79726-51-5)
isopulegol (89-79-2)
2(3H)-Benzofuranone, hexahydro-3,6-dimethyl-, [3R-(3α,3aβ,6β,7aα)]-
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