Checked by Leticia M. Diaz, Stan S. Hall, and Gabriel Saucy.
1. Procedure
A.
cis- and trans-5-Methyl-2-[1-methyl-1-(phenylmethylthio)ethyl]cyclohexanone (7-benzylthiomenthone). A
1-L, three-necked, round-bottomed flask equipped with a
magnetic stirring bar and a
Friedrich condenser connected by its upper joint to a
mineral oil bubbler through which passes
nitrogen gas is charged with
500 mL of tetrahydrofuran (Note
1),
202.0 g (1.33 mol) of (+)-pulegone (Note
2), and
181.0 g (1.46 mol) of benzyl mercaptan (Note
3). The flask is flushed with
nitrogen,
10 mL of aqueous 10% sodium hydroxide is added, the flask is stoppered, and the mixture is heated to reflux under a static pressure of
nitrogen. After 2 hr at reflux the pale-yellow solution is allowed to cool, transferred to a
2-L separatory funnel, and washed with two
500-mL portions of saturated aqueous sodium chloride. The combined
sodium chloride layers, in turn, are extracted with three
250-mL portions of ether, and the combined organic layers are dried over
magnesium sulfate for 2 hr, filtered and concentrated by rotary evaporation at aspirator vacuum. The residual liquid is distilled in a good vacuum to give a fraction of bp
167–174°C (0.4 mm) weighing
325–330 g (
89–90%). The product is a mixture of
cis and
trans isomers otherwise highly pure as evidenced by spectral analysis (Note
4).
B.
2-(1-Mercapto-1-methylethyl)-5-methylcyclohexanol (7-thiomenthol). A
5-L, three-necked, round-bottomed flask is equipped with a
variable speed Hershberg stirrer and a
500-mL Dewar condenser filled with
dry ice–
acetone and connected by its upper joint to a mineral oil bubbler through which passes dry
nitrogen gas. The flask is immersed in a
dry ice–acetone bath, flushed well with
nitrogen and
3000 mL of ammonia is condensed into the flask via a glass tube passed through a
rubber septum in the remaining neck of the flask (Note
5). Clean
sodium, 125 g (5.43 g-atom), is added slowly to the
ammonia with slow stirring (Note
6). Then
250.3 g (0.906 mol) of 5-methyl-2-[1-methyl-1-(phenylmethylthio)ethyl]cyclohexanone and
72.5 mL (1.8 mol) of methanol in
625 mL of anhydrous ether (Note
7) are added dropwise via a
pressure-equalized addition funnel over 5 hr to the vigorously stirred (ca. 500 rpm) solution (Note
8). Stirring is continued an additional 30 min following which
150 mL of methanol is added over 2.5 hr dropwise (to avoid a violent eruption). The solution is allowed to warm slowly (Note
9) and the addition funnel and the condenser are removed to allow the
ammonia to evaporate overnight. The reaction flask is immersed in an
ice bath and 700 mL of water is added cautiously over an hour to the yellow solid left by evaporation of the
ammonia (Note
10). The solution is transferred to a
2-L separatory funnel and extracted with two
200-mL portions of ether, which are discarded. The aqueous layer is poured into a mixture of
500 mL of concentrated hydrochloric acid and 1000 g of ice, transferred to a
4-L separatory funnel, and extracted with four
200-mL portions of ether. The combined
ether extracts are washed with 200 mL of water and
200 mL of saturated aqueous sodium chloride, dried over
magnesium sulfate, and concentrated by rotary evaporation at aspirator vacuum. The residual liquid is placed under reduced pressure (0.2 mm) for 1 hr to remove the remaining solvent to give
137–140 g (
80–82%) of an orange oil that is a diastereomeric mixture of which the major component constitutes
80%, as indicated by
13C NMR (Note
11).
C.
Hexahydro-4,4,7-trimethyl-4H-1,3-benzoxathiin. To a
1-L, one-necked, round-bottomed flask equipped with a magnetic stirrer and charged with
325 mL of benzene (Note
12) is added
140.0 g (0.753 mol) of 5-methyl-2-(1-methyl-1-thioethyl)cyclohexanol,
26.0 g (0.87 mol) of paraformaldehyde (Note
13) and
1 g of p-toluenesulfonic acid monohydrate (Note
14). The flask is fitted with a
Dean–Stark trap and a Friedrich condenser and the contents are refluxed for 4 hr, by which time the
benzene distillate is clear. After the solution is cooled,
5 g of anhydrous potassium carbonate is added and the solution is stirred overnight, filtered, and concentrated by rotary evaporation and the residual liquid is distilled in a good vacuum to give a fraction of bp 69–94°C (0.1 mm), which weighs 130–134 g (86–89%) (Note
15). This fraction is dissolved in
250 mL of pentane, cooled to −25°C, and seeded with a crystal of the product (Note
16). Crystallization is allowed to proceed in a freezer, and collection and concentration of the mother liquor to half the original volume are carried out every other day to yield, after four crops of crystals are collected,
55–60 g (
37–40%) of the spectrally pure product (Note
17).
2. Notes
2.
(+)-Pulegone was obtained from SCM Corporation, Jacksonville, FL or Givaudan Corporation, Clifton, NJ; the specific rotation ranged from +21.85 to 22.6°. The material is also available from Aldrich Chemical Company, Inc. Pure
pulegone has
2 [α]D23 + 22.5°. The discrepancy, if any, is probably due to chemical impurities since the
pulegone used has been shown to be enantiomerically pure.
3,4 The checkers used
(+)-pulegone from Givaudan Corporation,
[α]D20 +25.7°, which was
94.4% pure (GLC) and contained 4.8% of
isopulegone or
carvone.
4. Spectral data; IR (film), cm
−1: 1708, 1620, 1500, 1458, 1382, 1363, 1120, 710, 695;
13C NMR (50 MHz, CDCl
3) δ: 22.2, 23.8, 27.8, 29.6, 33.1, 34.5, 36.6, 48.0, 52.3, 57.8, 126.8, 128.4 (2 C), 128.9 (2 C), 138.7, and 210.2;
1H NMR (200 MHz, CDCl
3) δ, partial: singlets at 1.38, 1.60, and 3.73, and an intense doublet at 0.97 (
J = 5.9). The checkers noted that the product distillate was a pale-blue color, which turned pale yellow after a few minutes.
5. The submitters noted that at least 15 kg of dry ice was required for a reaction of this scale. Using the described apparatus the checkers found that the condensation of the
ammonia required 8–10 hr, which could be reduced to ca. 5 hr by using the following assembly. An over-dried,
5-L, three-necked, round-bottomed flask was equipped with a glass stirrer shaft fitted with a sleeve joint and a large Teflon blade and the shaft was connected to an overhead motor drive. The flask was also connected to two
450-mL Dewar condensers with a large soda-lime drying tube attached to the tube connector of one condenser while the tube connector of the other condenser was attached with Tygon tubing that led through a tower of solid
potassium hydroxide pellets to a tank of anhydrous
ammonia. While
ammonia was slowly flushed through the entire assembly, the Dewar condensers were filled with dry ice–acetone, and a dry ice–acetone bath was raised to cool the vessel by immersion. The
ammonia flow rate was increased to condense ca.
3000 mL of ammonia into the flask. The condenser with the inlet connection from the
ammonia was removed and the flask sealed with a
glass stopper.
6.
Sodium was stored under mineral oil and washed with
pentane before use. For convenience the checkers used 1/6–

-in.
sodium spheres (Matheson Coleman and Bell) that were weighed in mineral oil, then wiped free of oil, rinsed in
hexane, cut in half, rinsed in
hexane again, and immediately added to the reaction over a 2-hr period, during which time the dark-black mixture became extremely viscous.
7. At this point the checkers charged an
oven-dried,
1000-mL pressure-equalizing addition funnel with the ketone in
methanol and
ether, and then quickly mounted the sealed funnel on the reaction flask by removing the flask's glass stopper.
8.
Methanol was used as received from Fisher Scientific, Inc. Anhydrous
ether was used as received from freshly opened containers from Mallinckrodt, Inc. and Fisher Scientific, Inc.
9. It is important to let the reaction mixture warm slowly; otherwise the
ammonia will boil violently and carry some of the reaction material out of the flask.
10. This reaction is highly exothermic, and caution should be exercised since some active
sodium may occasionally be left on the sides of the flask.
11. The intense
13C NMR (50 MHz, CDCl
3) signals of the major isomer are at 21.9, 26.9, 29.0, 31.3, 34.5, 34.6, 45.4, 47.2, 54.6, and 72.9 ppm relative to
TMS;
1H NMR (200 MHz, CDCl
3) δ, partial: 0.91 (d, 3 H,
J = 6.5), 1.40 (s, 3 H), and 1.52 (s, 3 H).
12.
Benzene was used as received from Aldrich Chemical Company, Inc. Caution! Benzene has been identified as a carcinogen; OSHA has issued emergency standards on its use. All procedures involving benzene should be carried out in a well-ventilated hood, and glove protection is required.
15. Excess
paraformaldehyde may separate from the distillate. If this occurs, the liquid should be filtered prior to crystallization.
16. In the absence of seeding, crystallization may take several weeks. It is preferable to separate a small sample of the precursor
thiomenthol from its stereoisomers by HPLC (
3% ethyl acetate in
hexane as eluant) and prepare a small amount of pure
oxathiane from this material. Alternatively, a small amount of the product may be purified by GLC on a 5% FFAP column. The melting point of pure material is 37–38°C. The checkers, who did not have seeding crystals, found that the early crops of crystals melted when the flask was allowed to warm to ambient temperature. Consequently, the cold supernatant liquid was withdrawn from the crystals with a Pasteur pipette while the flask was maintained at ca. 0°C (
ice–water bath). The crystals were subsequently recrystallized several times in the same flask without filtration. By this technique, white crystals melting at
32–35°C were obtained; this material is spectrally pure and suitable for asymmetric synthesis. The supernatant liquid was also concentrated, as the submitters described, to obtain additional crops using this technique.
17. Spectral data; IR (film), cm
−1: 2970–2870, 1455, 1440, 1388, 1370, 1355, 1305, 1155, 1095, 1066, 985, 955, 900, 830, and 710;
13C NMR (50 MHz, CDCl
3) δ: 21.8, 22.1, 24.4, 29.4, 31.3, 34.7, 41.8 (2 C), 51.5, 67.1, 76.7 ppm;
1H NMR (200 MHz, CDCl
3) δ partial: 0.92 (d, 3 H,
J = 6.5), 1.27 (s, 3 H), 1.43 (s, 3 H), 3.35 (td, 1 H,
J = 10.5, 4.2, HCO), 4.69 (d, 1 H,
J = 11.5, SCH
2O), 5.03 (d, 1 H,
J = 11.5, SCH
2O).
3. Discussion
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