Checked by D. Zhao, D. Hughes, and I. Shinkai.
1. Procedure
A.
(−)-(1R,3R)-3-Chlorocamphoric anhydride. (+)-(1R,3S)-Camphoric acid (Note 1), (125 g, 0.625 mol) is added in small portions to a
1000-mL, three-necked flask charged with
455 g of phosphorus pentachloride (2.19 mol) and equipped with a
ground glass adaptor connected to a T-tube with one outlet open to the atmosphere and the remaining outlet connected to a
gas trap (Note
2). The mildly exothermic reaction is controlled by gently swirling the flask in an
ice bath as required (Note
3). After the addition is complete, the flask is equipped with a
reflux condenser topped by a
calcium chloride (CaCl2) drying tube, and the reaction mixture is heated under reflux (using an
oil bath at 125°C) for 12 hr. The reaction mixture is cooled to room temperature and the volatile material is removed by distillation using a bath temperature of 50°C under aspirator vacuum with the distillate boiling at 30–35°C (Note
4). The residual liquid is then added to a mechanically-stirred mixture of ice
(2 kg) and dimethylformamide (DMF, 125 ml), and stirring is continued until all the ice has melted. The resulting waxy white precipitate is collected by vacuum filtration while cold (2°C), washed with three, 500-mL portions of cold water, and dried under vacuum (Note
5). The crude white solid,
(−)-(1R,3R)-3-chlorocamphoric anhydride (
122 g,
90%), is of sufficient purity to be used in the next step (Note
6) and (Note
7).
B.
(−)-(1S,4R)-Camphanic acid. A
2000-mL, three-necked round-bottomed flask equipped with a
magnetic stirrer and reflux condenser is charged with
1000-mL of 0.1 N sulfuric acid and heated by means of an oil bath to 80°C. Finely powdered
(−)-(1R,3R)-3-chlorocamphoric anhydride (115 g, 0.53 mol) is added in portions over about 10 min to the stirred acid solution, the necks are sealed with
glass stoppers and the resulting suspension is brought to a gentle reflux (Note
2). After all the solids have dissolved (4–6 hr), the resulting solution is refluxed for an additional 2 hr (Note
8). The solution is allowed to cool to room temperature with stirring overnight (

12 hr), and the resulting off-while solid is collected by vacuum filtration and washed with water (3 × 250 mL). The remaining
camphanic acid is obtained by extraction of the aqueous filtrate with three
250-mL portions of chloroform (Note
9). After evaporation of the combined organic phases, the combined vacuum-dried solids are added to a
1000-mL, round-bottomed flask containing
500 mL of toluene, a condenser is added and the mixture is brought to gentle reflux until dissolution is complete (Note
2). The water/toluene azeotrope (85°C) is removed by distillation until no further water is obtained (Note
10). Distillation of the
toluene (110°C) is then continued until the residual volume has been reduced to

350 mL (Note
10) and (Note
11). The resulting solution is allowed to cool to room temperature during which time the acid crystallizes. After 4 hr at room temperature, the solids are collected by vacuum filtration and air-dried, affording
(−)-(1S,4R)-camphanic acid (
76 g,
72%) as colorless needles, mp
197–201°C, of sufficient purity for use in the next step (Note
12) and (Note
13).
2. Notes
3. The reactants initially form a paste that may form sizable lumps upon agitation, but the mixture liquifies upon further reaction as the result of the production of
phosphorus oxychloride (POCl3) and
phosphorus trichloride (PCl3).
4. The resulting liquid sometimes contains small amounts of white solid, but this solid does not require removal by filtration.
5. A freeze dryer (lyophilizer) was employed for vacuum drying (23°C at

0.05 mm).
6. If desired, a pure sample of the anhydride (mp
225–229°C) can be obtained by recrystallization of the crude anhydride from
carbon tetrachloride (CCl4) (1 g/5 mL).
7. Spectroscopic data for the purified anhydride are as follows:
1H NMR (300 MHz, CDCl
3) δ: 1.07 (s, 3 H), 1.14 (s, 3 H), 1.36 (s, 3 H), 2.11 (m, 2 H), 2.50 (m, 2 H);
13C NMR (75 MHz, CDCl
3) δ: 16.0, 17.9, 18.7, 31.5, 35.2, 48.7, 54.1, 166.0, 170.3; IR (cm
−1): 3019, 1821, 1773, 1215;
[α]D25 −17.6° (
chloroform,
c 2.04).
8. A total period of heating of 6–8 hr at 80–100°C was required.
9. Alternatively, a second crop of material can be obtained from the aqueous filtrate after several hours. However, a considerable amount of
camphanic acid still remains in the aqueous layer; thus
chloroform extraction of the aqueous phase as described is recommended.
To avoid undue exposure to the chloroform vapor, these extractions should be performed in a fume hood.
10. The volume of
toluene required will depend on the amount of water in the crude material. Additional
toluene should be added as required, so that the final, residual volume of dry
toluene solution is
350 mL as described.
11. Colored impurities, if produced, can be removed by treatment of the solution, prior to cooling, with charcoal (Norit) followed by filtration.
12. If desired, pure acid (mp
201–204°C) can be obtained by recrystallization of the crude acid from hot
toluene.
13. Spectroscopic data for the purified acid are as follows:
1H NMR (300 MHz, CDCl
3) δ: 1.03 (s, 3 H), 1.11 (s, 3 H), 1.15 (s, 3 H), 1.74 (ddd, 1 H, J = 4.3, 9.3, and 13.2), 1.98 (ddd, 1 H, J = 4.5, 10.6, and 13.2), 2.11 (ddd, 1 H, J = 4.5, 9.3, and 13.5), 2.48 (ddd, 1 H, J = 4.2, 10.6, and 13.5), 8.80 (br, 1 H, (s));
13C NMR (75 MHz, CDCl
3) δ: 9.60, 16.70, 16.73, 29.02, 30.73, 54.60, 55.11, 90.89, 172.41, 177.90; (IR cm
−1):3418, 3019, 1785, 1716, 1215;
[α]D25 −20.4° (
dioxane,
c 1.71).
15.
(−)-(1S,4R)-Camphanoyl chloride produced in this manner is of sufficient purity to be used directly in most acylation reactions. However, pure acid chloride (mp
69–71°C) can be conveniently obtained by recrystallization of the crude acid chloride from cold
CCl4 (1 g/1 mL,
75% recovery).
16. Spectroscopic data for the purified acid chloride are as follows:
1H NMR (300 MHz, CDCl
3) δ: 1.06 (s, 3 H), 1.12 (s, 3 H), 1.15 (s, 3 H), 1.76 (ddd, 1 H, J = 4.2, 9.3, and 13.3), 1.99 (ddd, 1 H, J = 4.6, 10.6, and 13.3), 2.18 (ddd, 1 H, J = 4.6, 9.3, and 13.6), 2.52 (ddd, 1 H, J = 4.2, 10.6, and 13.6);
13C NMR (75 MHz, CDCl
3) δ: 9.55, 16.55, 16.64, 28.76, 31.46, 55.40, 55.52, 94.86, 170.87, 176.52; IR (cm
−1): 2975, 1794, 1231;
[α]D25 −24.7° (
chloroform,
c 3.57).
3. Discussion
The resolution of alcohols by fractional crystallization or chromatography of diastereoisomeric esters with
(−)-camphanic acid was introduced some time ago.
3 The method has proven to be both convenient and efficient. A substructure search in the Chemical Abstracts Service (CAS) registry file has shown that more than 500 camphanic acid derivatives have been described in the last two decades. Besides resolution, camphanic acid esters of primary alcohols have been used to distinguish the signals of diastereotopic α-hydrogen atoms in
1H NMR spectra and to determine the optical purity of α-deutero primary alcohols.
4 Camphanoates are well suited for characterizing alcohols. They are easily prepared with
camphanoyl chloride in
pyridine and generally have high melting points.
Because both enantiomers,
(+)- and (−)-camphoric acid, are available by oxidation either from natural
(+)-D-camphor or from natural
(−)-L-borneol, both enantiomers of
camphanoyl chloride can be prepared conveniently.
3,5 The corresponding enantiomers of
camphanic acid were described for the first time by Wreden
6 and Aschan.
7 The three-step procedure, described above is an adaptation of procedures described by Aschan,
8 Zelinsky et al.,
9 Meyer et al.,
10 and Gerlach.
3
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