Org. Synth. 1993, 71, 48
[2-Oxabicyclo[2.2.1]heptane-1-carbonyl chloride, 4,7,7-trimethyl-3-oxo-, (1S)-)]
Submitted by Hans Gerlach1
, Dag Kappes, Robert K. Boeckman, Jr.2
, and Graham N. Maw.
Checked by D. Zhao, D. Hughes, and I. Shinkai.
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).
C. (−)-(1S,4R)-Camphanoyl chloride. A 500-mL, three-necked, round-bottomed flask, equipped for magnetic stirring and protected from moisture by a reflux condenser topped by a CaCl2 drying tube, is charged with 200 mL of thionyl chloride using a graduated cylinder. (−)-(1S,4R)-Camphanic acid (63.8 g, 0.322 mol) is added in portions using a powder funnel over 30 min, and the reaction mixture is heated under reflux for 3 hr, then allowed to cool to room temperature (Note 2). Excess thionyl chloride is removed by rotary evaporation (Note 14) to afford a solid that is freed of any residual thionyl chloride by the addition of toluene (500 mL) and subsequent evaporation under reduced pressure (repeated three times). The resulting solids are dried under high vacuum (Note 5) to afford 69 g of (−)-(1S,4R)-camphanoyl chloride (99%) as an off-white solid, mp 69–71°C (Note 15) and (Note 16).
(+)-(1R,3S)-Camphoric acid (99% purity) was obtained from Aldrich Chemical Company, Inc.
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)
The resulting liquid sometimes contains small amounts of white solid, but this solid does not require removal by filtration.
A freeze dryer (lyophilizer) was employed for vacuum drying (23°C at ~0.05 mm).
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)
Spectroscopic data for the purified anhydride are as follows: 1
H NMR (300 MHz, CDCl3
) 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); 13
C NMR (75 MHz, CDCl3
) 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°
A total period of heating of 6–8 hr at 80–100°C was required.
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
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
Colored impurities, if produced, can be removed by treatment of the solution, prior to cooling, with charcoal (Norit) followed by filtration.
If desired, pure acid (mp 201–204°C
) can be obtained by recrystallization of the crude acid from hot toluene
Spectroscopic data for the purified acid are as follows: 1
H NMR (300 MHz, CDCl3
) 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)); 13
C NMR (75 MHz, CDCl3
) 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°
Corrosive thionyl chloride
may destroy the rubber vacuum seals of a rotary evaporator
. Thionyl chloride
can also be removed by vacuum distillation.
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)
Spectroscopic data for the purified acid chloride are as follows: 1
H NMR (300 MHz, CDCl3
) 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); 13
C NMR (75 MHz, CDCl3
) 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°
Handling and Disposal of Hazardous Chemicals
The procedures in this article are intended for use only by persons with prior training in experimental organic chemistry. All hazardous materials should be handled using the standard procedures for work with chemicals described in references such as "Prudent Practices in the Laboratory" (The National Academies Press, Washington, D.C., 2011 www.nap.edu). All chemical waste should be disposed of in accordance with local regulations. For general guidelines for the management of chemical waste, see Chapter 8 of Prudent Practices.
These procedures must be conducted at one's own risk. Organic Syntheses, Inc., its Editors, and its Board of Directors do not warrant or guarantee the safety of individuals using these procedures and hereby disclaim any liability for any injuries or damages claimed to have resulted from or related in any way to the procedures herein.
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 1
H 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
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 Wreden6
The three-step procedure, described above is an adaptation of procedures described by Aschan,8
Zelinsky et al.,9
Meyer et al.,10
This preparation is referenced from:
Chemical Abstracts Nomenclature (Collective Index Number);
2-Oxabicyclo[2.2.1]heptane-1-carbonyl chloride, 4,7,7-trimethyl-3-oxo-, (1S)-)
(+)- and (−)-camphoric acid
sulfuric acid (7664-93-9)
phosphorus pentachloride (10026-13-8)
thionyl chloride (7719-09-7)
carbon tetrachloride (56-23-5)
Phosphorus Oxychloride (21295-50-1)
phosphorus trichloride (7719-12-2)
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