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Org. Synth. 2002, 79, 251
DOI: 10.15227/orgsyn.079.0251
[4+3] CYCLOADDITION IN WATER. SYNTHESIS OF 2,4-endo,endo-DIMETHYL-8-OXABICYCLO[3.2.1]OCT-6-EN-3-ONE
[ 8-Oxabicyclo[3.2.1]oct-6-en-3-one, 2,4-dimethyl-, (endo,endo)- ]
Submitted by Mark Lautens and Giliane Bouchain1 .
Checked by Patrick Foyle and Steven Wolff.
1. Procedure
A. 2-Chloropentan-3-one , 2 . A 500-mL, two-necked, round-bottomed flask, containing a magnetic stirring bar, is equipped with a 100-mL pressure-equalizing addition funnel and a reflux condenser fitted with a calcium chloride trap. The flask is charged with 85 mL (69.40 g, 0.80 mol) of pentan-3-one 1 (Note 1) and 200 mL of carbon tetrachloride and the mixture is heated to 45°C in an oil bath. The addition funnel is charged with 71 mL (0.88 mol, 1.1 mol equiv) of sulfuryl chloride that is added dropwise over a period of 2 hr. The resulting mixture is stirred for 3 hr at 45°C, carbon tetrachloride is removed by distillation under atmospheric pressure at 85°C (Note 2) and the residue is purified by distillation under reduced pressure (Note 3). After a forerun at 65-80°C (62 mm) containing mainly 3-pentanone , 2-chloropentan-3-one 2 is collected (bp 80-102°C, 62 mm) as a pale yellow liquid (77.0 g, 80%) (Notes 4, 5).
B. 2,4-endo,endo-Dimethyl-8-oxabicyclo[3.2.1]oct-6-en-3-one , 3 . A 500-mL round-bottomed flask is equipped with a magnetic stirring bar and a 50-mL pressure-equalizing addition funnel. The flask is charged with 15.0 g (0.12 mol) of 2 (Note 6), 36.1 mL (0.50 mol, 4 mol equiv) of furan and 125 mL of distilled water. The mixture is stirred vigorously at room temperature and triethylamine (18.05 mL, 0.13 mol, 1.05 mol equiv) is placed in the addition funnel and added dropwise to the reaction over a period of 30 min (Note 7). The reaction mixture is stirred for 12 hr and quenched by adding a saturated solution of ammonium chloride (50 mL). The mixture is poured into a 500-mL separatory funnel. The layers are separated and the aqueous layer is extracted with dichloromethane (3 × 50 mL). The combined organic layers are washed with brine, dried over anhydrous magnesium sulfate , and the organic layer is filtered and concentrated under reduced pressure. The crude reaction mixture is resubjected to the reaction conditions by adding additional furan and triethylamine (1.05 mol equiv based on the amount of unreacted starting material as determined by 1H NMR), (Notes 8, 9). After 5 hr of vigorous stirring at room temperature, the reaction is quenched by adding a saturated solution of ammonium chloride (50 mL). The layers are separated, the aqueous layer is extracted with dichloromethane (3 × 25 mL) and the combined organic layers are washed with brine and dried over anhydrous magnesium sulfate . After filtration, the solvent is removed with a rotatory evaporator and the crude reaction mixture is dried for 2 hr on a high vacuum pump. The oil is cooled to −20°C in the freezer overnight and pale yellow crystals are filtered on a Buchner funnel and washed with cold pentane . The mother liquors are concentrated, placed on a high vacuum pump for 5 hr, and cooled in the freezer. The procedure is repeated once more so that a total of 6.10 g (33%) of pure 3 (Note 10) is obtained.
The filtrate is concentrated under reduced pressure and the residue is purified by flash column chromatography on silica gel [500 mL, 230-400 mesh, eluted sequentially with hexane/ethyl acetate (90% to 70%)] to afford the cycloadduct 3 as a white powder (2.25 g, 12%); total 8.35 g (45%) (Note 11).
2. Notes
1. Pentan-3-one, furan and sulfuryl chloride were purchased from Aldrich Chemical Company, Inc. , and used without further purification.
2. The condenser and the addition funnel are removed and replaced by a simple distillation head and a condenser.
3. The residue is cooled to room temperature and transferred into a 200-mL round-bottomed flask equipped with a 6"-Vigreux column, distillation head, condenser and a cow receiver to be purified by distillation under reduced pressure.
4. A small quantity of 2,4-dichloropentan-3-one (5%) is obtained with the α-monochloropentanone 2 during the distillation. The NMR analysis for 2-chloropentan-3-one 2 is described by Wyman and Kaufman2.
5. The monochloroketone must be stored in a refrigerator.
6. Trace amounts of dichloroketone do not interfere with the [4+3] cycloaddition.
7. The mixture becomes a pale orange, biphasic solution. This mixture becomes red if the addition of triethylamine is too fast.
8. The reaction cannot be monitored by TLC because the monochloro ketone cannot be visualized.
9. The starting material remaining is usually about 40% of the crude weight.
10. Spectral data for the α,α-cycloadduct 3 are identical to that reported by Hoffmann and coworkers3.
11. The submitters report the isolation of 0.75 g (4%) of the corresponding exo-exo isomer; the checkers could not isolate this material in pure form.
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.
3. Discussion
Seven membered ring heterocycles are valuable synthetic intermediates for various natural products. The uses and synthesis of [4+3] cycloadducts have been the subject of extensive reviews.4 The usual method to prepare these compounds is the [4+3] cycloaddition between an oxyallylic cation and various dienes. The procedure described here provides a simple and efficient method for the construction of 8-oxabicyclo[3.2.1]oct-6-ene on a large scale in water using common reagents and mild conditions. To date, the two main routes reported in the literature involve the generation of oxyallylic cations starting from α,α'-dihalo ketones5 or α-monohalo ketones.6 All these reactions were carried out using sophisticated promotors [Zn-B(OEt)3,7 CeCl3-SnCl2,8 etc.] or an expensive and highly toxic reductive agent [Fe2(CO)9],9 under nitrogen in anhydrous solvents. Lubineau and Bouchain10 reported the [4+3] cycloaddition in water using α,α'-dibromo ketones or α-monochloro ketones to provide [3.2.1]oxabicyclic compounds in good yields. Moreover, these conditions afford a good to excellent stereoselectivity in favor of the α,α-cis isomers. By using the monochloro ketone in excess (2 equiv), the yield of the [4+3] cycloadduct is 88% based on furan , but this procedure, which uses furan in excess, is less cost effective. In order to optimize the yield, after a cycloaddition reaction, the crude mixture containing some starting monochloropentan-3-one was worked-up and resubjected to the same conditions without any intermediate purification. Moreover the pure α,α-cycloadduct is easily obtained by crystallization.
In conclusion, this is the most practical and least expensive method available for the synthesis of [3.2.1]oxabicyclic compounds.

References and Notes
  1. University of Toronto, Davenport Research Laboratories, Toronto, ON, M5S, 3H6, Canada.
  2. Wyman, D. P.; Kaufman, P. R. J. Org. Chem. 1964, 29, 1956).
  3. Hoffmann, H. M. R. Angew. Chem., Int. Ed. Engl. 1973, 12, 819-835; Hoffmann, H. M. R. Angew. Chem., Int. Ed. Engl. 1984, 23, 1-19; Noyori, R.; Hayakawa, Y. Org. React. 1983, 29, 163-344; Mann, J. Tetrahedron 1986, 42, 4611-4659; Chiu, P.; Lautens, M.; Top. Curr. Chem. 1997, 190, 1.
  4. Rawson, D. I.; Carpenter, B. K.; Hoffmann, H. M. R. J. Am. Chem. Soc. 1978, 100, 1765
  5. Fort, A. W. J. Am. Chem. Soc. 1962, 84, 4979-4981; Cookson, R. C.; Nye, M. J. Proc. Chem. Soc. 1963, 129-130.
  6. Föhlisch, B.; Gehrlach, E.; Herter, R. Angew. Chem., Int. Ed. Engl. 1982, 21, 137; Föhlisch, B.; Gehrlach, E.; Stezowski, J. J.; Kollat, P.; Martin, E.; Gottstein, W. Chem. Ber. 1986, 119, 1661-1682.
  7. Hoffmann, H. M. R.; Iqbal, M. N. Tetrahedron Lett. 1975, 4487-4490.
  8. Fukuzawa, S.; Fukushima, M.; Fujinami, T.; Sakai, S. Bull. Chem Soc.. Jpn. 1989, 62, 2348-2352.
  9. Takaya, H.; Makino, S.; Hayakawa, Y.; Noyori, R. J. Am. Chem. Soc. 1978, 100, 1765-1777.
  10. Lubineau, A.; Bouchain, G, Tetrahedron Lett. 1997, 38, 8031-8032, and citations therein.

Appendix
Chemical Abstracts Nomenclature (Collective Index Number);
(Registry Number)

2,4-endo,endo-Dimethyl-8-oxabicyclo[3.2.1]oct-6-en-3-one:
8-Oxabicyclo[3.2.1]oct-6-en-3-one, 2,4-dimethyl-, (endo,endo)- (9); (37081-58-6)

2-Chloropentan-3-one:
3-Pentanone, 2-chloro- (8,9); (17042-21-6)

Carbon tetrachloride: CANCER SUSPECT AGENT (8);
Methane, tetrachloro- (9); (56-23-5)

Sulfuryl chloride (8,9); (7791-25-5)

Furan (8,9); (110-00-9)

Triethylamine (8);
Ethanamine, N,N-diethyl- (9); (121-44-8)