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Org. Synth. 2003, 80, 9

DOI: 10.15227/orgsyn.080.0009

ASYMMETRIC EPOXIDATION OF trans-β-METHYLSTYRENE AND 1-PHENYLCYCLOHEXENE USING A D-FRUCTOSE-DERIVED KETONE: (R,R)-trans-β-METHYLSTYRENE OXIDE AND (R,R)-1-PHENYLCYCLOHEXENE OXIDE

[(Oxirane, 2-methyl-3-phenyl-, (2R,3R)- and 7-Oxabicyclo[4.1.0]heptane,1-phenyl-)]

Submitted by Zhi-Xian Wang, Lianhe Shu, Michael Frohn, Yong Tu, and Yian Shi¹.

Checked by Jason M. Diffendal and Rick L. Danheiser.

1. Procedure

A. (R,R)-trans-β-Methylstyrene oxide.² A 2-L, three-necked, round-bottomed flask (Note 1) equipped with a 5-cm, egg-shaped, Teflon-coated stir bar and two addition funnels is cooled in an ice-bath. The flask is charged with trans-β-methylstyrene (5.91 g, 50.0 mmol) (Note 2), 500 mL of a 2:1 mixture of dimethoxymethane (Note 2) and acetonitrile (CH₃CN) (Note 2), 300 mL of potassium carbonate-acetic acid buffer solution (Note 3), tetrabutylammonium hydrogen sulfate (0.375 g, 1.1 mmol), and the chiral ketone 1 (4.52 g, 17.5 mmol, 35 mol%) (Note 4). One addition funnel is charged with a solution of Oxone (46.1 g, 75.0 mmol) in 170 mL of aqueous 4 × 10⁻⁴M disodium ethylenediaminetetraacetate (Na₂EDTA) solution (Note 5) and the other addition funnel is charged with 170 mL of 1.47M aqueous potassium hydroxide (KOH) solution. The two solutions in the addition funnels are added dropwise at the same rate over 2.5 hr to the cooled reaction mixture which is stirred vigorously at 0°C (Notes 6, 7). The resulting suspension is stirred at 0°C for an additional hour and then 250 mL of pentane is added. The aqueous phase is separated and extracted with two 250-mL portions of pentane, and the combined organic phases are dried over Na₂SO₄, filtered, and concentrated by rotary evaporation at 0°C (Note 8). The resulting oil is loaded onto 50 g of Whatman 60 Å (230-400 mesh) silica gel (Note 9) packed in a 5-cm diameter column. The silica gel is first washed with 200 mL of hexane to remove trace amounts of unreacted olefin, then the product is eluted with 200 mL of 10:1 hexane:ether to afford 6.02-6.31 g (90-94%) of trans-β-methylstyrene oxide (Notes 10-12).

B. (R,R)-1-Phenylcyclohexene oxide.³ A 250-mL, round-bottomed flask (Note 1) equipped with a 4.5-cm, egg-shaped Teflon-coated magnetic stir bar is charged with 1-phenylcyclohexene (7.91 g, 50.0 mmol) (Note 2) and the chiral ketone 1 (1.29 g, 5.00 mmol, 10 mol%) (Note 4). The flask is cooled in an ice-bath, and 75 mL of CH₃CN and 75 mL of a solution which is 2.0M potassium carbonate and 4 × 10⁻⁴M EDTA are added. The reaction mixture is cooled to 0°C, and 20 mL (200 mmol) of 30% hydrogen peroxide (H₂O₂) is added. The resulting mixture is vigorously stirred at 0°C for 6 hr (Note 13), then diluted with 50 mL of hexane. The aqueous phase is separated and extracted with three 200-mL portions of hexane, and the combined organic phases are washed with two 50-mL portions of 1M aqueous sodium thiosulfate solution and 100 mL of brine, dried over Na₂SO₄, filtered, and concentrated by rotary evaporation at 0°C. The resulting oil is applied to 180 g of Whatman 60 Å (230-400 mesh) silica gel (Note 9) packed in a 5-cm diameter column, then the product is eluted with 600 mL of hexane and finally 1 L of 20:1 hexane:Et₂O to afford 6.88-8.01 g (79-92%) of (R,R)-1-phenylcyclohexene oxide as a colorless oil (Notes 14, 15).

2. Notes

1. All glassware used for the epoxidation reaction is carefully washed to remove trace metals, which may catalyze the decomposition of Oxone and H₂O₂. The checkers used Alconox, followed by water, and then acetone.

2. β-Methylstyrene (99%) and dimethoxymethane (99%) were obtained from Aldrich Chemical Company, Inc. and used as received. ACS grade acetonitrile and 30% H₂O₂ were purchased from Fisher Scientific and used as received. 1-Phenylcyclohexene (99%) was obtained from Alfa Aesar.

3. The buffer solution is prepared by adding 4.5 mL of glacial acetic acid (Fisher Scientific) to 1 L of a 0.1M solution of K₂CO₃ (Fisher Scientific).

4. The chiral ketone 1 was prepared as described in Org. Synth. 2003, 80, 1.

5. Oxone was obtained from the Aldrich Chemical Company, Inc. The activity of commercial Oxone in oxidation reactions occasionally varies with different batches. Na₂EDTA was purchased from Fisher Scientific.

6. The concentration of Oxone in the reaction mixture and the reaction pH are very important factors in determining the epoxidation efficiency. Both the Oxone and KOH solutions must be added to the reaction mixture in a steady, uniform manner over 2.5 hr.

7. As the reaction progresses, the organic and aqueous phases separate. Salts precipitate during the first 10-20 min of addition. Vigorous stirring is required to sufficiently mix the two phases; however, excessive splashing of the reaction mixture must be avoided in order to maximize conversion.

8. The epoxide product is volatile. Care should be taken to minimize the loss of the epoxide during concentration.

9. The silica gel is buffered by packing the column with hexane containing 1% triethylamine.

10. The product exhibits the following physical and spectral properties: ¹H NMR (500 MHz, CDCl₃) δ: 1.45 (d, 3 H, J = 5.1), 3.03 (qd, 1 H, J = 5.1, 2.1), 3.57 (d, 1 H, J = 2.1), 7.20-7.40 (m, 5 H); ¹³C NMR (125 MHz, CDCl₃) δ: 18.1, 59.2, 59.7, 125.7, 128.2, 128.6, 137.9; Anal. Calcd C, 80.56; H, 7.51. Found: C, 80.39; H, 7.37; [α]_D25 +45.3 (CHCl₃, c 1.84).

11. The submitters obtained the product in 91-92% ee as determined by chiral GC with a Chiraldex G-TA column (25 μm × 30 m) (oven temperature: 80°C; head pressure: 20 psi; retention time: minor isomer at 11.8 min, major isomer at 15.8 min). The checkers obtained epoxide with 89% ee.

12. The submitters report that the ee can be increased to 94% if the epoxidation is carried out at −8 to −10°C.

13. The reaction was monitored by TLC and was complete after 6 hr. The reaction rate is affected by the rate of stirring.

14. The product exhibits the following physical and spectral properties: ¹H NMR (500 MHz, CDCl₃) δ: 1.25-1.65 (m, 4 H), 1.95-2.03 (m, 2 H), 2.12 (dt, 1 H, J = 15.0, 5.1), 2.29 (ddd, 1 H, J = 15.0, 8.4, 5.1), 3.09 (br s, 1 H), 7.20-7.40 (m, 5 H); ¹³C NMR (125 MHz, CDCl₃) δ: 19.8, 20.1, 24.7, 28.9, 60.2, 61.9, 125.3, 127.1, 128.2, 142.5. Anal. Calcd: C, 82.72; H, 8.10. Found: C, 82.76; H, 8.13; [α]_D25 +113.0 (benzene, c 0.56).

15. The submitters obtained the product in 96-98% ee as determined by chiral GC with a Chiraldex G-TA column (25 μm × 30 m) (oven temperature: 80°C; head pressure: 25 psi; retention time: minor isomer at 68.0 min, major isomer at 71.8 min). The checkers obtained the product in 94-95% ee.

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

The epoxidation procedure described herein utilizes the fructose-derived ketone (1) as catalyst and Oxone^4a-j or H₂O₂ ^4k,l as oxidant. The procedure provides a valuable method for the preparation of enantiomerically-enriched epoxides from trans- and trisubstituted olefins. High enantioselectivies have been obtained for a variety of unfunctionalized trans-disubstituted and trisubstituted olefins,^4a-c vinylsilanes,^4j hydroxyalkenes,^4e conjugated dienes,^4d conjugated enynes,^4f,i and enol derivatives.^4g Representative examples are shown in Table I.

**Table 1.** Asymmetric Epoxidation of Representative Olefins by Ketone 1 (0.3 equiv) with Oxone

Previously, the generation of dioxiranes almost exclusively used potassium peroxomonosulfate (KHSO₅) as oxidant.⁵^,⁶ Recently, we found that hydrogen peroxide (H₂O₂) could be used as primary oxidant in combination with a nitrile for the epoxidation catalyzed by 1.^4k,l In this epoxidation, the peroxyimidic acid generated from the addition of H₂O₂ to CH₃CN is likely to be the active oxidant for the formation of the dioxirane.⁷ The Oxone procedure described herein can be applied to a wide variety of olefins without the need for extensive optimization. The more recent H₂O₂ procedure uses much less solvent and salts and is operationally simpler. However, this procedure is somewhat sensitive to the reactivity and solubility of olefins; some optimization (varying catalyst loading, reaction time, reaction temperature, amount of H₂O₂ and solvent) may be required for different substrates.^4l

References and Notes

Department of Chemistry, Colorado State University, Fort Collins, CO 80523.
Witkop, B.; Foltz, C. M. J. Am. Chem. Soc. 1957, 79, 197.
Berti, G.; Macchia, B.; Macchia, F.; Monti, L. J. Org. Chem. 1968, 33, 4045.
For examples of asymmetric epoxidation mediated by fructose-derived ketones see: (a) Tu, Y.; Wang, Z.-X.; Shi, Y. J. Am. Chem. Soc. 1996, 118, 9806; (b) Wang, Z.-X.; Tu, Y.; Frohn, M.; Shi, Y. J. Org. Chem. 1997, 62, 2328; (c) Wang, Z.-X.; Tu, Y.; Frohn, M.; Zhang, J.-R.; Shi, Y. J. Am. Chem. Soc. 1997, 119, 11224; (d) Frohn, M.; Dalkiewicz, M.; Tu, Y.; Wang, Z.-X.; Shi, Y. J. Org. Chem. 1998, 63, 2948; (e) Wang, Z.-X.; Shi, Y. J. Org. Chem. 1998, 63, 3099; (f) Cao, G.-A.; Wang, Z.-X.; Tu, Y.; Shi, Y. Tetrahedron Lett. 1998, 39, 4425; (g) Zhu, Y.; Tu, Y.; Yu, H.; Shi, Y. Tetrahedron Lett. 1998, 39, 7819; (h) Tu, Y.; Wang, Z.-X.; Frohn, M.; He, M.; Yu, H.; Tang, Y.; Shi, Y. J. Org. Chem. 1998, 63, 8475; (i) Wang, Z.-X.; Cao, G.-A.; Shi, Y. J. Org. Chem. 1999, 64, 7646; (j) Warren, J. D.; Shi, Y. J. Org. Chem. 1999, 64, 7675; (k) Shu, L.; Shi, Y. Tetrahedron Lett. 1999, 40, 8721; (l) Shu, L.; Shi, Y. Tetrahedron 2001, 57, 5213.
Oxone (2KHSO₅·KHSO₄·K₂SO₄) is currently the common source of potassium peroxomonosulfate (KHSO₅).
As close analogues of potassium peroxomonosulfate, arenesulfonic peracids generated from (arenesulfonyl)imidazole/H₂O₂/NaOH have also been shown to produce dioxiranes from acetone and trifluoroacetone as illustrated by ¹⁸O-labeling experiments see: Schulz, M.; Liebsch, S.; Kluge, R.; Adam, W. J. Org. Chem. 1997, 62, 188.
For leading references on epoxidation using H₂O₂ and RCN see: (a) Payne, G. B.; Deming, P. H.; Williams, P. H. J. Org. Chem. 1961, 26, 659; (b) Payne, G. B. Tetrahedron 1962, 18, 763; (c) McIsaac, J. E. Jr.; Ball, R. E.; Behrman, E. J. J. Org. Chem. 1971, 36, 3048; (d) Bach, R. D.; Knight, J. W. Org. Synth. Coll. Vol. VII 1990, 126; (e) Arias, L. A.; Adkins, S.; Nagel, C. J.; Bach, R. D. J. Org. Chem. 1983, 48, 888.

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

(R,R)-trans-β-Methylstyrene oxide:
Oxirane, 2-methyl-3-phenyl-, (2R,3R)- (9); (14212-54-5)

trans-β-Methylstyrene:
Benzene, (1E)-1-propenyl- (9); (873-66-5)

Dimethoxymethane: Methane, dimethoxy- (8, 9); (109-87-5)

1,2:4,5-Di-O-isopropylidene-D-erythro-2,3-hexodiulo-2,6-pyranose:
β-Dk-erythro-2,3-Hexodiulo-2,6-pyranose, 1,2:4,5-bis-O-(1-methylethylidene)- (9); (18422-53-2)

Tetrabutylammonium hydrogen sulfate:
1-Butanaminium, N,N,N-tributyl-, sulfate (1:1) (9); (32503-27-8)

Disodium ethylenediaminetetraacetate:
Glycine, N,N'-1,2-ethanediylbis [N-(carboxymethyl)-, disodium salt (9); (139-33-3)

(R,R)-1-Phenylcyclohexene oxide:
7-Oxabicyclo[4.1.0]heptane, 1-phenyl-, (1R,6R)- (9); (17540-04-4)

Oxone:
Peroxymonosulfuric acid, monopotassium salt, mixt. with
dipotassium sulfate and potassium hydrogen sulfate (9); (37222-66-5)

Notes

References/EndNotes

Article Compounds

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