Asymmetric Darzens-Type Epoxidation
via Chiral Ammonium Ylides

Hiroyo Kinoshita; Akiko Ihoriya; Motoharu Ju-ichi; Tetsutaro Kimachi

doi:10.1055/s-0030-1258015

LETTER

Asymmetric Darzens-Type Epoxidation via Chiral Ammonium Ylides

Hiroyo Kinoshita, Akiko Ihoriya, Motoharu Ju-ichi, Tetsutaro Kimachi*
School of Pharmaceutical Sciences, Mukogawa Women’s University, 11-68 Kyuban-cho Koshien, Nishinomiya 663-8179, Hyogo, Japan
Fax: +81(798)459952; e-Mail: tkimachi@mukogawa-u.ac.jp;

Abstract

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Abstract

Asymmetric Darzens-type epoxide formation of aryl aldehydes with chiral para-substituted benzylammonium ylides, prepared from brucine and corresponding benzylic chlorides and treated in situ under basic condition, was carried out to afford chiral 2,3-diaryl epoxides with moderate to good ee (84% ee). Brucine was found to be an excellent tertiary amine for a chirality transfer agent.

Key words

brucine - 2,3-diaryl epoxides - chiral tertiary amines - Darzens reaction

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Referenzen

References and Notes

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Alcoholysis:

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Aminolysis:

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9

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12

Typical Procedure for the Synthesis of (2 S ,3 S )-2-Phenyl-3-(4-trifluoromethylphenyl)oxirane (6) A THF (3 mL) solution of trifluoromethyl benzyl chloride (0.15 mL, 1.0 mmol) and brucine (591 mg, 1.5 mmol) in a flame-dried round-bottom flask (30 mL volume) was heated under reflux for 3 h. Subsequently, the reflux condenser was removed, and a septa cap was placed on the top of the flask. The resulting precipitate in THF was treated with further addition of THF (6 mL) and benzaldehyde (0.1 mL, 1.0 mmol) at r.t., and then the mixture was cooled to -40 ˚C under argon atmosphere. Two equiv of KOt-Bu (224 mg, 2.0 mmol) were slowly added, and the mixture was stirred at this temperature for 3 h. The mixture was warmed up to 0 ˚C and kept for 3 h and worked up. The general workup procedure is as follows. First, 5 mL of EtOAc and sat. aq NH₄Cl (5 mL) were added and then separated. The aqueous layer was extracted three times with EtOAc and combined. The organic layer was washed with H₂O, brine, and then dried over MgSO₄. Removal of the solvent and purification by flash chromatography afforded (2S,3S)-2-phenyl-3-(4-trifluoromethylphenyl)oxirane as a colorless solid; mp 57 ˚C; [α]_D ^²6 -173.4 (c 1.21 acetone). ^¹H NMR (400 MHz, CDCl₃): δ = 3.84 (d, 1 H, J = 1.8 Hz), 3.92 (d, 1 H, J = 1.8 Hz), 7.33-7.42 (m, 5 H), 7.46 (d, 2 H, J = 8.0 Hz), 7.64 (d, 2 H, J = 8.0 Hz). ^¹³C NMR (126 MHz, CDCl₃): δ = 62.0, 63.1, 124.1 (q, J = 271 Hz), 125.5, 125.6 (q, J = 3 Hz), 125.8, 128.6, 128.7, 130.5 (q, J = 33 Hz), 136.6, 141.2. IR (CHCl₃): 1620, 1320, 1160, 1120 cm^-¹. HRMS (EI⁺): m/z calcd for C₁₅H₁₁OF₃: 264.0762; found: 264.0753. The ee, found to be 79%, was obtained by HPLC on a CHIRALPAK AD-H column (250 × 4.6 mm, i.d.) from Daicel Co., using n-hexane-2-PrOH (90:10) as eluent (flow rate 1.0mL/min) at 254 nm. The major enantiomer (2S,3S) was eluted after 9.6 min, and the minor enantiomer after 5.0 min.
(2 S ,3 S )-2-(4-Methoxyphenyl)-3-(4-trifluoromethyl-phenyl)oxirane (7) Colorless solid; mp 63-67 ˚C; [α]_D ^²7 -164.4 (c 1.04 EtOH). ^¹H NMR (400 MHz, CDCl₃): δ = 3.78 (d, 1 H, J = 1.8 Hz), 3.83 (s, 3 H), 3.91 (d, 1 H, J = 1.8 Hz), 6.92 (d, 2 H, J = 8.8 Hz), 7.26 (d, 2 H, J = 8.8 Hz), 7.45 (d, 2 H, J = 8.4 Hz), 7.60 (d, 2 H, J = 8.4 Hz). ^¹³C NMR (126 MHz, CDCl₃): δ = 55.4, 61.8, 63.0, 114.2, 125.5, 125.7, 126.8, 128.5, 141.3, 160.1. IR (CHCl₃): 3000, 1610, 1510, 1320 cm^-¹. The ee, found to be 83%, was obtained by HPLC on a CHIRALPAK AD-H column (250 × 4.6 mm, i.d.) from Daicel Co., using n-hexane-2-PrOH (90:10) as eluent (flow rate 1.0 mL/min) at 254 nm. The major enantiomer (2S,3S) was eluted after 10 min, and the minor enantiomer after 6.6 min.
(2 S ,3 S )-2-(4- tert -Butylphenyl)-3-(4-trifluoromethyl-phenyl)oxirane (8) Colorless solid; mp 104-108 ˚C; [α]_D ^²² -156.8 (c 1.33 acetone). ^¹H NMR (400 MHz, CDCl₃): δ = 1.33 (s, 9 H), 3.81 (d, 1H, J = 1.8 Hz), 3.93 (d, 1 H, J = 1.8 Hz), 7.28 (d, 2 H, J = 8.2 Hz), 7.42 (d, 2 H, J = 8.2 Hz), 7.45 (d, 2 H, J = 8.2 Hz). ^¹³C NMR (126 MHz, CDCl₃): δ = 31.3, 34.7, 61.9, 63.0, 124.2 (q, J = 272 Hz), 125.4, 125.5(q, J = 4 Hz), 125.6, 125.8, 130.5 (q, J = 33 Hz), 133.6, 141.4, 151.9. IR (CHCl₃): 3000, 1620, 1170, 1130 cm^-¹. The ee, found to be 76%, was obtained by HPLC on a CHIRALPAK AD-H column (250 × 4.6 mm, i.d.) from Daicel Co., using n-hexane-2-PrOH (90:10) as eluent (flow rate 1.0 mL/min) at 254 nm. The major enantiomer (2S,3S) was eluted after 4.6 min, and the minor enantiomer after 5 min.
(2 S ,3 S )-2-(3-Pyridyl)-3-(4-trifluoromethylphenyl)-oxirane (9) Colorless solid; mp 54-56 ˚C; [α]_D ^²³ -77.4 (c 0.57 acetone). ^¹H NMR (400 MHz, CDCl₃): δ = 3.88 (d, 1 H, J = 1.8 Hz), 3.96 (d, 1 H, J = 1.8 Hz), 7.33 (dd, 1 H, J = 4.4, 8.1 Hz), 7.47 (d, 2 H, J = 8.1 Hz), 7.63 (dt, 1 H, J = 8.1, 1.8 Hz), 8.61 (dd, 1 H, J = 1.8, 4.4 Hz), 8.64 (d, 1 H, J = 1.8 Hz). ^¹³C NMR (100 MHz, CDCl₃): δ = 60.9, 61.9, 123.6, 124.3 (q, J = 272 Hz), 125.7 (q, J = 4 Hz), 125.9, 131.0, 132.2, 132.7, 140.5, 147.9, 150.0. IR (CHCl₃): 3000, 1600 cm^-¹. The ee, found to be 60%, was obtained by HPLC on a CHIRALPAK AD-H column (250 × 4.6 mm, i.d.) from Daicel Co., using n-hexane-2-PrOH (90:10) as eluent (flow rate 1.0 mL/min) at 254 nm. The major enantiomer (2S,3S) was eluted after 7.0 min, and the minor enantiomer after 9.2 min.
(2 S ,3 S )-2-(4-Cyanophenyl)-3-(4-trifluoromethylphenyl)-oxirane (10) Colorless solid; 87-91 ˚C; [α]_D ^²4 -43.5 (c 1.0 EtOH). ^¹H NMR (400 MHz, CDCl₃): δ = 3.89 (s, 2 H), 7.45-7.47 (m, 4 H), 7.65-7.70 (m, 4 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 62.0, 62.4, 112.5, 118.5, 124.0 (q, J = 272 Hz), 125.7 (q, J = 4 Hz), 125.9, 126.3, 131.0 (q, J = 33 Hz), 132.5, 140.3, 141.9. IR (CHCl₃): 3000, 2200, 1600, 1500 cm^-¹. The ee, found to be 29%, was obtained by HPLC on a CHIRALPAK AD-H column (250 × 4.6 mm, i.d.) from Daicel Co., using n-hexane-2-PrOH (90:10) as eluent (flow rate 1.0 mL/min) at 254 nm. The major enantiomer (2S,3S) was eluted after 10 min, and the minor enantiomer after 19.0 min.
(2 S ,3 S )-2-(4-Cyanophenyl)-3-phenyloxirane (11) Colorless solid; mp 76-83 ˚C; [α]_D ^²4 -227.0 (c 1.04 EtOH). ^¹H NMR (400 MHz, CDCl₃): δ = 3.82 (d, 1 H, J = 1.8 Hz), 3.91 (d, 1 H, J = 1.8 Hz), 7.32-7.42 (m, 5 H), 7.45 (d, 2 H, J = 8.4 Hz), 7.67 (d, 2 H, J = 8.4 Hz). IR (CHCl₃): 3000, 2210, 1605, 1500 cm^-¹. The ee, found to be 69%, was obtained by HPLC on a CHIRALPAK AD-H column (250 × 4.6 mm, i.d.) from Daicel Co., using n-hexane-2-PrOH (90:10) as eluent (flow rate 1.0 mL/min) at 254 nm. The major enantiomer (2S,3S) was eluted after 11.2 min, and the minor enantiomer after 20.0 min.
4-[(2 S ,3 S )-3-Phenyloxiranyl]benzoic Acid 1,1-Dimethyl-ethyl Ester (12) Colorless solid; mp 101-105 ˚C; [α]_D ^²6 -177.6 (c 1.13 acetone). ^¹H NMR (400 MHz, CDCl₃): δ = 1.60 (s, 9 H), 3.84 (d, 1 H, J = 1.8 Hz), 3.90 (d, 1 H, J = 1.8 Hz), 7.32-7.39 (m, 7 H), 7.99 (d, 2 H, J = 8.1 Hz). ^¹³C NMR (100 MHz, CDCl₃): δ = 28.2, 62.3, 63.0, 81.1, 125.2, 125.5, 128.5, 128.6, 129.7, 132.0, 136.7, 141.6, 165.4. IR (CHCl₃): 3000, 1700, 1610, 1160, 1120 cm^-¹. HRMS (EI⁺): m/z calcd for C₁₉H₂₀O₃: 296.1412; found: 296.1402. The ee, found to be 82%, was obtained by HPLC on a CHIRALPAK AD-H column (250 × 4.6 mm i.d.) from Daicel Co., using n-hexane-2-PrOH (90:10) as eluent (flow rate 1.0 mL/min) at 254 nm. The major enantiomer (2S,3S) was eluted after 8.4 min, and the minor enantiomer after 6.8 min.
N , N -Diethyl-4-[(2 S ,3 S )-phenyloxyranyl]benzamide (13) Colorless oil; [α]_D ^²4 -150.2 (c 1.16 acetone). ^¹H NMR (400 MHz, CDCl₃): δ = 1.20 (m, 6 H), 3.30 (m, 2 H), 3.54 (m, 2 H), 3.86 (d, 1 H, J = 1.83 Hz), 7.32-7.41 (m, 9 H). ^¹³C NMR (126 MHz, CDCl₃): δ = 13.0, 14.2, 39.3, 43.3, 62.4, 62.9, 125.6, 126.7, 128.5, 128.6, 136.9, 137.4, 138.2, 170.9. IR (CHCl₃): 3000, 1612, 1565, 1510 cm^-¹. The ee, found to be 86%, was obtained by HPLC on a CHIRALPAK IA column (250 × 4.6 mm i.d.) from Daicel Co., using n-hexane-2-PrOH (90:10) as eluent (flow rate 1.0 mL/min) at 254 nm. The major enantiomer (2S,3S) was eluted after 22.6 min, and the minor enantiomer after 27.8 min.
N , N -Diethyl 4-[(2 S ,3 S )-3-( p -Anisyl)oxiranyl]benzamide (14) Colorless oil; [α]_D ^²² -88.16 (c 1.01 CHCl₃). ^¹H NMR (400 MHz, CDCl₃): δ = 1.26 (m, 6 H), 3.40 (m, 4 H), 3.80 (d, 1 H, J = 1.8 Hz), 3.82 (s, 3 H), 3.87 (d, 1 H, J = 1.8 Hz), 6.91 (d, 2 H, J = 8.8 Hz), 7.27 (d, 2 H, J = 8.8 Hz), 7.36 (d, 2 H, J = 8.8 Hz), 7.39 (d, 2 H, J = 8.8 Hz). ^¹³C NMR (100 MHz, CDCl₃): δ = 13.0, 14.2, 39.4, 43.8, 55.4, 62.3, 62.8, 114.2, 125.5, 126.6, 126.9, 128.9, 137.3, 138.4, 160.0, 170.9. IR (CHCl₃): 3000, 1610, 1510 cm^-¹. The ee, found to be 80%, was obtained by HPLC on a CHIRALPAK IB column (250 × 4.6 mm i.d.) from Daicel Co., using n-hexane-2-PrOH (90:10) as eluent (flow rate 1.0 mL/min) at 254 nm. The major enantiomer (2S,3S) was eluted after 20.8 min, and the minor enantiomer after 23.3 min.