Organocatalyzed Asymmetric Inverse-Electron-Demand Hetero-Diels-Alder Reaction of α,β-Unsaturated Trifluoromethyl Ketones and Aldehydes

Abstract

The inverse-electron-demand hetero-Diels-Alder reaction of aldehydes and α,β-unsaturated trifluoromethyl ketones occurred under mild conditions using a chiral diphenylprolinol silyl ether as the catalyst. After subsequent chemical transformations, the corresponding 6-trifluoromethyl-3,4-dihydropyan-2-ones were obtained in good enantioselectivities.

Key words

organocatalyzed - hetero-Diels-Alder reaction - unsaturated trifluoromethyl ketone - aldehyde - dihydropyranone

References and Notes

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11

General Experimental Procedure
To a stirred solution of aldehyde 1 (1.2 mmol), catalyst 11 (0.20 mmol), p-fluorophenol (0.20 mmol), and SiO₂ (100 mg) in CH₂Cl₂ (10 ml) was added α,β-unsaturated trifluoromethyl ketones (1.0 mmol) at r.t. and the reaction mixture was stirred for the time as specified in Table [2] (monitored by TLC). The resulted mixture was directly purified by column chromatography on silica gel to give product 3. Jones reagent was added to the solution of 3 (0.8 mmol) in acetone (15 mL) at r.t. until the salmon pink of the solution did not disappear in one minute. The mixture was stirred at r.t. for 2 h and then quenched by MeOH (1 mL) and H₂O (2 ml). The resulted mixture was extracted with Et₂O
(3 ¥ 10 ml) and dried over Na₂SO₄. After removal of the solvent, the crude product of 7 was obtained and used in the next step directly without further purification. The solution of 7 (0.5 mmol) and Et₃N (1.4 mmol) in dry CH₂Cl₂ (5 ml) was stirred at -20 °C under nitrogen atmosphere for 5 min. Then, methanesulfonyl chloride (0.8 mmol) was added with a microsyringe and the resulted mixture was stirred at this temperature for 2 h. After the reaction was complete, the mixture was poured into 5 mL of 10% HCl. The solution was extracted with CH₂Cl₂ (3 × 10 mL), washed with sat. aq NaHCO₃ and NaCl solutions, and dried over Na₂SO₄. After removal of the solvent, the residue was subjected to fast column chromatography on silica gel to give product 8.
trans-3-Methyl-4-phenyl-6-trifluoromethyl-3,4-dihydro-
pyane-2-one (8a): colorless oil; [α]_D ²⁰ +69.9 (c 1.67, CHCl₃). ¹H NMR (300 MHz, CDCl₃): δ = 7.33-7.08 (m, 5 H), 5.88 (d, J = 2.7 Hz, 1 H), 3.46-3.41 (m, 1 H), 2.74-2.65 (dq, J ₁ = 11.4 Hz, J ₂ = 7.8 Hz, 1 H), 1.09 (d, J = 7.8 Hz, 3 H). ¹⁹F NMR (282 MHz, CDCl₃): δ = -72.20 (s, 3 F). ¹³C NMR (75 MHz, CDCl₃): δ = 168.10, 140.45 (q, J = 37.9 Hz), 139.46, 129.32, 128.16, 127.57, 118.50 (q, J = 269.7 Hz), 111.49, 43.81, 40.42, 13.91. IR (film): 3032, 1787, 1197
cm^-1. MS (70 eV): m/z (%) = 256 (16.53) [M⁺], 56 (100). HRMS: m/z calcd for C₁₃H₁₁F₃O₂: 256.0711; found: 256.0720. The chiral HPLC analytical data: Chiralpak OD column, detected at λ = 214 nm, eluent: n-hexane-i-PrOH (95:5), 0.3 mL/min, t _R(minor) = 24.1 min, t _R(major) = 26.4 min.