Enantioselective Michael Addition of Pyrazolin-5-ones to β-CF₃-β-Disubstituted Nitroalkenes Catalyzed by Squaramide Organocatalyst

Abstract

A highly enantioselective Michael addition of pyrazolin-5-ones with β-CF₃-β-disubstituted nitroalkenes catalyzed by bifunctional squaramide has been developed. Various chiral β-CF₃-β-5-hydroxy-pyrazolin-3-yl-disubstituted nitroalkane derivatives bearing all-carbon quaternary stereocenter were prepared in good yields (up to 88%) and excellent enantioselectivities (up to 97% ee).

Key words

Michael addition - pyrazolin-5-ones - β-CF₃-β-disubstituted nitroalkenes - squaramide organocatalyst - all-carbon quaternary stereocenter

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• 19 General Procedure for Asymmetric Michael Reactions To a dried small bottle were added (E)-β-F₃C-β-disubstituted nitroalkene 1 (0.2 mmol), pyrazolone 2 (0.2 mmol), catalyst VI (0.04 mmol, 20 mol%), and NaOH (0.01 mmol, 5 mol%) in CH₂Cl₂ (2.0 mL). The mixture was stirred at ice-bath for 24–50 h until TLC showed the reaction was completed, the reaction mixture was concentrated and directly purified by silica gel column chromatography, eluting with EtOAc–PE (1:2, v/v), to afford the corresponding desired product 3. 5-Methyl-2-phenyl-4-(2,2,2-trifluoro-1-nitromethyl-1-phenylethyl)-2H-pyrazol-3-ol (3aa) The title compound 3aa was obtained according to the general procedure as a colorless solid, 73.4 mg (81% yield), mp 188–190 °C. HPLC [Daicel Chiralpak AD-H column (25 cm × 0.46 cm ID), n-hexane–i-PrOH = 90:10, 1.0 mL/min, 254 nm; t _R (major) = 12.4 min, t _R (minor) = 32.1 min] 97% ee. IR (KBr): ν = 3053, 2615, 1606, 1559, 1500, 1459, 1407, 1374, 1332, 1314, 1298, 1215, 1172, 1148, 1120, 1030, 833, 763, 701 cm^–1. ¹H NMR (500 MHz, DMSO-d ₆): δ = 11.87 (s, 1 H), 7.71 (d, J = 7.9 Hz, 2 H), 7.61–7.36 (m, 7 H), 7.27 (t, J = 7.3 Hz, 1 H), 6.26 (d, J = 12.9 Hz, 1 H), 5.78 (d, J = 13.2 Hz, 1 H), 1.47 (s, 3 H) ppm. ¹³C NMR (126 MHz, DMSO-d ₆): δ = 149.09, 136.93, 135.52, 129.47, 129.04, 128.69, 128.49, 127.18 (q, J _C–F = 286.0 Hz), 125.92, 120.26, 99.54, 77.68, 53.96 (q, J _C–F = 26.5 Hz), 13.13 ppm. ¹⁹F NMR (471 MHz, DMSO-d ₆): δ = –66.61 (s, 3 F) ppm. ESI-HRMS: m/z calcd for C₁₉H₁₆F₃N₃NaO₃ [M + Na]⁺: 414.103597; found: 414.103795.
• 20 Synthesis of 4-(3-Amino-1,1,1-trifluoro-2-phenylpropan-2-yl)-3-methyl-1-phenyl-1H-pyrazol-5-ol (4) To a dried small bottle were added 3aa (0.2 mmol) in AcOH (4.0 mL) and excessive zinc powder. The mixture was stirred at room temperature for 6 h until TLC showed the reaction was completed. Then the precipitate was filtered off. The filtrate was adjusted pH to 5–6 with a sat. K₂CO₃ solution. The organic phase was separated, and the aqueous phase was extracted with CH₂Cl₂ (2 × 10 mL). The combined organic phase was washed with water (20 mL), then dried (Na₂SO₄). Removal of the solvent under reduced pressure gave a white crude residue, and the residue was purified with silica gel column chromatography, eluting with EtOAc–PE (1:5, v/v), to afford the desired product 4. Colorless solid, 70.8 mg (98% yield), mp 216–217 °C. HPLC [Daicel Chiralpak AD-H column (25 cm × 0.46 cm ID), n-hexane–i-PrOH = 90:10, 1.0 mL/min, 254 nm; t _R (major) = 9.6 min, t _R (minor) = 12.2 min] 93% ee. IR (KBr): ν = 3314, 3060, 3033, 2999, 1598, 1498, 1448, 1424, 1352, 1313, 1287, 1274, 1203, 1170, 1140, 1034, 996, 957, 911, 841, 769, 756, 730, 701, 655, 640, 616, 546 cm^–1. ¹H NMR (500 MHz, DMSO-d ₆): δ = 9.88 (s, 3 H), 7.99 (d, J = 7.8 Hz, 2 H), 7.48–7.38 (m, 4 H), 7.38–7.29 (m, 3 H), 7.06 (t, J = 7.3 Hz, 1 H), 3.37 (d, J = 13.8 Hz, 1 H), 3.22 (d, J = 13.6 Hz, 1 H), 1.18 (s, 3 H) ppm. ¹³C NMR (126 MHz, DMSO-d ₆): δ = 160.87, 147.31, 141.10, 139.32, 129.06, 128.72, 128.62 (q, J _C–F = 286.0 Hz), 127.98, 127.83, 123.44, 119.43, 93.22, 53.49 (q, J _C–F = 25.2 Hz), 47.56, 15.42 ppm. ¹⁹F NMR (471 MHz, DMSO-d ₆): δ = –64.84 (s, 3 F) ppm. ESI-HRMS: m/z calcd for C₁₉H₁₉F₃N₃O [M + H]⁺: 362.1480; found: 362.1428.
• 21 Synthesis of 3-Methyl-1-phenyl-4-[1,1,1-trifluoro-3-(4-nitrobenzamido)-2-phenylpropan-2-yl]-1H-pyrazol-5-yl-4-nitrobenzoate (5) To a dried small bottle were added 4 (0.125 mmol) and p-nitrobenzoyl chloride (0.3 mmol) in DMF (2.0 mL). The mixture was stirred at room temperature for 15 min, and Et₃N (0.025 mmol) was then added. The mixture was stirred at room temperature for 6 h until TLC showed the reaction was completed. Then water (10 mL) and CH₂Cl₂ (10 mL) were added. After stirring for 30 min, the organic phase was separated, and the aqueous phase was extracted with CH₂Cl₂ (2 × 10 mL). The combined organic phase was washed with water (20 mL), then dried ­(Na₂SO₄). Removal of the solvent under reduced pressure gave a white crude residue, and the residue was purified with silica gel column chromatography, eluting with EtOAc–PE (1:5, v/v), to afford the desired product 5. Colorless solid, 79.1 mg (96% yield), mp 158–161 °C. HPLC [Daicel Chiralpak AD-H column (25 cm × 0.46 cm ID), n-hexane–i-PrOH = 70:30, 1.0 mL/min, 254 nm; t _R (minor) = 15.8 min, t _R (major) = 26.5 min] 88% ee. IR (KBr): ν = 3421, 3110, 3074, 2960, 2867, 1767, 1675, 1598, 1530, 1506, 1488, 1441, 1386, 1348, 1320, 1296, 1237, 1215, 1171, 1109, 1059, 1012, 926, 867, 845, 854, 767, 714, 592, 533, 498 cm^–1. ¹H NMR (500 MHz, DMSO-d ₆): δ = 8.53 (s, 1 H), 8.38 (d, J = 8.6 Hz, 2 H), 8.31 (d, J = 8.6 Hz, 2 H), 8.19 (s, 2 H), 7.84 (d, J = 8.7 Hz, 2 H), 7.51 (dd, J = 13.5, 7.9 Hz, 4 H), 7.44–7.26 (m, 6 H), 4.58 (dd, J = 13.9, 5.9 Hz, 1 H), 4.50 (dd, J = 14.2, 6.6 Hz, 1 H), 1.79 (s, 3 H) ppm. ¹³C NMR (126 MHz, DMSO-d ₆): δ = 166.20, 161.60, 151.70, 149.46, 148.40, 142.23, 140.75, 137.79, 136.88, 131.99, 131.93, 131.17, 129.91, 129.29, 128.95, 128.91, 128.66, 128.20, 127.20 (q, J _C–F = 283.5 Hz) 124.79, 123.00, 105.73, 53.19 (q, J _C–F = 23.9 Hz), 42.13, 15.46 ppm. ¹⁹F NMR (471 MHz, DMSO-d ₆): δ = –66.96 (s, 3 F) ppm. ESI-HRMS: m/z calcd for C₃₃H₂₅F₃N₅O₇ [M + H]⁺: 660.1700; found: 660.1547.