Immobilization of Functionalized epi-Cinchonine Organocatalysts on Controlled Porous Glass Beads: Applications in Batch and ­Continuous Flow

Abstract

A well-known squaramide-cinchonine organocatalyst was immobilized in a controlled way onto three types of commercial porous glass beads EziG™ (EziG OPAL, EziG Amber, and EziG Coral) and applied in asymmetric Michael reactions. The performance of the immobilized catalysts was evaluated under batch and continuous-flow conditions, showing promising results in both approaches. In batch reactions, 0.8 and 1.6 mol% of the immobilized cinchonine-squaramide provided the products with excellent yields (up to 99%) and enantioselectivities (up to 99% ee). These excellent results were also verified in the case of continuous-flow reactions, where also 0.8 and 1.6 mol% of the catalyst immobilized onto the glass beads afforded the product with extraordinary yields (up to 99%) and very high enantioselectivities (up to 97% ee). The immobilized catalysts could be recycled (up to seven cycles) using both approaches.

Key words

cinchona alkaloids - EziG^TM - immobilizations - batch reactions - continuous flow reactions - organocatalysis

• References and Notes

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• 25 General Procedure for Batch ReactionsAcetylacetone or methyl 2-oxocyclopentane-1-carboxylate (1.1 equiv) and the EziG ™ immobilized cinchonine-squaramide (1.6 mol% of catalyst in the case of acetylacetone; 0.8 mol% of catalyst in the case of methyl 2-oxocyclopentane-1-carboxylate) were added to a solution of trans-β-nitrostyrene (1.0 equiv) in CH₂Cl₂ (3 mL). The reaction was carried out in an orbital shaker at room temperature at 300 rpm for 48 hours. The reaction mixture was then filtered to collect the catalyst, and the solvent was removed from the filtrate. The product was purified by flash column chromatography eluting with 5:1 (Hex:EtOAc). The filtered catalyst was used in the next cycle without further purification (see the Supporting Information for characterization data)
• 26 General Procedure for Continuous-Flow ReactionsA solution of acetylacetone or methyl 2-oxocyclopentane-1-carboxylate (1.1 equiv) and trans-β-nitrostyrene (1.0 equiv) in CH₂Cl₂ was pumped through a packed-bed reactor in an Omnifit® assembly loaded with the EziG™ immobilized cinchonine-squaramide (1.6 mol% of catalyst in the case of acetylacetone; 0.8 mol% of catalyst in the case of methyl 2-oxocyclopentane-1-carboxylate), at a flow rate of 0.08 mL min^–1, a residence time of 18.8 min, at room temperature, during 2 h. The reaction mixture was collected, concentrated, and purified by flash column chromatography eluting with 5:1 (Hex:EtOAc). The column was washed with 10 mL of CH₂Cl₂
• 27 Compound 3: Yellow solid. ¹H NMR (400 MHz, CDCl₃): δ = 1.94 (s, 3 H, CH₃), 2.29 (s, 3 H, CH₃), 4.21–4.27 (m, 1 H, CH), 4.38 (d, J = 12 Hz, 1 H, CH), 4.62–4.64 (m, 2 H, CH₂), 7.17–7.19 (m, 2 H, ArH), 7.29–7.35 (m, 3 H, ArH). ¹³C APT NMR (100 MHz, CDCl₃): δ = 29.55 (CH), 30.45 (CH), 42.80 (CH₃), 70.74 (CH₃), 78.20 (CH₂), 127.95 (2CH), 128.58 (CH), 129.36 (2CH), 135.99 (C), 201.03 (C=O), 201.80 (C=O)
• 28 Compound 5: Yellow oil. ¹H NMR (400 MHz, CDCl₃): δ = 1.81–2.08 (m, 4 H, 2CH₂), 2.33–3.43 (m, 2 H, CH₂), 3.77 (s, 3 H, CH₃), 4.09 (dd, J = 4 Hz, 12 Hz, 1 H, CH), 5.00–5.06 (m, 1 H, CH₂), 5.16–5.20 (m, 1 H, CH₂), 7.24–7.34 (m, 5 H, ArH). ¹³C APT NMR (100 MHz, CDCl₃): δ = 19.34 (CH₂), 31.13 (CH₂), 37.95 (CH₂), 46.17 (CH₃), 53.06 (CH), 62.46 (C), 76.42 (CH₂), 128.35 (CH), 128.86 (2CH), 129.30 (2CH), 135.26 (C), 169.83 (COOCH₃), 212.30 (C=O)
• 29 Experimental procedures for the synthesis of catalysts CD2-5 are described in the Supporting Information.Catalyst CD2: dark-brown oil. ¹H NMR (400 MHz, CDCl₃): δ = 0.65–0.71 (m, 1 H, CH₂), 1.35 (brt, J = 12 Hz, 1 H, CH₂), 1.47–1.51 (m, 2 H, CH₂), 1.54–1.55 (m, 1 H, CH), 2.23 (brs, 3 H, CH, NH₂), 2.69–2.79 (m, 2 H, CH₂), 2.96–3.08 (m, 1 H, CH), 3.13–3.24 (m, 2 H, CH₂), 4.65 (d, J = 8 Hz, 1 H, CH), 4.89–4.96 (m, 2 H, CH₂), 5.69–5.78 (m, 1 H, CH), 7.48 (d, J = 4 Hz, 1 H, ArH), 7.53 (t, J = 6 Hz, 1 H, ArH), 7.65 (t, J = 8 Hz, 1 H, ArH), 8.08 (d, J = 8 Hz, 1 H, ArH), 8.30 (brs, 1 H, ArH), 8.84 (d, J = 4 Hz, 1 H, ArH). ¹³C APT NMR (100 MHz, CDCl₃): δ = 26.0 (CH₂), 27.5 (2CH), 28.0 (CH₂), 39.8 (2CH), 40.9 (CH₂), 56.3 (CH₂), 114.3 (CH₂), 126.5 (CH), 127.8 (C), 128.9 (2CH), 130.4 (2CH), 141.8 (CH), 148.6 (C), 148.7 (C), 150.3 (CH).Catalyst CD3: white solid. ¹H NMR (400 MHz, DMSO-d ₆): δ = 0.63 (brs, 1 H, CH₂), 1.33 (brs, 1 H, CH₂), 1.53 (m, 3 H, CH, CH₂), 2.24 (brs, 1 H, CH), 2.61–2.69 (m, 2 H, CH₂), 3.12–3.18 (m, 1 H, CH), 3.35–3.43 (m, 2 H, CH₂), 4.84–5.01 (m, 4 H, 2CH₂), 5.83–5.92 (m, 1 H, CH), 6.04 (brs, 1 H, CH), 7.68–7.71 (m, 2 H, 2NH), 7.78 (t, J = 8 Hz, 1 H, ArH), 8.00–8.07 (m, 5 H, ArH), 8.28 (brs, 1 H, ArH), 8.49 (d, J = 8 Hz, 1 H ArH), 8.93 (d, J = 4 Hz, 1 H, ArH). ¹³C APT NMR (100 MHz, DMSO-d ₆): δ = 25.9 (CH₂), 27.2 (2CH), 27.3 (CH₂), 39.3 (2CH), 40.1 (CH₂), 45.8 (CH₂), 55.5 (CH₂), 114.3 (CH₂), 121.2 (CH), 121.9 (C), 123.5 (CH), 124.6 (C), 126.4 (C), 127.1 (CH), 128.7 (CH), 128.7 (CH), 129.4 (CH), 129.9 (CH), 130.3 (C), 130.6 (C), 142.1 (2CH), 142.32 (2C), 145.5 (C), 148.1 (C), 150.4 (CH), 167.3 (C), 182.2 (C=O), 182.6 (C=O).Catalyst CD4: brown oil. ¹H NMR (400 MHz, CDCl₃): δ = 0.68–0.73 (m,1 H, CH₂), 1.24–1.28 (m, 2 H, CH₂), 1.64–1.65 (m, 2 H, CH₂), 1.90 (brs, 1 H, CH₂), 2.89–2.93 (m, 1 H, CH), 3.04 (brs, 3 H, CH, NH₂), 3.31–3.33 (m, 1 H, CH), 3.43–3.53 (m, 2 H, CH₂), 4.72 (brs, 1 H, CH), 5.45 (d, J = 8 Hz, 2 H, CH₂), 7.20 (brs, 2 H, ArH), 7.26 (s, 1 H, TrzH), 7.34 (brs, 3 H, ArH), 7.47 (d, J = 4 Hz, 1 H, ArH), 7.58 (t, J = 8 Hz, 1 H, ArH), 7.70 (t, J = 8 Hz, 1 H, ArH), 8.12 (d, J = 8 Hz, 1 H, ArH), 8.32 (brs, 1 H, ArH), 8.83 (d, J = 4 Hz, 1 H, ArH). ¹³C APT NMR (100 MHz, CDCl₃): δ = 25.9 (CH₂), 27.5 (CH₂), 27.6 (2CH), 33.0 (2CH), 41.0 (CH₂), 54.1 (CH₂), 55.6 (CH₂), 120.5 (TrzCH), 126.7 (CH), 127.7 (C), 127.9 (2CH), 128.7 (2CH), 129.1 (3CH), 130.4 (2CH), 134.8 (C), 148.5 (C), 150.4 (CH), 151.0 (C), 151.1 (C). Catalyst CD5: brown oil. ¹H NMR (400 MHz, CDCl₃): δ = 0.81–0.87 (m, 1 H, CH₂), 1.10–1.15 (m, 1 H, CH₂), 1.52–1.73 (m, 4 H, 2CH₂), 1.73 (brs, 1 H, CH), 1.85–1.93 (m, 2 H, CH₂), 2.26–2.31 (m, 4 H, CH₂, NH₂), 2.93–3.07 (m, 4 H, 2CH₂), 3.17–3.23 (m, 1 H, CH), 3.61 (s, 3 H, CH₃), 3.78–3.83 (m, 1 H, CH), 4.26–4.35 (m, 2 H, CH₂), 4.99 (d, J = 4 Hz, 1 H, CH), 7.22 (s, 1 H, TrzH), 7.49 (t, J = 8 Hz, 1 H, ArH), 7.58 (brs, 1 H, ArH), 7.63 (t, J = 8 Hz, 1 H, ArH), 8.04 (d, J = 8 Hz, 1 H, ArH), 8.39 (brs, 1 H, ArH), 8.83 (d, J = 4 Hz, 1 H, ArH). ¹³C APT NMR (100 MHz, CDCl₃): δ = 21.6 (CH₂), 24.8 (CH₂), 26.5 (CH₂), 28.9 (2CH), 29.7 (CH₂), 33.1 (CH₂), 33.3 (2CH), 46.4 (CH₂), 49.6 (CH₂), 49.9 (CH₂), 51.7 (CH₃), 120.7 (TrzCH), 126.2 (CH), 127.9 (C), 128.9 (2CH), 130.1 (2CH), 148.5 (C), 150.2 (C), 150.3 (CH), 173.4 (C=O)