Base-Promoted Cascade Approach for the Preparation of Reduced Knoevenagel Adducts Using Hantzsch Esters as Reducing Agent in Water

Abstract

A cascade Knoevenagel condensation–reduction approach, which was carried out in water, has been reported. Using Hantzsch esters as reducing agent, under the promotion of base, a variety of reduced Knoevenagel adducts could be easily prepared by direct alkyl­ation of malononitrile, ethyl 2-cyanoacetate, and 2-(4-nitrophenyl)acetonitrile, respectively. Meanwhile, a gram-scale synthesis of the protocol was also realized with excellent isolated yield.

Key words

cascade reaction - Knoevenagel condensation - reduction - Hantzsch esters - alkylation

• References and Notes

• 1 These authors contributed equally to this work and should be considered co-first authors.
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• 57 General Experimental Procedures for the Preparation of Reduced Knoevenagel Adducts of Malononitrile The mixture of aldehydes (0.2 mmol), malononitrile (0.24 mmol), and Hantzsch ester (0.24 mmol) in water (2.0 mL) was stirred at 100 °C for 12 h. After the reaction mixtures were cooled to room temperature, the crude solution was extracted with EtOAc (3 × 3 mL). The combined organic layers were washed with brine and dried over anhydrous Na₂SO₄. After removal of solvents under reduced pressure, the residue was purified through column chromatograph on silica gel to give the pure products.
• 58 General Experimental Procedures for the Preparation of Reduced Knoevenagel Adducts of Ethyl 2-Cyanoacetate The mixture of aldehydes (0.2 mmol), ethyl 2-cyanoacetate (0.24 mmol), DEAE or K₂CO₃ (0.02 mmol), and Hantzsch ester (0.24 mmol) in water (2.0 mL) was stirred at 100 °C for 12 h. After the reaction mixtures were cooled to room temperature, the crude solution was extracted with EtOAc (3 × 3 mL). The combined organic layers were washed with brine and dried over anhydrous Na₂SO₄. After removal of solvents under reduced pressure, the residue was purified through column chromatograph on silica gel to give the pure products.
• 59 General Experimental Procedures the Preparation of Reduced Knoevenagel Adducts of 2-(4-Nitrophenyl)-acetonitrile The mixture of aldehydes (0.2 mmol), 2-(4-nitrophenyl)acetonitrile (0.24 mmol), DEAE or K₂CO₃ (0.2 mmol), and Hantzsch esters (0.24 mmol) in water (2.0 mL) was stirred at 100 °C for 12 h. After the reaction mixtures were cooled to room temperature, the crude solution was extracted with EtOAc (3 × 3 mL). The combined organic layers were washed with brine and dried over anhydrous Na₂SO₄. After removal of solvents under reduced pressure, the residue was purified through column chromatograph on silica gel to give the pure products.
• 60 Gram-Scale Synthesis of 3-(Naphthalen-2-yl)-2-(4-nitrophenyl)propanenitrile The mixture of 2-naphthaldehyde (1.00 g, 6.41 mmol), 2-(4-nitrophenyl)acetonitrile (1.25 g, 7.69 mmol), DEAE (169.5 μL, 1.28 mmol), and Hantzsch ester (1.94 g, 7.69 mmol) in water (10.0 mL) was stirred at 100 °C for 12 h. After the reaction mixtures were cooled to room temperature, the crude product was separated by filtration. The pure product was obtained through column chromatograph on silica gel.
• 61 2-(3-Nitrobenzyl)malononitrile (3aj) The crude mixture was purified by column chromatography using PE–EtOAc (10:1) to yield 3aj as light yellow solid. ¹H NMR (400 MHz, CDCl₃): δ = 3.46 (d, J = 6.76 Hz, 2 H), 4.06 (t, J = 6.76 Hz, 1 H), 7.65–7.76 (m, 2 H), 8.26–8.32 (m, 2 H). 2-(Furan-2-ylmethyl)malononitrile (3al) The crude mixture was purified by column chromatography using PE–EtOAc (10:1) to yield 3al as white solid. ¹H NMR (400 MHz, CDCl₃): δ = 3.40 (d, J = 7.0 Hz, 2 H), 4.07 (t, J = 7.04 Hz, 1 H), 6.41 (d, J = 1.56 Hz, 2 H), 7.45 (s, 1 H). Ethyl 2-Cyano-3-(3-nitrophenyl)propanoate (3bj) The crude mixture was purified by column chromatography using PE–EtOAc (10:1) to yield 3bj as light yellow solid. ¹H NMR (400 MHz, CDCl₃): δ = 1.31(t, J = 7.12 Hz, 3 H), 3.32–3.44 (m, 2 H), 3.84 (dd, J = 5.92, 8.00 Hz, 1 H), 4.29 (q, J = 7.16 Hz, 2 H), 7.58 (t, J = 7.92 Hz, 1 H), 7.69 (d, J = 7.64 Hz, 1 H), 8.12–8.29 (m, 2 H). Ethyl 2-Cyano-3-(furan-2-yl)propanoate (3bl) The crude mixture was purified by column chromatography using PE–CH₂Cl₂ (3:1) to yield 3bl as colorless oil. ¹H NMR (400 MHz, CDCl₃): δ = 1.33 (t, J = 7.12 Hz, 3 H), 3.26–3.38 (m, 2 H), 3.85 (dd, J = 6.20, 7.84 Hz, 1 H), 4.30 (q, J = 7.12 Hz, 2 H), 6.27 (d, J = 3.08 Hz, 1 H), 6.35 (t, J = 2.84 Hz, 1 H), 7.39 (s, 1 H). 3-(Furan-2-yl)-2-(4-nitrophenyl)propanenitrile (3cl) The crude mixture was purified by column chromatography using PE–EtOAc (10:1) to yield 3ci as white solid. ¹H NMR (400 MHz, CDCl₃): δ = 3.21 (dd, J = 7.12, 14.88 Hz, 1 H), 3.36 (dd, J = 7.44, 14.88 Hz, 1 H), 4.31 (t, J = 7.28 Hz, 1 H), 6.11 (d, J = 3.16 Hz, 1 H), 6.31 (t, J = 3.00 Hz, 1 H), 7.37 (d, J = 1.32 Hz, 1 H), 7.45 (d, J = 8.40 Hz, 2 H), 8.22 (d, J = 8.40 Hz, 2 H).