A Facile Synthesis of 1,6-Diketones via a Three-Component Michael Addition Reaction

Abstract

A convenient one-pot synthesis of 1,6-diketones has been accomplished by a three-component Michael addition reaction of α-bromoketone, malononitrile and α,β-unsaturated keto compounds.

1,6-diketone - three-component - Michael addition - malononitrile - α,β-unsaturated ketones

References

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16

Typical Procedure for Three-Component Reaction: Preparation of Ethyl-3,3-dicyano-4-( p -toluoyl)valerate (5d): A 100 mL round bottom flask, equipped with a magnetic stirrer, was charged with a mixture of 2-bromo-4′-methylacetophenone 1a (0.5 g, 2.34 mmol), malononitrile (0.17 g, 2.50 mmol) and ethyl acrylate 4d (0.25 g, 2.50 mmol) in MeOH (50 mL). The reaction mixture was cooled to 15 °C and to it was added finely powdered KOH (0.14 g, 2.50 mmol) in small portions at the maximum speed of the magnetic stirrer. The mixture was stirred vigorously at 15-20 °C for 25 min. On completion of reaction (TLC monitored), it was poured into 100 mL H₂O and extracted with CH₂Cl₂ (2 × 30 mL), washed with H₂O and dried over Na₂SO₄(anhyd). Removal of solvent afforded 5d in 78% yield, mp 70 °C (MeOH). IR (KBr): ν_max = 2975, 2251, 1733, 1678, 1605, 1453, 1237 cm^-1. ¹H NMR (CDCl₃): δ = 7.60 (2 H, d, J = 8.10 Hz), 7.10 (2 H, d, J = 8.10 Hz), 4.02 (2 H, q, J = 6.8 Hz), 3.55 (2 H, s), 2.50 (4 H, m), 2.20 (3 H, s), 1.20 ( 3H, t, J = 6.8Hz). ¹³C NMR (CDCl₃): δ = 216.7, 182.5, 127.8, 127.3, 125.6, 122.6, 119.6, 118.3, 115.3, 109.7, 59.2, 32.5, 30.2, 28.6, 20.7, 14.6, 13.6. MS (ESI): m/z = 321 (M⁺ + 23). Anal. Calcd for C₁₇H₁₈N₂O₃: C, 68.44; H, 6.08; N, 9.39. Found: C, 68.27; H, 6.19; N, 9.31.

17

Preparation of 1,1-Dicyano-3-( p -tolyl)-3-propanone (6): To a 50 mL round bottom flask charged with 2-bromo-4′-methylacetophenone 1a (0.5 g, 2.3 mmol) and malononitrile (0.24 g, 3.6 mmol) in MeOH (20 mL) was added powdered KOH (0.20 g, 3.6 mmol) in small portion and stirred at r.t. TLC monitoring showed completion of reaction after 20 min. The solvent was removed under reduced pressure in a rotavapor and the residue was extracted with chloroform (2 × 15 mL), washed with H₂O and dried over anhyd Na₂SO₄. Removal of solvent gave a crude product which was crystallized from hexane/chloroform (10/90) to obtain 6 in 92% yield, mp 98 °C. IR (KBr): ν_max = 2955, 1675, 1605, 1454, 1298 cm^-1. ¹H NMR (CDCl₃): δ = 7.68 (2 H, d, J = 8.0 Hz), 7.18 (2 H, d, J = 8.0 Hz), 4.30 (1 H, t, J = 6.5 Hz), 3.60 (2 H, d, J = 6.5 Hz), 2.40 (3 H, s). MS (ESI): m/z = 221 (M⁺ + 23). Anal. Calcd for C₁₂H₁₀N₂O: C, 72.71; H, 5.08; N, 14.13. Found: C, 72.89; H, 5.02; N, 14.24.

18

Preparation of 3-Benzoyl-2-phenyl-1,1-dicyano-propane (7): To a 50 mL round bottom flask charged with benzylidene acetophenone 4c (0.5 g, 2.4 mmol) and malononitrile (0.24 g, 3.6 mmol) in MeOH (20 mL) was added powdered KOH (0.20 g, 3.6 mmol) in small portions and the mixture stirred at r.t. After 20 min, the solvent was removed under reduced pressure and the residue was extracted with chloroform (2 × 15 mL), washed with H₂O, dried over anhyd Na₂SO₄ and solvent removed. The crude product was crystallized from hexane/chloroform (10/90) to obtain 7 in 88% yield, mp 116 °C. IR (KBr): ν_max = 2902, 1682, 1596, 1449, 1235 cm^-1. ¹H NMR (CDCl₃): δ = 7.80-6.95 (10 H, m), 4.50 (1 H, d, J = 6.0 Hz), 3.80 (1 H, m), 3.50 (2 H, d, J = 6.5 Hz). MS (ESI): m/z = 297 (M⁺ + 23). Anal. Calcd for C₁₈H₁₄N₂O: C, 78.81; H, 5.14; N, 10.21. Found: C, 78.96; H, 5.27; N, 10.42.