New Syntheses of 3-Aroylflavone Derivatives; Knoevenagel Condensation and Oxidation versus One-Pot Synthesis

Abstract

Two syntheses of 3-aroylflavones have been established. In the first synthesis the use of microwave irradiation led to an improvement in the yields of both the Knoevenagel condensation of β-diketones with aldehydes to afford 3-aroylflavanones and of their oxidation to 3-aroylflavones. In the second and more general synthesis, a novel and efficient procedure for 3-aroylflavones involves a one-pot reaction between 2′-hydroxyacetophenones and aroyl chlorides in the presence of lithium bis(trimethylsilyl)amide.

Key words

Claisen condensation - Knoevenagel condensation - lithium bis(trimethylsilyl)amide - microwaves

• References and Notes

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• 9 The optimal conditions were established after a study of the reaction times, ranging from 5 to 30 minutes, and microwave (MW) irradiation power, ranging from 200 to 500 W. The obtained results indicate that higher MW irradiation power gave lower yields (40–50%) and more degradation even when shorter reaction times were used. When using MW irradiation power lower than 300 W with shorter reaction times the starting β-diketones 1a and 1b were recovered (depending on the time and power 10–25%).
• 10 Optimized Experimental Procedure for the Synthesis of Flavanones 2a and 2b: A mixture of the appropriate1-(2-hydroxyaryl)-3-(3,4-dimethoxyphenyl)propan-1,3-dione 1a,b (0.5 mmol), 3,4-dimethoxybenzaldehyde (0.25 g, 1.5 mmol) and piperidine (0.4 mmol) in EtOH (15 mL), was poured in a two-necked glassware apparatus equipped with a magnetic stirring bar, fibre-optic temperature control and reflux condenser, and was then irradiated in an Ethos SYNTH microwave (Milestone Inc.) at 300 W constant power for 30 min. After that period, the reaction mixture was poured into a mixture of ice (10 g) and water (30 mL) and the pH was adjusted to 2 with dilute HCl (10%). Finally, the mixture was extracted with CHCl₃ (3 × 20 mL), dried over sodium sulfate, and evaporated to dryness. The obtained residue was purified by column chromatography (EtOAc–hexane, 1:1). After solvent evaporation, the obtained residue was recrystallized from EtOH to give the expected 3-aroylflavanones 2a (134 mg, 60%) or 2b (163 mg, 68%).
• 11 3′,4′,7-Trimethoxy-3-(3,4-dimethoxyphenyl)flavanone 2b: Yellow solid; mp 140–142 °C. ¹H NMR (300 MHz, CDCl₃): δ = 3.82 (s, 3 H, 3′-OCH ₃), 3.84 (s, 3 H, 4′-OCH ₃), 3.85 (s, 3 H, 7-OCH ₃), 3.89 (s, 3 H, 3′′-OCH ₃), 3.91 (s, 3 H, 4′′-OCH ₃), 5.06 (d, J = 11.9 Hz, 1 H, H-3), 5.91 (d, J = 11.9 Hz, 1 H, H-2), 6.51 (d, J = 2.3 Hz, 1 H, H-8), 6.63 (dd, J = 2.3, 8.9 Hz, 1 H, H-6), 6.80 (d, J = 8.4 Hz, 1 H, H-5′), 6.83 (d, J = 8.4 Hz, 1 H, H-5′′), 7.00 (br s, 1 H, H-2′), 7.02 (br d, J = 8.4 Hz, 1 H, H-6′), 7.40 (d, J = 1.9 Hz, 1 H, H-2′′), 7.45 (dd, J = 1.9, 8.4 Hz, 1 H, H-6′′), 7.86 (d, J = 8.9 Hz, 1 H, H-5). ¹³C NMR (75 MHz, CDCl₃): δ = 55.6, 55.7, 55.8, 55.9, 56.0 (5 × OCH₃), 58.7 (C-3), 82.2 (C-2), 100.8 (C-8), 109.9 (C-2′), 110.4 (C-5′′), 110.5 (C-5′), 110.6 (C-6), 111.0 (C-2′′), 114.4 (C-4a), 123.8 (C-6′′), 129.1 (C-5), 129.8 (C-1′), 131.1 (C-1′′), 148.9 (C-4′), 149.0 (C-3′′), 149.4 (C-3′), 157.7 (C-4′′), 163.2 (C-8a), 166.5 (C-7), 188.6 (C-4), 194.5 (C=O). Anal. Calcd for C₂₇H₂₆O₈·1/2 H₂O: C, 66.66; H, 5.39. Found: C, 66.52; H, 5.46.
• 12 The optimal conditions were established after a complete study of the reaction conditions. The amount of iodine was optimized in order to prevent the formation of iodinated derivatives. MW irradiation power was optimized to 500 W; with less power, a longer reaction time (30 min) was needed to perform the complete oxidation into flavones, without improvement in the obtained yields, and with higher power there was more degradation and consequently a lower yield (40–56%).
• 13 Optimized Experimental Procedure for the Synthesis of 3-Aroylflavones 3a and 3b: Iodine (5 mg, 0.02 mmol) was added to a solution of the appropriate 3′,4′-dimethoxy-3-(3,4-dimethoxybenzoyl)flavanone 2a and 2b (0.2 mmol) in DMSO (5 mL). The mixture was poured into a two-necked glassware apparatus equipped with a magnetic stirring bar, fibre-optic temperature control and reflux condenser, and was then irradiated in an Ethos SYNTH microwave (Milestone Inc.) at 500 W constant power for 8 min. After that period, the reaction mixture was poured into a mixture of ice (10 g) and water (20 mL), and Na₂S₂O₃·5H₂O was added. Finally, the mixture was extracted with CHCl₃ (3 × 20 mL), dried over sodium sulfate, and the organic solvent was evaporated to dryness. The residue was purified by preparative TLC (EtOAc–hexane, 1:1), affording 3-aroylflavones 3a (70 mg, 78%) or 3b (71 mg, 75%).
• 14 3′,4′-Dimethoxy-3-(3,4-dimethoxyphenyl)flavone (3a): Orange solid; mp 150–152 °C. ¹H NMR (300 MHz, CDCl₃): δ = 3.73 (s, 3 H, 3′-OCH ₃), 3.89 (s, 3 H, 4′-OCH ₃), 3.90 (s, 3 H, 4′′-OCH ₃), 3.92 (s, 3 H, 3′′-OCH ₃), 6.80 (d, J = 8.4 Hz, 1 H, H-5′′), 6.84 (d, J = 8.4 Hz, 1 H, H-5′), 7.19 (d, J = 2.0 Hz, 1 H, H-2′), 7.34 (dd, J = 2.0, 8.4 Hz, 1 H, H-6′), 7.44 (br d, J = 7.0, 8.0 Hz, 1 H, H-6), 7.48 (dd, J = 2.0, 8.4 Hz, 1 H, H-6′′), 7.60 (br d, J = 8.0 Hz, 1 H, H-8), 7.62 (d, J = 2.0 Hz, 1 H, H-2′′), 7.75 (ddd, J = 1.7, 7.0, 8.0 Hz, 1 H, H-7), 8.24 (dd, J = 1.7, 8.0 Hz, 1 H, H-5). ¹³C NMR (75 MHz, CDCl₃): δ = 55.7, 55.9, 56.0 (4 × OCH₃), 110.2 (C-5′′), 110.3 (C-2′′), 110.9 (C-5′), 111.2 (C-2′), 118.0 (C-8), 121.7 (C-1′), 122.1 (C-6′), 123.2 (C-3), 124.1 (C-4a), 125.3 (C-6′′), 125.4 (C-6), 126.0 (C-5), 130.4 (C-1′′), 134.1 (C-7), 148.8 (C-3′′), 149.3 (C-3′), 151.6 (C-4′), 153.9 (C-4′′), 155.9 (C-8a), 161.6 (C-2), 176.5 (C-4), 192.4 (C=O). Anal. Calcd for C₂₆H₂₂O₇·1/2 H₂O: C, 68.56; H, 5.09. Found: C, 68.43; H, 5.10.
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• 18 Optimized Procedure for the Synthesis of 3-Aroylflavones 6a–e: The appropriate acetophenone 4a–c (1 mmol) was dissolved in toluene (5 mL) in a screw cap vial equipped with a magnetic stirring bar and sealed with a septum. The solution was cooled at 0 °C under nitrogen and LiHMDS (4.2 mL in THF, 4.2 mmol) was quickly added by using a syringe. The solution was stirred for approximately 5 min before the addition of aroyl chlorides 5a–c (4 mmol) in one portion. The solution was then removed from the ice bath and stirred at room temperature [20 min (6a,b), 8 h (6c) and 12 h (6d,e)]. After that period, HCl (4 mL) [20% (6a,b) or 37% (6c–e)] was added and the resulting solution was stirred for 1 h (6a,b) or 8 h (6d,e) and then extracted with CH₂Cl₂ (3 × 15 mL). The organic layer was then washed with brine, dried over sodium sulfate, and evaporated under reduced pressure. The resulting residue was purified by column chromatography (4:1, hexane–EtOAc; in the case of 6d,e the eluent was CH₂Cl₂). After solvent evaporation and residue crystallization from EtOH, the expected 3-aroylflavones 6a–e were obtained (6a: 218 mg, 67%; 6b: 287 mg, 69%; 6c: 278 mg, 72%; 6d: 195 mg, 57%; 6e: 183 mg, 51%).
• 19 4′-Nitro-3-(4-nitrophenyl)flavone (6b): Yellow solid; ¹H NMR (500 MHz, CDCl₃): δ = 7.46 (ddd, J = 0.7, 7.2, 7.9 Hz, 1 H, H-6), 7.64 (br d, J = 7.9 Hz, 1 H, H-8), 7.81 (d, J = 7.0 Hz, 2 H, H-2′′, H-6′′), 7.85 (ddd, J = 1.6, 7.2, 7.9 Hz, 1 H, H-7), 8.08 (d, J = 7.0 Hz, 2 H, H-2′,6′), 8.24 (dd, J = 1.6, 7.9 Hz, 1 H, H-5), 8.27 (d, J = 7.0 Hz, 2 H, H-3′′5′′), 8.30 (d, J = 7.0 Hz, 2 H, H-3′,5′). ¹³C NMR (75 MHz, CDCl₃): δ = 118.3 (C-8), 123.1 (C-4a), 123.2 (C-3), 124.1 (C-3′′,5′′), 124.2.0 (C-3′,5′), 126.2 (C-6), 126.6 (C-5), 129.7 (C-2′′,6′′), 130.2 (C-2′,6′), 135.3 (C-7), 137.1 (C-1′), 141.0 (C-1′′), 149.4 (C-4′′), 150.8 (C-4′), 156.0 (C-8a), 161.3 (C-2), 176.0 (C-4), 191.6 (C=O). MS (ESI⁺): m/z (%) = 439 (100) [M + Na]⁺. Anal. Calcd for C₂₂H₁₂N₂O₇: C, 63.47; H, 2.91; N, 6.73; Found: C, 63.60; H, 3.19; N, 6.27.
• 20 2-Hydroxy-4′-methoxy-3-(4-methoxyphenyl)flavanone (9): Yellow solid; ¹H NMR (300 MHz, CDCl₃): δ = 3.84 (s, 3 H, OCH ₃), 3.88 (s, 3 H, OCH ₃), 6.65 (s, 1 H, H-3), 6.80 (d, J = 8.3 Hz, 2 H, H-3′′,5′′), 6.98 (d, J = 8.8 Hz, 2 H, H-3′,5′), 7.29 (dd, J = 1.3, 7.9 Hz, 1 H, H-8), 7.39 (ddd, J = 1.3, 7.6, 7.7 Hz, 1 H, H-6), 7.56 (ddd, J = 1.8, 7.6, 7.9 Hz, 1 H, H-7), 7.67 (d, J = 8.3 Hz, 1 H, H-2′′,6′′), 7.93 (dd, J = 1.8, 7.7 Hz, 1 H, H-5), 8.20 (d, 8.8 Hz, 2 H, H-2′,6′), 16.69 (1 H, 2-OH). ¹³C NMR (75 MHz, CDCl₃): δ = 55.4 (OCH₃), 55.5 (OCH₃), 96.4 (C-3), 105.0 (C-2), 113.7 (C-3′′,5′′), 114. 0 (C-3′,5′), 121.5 (C-1′), 123.9 (C-8), 126.2 (C-6), 127.9 (C-1′′), 129.3 (C-2′′,6′′), 129.5 (C-4a), 129.8 (C-5), 132.5 (C-2′,6′), 149.0 (C-8a), 163.1 (C-4′′), 164.1 (C-4′), 182.4 (C-4), 186.2 (C=O). MS (ESI⁺): m/z (%) = 427 (100) [M + Na]⁺. Anal. Calcd for C₂₄H₁₀O₆: C, 71.28; H, 4.98; Found: C, 70.95; H, 4.99.