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

Patrícia A. A. M. Vaz; Diana C. G. A. Pinto; Djenisa H. A. Rocha; Artur M. S. Silva; José A. S. Cavaleiro

doi:10.1055/s-0032-1317159

Synlett, Table of Contents

Synlett 2012; 23(16): 2353-2356
DOI: 10.1055/s-0032-1317159

letter

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

Authors

Patrícia A. A. M. Vaz

Department of Chemistry & QOPNA, University of Aveiro, 3810-193 Aveiro, Portugal Fax: +351(234)370084 Email: diana@ua.pt Email: artur.silva@ua.pt
Diana C. G. A. Pinto*

Department of Chemistry & QOPNA, University of Aveiro, 3810-193 Aveiro, Portugal Fax: +351(234)370084 Email: diana@ua.pt Email: artur.silva@ua.pt
Djenisa H. A. Rocha

Department of Chemistry & QOPNA, University of Aveiro, 3810-193 Aveiro, Portugal Fax: +351(234)370084 Email: diana@ua.pt Email: artur.silva@ua.pt
Artur M. S. Silva*

Department of Chemistry & QOPNA, University of Aveiro, 3810-193 Aveiro, Portugal Fax: +351(234)370084 Email: diana@ua.pt Email: artur.silva@ua.pt
José A. S. Cavaleiro

Department of Chemistry & QOPNA, University of Aveiro, 3810-193 Aveiro, Portugal Fax: +351(234)370084 Email: diana@ua.pt Email: artur.silva@ua.pt

Abstract

All articles of this category

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

Full Text

References

References and Notes
1 Verma AK, Pratap R. Nat. Prod. Rep. 2010; 27: 1571

2a Lin Y.-P, Hsu F.-L, Chen C.-S, Chern J.-W, Lee M.-H. Phytochemistry 2007; 68: 1189
2b Zhu JT. T, Choi RC. Y, Chu GK. Y, Cheung AW. H, Gao QT, Li J, Jiang ZY, Dong TT. X, Tsim KW. K. J. Agric. Food Chem. 2007; 55: 2438

3a Nagaoka T, Banskota AH, Tezuka Y, Midorikawa K, Matsushige K, Kadota S. Biol. Pharm. Bull. 2003; 26: 487
3b Moscatelli V, Hnatyszyn O, Acevedo C, Megias J, Alcaraz MJ, Ferrana G. Planta Med. 2006; 72: 72

4a Beyer G, Melzig MF. Planta Med. 2003; 69: 1125
4b Vaya J, Mahmood S, Goldblum A, Aviram M, Volkova N, Shaalan A, Musa R, Tamir S. Phytochemistry 2003; 62: 89

5a Filipe P, Silva AM. S, Seixas RS. G. R, Pinto DC. G. A, Santos A, Patterson LK, Silva JN, Cavaleiro JA. S, Freitas JP, Mazière J.-C, Santus R, Morlière P. Biochem. Pharmacol. 2009; 77: 957
5b Gomes A, Neuwirth O, Freitas M, Couto D, Ribeiro D, Figueiredo AG. P. R, Silva AM. S, Seixas RS. G. R, Pinto DC. G. A, Tomé AC, Cavaleiro JA. S, Fernandes E, Lima JL. F. Bioorg. Med. Chem. 2009; 17: 7218

6 Quintin J, Roullier C, Thoret S, Lewin G. Tetrahedron 2006; 62: 4038
7 Maicheen, C.; Jittikoon, J.; Ungwitayatorn, J. Meeting in Advances in Synthetic and Medicinal Chemistry, St. Petersburg, Russia, August 21–25, 2011, P103, 216.
8 Pinto DC. G. A, Silva AM. S, Cavaleiro JA. S. Synlett 2007; 1897
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.
15 Heller ST, Natarajan SR. Org. Lett. 2006; 8: 2675
16 Nagarathnam D, Cushman M. Tetrahedron 1991; 47: 5971
17 Cushman M, Nagarathnam D. Tetrahedron Lett. 1990; 31: 6497
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.