One-Pot Synthesis of 3-Methylflavones and Their Transformation into (E)-3-Styrylflavones via Wittig Reactions

Djenisa H. A. Rocha; Diana C. G. A. Pinto; Artur M. S. Silva

doi:10.1055/s-0033-1340013

Synlett, Table of Contents

Synlett 2013; 24(20): 2683-2686
DOI: 10.1055/s-0033-1340013

letter

One-Pot Synthesis of 3-Methylflavones and Their Transformation into (E)-3-Styrylflavones via Wittig Reactions

Authors

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
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
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

Abstract

All articles of this category

Abstract

An efficient one-pot synthesis of 3-methylflavone derivatives is established. Furthermore, their transformation into phosphorus ylides, which are then used in the diastereoselective synthesis of (E)-styrylflavones through Wittig reactions, is also studied.

Key words

3-methylflavones - lithium bis(trimethylsilyl)amide - phosphonium salts - Wittig reaction - 3-styrylflavones

Full Text

References

References and Notes
1 Andersen ØM, Markham KR. Flavonoids: Chemistry, Biochemistry and Applications . Taylor & Francis; Boca Raton: 2006
2 Birt DF, Hendrich S, Wang W. Pharmacol. Ther. 2001; 90: 157
3 Verma AK, Pratap R. Nat. Prod. Rep. 2010; 27: 1571

4a Cummings J, Double JA, Bibby MC, Farmer P, Evans S, Kerr DJ, Kaye SB, Smyth JF. Cancer Res. 1989; 49: 3587
4b Cárdenas M, Marder M, Blank VC, Roguin LP. Bioorg. Med. Chem. 2006; 14: 2966
4c Lin Y.-P, Hsu F.-L, Chen C.-S, Chern J.-W, Lee M.-H. Phytochemistry 2007; 68: 1189
4d 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

5a Park KY, Lee S.-H, Min B.-K, Lee K.-S, Choi J.-S, Chung SR, Min KR, Kim Y. Planta Med. 1999; 65: 457
5b Nagaoka T, Banskota AH, Tezuka Y, Midorikawa K, Matsushige K, Kadota S. Biol. Pharm. Bull. 2003; 26: 487
5c Moscatelli V, Hnatyszyn O, Acevedo C, Megias J, Alcaraz MJ, Ferrana G. Planta Med. 2006; 72: 72

6a Beyer G, Melzig MF. Planta Med. 2003; 69: 1125
6b Vaya J, Mahmood S, Goldblum A, Aviram M, Volkova N, Shaalan A, Musa R, Tamir S. Phytochemistry 2003; 62: 89

7 Painuly P, Tandon JS. Phytochemistry 1983; 22: 243
8 Seixas RS. G. R, Pinto DC. G. A, Silva AM. S, Cavaleiro JA. S. Aust. J. Chem. 2008; 61: 718
9 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
10 Jayashree BS, Alam A, Nayak Y, Kumar DV. Med. Chem. Res. 2012; 21: 1991
11 Vaz PA. A. M, Pinto DC. G. A, Rocha DH. A, Silva AM. S, Cavaleiro JA. S. Synlett 2012; 23: 2353
12 Heller ST, Natarajan SR. Org. Lett. 2006; 8: 2675
13 2-Propionylphenyl 4-Methoxybenzoate (4) Yield: 46 mg (15%). ¹H NMR (300.13 MHz, CDCl₃): δ = 1.11 (t, J = 7.2 Hz, 3 H, H-3), 2.92 (q, J = 7.2 Hz, 2 H, H-2), 3.90 (s, 3 H, 4′′-OCH ₃), 7.00 (d, J = 9.0 Hz, 2 H, H-3′′,5′′), 7.22 (dd, J = 1.3, 8.1 Hz, 1 H, H-3′), 7.34 (ddd, J = 1.3, 7.0, 8.1 Hz, 1 H, H-5′), 7.55 (ddd, J = 1.3, 7.0, 8.1 Hz, 1 H, H-4′), 7.81 (dd, J = 1.3, 8.1 Hz, 1 H, H-6′), 8.16 (d, J = 9.0 Hz, 2 H, H-2′′,6′′). 1-(2-Hydroxyphenyl)-3-(4-methoxyphenyl)-2-methyl-propane-1,3-dione (5) Yield: 137 mg (30%). ¹H NMR (300.13 MHz, CDCl₃): δ = 1.60 (d, J = 7.0 Hz, 3 H, 2-CH ₃), 3.87 (s, 3 H, 4′′-OCH ₃), 5.23 (q, J = 7.0 Hz, 1 H, H-2), 6.86 (ddd, J = 1.2, 7.2, 8.1 Hz, 1 H, H-5′), 6.95 (d, J = 8.1 Hz, 2 H, H-3′′,5′′), 7.00 (dd, J = 1.2, 8.1 Hz, 1 H, H-3′), 7.46 (ddd, J = 1.2, 7.2, 8.1 Hz, 1 H, H-4′), 7.69 (dd, J = 1.2, 8.1 Hz, 1 H, H-6′), 7.95 (d, J = 8.1 Hz, 2 H, H-2′′,6′′), 12.09 (s, 1 H, 2-OH). 2-[3-(4-Methoxyphenyl)-2-methyl-3-oxo-propanoyl]-phenyl 4-Methoxybenzoate (6) Yield: 77 mg (25%). ¹H NMR (300.13 MHz, CDCl₃): δ = 1.48 (d, J = 7.0 Hz, 3 H, 2-CH ₃), 3.83 (s, 3 H, 4′′-OCH ₃), 3.88 (s, 3 H, 4′′′-OCH ₃), 5.07 (q, J = 7.0 Hz, 1 H, H-2), 6.80 (d, J = 9.0 Hz, 2 H, H-3′′,5′′), 6.93 (d, J = 9.0 Hz, 2 H, H-3′′′,5′′′), 7.20 (dd, J = 1.1, 8.1 Hz, 1 H, H-6′), 7.32 (ddd, J = 1.1, 7.0, 8.1 Hz, 1 H, H-5′), 7.53 (ddd, J = 1.1, 7.0, 8.1 Hz, 1 H, H-4′), 7.77 (dd, J = 1.1, 8.1 Hz, 1 H, H-3′), 7.81 (d, J = 9.0 Hz, 2 H, H-2′′,6′′), 8.04 (d, J = 9.0 Hz, 2 H, H-2′′′,6′′′).
14 3-Methylflavones 3a–d, 8a,b; General Procedure 2′-Hydroxypropiophenone (1) (0.15 mL, 1.09 mmol) was dissolved in anhydrous toluene (5 mL) in a screw-cap vial, equipped with a magnetic stir bar and sealed with a septum. The solution was cooled to 0 °C under N₂ and LiHMDS (5.14 mL in THF, 5.13 mmol) was added quickly via a syringe. The solution was stirred for approximately 30 min before the addition of aroyl chloride 2a–d (1.42 mmol) in one portion. The mixture was removed from the ice-bath and stirred at r.t. for the appropriate period of time (Table 1). HCl (4 mL, 37%) was added and the resulting solution stirred at r.t. for the requisite amount of time (Table 1). H₂O (50 mL) and ice (30 g) were added and the mixture was extracted with EtOAc (3 × 30 mL). The organic layer was dried over Na₂SO₄, filtered and evaporated under reduced pressure. The residue was purified by column chromatography (gradient: PE→PE–EtOAc, 4:1). After solvent evaporation, the expected 3-methylflavones 3a–d and 8a,b were obtained in very good yields (see Table 1).
15 3-Methyl-5,7,4′-trimethoxyflavone (8b) Yield: 110 mg (31%); white powder; mp 188–190 °C. ¹H NMR (500.13 MHz, CDCl₃): δ = 2.10 (s, 3 H, 3-CH ₃), 3.87 (s, 3 H, 4′-OCH ₃), 3.88 (s, 3 H, 5-OCH ₃), 3.95 (s, 3 H, 7-OCH ₃), 6.34 (d, J = 2.3 Hz, 1 H, H-6), 6.44 (d, J = 2.3 Hz, 1 H, H-8), 7.01 (d, J = 6.9 Hz, 2 H, H-3′,5′), 7.58 (d, J = 6.9 Hz, 2 H, H-2′,6′). ¹³C NMR (75.47 MHz, CDCl₃ ): δ = 11.6 (3-CH₃), 55.4 (5-OCH₃), 55.6 (4′-OCH₃), 56.2 (7-OCH₃), 92.2 (C-8), 95.7 (C-6), 108.0 (C-4a), 113.7 (C-3′,5′), 118.5 (C-3), 125.7 (C-1′), 130.4 (C-2′,6′), 158.1 (C-2), 159.6 (C-8a), 160.7 (C-7), 160.8 (C-4′), 163.6 (C-5), 177.8 (C-4). MS (ESI): m/z (%) = 327 (100) [M + H]⁺, 349 (8) [M + Na]⁺. HRMS (EI): m/z calcd for C₁₉H₁₈O₅: 326.1154; found: 326.1153.
16 Aoki S, Matsuo Y, Ogura S, Ohwada H, Hisamatsu Y, Moromizato S, Shiro M, Kitamura M. Inorg. Chem. 2011; 50: 806
17 3-Bromomethylflavones 9a–d; General Procedure To a solution of the appropriate 3-methylflavone 3a–d (0.17 mmol) in CCl₄ (40 mL) was added benzoyl peroxide (8.2 mg, 0.033 mmol) and NBS (39 mg, 0.22 mmol). The mixture was heated at reflux temperature under an N₂ atm for 6–24 h (depending on the substituent). The solvent was evaporated and the residue was taken in CHCl₃ (40 mL) and the obtained solution washed with H₂O (3 × 20 mL). The organic layer was concentrated and purified by thin-layer chromatography (CH₂Cl₂–hexane, 8:2) affording 3-bromomethylflavones 9a–d (9a, 87%; 9b, 50%; 9c, 50%; 9d, 60%).
18 3-Bromomethyl-4′-methoxyflavone (9b) Yield: 30 mg (50%); yellow powder; mp 161–163 °C. ¹H NMR (500.13 MHz, CDCl₃): δ = 3.90 (s, 3 H, 4′-OCH ₃), 4.67 (s, 2 H, 3-CH ₂), 7.05 (d, J = 8.9 Hz, 2 H, H-3′,5′), 7.42 (br dd, J = 7.0, 8.0 Hz, 1 H, H-6), 7.49 (br d, J = 8.0 Hz, 1 H, H-8), 7.68 (ddd, J = 1.6, 7.0, 8.0 Hz, 1 H, H-7), 7.74 (d, J = 8.9 Hz, 2 H, H-2′,6′), 8.24 (dd, J = 1.6, 8.0 Hz, 1 H, H-5). ¹³C NMR (75.47 MHz, CDCl₃): δ = 30.9 (3-CH₂), 55.5 (4′-OCH₃), 114.2 (C-3′,5′), 117.9 (C-8), 118.1 (C-3), 122.7 (C-4a), 125.3 (C-6), 126.1 (C-5), 130.0 (C-2′,6′), 130.3 (C-1′), 133.9 (C-7), 156.0 (C-8a), 161.8 (C-4′), 163.8 (C-2), 176.6 (C-4). MS (ESI): m/z (%) = 345 (47) [⁷⁹Br, M]⁺, 347 (40) [⁸¹Br, M]⁺, 367 (100) [⁷⁹Br, M + Na]⁺, 369 (90) [⁸¹Br, M + Na]⁺. HRMS (ESI): m/z calcd for C₁₇H₁₃BrO₃: 345.0133; found: 345.0142.
19 Das J, Ghosh S. Tetrahedron Lett. 2011; 52: 7189
20 3-(Bromotriphenylphosphoranyl)methylflavones 10a–d; General Procedure To a solution of the appropriate 3-bromomethylflavone 9a–d (0.06 mmol) in anhydrous toluene (10 mL) was added PPh₃ (16 mg, 0.06 mmol). The mixture was heated at reflux temperature under an N₂ atm for 24 h, after which the solvent was evaporated to give the corresponding 3-(bromotriphenyl-phosphoranyl)methylflavone 10a–d (10a, 67%; 10b, 58%; 10c, 64%; 10d, 60%).
21 3-(Bromotriphenylphosphoranyl)methyl-4′-chloro-flavone (10c) Yield: 21 mg (64%); white powder; mp 282–284 °C. ¹H NMR (300.13 MHz, CDCl₃): δ = 5.33 (d, J = 13.8 Hz, 2 H, 3-CH ₂), 7.34 (ddd, J = 1.3, 7.0, 8.0 Hz, 1 H, H-6), 7.43 (br d, J = 8.0 Hz, 1 H, H-8), 7.46–7.52 (m, 8 H, PPh₃), 7.61–7.71 (m, 10 H, H-2′,6′, H-7 and 7 H of PPh₃), 7.77 (dd, J = 1.3, 8.0 Hz, 1 H, H-5), 7.87 (d, J = 9.0 Hz, 2 H, H-3′,5′). ¹³C NMR (75.47 MHz, CDCl₃): δ = 23.6 (d, J = 50.0 Hz, 3-CH₂), 111.8 (C-3), 118.0 (C-8), 119.1 (C-4a), 121.3 (C-1′), 125.4 (C-5), 125.7 (C-6), 129.5 (C-1 of PPh₃), 129.7 (C-3,5 of PPh₃), 129.9 (C-4 of PPh₃), 130.6 (C-3′,5′), 133.9 (C-2,6 of PPh₃), 134.5 (C-7), 134.6 (C-2′,6′), 137.8 (C-4′), 155.6 (C-8a), 163.7 (C-2), 176.4 (C-4). MS (ESI): m/z (%) = 531 (100) [³⁵Cl, M]⁺, 532 (56) [³⁵Cl, M + H]⁺, 533 (40) [³⁷Cl, M]⁺. HRMS (ESI): m/z calcd for C₃₄H₂₅ClO₂P: 531.1264; found: 531.1275.
22 Sandulache A, Silva AM. S, Pinto DC. G. A, Almeida LM. P. M, Cavaleiro JA. S. New J. Chem. 2003; 27: 1592
23 Silva VL. M, Silva AM. S, Pinto CD. G. A, Cavaleiro JA. S, Vasas A, Patonay T. Monatsh. Chem. 2008; 139: 1307
24 (E)-3-Styrylflavones 11a–f; General Procedure To a suspension of the appropriate 3-(bromotriphenyl-phosphoranyl)methylflavone 10a–d (0.022 mmol) in THF (20 mL) was added NaH (0.5 mg, 0.022 mmol) and the mixture was stirred for the appropriate amount of time (Table 2). The appearance of coloration and the disappearance of the suspension due to the phosphonium salt was indicative of ylide formation. The appropriate benzaldehyde (2.3 μL, 0.022 mmol) was added and the mixture was stirred for the time given in Table 2. The solvent was evaporated and the residue was taken in CH₂Cl₂ (20 mL) and then washed with H₂O (3 × 20 mL). The organic layer was dried over anhydrous Na₂SO₄, filtered, concentrated and purified by thin-layer chromatography (CH₂Cl₂) to give the desired (E)-3-styrylflavones 11a–f (see yields in Table 2) and 3-methylflavones 3a–d (3a, 19%; 3b, 40%; 3c, 28%; 3d, 20%).
25 (E)-3-(4-Nitrostyryl)flavone (11d) Yield: 6 mg (67%); orange powder; mp 174–176 °C. ¹H NMR (300.13 MHz, CDCl₃): δ = 6.72 (d, J = 16.2 Hz, 1 H, H-α), 7.26–7.30 (m, 1 H, H-4′′), 7.33 (t, J = 7.9 Hz, 2 H, H-3′′,5′′), 7.38 (br d, J = 7.9 Hz, 2 H, H-2′′,6′′), 7.48 (ddd, J = 1.7, 7.2, 8.3 Hz, 1 H, H-6), 7.52 (dd, J = 1.7, 7.2 Hz, 1 H, H-8), 7.73 (ddd, J = 1.7, 7.2, 8.3 Hz, 1 H, H-7), 7.95 (d, J = 16.2 Hz, 1 H, H-β), 7.97 (d, J = 9.1 Hz, 2 H, H-2′,6′), 8.33 (dd, J = 1.7, 7.2 Hz, 1 H, H-5), 8.40 (d, J = 9.1 Hz, 2 H, H-3′,5′). ¹³C NMR (75.47 MHz, CDCl₃): δ = 117.8 (C-8), 118.6 (C-α), 118.9 (C-3), 123.4 (C-4a), 123.7 (C-3′,5′), 125.5 (C-6), 126.4 (C-5), 126.6 (C-2′′,6′′), 128.1 (C-4′′), 128.7 (C-3′′,5′′), 130.9 (C-2′,6′), 133.9 (C-7), 136.3 (C-β), 137.5 (C-1′′), 139.2 (C-1′), 148.7 (C-4′), 155.4 (C-8a), 159.6 (C-2), 177.1 (C-4). MS (ESI): m/z (%) = 370 (60) [M + H]⁺, 392 (99) [M + Na]⁺. HRMS (ESI): m/z calcd for C₂₃H₁₅NO₄: 369.1001; found: 369.1003.
26 Rocha DH. A, Pinto DC. G. A, Silva AM. S, Patonay T, Cavaleiro JA. S. Synlett 2012; 23: 559
27 Vedejs E. J. Org. Chem. 2004; 69: 5159
28 Robiette R, Richardson J, Aggarwal VK, Harvey JN. J. Am. Chem. Soc. 2005; 127: 13468