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Synlett 2009(2): 306-309  
DOI: 10.1055/s-0028-1087523
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

A Facile Approach to 2-Substituted Isoflav-3-enes via Isoflavylium Salts

Jane Faragallaa, Andrew Heatonb, Renate Griffithc, John B. Bremner*a
a School of Chemistry, University of Wollongong, Wollongong, NSW 2522, Australia
Fax: +61(2)42214287; e-Mail: john_bremner@uow.edu.au;
b Novogen Ltd., 140 Wicks Road, North Ryde, NSW 2113, Australia
c School of Medical Sciences/Pharmacology, University of NSW, Sydney, NSW 2052, Australia
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Publication History

Received 4 September 2008
Publication Date:
15 January 2009 (online)

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Abstract

A compact and regioselective approach to 2-substituted isoflav-3-enes based on a preformed 2-unsubstituted isoflavene is described. Isoflavene oxidation by hydride ion abstraction to the corresponding isoflavylium salt using trityl hexafluorophosphate followed by nucleophilic addition to the 2-position resulted in the introduction of a range of substituent groups in generally moderate to good yields.

Key words

nucleophilic additions - isoflavonoid - isoflavylium - isoflavene - trityl salts

    References and Notes

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10

General Procedure (Table 1, Entry 3)
A mixture of powdered 3 Å MS, trityl hexafluorophosphate (2.2 mmol), and the isoflavene 1b (503 mg, 1.55 mmol) in freshly distilled, anhyd CH2Cl2 (50 mL, from CaH2) was stirred at r.t. under nitrogen for 30 min. Trimethylsilyl cyanide (0.480 g, 4.8 mmol) was then added, and the reaction mixture was stirred for a further hour at r.t. The reaction mixture was then filtered, washed with CH2Cl2, concentrated under vacuum filtration, and subjected to silica gel chromatography, using CH2Cl2 as the mobile phase to afford the product as a colorless crystalline solid (431 mg, 80%).

13

General Procedure (Table 2, Entry 1)
A mixture of powdered 3 Å MS, trityl hexafluorophosphate (2.2 mmol), and the isoflavene 1b (451 mg, 1.39 mmol) in freshly distilled, anhyd CH2Cl2 (50 mL, from CaH2) was stirred at r.t. under nitrogen for 30 min. The commercially available 2-trimethylsilylthiazole (0.403g, 2.564 mmol) was then added and the reaction mixture was stirred for a further hour at r.t. The reaction mixture was then filtered, washed with CH2Cl2, concentrated under vacuum filtration, and subjected to silica gel chromatography, using CH2Cl2 as the mobile phase to afford the product as a creamy white solid (430 mg, 76%).

14

Data for Selected Compounds7-Acetoxy-3- p -acetoxyphenyl-2-cyano-2 H -1-benzopyran (7b) White solid; mp 156-158 ˚C. ¹H NMR (500 MHz, CDCl3): δ = 7.49 (d, J = 8.7 Hz, 2 H, H-2′/6′), 7.23 (d, J = 8.0 Hz,
1 H, H-5), 7.18 (d, J = 8.6 Hz, 2 H, H-3′/5′), 6.97 (s, 1 H, H4), 6.85 (dd, J = 2.5, 8.1 Hz, 1 H, H-6), 6.84 (s, 1 H, H-8), 6.01 (s, 1 H, H-2), 2.32 (s, 3 H, CH3), 2.30 (s, 3 H, CH3). ¹³C NMR (75 MHz, CDCl3): δ = 169.1 (C=O), 168.9 (C=O), 151.9 (C7), 151.1 (C8a), 150.3 (C4′), 131.9 (C3), 128.3 (C5), 126.2 (C2′), 125.9 (C1′), 122.4 (C3′), 122.3 (C4), 119.1 (C4a), 117.0 (C6), 110.5 (C8), 64.3 (C2), 21.1 (CH3). MS (CI+): m/z (%) = 323 (100) [MH+ - HCN]. Anal. Calcd (%) for C20H15NO5: C, 68.76; H, 4.33; N, 4.01. Found: C, 69.20; H, 4.34; N, 3.67.
7-Acetoxy-3- p -acetoxyphenyl-2-(2-thiazoyl)-2 H -1-benzopyran (8a)
Creamy white solid; mp 136-138 ˚C. ¹H NMR (300 MHz, CDCl3): δ = 7.60 (br d, J = 2.7 Hz, 1 H, H-2′′), 7.37 (d, J = 8.7 Hz, 2 H, H-2′/6′), 7.23 (d, J = 6.3 Hz, 1 H, H-5), 7.08 (d, J = 2.7 Hz, 1 H, H-3′′), 6.93 (d, J = 8.4 Hz, 2 H, H-3′/5′), 6.89 (s, 1 H, H4), 6.57 (dd, J = 2.7, 8.4 Hz, 1 H, H-6), 6.53 (d, J = 2.4 Hz, 1 H,H-8), 6.44 (br s, 1 H, H-2), 2.13 (s, 3 H, CH3), 2.10 (s, 3 H, CH3). ¹³C NMR (75 MHz, CDCl3): δ = 169.5 (C=O), 169.3 (C=O), 169.3 (C1′′), 151.8 (C7), 151.7 (C8a), 150.8 (C4′), 143.3 (C4′′), 134.0 (C3), 131.5 (C1′), 127.9 (C5), 126.9 (C2′), 122.2 (C3′), 121.1 (C3′′), 120.9 (C4), 120.2 (C4a), 115.7 (C6), 110.6 (C8), 74.7 (C2), 21.3 (CH3). HRMS (CI+): m/z calcd for [M + H]+ C22H17NO5S + H: 408.0906; found: 408.0887.




7-Acetoxy-3- p -acetoxyphenyl-2-ethoxy-2 H -1-benzopyran (8f)
Creamy white solid; mp 134-136 ˚C. ¹H NMR (300 MHz, CDCl3): d = 7.53 (d, J = 9.0 Hz, 2 H, H-2′/6′), 7.23 (d, J = 8.4 Hz, 1 H, H-5), 7.12 (d, J = 8.4 Hz, 2 H, H-3′/5′), 6.98 (s, 1 H, H-4), 6.82 (d, J = 2.1 Hz, 1 H, H-8), 6.76 (dd, J = 8.4, 2.1 Hz, 1 H, H6), 5.95 (s, 1 H, H-2), 4.04-3.96 (m, 1 H, OCH 2CH3), 3.82-3.74 (m, 1 H, OCH 2CH3), 2.32 (s, 3 H, CH 3CO), 2.30 (s, 3 H, CH 3CO), 1.25 (t, J = 7.2 Hz, 3 H, CH2CH 3). ¹³C NMR (75 MHz, CDCl3): d = 169.5 (C=O), 169.3 (C=O), 151.4 (C7), 151.1 (C8a), 150.6 (C4′), 134.6 (C3), 129.7 (C1′), 128.0 (C5), 126.9 (C2), 122.1 (C3′), 121.5 (C4), 119.6 (C4a), 115.4 (C6), 110.4 (C8), 97.2 (C2), 64.1 (CH2CH3), 21.5 (CH3CO), 15.7 (CH2 CH3). MS (CI+): m/z (%) = 323 (100; 2-unsubstituted isoflavylium ion). Anal. Calcd (%) for C21H20O6: C, 68.40; H, 5.48. Found: C, 68.49; H, 5.53. 7-Acetoxy-3- p -acetoxyphenyl-2-[2-(7-acetoxy-3- p -acetoxyphenyl-2 H -1-benzopyranyl)ethynyl]-2 H -1-benzopyran (9) Solid; mp 237-238 ˚C (dec.). ¹H NMR (300 MHz, DMF-d 6; integrations and assignments for half dimer): d = 7.11 (d, J = 9.0 Hz, 2 H, H-2′/6′), 7.02 (d, J = 8.4 Hz, 1 H, H-5), 6.98 (s, 1 H, H4), 6.73 (dd, J = 2.4, 0.3 Hz, 1 H, H-8), 6.66 (d, J = 9.0 Hz, 1 H, H-3′), 6.53 (s, 1 H, H-2), 6.51 (dd, J = 8.4, 2.4 Hz, 1 H, H6), 1.94 (s, 3 H, CH3), 1.88 (s, 3 H, CH3). ¹³C NMR (75 MHz, DMSO-d 6): d = 169.2 (C=O), 169.1 (C=O), 151.8 (C7), 150.8 (C8a), 150.2 (C4′), 133.0 (C3), 128.4 (C1′), 128.2 (C5), 126.4 (C2′), 122.2 (C4), 121.5 (C3′), 119.4 (C6), 116.3 (C4a), 110.7 (C8), 92.5 (ethynyl C), 91.7 (C2), 20.4 (CH3), 20.3 (CH3). MS (ES+): m/z (%) = 323 (100; 2-unsubstituted isoflavylium ion). Anal. Calcd (%) for C41H34O10: C, 69.28; H, 4.60. Found: C, 69.27; H, 4.62.