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

Jane Faragalla; Andrew Heaton; Renate Griffith; John B. Bremner

doi:10.1055/s-0028-1087523

LETTER

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

Jane Faragalla^a, Andrew Heaton^b, Renate Griffith^c, 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

Abstract

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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

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References

References and Notes

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3 Grese TA. Pennington LD. Tetrahedron Lett. 1995, 36: 8913

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8a

Trityl perchlorate has been used previously to access chromylium salts from the dihydro precursors^8b but not, as far as we can ascertain, from 2-unsubstituted isoflav-3-enes. Isoflavylium salts can also be made, for example, by ring construction^8c or by trityl salt mediated elimination of 2-substituted isoflav-3-enes^8d

8b Canalini G. Degani I. Fochi R. Spunta G. Ann. Chim. (Rome) 1967, 57: 1045

8c Bouvier P. Andrieux J. Molho D. Tetrahedron Lett. 1974, 1033

8d Dean FM. Varma RS. J. Chem. Soc., Perkin Trans. 1 1982, 1193

9a

Compound 1a is accessible from the commercially available precursors daidzein^9c or daidzein diacetate^9d,e

9b Faragalla JE. PhD Thesis University of Wollongong; Australia: 2005.

9c Heaton A, and Jeoffreys G. inventors; WO 2005103025. ; Chem. Abstr. 2005, 143, 422198

9d Heaton A, and Kumar N. inventors; WO 2000049009. ; Chem. Abstr. 2000, 133, 177059

9e Liepa AJ. Aust. J. Chem. 1981, 34: 2647

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%).

11 Doodeman R. Rutjes FPJT. Hiemstra H. Tetrahedron Lett. 2000, 41: 5979

12 Deprotection of TBS ethers by the related trityl tetrafluoroborate has been reported with the anion acting as a fluoride ion source. See: Metcalf BW. Burkhart JP. Jund K. Tetrahedron Lett. 1980, 21: 35

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.