New Approach to Flavonols via
Base-Mediated Cyclization: Total Synthesis of 3,5,6,7-Tetramethoxyflavone

George A. Kraus; Vinayak Gupta; Aaron Kempema

doi:10.1055/s-0031-1290207

LETTER

New Approach to Flavonols via Base-Mediated Cyclization: Total Synthesis of 3,5,6,7-Tetramethoxyflavone

George A. Kraus*, Vinayak Gupta, Aaron Kempema
Department of Chemistry, Iowa State University, Ames, IA 50011, USA
Fax: +1(515)2940105; e-Mail: gakraus@iastate.edu;

Abstract

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Abstract

A new methodology for the synthesis of flavonols is described. The key step is a base-mediated cyclization-isomerization-elimination reaction which results in the formation of flavonols. Using this strategy, three flavonols are synthesized and characterized.

Key words

flavonols - base-mediated cyclization - 3,5,6,7-tetramethoxyflavone - LDA

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References

References and Notes

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General Procedure for Friedel-Crafts Acylation
To a solution of phenol 5, 6, or 7 (1.0 equiv) in CH₂Cl₂ was added TiCl₄ (1.1 equiv) at -20 ˚C under argon. To this dark brown solution, ethyl chlorooxoacetate (1.1 equiv) was added dropwise while maintaining temperature at or below -15 ˚C. The resulting reaction mixture was stirred for 4 h with a steady increase in temperature to 0 ˚C. After the completion of the reaction, the reaction mixture was diluted with CH₂Cl₂ and poured over cold HCl (1.0 M) solution. The aqueous layer was separated and extracted with CH₂Cl₂. The combined organic extracts were washed with HCl (1.0 M) solution and brine followed by drying over anhyd MgSO₄. The solvent was evaporated in vacuo to obtain the crude compound 8, 9, or 10. The crude compounds were then purified by silica gel column chromatography.

Spectroscopic Data for Compound 8
Yellow solid (15% EtOAc-hexanes, 80% yield), recrystallized from EtOAc-hexanes, mp 50-51 ˚C. ^¹H NMR (400 MHz, CDCl₃): δ = 11.95 (s, 1 H), 6.25 (s, 1 H), 4.38 (q, J = 7.2 Hz, 2 H), 3.91 (s, 3 H), 3.91 (s, 3 H), 3.77 (s, 3 H), 1.40 (t, J = 7.2 Hz, 3 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 189.3, 164.2, 162.9, 154.2, 134.1, 104.7, 96.0, 62.0, 61.6, 61.1, 56.5, 14.1. MS: m/z = 307 [M + Na⁺], 239, 211. HRMS: m/z calcd for C₁₃H₁₆O₇: 284.0900; found: 284.0896.

Spectroscopic Data for Compound 9
Orange solid (25% EtOAc-hexanes, 89% yield), recrystallized from EtOAc-hexanes, mp 52-53 ˚C. ^¹H NMR (400 MHz, CDCl₃): δ = 12.35 (s, 1 H), 6.09 (s, 1 H), 5.92 (s, 1 H), 4.38 (q, J = 8 Hz, 2 H), 3.85 (s, 3 H), 3.80 (s, 3 H), 1.40 (t, J = 8 Hz, 3 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 188.5, 168.9, 168.2, 164.5, 162.5, 102.3, 94.0, 91.4, 61.9, 56.3, 56.0. 14.3. MS: m/z = 277 [M + Na⁺], 209, 181. HRMS: m/z calcd for C₁₂H₁₅O₆: 255.0863; found: 255.0863.

Spectroscopic Data for Compound 10
Yellow oil (20% EtOAc-hexanes, 85% yield). ^¹H NMR (300 MHz, CDCl₃): δ = 11.76 (s, 1 H), 7.66 (d, J = 9.0 Hz, 1 H), 6.51 (d, J = 2.4 Hz, 1 H), 6.48 (dd, J = 6.0, 2.4 Hz, 1 H), 4.45 (q, J = 7.2 Hz, 2 H), 3.88 (s, 3 H), 1.43 (t, J = 7.2 Hz, 3 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 188.4, 167.8, 167.1, 162.8, 133.9, 110.4, 109.0, 101.0, 62.6, 55.9, 14.2. MS: m/z = 247 [M + Na⁺], 191, 170, 151. HRMS: m/z calcd for C₁₁H₁₃O₅: 225.0757; found: 225.0754.

General Procedure for O-Alkylation
To a slurry of NaH (1.1 equiv) in dry DMF under argon, phenol 8, 9, or 10 (1.0 equiv) was added at 0 ˚C. The resulting reaction mixture was stirred at 0 ˚C for 15 min followed by the addition of 2-bromo-2-phenylacetonitrile 11 (1.1-1.5 equiv) at the same temperature. The reaction mixture was then stirred at 60 ˚C for 2-10 h. After the completion of the reaction, the reaction mixture was quenched by adding sat. NH₄Cl solution. The reaction mixture was then extracted with EtOAc (3 ×). The combined organic extracts were then washed with H₂O and brine, dried over anhyd MgSO₄, filtered, and evaporated in vacuo. The crude compound was purified by column chromatography to give pure 12, 13, or 14 respectively.

Spectroscopic Data for Compound 12
Yellow oil (20% EtOAc-hexanes, 70% yield). ^¹H NMR (400 MHz, CDCl₃): δ = 7.63-7.69 (m, 2 H), 7.35-7.50 (m, 3 H), 6.62 (s, 1 H), 5.96 (s, 1 H), 4.21 (m, 2 H), 3.91 (s, 6 H), 3.83 (s, 3 H), 1.31 (t, J = 7.2 Hz, 3 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 184.7, 163.6, 158.5, 155.0, 152.9, 138.5, 132.5, 130.4, 129.3, 127.9, 116.9, 114.3, 100.0, 72.4, 62.4, 62.3, 61.2, 56.6, 14.2. MS: m/z = 399 [M⁺], 327, 325, 283, 282, 254, 211, 210, 209. HRMS: m/z calcd for C₂₁H₂₁NO₇: 399.1318; found: 399.1326.

Spectroscopic Data for Compound 13
Yellow solid (50% EtOAc-hexanes, 17% yield, 25% based on SM recovered), recrystallized from EtOAc-hexanes, mp 146 ˚C. ^¹H NMR (300 MHz, CDCl₃): δ = 7.67-7.64 (m, 2 H), 7.49-7.46 (m, 3 H), 6.41 (s, 1 H), 6.28 (s, 1 H), 5.95 (s, 1 H), 4.18-4.13 (m, 2 H), 3.88 (s, 3 H), 3.84 (s, 3 H), 1.28 (t, J = 7.5 Hz, 3 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 184.2, 164.5, 163.9, 162.6, 158.4, 132.1, 130.4, 129.3, 127.7, 117.5, 109.1, 95.8, 93.9, 70.4, 62.0, 56.4, 55.9, 14.2. MS: m/z = 392 [M + Na⁺], 370, 276, 256, 203, 144. HRMS: m/z calcd for C₂₀H₂₀NO₆: 370.1285; found: 370.1279.

Spectroscopic Data for Compound 14
Yellow oil (33% EtOAc-hexanes, 48% yield, 76% based on SM recovered). ^¹H NMR (300 MHz, CDCl₃): δ = 7.97 (d, J = 8.7 Hz, 1 H), 7.62-7.60 (m, 2 H), 7.53-7.51 (m, 3 H), 6.74 (dd, J = 9.0 Hz, 2.1 Hz 1 H), 6.64 (d, J = 2.1 Hz, 1 H), 5.91 (s, 1 H), 3.90 (s, 3 H), 3.81 (q, J = 7.5 Hz, 2 H), 1.14 (t, J = 6.6 Hz, 3 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 184.7, 166.4, 165.2, 158.2, 133.8, 131.5, 130.8, 129.5, 128.1, 116.7, 115.9, 108.7, 100.5, 69.0, 61.8, 56.1, 14.0. MS: m/z = 362 [M + Na⁺], 340, 266, 246. HRMS: m/z calcd for C₁₉H₁₇NNaO₅: 362.0999; found: 362.1004.

General Procedure for Reduction and Base-Mediated Cyclization
In a round-bottom flask, ketone 12, 13, or 14 (1.0 equiv) was suspended in anhyd EtOH under inert conditions in an ice-acetone bath. To this, NaBH₄ (1.1 equiv) was added, and the reaction mixture was warmed to r.t. over 1-3 h. After the completion of reaction, the reaction mixture was quenched with HCl (2.0 M) solution until the gas evolution stopped. The mixture was then diluted with H₂O and extracted with EtOAc (2 ×). The combined organic extracts were then washed with H₂O and brine, dried over anhyd MgSO₄, filtered, and evaporated in vacuo to obtain crude as a mixture of diastereomers. The crude compounds were purified by column chromatography and were taken to next step as diastereomeric mixtures.
To a solution of diisopropylamine (2.3 equiv) in dry THF under argon was added n-BuLi (2.5 M in hexanes, 2.2 equiv) at -78 ˚C. The mixture was warmed to -40 ˚C and stirred at this temperature for 45 min. The solution was returned to -78 ˚C, and a solution of a-hydroxyester in dry THF was added to it. The resulting reaction mixture was warmed to r.t. and then refluxed for 8 h. After the completion of the reaction, the reaction mixture was quenched with HCl (1.0 M) solution until acidic and then returned to neutral pH with sat. NaHCO₃ solution. Most of the THF was evaporated in vacuo. The residue was then diluted with H₂O and extracted with EtOAc (3 ×). The combined organic extracts were then washed with H₂O and brine, dried over anhyd MgSO₄, filtered, and evaporated in vacuo. The crude compound was then purified by column chromatography.

Spectroscopic Data for Compound 15
Brown solid (40% EtOAc-hexanes, 51% yield), recrystallized from EtOAc-hexanes, mp 150-152 ˚C. ^¹H NMR (400 MHz, CDCl₃): δ = 8.21 (d, J = 8.6 Hz, 2 H), 7.51 (t, J = 6.8 Hz, 2 H), 7.44 (t, J = 7.2 Hz, 1 H), 6.79 (s, 1 H), 4.03 (s, 3 H), 3.98 (s, 3 H), 3.92 (s, 3 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 172.0, 158.6, 154.0, 151.9, 142.7, 140.1, 138.3, 131.3, 130.0, 128.7, 127.5, 110.0, 96.3, 62.5, 61.8, 56.6. MS: m/z = 329 [M + H⁺], 328, 326, 314, 313, 267, 167, 105, 77, 69. HRMS: m/z calcd for C₁₈H₁₇O₆: 329.1011; found: 329.1020.

Spectroscopic Data for Compound 16
Brown solid (5% MeOH-CH₂Cl₂, 63% yield), recrystallized from EtOAc-hexanes, mp 169-170 ˚C. ^¹H NMR (300 MHz, CDCl₃): δ = 8.23 (d, J = 9 Hz, 2 H), 7.55-7.45 (m, 3 H), 6.59 (d, J = 3 Hz, 1 H), 6.38 (d, J = 3 Hz, 1 H), 4.00 (s, 3 H), 3.93 (s, 3 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 172.1, 164.6, 160.6, 159.0, 141.9, 138.4, 131.1, 129.7, 128.6, 127.3, 106.2, 95.9, 92.5, 56.5, 56.0. MS: m/z = 299 [M + H⁺], 237, 144. HRMS: m/z calcd for C₁₇H₁₅O₅: 299.0914; found: 299.0919.

Spectroscopic Data for Compound 17
Brown solid (2% MeOH-CH₂Cl₂, 60% yield), recrystallized from EtOAc-hexanes, mp 167-169 ˚C. ^¹H NMR (300 MHz, CDCl₃): δ = 8.25 (d, J = 9 Hz, 2 H), 8.16 (d, J = 9 Hz, 1 H), 7.57-7.47 (m, 3 H), 7.03-6.98 (m, 2 H), 3.95 (s, 3 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 173.0, 164.5, 157.6, 144.4, 138.3, 131.4, 130.1, 128.8, 127.7, 127.0, 115.1, 114.8, 100.1, 56.1. MS: m/z = 269 [M + H⁺], 239, 189, 150. HRMS: m/z calcd for C₁₆H₁₃O₄: 269.0808; found: 269.0808.

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Preparation of Flavonol 4
Flavonol 15 (0.04 g, 0.12 mmol) was taken in dry actone, and anhyd K₂CO₃ was added to it under argon. To this, MeI (0.03 g, 0.18 mmol) was added, and the resulting reaction mixture was refluxed for 6 h. After the completion of reaction, the reaction mixture was filtered through Celite and evaporated to dryness. The residue was then diluted with H₂O and extracted with EtOAc (3 × 20 mL). The combined organic extracts were then washed with H₂O and brine, dried over anhyd MgSO₄, filtered, and evaporated in vacuo to obtain crude 4. The crude compound was then purified by column chromatography using 50% EtOAc-hexanes as eluent to get pure flavonol 4 (0.03 g, 0.10 mmol) in 80% yield.

Spectroscopic Data for Compound 4
Yellow oil. ^¹H NMR (400 MHz, CDCl₃): δ = 8.06 (dd, J = 8.0, 2.0 Hz, 2 H), 7.45-7.53 (m, 3 H), 6.75 (s, 1 H), 4.00 (s, 3 H), 3.96 (s, 3 H), 3.91 (s, 3 H), 3.86 (s, 3 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 174.0, 157.9, 153.9, 153.5, 152.6, 141.6, 140.4, 131.0, 130.6, 128.7, 128.6, 128.4, 113.4, 96.3, 62.4, 61.8, 60.3, 56.5. MS: m/z = 342, 327, 323, 297, 284, 283, 241, 195, 167, 129, 105, 88, 76, 68. HRMS: m/z calcd for C₁₉H₁₈O₆: 342.1103; found: 342.1108.

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