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

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Synlett 2012(3): 385-388
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;

Further Information

Publication History

Received 15 August 2011
Publication Date:
26 January 2012 (online)

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

References and Notes

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13

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.

14

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.

15

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.

16

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.

17

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.

18

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.

19

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.

20

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.

21

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.

22

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.

23

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.

24

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.

30

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.

31

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.