The Synthesis of Wrightiadione via Directed Remote Metalation

Abstract

The application of directed remote metalation (DreM) and electrophilic substitution is reported for the synthesis of wrightiadione using N,N-diethylcarboxamide as a directed metalation group (DMG) and electrophilic group. The lithiation of N,N-diethylisoflavone-2′-carboxamide with LDA gave a carbanion at C-2 which further cyclized to wrightiadione.

Key words

directed remote metalation - wrightiadione - N,N-diethylisoflavone-2′-carboxamide - directed metalation group - electrophilic substitution

References

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10

Reaction of N,N-diethyl-O-toluamide (7) with methyl salicylate (6) in the presence of LDA: A solution of LDA in dry THF (200 mL) was prepared by adding diiso-propylamine (14.7 mL, 0.10 mol) dropwise to a 0.95 M solution of n-BuLi (95 mL, 0.10 mol) in hexane under argon at 0 °C. The ice-water bath was replaced by a dry ice/acetone bath. The stirring was continued for 30 min at -78 °C, and then N,N-diethyl-O-toluamide (7, 14.4 g, 75.0 mmol) in dry THF (30 mL) was added. The pale yellow solution turned to deep red, indicating anion formation. The reaction mixture was allowed to warm to 0 °C with an ice-water bath, stirred for 10 min and the ice-water bath was replaced by a dry ice/acetone bath. The stirring was continued for 1 h. A solution of methyl salicylate (6, 11.4 g, 75.0 mmol) in dry THF (30 mL) was added slowly via syringe to the above mixture. Stirring at this temperature was continued for 2 h and then the reaction mixture was warmed to room temperature. 2 N HCl was added and the entire mixture was stirred for 1 h. Removal of solvent under reduced pressure gave a residue which was extracted with CH₂Cl₂. The combined organic extracts were washed with aqueous sodium carbonate solution, water and brine solution, and dried over anhydrous sodium sulfate. After removal of solvent, the residue was column chromatographed on silica gel using EtOAc and hexane as eluents to provide the desired 2-(2-N,N-diethyl-carboxamidephenyl)-1-(2-hydroxyphenyl)ethan-1-one (5) as the major adduct (13.5 g, 58%) and 3-(2-methylphenyl) isochromen-1-one (10) as the minor adduct (1.9 g, 11%).

11

Compound 5: colorless crystals: mp 168-169 °C (EtOAc:hexane); IR (KBr) 3061 (OH), 1744 (C=O), 1648 (C=O), 1628, 1603, 1486, 1272, 1215 cm^-1; ¹H NMR (200 MHz, CDCl₃) δ 1.03 (t, 3 H, J = 7.2 Hz), 1.09 (t, 3 H, J = 7.2 Hz), 3.15 (q, 2 H, J = 7.2 Hz), 3.45 (m, 2 H), 4.44 (br s, 2 H), 6.95 (m, 2 H), 7.30 (m, 4 H), 7.47 (dd, 1 H, J = 1.2 Hz, 7.6 Hz), 7.90 (dd, 1 H, J = 1.0 Hz, 8.1 Hz), 12.09 (s, 1 H); ¹³C NMR (50 MHz, CDC l₃) δ 12.1, 13.7, 38.5, 42.0, 42.8, 118.3, 119.0, 119.2, 125.6, 127.0, 128.9, 130.3, 131.2, 131.3, 136.6, 137.3, 162.4, 170.3 (CON), CO not observed; MS (EI) m/z 311 (M⁺, 0), 238 (68), 210 (85), 181 (100), 152 (21). HRMS (FAB) calcd for C₁₉H₂₁NO₃ [MH⁺]: 312.1560; found 312.1560.

12

Compound 10: white solid: mp 80-82 °C (EtOH); IR (KBr) 1719 (C=O), 1648 (C=O) cm^-1; ¹H NMR (200 MHz, CDCl₃) δ 2.46 (s, 3 H), 6.56 (s, 1 H), 7.26 (m, 3 H), 7.46 (m, 3 H), 7.69 (dd, 1 H, J = 1.2 Hz, 7.2 Hz), 8.28 (dd, 1 H, J = 0.8 Hz, 8.0 Hz); ¹³C NMR (50 MHz, CDCl₃) δ 20.7, 105.9, 120.3, 125.8, 126.0, 128.2, 129.2, 129.5, 129.8, 131.0, 132.7, 134.8, 136.7, 137.5, 155.5, 162.6; MS (EI) m/z 236 (M⁺, 100), 208 (83), 207 (39), 193 (27), 179 (43) Anal. calcd. for C₁₆H₁₂O₂: C, 81.34; H 5.12. Found: C, 80.94; H 4.87.

14

3-(2-N,N-Diethylcarboxamidephenyl)-4H-chromen-4-one (4). 2-Hydroxydeoxybenzoin (6, 0.62 g. 2.0 mmol) was dissolved in distilled BF₃˙Et₂O (5 mL) under argon. A solution of methanesulfonyl chloride (3 mL) in dry DMF (15 mL) was slowly added and the mixture was heated at 70 °C for 2 h. The reaction was cooled to room temperature and poured into an ice-cold aq sodium acetate. The mixture was extracted with ethyl acetate. The combined organic extracts were washed with water and dried over anhydrous sodium sulfate. Solvent was removed under vacuum and the residue was purified by preparative layer chromatography on silica gel (elution with CH₂Cl₂) to give isoflavone 4 as a white solid (0.30 g, 48%).

15

Compound 4: mp 173-175 °C (EtOH); IR (KBr) 1639 (C=O), 1595, 1471, 1386, 1359, 1299, 1228 cm^-1; ¹H NMR (200 MHz, CDCl₃) δ 0.89 (m, 6 H), 3.04 (m, 4 H), 7.35 (m, 6 H), 7.63 (ddd, 1 H, J = 0.6 Hz, 1.2 Hz, 7.2 Hz), 7.57 (dd, 1 H, J = 1.2 Hz, 7.2 Hz), 7.61 (dd, 1 H, J = 1.6 Hz, 7.0 Hz, 8.6 Hz), 8.06 (s, 1 H), 8.18 (ddd, 1 H, J = 0.4 Hz, 1.6 Hz, 8.0 Hz); ¹³C NMR [50(16) MHz, CDCl₃] δ 12.1, 13.7, 38.5, 42.8, 118.2, 123.5, 124.2, 125.3, 126.0, 126.1, 128.3, 128.7, 131.4, 133.8, 137.5, 154.7, 156.3, 170.2, 176.2; MS (EI) m/z 321 (M⁺, 13), 320 (24), 249 (100), 221 (55), 192 (6), 165 (25) Anal. calcd. for C₂₀H₁₉NO₃: C, 74.75; H 5.96 N, 4.36. Found: C, 74.95; H 5.54 N, 4.07.

16

Compound 12: white solid (14%): mp 183-185 °C (EtOH); IR (KBr) 1719 (C=O), 1649 (C=O) cm^-1; ¹H NMR (200 MHz, CDCl₃) δ 7.19 (m, 2 H), 7.33 (m, 1 H), 7.70 (m, 2 H), 7.78 (m, 2 H), 7.92 (m, 1 H); ¹³C NMR (50 MHz, CDCl₃) δ 104.2, 113.7, 118.6, 122.6, 123.6, 125.8, 126.2, 127.1, 132.0, 135.2, 139.8, 142.3, 167.0, 171.3, 192.6; MS (EI)
m/z 252 (M⁺, 62), 224 (41), 223 (23), 196 (26), 195 (15), 180 (100), 168 (37) Anal. calcd. for C₁₅H₈O₄: C, 71.43; H 3.20. Found: C, 71.74; H 3.10.

18

Wrightiadione 1: A solution of LDA in dry THF (10 mL) was prepared as in ref. [10] using diisopropylamine (0.4 mL, 2.6 mmol) and 0.7 M solution of n-BuLi (3.0 mL, 2.5 mmol) in hexane. The LDA was stirred for 30 min at -78 °C, and then isoflavone 4 (0.15 g, 0.5 mmol) in dry THF (5 mL) was added. Stirring at this temperature was continued for 2 h and then the reaction mixture was warmed to room temperature. Water was added and the mixture was stirred for 30 min. The organic layer was separated and washed again with water, dried over Na₂SO₄, filtered, and evaporated under reduced pressure. The resulting orange residue was purified by preparative layer chromatography on silica gel using CH₂Cl₂ as eluent to give crystals of wrightiadione 1 (0.07 g, 49%).