Convenient Synthetic Routes to 5-Substituted 3-(4-Methoxyphenyl)-4(1H)-quinolones

Abstract

5-Substituted 3-(4-methoxyphenyl)-4(1H)-quinolones 5-18 have been synthesised in good yields from the corresponding 3-(4-methoxyphenyl)-5-trifluoromethanesulfonate-4(1H)-quinolo-nes 4 via palladium-mediated cross-coupling reactions or aromatic nucleophilic substitution (SN_Ar) reactions.

quinolones - Stille reaction - Suzuki reaction - nucleophilic aromatic substitutions - aminations.

References

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8 Pelter A. Ward RS. Whalley JL. Synthesis  1998,  1793 

9

Physical data of 4a: mp 184-185 °C (EtOAc); IR (KBr): 1628, 1593, 1513 cm^-1; ¹H NMR (250 MHz, CDCl₃): δ 3.76 (s, 3 H, NCH₃), 3.81 (s, 3 H, OCH₃), 3.94 (s, 3 H, OCH₃), 6.71 (s, 1 H, Ar-H), 6.74 (s, 1 H, Ar-H), 6.89 (d, 2 H, J = 8.5 Hz, Ar-H), 7.51 (d, 2 H, J = 8.5 Hz, Ar-H), 7.52 (s, 1 H, =CH); ¹³C NMR (62.90 MHz, DMSO-d ₆ ): δ 41.2, 55.1, 56.4, 99.5, 106.7, 113.2, 113.4 (2), 121.1, 127.2, 129.8 (2), 143.0, 143.1, 149.0, 158.3, 160.9, 172.9; MS (IS): m/z 444 (MH⁺). Physical data of 4b: mp 179-180 °C (EtOAc); IR (KBr): 1630, 1610, 1592, 1560, 1515 cm^-1; ¹H NMR (250 MHz, CDCl₃): δ 3.78 (s, 3 H, NCH₃), 3.93 (s, 3 H, OCH₃), 4.05 (s, 3 H, OCH₃), 6.85 (d, 2 H, J = 8.8 Hz, Ar-H), 6.98 (d, 1 H,
J = 8.8 Hz, Ar-H), 7.03 (d, 1 H, J = 8.8 Hz, Ar-H), 7.46 (s, 1 H, =CH), 7.53 (d, 2 H, J = 8.8 Hz, Ar-H); ¹³C NMR (62.90 MHz, DMSO-d ₆ ): δ 46.3, 54.4, 55.6, 110.8, 112.8 (2), 116.1, 121.1, 122.4, 125.9, 128.9 (2), 132.7, 141.2, 143.6, 149.2, 158.0, 173.0; MS (IS): m/z 444 (MH⁺).

10 Carrera GM. Sheppard GS. Synlett  1994,  93 

11

Typical procedure: To a solution of 4a (100 mg, 0.22 mmol) in anhyd 1,4-dioxane (10 mL) was added freshly prepared tetrakis(triphenylphosphine)palladium (17 mg, 0.014 mmol). The solution was stirred at r.t. for 30 min. Phenylboronic acid (42 mg, 0.34 mmol) diluted in absolute EtOH (2 mL) was then added, followed immediately by sat aq NaHCO₃ (3 mL). The heterogeneous solution was stirred at reflux for 3 h. After cooling, palladium catalyst was removed by filtration. Brine solution was then added, the two layers were separated and the aqueous phase was extracted with EtOAc (3 × 5 mL). The combined organic extracts were dried over MgSO₄ and evaporated. The crude residue was purified by flash chromatography on silica gel (CH₂Cl₂/EtOAc, 9:1) to afford 60 mg (71%) of 7a.

12

Typical procedure: A mixture of triflate 4a (200 mg, 0.45 mmol) and benzylamine (0.24 mL, 2.20 mmol) in 1,4-dioxane (2 mL) was heated at 100 °C for 6 h. After cooling, the solvent was evaporated. The crude residue was purified by flash chromatography on silica gel (petroleum ether/EtOAc/NH₄OH 4:6:0.1) to afford 150 mg (83%) of 9.

13

Physical data of 9: mp 176-177 °C (EtOAc); IR (KBr): 3174, 1632, 1607, 1570, 1557, 1508, 1471 cm^-1; ¹H NMR (250 MHz, CDCl₃): δ 3.62 (s, 3 H, NCH₃), 3.77 (s, 3 H, OCH₃), 3.82 (s, 3 H, OCH₃), 4.44 (d, 2 H, J = 5.6 Hz, CH₂), 5.85 (s, 1 H, Ar-H), 5.87 (s, 1 H, Ar-H), 6.94 (d, 2 H, J = 8.8 Hz, Ar-H), 7.22-7.33 (m, 3 H, Ar-H), 7.38-7.41 (m, 3 H, =CH + Ar-H), 7.48 (d, 2 H, J = 8.8 Hz, Ar-H), 11.02 (broad t, 1 H, J = 5.6 Hz, NH); ¹³C NMR (62.90 MHz, CDCl₃): δ 41.6, 47.3, 55.2, 55.5, 85.2, 89.7, 108.1, 113.8 (2), 122.0, 127.1, 127.4 (2), 128.1, 128.7 (2), 130.2 (2), 138.8, 140.5, 144.4, 153.8, 158.8, 163.6, 178.9; MS (IS): m/z 401 (MH⁺); Anal. Calcd for C₂₅H₂₄N₂O₃: C, 74.98; H, 6.04; N, 6.99. Found: C, 75.25; H, 5.89; N, 7.13.

14

All new compounds gave satisfactory spectroscopic (¹H NMR, ¹³C NMR, MS and IR) and analytical data.

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18

Physical data of 18: mp 161-162 °C (EtOAc/petroleum ether); IR (KBr): 3446, 3381, 1635, 1610, 1569, 1511 cm^-1; ¹H NMR (250 MHz, CDCl₃): δ 3.62 (s, 3 H, NCH₃), 3.82 (s, 3 H, OCH₃), 3.84 (s, 3 H, OCH₃), 5.92 (d, 1 H, J = 2.2 Hz Ar-H), 5.98 (d, 1 H, J = 2.2 Hz, Ar-H), 6.94 (d, 2 H, J = 8.8 Hz, Ar-H), 7.11 (broad s, 2 H, NH₂), 7.40 (s, 1 H, =CH), 7.49 (d, 2 H, J = 8.8 Hz, Ar-H); ¹³C NMR (62.90 MHz, CDCl₃): δ 41.5, 55.3, 55.5, 87.1, 93.8, 108.4, 113.8 (2), 121.8, 128.1, 130.2 (2), 140.9, 144.2, 153.7, 158.8, 163.2, 179.1; MS (IS): m/z 311 (MH⁺); Anal. Calcd for C₁₈H₁₈N₂O₃: C, 69.66; H, 5.85; N, 9.03. Found: C, 70.01; H, 5.69; N, 8.92.

19 Miki Y. Hachiken H. Kashima Y. Sugimura W. Yanase N. Heterocycles  1998,  48:  1