Synlett 2003(10): 1542-1544
DOI: 10.1055/s-2003-40845
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

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

Benoît Joseph*a,b, Aurélie Béhardb, Brigitte Lesurc, Gérald Guillaumetb
a Laboratoire de Chimie Organique 1, UMR-CNRS 5622, Université Claude Bernard - Lyon 1, CPE - Bâtiment 308, 43 Boulevard du 11 Novembre 1918, 69622 Villeurbanne Cedex, France
Fax: +33(4)72431214; e-Mail: benoit.joseph@univ-lyon1.fr;
b Institut de Chimie Organique et Analytique, UMR-CNRS 6005, Université d’Orléans, B.P. 6759, 45067 Orléans Cedex 2, France
c Cephalon France, Centre de Recherche et de Développement, 19 Avenue du Professeur Cadiot, 94701 Maisons-Alfort Cedex, France
Further Information

Publication History

Received 26 May 2003
Publication Date:
24 July 2003 (online)

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 (SNAr) reactions.

    References

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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+).

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.

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.