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Synlett 2012(3): 448-452  
DOI: 10.1055/s-0031-1290079
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Synthetic Protocols Mutually Applicable to 4-Oxoquinolines and 4-Oxo-1,8-naphthyridines: Synthesis of 1-Aryl-2-substituted and 1-Aryl-3-fluoro-4-oxoquinolines and 4-Oxo-1,8-naphthyridines

Ken-ichiro Awasaguchi*, Hiromi Hayashi, Hyouei Kawai, Hiroko Tominaga, Yuichiro Sato, Kazuya Hayashi, Yozo Todo
Discovery Research Department, Research Laboratories, Toyama Chemical Co., Ltd., 2-4-1 Shimookui, Toyama 930-8508, Japan
Fax: +81(76)4318208; e-Mail: kenichiro_awasaguchi@toyama-chemical.co.jp;
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Publication History

Received 5 October 2011
Publication Date:
03 January 2012 (online)

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Abstract

We have achieved the synthesis of 1-aryl-2-substituted 4-oxoquinoline and 4-oxo-1,8-naphthyridine derivatives, which cannot be synthesized by known methods, via two useful synthons, 2-formyl-4-oxoquinoline and 2-methylsulfonyl-4-oxo-1,8-naphthyridine. We also succeeded in the synthesis of 1-aryl-3-fluoro-4-oxoquinoline by fluorocyclization of N-arylenaminone with Selectfluor® and potassium carbonate in DMF in a one-pot procedure. To the best of our knowledge, this is the first synthesis of 3-fluoro-4-oxoquinoline derivatives. We confirmed that these protocols were mutually applicable to the synthesis of 4-oxoquinoline and 4-oxo-1,8-naphthyridine derivatives.

Key words

antiviral agents - heterocycles - HIV - 4-oxoquinoline - 4-oxo-1,8-naphthyridine - fluorocyclization

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13

Analytical and Spectral Data of N -Arylenaminone 5: pink solid; mp 112-113 ˚C. ¹H NMR (400 MHz, CDCl3): δ = 7.75 (dd, J = 8.3, 8.0 Hz, 1 H), 7.36 (dd, J = 8.3, 1.7 Hz, 1 H), 7.29 (dd, J = 10.4, 1.7 Hz, 1 H), 7.22 (ddd, J = 8.8, 8.5, 5.8 Hz, 1 H), 6.88-6.98 (m, 2 H), 5.89 (d, J = 2.2 Hz, 1 H), 2.02 (s, 3 H). ¹³C NMR (100 MHz, CDCl3): δ = 184.6 (d, J = 4.1 Hz), 163.8, 161.1 (dd, J = 249.6, 10.8 Hz), 160.1 (d, J = 256.2 Hz), 157.0 (dd, J = 250.4, 12.4 Hz), 131.7 (d, J = 3.3 Hz), 128.5 (d, J = 9.1 Hz), 127.7 (d, J = 3.3 Hz), 127.2 (d, J = 13.2 Hz), 125.1 (d, J = 9.9 Hz), 122.6 (dd, J = 13.2, 4.1 Hz), 119.8 (d, J = 27.2 Hz), 111.6 (dd, J = 22.3, 4.1 Hz), 104.9 (dd, J = 26.0, 24.4 Hz), 98.6 (d, J = 10.7 Hz), 19.8 (d, J = 2.5 Hz). IR (neat): 1590, 1568, 1541, 1433, 1395, 1318, 1304, 1283, 1094, 882, 857, 778 cm-¹. HRMS (DART):
m/z [M + H]+ calcd for C16H12BrF3NO: 370.00544; found: 370.00546.

18

General Procedure for the Synthesis of Aldehyde 3: To a solution of 1-aryl-2-methyl-4-oxoquinoline 2 (1.58 g, 4.51 mmol) in 1,4-dioxane (18 mL) was added selenium dioxide (0.53 g, 4.51 mmol) at r.t. The mixture was heated under reflux for 4 h. The solvent was concentrated in vacuo, then the residue was diluted with EtOAc and the suspension was filtered. The filtrate was washed with sodium thiosulfate solution and brine, dried over MgSO4, filtered and concen-trated in vacuo. The residue was subjected to silica gel column chromatography (hexane-EtOAc, 2:1 → 1:1, gradient) to afford aldehyde 3 (0.99 g, 60% yield) as a pale yellow solid. Analytical and Spectral Data of Aldehyde 3: pale yellow solid; mp 195-196 ˚C. ¹H NMR (400 MHz, DMSO-d 6): δ = 9.64 (s, 1 H), 8.16 (d, J = 8.5 Hz, 1 H), 7.75 (ddd, J = 8.9, 8.9, 6.0 Hz, 1 H), 7.68 (dd, J = 8.5, 1.7 Hz, 1 H), 7.64-7.72 (m, 1 H), 7.36-7.42 (m, 1 H), 7.01 (br s, 1 H), 6.97 (s, 1 H). ¹³C NMR (100 MHz, DMSO-d 6): δ = 188.4, 177.3, 163.0 (dd, J = 250.0, 12.0 Hz), 158.3 (dd, J = 250.9, 13.6 Hz), 143.9, 142.7, 132.2 (d, J = 10.7 Hz), 128.2, 127.9, 127.8, 125.2, 121.1 (dd, J = 13.2, 4.1 Hz), 119.4, 118.5, 113.3 (dd, J = 22.3, 3.3 Hz), 105.7 (dd, J = 26.9, 23.6 Hz). IR (neat): 1702, 1631, 1595, 1512, 1448, 1271, 1149, 1008, 972, 947, 856, 830 cm-¹. HRMS (DART): m/z [M + H]+ calcd for C16H9BrF2NO2: 363.97847; found: 363.97898.

19

General Procedure for the Synthesis of Ketene- S , N -acetal 8: To a solution of 3-acetyl-2,6-dichloropyridine (7) in THF (26 mL) was added lithium diisopropylamide (2.0 M, 3.0 mL, 6.05 mmol) dropwise at -40 ˚C under nitrogen atmosphere. After stirring at -40 ˚C for 30 min, to the mixture was added a solution of 2,6-difluorophenyl isothiocyanate (2.08 g, 12.1 mmol) in THF (11 mL). The mixture was gradually warmed up to r.t. while stirring for 1.5 h. After stirring, the mixture was cooled in an ice bath. To the mixture was added iodomethane (0.75 mL, 12.1 mmol) at 5 ˚C and the mixture was warmed up to r.t. while stirring for 20 min. The reaction was quenched with sat. NH4Cl solution at 5 ˚C and the mixture was extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was subjected to silica gel column chromatography (hexane-EtOAc, 20:1 → 10:1, gradient) to afford ketene-S,N-acetal 8 (0.66 g, 35% yield) as a pale yellow solid. Analytical and Spectral Data of Ketene- S , N -acetal 8: pale yellow solid; mp 164-165 ˚C. ¹H NMR (400 MHz, CDCl3): δ = 12.78 (br s, 1 H), 7.91 (d, J = 8.1 Hz, 1 H), 7.41 (ddd, J = 8.7, 8.7, 5.9 Hz, 1 H), 7.35 (d, J = 8.1 Hz, 1 H), 6.90-7.00 (m, 2 H), 5.70 (s, 1 H), 2.41 (s, 3 H). ¹³C NMR (100 MHz, CDCl3): δ = 183.6, 170.5, 161.7 (dd, J = 250.4, 10.8 Hz), 157.3 (dd, J = 252.5, 12.8 Hz), 150.5, 146.7, 141.0, 135.6, 129.4 (d, J = 10.7 Hz), 123.1, 121.8 (dd, J = 12.4, 4.1 Hz), 111.5 (dd, J = 22.3, 4.1 Hz), 105.0 (dd, J = 26.5, 24.0 Hz), 92.9, 14.7. IR (neat): 1575, 1512, 1468, 1411, 1260, 1143, 1045, 966, 846, 730 cm-¹. HRMS (DART): m/z [M + H]+ calcd for C15H11Cl2F2N2OS: 374.99372; found: 374.99405.

20

General Procedure for the Synthesis of 1-Aryl-3-fluoro-4-oxoquinoline 15: To a solution of N-arylenaminone 14 (100 mg, 0.28 mmol) in DMF (2.8 mL) was added Selectfluor® (149 mg, 0.42 mmol) at r.t. The mixture was stirred for 30 min at the same temperature. To the mixture was added K2CO3 (116 mg, 0.84 mmol) and the mixture was heated to 80 ˚C. After stirring for 30 min at 80 ˚C, the mixture was cooled and diluted with EtOAc and H2O. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was subjected to silica gel column chromatography (hexane-EtOAc, 3:1) to afford 1-aryl-3-fluoro-4-oxoquinoline 15 (38 mg, 38% yield) as a pale yellow solid. Analytical and Spectral Data of 1-Aryl-3-fluoro-4-oxoquinoline 15: pale yellow solid; mp 197-198 ˚C. ¹H NMR (400 MHz, DMSO-d 6): δ = 8.66 (d, J = 8.3 Hz, 1 H), 8.24 (d, J = 8.6 Hz, 1 H), 7.89 (ddd, J = 8.8, 8.8, 5.9 Hz, 1 H), 7.69-7.76 (m, 1 H), 7.64 (dd, J = 8.6, 1.6 Hz, 1 H), 7.40-7.46 (m, 1 H), 7.17 (s, 1 H). ¹³C NMR (100 MHz, DMSO-d 6): δ = 167.8 (d, J = 14.9 Hz), 162.9 (dd, J = 249.6, 11.6 Hz), 157.7 (dd, J = 252.5, 13.6 Hz), 146.6 (d, J = 238.0 Hz), 140.6, 132.0 (d, J = 28.9 Hz), 131.7 (d, J = 3.3 Hz), 127.8 (d, J = 4.1 Hz), 127.2, 126.6, 125.4 (d, J = 9.9 Hz), 123.5 (dd, J = 12.8, 3.7 Hz), 119.1, 113.4 (dd, J = 22.7, 3.7 Hz), 106.0 (dd, J = 27.3, 23.1 Hz). IR (neat): 1624, 1587, 1509, 1328, 1217, 1193, 1143, 1101, 968, 926, 853, 834, 772 cm-¹. HRMS (DART): m/z [M + H]+ calcd for C15H8BrF3NO: 353.97414; found: 353.97405.