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Synlett 2007(17): 2639-2642  
DOI: 10.1055/s-2007-991058
LETTER
© Georg Thieme Verlag Stuttgart · New York

A Novel and Facile Method for the Synthesis of 2,3-Disubstituted Quinolines by a Three-Component Coupling Reaction

Satoshi Kikuchi, Masahiro Iwai, Shin-ichi Fukuzawa*
Department of Applied Chemistry, Institute of Science and Engineering, Chuo University, 1-13-27 Kasuga, Bunkyo-ku, Tokyo 112-8551, Japan
Fax: +81(3)38171895; e-Mail: fukuzawa@chem.chuo-u.ac.jp;
Further Information

Publication History

Received 17 July 2007
Publication Date:
25 September 2007 (online)

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Abstract

A Lewis acid effectively catalyzed the three-component coupling reaction of an aromatic amine and aldehyde with ethyl propiolate, and the 2,3-disubstituted quinoline was regioselectively obtained in a good yield (up to 83% GC yield).

Key words

Lewis acid - quinolines - three-component coupling ­reaction - regioselectively

6

When this reaction was carried out at reflux in toluene, the major product was the 1,4-dihydropyridines. The investiga-tion regarding the synthesis of 1,4-dihydropyridines will be reported elsewhere in due course.

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General Procedure: To the EtOH (5 mL) solution of 1a (53.9 mg, 0.5 mmol), 2a (55 µL, 0.54 mmol) and Lewis acid (0.05 mmol, 10 mol%) was added 3 (61 µL, 0.6 mmol) using a microsyringe and then the mixture was refluxed for 24 h. The reaction was quenched with sat. aq NaHCO3 and the mixture was extracted with EtOAc. The combined organic layers were dried over MgSO4. The organic layer was filtered and concentrated under reduced pressure. The yield of 4aa was determined by GC using biphenyl as the internal standard. The quinoline 4aa was purified by preparative TLC (SiO2; hexane-EtOAc, 7:1) and/or recycling preparative HPLC (GPC column, CHCl3 as an eluent) and was fully characterized.
Ethyl 6-Methyl-2-phenylquinoline-3-carboxylate (4aa): 1H NMR (300 MHz, CDCl3): δ = 1.06 (t, J = 6.9 Hz, 3 H), 2.55 (s, 3 H), 4.17 (q, J = 6.9 Hz, 2 H), 7.44 (m, 3 H), 7.62 (m, 4 H), 8.07 (d, J = 9.0 Hz, 1 H), 8.55 (s, 1 H). 13C NMR (CDCl3): δ = 13.6, 21.5, 61.4, 125.4, 125.8, 126.8, 128.1, 128.3, 128.4, 129.1, 133.8, 137.2, 138.3, 140.8, 146.9, 157.2, 168.1.

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The reaction with imine 5, which was prepared from 1a and 2a, using Sc(OTf)3 yielded the quinoline 4aa in 60% yield.

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CCDC 650434 contains the supplementary crystallographic data for compound 4ha. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing data_request@ccdc.cam.ac.uk, or by contacting The Cambridge Crystallographic Data Centre, 12, Union Road, Cambridge CB2 1EZ, UK; fax: +44(1223)336033.

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Typical Procedure (Scheme 2): To the EtOH (7 mL) solution of 1a (107.2 mg, 1.0 mmol), 2d (110 µL, 1.1 mmol), which was distilled from P2O5 before use, and Sc(OTf)3 (49.2 mg, 0.10 mmol) was added 3 (122 µL, 1.2 mmol) using a microsyringe and then the mixture was refluxed for 24 h. The reaction was quenched with sat. aq NaHCO3 and the mixture was extracted with EtOAc. The combined organic layers were dried over MgSO4. This organic layer was filtered and concentrated under reduced pressure. The residue was purified by short column chromatography (hexane-EtOAc, 6:1) and recycling preparative HPLC (GPC column, CHCl3 as an eluent) to give the pure 4ad in 34% yield.
Diethyl 6-Methylquinoline-2,3-dicarboxylate (4ad): 1H NMR (300 MHz, CDCl3): δ = 1.45 (m, 6 H), 2.57 (s, 3 H), 4.43 (q, J = 7.0 Hz, 2 H), 4.52 (q, J = 7.0 Hz, 2 H), 7.67 (m, 2 H), 8.09 (d, J = 5.8 Hz, 1 H), 8.67 (s, 1 H). 13C NMR (CDCl3): δ = 14.1, 21.6, 61.4, 62.2, 122.5, 127.1, 127.3, 129.4, 134.6, 138.7, 138.9, 146.6, 147.0, 165.3, 166.9.

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In this reaction, ethyl 3,3-diethoxypropionate was obtained predominantly.