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Synlett 2007(9): 1431-1435  
DOI: 10.1055/s-2007-980368
LETTER
© Georg Thieme Verlag Stuttgart · New York

Novel Solid-Phase Synthetic Method for Combinatorial Generation of a 4-Hydroxyquinolin-2(1H)-one-Based Library

Moon-Kook Jeona, Hyun Ju Laa,b, Deok-Chan Hab, Young-Dae Gong*a
a Korea Research Institute of Chemical Technology, P.O. Box 107, Yuseong-gu, Daejeon 305-600, South Korea
Fax: +82(42)8607698; e-Mail: ydgong@krict.re.kr;
b Department of Chemistry, Korea University, Seoul 151-742, South Korea
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Publication History

Received 19 March 2007
Publication Date:
23 May 2007 (online)

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Abstract

Utilizing polymer-bound anthranilic acid derivatives, we were able to obtain 4-hydroxyquinolin-2(1H)-ones in 50-99% five- or six-step overall yields and 65-95% purities through the adaptation of a Dieckmann-type condensation reaction to a C-C bond-forming cyclative cleavage step. The reactions on solid phase were monitored by on-bead ATR-FTIR spectroscopic methods, colorimetric tests, and/or cleavage experiments.

Key words

combinatorial chemistry - solid-phase synthesis - quinolinone - Dieckmann condensation - cyclative cleavage

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Another reason for selection of KHMDS as a standard base was the known favorable character of potassium enolates for O-alkylation, which is needed to obtain the 4-alkoxy derivatives in high purities through a subsequent in situ alkylation of the cleaved products. The study on the efficient alkylation is in progress using polymer-supported alkylating agents and will be reported elsewhere.

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Representative Procedure for Preparation of Compounds 9
Preparation of 2-Benzylaminobenzoate Resin (7a; X = H, R ¹ = Ph)
To a mixture of the resin 1a (X = H; 4.00 g, theoretically 3.59 mmol), prepared from Wang resin (1.00 mmol/g), and benzaldehyde (1.14 g, 10.8 mmol) in DCE (60 mL) at r.t. was added NaBH(OAc)3 (2.28 g, 10.8 mmol). The mixture was stirred at r.t. for 12 h and the resin was filtered, washed several times with CH2Cl2, DMF, MeOH, H2O, and MeOH, and dried in a vacuum oven to give 7a (4.30 g, 99%): on-bead ATR-FTIR: 3365 (NH), 3025, 2922, 1680 (C=O), 1602, 1581, 1512, 1492, 1451, 1221, 1172, 1097, 822, 750, 697 cm-1.
Preparation of 2-{Benzyl[3-(4-methoxyphenyl)acet-yl]amino}benzoate Resin (8a; X = H, R ¹ = Ph, R ² = 4-MeOC 6 H 4 )
To a mixture of the resin 7a (X = H, R1 = Ph; 1.00 g, theoretically 0.830 mmol) and 4-methoxyphenylacetic acid (413 mg, 2.49 mmol) in CH2Cl2 (30 mL) at r.t. was added pyridine (391 mg, 4.98 mmol) and phosphorus oxychloride (385 mg, 2.49 mmol). The mixture was stirred at r.t. for 2 h and the resin was filtered, washed several times with CH2Cl2, DMF, MeOH, H2O, and MeOH, and dried in a vacuum oven to give 8a (1.09 g, 97%): on-bead ATR-FTIR: 3026, 2921, 1719 (O-C=O), 1662 (N-C=O), 1605, 1510, 1492, 1448, 1380, 1243, 1176, 1078, 1025, 822, 755, 697 cm-1.
Preparation of 1-Benzyl-4-hydroxy-3-(4-methoxy-phenyl)-1 H -quinolin-2-one (9a; X = H, R ¹ = Ph, R ² = 4-MeOC 6 H 4 )
To a suspension of the resin 8a (X = H, R1 = Ph, R2 = 4-MeOC6H4; 100 mg, theoretically 0.0739 mmol) in THF (3 mL) at r.t. was added 0.5 M KHMDS in toluene (0.440 mL, 0.227 mmol) and the mixture was stirred at r.t. for 6 h. The mixture was filtered and washed with MeOH (about 10 mL). The filtrate was evaporated in vacuo, acidified to pH 4-5 with 3 N HCl, and extracted with EtOAc (2 × 3 mL). The organic layer was dried over MgSO4. The solvent was evaporated in vacuo and the residue (18 mg, 68%; 91% purity on the basis of LC-UV-MS spectrum) was purified by a silica gel column chromatography (n-hexane-EtOAc, 2:1) to afford 9a (14 mg, 53%; 99% purity on the basis of LC-UV-MS spectrum): 1H NMR (500 MHz, CDCl3): δ = 3.86 (s, 3 H), 5.56 (br s, 2 H), 7.05 (d, J = 8.7 Hz, 2 H), 7.20-7.23 (m, 2 H), 7.25-7.31 (m, 5 H), 7.43-7.47 (m, 3 H), 8.04 (dd, J = 8.0, 1.3 Hz, 1 H). 13C NMR (125 MHz, CDCl3): δ = 46.2, 55.4 111.2, 114.8, 115.0, 115.7, 121.9, 123.4, 124.1, 126.8, 127.2, 128.7, 131.1, 132.0, 137.0, 138.8, 156.0, 159.8, 162.8. ESI-MS: m/z = 358 [M + H]+.