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

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

References and Notes

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  For an example of the substitution, see ref. 4e.

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16

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.

17

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]⁺.