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Synlett 2005(2): 251-254  
DOI: 10.1055/s-2004-837227
LETTER
© Georg Thieme Verlag Stuttgart · New York

A Convenient Synthesis of Quinolin-2(1H)-one Ring System as Precursor of Active Drugs

Gamal Giuglio-Tonolo, Thierry Terme, Patrice Vanelle*
Laboratoire de Chimie Organique Pharmaceutique (LCOP), UMR CNRS 6517 Faculté de Pharmacie, 27 Bd J. Moulin, 13385 Marseille Cedex 05, France
e-Mail: patrice.vanelle@pharmacie.univ-mrs.fr;
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Publikationsverlauf

Received 22 October 2004
Publikationsdatum:
22. Dezember 2004 (online)

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Abstract

A series of new substituted quinolin-2(1H)-ones was prepared in good yields according to a two-step synthesis using TDAE methodology from substituted o-nitrobenzyl chlorides ­followed by a reduction-cyclization step.

Key words

TDAE - quinolin-2(1H)-one - reduction - nucleophilic addition - nitrobenzyl anions

11

General Procedure for the Reaction of o -Nitrobenzyl Chloride (1-3) and Keto Esters (4a-c), Using TDAE.
Into a two-necked flask equipped with a silica gel drying tube and a nitrogen inlet was added, under nitrogen at
-20 °C, 7 mL of anhyd DMF solution of o-nitrobenzyl chloride (1-3, 0.52 g, 3 mmol) and corresponding carbonyl derivatives (4a-c, 9 mmol, 3 equiv). The solution was stirred and maintained at this temperature for 30 min and then was added dropwise (via a syringe) the TDAE (0.60 g, 3.3 mmol). A red color immediately developed with the formation of a white fine precipitate. The solution was vigorously stirred at -20 °C for 1 h and then warmed up to r.t. for 2 h. After this time TLC analysis (CH2Cl2) clearly showed that compounds (1-3) was totally consumed. The orange-red turbid solution was filtered (to remove the octamethyl-oxamidinium dichloride) and hydrolyzed with 80 mL of H2O. The aqueous solution was extracted with toluene (3 × 40 mL), the combined organic layers washed with H2O (3 × 40 mL) and dried over MgSO4. Evaporation of the solvent left an orange viscous liquid as crude product. Purification by silica gel chromatography (CH2Cl2) and recrystallization from hexane-EtOH (9:1) gave the corresponding α-hydroxy derivatives.
New products:
Compound 6a: yellow oil. 1H NMR (200 MHz, CDCl3): δ = 1.26 (t, J = 7.2 Hz, 3 H), 1.42 (s, 3 H), 2.36 (s, 3 H), 3.42 (s, 2 H), 4.15 (q, J = 7.2 Hz, 2 H), 7.14 (d, J = 8.1 Hz, 1 H), 7.16 (s, 1 H), 7.72 (d, J = 8.1 Hz, 1 H). 13C NMR (50 MHz, CDCl3): δ = 14.0, 21.2, 26.0, 40.7, 62.2, 74.7, 124.7, 128.3, 130.4, 133.7, 142.9, 144.0, 175.9. Anal. Calcd for C13H17NO5: C, 58.42; H, 6.41; N, 5.24. Found: C, 58.32; H, 6.20; N, 5.29.
Compound 6b: white needles; mp 98.2 °C. 1H NMR (200 MHz, CDCl3): δ = 2.40 (s, 3 H), 3.72 (d, J AB = 9.1 Hz, 1 H), 3.78 (d, J AB = 9.1 Hz, 1 H), 3.83 (s, 3 H), 7.19 (d, J = 8.9 Hz, 1 H), 7.21 (s, 1 H), 7.75 (d, J = 8.9 Hz, 1 H). 13C NMR (50 MHz, CDCl3): δ = 21.3, 32.9, 54.3, 77.7, 125.0, 127.2, 128.7, 129.2, 133.9, 143.5, 148.7, 169.2. Anal. Calcd for C12H12F3NO5: C, 46.91; H, 3.94; N, 4.56. Found: C, 46.82; H, 4.02; N, 4.59.
Compound 6c: yellow solid; mp 65 °C. 1H NMR (200 MHz, CDCl3): δ = 1.26 (t, J = 7.1 Hz, 6 H), 2.35 (s, 3 H), 3.78 (s, 2 H), 4.21 (q, J = 7.1 Hz, 4 H), 7.14 (d, J = 8.3 Hz, 1 H), 7.22 (s, 1 H), 7.69 (d, J = 8.3 Hz, 1 H). 13C NMR (50 MHz, CDCl3): δ = 13.8 (2 C), 21.2, 35.4, 62.8 (2 C), 78.7, 124.6, 128.6, 129.0, 133.7, 142.9, 148.9, 169.5 (2 C). Anal. Calcd for C15H19NO7: C, 55.38; H, 5.89; N, 4.31. Found: C, 55.35; H, 5.94; N, 4.29.
Compound 7a: white needles; mp 112 °C. 1H NMR (200 MHz, CDCl3): δ = 1.28 (t, J = 7.1 Hz, 3 H), 1.43 (s, 3 H), 3.20 (br s, 1 H), 3.42 (s, 2 H), 4.17 (q, J = 7.1 Hz, 2 H), 7.35 (d, J = 8.4 Hz, 1 H), 7.46 (dd, J = 8.4 and 2.1 Hz, 1 H), 7.79 (d, J = 2.1 Hz, 1 H). 13C NMR (50 MHz, CDCl3): δ = 14.0, 26.3, 40.0, 62.5, 74.6, 124.6, 128.9, 132.0, 133.3, 134.2, 151.2, 175.7. Anal. Calcd for C12H14ClNO5: C, 50.10; H, 4.90; N, 4.87. Found: C, 49.99; H, 4.91; N, 5.05.
Compound 7b: white needles; mp 99.6 °C. 1H NMR (200 MHz, CDCl3): δ = 3.71 (s, 2 H), 3.84 (s, 3 H), 7.35 (d, J = 8.4 Hz, 1 H), 7.50 (dd, J = 8.4 and 2.1 Hz, 1 H), 7.83 (d, J = 2.1 Hz, 1 H). 13C NMR (50 MHz, CDCl3): δ = 32.3, 54.5, 77.5, 125.0, 125.7, 128.6, 132.4, 134.4, 134.6, 151.3, 168.9. Anal. Calcd for C11H9ClF3NO5: C, 40.32; H, 2.77; N, 4.28. Found: C, 40.60; H, 2.74; N, 4.24.
Compound 7c: white needles; mp 97 °C. 1H NMR (200 MHz, CDCl3): δ = 1.27 (t, J = 7.1 Hz, 6 H), 3.78 (s, 2 H), 4.23 (q, J = 7.1 Hz, 4 H), 7.44 (m, 2 H), 7.79 (s, 1 H). 13C NMR (50 MHz, CDCl3): δ = 13.9 (2 C), 34.8, 63.0 (2 C), 78.5, 123.9, 124.7, 127.6, 132.1, 133.9, 134.4, 151.4, 169.3. Anal. Calcd for C14H16ClNO7: C, 48.64; H, 4.66; N, 4.05. Found: C, 48.79; H, 4.70; N, 4.15.

13

General Procedure for Reduction-Cyclization Step.
Iron powder (0.70 g, 12.5 mmol) was added over a period of 0.5 h to a stirred solution of 5a-c, 6a-c or 7a-c (0.6 mmol) in glacial HOAc (30 mL) while heating at 110 °C, then the mixture was maintained at 110 °C for 1 h. After filtration on celite the solvent was evaporated under reduced pressure and the residue was neutralized with an aq solution of NaHCO3. The precipitate was filtered, solubilized in EtOH and dried over MgSO4. Evaporation of the solvent and purification by recrystallization from hexane-EtOH (9:1) gave the corresponding 3,4-dihydro-1H-quinolin-2-one (8a-c, 9a-c and 10a-c).
New products:
Compound 8a: white needles; mp 152 °C. 1H NMR (200 MHz, CDCl3): δ = 1.32 (s, 3 H), 2.97 (d, J AB = 15.7 Hz, 1 H), 3.20 (d, J AB = 15.7 Hz, 1 H), 3.85 (br s, 1 H), 6.83 (m, 1 H), 7.04 (m, 1 H), 7.21 (m, 2 H), 8.49 (br s, 1 H). 13C NMR (50 MHz, CDCl3): δ = 25.0, 39.5, 69.6, 115.3, 123.2, 123.7, 127.8, 128.9, 136.0, 175.2. Anal. Calcd for C10H11NO2: C, 67.78; H, 6.26; N, 7.90. Found: C, 66.82; H, 6.19; N, 7.76.
Compound 8b: white solid; mp 214 °C. 1H NMR (200 MHz, DMSO-d 6): δ = 3.13 (d, J AB = 16.6 Hz, 1 H), 3.27 (d, J AB = 16.6 Hz, 1 H), 6.87-7.25 (m, 4 H), 10.70 (br s, 1 H). 13C NMR (50 MHz, DMSO-d 6): δ = 33.3, 71.6, 115.0, 120.1, 122.0, 122.8, 127.7, 128.8, 136.7, 164.6. Anal. Calcd for C10H8F3NO2: C, 51.96; H, 3.49; N, 6.06. Found: C, 51.67; H, 3.65; N, 6.05.
Compound 8c: pink solid; mp 125 °C. 1H NMR (200 MHz, CDCl3): δ = 1.11 (t, J = 7.1 Hz, 3 H), 3.20 (d, J AB = 15.7 Hz, 1 H), 3.51 (d, J AB = 15.7 Hz, 1 H), 4.15 (q, J = 7.1 Hz, 2 H), 4.55 (br s, 1 H), 6.87 (m, 1 H), 7.04 (m, 1 H), 7.17 (m, 2 H), 9.19 (br s, 1 H). 13C NMR (50 MHz, CDCl3): δ = 13.7, 36.2, 62.4, 74.1, 115.7, 121.1, 124.0, 128.0, 128.6, 135.7, 169.1, 170.0. Anal. Calcd for C12H13NO4: C, 61.27; H, 5.57; N, 5.95. Found: C, 61.10; H, 5.58; N, 5.99.
Compound 9a: yellow solid; mp 218.9 °C. 1H NMR (200 MHz, DMSO-d 6): δ = 1.16 (s, 3 H), 2.21 (s, 3 H), 2.75 (d, J AB = 15.8 Hz, 1 H), 2.91 (d, J AB = 15.8 Hz, 1 H), 5.25 (br s, 1 H), 6.73 (d, J = 7.8 Hz, 1 H), 6.93 (d, J = 7.8 Hz, 1 H), 6.95 (s, 1 H), 10.00 (br s, 1 H). 13C NMR (50 MHz, DMSO-d 6): δ = 20.4, 24.6, 40.1, 68.7, 114.6, 123.0, 127.5, 129.0, 130.8, 135.2, 173.0. Anal. Calcd for C11H13NO2: C, 69.09; H, 6.85; N, 7.32. Found: C, 69.24; H, 6.81; N, 7.43.
Compound 9b: white needles; mp 256.7 °C. 1H NMR (200 MHz, DMSO-d 6): δ = 2.21 (s, 3 H), 3.14 (d, J AB = 16.6 Hz, 1 H), 3.21 (d, J AB = 16.6 Hz, 1 H), 6.76 (d, J = 7.9 Hz, 1 H), 6.95 (s, 1 H), 7.01 (d, J = 7.9 Hz, 1 H), 10.59 (br s, 1 H). 13C NMR (50 MHz, DMSO-d 6): δ = 20.8, 33.7, 71.9, 115.2, 120.2, 125.1, 128.4, 129.5, 132.1, 134.6, 164.8. Anal. Calcd for C11H10F3NO2: C, 53.88; H, 4.11; N, 5.71. Found: C, 53.69; H, 3.97; N, 5.71.
Compound 9c: yellow solid; mp 210 °C. 1H NMR (200 MHz, DMSO-d 6): δ = 1.10 (t, J = 7.1 Hz, 3 H), 2.21 (s, 3 H), 2.95 (d, J AB = 16.0 Hz, 1 H), 3.29 (d, J AB = 16.0 Hz, 1 H), 4.08 (q, J = 7.1 Hz, 2 H), 6.34 (br s, 1 H), 6.76 (d, J = 8.5 Hz, 1 H), 6.95 (d, J = 8.5 Hz, 1 H), 6.97 (s, 1 H), 10.35 (br s, 1 H). 13C NMR (50 MHz, DMSO-d 6): δ = 14.0, 20.4, 36.7, 61.1, 75.5, 114.9, 121.0, 127.8, 129.0, 131.3, 134.7, 167.6, 171.0. Anal. Calcd for C13H15NO4: C, 62.64; H, 6.07; N, 5.62. Found: C, 62.50; H, 6.05; N, 5.95.
Compound 10a: white solid; mp 219 °C. 1H NMR (200 MHz, DMSO-d 6): δ = 1.19 (s, 3 H), 2.82 (d, J AB = 15.6 Hz, 1 H), 2.93 (d, J AB = 15.6 Hz, 1 H), 5.42 (br s, 1 H), 6.87 (d, J = 2.1 Hz, 1 H), 6.95 (dd, J = 8.0 and 2.1 Hz, 1 H), 7.17 (d, J = 8.0 Hz, 1 H), 10.21 (br s, 1 H). 13C NMR (50 MHz, DMSO-d 6): δ = 24.4, 39.5, 68.4, 114.2, 121.5, 122.2, 130.1, 131.3, 139.2, 172.8. Anal. Calcd for C10H10ClNO2: C, 56.75; H, 4.76; N, 6.62. Found: C, 56.61; H, 4.75; N, 7.03.
Compound 10b: white needles; mp 227 °C. 1H NMR (200 MHz, DMSO-d 6): δ = 3.21 (d, J AB = 16.6 Hz, 1 H), 3.27 (d, J AB = 16.6 Hz, 1 H), 6.92 (d, J = 2.1 Hz, 1 H), 7.03 (dd, J = 8.1 and 2.1 Hz, 1 H), 7.16 (br s, 1 H), 7.28 (d, J = 8.1 Hz, 1 H), 10.81 (br s, 1 H). 13C NMR (50 MHz, DMSO-d 6): δ = 32.7, 71.4, 114.5, 119.2, 122.4, 124.6, 130.4, 131.8, 138.2, 164.5. Anal. Calcd for C10H7ClF3NO2: C, 45.22; H, 2.66; N, 5.27. Found: C, 45.50; H, 2.53; N, 5.25.
Compound 10c: white needles; mp 136.7 °C. 1H NMR (200 MHz, DMSO-d 6): δ = 1.10 (t, J = 7.1 Hz, 3 H), 3.02 (d, J AB = 16.3 Hz, 1 H), 3.31 (d, J AB = 16.3 Hz, 1 H), 4.10 (q, J = 7.1 Hz, 2 H), 6.52 (br s, 1 H), 6.90 (d, J = 2.1 Hz, 1 H), 6.99 (dd, J = 8.0 and 2.1 Hz, 1 H), 7.20 (d, J = 8.0 Hz, 1 H), 10.85 (br s, 1 H). 13C NMR (50 MHz, DMSO-d 6): δ = 14.0, 36.1, 61.2, 74.3, 114.5, 120.3, 122.0, 130.1, 131.6, 138.7, 167.8, 170.7. Anal. Calcd for C12H12ClNO4: C, 53.44; H, 4.49; N, 5.19. Found: C, 53.52; H, 4.44; N, 5.17.