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

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

References

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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.