N-{2-[3-(3-Formyl-2-oxoquinolin-1(2H)-yl)prop-1-ynyl]phenyl}acetamide

Abstract

The title compound, N-{2-[3-(3-formyl-2-oxoquinolin-1(2H)-yl)prop-1-ynyl]phenyl}acetamide was synthesized in high yield by Sonogashira cross coupling of 2-oxo-1-(prop-2-ynyl)-1,2-dihydroquinoline-3-carbaldehyde with N-(2-iodophenyl)acetamide. The structure of the compound was fully characterized by IR, ¹H-NMR, ¹³C-NMR, Mass spectral analysis and elemental analysis.

The usefulness of 2-quinolone framework has been well demonstrated in the development of a broad range of pharmacologically active compounds including antibacterial, antiulcer, anti HIV, anti-allergic, anti-inflammatory and antifungal agents [1,2,3,4,5,6,7]. In continuation of our efforts to identify novel small molecules of potential pharmacological interest, we have recently reported the synthesis and PDE4 inhibitory properties of 2-quinolone derivatives [8]. In further continuation of our earlier work, we now report the synthesis of a novel analogue i.e., N-{2-[3-(3-formyl-2-oxoquinolin-1(2H)-yl)prop-1-ynyl]phenyl}acetamide. The alkynylation of iodoarenes via C-C bond forming reaction under Pd-Cu catalysis (the Sonogashira coupling) [9] was used in our earlier synthesis [8]. The methodology offered a very convenient, mild and one-step process for the direct coupling of terminal alkynes with iodoarene to provide the desired internal alkynes of medicinal value [10]. We adopted the same strategy for the preparation of our present target molecule and the corresponding synthesis is shown in Scheme 1.

Preparation of N-{2-[3-(3-formyl-2-oxoquinolin-1(2H)-yl)prop-1-ynyl]phenyl}acetamide

To a solution of N-(2-iodophenyl)acetamide (2) (2.96 g, 11.36 mmol) in THF (20 mL) and DMF (4 mL) were added diisopropylethyl amine (2.44 g, 18.92 mmol), Pd(OAc)₂ (0.21 gm, 0.946 mmol) and copper iodide (0.18 g, 0.946 mmol). The mixture was stirred for 15 min at room temperature. Then the terminal alkyne i.e., 2-oxo-1-(prop-2-ynyl)-1,2-dihydroquinoline-3-carbaldehyde (1) [11] (2.0 g, 9.46 mmol) was added. The reaction mixture was heated to reflux for 28 h and the progress of the reaction was monitored by checking TLC (thin layer chromatography) at a regular interval. After completion, the reaction mixture was concentrated under reduced pressure to afford the crude product that was purified by column chromatography using cyclohexane/ethyl acetate (9.5:0.5) to give the title compound 3.

The compound 3 was well characterized by spectral data. In the ¹H-NMR spectrum (DMSO-d₆ as a solvent), two characteristic singlets appeared at δ 10.50 and 8.40 ppm due to the aldehyde hydrogen and NH hydrogen respectively. The NH signal was confirmed by its disappearance during D₂O exchange experiment. The methylene and methyl group appeared as two singlets at δ 5.36 and 2.17 ppm respectively. In the BB decoupled ¹³C-NMR spectrum of compound 3, the two characteristic signals of acetylenic carbon atoms appeared at δ 83.2 and 83.1 ppm. The appearance of a signal at δ 189.7 ppm confirmed the presence of an aldehyde carbonyl group. The formation of the desired compound 3 was also supported by the mass spectrum which showed molecular ion peak (M+1) at m/z 344.9.

Description of the compound: Pale yellow crystalline powder.

Yield: 75%.

Mp: 220–225 °C.

R_f: 0.4 (Cyclohexane:EtOAc = 3:2).

IR υ_max (KBr cm⁻¹): 3266, 1698, 1648, 1609, 1560.

Mass (ES): m/z 344.9 (M+1, 100%).

¹H-NMR (400 MHz, DMSO-d₆): δ 10.50 (s, 1H, CHO), 8.4 (s, 1H, NH), 7.78–7.66 (m, ArH, 3H), 7.44–7.32 (m, ArH, 5H), 7.20 (s, 1H, ArH), 4.36 (s, 2H), 2.17 (s, 3H).

¹³C-NMR (100 MHz, DMSO-d₆): δ 189.7 (CHO), 168.5, 160.1, 157.0, 142.0, 140.4, 139.8, 134.2, 133.6, 132.2 (2C), 124.7, 123.2, 119.1, 116.1, 115.5, 115.4, 83.2 (acetylenic C), 83.1 (acetylenic C), 54.9 (NCH₂), 24.3 (CH₃).

Anal. calc. for C₂₁H₁₆N₂O₃: C, 73.24, H, 4.68, N, 8.13, O, 13.94; Found: C, 73.21, H, 4.61, N, 8.03.