1,1′-{1,4-Phenylene bis[3-(6-chloro-2-methyl-4-phenylquinolin-3-yl)-4,5-dihydro-1H-pyrazole-5,1-diyl]}dibutan-1-one

Abstract

A new polycyclic compound, 1,1′-{1,4-phenylene bis[3-(6-chloro-2-methyl-4-phenylquinolin-3-yl)-4,5-dihydro-1H-pyrazole-5,1-diyl]}dibutan-1-one (3) has been synthesized by cyclocondensation of (2E,2′E)-1,1′-bis(6-chloro-2-methyl-4-phenylquinolin-3-yl)-3,3′-(1,4-phenylene)diprop-2-en-1-one (2) and hydrazine hydrate in butanoic acid. The structure of this compound was established by elemental analysis, ¹H-NMR, ¹³C-NMR, mass and IR spectroscopy.

1. Introduction

Quinoline nucleus is an important pharmacophore found in a large number of natural products and synthetic compounds with a wide range of applications. Indeed quinoline derivatives are some of the oldest compounds which have been utilized for the treatment of a variety of diseases; the bark of Cinchona plants containing quinine has been utilized to treat palpitations [1]. Compounds containing quinoline motif are most widely used as antimalarials [2], antibacterials [3], antifungals [4] and anticancer agents [5]. On the other hand, the pyrazoline moiety is an important nitrogen-containing 5-membered heterocyclic compound and various synthetic methods for their preparation have been reported [6]. Numerous pyrazoline derivatives have been found to possess considerable biological activities, which has stimulated the research activity in this field. They have several prominent effects, such as antimicrobial [7], antimycobacterial [8], anti-inflammatory, analgesic [9] and antiamoebic activity [10]. 2-Pyrazolines seem to be the most frequently studied pyrazoline type compounds. As a result, a large number of 2-pyrazolines using different synthetic methods for their preparation have been described in the chemistry literature. An especially popular procedure is based on the reaction of α,β-unsaturated ketones with hydrazines [11,12,13]. The coupling of this chemical entity with a quinoline unit might be considered to have some biological activities. Here we are reporting a novel bis[3-(quinol-3-yl)pyrazoline] prepared by cyclocondensation of the known (2E,2′E)-1,1′-bis(6-chloro-2-methyl-4-phenylquinolin-3-yl)-3,3′-(1,4-phenylene)diprop-2-en-1-one (2) in presence of hydrazine hydrate (Scheme 1).

2. Experimental Section

2.1. General Methods

The starting materials were generally used as received (Acros, Fontenay-sous-Bois, France) without any further purification. Melting points were determined on an electrothermal capillary fine-control apparatus and are uncorrected. All IR spectra were performed on Shimadzu FT-IR-8201 PC spectrophotometer (Constantine, Algeria) and only significant absorption-band frequency is cited. ¹H-NMR and ¹³C-NMR spectra were recorded in deuterated chloroform on a Brüker Avance DPX 250 spectrometer (Constantine, Algeria) at 250 MHz for proton and at 62.9 MHz for ¹³C. Chemical shifts are given in ppm and J values in Hertz (Hz). The mass spectrum was scanned on a Shimadzu GCMS-QP2010 and the elemental analysis was obtained using a LECO CHNS-900 elemental analyzer (Lyon, France) and the values are within ±0.4% of the theoretical values.

3-Acetyl-6-chloro-2-methyl-4-phenylquinoline (1) has been synthesized in accordance with established methods [14]. Spectroscopic results and physical properties are in agreement with literature reports [15,16].

2.2. Synthesis of 1,1′-{1,4-phenylene bis[3-(6-chloro-2-methyl-4-phenylquinolin-3-yl)-4,5-dihydro-1H-pyrazole-5,1-diyl]}dibutan-1-one (3)

A solution of 3-acetyl-6-chloro-2-methyl-4-phenylquinoline (2.00 g, 6.7682 mmol, 2 eq.) and terephthalaldehyde (0.4568 g, 3.3841 mmol, 1 eq.) in an ethanolic solution of NaOH 10% (1.0 g in 10 mL of ethanol) was stirred for 8 h at room temperature. The solution was poured into ice cold water and solution was adjusted to pH ~ 2 by HCl (1 N). The solid was separated off and then dissolved in CH₂Cl₂. The organic layer was washed with a saturated solution of NaHCO₃ and the solvent was evaporated to dryness. The residue was recrystallized from ethyl acetate/petroleum ether (1/1) solution to give the intermediate compound (2), m.p.: ˃300 °C, yield: 75%. Compound 2 is known in literature [17] and its structure has been confirmed by spectroscopic methods. Next, the title compound (3) was prepared by heating (2E,2′E)-1,1′-Bis(6-chloro-2-methyl-4-phenylquinolin-3-yl)-3,3′-(1,4-phenylene)diprop-2-en-1-one 2 (1.0 g, 0.0014 mol) and hydrazine hydrate (0.1451 g, 0.0029 mol) in butanoic acid (20 mL) at 115–120 °C for 6 h. After completion, the solution was cooled, and then poured onto ice. The resulting solid was filtered, washed with water, dried, and then recrystallized from chloroform/ethyl acetate mixture (1:1).

White powder; (50% EtOAc in CH₃Cl, R_f = 0.46); Yield: 86%; m.p. ˃ 300 °C.

HRMS (ESI): [M + H]⁺ calculated for C₅₂H₄₇Cl₂N₆O₂ = 857.3138; found 857.3126.

IR (KBr) v_max cm⁻¹: 1639.4 (C=O ketone), 1566.1 (C=N pyrazoline).

¹H-NMR (250 MHz, CDCl₃) δ: 8.66 (d, J = 8.4 Hz, 2H, H-8 quinoline), 8.28 (dd, J = 8.4 Hz, J = 1.7 Hz, 2H, H-7 quinoline), 8.07-7.91 (m, 10H, H-Ar), 7.87–7.79 (m, 4H, H-Ar), 7.21 (s, 4H, phenylene), 5.86 (dd, J = 12.0 Hz, J = 5.0 Hz, 2H, H-5 pyrazoline), 3.64 (dd, J = 18.4 Hz, J = 12.0 Hz, 2H, H-4 pyrazoline), 3.36 (s, 6H, 2CH₃), 3.33-3.16 (m, 4H, 2CH₂), 2.98 (dd, J = 18.4 Hz, J = 5.0 Hz, 2H, H-4′ pyrazoline), 2.12–2.35 (m, 4H, 2CH₂), 1.52 (t, J = 7.5 Hz, 6H, 2CH₃).

¹³C-NMR (62.9 MHz, CDCl₃) δ: 171.82 (2CO), 156.55 (2C, C2 quinoline), 154.07(2C, C3 pyrazoline), 148.43, 147.52, 140.72, 135.67, 130.48, 130.02, 129.60, 128.87, 128.76, 128.65, 126.64, 126.48, 126.04, 125.80, 124.68 (C, CH phenyl and quinoline, 34C), 59.28 (2CH, C5 pyrazoline), 46.30 (2CH₂, C4 pyrazoline), 36.42 (2CH₂), 24.87 (2CH₂), 18.77 (2CH₃), 14.10 (2CH₃).

Anal. calcd. For C₅₂H₄₆Cl₂N₆O₂: C, 72.80; H, 5.40; N, 9.80; Found C, 72.82; H, 5.39; N, 9.83.

Copies of these spectra should be provided in the Supplementary Materials.