1-(4-Chlorophenyl)-2-methyl-2-phenyl-5-(thiophen-2-yl)-1,2-dihydro-3H-pyrrol-3-one

Abstract

1-(4-Chlorophenyl)-2-methyl-2-phenyl-5-(thiophen-2-yl)-1,2-dihydro-3H-pyrrol-3-one, was synthesized for the first time in 75% yield by the base-catalyzed intramolecular cyclization of 4-((4-chlorophenyl)amino)-4-phenyl-1-(thiophen-2-yl)pent-2-yn-1-one. The starting aminoacetylenic ketone was prepared by cross-coupling of available propargylamines with acyl chlorides in the presence of the PdCl₂/CuI/Ph₃P catalytic system.

1. Introduction

Pyrrol-3-ones are one of the most attractive classes of heterocyclic compounds [1,2]. Functional pyrrol-3-ones exhibit pronounced anticancer, antihypertensive, anti-HIV, antiviral, and antimalarial activity [1,2,3,4,5,6]. Their structures are found in such natural compounds as isatin, isatisine, fascaplysin, tryptanthrin, and duocarmycin [2,3,7,8,9]. In addition, pyrrol-3-one derivatives are actively used as flame retardants [10] and ligands for the design of metal complex nanocatalysts [11], as well as building blocks in organic synthesis [2,12].

However, the broader applications of this class of heterocyclic compounds is hampered by the lack of convenient approaches to their synthesis [2], the most synthetically acceptable reactions being intramolecular cyclization [2,13,14,15,16]. This includes the cyclization of aminoacylmalononitriles in the presence of strong acids [2,13], ring-closure of acetylenic ketones containing an amide group with the use of palladium and gold salts [2,14,15], and the aminolysis of chloroenaminines [16]. Therefore, the search for alternative methods for the preparation of pyrrol-3-ones is an important task.

Here, we have reported a direct method for the synthesis of 1-(4-chlorophenyl)-2-methyl-2-phenyl-5-(thiopheno-2-yl)-1,2-dihydro-3H-pyrrol-3-one by the base-catalyzed intramolecular cyclization of 4-((4-chlorophenyl)amino)-4-phenyl-1-(thiophen-2-yl)pent-2-yn-1-one under mild reaction conditions. The latter became available due to the development of a chemoselective palladium/copper-catalyzed cross-coupling reaction of terminal propargylamines (originally obtained by the addition of gaseous acetylene to available ketimines in the Bu^tOK/DMSO superbasic system [17]) with aromatic and heteroaromatic acyl chlorides (Scheme 1) [18].

2. Results and Discussion

The intramolecular cyclization of 4-((4-chlorophenyl)amino)-4-phenyl-1-(thiophen-2-yl)pent-2-yn-1-one (1) is performed in the presence of 0.5 equivalents of KOH in ethanol solution at 40–45 °C for 8 h (Scheme 2). The target 1-(4-chlorophenyl)-2-methyl-2-phenyl-5-(thiophen-2-yl)-1,2-dihydro-3H-pyrrol-3-one (2) has been obtained in 75% yield.

The reaction was monitored by both thin-layer chromatography (TLC) and IR spectroscopy through the disappearance of the absorption band of the triple bond of the starting aminoacetylenic ketone 1 in the region of ~2240 cm⁻¹.

The structure of the target product 2 was confirmed by the use of ¹H, ¹³C NMR, and IR spectroscopy (see Supplementary Materials). The assignment of 1,2-dihydro-3H-pyrrol-3-one 2 characteristic signals was performed using 2D homo- and heteronuclear HMBC, HSQC, COSY, and NOESY NMR spectroscopy.

The characteristic singlet of the pyrrolone ring H4 is present in the region of 5.71 ppm in the ¹H NMR spectrum, while the signal of the Me group appears in the form of a singlet in the region of 1.59 ppm. In the ¹³C NMR spectrum, the pyrrolone ring appears as separate C2, C4, and C5 signals at 75.7, 99.1, and 167.3 ppm, respectively. The C=O group signal has a characteristic shift value of 201.8 ppm.

In the 2D NOESY spectrum (Figure 1), the protons of the methyl group in position 2 of the pyrrolone ring give cross peaks both with the ortho-protons of the phenyl group in the same 2-position and with the H2′,6′ of protons the aromatic group at the nitrogen atom. This indicates that the Me and aryl groups are on the same side of the five-membered 3H-pyrrol-3-one cycle. In addition, the NOESY spectrum contains a cross peak between the H4 of the pyrrolone ring and the H3″ of the thienyl ring.

The IR spectrum reveals the characteristic bands of the C-Cl group (1092 and 836 cm⁻¹), a C=O bond (1680 cm⁻¹), and a C=C double aromatic and heteroaromatic ring (1650–1504 cm⁻¹). Symmetric and asymmetric C-N stretching bands cannot be assigned because they overlap with the absorption bands of the aromatic and heteroaromatic rings. Moreover, in the IR spectrum of the resulting 3H-pyrrol-3-one 2, there are no characteristic absorption bands of the C≡C and N-H bonds of the starting 4-((4-chlorophenyl)amino)-pent-2-yn-1-one 1 in the regions of 3309 and 2216 cm^–1, respectively.

The cyclization of aminoacetylenic ketone 1 probably starts with the addition of a water molecule to afford the rearrangement of enol A to 1,3-diketone B (Scheme 3). The latter undergoes ring closure by the attack of NH moiety at the remote carbonyl group to give hydroxypyrrolidinone C, which produces pyrrolone 2 after the elimination of water.

It should be noted that the reaction does not occur without potassium hydroxide. At the same time, an increase in the amount of the base to one equivalent led to a decrease in the preparative yield of the target product 2 because of more intense resinification of the reaction mixture due to the polymerization of the initial electron-deficient acetylene 1.

In aprotic solvents such as dioxane, DMSO, and MeCN, the reaction proceeded too slowly (96 h in dioxane, 50 h in MeCN) or resulted in a much lower yield (40% in dioxane and MeCN, 62% in DMSO) than in aqueous ethanol. In ethyl acetate, the reaction did not give the target product at all. These results confirm that the presence of water is required for the successful synthesis of pyrrolone 2 and that in the “anhydrous” medium, the reaction proceeded only with the participation of the trace water always present in the aforementioned solvents.

In conclusion, using the base-catalyzed cyclization of 4-((4-chlorophenyl)amino)-4-phenyl-1-(thiophen-2-yl)pent-2-yn-1-one, we implemented a convenient method for the synthesis of 1-(4-chlorophenyl)-2-methyl-2-phenyl-5-(thiophen-2-yl)-1,2-dihydro-3H-pyrrol-3-one, a representative of a highly in-demand class of heterocyclic compounds with promising pharmacological activity.

3. Materials and Methods

General. The ¹H and ¹³C NMR spectra were recorded on a Bruker DPX 400 and Bruker AV-400 spectrometer (400.13 and 100.62 MHz, respectively) in CDCl₃ solution and referenced to HMDS (¹H, ¹³C). The assignment of signals in ¹H spectra was performed using 2D homonuclear correlation methods COSY and NOESY. Resonance signals of ¹³C were assigned by applying 2D heteronuclear correlation methods HSQC and HMBC. FT-IR spectra were obtained with a Varian 3100 FT-IR spectrometer in vaseline oil. Mass spectra were recorded on an Agilent 6210 HRMS−TOF−ESI mass spectrometer with electrostatic sputtering and registration of positive ions. Sample solvent was MeCN with the addition of 0.1% HCOOH and with the addition of calibration mixture for mass spectrometer. Melting points were determined on a Kofler hot stage apparatus.

1-(4-Chlorophenyl)-2-methyl-2-phenyl-5-(thiophen-2-yl)-1,2-dihydro-3H-pyrrol-3-one (2). To a solution of aminoacetylenic ketone 1 (0.365 g, 1.0 mmol) in EtOH (2 mL), KOH (0.033 g, 0.5 mmol) was added. The mixture was stirred under an argon atmosphere at 40–45 °C for 8 h (see also Scheme 2). After completion of the reaction (TLC monitoring, eluent: toluene/Et₂O, 1:2), the solvent was removed under reduced pressure, the residue was purified by column chromatography on SiO₂ (eluent: toluene/Et₂O, 1:2), and the solution was dried in vacuo to obtain the corresponding pyrrolone 2 (0.273 g, 75%) as a light-brown solid. R_f = 0.50 (toluene/Et₂O = 1:2); m.p. 117–118 °C; IR (oil): 3087, 3051, 2953, 2923, 2854, 2725, 2360, 1898, 1666, 1650, 1540, 1529, 1489, 1460, 1407, 1377, 1365, 1339, 1293, 1247, 1225, 1205, 1143, 1089, 1064, 1013, 973, 921, 879, 846, 833, 793, 784, 769, 756, 722, 699, 652, 578, 553, 520, 494, 480, 461 cm⁻¹; ¹H NMR (400.13 MHz, CDCl₃): δ 7.46 (dd, ³J_5″-4″ = 5.0 Hz, ⁴J_5″-3″ = 1.6 Hz, 1H, H5″), 7.31–7.38 (m, 5H, Ho,m,p), 7.17–7.13 (m, 2H, H3′,5′), 7.16 (d, ³J_3″-4″ = 3.9 Hz, 1H, H3″), 6.99 (dd, ³J_4″-3″ = 3.9 Hz, ³J_4″-5″ = 5.0 Hz, 1H, H4″), 6.78–6.74 (m, 2H, H2′,6′), 5.71 (s, 1H, H4), 1.59 (s, 3H, 2-Me); ¹³C{¹H} NMR (100.62 MHz, CDCl₃): δ 201.8 (C=O), 167.3 (C5), 138.7 (Ci), 137.6 (C4′), 133.3 (C1), 132.0 (C2″), 131.6 (C3″), 131.0 (C5″), 129.6 (C2′,6′), 129.3 (C3′,5′), 128.8 (Cm), 128.1 (Cp), 127.8 (C4″), 126.3 (Co), 99.1 (C4), 75.7 (C2), 20.3 (2-Me); HRMS (ESI-TOF) calcd for [C₂₁H₁₆ClNOS + H]⁺: 366.0719, found 366.0717.