Ultrasound-Assisted Wittig Reaction for the Synthesis of 3-Substituted 4-Chloroquinolines and Quinolin-4(1<i>H</i>)-ones with Extended <i>π</i>-Conjugated Systems

Frites, Wahiba; Khalfaoui, Massaab; Hammal, Lamouri; Silva, Vera L. M.; Silva, Artur M. S.

doi:https://doi.org/10.1155/2022/4807767

Journal of Chemistry

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Abstract Introduction Materials and Methods Results and Discussion Conclusion Data Availability Conflicts of Interest Acknowledgments Supplementary Materials References Copyright Related Articles

Research Article | Open Access

Volume 2022 | Article ID 4807767 | https://doi.org/10.1155/2022/4807767

Ultrasound-Assisted Wittig Reaction for the Synthesis of 3-Substituted 4-Chloroquinolines and Quinolin-4(1H)-ones with Extended π-Conjugated Systems

Wahiba Frites,¹Massaab Khalfaoui,¹Lamouri Hammal,¹Vera L. M. Silva,²and Artur M. S. Silva²

Academic Editor: Dario Pasini

Received16 Sept 2022

Revised06 Nov 2022

Accepted11 Nov 2022

Published05 Dec 2022

Abstract

3-(Vinyl-/buta-1,3-dien-1-yl/4-phenylbuta-1,3-dien-1-yl)-4-chloro quinolines and quinolin-4(1H)-ones were synthesized by ultrasound-assisted Wittig reaction of the corresponding 4-chloro-3-formylquinoline and 3-formylquinolin-4(1H)-ones with nonstabilized ylides. Ease execution, mild conditions, and high yields make this method exploitable for the generation of libraries of 3-substituted 4-chloroquinolines and quinolin-4(1H)-ones with extended π-conjugated systems. To demonstrate the usefulness of these compounds as precursors for the synthesis of more complex structures, 3-vinylquinolin-4(1H)-ones were used as dienes in the Diels–Alder reaction with N-methylmaleimide to produce novel acridone derivatives. The attempted Diels–Alder reaction with 3-(buta-1,3-dien-1-yl)quinolin-4(1H)-one did not afford the expected cycloadduct; instead, 2-methyl-2H-pyrano[3,2-c]quinoline was obtained. The structures and stereochemistry of the new compounds were established by NMR studies.

1. Introduction

Quinolines (I), also known as 1-azanaphthalene or benzo[b]pyridine, are aromatic nitrogen heterocyclic compounds of natural or synthetic origin (Figure 1). These compounds were first isolated in 1834 by Runge from coal tar, which has remained the main source of commercial quinoline [1]. The reactivity of quinolines as well as their physicochemical and biological properties have always attracted the attention of researchers. For instance, quinolines behave as weak tertiary amine bases, can form salts with acids, and undergo reactions similar to those of pyridine and benzene [2–5]. Moreover, quinolines have been found to possess antimalarial, antibacterial, antifungal, anticancer, and anti-HIV activities [6]. The most common quinoline-related derivatives are the 4-quinolones (II) (or quinolin-4(1H)-ones, Figure 1) [7]. Since the discovery of nalidixic acid in the early 1960s by Lescher and his colleagues, the use and development of 4-quinolones have increased impressively [8–14]. 4-Quinolones consist of an aromatic ring fused with a pyridine ring with a nitrogen atom at position 1 and a ketone group at C-4 [8, 9].

Quinolones and their analogues are ubiquitous in nature and synthetically accessible. They play a very important role in organic synthesis, as evidenced by the huge number of synthetic methods developed to achieve these scaffolds and for their synthetic modifications [15–17], and are well recognized for their remarkable pharmacological activities, such as antibacterial, anti-inflammatory, antifungal, antioxidant, antimalarial, anticancer, and anti-HIV, among other important activities [18, 19]. In particular, 2-vinyl-(III) and 2-alkenyl (IV) derivatives of 4-quinolones (Figure 1), which were identified from a Chinese Pseudomonas aeruginosa isolate, are known to possess interesting antimicrobial activities [20]. Since this discovery, related compounds have been synthesized for biological studies [21], but to the best of our knowledge, studies on the isomeric 3-substituted (3-vinyl and 3-alkenyl) derivatives are rare.

Despite the interesting structure of vinyl- and alkenyl-quinolones, access to these molecules remains very restricted, limiting their use in organic synthesis. As far as we know, only a few studies have been carried out in this field [22–24]. In 2012, Bach and coworkers reported the use of the Wittig reaction in the synthesis of some 3-vinyl- and 3-alkenyl-2-quinolones from 3-formyl-2-quinolone. The exocyclic double bond of the formed product undergoes enantio- and regioselective epoxidation catalyzed by a ruthenium(II) porphyrin [22]. Coppola reported the formation of 3-vinyl-4-quinolones via the Horner reaction of phosphonates with aldehydes [23]. In 2018, Boháč and coworkers described an efficient method for the synthesis of 2H-pyrano[3,2-c]quinolin-2-ones from 3-formyl-4-quinolones and monosubstituted acetic acid. The treatment of the obtained products with a solution of sodium hydroxide led to the formation of 3-(2-arylvinyl)-4-quinolones containing a carboxylic acid group at the β-position [24]. Based on these works, we envisioned that 3-formyl(quinoline and quinolones) (Figure 2) can be suitable substrates for the preparation of their corresponding highly conjugated 3-vinyl and 3-buta-1,3-dien-1-yl derivatives via Wittig reactions with nonstabilized ylides.

The advantages of ultrasound-assisted synthesis over conventional thermal methods, such as high reaction rates, better yields, high purity of the products, and high product selectivity, have been reported in recent publications [25, 26]. Moreover, ultrasound-assisted synthesis is considered more environmentally friendly and cost-effective [27]. In fact, ultrasonic irradiation has been used to assist diverse reactions at ambient temperature [28], in aqueous media [29], or using ionic liquids [30] as an alternative to organic solvents, as well as catalyst-free organic reactions for the synthesis of biologically relevant heterocycles, including the synthesis of dihydroquinolines and diverse fused quinolone derivatives [31]. Therefore, we have also explored the benefits of ultrasound irradiation to promote the Wittig reactions studied in this work.

2. Materials and Methods

2.1. General

Reagents and solvents were purchased as reagent-grade and used without further purification unless otherwise stated. Methyltriphenylphosphonium bromide (CAS 1779-49-3), allyltriphenylphosphonium bromide (CAS 1560-54-9), and cinnamyltriphenylphosphonium bromide (CAS 7310-74-9) were purchased from Sigma-Aldrich. Ethyl 3-formyl-6-methoxyquinolone-1(4H)-carboxylate (2c) was available in our laboratory. Melting points were determined with a Büchi melting point B-540 apparatus and are uncorrected. NMR spectra were recorded with 300 or 500 MHz (300.13 MHz (¹H), 75.47 MHz (¹³C), or 500.16 MHz (¹H), 125.77 MHz (¹³C)) Bruker Avance III NMR spectrometers, with tetramethylsilane (TMS) as the internal reference and CDCl₃ as the solvent, unless otherwise stated. Unequivocal ¹H assignments (δ, ppm) and ¹³C assignments (δ, ppm) were made based on NOESY and 2D HSQC (¹H/¹³C) and HMBC (delays for one-bond and long-range J_C/H couplings were optimised for 145 and 7 Hz, respectively) experiments. Positive-ion electrospray (ESI⁺) mass spectra were performed using a linear ion trap mass spectrometer LXQ (ThermoFinnigan, San Jose, CA). Data acquisition and analysis were performed using the Xcalibur Data System (version 2.0, ThermoFinnigan, San Jose, CA). High-mass-resolving ESI-MS were conducted in a Q-Exactive® hybrid quadrupole Orbitrap® mass spectrometer (Thermo Fisher Scientific, Bremen, Germany). The instrument was operated in positive mode with a spray voltage at 3.0 kV and interfaced with a HESI II ion source. The analysis was performed through direct infusion of the prepared solutions at a flow rate of 10 μL·min⁻¹ into the ESI source, and the operating conditions were as follows: sheath gas (nitrogen) flow rate 5 (arbitrary units), auxiliary gas (nitrogen) 1 (arbitrary units), capillary temperature 320°C, and S-lens rf level 50. Spectra were analysed using the acquisition software Xcalibur version 4.0 (Thermo Scientific, San Jose, CA, USA).

2.2. Preparation Procedure of the Target Compounds 1, 2a-2b

The synthesis of 4-chloroquinoline-3-carbaldehyde (1) was performed following a procedure already reported in the literature [32]. The compound was obtained as a yellow solid with a 66% yield at mp 138-139°C (mp 141-142°C, Lit.) [33]. Structural characterization data (¹H and ¹³C NMR spectra) of this compound are presented in the Electronic Supporting Information (ESI).

The synthesis of 4-oxo-1,4-dihydroquinoline-3-carbaldehyde (2a) was performed following a procedure already reported in the literature [32]. The compound was obtained as a yellow solid in 96% yield, mp 260–275°C (decomposition) (mp ˃ 278°C (decomposition), Lit.) [32]. Structural characterization data (¹H and ¹³C NMR spectra) of this compound are presented in the ESI.

2.2.1. Synthesis of 1-Methyl-4-oxo-1,4-dihydroquinoline-3-carbaldehyde (2b)

NaH (69.1 mg, 2.88 mmol) was added to a stirred suspension of 4-oxo-1,4-dihydroquinoline-3-carbaldehyde (2a) (500 mg, 2.88 mmol) in anhydrous THF (40 mL), and the mixture was stirred at room temperature for 30 min. After that period, excess CH₃I (3.62 ml, 58.2 mmol) was added, and the reaction mixture was stirred for 22 h. Then, it was poured over H₂O (20 mL), ice (20 g), and Et₃N and acidified with HCl to pH 6. The obtained solution was extracted with CHCl₃ (3 × 50 mL), dried with anhydrous Na₂SO_4, and concentrated to dryness. Compound 2b was obtained as a white solid (523 mg, 97% yield), mp 207–209°C ( mp 212-213°C, Lit.) [23]. Structural characterization data (¹H and ¹³C NMR spectra) of this compound are presented in the ESI.

2.2.2. General Procedure for the Wittig Reaction of 4-Chloroquinoline-3-carbaldehyde (1) with Ylides 4a and 4b

A mixture of NaH (2.6 mmol, 62.4 mg) and the appropriate triphenylphosphonium bromide salt (1.3 mmol), in freshly dried THF (10 mL), was stirred in the ultrasound bath under nitrogen for 25–45 min at room temperature; the appearance of a yellow to red color (depending on the triphenylphosphonium bromide salt used) and disappearance of the suspension of the phosphonium salt indicated the ylide formation. Subsequently, 4-chloroquinoline-3-carbaldehyde (1) (0.26 mmol) was added. The mixture was stirred at room temperature until the complete consumption of the starting 4-chloroquinoline-3-carbaldehyde (1). After, the reaction mixture was poured onto ice (20 g) and water (20 mL), and the pH was adjusted to 4-5 with diluted (10%) hydrochloric acid. The organic layer was extracted with CHCl₃ (3 × 50 mL), dried with anhydrous Na₂SO₄ and the organic solvent was evaporated to dryness.

2.2.3. Data for Compound 4-Chloro-3-vinylquinoline (5a)

Yield: 50% (24.7 mg), white solid crystals obtained after purification by TLC (EtOAc/hexane, 6 : 4), mp 91.4°C. ¹H NMR (CDCl₃, 300.13 MHz): δ = 9.06 (s, 1H, H-2), 8.27 (ddd, J 8.3, 1.5, 0.6 Hz, 1H, H-5), 8.10 (dd, J 8.3, 1.2 Hz, 1H, H-8), 7.73 (ddd, J 8.3, 6.9, 1.5 Hz, 1H, H-7), 7.64 (ddd, J 8.3, 6.9, 1.2 Hz, 1H, H-6), 7.24 (dd, J 17.7, 11.3 Hz, 1H, H-α), 6.00 (d, J 17.7 Hz, 1H, H-β), 5.61 (dd, J 11.3, 0.5 Hz, 1H, H-β'). ¹³C NMR (CDCl₃, 75.47 MHz): δ = 148.1 (C-2), 147.8 (C-8a), 139.8 (C-4), 131.0 (C-α), 130.0 (C-7), 129.4 (C-8), 128.2 (C-3), 128.0 (C-6), 126.3 (C-4a), 124.5 (C-5), and 119.0 (C-β). MS (ESI⁺): m/z (%) = 192 (³⁷Cl, 33) [M + H]⁺; 190 (³⁵Cl, 100) [M + H]⁺. HRMS (ESI⁺): m/z [M + H]⁺ calcd for C₁₁H₉ClN: 190.0418; found: 190.0405.

2.2.4. Data for Compound (1Z,3E)-3-(Buta-1,3-dien-1-yl)-4-chloroquinoline (5b)

Yield: 63% (35.3 mg), white crystals obtained after purification by TLC (hexane/EtOAc, 8 : 2 then 7 : 3), mp 85.7°C. ¹H NMR (CDCl₃, 300.13 MHz): δ = 8.86 (s, 1H, H-2), 8.28 (dd, J 8.4, 1.5 Hz, 1H, H-5), 8.11 (d, J 8.4 Hz, 1H, H-8), 7.76 (ddd, J 8.4, 6.9, 1.5 Hz, 1H, H-7), 7.65 (ddd, J 8.4, 6.9, 1.3 Hz, 1H, H-6), 6.74–6.51 (m, 3H, H-γ, H-α, H-β), 5.55–5.48 (m, 1H, H-δ), 5.38–5.30 (m, 1H, H-δ). ¹³C NMR (CDCl₃, 75.47 MHz): δ = 151.2 (C-2), 147.7 (C-8a), 140.6 (C-4), 133.9 (C-β), 132.3 (C-γ), 130.0 (C-7), 129.6 (C-8), 128.9 (C-3), 127.9 (C-6), 126.3 (C-4a), 124.3 (C-α), 124.2 (C-5), and 122.1 (C-δ). MS (ESI⁺): m/z (%) = 218 (³⁷Cl, 33) [M + H]⁺; 216 (³⁵Cl, 100) [M + H]⁺. HRMS (ESI⁺): m/z [M + H]⁺ calcd for C₁₃H₁₁ClN: 216.0575; found: 216.0577.

2.2.5. Data for Compound (1E,3E)-3-(Buta-1,3-dien-1-yl)-4-chloroquinoline (6b)

Yield: 20% (11.2 mg), obtained after purification by TLC (hexane/EtOAc, 8 : 2 then 7 : 3), mp 60°C. ¹H NMR (CDCl₃, 500.16 MHz): δ = 9.09 (s, 1H, H-2), 8.26 (dd, J 8.2, 1.3 Hz, 1H, H-5), 8.09 (d, J 8.4 Hz, 1H, H-8), 7.72 (ddd, J 8.4, 6.9, 1.3 Hz, 1H, H-7), 7.64 (ddd, J 8.2, 6.9, 1.2 Hz, 1H, H-6), 7.12–6.98 (m, 2H, H-α, H-γ), 6.67–6.60 (m, 1H, H-β), 5.54–5.49 (m, 1H, H-δ), 5.36 (d, J 10.0 Hz, 1H, H-δ). ¹³C NMR (CDCl₃, 125.77 MHz): δ = 147.9 (C-2), 147.6 (C-8a), 139.5 (C-4), 136.8 (C-β), 133.9 (C-γ), 129.9 (C-7), 129.6 (C-8), 128.0 (C-6), 127.8 (C-3), 126.4 (C-4a), 126.3 (C-α), 124.5 (C-5), and 120.5 (C-δ). MS (ESI⁺): m/z (%) = 433 (³⁷Cl, 59) [2M + H]⁺, 431 (³⁵Cl, 93) [2M + H]⁺, 218 (³⁷Cl, 38) [M + H]⁺, 216 (³⁵Cl, 100) [M + H]⁺. HRMS (ESI⁺): m/z [M + H]⁺ calcd for C₁₃H₁₁ClN: 216.0575; found: 216.0582.

2.2.6. General Procedure for the Wittig Reaction of 4-Chloroquinoline-3-carbaldehyde (1) with Ylide 4c

A mixture of NaH (1.1 mmol, 26.4 mg) and the appropriate triphenylphosphonium bromide salt 3c (0.55 mmol), in freshly dried THF (10 mL), was stirred in the ultrasound bath under nitrogen for 45 min at room temperature; the appearance of a red to brown color and disappearance of the suspension of the phosphonium salt indicated the ylide formation. Subsequently, 4-chloroquinoline-3-carbaldehyde (1) (0.11 mmol) was added, and the mixture was stirred at room temperature until the complete consumption of the starting material. After, the reaction mixture was poured onto ice (20 g) and water (20 mL), and the pH was adjusted to 4-5 with diluted (10%) hydrochloric acid. The organic layer was extracted with CHCl₃ (3 × 50 mL), dried with anhydrous Na₂SO₄ and the organic solvent was evaporated to dryness.

2.2.7. Data for Compound (1Z,3E)-4-Chloro-3-(4-phenylbuta-1,3-dien-1-yl)quinoline (5c)

Yield: 60% (19.2 mg), obtained after purification by TLC (hexane/EtOAc, 8 : 2), mp 108-109°C. ¹H NMR (CDCl₃, 300.13 MHz): δ = 8.98 (s, 1H, H-2), 8.29 (dd, J 8.3, 1.5 Hz, 1H, H-5), 8.13 (dd, J 8.4, 1.3 Hz, 1H, H-8), 7.77 (ddd, J 8.4, 6.9, 1.5 Hz, 1H, H-7), 7.66 (ddd, J 8.3, 6.9, 1.3 Hz, 1H, H-6), 7.38 (dd, J 8.2, 1.7 Hz, 2H, H-2′, 6′), 7.33–7.21 (m, 3H, H-4′, 3′, 5′), 7.20–7.06 (m, 1H, H-γ), 6.83 (d, J 15.4 Hz, 1H, H-δ), 6.71 (dd, J 5.1, 1.7 Hz, 2H, H-α, H-β). ¹³C NMR (CDCl₃, 75.47 MHz): δ = 151.2 (C-2), 147.7 (C-8a), 140.6 (C-4), 137.2 (C-δ), 136.6 (C-1′), 133.5 (C-β), 130.0 (C-7), 129.7 (C-8), 129.2 (C-3), 128.8 (C-3′, 5′), 128.3 (C-4′), 127.9 (C-6), 126.9 (C-2′, 6′), 126.5 (C-4a), 124.2 (C-5), 124.0, and 123.9 (C-α and C-γ). MS (ESI⁺): m/z (%) = 294 (³⁷Cl, 29) [M + H]⁺; 292 (³⁵Cl, 87) [M + H]⁺. HRMS (ESI⁺): m/z [M + H]⁺ calcd for C₁₉H₁₅ClN: 292.0888; found: 292.0874.

2.2.8. Data for Compound (1E,3E)-4-Chloro-3-(4-phenylbuta-1,3-dien-1-yl)quinoline (6c)

Yield: 39% (12.4 mg), yellow crystals obtained after purification by TLC (hexane/EtOAc, 8 : 2), mp 151–153°C. ¹H NMR (CDCl₃, 300.13 MHz): δ = 9.03 (s, 1H, H-2), 8.14 (dd, J 8.4, 1.4 Hz, 1H, H-5), 7.97 (dd, J 8.4, 1.2 Hz, 1H, H-8), 7.60 (dt, J 8.4, 6.9, 1.4, 1H, H-7), 7.52 (td, J 8.4, 6.9, 1.2 Hz, 1H, H-6), 7.38 (dd, J7.7, 1.5 Hz, 2H, H-2′, 6′), 7.26 (t, J 7.7 Hz, 2H, H-3′, 5′), 7.17 (tt, J 7.7, 1.5 Hz, 1H, H-4′), 7.11–7.03 (m, 2H, H-α, H-β), 6.96 (ddd, J 15.1, 6.1, 3.9 Hz, 1H, H-γ), 6.72 (d, J 15.1, 1H, H-δ). ¹³C NMR (CDCl₃, 75.47 MHz): δ = 148.0 (C-2), 147.6 (C-8a), 139.0 (C-4), 136.8 (C-1′), 135.6 (C-δ), 133.5 (C-β), 129.7 (C-7), 129.6 (C-8), 128.8 (C-3′, 5′ and C-γ), 128.2 (C-4′), 128.1 (C-3), 128.0 (C-6), 126.8 (C-2′, 6′), 126.5 (C-4a), 126.0 (C-α), and 124.5 (C-5). MS (ESI⁺): m/z (%) = 294 (³⁷Cl, 32) [M + H]⁺; 292 (³⁵Cl, 100) [M + H]⁺. HRMS (ESI⁺): m/z [M + H]⁺ calcd for C₁₉H₁₅ClN: 292.0888; found: 292.0874.

2.2.9. General Procedure for the Wittig Reaction of 4-Oxo-1,4-dihydroquinoline-3-carbaldehyde (2a) and 1-Methyl-4-oxo-1,4-dihydroquinoline-3-carbaldehyde (2b) with Ylides 4a–4c

A mixture of NaH (10 equiv) and the appropriate triphenylphosphonium bromide salt (5 equiv) in freshly dried THF (25 mL) was stirred in the ultrasound bath under nitrogen for 45–90 min (depending on the triphenylphosphonium bromide salt used) at room temperature. The appearance of an orange, red, brown, or yellow color and the disappearance of the suspension of the phosphonium salt indicated ylide formation. Subsequently, 4-oxo-1,4-dihydroquinoline-3-carbaldehyde (2a) (0.78 mmol for 7a, 8d and 0.11 mmol for 8f), 1-methyl-4-oxo-1,4-dihydroquinoline-3-carbaldehyde (2b) (0.78 mmol for 7b, 0.39 mmol for 7e, and 0.11 mmol for 7g), or ethyl 3-formyl-6-methoxy-4-oxoquinoline-1(4H)-carboxylate (2c) (0.36 mmol) was added. The mixture was stirred normally at room temperature until the total consumption of the starting material was reached. After, the reaction mixture was poured onto ice (20 g) and water (20 mL), and the pH was adjusted to 4-5 with dilute (10%) hydrochloric acid. The organic layer was extracted with CHCl₃ (3 × 50 mL), dried with anhydrous Na₂SO₄ and the organic solvent was evaporated to dryness.

2.2.10. Data for Compound 3-Vinylquinolin-4(1H)-one (7a)

Yield: 97% (130 mg), white crystals obtained after purification by TLC (CHCl₃/acetone, 8 : 2), mp 210.2°C. ¹H NMR (CD₃OD, 300.13 MHz): δ = 8.32 (ddd, J 8.2, 1.5, 0.6 Hz, 1H, H-5), 8.17 (s, 1H, H-2), 7.69 (ddd, J 8.3, 6.9, 1.5 Hz, 1H, H-7), 7.57 (d, J 8.3 Hz, 1H, H-8), 7.42 (ddd, J 8.2, 6.9, 1.2 Hz, 1H, H-6), 6.90 (dd, J 17.8, 11.4 Hz, 1H, H-α), 6.00 (dd, J 17.8, 1.8 Hz, 1H, H-β), and 5.24 (dd, J 11.4, 1.8 Hz, 1H, H-β′). ¹³C NMR (CD₃OD, 75.47 MHz): δ = 176.9 (C-4), 139.1 (C-8a), 137.5 (C-2), 131.7 (C-7), 130.2 (C-α), 125.4 (C-4a), 125.2 (C-5), 123.9 (C-6), 118.4 (C-3), 118.0 (C-8), and 112.4 (C-β). MS (ESI⁺): m/z (%) = 172 (100) [M + H]⁺. HRMS (ESI⁺): m/z [M + H]⁺ calcd for C₁₁H₁₀NO: 172.0757; found: 172.0760.

2.2.11. Data for Compound 1-Methyl-3-vinylquinolin-4(1H)-one (7b)

Yield: 96% (139 mg), obtained after purification by TLC (CH₂Cl₂), 175–235°C (decomposition). ¹H NMR (CDCl₃, 300.13 MHz): δ = 8.47 (dd, J 8.3, 1.7 Hz, 1H, H-5), 7.65–7.59 (m, 1H, H-7), 7.62 (s, 1H, H-2), 7.39–7.34 (m, 2H, H-6,8), 6.78 (dd, J 17.7, 11.3 Hz, 1H, H-α), 6.03 (dd, J 17.7, 1.8 Hz, 1H, H-β), 5.23 (dd, J 11.3, 1.8 Hz, 1H, H-β'), and 3.80 (s, 3H, NCH₃). ¹³C NMR (CDCl₃, 75.47 MHz): δ = 176.2 (C-4), 141.7 (C-2), 139.6 (C-8a), 131.9 (C-7), 130.5 (C-α), 127.2 (C-5), 126.8 (C-4a), 123.8 (C-6), 118.7 (C-3), 115.2 (C-8), 113.6 (C-β), and 40.9 (NCH₃). MS (ESI⁺): m/z (%) = 186 (100) [M + H]⁺.

2.2.12. Data for Compound 6-Methoxy-3-vinylquinolin-4(1H)-one (7c)

Yield: 98% (71 mg), yellow crystals obtained after purification by TLC (EtOAc/acetone, 9 : 1), mp 128–130°C. ¹H NMR (CD₃OD, 300.13 MHz): δ = 8.14 (s, 1H, H-2), 7.72 (d, J 2.9 Hz, 1H, H-5), 7.54 (d, J 9.1 Hz, 1H, H-8), 7.34 (dd, J 9.1, 2.9 Hz, 1H, H-7), 6.93 (dd, J 17.8, 11.4 Hz, 1H, H-α), 5.98 (dd, J 17.8, 1.8 Hz, 1H, H-β), 5.24 (dd, J 11.4, 1.8 Hz, 1H, H-β′), 3.93 (s, 3H, 6-OCH₃). ¹³C NMR (CD₃OD, 75.47 MHz): δ = 176.0 (C-4), 157.0 (C-6), 136.5 (C-2), 133.9 (C-8a), 130.3 (C-α), 126.4 (C-4a), 122.9 (C-7), 119.7 (C-8), 117.5 (C-3), 112.2 (C-β), 103.8 (C-5), and 54.7 (6-OCH₃). MS (ESI⁺): m/z (%) = 202 (100) [M + H]⁺. HRMS (ESI⁺): m/z [M + H]⁺ calcd for C₁₂H₁₂NO₂: 202.0863; found: 202.0869.

2.2.13. Data for Compound (1E,3E)-3-(Buta-1,3-dien-1-yl)quinolin-4(1H)-one (8d)

¹H NMR (CDCl₃, 300.13 MHz): δ = 12.44 (s, 1H, NH), 8.41–8.30 (dd, J 8.2, 1.3 Hz, 1H, H-5), 7.21 (ddt, J 8.2, 6.8, 1.3, 2H, H-6,7), 6.67–6.50 (m, 2H), 6.19 (t, J 11.3 Hz, 1H), 5.08–4.93 (m, 1H), and 5.30–5.17 (m, 1H). ¹³C NMR (CDCl₃, 75.47 MHz): δ = 177.2 (C-4), 139.7, 138.3, 133.3, 133.0, 131.6, 131.3, 129.2, 129.0, 126.0, 125.6, 125.0, 123.3, 118.4, 118.3, 117.9. MS (ESI⁺): m/z (%) = 395 (10) [2M + H]⁺; 198 (100) [M + H]⁺.

2.2.14. Data for Compound (1Z,3E)-3-(Buta-1,3-dien-1-yl)-1-methylquinolin-4(1H)-one (7e)

Yield: 83% (68.4 mg), white crystals obtained after purification by TLC (CH₂Cl₂/acetone, 9 : 1), mp 153.1°C. ¹H NMR (CDCl₃, 300.13 MHz): δ = 8.51 (dd, J 8.4, 1.6 Hz, 1H, H-5), 7.72–7.66 (m, 1H, H-7), 7.66 (br s, 1H, H-2), 7.43–7.38 (m, 2H, H-6,8), 6.75 (dddd, J 16.9, 11.4, 10.1, 1.2 Hz, 1H, H-γ), 6.61 (dt, J 11.4, 1.2 Hz, 1H, H-α), 6.32 (tt, J 11.4, 0.9 Hz, 1H, H-β), 5.38 (ddt, J 16.9, 1.8, 0.9 Hz, 1H, H-δ), 5.25–5.11 (m, 1H, H-δ), 3.85 (s, 3H, NCH₃). ¹³C NMR (CDCl₃, 75.47 MHz): δ = 176.5 (C-4), 143.0 (C-2), 139.9 (C-8a), 133.0 (C-γ), 132.0 (C-7), 129.8 (C-β), 127.0 (C-5), 126.3 (C-4a), 124.1 (C-α), 123.7 (C-6), 119.0 (C-δ), 118.5 (C-3), 115.4 (C-8), 40.9 (NCH₃). MS (ESI⁺): m/z (%) = 212 (100) [M + H]⁺. HRMS (ESI⁺): m/z [M + H]⁺ calcd for C₁₄H₁₄NO: 212.1070; found: 212.1056.

2.2.15. Data for Compound (1E,3E)-3-(4-Phenylbuta-1,3-dien-1-yl)quinolin-4(1H)-one (8f)

Yield: 96% (28.9 mg), yellow solid obtained after purification by TLC (CHCl₃/acetone, 8 : 2), 292–294°C. ¹H NMR (DMSO-d₆, 300.13 MHz): δ = 12.14 (d, J 6.3 Hz, 1H, NH), 8.24 (d, J 6.3 Hz, 1H, H-2), 8.19 (dd, J 8.2, 1.5 Hz, 1H, H-5), 7.65 (ddd, J 8.4, 6.8, 1.5 Hz, 1H, H-7), 7.59–7.52 (m, 1H, H-8), 7.58–7.48 (m, 1H, H-β), 7.51 (d, J 7.1 Hz, 2H, H-2′, 6′), 7.35 (m, 3H, H-6, H-3′, 5′), 7.28–7.18 (m, 1H, H-4′), 7.05 (dd, J 15.6, 10.8 Hz, 1H, H-γ), 6.78 (d, J 15.6 Hz, 1H, H-α), 6.62 (d, J 15.6 Hz, 1H, H-δ). ¹³C NMR (DMSO-d₆, 75.47 MHz): δ = 175.5 (C-4), 139.0 and 138.9 (C-2 and C-8a), 137.9 (C-1′), 131.9 (C-7), 131.5 (C-γ), 130.6 (C-δ), 129.1 (C-3′, 5′), 129.0 (C-α), 128.3 (C-β), 127.6 (C-4′), 126.5 (C-2′, 6′), 125.9 (C-5), 125.7 (C-4a), 124.0 (C-6), 118.9 (C-8), 117.4 (C-3). MS (ESI⁺): m/z (%) = 547 (100) [2M + H]⁺; 274 (100) [M + H]⁺. HRMS (ESI⁺): m/z [M + H]⁺ calcd for C₁₉H₁₆NO: 274.1226; found: 274.1208.

2.2.16. Data for Compound (1Z,3E)-1-Methyl-3-(4-phenylbuta-1,3-dien-1-yl)quinolin-4(1H)-one (7g)

Yield: 45% (14.1 mg), yellow residue obtained after purification by column chromatography (CH₂Cl₂ and then CH₂Cl₂/acetone 9 : 1), mp 218–220°C. ¹H NMR (CDCl₃, 300.13 MHz): δ = 8.54 (dd, J 8.3, 1.4 Hz, 1H, H-5), 7.72 (s, 1H, H-2), 7.71 (ddd, J 8.3, 7.6, 1.4 Hz, 1H, H-7), 7.44 (d, J 7.6 Hz, 1H, H-8), 7.42–7.34 (m, 1H, H-6), 7.39 (d, J 7.2 Hz, 2H, H-2′, 6′), 7.31 (t, J 7.2 Hz, 2H, H-3′, 5′), 7.22 (m, 1H, H-4′), 7.15 (dd, J 16.0, 11.0 Hz, 1H, H-γ), 6.73 (d, J 16.0 Hz, 1H, H-δ), 6.68 (d, J 11.0 Hz, 1H, H-α), 6.48 (t, J 11.0 Hz, 1H, H-β), 3.88 (s, 3H, NCH₃). ¹³C NMR (CDCl₃, 75.47 MHz): δ = 176.7 (C-4), 143.0 (C-2), 139.9 (C-8a), 137.5 (C-1′), 134.1 (C-δ), 132.2 (C-7), 129.5 (C-β), 128.7 (C-3′,5′), 127.6 (C-4′), 127.5 (C-5), 126.5 (C-2′,6′), 126.3 (C-4a), 125.1 (C-γ), 124.4 (C-α), 123.9 (C-6), 119.2 (C-3), 115.3 (C-8), 41.0 (NCH₃). MS (ESI⁺): m/z (%) = 575 (35) [2M + H]⁺; 288 (100) [M + H]⁺. HRMS (ESI⁺): m/z [M + H]⁺ calcd for C₂₀H₁₈NO: 288.1383; found: 288.1383.

2.2.17. General Procedure for the Diels–Alder Reaction of 3-Vinylquinolin-4(1H)-ones 7a, 7b with N-Methylmaleimide 9

To a solution of the appropriate 3-vinylquinolin-4(1H)-one 7a, 7b (0.29 mmol) in dry toluene (20 mL), N-methylmaleimide 9 (1.45 mmol, 161 mg) was added, and the mixture was heated at reflux for 1.5 h. Then, chloranil (1.45 mmol, 356 mg) was added and the mixture was heated for more 20 h. After that period, the solvent was removed under reduced pressure, and the obtained residue was dissolved in chloroform and purified by thin-layer chromatography.

2.2.18. Data for Compound 2-Methyl-1H-pyrrolo[3,4-c]acridine-1,3,6(2H,11H)-trione (11a)

Yield 37% (30 mg), dark yellow residue obtained after purification by TLC (hexane/acetone, 6 : 4). ¹H NMR (CDCl₃, 300.13 MHz): δ = 9.67 (br s, 1H, NH), 8.80 (d, J 7.9 Hz, 1H, H-5), 8.47 (dd, J 7.4, 1.3 Hz, 1H, H-10), 7.76 (ddd, J 8.3, 7.4, 1.5 Hz, 1H, H-9), 7.66 (d, J 7.9 Hz, 1H, H-4), 7.43 (d, J 8.3 Hz, 1H, H-7), 7.37 (ddd, 1H, J 8.3, 7.4, 1.3 Hz, 1H, H-8), 3.25 (s, 3H, NCH₃). ¹³C NMR (CDCl₃, 75.47 MHz) δ = 177.2 (C-6), 169.7 (C-3), 167.8 (C-1), 140.1 (C-10a), 136.8 (C-11a), 136.2 (C-3a), 135.2 (C-5), 134.8 (C-9), 127.7 (C-10), 125.6 (C-5a), 123.2 (C-8), 122.3 (C-6a), 117.1 (C-7), 115.9 (C-11b), 115.1 (C-4), 29.4 (NCH₃). MS (ESI⁺): m/z (%) = 301(15) [M + Na]⁺; 279 (100) [M + H]⁺. HRMS (ESI⁺): m/z [M + H]⁺ calcd for C₁₆H₁₁N₂O₃: 279.0765; found: 279.0764.

2.2.19. Data for Compound 2,11-Dimethyl-1H-pyrrolo[3,4-c]acridine-1,3,6(2H,11H)-trione (11b)

Yield: 45% (38.1 mg), orange solid obtained after purification by TLC (two elutions with hexane: EtOAc, 7 : 3, then 8 : 2), mp 221-222°C. ¹H NMR (CDCl₃, 500.13 MHz): δ = 8.90 (d, J 7.7 Hz, 1H, H-5), 8.47 (dd, J 8.3, 1.4 Hz, 1H, H-10), 7.82 (ddd, J 8.3, 7.1, 1.7 Hz, 1H, H-9), 7.75 (d, J 7.7 Hz, 1H, H-4), 7.60 (d, J 8.3 Hz, 1H, H-7), 7.40 (ddd, J 8.3, 7.1, 1.4 Hz, 1H, H-8), 4.11 (s, 3H, NCH₃), 3.24 (s, 3H, NCH₃). ¹³CNMR (CDCl₃, 125.77 MHz): δ = 177.5 (C-6), 167.5 (C-1), 167.2 (C-3), 144.6 (C-10a), 141.3 (C-11a), 138.8 (C-3a), 135.4 (C-5), 134.9 (C-9), 128.4 (C-5a), 127.5 (C-10), 123.3 (C-6a), 123.2 (C-8), 118.0 (C-11b), 116.9 (C-7), 115.7 (C-4), 43.9 (NCH₃), 24.4 (NCH₃). MS (ESI⁺): m/z (%) = 293 (18) [M + H]⁺. HRMS (ESI⁺): m/z [M + H]⁺ calcd for C₁₇H₁₃N₂O₃: 293.0921; found: 293.0921.

2.2.20. Data for Compound 2-Methyl-2H-pyrano[3,2-c]quinoline (14)

Yield: 23% (9.0 mg) obtained after purification by TLC (EtOAc/hexane, 3 : 2). ¹H NMR (CDCl₃, 300.13 MHz) δ = 8.49 (s, 1H, H-5), 8.10 (dd, J 8.2, 1.5 Hz, 1H, H-10), 7.96 (dd, J 8.5, 1.1 Hz, 1H, H-7), 7.64 (ddd, J 8.5, 6.9, 1.5 Hz, 1H, H-8), 7.46 (ddd, J 8.2, 6.9, 1.1 Hz, 1H, H-9), 6.53 (dd, J 9.9, 1.7 Hz, 1H, H-4), 5.71 (dd, J 9.9, 3.3 Hz, 1H, H-3), 5.34 (qdd, J 6.6, 3.3, 1.7 Hz, 1H, H-2), 1.57 (d, J 6.6 Hz, 3H, CH₃). ¹³C NMR (CDCl₃, 75.47 MHz) δ = 156.1 (C-10b), 149.4 (C-6a), 148.7 (C-5), 129.7 (C-8), 129.0 (C-7), 125.7 (C-9), 125.4 (C-3), 121.7 (C-10), 120.7 (C-4), 120.1 (C-10a), 111.9 (C-4a), 73.5 (C-2), and 22.0 (CH₃). MS (ESI⁺): m/z (%) = 198 (87) [M + H]⁺. HRMS (ESI⁺): m/z [M + H]⁺ calcd for C₁₃H₁₂NO: 198.0913; found: 198.0901.

3. Results and Discussion

3.1. Chemistry

The Wittig reaction of 4-chloro-3-formylquinoline 1 with methyltriphenylphosphorane 4a was initially attempted using the conditions reported by Seixas et al. for the synthesis of 4-chloro-3-styrylquinolines [32, 33]. In the first step, the methyltriphenylphosphorane was prepared from the reaction of the methyltriphenylphosphonium bromide 3a with 1 molar equiv of sodium hydride (NaH) in freshly dried tetrahydrofuran (THF) at reflux in a nitrogen atmosphere. After the appearance of a yellow color, which is indicative of the formation of the corresponding ylide, the 4-chloro-3-formylquinoline 1 (1 equiv) was added, and the reaction was heated until its complete consumption. However, after the reaction workup, the expected product was not isolated. Wu and coworkers reported that the use of ultrasound in the Wittig reaction contributed to reducing the reaction time and improving the yields [34]. Therefore, it was decided to use ultrasound to promote the Wittig reaction, especially the first step corresponding to the formation of the nonstabilized ylide methyltriphenylphosphorane 4a. In a first attempt, the ultrasound-assisted Wittig reaction of 4-chloro-3-formylquinoline 1 with methyltriphenylphosphorane 4a was performed at room temperature (Scheme 1). Ylide 4a was prepared in situ from the treatment of methyltriphenylphosphonium bromide 3a (5 equiv) with NaH (2 equiv, relatively to the amount of 3a) in freshly dried THF, under a nitrogen atmosphere, in an ultrasound bath for 25–45 min. The appearance of a yellow to brown color and disappearance of the phosphonium salt indicated the formation of the methyltriphenylphosphorane 4a (see Materials and Methods section). Then, 4-chloro-3-formylquinoline 1 (1 equiv) was added, and the reaction was stirred at room temperature for 72 h. After the reaction workup, 4-chloro-3-vinylquinoline 5a was isolated in moderate yield (50%) (Scheme 1). Under similar conditions, the reactions with ylides 4b and 4c were performed (Scheme 1) and afforded a diastereomeric mixture of the corresponding quinoline derivatives, (1Z,3E)-(5b) and (1E,3E)-(6b) 3-(buta-1,3-dien-1-yl)-4-chloroquinoline and (1Z,3E)-(5c) and (1E,3E)-(6c) 4-chloro-3-(4-phenylbuta-1,3-dien-1-yl)quinoline in 83% and 99% overall yield, respectively, but in shorter reaction time (Scheme 1).

The Wittig reaction of 3-formylquinolone 2a with methyltriphenylphosphorane 4a was also carried out with the use of ultrasound. The best conditions found for the formation of the methyltriphenylphosphorane 4a, with sonication, require the use of an excess of NaH (2 equiv, relatively to the amount of 3a) in the reaction with the appropriate phosphonium salt 3a (5 equiv), in freshly dry THF under nitrogen atmosphere (Scheme 2). After the formation of 4a, 3-formyl-4-quinolone (2a, R¹ = R² = H) (1 equiv) was added, and the reaction mixture was stirred at room temperature for about 2 h, giving 3-vinyl-4-quinolone (7a) in a very good yield (97%) after purification by thin layer chromatography (TLC). The reaction of 2a with ylides 4b gave the expected (E,E)-3-(buta-1,3-dien-1-yl)-4-quinolone 8d, but in very low amounts, since several purification procedures were necessary to isolate the compound due to difficulties in separating it from the phosphine oxide formed in the reaction. In turn, the reaction of 2a with ylide 4c gave only the diastereomer (1E,3E)-3-(4-phenylbuta-1,3-dien-1-yl)-4-quinolone 8f in very good yields. The reactions with 1-methyl-3-formyl-4-quinolone (2b, R¹ = CH₃, R² = H) with ylides 4a–c were performed under similar conditions and afforded the expected compounds 7b,e in very good yields and 7g in a moderate yield (Scheme 2). On the other hand, the reaction of ethyl 3-formyl-6-methoxy-4-quinolone-1-carboxylate (2c, R¹ = CO₂Et, R² = OCH₃) with ylide 4a afforded 6-methoxy-3-vinyl-4-quinolone 7c in a 98% yield because of the cleavage of the N-1 carbamate protecting group (Scheme 2).

To demonstrate the synthetic utility of the synthesized 3-vinyl-4-quinolones 7a,b, these compounds were used as dienes in the Diels–Alder reaction with N-methylmaleimide 9 to prepare acridone-type compounds 11a,b (Scheme 3). An excess of N-methylmaleimide (5 equiv) was added to a solution of the 3-vinyl-4-quinolone 7a in toluene, and the mixture was heated at reflux for 45–60 min. After this period, the TLC of the reaction mixture showed complete consumption of the starting material and the formation of cycloadduct 10. So, an excess of chloranil (5 equiv) was added to the reaction mixture to promote the formation of the expected acridone 11a by dehydrogenation of 10a by refluxing the reaction mixture for 22–24 h. Under this protocol, novel 2-methyl-1H-pyrrolo[3,4-c]acridine-1,3,6(2H,11H)-triones (11a,b) were obtained in moderate yields (37–45%).

Encouraged by these results, we then focused our attention on the Diels–Alder reaction of (1E,3E)-3-(buta-1,3-dien-1-yl)-quinolin-4(1H)-one (8d) with N-methylmaleimide 9 (Scheme 4). The analysis of the ¹H NMR spectra of the isolated compound did not match with the structure of the expected cycloadduct 12, but it fits with the structure of 2-methyl-2H-pyrano[3,2-c]quinoline (14) (see NMR Spectroscopy section and ESI). In fact, the formation of this compound can be explained considering the tautomerization of quinolone 8d into the corresponding 4-hydroxyquinoline 13, which after a nucleophilic attack of the hydroxy oxygen atom to the γ-position of the allyl group led to the formation of 14 (Scheme 4). In fact, we have previously reported a similar reaction on the formation of (E)-2-aryl-4-styrylfuro[3,2-c]quinolines from (E,E)-2,3-distyryl-4-quinolones [35, 36].

3.2. NMR Spectroscopy

All the new synthesized compounds have been characterized by 1D (¹H, ¹³C) and 2D (HSQC, HMBC, and NOESY) NMR techniques. The most characteristic signals in the NMR spectra of 4-chloro-1-vinylquinolines 5a–c are due to the resonances of H-2 at high frequency values and of the protons of the 3-substituent. For compound 5a, the resonance of H-2 appears as a singlet at δ_H 9.06 ppm (δ_C 148.1 ppm). For compounds 5b,c and 6b,c, the chemical shift of H-2 is affected by the stereochemistry of the exocyclic double bonds, being more deshielded in the (E,E)-isomers 6b,c (δ_H 9.03–9.09 ppm) than in the (Z,E)-isomers 5b,c (δ_H 8.86–8.98 ppm). Regarding the 3-substituent, in the case of 4-chloro-3-vinylquinoline (5a), three signals were assigned to the vinyl group: a doublet of doublets at δ_H 5.61 ppm due to H-β' (J 11.3, 0.5 Hz), a doublet at 6.00 ppm assigned to H-β (J 17.7 Hz), and a doublet of doublets at δ_H 7.24 ppm due to the resonance of H-α (J 17.7, 11.3 Hz). Additionally, were observed two signals in the ¹³C NMR spectra corresponding to the resonance of C-β at δ_C 119.0 ppm and C-α at δ_C 131.0 ppm.

The most characteristic signals in the NMR spectra of 3-vinyl-4-quinolones 7a–c are due to the 3-vinyl group. Three sets of doublet of doublets were observed; the most protected is due to the resonance of H-β′ at δ_H 5.23–5.24 ppm, followed by the signal of H-β at δ_H 5.98–6.03 ppm and the signal of H-α at δ_H 6.78–6.93 ppm. Depending on the conformation of the double bond, both H-α and H-β can be deprotected by the anisotropic effect of the carbonyl group, as shown in Figure 3. Three different coupling constants were calculated for the protons of the vinyl group: the trans coupling ³J_trans 17.7–17.8 Hz, the cis coupling ³J_cis 11.3–11.4 Hz, and the geminal coupling ²J_gem 1.8 Hz. The strong NOE cross peaks between H-2 and H-β and H-α indicate a free rotation around the C3-Cα bond and explain the high-frequency values of the resonance of H-α and H-β due to the anisotropic deshielding effect of the carbonyl group.

Another typical signal found in the spectra of compounds 7a–c is the singlet due to the resonance of H-2 at high frequency (δ_H 7.62–8.17 ppm; δ_C 136.5–141.7 ppm), due to the inductive and mesomeric deshielding effects of the heterocyclic nitrogen atom and the carbonyl group, respectively. Moreover, in compound 7c, the absence of signals due to the resonance of the protons and carbons of the ethyl carboxylate group of 2c confirms the cleavage of this group in the Wittig reaction conditions.

The most important signals in the NMR spectra of the diastereomers (1Z,3E)-(5b) and (1E,3E)-(6b) 3-(buta-1,3-dien-1-yl)-4-chloroquinoline are the protons’ resonances of the exocyclic double bonds (Figure 4). Although the accurate calculation of the coupling constants ³J_Hα-Hβ and ³J_Hγ-Hδ was difficult because the signals overlapped, some differences were observed when comparing the spectra of 5b and 6b. For example, in the case of 6b, a multiplet was assigned to the H-α and H-γ resonances that appears at higher frequency values (δ_H 6.98–7.12 ppm) than in the diastereomer 5b (δ_H 6.51–6.74 ppm). Moreover, H-2 is more deshielded in 6b (δ_H 9.09 ppm) than in 5b (δ_H 8.86 ppm). For (1Z,3E)-4-chloro-3-(4-phenylbuta-1,3-dien-1-yl]quinoline (5c), the resonance of H-γ (δ_H 7.06–7.20 ppm) appears at high frequency than the other vinylic protons, H-α and H-β (δ_H 6.71 ppm) and H-δ (δ_H 6.83 ppm). The typical coupling constant value of ³J_Hγ ₌ _Hδ 15.4 Hz confirmed the trans-stereochemistry of the C_γ = C_δ double bond. For (1E,3E)-4-chloro-3-(4-phenylbuta-1,3-dien-1-yl]quinoline (6c), the resonance of H-α and H-β (δ_H 7.03–7.11 ppm) appears at higher frequency values than H-γ (δ_H 6.96 ppm) and H-δ (δ_H 6.72 ppm). The coupling constant value ³J_Hγ ₌ _Hδ 15.1 Hz confirms the trans-configuration of this vinylic system. In the ¹H NMR spectra of (1E,3E)-3-(4-phenylbuta-1,3-dien-1-yl)quinolin-4(1H)-one (8f), the resonance of H-β (δ 7.48–7.58 ppm) appears at higher frequency values than the other vinylic protons, H-γ (δ 7.05 ppm), H-α (δ 6.78 ppm), and H-δ (δ 6.62 ppm). The stereochemistry of both vinylic systems was established as trans based on the characteristic coupling constant values (³J_Hα-Hβ 15.6 Hz and ³J_Hγ-Hδ 15.6 Hz). In the ¹H NMR spectrum of (1Z,3E)-1-methyl-3-(4-phenylbuta-1,3-dien-1-yl)quinolin-4(1H)-one (7g), the resonance of H-β (δ 6.48 ppm) appears at lower frequency values than the other vinylic protons, H-α (δ 6.68 ppm), H-δ (δ 6.73 ppm), and H-γ (δ 7.15 ppm). The stereochemistry of both vinylic systems was established as cis, trans-based on the characteristic coupling constant values (³J_Hα-Hβ 11.0 Hz and ³J_Hγ-Hδ 16.0 Hz) and supported by the NOE cross peaks observed in NOESY spectrum (see ESI) of (1Z,3E)-1-methyl-3-(4-phenylbuta-1,3-dien-1-yl)quinolin-4(1H)-one, between H-β and H-δ and this with H-2′, 6′, and also between H-2 and H-γ (Figure 4).

The most characteristic signals in the NMR spectra of 2-methyl-1H-pyrrolo[3,4-c]acridine-1,3,6(2H,11H)-triones 11a,b are as follows: (i) the singlet due to the resonance of the methyl protons of the maleimide unit at δ_H 3.24–3.25 ppm (δ_C 24.4–29.4 ppm); (ii) the doublet at δ_H 7.66–7.75 ppm due to the resonance of H-4; and the doublet at δ_H 8.80–8.90 ppm (H-5) at a higher frequency due to the anisotropic deshielding effect of the carbonyl group. In the ¹³C NMR spectra, it is possible to observe the presence of a signal at δ_C 177.2–177.5 ppm due to the resonance of the carbonyl (C-6) of the acridone and the signals at δ_C 167.5–167.8 and 167.2–169.7 ppm (C-1 and C-3) due to the resonance of the two carbonyl groups of the maleimide moiety.

The formation of the 2-methyl-2H-pyrano[3,2-c]quinoline 14 was corroborated by the most typical signals observed in the NMR spectra: (i) the doublet at δ_H 1.57 ppm (δ_C 22.0 ppm) due to the resonance of the protons of the methyl group; (ii) the signal of H-2 that appears as a quartet of doublet of doublets at δ_H 5.34 ppm (δ_C 73.5 ppm); (iii) the doublet of doublets at δ_H 5.71 ppm (δ_C 125.4 ppm) assigned to the resonance of H-3; (iv) the doublet of doublets at δ_H 6.53 ppm (δ_C 120.7 ppm) due to the resonance of H-4; and (v) the singlet at high frequency, δ_H 8.49 ppm (δ_C 148.7 ppm) assigned to the resonance of H-5. The assignments of C-2 and the quaternary carbons C4a, C-10a, C-6a, and C-10b at δ_C 111.9, 120.1, 149.4, and 156.1 ppm, respectively, were made based on the correlations observed in the HMBC spectra, as shown in Figure 5.

4. Conclusion

In conclusion, 3-substituted 4-chloroquinolines and 4-quinolones with extended π-conjugated systems were synthesized in very good yields by ultrasound-promoted Wittig reaction of the corresponding 4-chloro-3-formylquinoline and 3-formyl-4-quinolones with nonstabilized ylides. The structure of the novel compounds was unequivocally established by means of 1D and 2D NMR spectroscopy. It was demonstrated that 3-vinyl-4-quinolones can be used as building blocks for the synthesis of more complex structures, namely, 2-methyl-1H-pyrrolo[3,4-c]acridine-1,3,6(2H,11H)-triones. These compounds were obtained through the Diels-Alder reaction of 3-vinyl-4-quinolones with N-methylmaleimide and further oxidation with chloranil. Moreover, it was demonstrated that 3-(buta-1,3-dien-1-yl)-4-quinolones are useful as precursors for the synthesis of 2-methyl-2H-pyrano[3,2-c]quinoline.

Data Availability

The data included in this study are available from the corresponding author upon request.

Conflicts of Interest

The authors declare that there are no conflicts of interest.

Acknowledgments

The authors thank the University of Aveiro and FCT/MEC for providing financial support to the LAQV-REQUIMTE (UIDB/50006/2020) and POCI-01-0145-FEDER-029767 research projects, financed by national funds and, when appropriate, cofinanced by FEDER under the PT2020 Partnership Agreement. V. L. M. Silva acknowledges funding from FCT under the Scientific Employment Stimulus, Institutional Call, reference CEECINST/00026/2018.

Supplementary Materials

The supporting information contains ¹H NMR and ¹³C NMR spectra for all the target compounds. (Supplementary Materials)

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Copyright © 2022 Wahiba Frites et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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