Regioselective synthesis of new 7,8-dichlorobenzofuro[3,2- c ]quinoline-6,9,10(5 H )-triones from reactions of 4-hydroxy-2-quinolones with 3,4,5,6-tetrachloro-1,2-benzoquinone

Abstract

A novel series of 7,8-dichlorobenzofuro[3,2-c]quinoline-6,9,10(5H)-triones was obtained regioselectively in good yields. The products were formed by the reactions of the 4-hydroxy-2(1H)-quinolinones with 3,4,5,6-tetrachloro-1,2-benzoquinone in tetrahydrofuran as the solvent. Infrared, nuclear magnetic resonance (two-dimensional nuclear magnetic resonance), mass spectra and elemental analysis were used to elucidate the structures of new compounds.

Keywords

2-quinolones nuclear magnetic resonance 3,4,5,6-tetrachloro-1,2-benzoquinone regioisomer

Introduction

2-Quinolones have considerable interest as anticancer¹ and antiviral² reagents. 4-Substituted 3-phenyl-2-quinolones exhibit high affinity in binding to the glycine site of the N-methyl- d -aspartate receptor, and such antagonists have promise for the treatment of several central nervous system disorders.³ Amides of 3-hydroxy- and 3-alkyl-4-carboxylic acids of 2-quinolones also exhibit high affinity for the 5-HT3 serotonin receptor.⁴ Generally, quinolines are also valuable intermediates in organic synthesis, since they are easily converted into 2-chloro- and then 2-aminoquinoline derivatives.⁵ Figure 1 shows representative examples of quinolines as naturally occurring compounds such as Skimmianine⁶ and γ-Fagarine⁷ (both were proved to have anticancer activity), Dictamnine and Kokusaginine.⁶

Previously, we prepared ethyl pyrano[3,2-c]quinoline-4-carboxylates (I, Figure 2), in good yields.⁸ The reactions of 4-hydroxy-1-phenylquinolin-2(1H)-one with 2-(2-oxo-1,2-dihydroindol-3-ylidene)malononitrile produced spiro(indoline-3,4′-pyrano[3,2-c]quinoline)-3′-carbonitriles (II, Figure 2)⁹ in addition to our synthesis of 2,3-bis-(4-hydroxy-2-oxo-1,2-dihydroquinolin-3-yl)succinates and arylmethylene-bis-3,3′-quinoline-2-ones (III, Figure 2).¹⁰

N-2,3-Bis(6-substituted-4-hydroxy-2-oxo-1,2-dihydro-quinolin-3-yl)naphthalene-1,4-diones and their substituted triethylammonium salts (IV, Figure 2) were also synthesized as potential antineoplastic reagents.¹¹ Moreover, we demonstrated on the design and synthesis of fused naph-thofuro[3,2-c]quinoline-6,7,12-triones (V, Figure 2) and pyrano[3,2-c]quinoline-6,7,8,13-tetraones (VI, Figure 2), which have shown inhibition towards extracellular-signal-regulated kinase (ERK).¹²

In general, quinolones and their fused analogues are in high demand for pharmaceuticals. Therefore, the development of simple and mild methods for synthesizing quinolone derivatives is always needed. Consequently, we have an interest in investigating the reaction of 4-hydroxy-2(1H)-quinolinones 1a–f and 3,4,5,6-tetrachloro-1,2-benzoquinone (2) to synthesize new benzofuroquinolone derivatives that might have biological and/or pharmaceutical activity.

Results and discussion

The reaction of 4-hydroxy-2(1H)-quinolinones 1a–f and 3,4,5,6-tetrachloro-1,2-benzoquinone (2) in tetrahydrofuran (THF) under reflux for 10–15 h yielded the corresponding 7,8-dichloro-benzofuro[3,2-c]quinoline-6,9,10(5H)-triones 3a–f (Scheme 1).

The structures of the products were established by including infrared (IR), mass spectra, nuclear magnetic resonance (NMR) spectra and elemental analyses. Table 1 summarizes the results obtained.

Table 1.

The novel quinolones prepared in this work.

Compound numbers	Names	Yields (%)
1a	7,8-Dichlorobenzo-furo[3,2-c]quinolin-6,9,10(5H)-trione (3a)	74
1b	7,8-Dichloro-2-methyl-benzo-furo[3,2-c]quinolin-6,9,10(5H)-trione (3b)	78
1c	7,8-Dichloro-3-methyl-benzo-furo[3,2-c]quinolin-6,9,10(5H)-trione (3c)	76
1d	2,7,8-Trichlorobenzo-furo[3,2-c]quinolin-6,9,10(5H)-trione (3d)	70
1e	3,7,8-Trichlorobenzo-furo[3,2-c]quinolin-6,9,10(5H)-trione (3e)	66
1f	3-Bromo-7,8-dichlorobenzofuro[3,2-c]quinolin-6,9,10(5H)-trione (3f)	75

The structure of product 3b was assigned on the basis of NMR studies. The methyl protons are distinctive at δ_H 2.41 ppm and the methyl carbon appears at δ_C 20.3 ppm. The methyl protons give a weak COrrelated SpectroscopY (COSY) correlation to the methyl carbon and give weak heteronuclear multiple bond correlation (HMBC) to a broadened singlet at δ_H 7.69 assigned to H-1 and to a broadened doublet at δ_H 7.64 assigned to H-3. The broadening of these signals reflects the weak coupling between them. HMBC of H-1 and H-3 with a non-protonated at δ_C 137.6 identified as C-2 via three-bond correlations were observed, whereas H-4 shows an HMBC with the C-2 carbon (δ_C 137.6). Also, C-11b (108.7) gives HMBC with an NH proton at δ_H 11.98; the nitrogen appears at δ_N 151.1 ppm. The remaining carbons of the quinolone appeared at δ_C 107.5 for C-6a and 146.9 for C-7. The three carbons resonated at δ_C 177.5, 174.6 and 166.5 ppm due to C-9, C-10 and C-11a, respectively. There is a possibility of forming compound 4 as a regioisomer of 3 (Figure 3) but NMR spectra excluded this since there was a good HMBC between C-11a and C-10. For example, in compound 3b, a good correlation was observed between the carbon at δ_C 166.5 and at the carbon δ_C 174.5 ppm. A third alternative structure 5 (Figure 3) which might be formed was also ruled out, since there no observed correlation was noted between the carbonyl-7 and C-6a.

The mechanism of the reaction may involve a Michael addition at C-3 of the quinolone to the α-carbon of its quinone 2 to form the zwitter-ion A (Scheme 2) via 1,6-addition. Subsequently elimination of HCl would give the intermediate B, which would be found in its enolate form (Scheme 2). A nucleophilic attack by the oxygen-lone pair, the vinylic-carbon, would lead to cyclization after elimination of HCl to provide the products 3a–f (Scheme 2). The mechanism was supported by formation of fused naphthofuro[3,2-c]quinoline-6,7,12-triones during reactions of 1a–f with 2,3-dichloro-1,4-naphthoquinone.¹²

Conclusion

In this study, a series of novel 7,8-dichloro-benzofuro[3,2-c]quinoline-6,9,10(5H)-triones was successfully regioselectively prepared.

Experiment

Materials and methods

Melting points were measued on a Gallenkamp melting point apparatus (Weiss-Gallenkamp, Loughborough, UK) and are uncorrected. The IR spectra were obtained with a FT device at the Minia University, Egypt. Elemental analyses were obtained at the Microanalytical Centre at the Cairo University, Egypt (a Bruker AV-400 spectrometer; 400 MHz for ¹H, 100 MHz for ¹³C and 40.55 MHz for ¹⁵N) was used to measure NMR spectra. The new compounds were dissolved in dimethyl sulphoxide (DMSO)-d₆; and the chemical shifts are expressed in δ (ppm), versus internal tetramethylsilane (TMS) = 0 for ¹H and ¹³C, and external liquid ammonia = 0 for ¹⁵N. A Finnigan Fab spectrometer (70 eV) device was used to record mass spectra at the Institute of Organic Chemistry, Karlsruhe University, Karlsruhe, Germany. Thin layer chromatography (TLC) was carried out on silica aluminum sheets (Kieselgel 60) with PF₂₅₄ indicator at λ_max = 254 nm.

Starting materials

Compounds 1a–e were prepared according to the literature,¹³ whereas compound 2 (Aldrich) was used as received.

Products

A suspension of compounds 1a–f (1 mmol) in THF (50 mL) was added to a solution of 2 (245 g, 1 mmol) in 15 mL (THF). The reaction mixture was gently heated under reflux for 10–15 h, until the reactants had disappeared (monitored by TLC). The resulting precipitates of 3a–f were filtered off and dried. The precipitates were recrystallized from the solvents given.

7,8-Dichlorobenzofuro[3,2-c]quinolin-6,9,10(5H)-trione (3a): Pale brown crystals (DMF/EtOH), yield: 0.246 g (74%), m.p. >350 °C. IR (KBr, cm⁻¹): ѵ = 3328 (NH), 1720, 1665 (CO), 1600, 1585 (ArC=C) cm⁻¹; ¹H NMR (400 MHz, DMSO-d₆): δ_H 12.20 (s, 1H, NH), 7.78–7.76 (m, 2H, ArH), 7.37–7.34 ppm (m, 2H, ArH); ¹³C NMR (100 MHz, DMSO-d₆): δ_C 177.8 (C-9), 174.0 (C-10), 163.5 (C-11a), 157.2 (C-6), 151.0, 148.8, 144.0, 140.6, 130.6 (ArC), 128.0, 127.4, 125.6, 124.4 ppm (ArCH), 110.0, 108.0 ppm (ArC); mass spectrometry (MS) (fast atom bombardment (FAB)) m/z (%) = 334/336 (M⁺/M + 2, 20/54), 334 (M⁺, 48), 289 (18), 175 (30), 154 (100); Anal. calcd for C₁₅H₅Cl₂NO₄ (334.11): C, 53.92; H, 1.51; N, 4.19; found, C, 54.10; H, 1.55; N, 4.30%.

7,8-Dichloro-2-methyl-benzofuro[3,2-c]quinolin-6,9,10(5H)-trione (3b): Pale brown crystals (DMF/EtOH), yield: 0.256 g (78%), m.p. >350 °C. IR (KBr): ѵ = 3330 (NH), 1722, 1668 (CO), 1600, 1585 cm⁻¹ (ArC=C); ¹H NMR (400 MHz, DMSO-d₆): δ_H 11.98 (s, 1H, NH), 7.69 (d, 1H, J = 0.8 Hz, ArH-1), 7.64 (dd, 1H, J = 1.2, 0.7 Hz, ArH), 7.34 (d, 1H, J = 1.2 Hz, ArCH-4), 2.41 ppm (s, 3H, CH₃); ¹³C NMR (100 MHz, DMSO-d₆): δ_C 177.5 (C-9), 174.6 (C-10), 166.5 (C-11a), 156.4 (C-6), 146.9 (C-7), 141.0 (C-8), 140.9 (C-4a), 137.6 (C-2), 136.9 (C-6b), 133.3 (C-10a), 132.4 (CH-3), 128.0 (CH-4), 121.4 (CH-1), 108.7 (C-11b), 107.5 (C-6a); 20.30 ppm (CH₃); MS (FAB) m/z (%) = 348/350 (M⁺/M + 2, 24/50), 348 (M⁺, 52), 289 (24), 175 (32), 154 (100); Anal. calcd for C₁₆H₇Cl₂NO₄ (348.14): C, 55.20; H, 2.03; N, 4.02; found, C, 55.30; H, 2.15; N, 3.93%.

7,8-Dichloro-3-methyl-benzofuro[3,2-c]quinolin-6,9,10(5H)-trione (3c): Brown crystals (DMF), yield: 0.264 g (76%), m.p. >360 °C. IR (KBr): ѵ = 3310 (NH), 1725, 1670 (CO), 1600, 1585 cm⁻¹ (ArC=C); ¹H NMR (400 MHz, DMSO-d₆): δ_H 11.98 (s, 1H; NH), 7.76 (dd, 1H, J = 1.0, 0.7 Hz, ArH), 7.60–7.54 (m, 2H, ArH), 2.35 ppm (s, 3H, CH₃); ¹³C NMR (100 MHz, DMSO-d₆): δ_C 178.8 (C-9), 174.0 (C-10), 166.6 (C-11a), 156.2 (C-6), 153.0 (C-10a), 146.7 (C-7), 141.5 (C-8), 141.0 (C-4a), 137.0 (C-6b), 135.4 (CH-2), 132.2, 128.2, 122.4 (ArCH), 112.0, 110.0 (ArC), 20.3 ppm (CH₃); MS (FAB) m/z (%) = 348/350 (M⁺/M + 2, 22, 56), 348 (M⁺, 50), 289 (20), 175 (30), 154 (100); Anal. calcd for C₁₆H₇Cl₂NO₄ (348.14): C, 55.20; H, 2.03; N, 4.02; found, C, 55.35; H, 2.10; N, 4.10%.

2,7,8-Trichlorobenzofuro[3,2-c]quinolin-6,9,10(5H)-trione (3d): Plae brown crystal (DMF), yield: 0.256 g (70%), m.p. >350 °C. IR (KBr): ѵ = 3328 (NH), 1723, 1666 (CO), 1597, 1585 cm⁻¹ (ArC=C); ¹H NMR (400 MHz, DMSO-d₆): δ_H 11.90 (s, 1H; NH), 7.78 (d, 1H, J = 0.8 Hz, ArH), 7.56–7.54 ppm (m, 2H, ArH); ¹³C NMR (100 MHz, DMSO-d₆): δ_C 179.8 (C-9), 174.8 (C-10), 166.5 (C-11a), 156.5 (C-6), 152.0, 150.0, 136.9, 133.0, 131.0, 128.6 (ArC), 128.0, 127.4, 126.0 (ArCH), 110.0, 108.0 ppm (ArC); MS (FAB) m/z (%) = 371 (M + 3, 20), 370 (M + 2, 26), 369 (M + 1, 38), 368 (M⁺, 60), 289 (34), 175 (28), 156 (100); Anal. calcd for C₁₅H₄Cl₃NO₄ (368.55): C, 48.88; H, 1.09; N, 3.80; found, C, 48.74; H, 1.12; N, 3.70%.

3,7,8-Trichlorobenzofuro[3,2-c]quinolin-6,9,10(5H)-trione (3e): Brown crystals (DMF/CH₃OH), yield: 0.242 g (66%), m.p. >350 °C. IR (KBr): ѵ = 3330 (NH), 1722, 1670 (CO), 1590, 1580 cm⁻¹ (ArC=C); ¹H NMR (400 MHz, DMSO-d₆): δ_H 11.80 (s, 1H; NH), 7.74–7.72 (m, 1H, ArH), 7.55–7.52 ppm (m, 2H, ArH); ¹³C NMR (100 MHz, DMSO-d₆): δ_C 179.0 (C-9), 173.2 (C-10), 164.8 (C-11a), 158.5 (C-6), 151.0, 150.4, 136.4, 133.0, 130.4, 128.6 (ArC), 128.06, 127.2, 124.6 (ArCH), 111.0, 108.0 ppm (ArC); MS (FAB) m/z (%) = 371 (M + 3, 18), 370 (M + 2, 24), 369 (M + 1, 34), 368 (M⁺, 52), 289 (28), 175 (24), 156 (100); Anal. calcd for C₁₅H₄Cl₃NO₄ (368.55): C, 48.88; H, 1.09; N, 3.80; found, C, 48.70; H, 1.00; N, 3.60%.

2-Bromo-7,8-dichlorobenzofuro[3,2-c]quinolin-6,9,10(5H)-trione (3f): Brown crystals (DMF/CH₃CN), yield: 0.310 g (75%), m.p. >350 °C. IR (KBr): ѵ = 3328 (NH), 1720, 1665 (CO), 1600, 1585 cm⁻¹ (ArC=C); ¹H NMR (400 MHz, DMSO-d₆): δ_H 12.10 (s, 1H; NH), 7.66 (d, 1H, J = 1.2 Hz, ArH), 7.45–7.40 ppm (m, 2H, ArH); ¹³C NMR (100 MHz, DMSO-d₆): δ_C 179.2 (C-9), 174.1 (C-10), 166.2 (C-11a), 160.0 (C-6), 156.0 (C-10a), 149.0, 135.0, 133.0, 131.0, 128.6 (ArC), 128.0, 126.0, 124.8 (ArCH), 110.0, 108.0 ppm (ArC); MS (FAB) m/z (%) = 417 (M + 4, 10), 416 (M + 3, 24), 415 (M + 2, 34), 414 (M + 1, 52), 413 (M⁺, 64), 290 (28), 177 (34), 154 (30); Anal. calcd for C₁₅H₄BrCl₂NO₄ (413.00): C, 43.62; H, 0.98; N, 3.39; found, C, 43.50; H, 1.08; N, 3.50%.

Supplemental Material

Supplm_Data_19-12-2019 – Supplemental material for Regioselective synthesis of new 7,8-dichlorobenzofuro[3,2-c]quinoline-6,9,10(5H)-triones from reactions of 4-hydroxy-2-quinolones with 3,4,5,6-tetrachloro-1,2-benzoquinone

Supplemental material, Supplm_Data_19-12-2019 for Regioselective synthesis of new 7,8-dichlorobenzofuro[3,2-c]quinoline-6,9,10(5H)-triones from reactions of 4-hydroxy-2-quinolones with 3,4,5,6-tetrachloro-1,2-benzoquinone by Ashraf A Aly, Alaa A Hassan, Nasr K Mohamed, Lamiaa E Abd El-Haleem and Stefan Bräse in Journal of Chemical Research

Footnotes

Acknowledgements

The authors thank DFG and the Egyptian Mission for providing fellowships to Prof. Ashraf A. Aly and to Mrs Lamiaa E. Abd El-Haleem to enable them to perform analytical measurements at the Karlsruhe Institute of Technology, Institute of Organic Chemistry, 76131 Karlsruhe, Germany.

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship and/or publication of this article.

ORCID iD

Ashraf A Aly

Supplemental material

Supplemental material for this article is available online.

References

Ferrer

Avendaño

Söllhuber

. Liebigs Ann 1995; 1895–1899.

Alfonso

Weinstein

Gentles

. PCT Int Appl WO 9,203,327, 1992.

Hayashi

Miwa

Miki

, et al. J Med Chem 1992; 35: 4893–4902.

Godard

Fourquez

Tamion

, et al. Synlett 1994; 4: 235–236.

Morel

Larghi

Selvero

. Synlett 1995; 18: 2755–2758.

Mizuta

Kanamori

. Res Lett 1985; 144: 221–225.

Liu

Zhu

Fan

, et al. Front Chem 2018; 6: 1–36.

El-Sheref

Aly

Mourad

A-FE

, et al. Chem Pap 2018; 72: 181–190.

Aly

El-Sheref

Mourad

A-FE

, et al. Monatsh Chem 2019; 149: 635–644.

10.

Aly

El-Sheref

Mourad

AFE

, et al. Chem Pap 2019; 73: 27–37.

11.

Aly

El-Sheref

Bakheet

MEM

, et al. Bioorg Chem 2018; 81: 700–712.

12.

Aly

El-Sheref

Bakheet

MEM

, et al. Bioorg Chem 2019; 82: 290–305.

13.

Kappe

. Farmaco 1999; 54: 309–311.

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