A direct synthetic route to fused tricyclic quinolones from 2,3-diaminoquinolin-4(1H)one

Enrique de J. Mauriño-Reyes; Edgar González-Rodríguez; Francisco Reyes-Rangel; Alfonso Lira-Rocha; Marco A. Loza-Mejía

doi:10.1515/hc-2016-0059

Article Open Access

A direct synthetic route to fused tricyclic quinolones from 2,3-diaminoquinolin-4(1H)one

Enrique de J. Mauriño-Reyes , Edgar González-Rodríguez , Francisco Reyes-Rangel , Alfonso Lira-Rocha and Marco A. Loza-Mejía

Published/Copyright: May 13, 2016

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From the journal Heterocyclic Communications Volume 22 Issue 3

Abstract

Fused tricyclic heterocycles are useful compounds in many areas of chemistry. In this study, 2,3-diaminoquinolin-4(1H)one (5), a key intermediate for the preparation of tricyclic compounds, was prepared from isatoic anhydride in four steps with high yields under mild conditions and an easy workup, with most of the reactions carried out in aqueous medium. Compound 5 was transformed into a series of tricyclic fused products 8 and 9.

Keywords: aqueous media; fused heterocycles; green chemistry; quinolones; tricyclic compounds

Introduction

Nitrogen-containing heterocycles including many fused heterocyclic compounds are present in a wide variety of biologically active natural products and pharmaceuticals [1–4]. Among these compounds, several fused tricyclic quinolines have been studied in the search for more effective anticancer agents [5]. For example, acridine 1, thiazolo[5,4-b]quinoline 2 [6–9], furo[2,3-b]quinoline 3 [10, 11], and pyrazolo[3,4-b]quinoline 4 [12] derivatives (Figure 1), all exhibit moderate to high cytotoxic activity. As noted in a recent review on DNA intercalators, a better understanding of the mechanisms involved in the process of intercalation is required for the design of more selective and potent intercalators of this type [13]. Fluorescent labels have many applications for the sensitive detection of analytes, including biological macromolecules and metallic cations of environmental importance, as well as in cell and tissue labeling. Fluorescent quinolones [14–16], including some quinolones fused with other heterocycles [17, 18], that are potentially useful in these applications, have recently been reported. Accordingly, efficient synthesis routes for the preparation of fused quinolones are needed.

Figure 1

Examples of cytotoxic tricyclic fused quinoline compounds.

Results and discussion

For the preparation of compounds similar to those in Figure 1, one interesting synthon would be 2,3-diaminoquinolin-4(1H)-one (5). For the preparation of compound 5, we proposed the synthetic route depicted in Scheme 1 starting from 2-aminoquinolin-4(1H)-one 6. Compound 6 was initially prepared from aniline sulfate and ethyl cyanoacetate at 200°C [19] in low yields (20–30%). In this work, compound 6 was prepared from isatoic anhydride and malononitrile under basic conditions with posterior hydrolysis of the nitrile group and decarboxylation in a refluxing 6 m KOH solution, achieving higher yield (86% from isatoic anhydride) [20].

Several attempts were made to prepare the desired compound 5 from a 3-nitro derivative of compound 6. For example, 6 was treated with hot HNO₃/AcOH as reported for other 4-quinolones [21, 22] to obtain the 3-nitro substituted derivative. However, the presence of a single signal in the ¹H NMR spectrum at 5.90 ppm indicated that nitration occurred in the benzenoid ring, not in the pyridinoid ring. Additional experiments with various nitrating mixtures and under various conditions gave the same result.

Scheme 1

Reagents and conditions (a) malononitrile, DMF, TEA, 90°C, 90 min, then 6 N KOH, reflux, 24 h; (b) R-C₆H₄N₂⁺Cl^-, AcOK 30%, 0°C, 1 h; (c) Na₂S₂O₄, 15% NaOH, 60–75°C, 1 h; (d) 1,2-dicarbonyl compound, EtOH, 70°C, 30 min; (e) NaNO₂, HCl, 0°C; (f) ArCHO, DMF, Na₂S₂O₅, reflux.

Another approach involved the preparation of a 3-phenylazo substituted compound 7a followed by reductive cleavage of the azo group to yield compound 5. The preparation of compound 7a is described in the literature [23] but it requires long reaction times (24 h at 0–5°C) with pyridine as the reaction medium. In our hands, the azo coupling was accomplished in approximately 1 h at room temperature. In addition, it was found that conducting the reaction in a slightly basic aqueous medium (sodium acetate 30% solution) substantially increases the yield to 80%. Purification with hot methanol rendered pure 7a. Reductive cleavage of 7a was carried out by treatment with Zn/methanolic HCl or Zn/formic acid [24]. Chromatographic analysis by TLC indicated the presence of two products, namely aniline and compound 5. However, purification was difficult due to the presence of inorganic salts and the low solubility of 5 in the organic solvents used for extraction. A slight improvement was noticed by using sodium hydrosulfite in a DMF/phosphate buffer for reductive cleavage of the azo group in 7a. This modification [25] increased the yield of 5 to 30–40%.

A more practical synthesis of 5 involves a high-yield coupling (93%) of 6 with p-benzenediazonium sulfonate followed by reduction of the resultant product 7b. Compound 7b is more soluble than 7a in a hot NaOH solution, which contributes to the preparation of 5 in a high yield of 87%. The reaction workup involves simple acidification of the basic solution to pH 8, which results in the precipitation of 5 as a white powder. Additional washing with hot acetone renders a pure product. Sulfanilic acid can be recovered from the mother liquor for reuse in another reaction.

To demonstrate the application of 5 for the preparation of tricyclic fused heterocycles, several quinolones fused with six-membered (compounds 8a–d) and five-membered rings (compounds 9a–e) were prepared. Compound 5 was allowed to react with a variety of 1,2-dicarbonyl compounds at room temperature to obtain products 8a–d in 80–90% yields. Similar yields were obtained for the reactions carried out under microwave irradiation for 10 min in EtOH–AcOH [26]. Heterocycles with structures similar to 8a–d may have antifungal properties [27].

Treatment of 5 with a cold solution of sodium nitrite in hydrochloric acid gave tricyclic product 9a in a 90% yield. In addition to its potential biological activity [28], compound 9a may be of interest for use in materials sciences [29]. In the preparation of 9b–e, compound 5 was allowed to react with aromatic aldehydes in DMF in the presence of Na₂S₂O₅. In contrast to the preparation of products 8, the yields of 9b–e increased when microwave irradiation was used. Table 1 summarizes the reaction conditions tested and yields obtained.

Table 1

Reaction conditions tested and obtained yields.

Transformation	Conditions	Yield
5→8a–d	EtOH, 70°C^a	70–90%
	MeOH, AcOH (catalytic), 400 W, 10 min^b	80–90%
5→9a	NaNO₂, 1 h^a	90%
5→9b–e	ArCHO, DMF, Na₂S₂O₅, reflux, 6 h^a	40–50%
	ArCHO, DMF, Na₂S₂O₅, 800 W, 60 min^b	55–65%

^aConventional heating; ^bmicrowave irradiation.

Conclusions

We developed a novel, easy and direct method for the preparation of 2,3-diaminoquinolin-4(1H)-one 5, which can be used for the synthesis of tricyclic fused heterocycles. All reactions in the synthetic sequence proceed with high yields and the workup and purification procedures are simple.

Experimental

All starting materials were commercially available research-grade chemicals and used without further purification. Reactions were monitored by TLC on precoated silica gel 60 F254 plates (Aldrich). Column chromatography was carried out on silica gel 60 (70–230 mesh, Merck). Melting points were determined on a Fisher–Jones apparatus and are uncorrected. Infrared spectra were recorded in KBr pellets on a Nicolet FT-5SX spectrophotometer. ¹H NMR (300 MHz) and ¹³C NMR (75 MHz) spectra were recorded in DMSO-d₆ on a Varian VxR-300S spectrometer. FAB-MS was carried out on a JEOL Sx102 apparatus.

2-Amino-(1H)-quinolin-4-one (6)

The preparation was carried out as previously reported by Kadin and Lamphere [20]; mp >300°C; IR (cm^-1): 3306, 3168, 1646, 1596, 1550, 1509, 1497; ¹H NMR: δ 5.25 (s, 1H), 6.18 (s, 2H), 7.09 (ddd, J = 8.7, 6.9, 0.9 Hz; 1H), 7.25 (d, J = 8.7 Hz, 1H), 7.42 (ddd, J = 8.7, 6.9, 1.5 Hz, 1H), 7.90 (dd, J = 8.7, 1.5 Hz, 1H).

4-[2-(Amino-4-oxo-1,4-dihydroquinolin-3-yl)diazenyl]benzensulfonic acid (7b)

The preparation was carried out as previously reported by Stýskala et al. [23] with the following modifications. Sulfanilic acid sodium salt (11.5 g, 66.4 mmol) was suspended in 20 mL of a 50% HCl solution, and the grayish suspension was cooled to 0°C. Then, a solution of 4.7 g (68.1 mmol) of sodium nitrite in 4 mL of water was added dropwise without allowing the temperature to exceed 15°C. The mixture was stirred for 1 h. Meanwhile, in 50 mL of a 30% potassium acetate solution, 10.0 g (62.5 mmol) of 6 was suspended. The suspension was cooled to 0°C. Then, the azo coupling was carried out by pouring the diazonium salt suspension in small portions into the compound 6 suspension, which resulted in the immediate formation of an orange precipitate. The mixture was stirred for an additional hour. The resultant precipitate was collected by vacuum filtration and washed several times with water and hot methanol to obtain 7b as an orange solid: yield 19.9 g (93%); mp >300°C; IR (cm^-1): 3278, 3080, 1682, 1620, 1510, 1497, 1475; ¹H NMR: δ 7.23 (ddd; J = 8.4, 6.9, 1.2 Hz; 1H), 7.31 (d, J = 8.4 Hz, 1H), 7.58 (ddd; J = 8.4, 6.9, 0.9 Hz, 1H), 7.68 (br, 4H), 8.10 (d, J= 8.4 Hz, 1H); MS: m/z 345 (M⁺+1, 100%). Anal. Calcd for C₁₅H₁₂N₄O₄S: C, 52.32; H, 3.51; N, 16.27. Found: C, 52.14; H, 3.35; N, 16.13.

2,3-Diamino-(1H)-quinolin-4-one (5)

To 75 mL of a 15% NaOH solution at 60°C, 10.0 g (29 mmol) of compound 7b was slowly added. The resulting carmine solution was heated to 75°C, and 20 g of technical grade sodium dithionite was added in small portions. The mixture was stirred for 1 h. Then, acetic acid was added to the yellowish solution until a pH of 8 was achieved and a white precipitate formed. This precipitate was collected by vacuum filtration and washed with water and acetone to obtain 5 as a white solid: yield 4.36 g (86%); mp >300°C; IR (cm^-1): 3342, 3133, 1649, 1605, 1565, 1493; ¹H NMR: δ 5.99 (s, 2H), 7.09 (ddd; J = 8.7, 6.9, 1.2 Hz; 1H), 7.25 (d, J = 8.7 Hz, 1H), 7.42 (ddd; J = 8.7, 6.9, 1.5 Hz, 1H), 7.90 (dd, J = 8.7, 1.5 Hz, 1H); ¹³C NMR: δ 118.6, 121.7, 123.1, 126.5, 133.6, 133.6, 141.0, 140.7, 148.5, 169.5; MS: m/z 176 (M⁺+1, 100%). Anal. Calcd for C₉H₉N₃O: C, 61.70; H, 5.18; N, 23.99. Found: C, 61.81; H, 5.04; N, 23.85.

General procedure for the preparation of pyrazino[2,3-b]quinolin-10-(5H)-ones 8a–d

Conventional heating

To 20 mL of a ethanolic solution of the 1,2-dicarbonyl compound (19 mmol) at 70°C with magnetic stirring, 3.0 g (17.1 mmol) of compound 5 was slowly added in small portions. During the addition, the color of the solution changed from yellow to amber. Then, the mixture was stirred at 70°C for an additional 30 min, cooled to room temperature and poured onto 30 mL of ice-cold acetone. A sand-colored solid precipitate was collected by vacuum filtration and washed with acetone to give 8a–d.

Microwave irradiation

A suspension of 1 mL of an ethanolic solution of the 1,2-dicarbonyl compound (3 mmol), 0.5 g of compound 5 (2.85 mmol) and two drops of acetic acid in 3 mL of ethanol was allowed to react under microwave irradiation at 400 W power and 100°C for 10 min. The reaction vessel was cooled in an ice bath and a yellowish solid precipitate was collected by filtration. Yields of 8 reported below were obtained by using this technique.

Pyrazino[2,3-b]quinolin-10(5H)-one (8a)

This compound was obtained in 90% yield as a light yellow fine powder; mp >300°C; IR (cm^-1): 3208, 1551, 1617; ¹H NMR: δ 7.31 (t, J = 7.4 Hz, 1H), 7.65 (d, J = 8.2 Hz, 1H), 7.78 (td, J = 8.2, 1.2 Hz, 1H), 8.23 (dd, 8.2, 1.2 Hz, 1H); 8.66 (d, J = 1.9 Hz, 1H), 8.79 (d, J = 1.9 Hz, 1H), 12.4 (s, 1H); ¹³C NMR: δ 118.4, 122.7, 124.4, 126.8, 131.3, 134.9, 140.6, 140.7, 148.2, 149.0, 177.3; MS: m/z 198 (M⁺+1, 100%). Anal. Calcd for C₁₁H₇N₃O: C, 67.00; H, 3.58; N, 21.31. Found: C, 67.14; H, 3.37; N, 21.10.

2,3-Dimethylpyrazino[2,3-b]quinolin-10-(5H)-one (8b)

This compound was obtained in 87% yield as a light yellow fine powder; mp >300°C; IR (cm^-1): 2927, 1572, 1605, 1565, 1493; ¹H NMR: δ 2.60 (s, 3H); 2.62 (s, 3H); 7.28 (t, J= 7.4 Hz, 1H); 7.65 (d, J= 8.2 Hz, 1H); 7.74 (td, J = 8.2, 1.2 Hz, 1H), 8.24 (dd, 8.2, 1.2 Hz, 1H), 8.32 (br); MS: m/z 226 (M⁺+1, 100%). Anal. Calcd for C₁₃H₁₁N₃O: C, 69.32; H, 4.92; N, 18.66. Found: C, 69.41; H, 4.99; N, 18.49.

2,3-Diphenylpyrazino[2,3-b]quinolin-10(5H)-one (8c)

This compound was obtained in 82% yield as a light yellow fine powder; mp >300°C; IR (cm^-1): 3176, 1646, 1605, 1565, 1493; IR (cm^-1): 2927, 1572, 1605, 1565, 1493; ¹H NMR: δ 5.88 (br, 1H), 7.40 (m, 8H), 7.54 (d, J = 7.04 Hz, 2H), 7.73 (d, J = 8. Hz, 1H), 7.84 (dd, J = 7.6, 7.3 Hz, 1H), 8.00 (d, J = 7.6 Hz, 1H), 8.32 (d, J = 8. Hz, 1H). MS (FAB, m/z): 350 (M⁺+1, 100%). Anal. Calcd for C₂₃H₁₅N₃O: C, 79.07; H, 4.33; N, 12.03. Found: C, 79.27; H, 4.61; N, 11.88.

2,3-Di(pyridin-2-yl)pyrazino[2,3-b]quinolin-10(5H)-one (8d)

This compound was obtained in 80% yield as a bright yellow fine powder; mp >300°C; IR (cm^-1): 3200, 1609, 1605, 1565, 1493; ¹H NMR: δ 7.33 (m, 2H), 7.43 (dd, J = 8.0, 7.4 Hz, 1H), 7.75 (d, J = 8.0 Hz, 1H), 7.86 (dd, J = 7.6, 7.0 Hz, 1H), 7.96 (dd, J = 6.7, 4.7 Hz, 1H), 7.99 (d, J = 4.6 Hz, 1H), 8.26 (d, J = 7.6. Hz, 1H), 8.36 (d, J = 4.69 Hz, 1H), 8.36 (br, 1H), 8.37 (d, J= 4.69 Hz, 1H); MS: m/z 352 (M⁺+1, 100%). Anal. Calcd for C₂₁H₁₃N₅O: C, 71.79; H, 3.73; N, 19.93. Found: C, 71.91; H, 3.88; N, 19.71.

Preparation of 3,4-dihydro-9H-[1,2,3]triazolo[4,5-b]quinolin-9-one (9a)

Sodium nitrite (1.53 g, 22.1 mmol) was suspended in concentrated HCl (30 mL) with efficient cooling and stirring in an ice bath (5°C). Compound 5 (3.0 g, 17.1 mmol) was then added in small portions and the mixture was kept at 5°C for 20 min. The ice bath was removed, the mixture was allowed to reach room temperature, and stirring was continued for an additional 60 min. The yellowish suspension was added dropwise to 70 mL of cold water and the mixture stirred at room temperature for 10 min. The slightly colored precipitate was collected by filtration and washed with cold water to give 9 as a white solid: yield 2.87 g (90%); mp >300°C; IR (cm^-1): 3198, 1731, 1680, 1615; ¹H NMR: δ 6.16 (br, 1H), 7.24 (td, J = 6.9, 1.6 Hz, 1H), 7.60 (d, J = 8.2 Hz, 1H), 7.69 (td, J = 6.9, 1.6 Hz, 1H), 8.23 (dd, J = 8.1, 1.5 Hz, 1H), 12.6 (s, 1H); MS: m/z 187 (M⁺, 100%). The spectroscopic data are in agreement with those reported by Šimáček et al. [30].

General preparation of 2-phenyl-3,4-dihydro-9H-imidazo[4,5-b]quinolin-9-ones 9b–e

Conventional heating

To a suspension of 0.3 g (1.7 mmol) of compound 5 in 5 mL of DMF, 0.35 g (1.8 mmol) of sodium metabisulfite and 2.04 mmol of the aromatic aldehyde were added. The mixture was heated under reflux for 5 h and then added to 40 mL of cold water. The slightly colored precipitate was collected by filtration and washed with acetone until filtrate was clear.

Microwave irradiation

A mixture of 0.3 g (1.7 mmol) of compound 5, sodium metabisulfite (0.35 g, 1.8 mmol), the aromatic aldehyde (2 mmol) and 5 mL DMF was allowed to react under microwave irradiation at 800 W power and 150°C for 60 min in six cycles of 10 min each. The workup was identical to that described above for conventional heating procedure.

2-Phenyl-3,4-dihydro-9H-imidazo[4,5-b]quinolin-9-one (9b)

This compound was obtained in 75% yield as a white fine powder; mp >250°C; IR (cm^-1): 3198, 1731, 1680, 1615; ¹H NMR: δ 6.16 (br, 1H), 7.24 (td, J = 6.9, 1.6 Hz, 1H), 7.60 (d, J = 8.2 Hz, 1H), 7.69 (td, J = 6.9, 1.6 Hz, 1H), 8.23 (dd, J = 8.1, 1.5 Hz, 1H), 12.6 (s, 1H); ¹³C NMR: δ 118.6, 121.7, 123.1, 126.5, 133.6, 141.0, 140.7, 148.5, 169.5; MS: m/z 187 (M⁺, 100%). Anal. Calcd for C₁₆H₁₁N₃O: C, 73.55; H, 4.24; N, 16.08. Found: C, 73.74; H, 4.07; N, 15.98.

2-(4-Hydroxy-3-methoxyphenyl)-3,4-dihydro-9H-imidazo[4,5-b]quinolin-9-one (9c)

This compound was obtained in 55% yield as a white fine powder; mp >250°C; IR (cm^-1): 3306, 3024, 1643, 1285, 1605, 1565, 1493; ¹H NMR: δ 3.91 (s, 3H); 6.94 (d, J = 8.21 Hz, 1H), 7.27 (dd, J = 7.6, 7.0 Hz, 1H), 7.60 (td, J = 7.6 Hz, 1H), 7.64 (dd, J = 7.6, 7.0 Hz, 1H), 7.74 (dd, J = 8.2, 1.5 Hz, 1H); 7.91 (d, J = 1.5 Hz, 1H), 8.30 (d, J = 7.6 Hz, 1H); MS: m/z 308 (M⁺, 100%). Anal. Calcd for C₁₇H₁₃N₃O₃: C, 66.44; H, 4.26; N, 13.67. Found: C, 66.48; H, 4.17; N, 13.96.

2-(Pyridin-2-yl)-3,4-dihydro-9H-imidazo[4,5-b]quinolin-9-one (9d)

This compound was obtained in 60% yield as a gray powder; mp >250°C; IR (cm^-1): 3173, 1632, 1605, 1565, 1493; ¹H NMR: δ 7.24 (dd, J = 7.6, 6.7 Hz, 1H); 7.52 (dd, J = 7.0, 4.9 Hz, 1H); 7.62 (m, 2H); 8.00 (dd, J = 7.9, 7.0 Hz, 1H); 8.26 (t, J = 8.0, 1H); 8.72 (d, J = 4.9 Hz, 1H); MS: m/z 263 (M⁺, 100%). Anal. Calcd for C₁₅H₁₀N₄O: C, 68.69; H, 3.84; N, 21.36. Found: C, 68.47; H, 3.71; N, 21.60.

2-(Pyridin-4-yl)-3,4-dihydro-9H-imidazo[4,5-b]quinolin-9-one (9e)

This compound was obtained in 62% yield as a white fine powder; mp >250°C; IR (cm^-1): 3299, 1642, 1605, 1565, 1493; ¹H NMR: δ 6.90 (br, 1H), 7.20 (dd, J = 7.3, 7.3 Hz, 1H), 7.34 (d, J = 8.0 Hz, 1H), 7.44 (d, J = 5 Hz, 1H), 7.50 (dd, J = 7.5, 7.3 Hz, 1H), 8.07 (d, J = 7.90 Hz, 1H), 8.60 (d, J = 5 Hz, 1H), 10.93 (br, 1H); MS: m/z 263 (M⁺, 100%). Anal. Calcd for C₁₅H₁₀N₄O: C, 68.69; H, 3.84; N, 21.36. Found: C, 68.78; H, 3.92; N, 21.28.

Acknowledgments

We wish to thank DGAPA-UNAM for financing the project PAPIIT IN218910 as well as Facultad de Química, UNAM for financial support (PAIP 6390-10). M.A.L-M. wishes to thank Universidad La Salle for additional financial support (project SAL-01/15).

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Received: 2016-4-22

Accepted: 2016-4-25

Published Online: 2016-5-13

Published in Print: 2016-6-1

This article is distributed under the terms of the Creative Commons Attribution Non-Commercial License, which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Articles in the same Issue

https://doi.org/10.1515/hc-2016-0059

Keywords for this article

aqueous media; fused heterocycles; green chemistry; quinolones; tricyclic compounds

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