Next Article in Journal
Analysis of Vicinal Water in Soft Contact Lenses Using a Combination of Infrared Absorption Spectroscopy and Multivariate Curve Resolution
Previous Article in Journal
Heteroctanuclear Au4Ag4 Cluster Complexes of 4,5-Diethynylacridin-9-One with Luminescent Mechanochromism
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Molecules
Volume 27
Issue 7
10.3390/molecules27072125
molecules-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Article

Autoxidation of 4-Hydrazinylquinolin-2(1H)-one; Synthesis of Pyridazino[4,3-c:5,6-c′]diquinoline-6,7(5H,8H)-diones

by
Sara M. Mostafa
1,
Ashraf A. Aly
1,*,
Alaa A. Hassan
1,
Esraa M. Osman
1,
Stefan Bräse
2,3,*,
Martin Nieger
4,
Mahmoud A. A. Ibrahim
1 and
Asmaa H. Mohamed
1
1
Chemistry Department, Faculty of Science, Minia University, El Minia 61519, Egypt
2
Institute of Organic Chemistry, Karlsruhe Institute of Technology, Eggenstein-Leopoldshafen, 76131 Karlsruhe, Germany
3
Institute of Biological and Chemical Systems (IBCS-FMS), Karlsruhe Institute of Technology, Eggenstein-Leopoldshafen, 76131 Karlsruhe, Germany
4
Department of Chemistry, University of Helsinki, P.O. Box 55 (A. I. Virtasen aukio I), 00014 Helsinki, Finland
*
Authors to whom correspondence should be addressed.
Molecules 2022, 27(7), 2125; https://doi.org/10.3390/molecules27072125
Submission received: 11 February 2022 / Revised: 16 March 2022 / Accepted: 21 March 2022 / Published: 25 March 2022
Browse Figures
Review Reports Versions Notes

Abstract

:
An efficient synthesis of a series of pyridazino[4,3-c:5,6-c′]diquinolines was achieved via the autoxidation of 4-hydrazinylquinolin-2(1H)-ones. IR, NMR (1H and 13C), mass spectral data, and elemental analysis were used to fit and elucidate the structures of the newly synthesized compounds. X-ray structure analysis and theoretical calculations unequivocally proved the formation of the structure. The possible mechanism for the reaction is also discussed.

Graphical Abstract

1. Introduction

Compounds with quinolin-2(1H)-one (carbostyril) skeletons are present in a large number of biologically active compounds [1,2,3,4,5,6,7,8,9,10,11,12]. During the twentieth century [13], various research groups dealt with the chemistry and biological applications of quinolines [14].
Pyridazine and its polycyclic structures have still played an interesting role in organic chemistry because of their remarkable properties in forming supramolecular assembly [15,16,17,18]. Pyridazine molecules are important heterocycle scaffolds that reveal diverse biological activities in medicine [19,20,21,22,23,24,25] and agriculture [26]. For example, Pyridazomycin is an antifungal and antibiotic compound, the first pyridazine derivative isolated from a natural source [27]. In contrast, Pyridaben is widely used as an acaricide with a long residual action, whereas Chloridazone has a long history of use as an herbicide [28]. Minaprine is a psychotropic drug that has effectively treated various depressive states [29] (Figure 1).
Functionalized pyridazines have high electron-deficient properties, encouraging their utilization as electrochromic materials and metal–organic frameworks [30,31].
Hydrazines have shown basic and reducing characteristics that enable their utility in many industrial and medical applications. Accordingly, hydrazines have served as rocket fuel, antioxidants, oxygen scavengers, and as intermediates for the production of explosives, propellants, and pesticides [32].
It has been demonstrated that oxygen makes hydrazine solutions unstable, especially under alkaline or neutral conditions. However, hydrazines are stable under strongly acidic conditions or without oxygen [33].
Wagnerova et al. [34] have reported that cobalt-tetrasulphophthalocyanines enhance the autoxidation process of hydrazines [34]. On the other hand, Ichiro Okura et al. [35] reported that the autoxidation of hydrazine occurred with manganese (III)-hematoporphyrin at room temperature, and that has an advantage because of its reactivity for the formation of oxygen coordinated Mn(III)-Hm peroxide adduct [36]. Andrew P. Hong et al. [37] reported that satisfactory autoxidation of hydrazines occurred using cobalt (II) 4,4′,4″,4‴-tetrasulfophthalocyanine (CoIITSP).
Previously, it was reported [38] that 1-ethyl-4-hydroxyquinolin-2(1H)-one (1) reacted with hydrazine hydrate, in 1,2-dichlorobenzene (o-DCB), to give a mixture of two compounds. These compounds were separated using fractional recrystallization to give quinolinylhydrazine 2a in 19% yield and diquinopyridazine 3a in 41% yield (Scheme 1).
A convenient microwave-assisted, one-pot, four-component synthetic approach was developed as a route to functionalized benzo[a]pyridazino[3,4-c]phenazine derivatives starting from 2-hydroxy-1,4-naphthoquinone, aromatic aldehydes, methyl hydrazine, and o-phenylenediamine. Compounds of a similar pentacyclic structure such as bisanthranilate showed an intramolecular electrophilic cyclization and afforded an angular cis-quinacridone compound, which condensed with hydrazine to give a phthalazine derivative [39]. The biological profiles of some of the compounds mentioned above exhibited good cytotoxic activities against KB, HepG2, Lu1, and MCF7 human cancer cell lines. In addition, a compound of the derivatives exhibited promising antimicrobial activities toward Staphylococcus aureus and Bacillus subtilis bacterial strains with IC50 < 6 μM [40].
Recently, it has been reported that hydrazines can be used as catalysts for removing oxygen in the closing carbonyl–olefin metathesis process [41]. We have also found that prolongated reflux during the formylation process of 2-quinolones via a DMF/Et3N mixture caused dimerization to occur, and unexpected 3,3′-methylenebis(4-hydroxyquinolin-2(1H)-ones) were obtained [42].
The above-mentioned findings encouraged us to generalize the method of preparation for heteroannulated pentacyclic compounds with the structure of this interesting molecule.

2. Results and Discussion

The strategy started with the preparation of derivatives of compounds 1, 2, 4, and 5 according to reported methods, and their structures were confirmed by matching their spectral data with those reported [43,44,45]. The key intermediates, hydrazine quinolones 2a–g, were prepared by refluxing compounds 4a–g with hydrazine hydrate (Scheme 2) [46]. During the heating of 4-hydrazinylquinolin-2(1H)-ones 2a–g in pyridine, we observed the abnormal formation, in good yields, of pyridazino[4,3-c:5,6-c′]diquinoline-6,7- (5H,8H)-diones 3a–g. As had been suggested, compounds 2a–g underwent an autoxidation reaction.
The structures of the products 3a–g were proved from their elemental analyses and IR, 1H NMR, and 13C NMR spectra. For example, the mass spectrum and elemental analysis of 3a established its molecular formula as C22H18N4O2. The 1H NMR spectrum of 3a exhibited the ethyl protons as a triplet at δH = 1.22 (J = 7.6 Hz) for CH3 and a quartet at δH = 4.39 ppm (J = 7.6 Hz) for CH2. The eight aromatic protons appeared as three multiplets at δH = 7.36–7.40 for 2H, 7.68–7.78 for 4H, and 8.06–8.08 ppm for 2H. The reported spectroscopic data for the 13C NMR spectrum of compound 3a showed the carbonyl-quinolone, 2NCH2, and CH3 carbon signals at δC = 165.72, 39.11, and 14.11 ppm, respectively. Similar spectroscopic results of compound 3a were also reported [38]. The structure of 3a was unambiguously determined by a single crystal structure (Figure 2).
We carried out the reaction in different conditions using compound 1a as an example with the optimized reaction conditions. In EtONa/EtOH (Method B, Table 1), it was found that the yield of 3a was decreased (74%). Refluxing of 1a in toluene/Et3N (Method C, Table 1) did not increase the yield (60%), and the time taken to obtain 3a was increased (2d). Furthermore, adding a few drops of Et3N to DMF (Method D, Table 1) improved the yield of 3a compared with methods B and C, but it was still lower compared with our method A. Using Na/toluene, the oxidation of 1a occurred satisfactorily; however, it was lower compared with method A. In our trial of an acidic medium using HCl/EtOH mixture, the reaction failed. Thus, the best condition to obtain high yields and a short reaction time of 3a–g is reflux in dry pyridine (Method A, Table 1).
The formation of pyridazino[4,3-c:5,6-c′]diquinoline-6,7(5H,8H)-diones 3a–g can be rationalized as depicted in Scheme 3. It is clear from the suggested mechanism (Scheme 3) that it constitutes several steps of nucleophilic substitution, dimerization, autoxidation, and electrocyclic reactions in a one-pot process leading to the pentacyclic final products 3a–g. The mechanism starts with a proton shift of compound 2 to its isomer 2′ (Scheme 3). Then, the starting molecule of 2 reacts with its isomer 2′ to give 6 (Scheme 3). The elimination of a hydrazine molecule in 6 would give the dimerized hydrazone 7, which undergoes another proton shift to give the intermediate 7′. Because the reaction did not proceed under an inert argon atmosphere (i.e., under argon atmosphere, the starting quinolinyl-hydrazines 2a–g were recovered), we proposed that the intermediate 7′ undergo an aerial oxidation NH-NH group to give the intermediate 8. After that, the intermediate 8 would undergo internal electrocyclization to give 9. Finally, another mode of aerial oxidation of 9 would produce compound 3 (Scheme 3).
The preceding literature supports the mechanism [47] describing aryl hydrazine chlorides’ aerial oxidation into diazines. Accordingly, it supports the steps of transformations of 7′ into 8 and 9 into 3. Moreover, aerial catalytic oxidation in pyridine transformed hydrazones into diazo compounds [48].
Firstly, the stability of compound 3a (Figure 3), as an example, was described. Therefore, the quantum mechanical calculations were performed for compound 3a. The investigated compound was first optimized using the DFT method (see the Methods section for details). The optimized structure was then subjected to vibrational frequency and single-point energy calculations. The quantum theory of atoms in molecules (QTAIM) was invoked to achieve an in-depth insight into the topological features of compound 3a [49]. In the context of QTAIM, the (3,–1) bond critical points (BCPs) and bond paths (BPs) were generated, and the electron density was computed. Moreover, noncovalent interaction (NCI) index analysis was executed to pictorially elucidate the origin and nature of intramolecular interactions within compound 3a [50]. According to the results, no imaginary frequencies were observed for the investigated structure of compound 3a, confirming that this conformer is a true minimum. Based on the QTAIM results presented in Figure 4a, the occurrence of intramolecular bonds within the inspected compound was revealed by the existence of BPs and BCPs. Chalcogen∙∙∙chalcogen intramolecular interaction was also noticed in compound 3a via the BP and BCP between the two oxygen atoms (O∙∙∙O). The BCP at the BP O∙∙∙O within compound 3a exhibited electron density with a value of 0.0144 au.
The stability of compound 3a might also be interpreted as a consequence of the aromatic planarity, which could be detected from Figure 4a via dihedral angles (Φ) with a value of 1.83°. Notably, the difference between the dihedral angle of the optimized geometry of compound 3a and the X-ray data was nearly 0.36°.
As shown in Figure 4b, the NCI results (green isosurfaces) occurred at the interatomic space between the interacting atoms, asserting the occurrence of the intramolecular interactions towards the investigated compound. Large, green, round domains within the intramolecular forces N13∙∙∙HC12 and N14∙∙∙HC1 of compound 3a were crucially denoted, reflecting the favorable contribution of such intramolecular forces to the further stability of compound 3a.

3. Conclusions

The unprecedented dimerization and oxidation cascade of 4-hydrazinylquinolin-2(1H)-ones delivered pyridazino[4,3-c:5,6-c′]diquinoline-6,7(5H,8H)-diones in good yields. The synthesis of the obtained pyridazino-diquinolones was achieved in different conditions. Heating 4-hydrazinylquinolin-2(1H)-ones in pyridine was the best condition in which to obtain the corresponding products. Quantum mechanical calculations were also performed using the DFT method to prove the stability of the formed products. The method above can be used as a general method for the preparation of various classes of pentacyclic heterocycles from compounds with structural features similar to 4-hydroxy-2-quinolones. Importantly, the biological activity of the obtained products could assist in the development of new drugs.

4. Experimental Section

4.1. Chemistry

The IR spectra were recorded using the ATR technique (ATR = Attenuated Total Reflection) with an FT device (FT-IR Bruker IFS 88), Institute of Organic Chemistry, Karlsruhe University, Karlsruhe, Germany. The NMR spectra were measured in DMSO-d6 on a Bruker AV-400 spectrometer, 400 MHz for 1H, and 100 MHz for 13C; the chemical shifts are expressed in δ (ppm), versus internal tetramethylsilane (TMS) = 0 for 1H and 13C, and external liquid ammonia = 0. The description of signals includes: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, dd = doublet of doublet, and m = multiplet. Mass spectra were recorded on a FAB (fast atom bombardment) Thermo Finnigan Mat 95 (70 eV). Elemental analyses were carried out at the Microanalytical Center, Cairo University, Egypt. TLC was performed on analytical Merck 9385 silica aluminum sheets (Kieselgel 60) with Pf254 indicator; TLCs were viewed at λmax = 254 nm.

4.1.1. Starting Materials

4-Chloro-quinolin-2(1H)-ones 4a–g were prepared according to the literature [43,44,45], whereas 4-hydrazinylquinolin-2(1H)-ones 2a–g were synthesized according to the literature [46].

4.1.2. General Procedure

4-Hydrazinylquinolin-2(1H)-ones 2a–g (1 mmol) were heated in pyridine for 6–12 h until the reactants had disappeared, as mentioned in Scheme 1. The reaction was monitored using TLC (using toluene: EtOAc; 10:1). Then, the mixture was cooled and poured into iced water; the formed precipitate was filtered, washed with water, and recrystallized from the stated solvents to give pure crystals 3a–g.

5,8-Diethylpyridazino[4,3-c:5,6-c’]diquinoline-6,7(5H,8H)-dione (3a)

Orange crystals (DMF/H2O), yield: 0.31 g (86%); mp 330–332 °C. IR (KBr): υ = 3013 (Ar-CH), 2927 (Ali-CH), 1653 (C=O), 1603, 1561 (Ar-C=C) cm−1; NMR as reported in ref [38].

5,8-Dimethylpyridazino[4,3-c:5,6-c’]diquinoline-6,7(5H,8H)-dione (3b)

Orange crystals (DMF/EtOH), yield: 0.30 g (88%); mp 320–322 °C. IR (KBr) υ = 3023 (Ar-CH), 2929 (Ali-CH), 1652 (C=O), 1604, 1586 (Ar-C=C) cm−1; 1H NMR (400 MHz, DMSO-d6) δH = 3.72 (s, 6H, CH3), 7.38–7.40 (m, 2H, Ar-H), 7.71–7.76 (m, 4H, Ar-H), 8.03–8.06 (m, 2H, Ar-H); 13C NMR (100 MHz, DMSO-d6): δC = 39.91 (2 CH3), 115.87, 115.78, 119.12, 122.14, 122.25, 131.66, 136.82, 156.61, 165.81 ppm (C-6 and C-7); MS (Fab, 70 eV, %): m/z = 342 (M+, 82), 289 (6), 197 (13), 171 (23), 169 (36), 157 (100), 134 (48), 105 (15). Anal. Calcd. for C20H14N4O2 (342.35): C, 70.17; H, 4.12; N, 16.37. Found: C, 70.09; H, 4.23; N, 16.44.

Pyridazino[4,3-c:5,6-c’]diquinoline-6,7(5H,8H)-dione (3c)

Orange crystals (DMF/H2O), yield: 0.257 g (82%); mp 348–350 °C. IR (KBr) υ =3174 (NH), 3044 (Ar-CH), 1640 (C=O), 1602, 1585 (Ar-C=C) cm−1; 1H NMR (400 MHz, DMSO-d6) δH = 7.05–7.09 (m, 2H, Ar-H), 7.18–7.23 (m, 2H, Ar-H), 7.33–7.38 (m, 2H, Ar-H), 7.68 (dd, 2H, J = 7.8, 1.2 Hz, Ar-H), 11.99 (s, 2H, NH); 13C NMR (100 MHz, DMSO-d6): δC = 115.85, 115.96, 119.12, 122.52, 122.78, 130.87, 136.80, 157.77, 165.94 ppm (C-6 and C-7); MS (Fab, 70 eV, %): m/z = 314 (M+, 15), 287 (45), 243 (6), 228 (70), 171 (12), 157 (84). Anal. Calcd. for C18H10N4O2 (314.30): C, 68.79; H, 3.21; N, 17.83. Found: C, 68.68; H, 3.35; N, 17.77.

2,11-Dimethylpyridazino[4,3-c:5,6-c’]diquinoline-6,7(5H,8H)-dione (3d)

Orange crystals (DMF/H2O), yield: 0.287 g (84%); mp 352–354 °C. IR (KBr) υ = 3178 (NH), 3052 (Ar-CH), 1643 (C=O), 1606, 1581 (Ar-C=C) cm−1; 1H NMR (400 MHz, DMSO-d6) δH = 2.37 (s, 6H, CH3), 7.20–7.29 (m, 2H, Ar-H), 7.30–7.40 (m, 2H, Ar-H), 7.70 (d, 2H, J = 1.7 Hz, Ar-H), 12.21 (s, 2H, NH); 13C NMR (100 MHz, DMSO-d6): δC = 20.59 (2 CH3), 115.77, 115.88, 119.12, 122.14, 131.66, 132.15, 134.82, 157.62, 165.71 ppm (C-6 and C-7); MS (Fab, 70 eV, %): m/z = 342 (M+, 25), 327 (20), 312 (5), 271 (38), 171 (100), 157 (30). Anal. Calcd. for C20H14N4O2 (342.35): C, 70.17; H, 4.12; N, 16.37. Found: C, 70.25; H, 4.03; N, 16.25.

2,11-Dichloropyridazino[4,3-c:5,6-c’]diquinoline-6,7(5H,8H)-dione (3e)

Orange crystals (DMF/H2O), yield: 0.325 g (85%); mp 358–360 °C. IR (KBr) υ = 3177 (NH), 3023 (Ar-CH), 1640 (C=O), 1605, 1560 (Ar-C=C) cm−1; 1H NMR (400 MHz, DMSO-d6) δH = 7.34–7.35 (m, 2H, Ar-H), 7.36–7.37 (m, 2H, Ar-H), 7.68–7.70 (m, 2H, Ar-H), 12.19 (s, 2H, NH); 13C NMR (100 MHz, DMSO-d6): δC = 115.78, 115.92, 119.12, 122.10, 128.78, 132.87, 136.80, 157.52, 165.12 ppm (C-6 and C-7); MS (Fab, 70 eV, %): m/z = 383 (M+, 100), 348 (9), 313 (49), 305 (6), 227 (37), 191 (14). Anal. Calcd. for C18H8Cl2N4O2 (383.19): C, 56.42; H, 2.10; N, 14.62. Found: C, 56.51; H, 2.17; N, 14.53.

3,10-Dichloropyridazino[4,3-c:5,6-c’]diquinoline-6,7(5H,8H)-dione (3f)

Orange crystals (DMF/EtOH), yield: 0.341 g (89%); mp 358–360 °C. IR (KBr) υ = 3180 (NH), 3041 (Ar-CH), 1645 (C=O), 1610, 1567 (Ar-C=C) cm−1; 1H NMR (400 MHz, DMSO-d6) δH = 7.20–7.35 (m, 2H, Ar-H), 7.37–7.38 (m, 2H, Ar-H), 7.70 (d, 2H, J = 7.8 Hz, Ar-H), 12.20 (s, 2H, NH); 13C NMR (100 MHz, DMSO-d6): δC = 115.77, 115.88, 119.12, 122.14, 131.12, 132.15, 136.82, 157.62, 164.71 ppm (C-6 and C-7); MS (Fab, 70 eV, %): m/z = 383 (M+, 70), 313 (31) 227 (14), 191 (100), 153 (89), 137 (31), 110 (18). Anal. Calcd. for C18H8Cl2N4O2 (383.19): C, 56.42; H, 2.10; N, 14.62. Found: C, 56.30; H, 2.19; N, 14.55.

2,11-Dimethoxypyridazino[4,3-c:5,6-c’]diquinoline-6,7(5H,8H)-dione (3g)

Orange crystals (DMF/EtOH), yield: 0.325 g (87%); mp 354–356 °C. IR (KBr) υ = 3186 (NH), 3039 (Ar-CH), 1648 (C=O), 1607, 1577 (Ar-C=C) cm−1; 1H NMR (400 MHz, DMSO-d6) δH = 3.82 (s, 6H, OCH3), 7.20–7.23 (m, 2H, Ar-H), 7.32–7.33 (m, 2H, Ar-H), 7.34–7.37 (m, 2H, Ar-H), 12.13 (s, 2H, NH); 13C NMR (100 MHz, DMSO-d6): δC = 55.37 (2 OCH3), 116.53, 117.54, 120.53, 122.52, 131.30, 132.80, 134.47, 157.77, 165.73 ppm (C-6 and C-7); MS (Fab, 70 eV, %): m/z = 374 (M+, 100), 313 (36), 284 (55), 268 (46), 187 (50), 106 (18). Anal. Calcd. for C20H14N4O4 (374.35): C, 64.17; H, 3.77; N, 14.97. Found: C, 64.23; H, 3.60; N, 15.09.

4.1.3. Crystal Structure Determination

Single crystals were obtained via recrystallization from DMF/Water. The single-crystal X-ray diffraction study of 3a was carried out on a Bruker D8 VENTURE diffractometer with a PhotonII CPAD detector at 298 K using Cu-Kα radiation (λ = 1.54178 Å). Dual space methods (SHELXT) [51] were used for structure solution, and refinement was carried out using SHELXL [51] (full-matrix least-squares on F2). Hydrogen atoms were localized using difference electron density determination and refined using a riding model (H(N) free). A semi-empirical absorption correction was applied. The absolute structure was determined via the refinement of Parsons’ x-parameters [52].
3a: Orange crystals: C22H18N4O2, Mr = 370.40 g mol−1, size 0.20 × 0.12 × 0.04 mm, Orthorhombic, Pca21 (no.29), a = 21.1937 (4) Å, b = 9.2208 (2) Å, c = 17.9646 (3) Å, V = 3510.69 (12) Å3, Z = 8, Dcalcd = 1.402 Mg m−3, F(000) = 1552, μ (Cu-Kα = 0.75 mm−1, T = 298 K, 36,156 measured reflection (2θmax = 144.40), 6865 independent (Rint = 0.057), 506 parameters, 1 restraint, R1 (for 6684 I > 2σ(1)) = 0.042, wR2 (for all data) = 0.115, S = 1.02, largest diff. peak and hole = 0.34 eÅ−3/−0.22 eÅ−3, x = −0.05(11).
CCDC 2,128,843 (3a) contains the supplementary crystallographic data for this paper (see the Supplementary Materials). These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif (accessed on 10 February 2022).

4.1.4. Theoretical Calculations

Geometrical optimization and vibrational frequency calculations were carried out at the B3LYP/6-31G* level of theory [53,54] for the compounds under consideration. Upon the optimized structures, the energetic features were then evaluated at MP2/6-311 + G** [55]//B3LYP/6-31G* levels of theory. QTAIM and NCI calculations were performed with the help of Multiwfn 3.7 package [56] and were plotted using Visual Molecular Dynamics (VMD) software [57]. All quantum mechanical calculations were carried out at the B3LYP/6-31G* level of theory using Gaussian 09 software (Gaussian, Inc.: Wallingford, CT, USA) [58].

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/molecules27072125/s1. Figure S1: ORTEP diagram of compound 3a; Tables S1–S7: Crystal data of 3a; S14–S22: 1H, 13C NMR and Mass spectra of compounds 3a–g; S23–S24: Cartesian coordinates of the compound 3a used in DFT calculation.

Author Contributions

S.M.M. (writing and revision), A.A.A. (concept, writing, edit, revision, and submission), A.A.H. (editing), E.M.O. (experimental), S.B. (editing and revision), M.N. (X-ray analysis, writing); A.H.M. (writing, editing, and revision); M.A.A.I. (theoretical calculations, writing and editing). All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

All pertinent data have been supplied in the Supporting Information that accompanies this article.

Acknowledgments

The authors thank DFG for providing Ashraf A. Aly with a one-month fellowship, enabling him to conduct the compound analysis at the Karlsruhe Institute of Technology, Karlsruhe, Germany, in July and August 2019. We also acknowledge support from the KIT-Publication Fund of the Karlsruhe Institute of Technology.

Conflicts of Interest

The authors declare no conflict of interest.

Sample Availability

Samples of the compounds are not available from the authors.

References

  1. Larghi, E.L.; Bruneau, A.; Sauvage, F.; Alami, M.; Vergnaud-Gauduchon, J.; Messaoudi, S. Synthesis and Biological Activity of 3-(Heteroaryl)quinolin-2(1H)-ones Bis-Heterocycles as Potential Inhibitors of the Protein Folding Machinery Hsp90. Molecules 2022, 27, 412. [Google Scholar] [CrossRef] [PubMed]
  2. Shruthi, T.G.; Subramanian, S.; Eswaran, S. Design, Synthesis and Study of Antibacterial and Antitubercular Activity of Quinoline Hydrazone Hybrids. Heterocycl. Commun. 2020, 26, 137–147. [Google Scholar]
  3. Elenich, O.V.; Lytvyn, R.Z.; Blinder, O.V.; Skripskaya, O.V.; Lyavinets, O.S.; Pitkovych, K.E. Synthesis and Antimicrobial Activity of 3-Phenyl-1-Methylquinolin-2-One Derivatives. Pharmaceut. Chem. J. 2019, 52, 969–974. [Google Scholar] [CrossRef]
  4. Sharma, M.; Goyal, R.; Ahuja, D.; Sharma, A.; Soni, S.L. Antimicrobial and Antifungal Activity of Newly Synthesized 4-Hydroxy Quinoline Derivatives. Eur. J. Mol. Clin. Med. 2020, 7, 2082–2094. [Google Scholar]
  5. Diaz, J.; Rodenas, D.; Ballester, F.J.; Alajarin, M.; Orenes, R.A.; Sanchez-Andrada, P.; Vidal, A. Unlocking the synthetic potential of aziridine and cyclopropane-fused quinolin-2-ones by regioselective fragmentation of its three-membered rings. Arab. J. Chem. 2020, 13, 2702–2714. [Google Scholar] [CrossRef]
  6. Aly, A.A.; Ramadan, M.; Abuo-Rahma, G.E.A.; Elshaier, Y.A.M.M.; Elbastawesy, M.A.I.; Brown, A.B.; Bräse, S. Chapter Three—Quinolones as prospective drugs: Their syntheses and biological applications. Adv. Heterocycl. Chem. 2021, 135, 147–196. [Google Scholar]
  7. Scavone, C.; Mascolo, A.; Ruggiero, R.; Sportiello, L.; Rafaniello, C.; Berrino, L.; Capuano, A. Quinolones-Induced Musculoskeletal, Neurological, and Psychiatric ADRs: A Pharmacovigilance Study Based on Data From the Italian Spontaneous Reporting System. Front. Pharmacol. 2020, 11, 428. [Google Scholar] [CrossRef]
  8. Khamkhenshorngphanuch, T.; Kulkraisri, K.; Janjamratsaeng, A.; Plabutong, N.; Thammahong, A.; Manadee, K.; Pombejra, S.N.; Khotavivattana, T. Synthesis and Antimicrobial Activity of Novel 4-Hydroxy-2-quinolone Analogs. Molecules 2020, 25, 3059. [Google Scholar] [CrossRef]
  9. Hassan, M.M.; Hassanin, H.M. An Efficient New Route for the Synthesis of Some 3-Hterocyclylquinolinones via Novel 3-(1,2-Dihydro-4-hydroxy-1-methyl-2-oxoquinolin-3-yl)-3-oxopropanal and Their Antioxidant Screening. J. Heterocycl. Chem. 2017, 54, 3321–3330. [Google Scholar] [CrossRef]
  10. Wenjie, X.; Xueyao, L.; Guixing, M.; Hongmin, Z.; Ya, C.; Johannes, K.; Jie, X.; Song, W. N-thiadiazole-4-hydroxy-2-quinolone-3-carboxamides bearing heteroaromatic rings as novel antibacterial agents: Design, synthesis, biological evaluation and target identification. Eur. J. Med. Chem. 2020, 188, 112022. [Google Scholar]
  11. Tzeng, C.C.; Lee, K.H.; Wang, T.C.; Han, C.H.; Chen, Y.L. Synthesis and Cytotoxic evaluation of a series of γ-substituted γ-aryloxymethyl-α-methylene-γ-butyrolactones against cancer cells. Pharmaceut. Res. 2000, 17, 715–719. [Google Scholar] [CrossRef] [PubMed]
  12. Prajapati, S.M.; Patel, K.D.; Vekariya, R.H.; Panchal, S.N.; Patel, H.D. Recent advances in the synthesis of quinolines: A review. RSC Adv. 2014, 4, 24463–24476. [Google Scholar] [CrossRef]
  13. Navneetha, O.; Deepthi, K.; Rao, A.M.; Jyostna, T.S. A review on chemotherapeutic activities of quinoline. Int. J. Pharm. Chem. Biol. Sci. 2017, 7, 364–372. [Google Scholar]
  14. Constable, E.C.; Housecroft, C.E.; Neuburger, M.; Reymann, S.; Schaffner, S. 4-Substituted and 4,5-disubstituted 3,6-di(2-pyridyl)pyridazines: Ligands for supramolecular assemblies. Eur. J. Org. Chem. 2008, 9, 1597–1607. [Google Scholar] [CrossRef]
  15. Bodman, S.E.; Fitchett, C.M. Silver complexes of symmetrically 4,5-disubstituted 3,6-di(3,5-dimethyl-1H-pyrazol-1-yl)pyridazine. Supramol. Chem. 2015, 27, 840–846. [Google Scholar] [CrossRef]
  16. Wu, X.; Ji, H. Rhodium-Catalyzed [4 + 1] Cyclization via C–H Activation for the Synthesis of Divergent Heterocycles Bearing a Quaternary Carbon. J. Org. Chem. 2018, 83, 4650–4656. [Google Scholar] [CrossRef] [PubMed]
  17. Allart-Simon, I.; Moniot, A.; Bisi, N.; Ponce-Vargas, M.; Audonnet, S.; Laronze-Cochard, M.; Sapi, J.; Hénon, E.; Velard, F.; Gérard, S. Pyridazinone derivatives as potential anti-inflammatory agents: Synthesis and biological evaluation as PDE4 inhibitors. RSC Med. Chem. 2021, 12, 584–592. [Google Scholar] [CrossRef]
  18. Elmasry, G.F.; Aly, E.E.; Awadallah, F.M.; El-Moghazy, S.M. Design and synthesis of novel PARP-1 inhibitors based on pyridopyridazinone scaffold. Bioorg. Chem. 2019, 17, 655–666. [Google Scholar] [CrossRef]
  19. Besada, P.; Viña, D.; Costas, T.; Costas-Lago, C.M.; Vila, N.; Torres-Terán, I.; Sturlese, M.; Moro, S.; Terán, C. Pyridazinones containing dithiocarbamoyl moieties as a new class of selective MAO-B inhibitors. Bioorg. Chem. 2021, 115, 105203. [Google Scholar] [CrossRef]
  20. Li, B.; Wen, H.-M.; Wang, H.; Wu, H.; Yildirim, T.; Zhou, W.; Chen, B. Porous metal-organic frameworks with Lewis basic nitrogen sites for high-capacity methane storage. Energy Environ. Sci. 2015, 8, 2504–2511. [Google Scholar] [CrossRef]
  21. Saquib, M.; Ansari, M.; Johnson, C.R.; Khatoon, S.; Hussain, M.K.; Coop, A. Recent advances in the targeting of human DNA ligase I as a potential new strategy for cancer treatment. Eur. J. Med. Chem. 2019, 182, 111657. [Google Scholar] [CrossRef] [PubMed]
  22. Hamed, M.Y.; Aly, A.M.; Abdullah, N.H.; Ismail, M.F. Synthesis, Characterization and Antifungal Evaluation of Novel Pyridazin-3(2H)-One Derivatives. Polycyc. Aromat. Compd. 2022. [Google Scholar] [CrossRef]
  23. Gokce, M.; Utku, S.; Kupeli, E. Synthesis and analgesic and anti-inflammatory activities 6-substituted-3(2H)-pyridazinone-2-acetyl-2-(p-substituted/nonsubstituted benzal)hydrazone derivatives. Eur. J. Med. Chem. 2009, 44, 3760–3764. [Google Scholar] [CrossRef]
  24. Rubat, C.; Coudert, P.; Tronche, P.; Bastide, J.; Bastide, P.; Privat, A.M. Synthesis and pharmacological evaluation of N-substituted 4, 6-diaryl-3-pyridazinones as analgesic, antiinflammatory and antipyretic agents. Chem. Pharm. Bull. 1989, 37, 2832–2835. [Google Scholar] [CrossRef] [Green Version]
  25. Rathish, I.G.; Javed, K.; Bano, S.; Ahmad, S.; Alam, M.S.; Pillai, K.K. Synthesis and blood glucose lowering effect of novel pyridazinone substituted benzenesulfonylurea derivatives. Eur. J. Med. Chem. 2009, 44, 2673–2678. [Google Scholar] [CrossRef]
  26. Abouzid, K.; Hakeem, M.A.; Khalil, O.; Maklad, Y. Pyridazinone derivatives: Design, synthesis, and In Vitro vasorelaxant activity. Bioorg. Med. Chem. 2008, 16, 382–389. [Google Scholar] [CrossRef]
  27. Cao, S.; Qian, X.; Song, G.; Chai, B.; Jiang, Z. Synthesis and antifeedant activity of new oxadiazolyl 3(2H)-pyridazinones. J. Agric. Food Chem. 2003, 51, 152–155. [Google Scholar] [CrossRef]
  28. Asif, M.; Singh, A.; Siddiqui, A.A. Effect of pyridazine compounds on cardiovascular system. Med. Chem. Res. 2012, 21, 3336–3346. [Google Scholar] [CrossRef]
  29. Contreras, J.M.; Rival, Y.M.; Chayer, S.; Bourguignon, J.J.; Wermuth, C.G. Aminopyridazines as acetylcholinesterase inhibitors. J. Med. Chem. 1999, 42, 730–741. [Google Scholar] [CrossRef]
  30. Grote, R.; Chen, Y.; Zeeck, A.; Chen, Z.X.; Zähner, H.; Mischnick-Lübbecke, P.; König, W.A. Metabolic products of microorganisms. 243. Pyridazomycin, a new antifungal antibiotic produced by Streptomyces violaceoniger. J. Antibiot. 1988, 41, 595–601. [Google Scholar] [CrossRef] [Green Version]
  31. Horkel, E. Metalation of Pyridazine, Cinnoline, and Phthalazine. Top Heterocycl. Chem. 2013, 31, 223–268. [Google Scholar]
  32. Schmidt, E.W. One Hundred Years of Hydrazine Chemistry. In Proceedings of the 3rd Conference on Environmental Chemistry of Hydrazine Fuels, Panama City Beach, FL, USA, 17 September 1988; pp. 4–16. [Google Scholar]
  33. Moliner, A.M.; Street, J.J. Decomposition of Hydrazine in Aqueous Solutions. J. Environ. Qual. 1989, 18, 483–487. [Google Scholar] [CrossRef]
  34. Wagnerová, D.M.; Schewertnerová, E.; Vepřek-Šiška, J. Autooxidation of hydrazine catalyzed by tetrasulphophthalocyanines. Collect. Czech Chem. Commun. 1973, 38, 756–764. [Google Scholar] [CrossRef]
  35. Helal, A.; Qamaruddin, M.; Aziz, M.A.; Shaikh, M.N.; Yamani, Z.H. MB-UiO-66-NH2 metal-organic framework as chromogenic and fluorogenic sensor for hydrazine hydrate in aqueous solution. ChemistrySelect 2017, 2, 7630–7636. [Google Scholar] [CrossRef]
  36. Sahin, T.; Vairaprakash, P.; Borbas, K.E.; Balasubramanian, T.; Lindsey, J.S. Hydrophilic bioconjugatable trans-AB-porphyrins and peptide conjugates. J. Porphyr. Phthalocyanines 2015, 19, 663–678. [Google Scholar] [CrossRef]
  37. Hong, A.P.; Chen, T.-C. Catalyzed autoxidation of hydrazine by cobalt(II) 4,4′,4″,4‴-tetrasulfophthalocyanine. Environ. Sci. Technol. 1993, 27, 2404–2411. [Google Scholar] [CrossRef]
  38. Hassan, H. Unanticipated Heterocyclization from Reaction of Hydrazine Hydrate and/or Hydrazine Dihydrochloride with 1-Ethyl-4-hydroxyquinolin-2(1H)-one. J. Heterocycl. Chem. 2019, 56, 646–650. [Google Scholar] [CrossRef]
  39. Guanxing, Z.; Gang, Z. Access to a Phthalazine Derivative Through an Angular cis-Quinacridone. J. Org. Chem. 2021, 86, 1198–1203. [Google Scholar]
  40. Le-Nhat-Thuy, G.; Thi, T.A.D.; Thi, Q.G.N.; Thi, P.H.; Nguyen, T.A.; Nguyen, H.T.; Thi, T.H.N.; Nguyen, H.S.; Nguyen, T. Synthesis and biological evaluation of novel benzo[a]pyridazino[3,4-c]phenazine derivatives. Biorgan. Med. Chem. Lett. 2021, 43, 128054. [Google Scholar] [CrossRef]
  41. Zhang, Y.; Sim, J.H.; MacMillan, S.N.; Lambert, T.H. Synthesis of 1,2-Dihydroquinolines via Hydrazine-Catalyzed Ring-Closing Carbonyl-Olefin Metathesis. Org. Lett. 2020, 22, 6026–6030. [Google Scholar] [CrossRef]
  42. Aly, A.A.; Hassan, A.A.; Mohamed, A.H.; Osman, E.M.; Bräse, S.; Nieger, M.; Ibrahim, M.A.A.; Mostafa, S.M. Synthesis of 3,3′-methylenebis- (4-hydroxyquinolin-2(1H)-ones) of prospective anti-COVID-19. Mol. Divers. 2021, 25, 461–471. [Google Scholar] [CrossRef] [PubMed]
  43. Abass, M. Chemistry of substituted quinolinones. Part II synthesis of novel 4-pyrazolylquinolinone derivatives. Synth. Commun. 2000, 30, 2735–2757. [Google Scholar] [CrossRef]
  44. Ismail, M.; Abass, M.; Hassan, M. Chemistry of substituted quinolinones. Part VI. Synthesis and nucleophilic reactions of 4-chloro-8-methylquinolin-2(1H)-one and its thione analogue. Molecules 2000, 5, 1224–1239. [Google Scholar] [CrossRef] [Green Version]
  45. Ismail, M.; Abdel-Megid, M.; Hassan, M. Some reactions of 2-and 4-substituted 8-methylquinolin-2(1H)-ones and their thioanalogues. Chem. Papers Slovak Acad. Sci. 2004, 58, 117–125. [Google Scholar]
  46. Aly, A.A.; Sayed, S.M.; Abdelhafez, E.M.N.; Abdelhafez, S.M.N.; Abdelzaher, W.Y.; Raslan, M.A.; Ahmed, A.E.; Thabet, K.; El-Reedy, A.A.M.; Brown, A.B.; et al. New quinoline-2-one/pyrazole derivatives; design, synthesis, molecular docking, antiapoptotic evaluation, and caspase-3 inhibition assay. Bioorg. Chem. 2020, 94, 103348. [Google Scholar] [CrossRef]
  47. Hofmann, J.; Jasch, H.; Heinrich, M.R. Oxidative Radical arylation of anilines with arylhydrazines and dioxygen from Air. J. Org. Chem. 2014, 79, 2314–2320. [Google Scholar] [CrossRef]
  48. Liu, W.; Twilton, J.; Wei, B.; Lee, M.; Hopkins, M.N.; Bacsa, J.; Stahl, S.S.; Davies, H.M.L. Copper-catalyzed oxidation of hydrazones to diazo compounds using oxygen as the terminal oxidant. ACS Catal. 2021, 11, 2676–2683. [Google Scholar] [CrossRef]
  49. Bader, R.F.W. Atoms in Molecules. Acc. Chem. Res. 1985, 18, 9–15. [Google Scholar] [CrossRef]
  50. Johnson, E.R.; Keinan, S.; Mori-Sanchez, P.; Contreras-Garcia, J.; Cohen, A.J.; Yang, W. Revealing noncovalent interactions. J. Am. Chem. Soc. 2010, 132, 6498–6506. [Google Scholar] [CrossRef] [Green Version]
  51. Sheldrick, G.M. SHELXT—Integrated space-group and crystal-structure determination. Acta Crystallogr. 2015, 71A, 3–8. [Google Scholar] [CrossRef] [Green Version]
  52. Parson, S.; Flack, H.D.; Wagner, T. Use of intensity quotients and differences in absolute structure refinement. Acta Crystallogr. 2013, 69B, 249–259. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  53. Becke, A.D. Density-functional exchange-energy approximation with correct asymptotic behavior. Phys. Rev. A 1988, 38, 3098–3100. [Google Scholar] [CrossRef] [PubMed]
  54. Lee, C.; Yang, W.; Parr, R.G. Development of the Colle-Salvetti correlation-energy formula into a functional of the electron density. Phys. Rev. B 1988, 37, 785–789. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  55. Krishnan, R.; Binkley, J.S.; Seeger, R.; Pople, J.A. Self-consistent molecular orbital methods. XX. A basis set for correlated wave functions. J. Chem. Phys. 1980, 72, 650–654. [Google Scholar] [CrossRef]
  56. Lu, T.; Chen, F.; Multiwfn, F. A multifunctional wavefunction analyzer. J. Comput. Chem. 2012, 33, 580–592. [Google Scholar] [CrossRef]
  57. Humphrey, W.; Dalke, A.; Schulten, K. VMD: Visual molecular dynamics. J. Mol. Graph. 1996, 14, 33–38. [Google Scholar] [CrossRef]
  58. Frisch, M.J.; Trucks, G.W.; Schlegel, H.B.; Scuseria, G.E.; Robb, M.A.; Cheeseman, J.R.; Scalmani, G.; Barone, V.; Mennucci, B.; Petersson, G.A.; et al. Gaussian 09, Revision E.01; Gaussian, Inc.: Wallingford, CT, USA, 2009. [Google Scholar]
Molecules 27 02125 g001 550
Figure 1. Chemical structures of biologically active Pyridazomycin, Minaprine, Pyridaben and Chloridazone.
Figure 1. Chemical structures of biologically active Pyridazomycin, Minaprine, Pyridaben and Chloridazone.
Molecules 27 02125 g001
Molecules 27 02125 sch001 550
Scheme 1. Formation of compound 3a from the reaction of 1-ethyl-4-hydroxyquinolin-2(1H)-one (1) with hydrazine in o-DCB.
Scheme 1. Formation of compound 3a from the reaction of 1-ethyl-4-hydroxyquinolin-2(1H)-one (1) with hydrazine in o-DCB.
Molecules 27 02125 sch001
Molecules 27 02125 sch002 550
Scheme 2. Synthesis of pyridazino[4,3-c:5,6-c′]diquinoline-6,7(5H,8H)-diones 3a–g. Reagents and conditions: (a) POCl3, reflux, 2 h; (b) AcOH, reflux 12 h; (c) NH2.NH2.H2O, reflux 12 h; (d) pyridine reflux, 6–12 h.
Scheme 2. Synthesis of pyridazino[4,3-c:5,6-c′]diquinoline-6,7(5H,8H)-diones 3a–g. Reagents and conditions: (a) POCl3, reflux, 2 h; (b) AcOH, reflux 12 h; (c) NH2.NH2.H2O, reflux 12 h; (d) pyridine reflux, 6–12 h.
Molecules 27 02125 sch002
Molecules 27 02125 g002 550
Figure 2. Molecular structure of one of the crystallographic independent molecules of 3a.
Figure 2. Molecular structure of one of the crystallographic independent molecules of 3a.
Molecules 27 02125 g002
Molecules 27 02125 sch003 550
Scheme 3. The suggested mechanism describes the formation of compounds 3a–g.
Scheme 3. The suggested mechanism describes the formation of compounds 3a–g.
Molecules 27 02125 sch003
Molecules 27 02125 g003 550
Figure 3. The assigned structure of compound 3a.
Figure 3. The assigned structure of compound 3a.
Molecules 27 02125 g003
Molecules 27 02125 g004 550
Figure 4. (a) Quantum theory of atoms in molecules (QTAIM) and (b) 3D noncovalent interaction (NCI) isosurfaces for compound 3a. The isosurfaces were generated with a reduced density gradient value of 0.50 au and colored from blue to red according to sign (λ2), ρ ranging from −0.035 (blue) to 0.020 (red) au.
Figure 4. (a) Quantum theory of atoms in molecules (QTAIM) and (b) 3D noncovalent interaction (NCI) isosurfaces for compound 3a. The isosurfaces were generated with a reduced density gradient value of 0.50 au and colored from blue to red according to sign (λ2), ρ ranging from −0.035 (blue) to 0.020 (red) au.
Molecules 27 02125 g004
Table
Table 1. The reaction optimization for the formation of 3a.
Table 1. The reaction optimization for the formation of 3a.
EntryMethodYields of 3a (%)
APyridine, reflux, 8 h88
BEtONa/EtOH, reflux 24 h a 74
CToluene/Et3N, reflux, 2 d b60
DDMF/Et3N, reflux 20 h c78
ENa/Toluene, reflux 18 h d82
FEtOH/HCl, reflux eNo reaction
a 1 mmol of 2a and 0.1 mmol of EtONa in 100 mL of absolute EtOH at 70 °C. b 1 mmol of 2a + 0.5 mL of Et3N in 30 mL of toluene at 80 °C. c 1 mmol of 2a + 0.5 mL of Et3N in 15 mL of DMF at 100 °C. d 1 mmol of 2a + 0.5 mol of Na in 30 mL of toluene at 80 °C. e 1 mmol of 2a + 1 mL of 0.1 M HCl in 100 mL of absolute EtOH at 70 °C.
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Share and Cite

MDPI and ACS Style

Mostafa, S.M.; Aly, A.A.; Hassan, A.A.; Osman, E.M.; Bräse, S.; Nieger, M.; Ibrahim, M.A.A.; Mohamed, A.H. Autoxidation of 4-Hydrazinylquinolin-2(1H)-one; Synthesis of Pyridazino[4,3-c:5,6-c′]diquinoline-6,7(5H,8H)-diones. Molecules 2022, 27, 2125. https://doi.org/10.3390/molecules27072125

AMA Style

Mostafa SM, Aly AA, Hassan AA, Osman EM, Bräse S, Nieger M, Ibrahim MAA, Mohamed AH. Autoxidation of 4-Hydrazinylquinolin-2(1H)-one; Synthesis of Pyridazino[4,3-c:5,6-c′]diquinoline-6,7(5H,8H)-diones. Molecules. 2022; 27(7):2125. https://doi.org/10.3390/molecules27072125

Chicago/Turabian Style

Mostafa, Sara M., Ashraf A. Aly, Alaa A. Hassan, Esraa M. Osman, Stefan Bräse, Martin Nieger, Mahmoud A. A. Ibrahim, and Asmaa H. Mohamed. 2022. "Autoxidation of 4-Hydrazinylquinolin-2(1H)-one; Synthesis of Pyridazino[4,3-c:5,6-c′]diquinoline-6,7(5H,8H)-diones" Molecules 27, no. 7: 2125. https://doi.org/10.3390/molecules27072125

Article Metrics

Back to TopTop