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

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.

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).
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 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].
Hydrazines have shown basic and reducing characteristics that enable their uti many industrial and medical applications. Accordingly, hydrazines have served as fuel, antioxidants, oxygen scavengers, and as intermediates for the production of sives, propellants, and pesticides [32].
It has been demonstrated that oxygen makes hydrazine solutions unstable, espe under alkaline or neutral conditions. However, hydrazines are stable under str acidic conditions or without oxygen [33].
Previously, it was reported [38] that 1-ethyl-4-hydroxyquinolin-2(1H)-one (1) re with hydrazine hydrate, in 1,2-dichlorobenzene (o-DCB), to give a mixture of two pounds. These compounds were separated using fractional recrystallization to give olinylhydrazine 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 IC 50 < 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/Et 3 N 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.
tion, 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.

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, 1 H NMR, and 13 C NMR spectra. For example, the mass spectrum and elemental analysis of 3a established its molecular formula as C 22 H 18 N 4 O 2 . The 1 H NMR spectrum of 3a exhibited the ethyl protons as a triplet at δ H = 1.22 (J = 7.6 Hz) for CH 3 and a quartet at δ H = 4.39 ppm (J = 7.6 Hz) for CH 2 . The eight aromatic protons appeared as three multiplets at δ H = 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 13 C NMR spectrum of compound 3a showed the carbonyl-quinolone, 2NCH 2, and CH 3 carbon signals at δ C = 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). 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 13 C 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). 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/Et 3 N (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 Et 3 N 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. 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]. ..

Scheme 3.
The suggested mechanism describes the formation of compounds 3a-g.
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 singlepoint 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 Scheme 3. The suggested mechanism describes the formation of compounds 3a-g.
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   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.

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 1     The stability of compound 3a might also be interpreted as a consequence of matic planarity, which could be detected from Figure 4a via dihedral angles (Φ value of 1.83°. Notably, the difference between the dihedral angle of the optimized etry 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 inte space between the interacting atoms, asserting the occurrence of the intramolecul actions towards the investigated compound. Large, green, round domains within tramolecular forces N13•••HC12 and N14•••HC1 of compound 3a were crucially deno flecting the favorable contribution of such intramolecular forces to the further sta compound 3a.

Chemistry
The IR spectra were recorded using the ATR technique (ATR = Attenuated T flection) with an FT device (FT-IR Bruker IFS 88), Institute of Organic Chemistry ruhe University, Karlsruhe, Germany. The NMR spectra were measured in DMS a Bruker AV-400 spectrometer, 400 MHz for 1   The isosurfaces were generated with a reduced density gradient value of 0.50 au and colored from blue to red according to sign (λ 2 ), ρ ranging from −0.035 (blue) to 0.020 (red) au.

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.

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-d 6 on a Bruker AV-400 spectrometer, 400 MHz for 1 H, and 100 MHz for 13 C; the chemical shifts are expressed in δ (ppm), versus internal tetramethylsilane (TMS) = 0 for 1 H and 13 C, 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.