Synthesis of A New Class of Pyridazin-3-one and 2-Amino-5-arylazopyridine Derivatives and Their Utility in the Synthesis of Fused Azines

A general route for the synthesis of a novel class of pyridazin-3-one derivatives 3 by the reaction in acetic anhydride between 3-oxo-2-arylhydrazonopropanals 1 and some active methylene compounds like p-nitrophenylacetic acid and cyanoacetic acid was established. Under these conditions the pyridazin-3-one derivatives 3 were formed as the sole isolable products in excellent yield. The 6-acetyl-3-oxopyridazine derivative 3l was reacted with DMF-DMA to afford the corresponding enaminone derivative 4, which reacts with a variety of aminoazoles to afford the corresponding azolo[1,5-a]pyrimidine derivatives 5–7. Also, in order to explore the viability and generality of a recently uncovered reaction between 3-oxo-2-arylhydrazonopropanals and active methylene compounds, a variety of 2-amino-6-aryl-5-arylazo-3-aroylpyridines 16–19 were prepared by reacting 3-oxo-2-arylhydrazonopropanals with miscellaneous active methylene compounds like 3-oxo-3-phenylpropionitrile, hetaroylacetonitriles and cyanoacetamides. These 2-aminopyridine derivatives undergo smooth reactions with cyanoacetic acid that led to the formation in high yield of a new class of 1,8-naphthyridine derivatives 24. The structures of all new substances prepared in this investigation were determined by the different analytical spectroscopic methods, in addition to the X-ray crystallographic analysis.


Results and Discussion
In earlier investigations we developed methods for the efficient synthesis of a variety of polyfunctional azoles, azines and their fused derivatives [32][33][34][35][36]. Recent efforts in our laboratories have led to the design of new and general strategies for the preparation of 2-amino-5-arylazonicotinates and pyridazinones [37] that involve reactions of 3-oxo-2-arylhydrazonopropanals 1 with active methylene compounds, including ethyl cyanoacetate, and malononitrile, depending on the effect of the substituent present in the arylazo moiety. Now it was of interest to explore the scope and limitations and generality of the 3-oxo-2-arylhydrazonopropanals 1 as a precursor for the synthesis of some new polyfunctionally substituted pyridazines and pyridines. In order to establish a general route for the synthesis of pyridazin-3-one derivatives 3 as sole products we conducted the reaction between 3-oxo-2-arylhydrazonopropanals 1 and some active methylene compounds, namely p-nitrophenylacetic acid (2a), o-nitrophenylacetic acid (2b) and cyanoacetic acid (2c) in acetic anhydride. Under these conditions only the pyridazin-3-one derivatives 3 were formed as sole isolable products in excellent yield. The structure of the pyridazin-3-one derivatives 3 was established based on their spectroscopic analyses and X-ray crystallographic analysis (Scheme 1, Figures 2 and 3 . ORTEP plot of the X-ray crystallographic data determined for 3d [38]. . ORTEP plot of the X-ray crystallographic data determined for 3l [39]. A plausible mechanism for the formation of pyridazin-3-ones 3 (Scheme 2) involves a condensation reaction between the two substrates 1 and 2 to generates the alkylidene intermediate A, which then undergoes cyclization via elimination of another water molecule to afford smoothly the pyridazin-3ones 3. As illustrated in this mechanism, only two consecutive eliminations of water molecules in the presence of acetic anhydride as a reaction medium were needed to afford only the pyridazin-3-ones 3 in all cases and the formation of the 5-arylazopyridines not observed, due to the absence of ammonium acetate which furnishes the ammonia that plays an essential rule in the formation of the 5-arylazopyridines as described in previous studies [37,40]  In order to synthesize a new class of enaminone derivatives the 6-acetyl-3-oxopyridazine derivative 3l was condensed with dimethylformamide dimethylacetal (DMF-DMA) in dioxane to yield the corresponding enaminone 4, whose 1 H-NMR spectrum revealed the characteristic two doublet bands for the two olefinic CHs at δ 5.88 and 7.81, respectively, and two signals due to the two methyl groups at δ 2.84 and 3.15, respectively. Moreover MS and HRMS showed its expected M + ion. The foregoing results prompted us to investigate the behaviour of the enaminone 4 towards some N-nucleophiles such as heterocyclic amines, as potential precursors of polyfunctionally-substituted fused pyrimidine derivatives for which we expect a broad spectrum of biological activity (Scheme 3). Thus the enaminone 4 was reacted with 3-amino-1,2,4-triazole, 3-phenyl-5-aminopyrazole and 2-aminobenzimidazole in refluxing pyridine to afford the corresponding azolo[1,5-a]pyrimidine derivatives 5-7 that incorporate the pyridazin-3-one moiety. A plausible mechanism for the formation of triazolo[1,5-a]pyrimidine derivatives 5 is taken as a representative example to explain the reaction between the enaminone 4 and heterocyclic amines (Scheme 4). In a recent study [40] we have also demonstrated that 2-amino-6-aryl-5-arylazo-3-benzoylpyridines 10 were formed as the sole isolable products in the reaction between 3-oxo-3-phenylpropionitrile (9) and 3-oxo-2-arylhydrazonopropanals 8a-b containing electron poor arylhydrazone groups as substrates, possessing two electron-withdrawing nitro and Cl groups on the aryl ring of this moiety (Scheme 5).

Scheme 5.
Synthesis of 2-aminopyridines 10 [40]. It was therefore of interest to explore the scope, limitations and extend the generality of reaction between 3-oxo-2-arylhydrazonopropanals 8a with miscellaneous active methylene compounds like 3-oxo-3-phenylpropionitrile, hetaroylacetonitriles and cyanoacetamides to afford polyfunctionally substituted 2-aminopyridines and their utility in the synthesis of 1,8-naphthyridine derivatives. Thus we explored reactions between 3-oxo-2-arylhydrazonopropanal 8a and cyanoacetylindoles 11,12 and different cyanoacetamides 13,14. These processes afford products which were shown to be the respective 2-aminopyridine derivatives 16-19 and it is believed that these 2-aminopyridines were formed via the intermediacy of E-G, as illustrated in the mechanistic pathway presented in (Scheme 6).

Scheme 6.
A plausible mechanism for the formation of 2-aminopyridines.
In contrast to the observed behaviour of 11-14 towards 8a the thiophene cyanoacetamide 15 behaves differently, affording the pyridazinimine derivatives 20 and not the 2-aminopyridine derivatives 21 or the 2-oxopyridines 22 according to the 1 H-NMR spectra which showed two signals at δ ≈ 9.80 and 13.3 ppm corresponding to two NH groups, one for the imine NH and the other for the amide NH. Also the 13 C-NMR spectrum showed a signal at δ ≈ 187.5 corresponding to a true ketone CO and not an amide CO. Till now the factors that make the thiophene cyanoacetamide afford the pyridazine and not pyridine are not clear, but this behaviour may be related to the nature of the thiophene heterocyclic ring and is compatible with an earlier study in which when 3-oxo-2thiophenehydrazonopropanal reacts with ethyl cyanoacetate, it also affords the pyridazine and not the pyridine system [41]. The structures of these substances were assigned based on their spectroscopic and mass spectrometric properties and X-ray single crystal determination (Scheme 7, Figure 4).
In order to complete the goal of this study we conducted a reaction between the 2-aminopyridine derivatives 10a,b and cyanoacetic acid in the presence of acetic anhydride to smoothly afford the desired 1,8-naphthyridinecarbonitrile derivatives 24a,b in very good yield. The reaction proceeds most likely via the intermediacy of 23 (Scheme 8).

General
Melting points were recorded and are reported uncorrected. The IR spectra were recorded using KBr pellets on a JASCO FTIR-6300 FT-IR spectrophotometer (Mary's Court, Easton, MD, USA). 1 H-NMR (400 MHz) or (600 MHz) and 13 C-NMR (100 MHz) or (150 MHz) spectra were recorded at 25 °C using CDCl 3 or DMSO-d 6 solutions with TMS as an internal standard on a Bruker DPX 400 or 600 super-conducting NMR spectrometer (Rheinstetten, Germany). Chemical shifts are reported in ppm. Low-resolution electron impact mass spectra [MS (EI)] and high-resolution electron impact mass spectra [HRMS (EI)] were measured using a high resolution GC-MS (DFS) thermo spectrometer at 70.1 eV using magnetic sector mass analyzer (Bremen, Germany). Microanalyses were performed on Elementar-Vario Micro cube Analyzer (Hanau, Germany). Monitoring reactions and determining the homogeneity of the prepared compounds were performed by using thin layer chromatography (TLC) (Sigma-Aldrich). The crystal structures were determined by a Rigaku R-AXIS RAPID diffractometer (Tokyo, Japan) and Bruker X8 Prospector (Madison, WI, USA) and the crystal data collections were made by using Cu-Kα radiation. The data were collected at room temperature. The structure was solved by direct methods and was expanded using Fourier techniques. The non-hydrogen atoms were refined anisotropically. The structure was solved and refined using the Bruker SHELXTL Software Package (Structure solution program-SHELXS-97 and Refinement program-SHELXL-97) [43]. Data were corrected for the absorption effects using the multi-scan method (SADABS). Compounds 10a and 10b were prepared according to a literature procedure [40]. temperature. The formed solids were collected by filtration washed by EtOH and recrystallized from the appropriate solvent.

General Procedure for the Synthesis of Azolopyrimidines 5-7
Independent mixtures of 4 (0.78 g, 2 mmol) and the appropriate heteroaromatic amine (2 mmol) in pyridine (20 mL) were stirred at reflux for 24 h. The reaction mixtures were cooled to room temperature and poured into ice cold water then acidified with hydrochloric acid (2 N), forming solids that were collected by filtration and washed with water then MeOH and recrystallized from the appropriate solvent.

Conclusions
The results of the study described above have led to the development of a simple approach for the synthesis of a novel class of pyridazin-3-one and 2-aminopyridine derivatives. Furthermore, the observations made during this work showed that these compounds are versatile precursors for the synthesis of some very important fused azines like azolo[1,5-a]pyrimidines and 1,8-naphthyridines, for which we expect a wide range of biological activity.