Condensation Reactions of 3-Oxo-2-arylhydrazonopropanals with Active Methylene Reagents: Formation of 2-Hydroxy- and 2-Amino-6-substituted-5-arylazonicotinates and Pyrido[3,2-c]cinnolines via 6π-Electrocyclization Reactions

3-Oxo-3-phenyl-2-(p-tolylhydrazono)propanal (1a) undergoes condensation with ethyl cyanoacetate in acetic acid in the presence of ammonium acetate to yield either 2-hydroxy-6-phenyl-5-p-tolylazonicotinic acid ethyl ester (6a) or 2-amino-6-phenyl-5-p-tolyl-azonicotinic acid ethyl ester (8), depending on the reaction conditions. Similarly, other 3-oxo-3-aryl-2-arylhydrazonopropanals 1a,b condense with active methylene nitriles 2c,d to yield arylazonicotinates 6b,c. In contrast, 2-[(4-nitrophenyl)-hydrazono]-3-oxo-3-phenyl-propanal (1c) reacts with ethyl cyanoacetate to yield ethyl 6-(4-nitrophenyl)-2-oxo-2,6-dihydropyrido[3,2–c]cinnoline-3-carboxylate (11), via a novel 6π-electrocyclization pathway. Finally, 3-oxo-2-(phenylhydrazono)-3-p-tolylpropanal (1d) condenses with 2a–c to yield pyridazinones 13a–c.


OPEN ACCESS
Although condensation reactions of arylhydrazonopropanals with active methylene nitriles were originally reported to afford pyridazin-6-imines [3], more recent studies in our laboratories have demonstrated that arylazonicotinates are also formed in some of these processes [7][8][9].
Because arylazonicotinates are a valuable class of arylazopyridine dyes whose chemistry has attracted some interest as new disperse dyes [10,11], it seemed of value to undertake an investigation aimed at exploring the potential utility of arylhydrazonopropanals as precursors for the preparation of these targets. A recent investigation, described below, has led to the synthesis of two different types of substances, including 2-hydroxyarylazonicotinic acid ethyl esters and 2-aminoarylazonicotinic acid ethyl esters, along with ethyl 6-(4-nitrophenyl)-2-oxo-2,6-dihydropyrido [3,2-c]cinnoline-3carboxylate, which forms via a pathway involving a novel 6-electrocyclization reaction.

Results and Discussion
In the first phase of the current effort, we observed that reaction of the 3-oxo-3-phenyl-2-(ptolylhydrazono)propanal (1a) with ethyl cyanoacetate in acetic acid for 30 min in the presence of a catalytic amount of ammonium acetate leads to formation of the ethyl 2-hydroxy-6-phenyl-5-ptolylazonicotinate (6a; Scheme 1) whose structure was established by X-ray crystallographic analysis ( Figure 1) [12].
In contrast, when the condensation reaction of 1a with ethyl cyanoacetate is conducted in the presence of excess of ammonium acetate, ethyl 2-amino-6-phenyl-5-p-tolylazonicotinate (8) is produced. The structure of 8 was also assigned by using X-ray crystallographic methods ( Figure 2) [12].
It is believed that these processes involve initial reaction of 1a with ethyl cyanoacetate to yield the hydrazono-enone 3 that then cyclizes to generate the pyran-imine 4. In the absence of ammonium ion, 4 undergoes a Dimroth type rearrangement to yield 6a. However, in the presence of a high concentration of ammonium acetate, pyran-imine 4 participates in a ring opening to yield amidine 7 that then cyclizes followed by water elimination to yield 8.
In the final phase of the current effort, we observed that reactions of the 3-oxo-2-(phenylhydrazono)-3-p-tolylpropanal (1d) with active methylene nitriles 2a-c in the presence of catalytic amounts of ammonium acetate in acetic acid for 30 min lead to the respective pyridazinones 13a-c, which are likely formed via the intermediacy of the readily hydrolyzed imine analogs 12 (Scheme 3). The structure of 13a was established by X-ray crystallography ( Figure 3) [12].

General
Melting points were recorded on a Gallenkamp apparatus. IR spectra were recorded using KBr pellets on a Jasco FTIR-6300 FT-IR spectrophotometer. 1 H-and 13 C-NMR spectra were recorded on Bruker DPX 400 MHz or AvanceII 600 MHz super-conducting NMR spectrometers (proton spectra measured at 400, 600 MHz and carbon spectra at 100 and 150 MHz, respectively). Mass spectra were measured on a high resolution GC/MS DFS-Thermo. Microanalyses were performed on Elementar-Vario Micro cube Analyzer. X-Ray analyses were performed using a Rigaku Rapid II diffractometer.

General Procedure for the Preparation of Compounds 6a-c
Independent mixtures of 1a,b (0.01 mol), active methylenenitrile derivatives 2a or 2c or 2d (0.01 mol), and ammonium acetate (0.5 g) in acetic acid (10 mL) were stirred at reflux for 30 min (progress of the reactions was monitored by using TLC using 1:1 ethyl acetate-petroleum ether as eluent). The mixtures were cooled and then poured into ice-water. The solids that formed were collected by using filtration and crystallized from proper solvents to give 6a-c.  (8) Independent mixtures of 1a (0.01 mol), ethyl cyanoacetate 2a (0.01 mol), and ammonium acetate (3 g) in acetic acid (10 mL) were stirred at reflux for 30 min (progress of the reactions was monitored by using TLC using 1:1 ethyl acetate-petroleum ether as eluent). The mixtures were cooled and then poured into ice-water. The solids that formed were collected by using filtration and crystallized from proper solvents to give 8 as wine red crystals (83%) (

General Procedure for the Preparation of Compounds 13a-c
Independent mixtures of 1d (0.01 mol), active methylenenitrile derivatives 2a-c (0.01 mol), and ammonium acetate (0.5 g) in acetic acid (10 mL) were stirred at reflux for 30 min (progress of the reactions was monitored by using TLC using 1:1 ethyl acetate-petroleum ether as eluent). The mixtures were cooled and then poured into ice-water. The solids that formed were collected by using filtration and crystallized from proper solvents to give 13a-c.

Conclusions
In conclusion, in the investigation described above, we have observed that 3-oxo-2arylhydrazonopropanals that do not possess strongly electron-withdrawing aryl substituents react with active methylene nitriles to afford 2-arylhydroxyazonicotinates and 2-arylaminoazonicotinates, in a manner that depends on the concentrations of ammonium acetate. In the case of the p-nitro-substituted members of this family, a facile 6π-electrocyclization reaction takes place on the hydrazono-pyridone intermediate to yield the corresponding ethyl 6-(4-nitrophenyl)-2-oxo-2,6-dihydropyrido[3,2c]cinnoline-3-carboxylate, a likely result of a substituent effect on frontier orbital interactions that favor the pericyclic process.