Scope and Limitations of a Novel Synthesis of 3-Arylazonicotinates

The reaction of 3-oxo-3-phenyl-2-phenylhydrazonal with functionally substituted and heteroaromatic substituted acetonitrile to yield arylazonicotinic acid derivatives and 5-arylsubstituted pyridines was established. In some cases the produced nicotinates could not be isolated as they underwent thermally induced 6π-electrocyclization yielding polynuclear pyridine derivatives.

In the past we have reported novel synthesis of polyfunctional pyridazines 4 via heating 1 with dimethyl acetylenedicarboxylate (2) as well as acrylonitrile (3) in presence of triphenylphosphine or a tertiary amine base [4,5] (Scheme 1). We have also reported that condensing active methylene nitriles 5 with 1 affords products that were believed to be the pyridazine imines 6 [6]. Recently however Al-Mousawi et al. [7,8] realized that this structure cannot be correct as reported 13 C-NMR data for the OPEN ACCESS product lacked a carbonyl carbon at δ < 175 ppm. It was revealed that the products of condensing 1 with ethyl cyanoacetate are really the arylazonicotinates 7 (cf. Scheme 1), as clearly revealed by the X-ray crystal structure ( Figure 1). Scheme 1. Chemical reactivies of 3-oxo-3-substituted-2-arylhydrazonals 1. However, in some case pyridazinones 8 were the reaction products rather than nicotinates. In light of the enormous potential of arylazonicotinates both as new pyridone dyes [9] and as biologically active compounds with anticonvulsant activity that act due to synaptic and non-synaptic mechanisms and some studies that have proved their antitumor and antimicrobial activities [10], we were interested in defininh further the behavior of 1 toward 5 to see if the reaction would afford 7 or 8. In the present article we report on the reactivity of 1a-d toward a variety of derivatives of 5 where we noted that this reaction may produce derivatives of 7 or 8 depending on the nature of 5. Distinguishing between 7 and 8 could be easily accomplished based on 13 C-NMR data as the absence of a carbonyl carbon signal would mean that the product is not an arylpyridazine derivative. Also with some derivatives of 7 electrocyclization and loss of hydrogen leading to novel 6-aryl-6H-pyrido[3,2-c]cinnolin-2-ones 9 seems probable.

Results and Discussion
Compounds 1a-d reacted with malononitrile 5b yielding the arylazonicotinonitriles 7b,h, respectively as indicated by the absence of carbonyl carbon absorptions in the 13 C-NMR of the products. Similar to their behavior toward malononitrile compounds, 1a-d condensed with 5a,c-k to yield phenylazonicotinates 7a,c-g (Scheme 2).

Scheme 2.
Syntheses of phenylazonicotinates 7a,c-g.  The reaction of 1a,b with 5c,d,k in ethanolic piperidine solution resulted in the formation of 12a-c. It is believed that the initially formed derivative of 7 readily underwent a 6π electrocyclization yielding 11a-c that then aromatized to the final products 12a-c (Scheme 4). We believe that the decreased aromaticity of the thiophene ring as compared to benzene is behind this ready electrocyclization, and in support of this conclusion we have found that 1c also afforded 14b-d,g,k upon reaction with 5b-d,g,k; again the initially formed derivative of 7 underwent electro-cyclization to 13 and then aromatized to yield 14b-d,g,k (Scheme 5). In summary, we could clearly demonstrate that the structures of the products obtained by reacting 1a-d with active methylenes can be readily concluded via inspection of position of the carbonyl carbon signals in the corresponding 13 C-NMR spectra. When a arylhydrazone moiety in the intermediates cyclises via addition to a CN function subsequent hydrolysis of the formed imine usually occured leading to pyridazinones.

General
Melting points are reported uncorrected and were determined with a Sanyo (Gallaenkamp) instrument. Infrared spectra were recorded using KBr pellets and a Perkin-Elmer 2000 FT-IR instrument. 1 H-and 13 C-NMR spectra were determined using a Bruker DPX instrument at 400 MHz for 1 H-NMR and 100 MHz for 13 C-NMR and DMSO-d 6 solutions with TMS as internal standard. Chemical shifts are reported in δ (ppm). Mass spectra were measured using a VG Autospec Q MS 30 and MS 9 (AEI) spectrometers, using the EI (70 EV) mode. Elemental analyses were carried out using a LEO CHNS-932 Elemental Analyzer

General Procedure for the Synthesis of Compounds 7a,c-g
A mixture of 1a-d (0.01 mmol), and active methylenenitrile derivatives 5a-l (0.01 mmol) in the presence of piperidine (5 drops) and ethanol (10 mL) as a solvent was refluxed for 1-2 h. The reaction mixture was evaporated. The solid product, so formed, was crystallized from a suitable solvent.

Conclusions
In conclusion it has been found that 5 condenses with 1a to yield pyridazinones 7 as indicted from the presence of a carbonyl carbon as δ = 165 ppm in the 13 C-NMR. Initially formed imines 6 in this case are readily hydrolysed under the reaction conditions to yield the final products. In fact this finding supports our belief that heterocyclic imines like 6 are difficult to isolate as they readily afford the more stable aromatic derivative.