Enaminones as Building Blocks in Heterocyclic Syntheses: Reinvestigating the Product Structures of Enaminones with Malononitrile. A Novel Route to 6-Substituted-3-Oxo-2,3-Dihydropyridazine-4-Carboxylic Acids

The reported structures of reaction products of enaminones with malononitrile in ethanolic piperidine are revised. A novel route to 2,3-dihydropyridazine-4-carboxylic acids 4a-c via reactions of 2-cyano-5-(dimethylamino)-5-arylpenta-2,4-dienamides 8a-c with nitrous acid or with benzenediazonium chloride is reported. Compounds 8a-c are converted to 1,2-dihydropyridine-3-carboxylic acid and 1,2-dihydropyridine-3-carbonitrile derivatives upon reflux in EtOH/ HCl and in AcOH.


Introduction
Enaminones are polydentate reagents that have been utilized extensively in this decade as building blocks in organic synthesis [1][2][3][4][5][6]. In previous work at our laboratories, we reported several efficient routes to polyfunctionally substituted heterocycles utilizing enaminones as starting materials [7][8][9][10][11]. We have also reported that the reaction of 1a with malononitrile in ethanolic sodium ethoxide afforded OPEN ACCESS 2a in good yield [12], while reacting 1a-c with malononitrile in ethanolic piperidine was believed to afford 3a-c [13] (cf. Scheme 1). In continuation to this work, the chemical reactivity of the products believed to be 3a-c was reinvestigated. The work has led us to revise the initially proposed structures of these products.

Results and Discussion
The reaction of 1a-c with malononitrile in ethanolic piperidine afforded products of molecular formulae corresponding to the formation of 1:1 adducts. As reported earlier [13], the reaction products showed in the 1 H-NMR spectrum, in addition of the dimethylamino moiety, two olefinic proton doublets at δ H = ca. 5.77 and 7.23 ppm with J = 13 Hz, which fits well with the previously assumed initial 1,2-addition of malononitrile at the carbonyl moiety. Subsequent water elimination and hydrolysis of one of the cyano groups into an amide yielded 3a-c. However, treating these reaction products with sodium nitrite in EtOH/HCl in presence of sodium acetate affords products for which structures 4a-c are assigned, based on X-ray crystal structure determination [14]. Although the described conditions may not normally lead to hydrolysis of nitriles, however a ready hydrolysis in this case may be prompted by the stabilization of products by potential hydrogen bonding and high reactivity of the nitrile group as part of a π-deficient system. Quite unexpectedly, coupling the products, obtained from the reaction of malononitrile with enaminones 1a-c, with benzenediazonium chloride in dioxane/AcONa resulted in the formation of the same products 4a-c, in good yields.
There is indication of extensive delocalization of N-1 lone-pair at carbonyl carbon. Thus N-3 bond angles are more like those of sp 2 nitrogen, while those of N-7-C10-C8 are more like sp 3 carbon (cf. Figure 1 and Table 1).  Disconnection of 4a-c and consideration of the reported data has led us to believe that the products initially thought to be 3a-c are in fact 8a-c, which are formed via initial 1,4-addition of malononitrile across the double bond to yield 5 that cyclized to 6 then rearranged to 7, that finally afforded 8 via an allowed 1,3-nitrogen shift (cf. Scheme 2). However, a possible conversion of 3 to 8 involving migration of R via a 1,3 shift should not be overlooked. We wish to state that both 8 and 3 have the same molecular formulae and same spectral data, which after further inspection, established the structures 8a-c. Thus, assuming that H-4 are shielded by nitrogen lone pair anisotropic effect, while H-3 are deshielded by electron attracting substituents; it is hence logic to assign the doublets at δ H = ca. 5.68 ppm to H-4, while the doublets at δ H = ca. 7.39 ppm would correspond to H-3. If the reaction products were 3a-c, then H-4 in these assumed structures are shielded and H-5 are deshielded. We note that the deshielded doublet for 8a at δ H = ca. 7.39 ppm are correlated in the HMBC experiments with the amide carbonyl group at δ C = ca. 164.90 ppm. If the reaction product was 3a, such a correlation should not exist. Moreover, the methyl protons at δ H = ca. 2.99 ppm show a cross peak correlation with C-5 at δ C = ca. 157.93 ppm. This carbon was proven by DEPT experiments to be quaternary, consistent with structure 8a. If, on the other hand, the reaction product were 3a, then the methyl protons should be correlated with a carbon bearing a proton.  Consequently, a plausible mechanism for the formation of compounds 4a-c is illustrated in Scheme 3. It is assumed that the initially formed 9 is subject to an intramolecular cyclization to 10, which is further hydrolysed into 11 under the reaction conditions. Finally, the lone pairs on the amide nitrogen then react with the oxime nitrogen or the hydrazone nitrogen kicking out either a water molecule or aniline, thus producing 4a-c. To our knowledge, this is the first reported cyclization via aniline elimination in such a system. It is worth mentioning that condensing 3-aroyl-2-(2phenylhydrazono)propanals 12a,b with cyanoacetamide has been reported to yield the 2,3dihydropyridazine-4-carboxamides 14a,b [15] (cf. Scheme 4). Conversions of 8a-c into nicotinic acid derivatives 15a-c were achieved by boiling in EtOH/HCl. When however compounds 8a-c are heated under reflux in AcOH, nicotinic nitrile derivatives 16a-c are obtained (cf. Scheme 5).  It has been reported earlier [16] that hydrolysis of 18 obtained via condensation of 17 with dimethylformamide dimethylacetal afforded the pyridone derivatives 19. We have repeated this experiment and came to the conclusion that hydrolysis of 18 in KOH affords in fact isomeric pyridone 19, which in turn gives spectra very similar to those of 16. Indeed, the mixed m.p. of the two products proves that they are different (cf. Scheme 6).

Conclusions
We are now able to correct a previously reported initial 1,2-addition of malononitrile at the carbonyl moiety of enaminones 1a-c and suggest instead the novel compounds 8a-c as precursors for syntheses of pyridazinones and pyridones derivatives.

General
Melting points were determined on a Shimadzu-Gallenkamp apparatus and are uncorrected. Elemental analyses were obtained by means of a LECO CHNS-932 Elemental Analyzer. NMR spectra were measured in DMSO-d 6 using a Bruker DPX 400 MHz superconducting spectrometer; HMQC, DEPT and NOE spectra were measured using Bruker Avance II 600 MHz superconducting spectrometer, and FT-IR measurements were from a Perkin Elmer 2000 FT-IR system. Mass spectrometric analysis was carried out on a VG-Autospec-Q high performance tri-sector GC/MS/MS.

General procedure for the preparation of compounds 8a-c
A mixture of equimolecular amounts of each of enaminones 1a-c (10 mmol) and malononitrile (10 mmol, 066 g) in EtOH (10 mL) was refluxed for 1 hr in the presence of few drops of piperidine. Upon cooling to r.t. a solid product precipitated, which was collected by filtration and crystallized from dioxane.

General procedure for the preparation of compounds 4a-c
Procedure A: To a solution of each of compound 8a-c (10 mmol) in dioxane (15 mL) and HCl (2 mL), was added dropwise a prepared solution of NaNO 2 (0.85 g, 10 mmol) and sodium acetate (15 mmol) in water (10 mL). The mixture was stirred for 1h. and allowed to warm up to r.t. During this time a precipitate is formed. The reaction mixture is then filtered off and recrystallized from dioxane.

Procedure B:
Coupling reaction was carried out following procedure described earlier [17], which involves coupling each of compounds 8a-c with phenyldiazonium chloride in dioxane /AcONa.

General procedure for the preparation of compounds 15a-c
Each of compounds 8a-c (10 mmol) was refluxed in an EtOH/HCl mixture (3:1, 10 mL) for 30 min. Upon cooling to r.t. a solid product precipitated that was collected by filtration and recrystallized from EtOH.

General procedure for the preparation of compounds 16a-c
Each of compounds 8a-c (10 mmol) was refluxed in AcOH (10 mL) for 30 min. Upon cooling to r.t. a solid product precipitated that was collected by filtration and crystallized from AcOH.