Synthesis of novel bis(dihydropyridine) and terpyridine derivatives

A synthesis of novel bis(cyanopyridones) by the reaction of the appropriate bis(cyanoacetamide) with the corresponding arylidenmalononitrile in the presence of basic catalysts was reported. In some cases, the corresponding bis(2-cyano-3-arylacrylamide) derivatives were isolated from these reactions as single products. The multicomponent strategy for the synthesis of the target compounds was also investigated. The utility of bis(cyanoacetamides) as building blocks for novel bisquinolinones was also studied.


Figure 1.
Representative examples of some drugs incorporated pyridine moiety.

Scheme 1. Synthesis of bis-cyanoacetamides 3a,b.
The reaction of biscyanoacetamide 3a with benzylidenemalononitrile derivative 4a was investigated as a simple model system to find the optimal reaction conditions for the synthesis of the corresponding novel 1,1'-(1,3-phenylene)bis(6-amino-2-oxo-4-phenyl-1,2-dihydropyridine-3,5-dicarbonitrile) derivatives 5a.The reaction was performed in ethanol or dioxane in the presence of different bases including trimethylamine, piperidine, chitosan, DABCO and DBU (Scheme 2).Although the reaction worked well in refluxing ethanol or dioxane in most catalysts, the best results were achieved using piperidine in ethanol at reflux (Method A).The percentage yields in all cases are cited in Table 1.Scheme 2. Reaction of bis(cyanoacetamide) 3a with benzylidenemalononitrile 4a.The successful synthesis of 5a encouraged us to develop the scope of this reaction.Thus, bis(cyanoacetamide) 3a was allowed to react with a variety of arylidenemalononitriles 4b-f under the optimized conditions (Method A).The results showed that all reactions afforded the desired products 5b-f with good yields (Scheme 3).Scheme 3. Reaction of bis(cyanoacetamide) 3a with a variety of arylidenemalononitriles 4b-f.Compounds 5 were also obtained in good to excellent yields via a three-component reaction of two equivalents of both arylaldehyde 6 and malononitrile 7 with one equivalent of biscyanoacetamides 3a in refluxing ethanol in the presence of piperidine as a catalyst (Method B) (Scheme 4).Scheme 4. Three-component reaction of bis(cyanoacetamides) 3 with two equivalents of both arylaldehyde 6 and malononitrile 7.
Depending on the above results, one can propose the following mechanism for the formation of compounds 5 and 8 (Scheme 7).Thus, the pyridines 5 and 8 are formed through the initial addition of the active methylene in the cyanoacetamides 3 to the double bond of cinnamonitriles 4 to give the adduct 12 followed by cyclization involving NH of the amide to afford 13.Subsequent air oxidation of 13 led to the formation of the target compounds 5 and 8.It is noteworthy to mention that piperidine acts as basic catalyst which generates the carbanionic species 3 (I), through carrying the labile protons.The formation of 10 and 11 is assumed to proceed via initial formation of the adduct 12, which then decompose to give 10 and 11, respectively, via elimination of two molecules of malononitrile.
The spectroscopic data and elemental analyses of the obtained products 5 and 8 supported the assigned structures.The IR spectrum of 5d as a representative example exhibits strong stretching frequencies in the region of 3580 and 3476 cm −1 , attributable to the amino group, in addition to the presence of a strong absorption band at 2222 cm −1 due to a C≡N group.Its 1 H NMR spectrum displayed a singlet signal at δ H 3.86 assigned to the methoxy protons in addition to the presence of a singlet signal at δ H 8.60 exchangeable with D 2 O assignable to the NH 2 protons.Additional evidence supporting this structure was obtained by mass spectrum, which gave a molecular ion at m/z 606 [M] + .The structures of compounds 10 and 11 were assigned based on their elemental analyses and spectral data.For example, 1 H NMR spectrum of 10g revealed a singlet signal at δ H 3.08 assignable to the four methyl protons, besides the aromatic and NH protons.

Conclusions
We developed an efficient synthesis of bis(cyanoacetamides) and investigated their utility as building blocks for regioselective synthesis of novel biscyanopyridones via facile Michael addition reactions with various arylidenemalononitriles.The structures of the new compounds were supported by elemental analyses as well as spectral data.The mechanism proposed for their formation was also discussed.The straightforward synthesis of these compounds from readily available starting material should open a new access for novel bis functionalized heterocycles with potentially interesting biological and pharmaceutical activities.

Experimental Section
General.Melting points were measured with a Stuart melting point apparatus and are uncorrected.The IR spectra were recorded using an FTIR Bruker-vector 22 spectrophotometer as KBr pellets.The 1 H NMR spectra were recorded in DMSO-d 6 as solvent on Varian Gemini NMR spectrometer at 400 MHz using TMS as internal standard.Chemical shifts are reported as δ values in ppm.Mass spectra were recorded with a Shimadzu GCMS-QP-1000 EX mass spectrometer in EI (70 eV) model or on an AccuTOF-T100LP (JEOL) mass spectrometer in ESI.The elemental analyses were performed at the Micro analytical center, Cairo University.Analytical thin layer chromatography was performed using pre-coated silica gel 60.778 plates (Fluka), and the spots were visualized with UV light at 254 nm.