Synthesis and reactions of 2 , 6-bis [ 3-oxo-3-propanenitrile-2-( N , N-dimethylamino ) methylene ] pyridine

The versatile multifunctional hitherto unreported 2,6-bis-[3-oxo-3-propanenitrile-2-(N,Ndimethylamino)methylene]pyridine 3 was prepared by the reaction of pyridine-2,6-bis-(3-oxo-3propanenitrile) 2 with dimethylformamide-dimethylacetal (DMF-DMA). Several new pyrazole, isoxazole, pyrimidine, pyrazolopyrimidine, triazolopyrimidine and imidazopyrimidine derivatives have been synthesized by the reactions of 2,6-bis[3-oxo-3-propanenitrile-2-(N,Ndimethylamino)methylene]pyridine 3 with several nitrogen binucleophiles.


Introduction
Multifunctional building blocks are of special interest for drug design and organic synthesis due to three reasons, at least.First, these compounds can be used to tether two molecular fragments responsible for binding to the biological target, thus they can act as linkers.Second, if one functional group is not engaged in connection between the core of building block and the rest of a molecule being constructed, then it can participate in important interactions with a biological target.Finally, many multifunctional building blocks can undergo cyclization reactions, allowing rapid advance toward prospective heterocyclic units.

Scheme 1
The reactivity of the enaminonitrile 3 towards some nitrogen nucleophiles was investigated.Thus, treatment of compound 3 with hydrazine hydrate, in refluxing ethanol, afforded a product for which two possible structures 5a and 6a can be formulated (Scheme 2).The spectral data of the isolated product was incomplete agreement with structure 5a.Similarly, compound 3 reacted with phenyl hydrazine in refluxing ethanol, in the presence of a catalytic amount of piperidine, and afforded a yellow crystalline product of 5b (Scheme 2).The other possible structure 6b was easily excluded on the basis of spectral data [see experimental part].The formation of compounds 5a and 5b are assumed to take place via a Michael type addition of the amino group of hydrazines to the enamine double bond in 3 to form non-isolable intermediate 4 which readily undergoes intramolecular cyclization into the pyrazole derivatives 5a and 5b via the loss of dimethylamine and water molecules (type A, Scheme 2).The structures of the expected pyrazoles 6a,b were excluded as a result of the lack of carbonyl group in IR and 13 C NMR spectra.Moreover, the absolute structure of 5b was completely solved by X-ray diffraction analysis as shown in Figure 1.In a similar manner, the enaminonitrile 3 reacted with hydroxylamine hydrochloride, in the presence of potassium carbonate, and afforded white solid of 2,6-bis[4-cyano-isoxazol-5yl]pyridine (8) that not readily soluble in most of organic solvent.Compound 8 is assumed to be formed via the Michael type addition of the amino group of hydroxylamine to the enamine double bond in the enaminonitrile 3 [18][19][20][21] to form non-isolable intermediate 7 which underwent intramolecular cyclization via the loss of dimethylamine and water molecules to afford the isoxazole derivative 8 (type A, Scheme 2).The IR spectrum of the later product revealed the lack of absorption band corresponding to carbonyl group and showed band at 2206 cm -1 corresponding to nitrile function, its mass spectrum revealed molecular ion peak at m/z 263 (M + ).
Enaminonitrile 3 reacts also with guanidine hydrochloride in refluxing ethanol, in the presence of anhydrous potassium carbonate to give a single product (as examined by TLC) that was identified as 2,6-bis[2-amino-5-cyanopyrimidin-4-yl]pyridine 10 according to its elemental analysis and spectral data.Thus, the IR spectrum of compound 10, showed an amino and nitrile absorption bands at 3317, 3184 and 2219, respectively, which are compatible with the assigned structure which seemed to be formed via the cyclization mode of type A (Scheme 3).
The foregoing results and our synthetic strategy towards new class of 2,6-disubstituted pyridines prompted us to investigate the behavior of the enaminonitrile 3 towards urea derivatives.
Few examples of acid catalyzed dimethylamine substitution reactions of enaminones with amido-N-nucleophiles such as ureas have been described in the literature, 22,.23 probably due to the very low nucleophilic reactivity of amide nitrogen atoms.Thus, treatment of the enaminonitrile 3 and excess of urea (6 equiv) in DMF as polar solvent at 60 o C, in the presence of excess HCl, afforded the corresponding uriedopropenate and thiouriedopropenate derivatives 11a,b which subsequently cyclized into pyridyl uraciles 12a,b when treated with sodium ethoxide solution (Scheme 3).The structures of the synthesized products were established on the basis of their elemental analysis and spectral data [see the experimental part].The behaviors of the enaminonitrile 3 towards some heterocyclic amines as potential precursors for fused heterocyclic systems 24 were also investigated.Thus, treatment of compound 3 with 5-amino-3-phenyl-1H-pyrazole 13, in refluxing ethanol in the presence of a catalytic amount of piperidine, furnished a single product identified as 2,6-bis[6-cyano-2phenylpyrazolo[1,5-a]pyrimidin-7-yl]pyridine 14 (Scheme 3).Further evidence for the proposed structure 14 was obtained by an independent synthesis of compound 14 via treatment of 5-N-(N,N-dimethylaminomethylene)imino-3-phenyl-1H-pyrazole 17 with the oxopropanenitrile 2, in refluxing ethanol and in the presence of a catalytic amount of piperidine, to afford a product identical in all respects (mp, TLC and spectra) with that obtained from the reaction of the enaminonitrile 3 with 5-amino-3-phenyl-1H-pyrazole 13.The formation of compound 14 can be explained on the basis of an initial Michael addition of exocyclic NH2 in 13 to the enamine double bond in 3 to afford non-isolable intermediate undergo intramolecular cyclization to afford compound 14 (Scheme 4).However, structures 15 and 16 were easily excluded on the basis of elemental analysis and spectral data (see experimental part).

Experimental Section
General.All melting points were measured on a Gallenkamp melting point apparatus.The infrared spectra were recorded in potassium bromide discs on a Pye Unicam SP 3-300 and Shimadzu FT IR 8101 PC infrared spectrophotometers.The NMR spectra were recorded on a Varian Mercury VXR-300 NMR spectrometer. 1 H NMR (300 MHz) and 13 C NMR (75.46 MHz) were run in deuterated chloroform (CDCl3) or dimethylsulfoxide (DMSO-d6).Chemical shifts were related to that of the solvent.Mass spectra were recorded on a Shimadzu GCMS-QP1000 EX mass spectrometer at 70 eV.Elemental analyses were carried out at the Microanalytical Centre of Cairo University, Giza, Egypt.All reactions were followed by TLC (Silica gel, Aluminum Sheets 60 F254, Merck).Compounds 13, 25-27 17 28 and 2 29 were prepared according to literature procedures.

Solvents
Acetonitrile, THF, diethyl ether, dimethylformamide, and pyridine purchased from Aldrich Chemical CO.Ethanol, methanol, petroleum ether; chloroform were BDH reagents.Acetic acid and acetic anhydride were purchased from EL-Nasr Pharmaceutical and Chemical Co.

Crystallographic analysis
The crystals were mounted on a glass fiber.All measurements were performed on an ENRAF NONIUS FR 590.The data were collected at a temperature of 25 o C using the ω scanning technique to a maximum of a 20 of 22.986o.The structure was solved by direct method using SIR 92 and refined by full-matrix least squares.Non-hydrogen atoms were refined anisotropically.Hydrogen atoms were located geometrically and were refined isotropically.

Pyridine-2,6-bis-(1H-1-phenyl-pyrazol-5-yl-4-carbonitrile) (5b).
To a solution of the enaminonitrile 3 (0.32 g, 1 mmol) in ethanol (10 mL), were added phenyl hydrazine (0.32 g, 3 mmol) and few drops of piperidine.The reaction mixture was refluxed for 5 h, then left to cool.The yellowish solid precipitate was collected by filtration, washed with ethanol and dried.with hydroxylamine hydrochloride and guanidine.To a mixture of the enaminonitrile 3 (0.32 g, 1 mmol) and hydroxylamine hydrochloride (0.14 g, 2 mmol) or guanidine hydrochloride (0.19 g, 2 mmol) in ethanol (10 mL), was added anhydrous potassium carbonate (0.28 g, 2 mmol).The resulting mixture was refluxed for 10 h, and allowed to cool to room temperature then diluted with water (30 mL).The solid products that formed were collected by filtration, washed with water and dried and recrystallized from the proper solvent to afford compounds 8 and 10 respectively.
H NMR spectrum displayed a singlet signals at δ 2.98, 3.11 and 6.75 characteristics for methyl groups and CH of enamine protons, respectively.

Table 1 .
Selected bond angles and bond lengths of compound 5b

Reaction of 2,6-Bis[3-oxo-3-propanenitrile-2-(N,N-dimethylamino)methylene]pyridine (3) with
The resulting mixture was refluxed with stirring for 10 h. the reaction mixture was neutralized with HCl and the obtained suspension was poured on ice water.The formed solid products were collected by filtration, washed with water, dried and finally recrystallized from the appropriate solvent, to afford the corresponding pyridiy derivatives 12a,b.