Studies with Azinylacetonitriles: 2-Pyridylacetonitrile as a Precursor to Functionally Substituted Pyridines

2-Pyridylacetonitrile (1) couples with aromatic diazonium salts to yield arylhydrazones 2a-c, that were shown to exist in the syn-form 2 rather than the anti-form 4. Compounds 2a,c reacted with hydroxylamine in refluxing DMF to yield the interesting 1,2,3-triazolylpyridines 6. Attempts to cyclize 2 to give the corresponding fused pyrazolopyridines 9 failed. On the other hand, compound 1 condensed with dimethylformamide dimethyl acetal to yield enaminonitrile 10 that could be converted into pyrazolylpyridine 11.


Introduction
It is well accepted that the methylene moieties in heteroaromatic substituted acetonitriles are reactive toward electrophiles under mild conditions [1][2][3]. This reactivity has been utilized for synthesis of a variety of functionally substituted azoles [4,5] and condensed azoles [6,7]. However, little has been reported on the utility of azinylacetonitriles for synthesis of functionally substituted azines [8].

Results and Discussion
In conjunction with our interest in using aromatic and heteroaromatic substituted acetonitriles as precursors for the synthesis of heteroaromatics, we report herein the reactivity of 2-pyridylacetonitrile (1) as a good precursor to several azolylpyridines. Thus, compound 1 coupled with aromatic diazonium salts to yield arylhydrazones 2a-c. Although a mixture of the two geometrical isomers was expected based on an earlier report [9], the existence of only the syn-structure 2 could be established, at least in the solid state, based on X-ray crystal structure determination [10] (cf. Figure 1 and Table 1 for bond angles and bond lengths).  Table 1. Crystal data and structure refinement for compound 2a.
Inspection of Table 1 indicates that the acetonitrile N4-C8-C14 bond angle is larger than a typical sp 2 bond angle (120 o ), perhaps to reduce the steric interaction between hydrogen NH, and the pyridyl ring N3-N4 bond length is more like a double bond. We assume that nitrogen lone pair is delocalized at the ring nitrogen and that electrostatic attraction between the positively charged hydrazone moiety and the negatively charged ring nitrogen holds the molecule in the syn-form. It is thus concluded that charge separation in 2 contributes significantly to the actual structure [10][11][12].
Compounds 2a,b reacted with hydroxylamine hydrochloride in refluxing DMF and in the presence of sodium acetate to yield the products of addition and water elimination which can thus be formulated as 1,2,3-triazoles 6a,b or their isomeric structures 1,2,4-triazoles 7, and are assumed to be formed via the intermediately formed amidoximes 5a,b that could be isolated (Scheme 2). NOE difference spectra enabled the assignment of structure 6 for the products as irradiation of the NH 2 protons at δ = 6.3 ppm did not enhance the aryl protons. If the reaction product were 7 enhancement of these aryl protons should have been observed. The behavior of 2 towards hydroxylamine is thus similar to that of other hydrazononitriles and differs from that of 2-p-nitrophenyl-2-arylhydrazonoacetonitrile where rearrangement preceded cyclization affording 1,2,4-triazoles 7. Although 2-arylhydrazono-2acetylpyridine 8 has been recently reported to afford 9 when heating in dichlorobenzene at 190 °C, in our hands, compounds 2a-c have been recovered unaffected under these conditions [13]. It seems that replacing a methyl by a cyano group affects the HOMO-LUMO energy of the cyclised 6π electron system as this cyclization is believed to proceed by a pericyclic rule. Next, compound 1 was reacted Compound 10 reacted with p-chloroaniline 12 to give compound 13. Structure 14 was excluded based on 1 H-NMR and 13 C-NMR that revealed the absence of signals for a sp 3 carbon or protons linked to such a carbon (Scheme 3). It can thus be concluded that while compound 1 is a versatile precursor to azolylpyridines, conversion of compound 2 to pyrazolo [4,3-b]pyridine via a route similar to that reported for converting 8 into 9 could not be effected, at least under the conditions reported in the published work [13].

General
All melting points were measured on Gallenkamp electrothermal melting point apparatus and are uncorrected. Microwave synthesis were carried out in SJO390W microwave oven. IR spectra were recorded as KBr pellets on a Pye Unicam SP 3-300 spectrophotometer. 1 H-NMR spectra were recorded in deuterated dimethylsulfoxide (DMSO-d 6 ) at 300 MHz on a Varian Gemini NMR spectrometer using tetramethylsilane (TMS) as an internal reference and results are expressed as δ values. Mass spectra were performed on a Shimadzu GCMS-QP 1000 Ex mass spectrometer at 70 eV. Elemental analyses were performed by the Microanalytical Center at Cairo University. The crystal structure was determined by the X-ray unit at the National Research Center, Dokki, Cairo.

General procedure for the synthesis of arylhydrazones 2a-c
A cold solution of aryldiazonium salt (10 mmol), prepared by adding a solution of sodium nitrite (10 mmol in 10 mL of water) to a cold solution of arylamine hydrochloride (10 mmol of arylamine in 6 mL of HCl) with stirring, was added to a cold solution of 2-pyridylacetonitrile (1, 10 mmol) in ethanol (50 mL) containing sodium acetate trihydrate (10 mmol). The mixture was then stirred at room temperature for 1 h and the resulting solid product was collected by filtration, washed well with water, dried and recrystallized from ethanol.

General procedure for the synthesis of compounds 5a,b
To a mixture of arylhydrazononitriles 2a,b (10 mmol) and hydroxylamine hydrochloride (10 mmol) in absolute ethanol (20 mL), anhydrous sodium acetate (2g) was added and the reaction mixture was then refluxed for 3 hrs. After cooling to room temperature, the mixture was poured into water and the resulting precipitate collected by filtration, washed with water, dried and recrystallized from ethanol.  General procedure for the synthesis of compounds 6a,b

2-[(4-Nitrophenyl)hydrazono]-N-hydroxy-2-yl-acetamidine
To a mixture of arylhydrazononitriles 2a,b (10 mmol) and hydroxylamine hydrochloride (10 mmol) in DMF (20 mL), anhydrous sodium acetate (2 g) was added. Then, the reaction mixture was refluxed for 8 hrs. The solvent was evaporated under vacuum and the crude product was collected by filtration, washed with ethanol, dried and recrystallized from ethanol/dioxane. [1,2,3] (13): To a mixture of p-chloroaniline 12 (10 mmol) and compound 10 (10 mmol), a drop of AcOH was added, then the mixture was irradiated in a domestic microwave oven for 2 minutes at 280 W. The resulting solid product was collected by filtration, washed with ethanol, dried and recrystallized from ethanol to give compound