Studies with β-Oxoalkanonitriles: Simple Novel Synthesis of 3-[2,6-Diaryl-4- pyridyl]-3-oxopropanenitriles

Heteroaromatization of ethyl 2-cyano-4-oxo-2-(2-oxo-2-arylethyl)-4-aryl-butanoates 3a,b with ammonium acetate gave ethyl 2,6-diarylisonicotinates 4a,b.Treatment of the latter with acetonitrile afforded novel β-oxoalkanonitriles 6a,b. Reactions of 6a,b with phenyl hydrazine and hydroxylamine gave the corresponding pyridyl aminopyrazoles 8a,b and pyridyl aminoisoxazoles 10a,b, respectively.


Results and Discussion
β-Oxoalkanonitriles are generally prepared via: i) acylation of active nitriles in the presence of suitable basic catalysts [16][17][18]; ii) reacting α-haloketones with cyanide ion [19], and iii) hydrolysis of β-enaminonitriles [7]. We decided to develop our synthesis via reaction of acetonitrile with ethyl 2,6diarylisonicotinate. Although the parent ethyl 2,6-diphenylisonicotinate (3a) is a known compound, [20] the 2,6-diarylsubsubstituted derivatives have not, to our knowledge, been previously reported. Consequently, a method for their synthesis was developed. Reaction of phenacyl bromide (1a) with ethyl cyanoacetate (2) afforded the dialkylated derivative 3a [21]. Similarly, 3b was obtained by reacting 1b with ethyl cyanoacetate. Refluxing 3a,b in acetic acid in the presence of ammonium acetate afforded the target pyridines 4a,b (Scheme 1). Attempts to condense acetonitrile in an aqueous protic solvent with pyridines 4a,b under different conditions afforded only the carboxylic acid derivatives 5a,b [22]. However, the target β-oxoalkanonitriles 6a,b were obtained by reacting 4a,b with acetonitrile in dry benzene in the presence of sodium hydride (Scheme 2).

Scheme 2.
Synthetic pathway for preparation of compounds 5a,b and 6a,b. As would be expected, β-oxoalkanonitriles 6a,b reacted with phenyl hydrazine hydrochloride to yield the corresponding 5-aminopyrazoles 7a,b or 3-aminopyrazoles 8a,b. Despite literature reports [23,24], the δ value for the pyrazole ring H-4 for both isomers vary over the range between 5.3-6.1 ppm. To substantiate the regioselectivity of the reaction products, NOE difference experiments were performed, which showed that irradiation of the amino protons at δ 4.45 ppm did not enhance the aryl protons at δ 7.5 ppm and vice versa, irradiation of the o-aryl protons at δ 7.5 ppm did not enhance the amino protons. These results allowed us to conclude that the amino and aryl protons are not proximal (Scheme 3); that is, the compounds have the structures 8a,b. Moreover, the reaction of β-oxoalkanonitriles 6a,b with hydroxylamine hydrochloride in the presence of sodium acetate could yield 5aminoisoxazoles 9a,b or the isomeric 3-aminoisoxazole structures 10a,b. 1 H-NMR revealed a singlet signal at δ = 7.00 ppm correlated to the isoxazole ring H-4. It was reported that the H-4 of 3-aminoisoxazole appears at lower field (δ ~ 6.1 ppm) than that of 5-aminoisoxazole (δ ~ 5.5 ppm) [25,26]. Moreover, 15 N, 1H-heteronuclear multiple bond correlation (HMBC) of the product indicated that amino proton at δ 5.85 ppm has a cross peak at δ 350 ppm ( 3 J coupling). These results indicated that structures 10a,b are the most probable for the reaction products (cf. Scheme 3). The reaction of 2substituted-3-oxoalkanonitriles with hydroxylamine hydrochloride in presence of sodium acetate has been reported by Elnagdi et al. [27] to yield amidoximes that cyclised into 3-aminoisoxazoles. On the other hand formation of 5-aminoisoxazoles from the reaction of isonicotinylacetonitriles with hydroxylamine hydrochloride was reported in the patent literature [28,29], although there is no mention of added base in those cases.

Conclusions
A novel route for the synthesis of β-oxoalkanonitriles has been developed. The products from this synthesis were further reacted with nitrogen nucleophiles to give azoles. The features of the present method include the ready availability of the starting materials, mild reaction conditions, and the simplicity of the workup.

General
Melting points were recorded on a Gallenkamp apparatus and are uncorrected. Infrared spectra (KBr) were determined on a Perkin-Elmer 2000 FT-IR system. 1 H-NMR spectra were recorded on a Bruker DPX 600 MHz superconducting spectrometer using DMSO-d 6 as solvent and TMS as internal standard. Mass spectra were measured on MS 30 and MS 9 (AEI) spectrometers, operating at EI 70 ev. Elemental analyses were measured by means of LECO CHNS-932 Elemental Analyzer.

Synthesis of 2,6-diarylisonicotinic acids 5a,b
A solution of ethyl 2,6-diarylisonicotinate (10 mmol) in ethanol (20 mL) was treated with potassium hydroxide solution (15 mmol in 10 mL water) and refluxed for 4 hours. The reaction mixture was poured into ice/HCl. The solid precipitate was collected by filtration and recrystallized from ethanol.