Convenient synthetic route to 3-cyanopyridine-2(1H)-one derivatives with aromatic substituents

Introduction

The development of new routes to substituted pyridines with a wide variety of substituents continues to attract considerable attention for application in heterocyclic chemistry, natural product synthesis and medicinal chemistry. Compounds have been associated with antitumor, antifungal, antibacterial, antiviral, antithrombotic, psychotherapeutic and anti-HIV properties (Cox and O’Hagan, 1991; Curran and Liu, 1992; Kozikowski et al., 1996; Williams et al., 1997; Fraley et al., 2003). They are the structural basis of some natural alkaloids, e.g., ricinine and nudiflorine (Mukherjee and Chaterjee, 1966; Yuldashev, 2001; Leite et al., 2005). Substituted 3-cyanopyridine-2(1H)-ones are also effective cardiotonic (e.g., milrinone) agents (Hopkins, 1990; Kulnevich et al., 1990; Shiao et al., 1990; Litvinov et al., 1999; Saad et al., 2002; El-Sayed et al., 2011). Some authors consider that biological activity of 3-cyanopyridine-2(1H)-ones depends on the substituent at a nitrogen atom of the pyridinone ring (Kulnevich et al., 1990). Serious changes in biological activity by replacing one alkyl group with another have been reported.

The routine method for the synthesis of 3-cyanopyridine-2(1H)-ones is the condensation of β-enamino derivatives of carbonyl compounds with cyanoacetic acid amides or malononitrile (Ratemi et al., 1993; Litvinov et al., 1999). However, these approaches do not allow obtaining the variety of substituents at the pyridinone ring which could be a tempting idea for the application in combinatorial chemistry and drug design. Other methods allow obtaining 4,5,6-substituted 3-cyanopyridinones with a large variety of substituents, but they are not convenient for introducing substituents at the nitrogen atom of the pyridinone ring (Nalage et al., 2010; Elassar, 2011).

Some pyridinone derivatives containing aromatic substituents have valuable properties and display a variety of biological activities (Litvinov et al., 1999). In our previous report, we described the synthesis of some substituted 3-cyanopyridine-2(1H)-ones with various aliphatic substituents at positions 1 and 4 of the pyridinone ring (Melikyan and Piroyan, 2006). Taking this into account, we report herein a new and simple path for synthesizing N-substituted 3-cyanopyridine-2(1H)-ones with aromatic substituents.

Results and discussion

We started from various ethyl ylidenecyanoacetates obtained by the condensation of methyl ketones with ethyl cyanoacetate. These ylidene derivatives were condensed with dimethylformamide dimethyl acetal to yield the new dimethylaminovinyl derivatives 1 and 2 in good yields. The reaction was carried out in anhydrous xylenes under reflux for 3 h (Scheme 1).

Scheme 1

The key point of our investigation was the reaction of dimethylaminovinyl derivatives 1 and 2 with aromatic amines in glacial acetic acid at 90°C to give new arylaminovinyl derivatives 3–10. Compounds 3–10 are brightly colored (yellow, orange, red), which can be explained by the presence of a chromophorous moiety (the arylamino group) conjugated through the system of double bonds with the cyano group.

Compounds 3–10 undergo intramolecular cyclization in refluxing xylenes. The products obtained in high yields are new derivatives of substituted 3-cyanopyridine-2(1H)-ones 11–18 containing variable substituents at position 4 of the pyridinone ring and several aromatic substituents at the nitrogen atom of the ring.

It is important to note that refluxing compounds 1, 2 in acetic acid, as reported for the synthesis of condensed pyridazinones (Abu-Shanab et al., 1995), did not result in ring closure and the desired 3-cyanopyridine-2(1H)-ones 11–18 were not obtained. Instead, impure compounds 3–10 with low yields were obtained.

It has been previously shown that some vinyl-substituted heterocycles are of practical interest (Melikyan et al., 1993; Leite et al., 1999). Considering this, we carried out condensation of 4-methyl-2-oxo-1,2-dihydropyridine 12 with a number of aromatic and heterocyclic aldehydes in dry ethyl alcohol media in the presence of catalytic amount of sodium hydroxide. The resulting 3-cyano-4-(substituted vinyl)pyridin-2(1H)-ones 19–26 were obtained in high yields. It was estimated by the analysis of coupling constants in the ¹H NMR spectra that these products are trans-isomers (Scheme 2).

Scheme 2

Taking into account a wide spectrum of the applications of phthalic acid derivatives, we extended the condensation reactions on phthalic acid anhydride. Condensation of 12 with phthalic anhydride was carried out at 120–130°C for 2 h in acetic anhydride in the presence of potassium acetate catalytic amounts to give the expected product 27.

Conclusions

A new convenient synthesis of 3-cyano-pyridine-2(1H)-ones with aromatic substituents was developed. Easy variability of substituents allows using this method to be used in combinatorial chemistry and drug design. The availability of the substrates, efficient work-up and high yields make this route an attractive methodology.

Experimental section

Melting points were determined on a Kofler hot-stage microscope and are uncorrected. ¹H NMR (300 MHz) and ¹³C NMR (75 MHz) spectra were obtained in DMSO-d₆ or a mixture of DMSO-d₆ and CCl₄ on a Varian Mercury 300 spectrometer at 303 K.