Facile approach to prepare 3-cyanopyridin-2(1 H )-one derivatives

A new and efficient high yielding synthesis of N-substituted 3-cyanopyridin-2-ones has been developed. The reaction of ylidencyanoacetic acid ethyl esters and dimethylformamide dimethyl acetal has been investigated. Intermediate dimethylamino derivatives so formed were treated with various primary amines in xylene. The targeted 3-cyanopyridin-2-ones were obtained in good yields.


Introduction
The pharmacological and physiological activity of 3-cyanopyridin-2-ones has attracted much attention in recent years with the synthesis and the study of the non-glycosidic cardiotonic agent milrinone, 1,2 as well as with a number of 3-cyanopyridin-2-one derivatives which proved to be active against the herpes virus and the human immunodeficiency virus. 3,4The 3-cyanopyridin-2one nucleus is also the structural basis of the alkaloid ricinine -the first known alkaloid containing a cyano-group (Figure 1).

Figure 1
There are many reported methods for the formation of 3-cyanopyridin-2-ones.The main strategy involves the condensation of β-enaminoderivatives of carbonyl compounds with cyanoacetic acid amides or malononitrile. 5,6e report herein a new, efficient and convenient synthetic approach to 3-cyanopyridin-2ones utilizing various ylidenecyanoacetic acid ethyl esters and dimethylformamide dimethyl acetal as starting materials.The reaction was carried out in anhydrous xylene under reflux for 3 hours.The intermediate dimethylamino derivatives 1-3 so formed were treated with primary amines in xylene under reflux for 13-15 hours to yield the targeted 3-cyanopyridin-2-ones 4-15 in good yields.The course of the reaction was monitored by the evolution of gaseous dimethylamine (Scheme 1).

Scheme 1
It is known that bis lactams are the structural component of some natural compounds. 7onsidering this fact we have prepared the corresponding bis-pyridinone 16 using ethylene diamine as the primary amine (Scheme 2).

Scheme 2
Taking into account that pyridinones with functionalized substituents, in particular containing unsaturated bonds are an interesting class of compounds, we also carried out the condensation of 1-oxyethyl-and 1-oxypropyl-3-cyano-4-methylpyridin-2-ones with

Scheme 3
In conclusion, we have developed a new and efficient high yielding synthesis of Nsubstituted 3-cyanopyridin-2-ones.