Multicomponent Assembling of Aldehydes, N,N‐Dimethylbarbituric Acid, Malononitrile, and Morpholine Into Unsymmetrical Ionic Scaffold and Its Efficient Cyclization

• Published in: Journal of heterocyclic chemistry 2024-11, Vol.61 (11), p.1752-1761
• Main Authors: Elinson, Michail N., Ryzhkova, Yuliya E., Kalashnikova, Varvara M., Chizhov, Alexander O., Egorov, Mikhail P.
• Format: Article
• Language: English
• Subjects: Acids; Alcohols; Aldehydes; Ambient temperature; Anticonvulsants; Biomedical materials; cyclization; Cyclopropane; Immunology; Malononitrile; Michael reaction; morfoline; Morpholine; multicomponent reactions; N,N′,‐dimethylbarbituric acid; Organic compounds; Pharmacology; Scaffolds; Substitutes; unsymmetrical ionic scaffold
• ISSN: 0022-152X; 1943-5193
• DOI: 10.1002/jhet.4888

ABSTRACT The new type of the four‐component tandem Knoevenagel–Michael reaction was discovered: the transformation of arylaldehydes, N,N′‐dimethylbarbituric acid, malononitrile, and morpholine in alcohols and other organic solvents without any other additives at ambient temperature resulted in the selective formation of a new substituted unsymmetrical ionic scaffold with two pharmacology‐active heterocyclic rings. This new four‐component reaction is a simple and efficient route to a previously unknown substituted ionic unsymmetrical scaffold containing N,N′‐dimethylbarbituric acid and morpholine. These ionic scaffolds are promising for various biomedical applications, for example, as anticonvulsants and anti‐inflammatory drugs, as well as anti‐AIDS agents. In this research, we also accomplished the efficient cyclization of morpholin‐4‐ium 5‐(2,2‐dicya‐no‐1‐arylethyl)‐1,3‐dimethyl‐2,6‐di‐oxo‐1,2,3,6‐tetrahydro‐pyrimidin‐4‐olates by the action of NBS–NaOAc system, with the formation of 5,7‐dimethyl‐4,6,8‐trioxo‐2‐aryl‐5,7‐diazaspiro[2.5]octane‐1,1‐dicarbonitriles in 83%–98% yields. In the final stage of our research, direct one‐pot multicomponent transformation of benzaldehydes, N,N′‐dimethylbarbituric acid, and malononitrile into spirobarbituric cyclopropanes was accomplished in 75%–97% yields. The spiro‐barbituric cyclopropanes are potentially active as remedies against various inflammatory, infectious, immunological, or malignant diseases. Multicomponent assembling of aldehydes N,N‐dimethylbarbituric acid, malononitrile, and morpholine into unsymmetrical ionic scaffold and its efficient cyclization.