Unexpected formation of 4,4,6-trimethyl-2-oxo-1-phenyl-1,2,3,4-tetrahydropyridine-3-carbonitrile via Tandem Knoevenagel condensation-Michael addition-intramolecular cyclization

Abstract

Knoevenagel condensation (Cope version) of acetone with cyanoacetanilide resulted in the formation of 4,4,6-trimethyl-2-oxo-1-phenyl-1,2,3,4-tetrahydropyridine-3-carbonitrile whose structure was determined by X-ray analysis. Prospects in the design of pharmacologically active compounds on the basis of 4,4-disubstituted tetrahydropyridines stimulated studies on new accessible methods for their synthesis [1]. Such structures are generally obtained by condensation of aliphatic ketones with cyanoacetamides [2] or of cinnamic acid chloride with substituted 3-aminoacrylonitriles [3]. We previously proposed a new synthesis of 4,4-disubstituted tetrahydropyridines by reaction of substituted ethyl crotonoates with cyanothioacetamide and N-methylmorpholine [4].In the present work we examined the condensation of acetone (I) with cyanoacetanilide (II) according to Knoevenagel (Cope version) [5]. However, we failed to isolate the corresponding alkene A, for the latter underwent further transformations. Presumably, Michael addition of acetone I to alkene A gave adduct B, and its subsequent intramolecular condensation resulted in the formation of previously unknown 4,4,6-trimethyl-2-oxo-1-phenyl-1,2,3,4-tetrahydropyridine-3-carbonitrile (III) (Scheme 1). The structure of compound III was unambiguously proved by X-ray anal-

New Options of Multicomponent Condensations Leading to Functional Derivatives of 2-Pyridons

“…A number of functionalized 2-pyridone derivatives are applied dyes [1][2][3], showed antimicrobial [4] and anti-infl ammatory [5][6][7] effects, and are contained in drugs for the treatment of Parkinsonʼs disease [8], diabetes [9], and atherosclerosis [10]. Contunuing research into the chemistry of 2-pyridones [11][12][13][14], we have developed new options for preparing representatives of the above type of organic compounds, based on such a modern approach as multicomponent reactions [15,16]. In the present work was have studied new options of 2-pyridone synthesis.…”

Synthesis and alkylation of new functionally substituted 4,4-dimethylpiperidin-2-ones

“…4,4-Disubstituted partially hydrogenated pyridin-2-ones and thiones, promising semiproducts in the designing of drugs for treating antidepressant states [1], we obtained by Michael reaction of ethyl isopropylidenecyanoacetate [2] or isopropylidenemalononitrile [3] with cyanothioacetamide and by Knoevenagel reaction in Cope version by acetone condensation with cyanoacetanilide [4].…”