1,3-Dipolar Cycloaddition of Difluoro-Substituted Azomethine Ylides. Synthesis and Transformations of 2-Fluoro-4,5-dihydropyrroles

Abstract

2-Fluoro-4,5-dihydropyrrole-3,4-dicarboxylic acid derivatives were obtained by reaction of difluorocarbene with N-substituted ketone imines in the presence of fumaronitrile, maleonitrile, or dimethyl maleate. The reaction involves intermediate formation of azomethine ylides and their subsequent cycloaddition at the double bond. 11H-Dibenz[b,e]azepine and 3,4-dihydroisoquinolines react with difluorocarbene in the presence of fumaronitrile to give fluoro-substituted dibenzo[c,f]pyrrolo[1,2-a]azepine and pyrrolo[2,1-a]-isoquinoline derivatives. Treatment of 2-fluoro-4,5-dihydropyrrole-3,4-dicarbonitrile with amines and alkoxides affords the corresponding 2-amino-and 2-alkoxy derivatives, while its reactions with hydrazine hydrate and benzimidamide lead to formation of substituted pyrrolo[2,3-c]pyrazole and pyrrolo[2,3-d]-pyrimidine derivatives.Pyrrole derivatives are widely used in synthetic and medical practice [1]. In the recent years, much attention was given to fluorinated pyrroles as potential biologically active substances. Several synthetic approaches to fluoropyrroles have been reported. Among these, direct fluorination of pyrrole derivatives [2, 3], transfunctionalization according to Schiemann [4], heterocyclization of fluorinated linear precursors [5], and 1,3-dipolar cycloaddition with participation of either fluorine-containing azomethine ylides [6][7][8] or fluorinated dipolarophiles [9, 10] must be noted.2-Fluoro-4,5-dihydropyrroles attract interest not only as potential biologically active substances but also as useful building blocks having a labile fluorine atom in the -position with respect to nitrogen. However, there are no convenient methods for the preparation of such compounds. Only two kinds of transformations are known to produce 2-fluoro-4,5-dihydropyrrole systems [11,12]. Photolytic ring contraction in N-substituted perfluoroazepines to give perfluoro-(3a,5a-dihydrocyclobuta[b]pyrroles) cannot be regarded as an acceptable synthetic route to 2-fluoro-4,5-dihydropyrroles, for its scope is limited to perfluorinated derivatives [11]. The reaction of N-methylpyrrolidone with carbonyl fluoride in the presence of cesium fluoride resulted in formation of only 4% of 2-fluoro-1-methyl-2,3-dihydropyrrole-3-carbonyl fluoride [12].We recently found that reactions of difluorocarbene with Schiff bases in the presence of 2-butenedioic acid derivatives could lead to 2-fluoro-4,5-dihydropyrroles in good yields [13]. The present article reports the results of our detailed study on the reactions of various ketone imines with difluorocarbene in the presence of fumaric and maleic acid derivatives as a method of synthesis of substituted 2-fluoro-4,5-dihydropyrroles and building up of a 2-fluoro-4,5-dihydropyrrole fragment as a part of a polycyclic system. Difluorocarbene was generated in situ by reduction of dibromodifluoromethane with lead in the presence of tetrabutylammonium bromide.The reactions of Schiff bases Ia-Id with difluorocarbene in the presence of fumaronitrile, maleonitrile, or dimethyl fumarate af...

One-Pot Multicomponent Synthesis of 2-Azapyrrolizidine Alkaloid Derivatives under Microwave Irradiation

“…Five and six-membered nitrogen heterocycles belong to a largest class of heterocyclic compounds possessing a diverse biological activities [1][2] .The biological activity of hydantoin and 2-thiohydantoin derivatives has been known for a long time. The hydantoin nucleus containing an active urea moiety is responsible for a variety of biological activities such as antiarrhythmic, antihypertensive, antiviral, antineoplastic, anticonvulsant, antimycobacterial, antiulcer, anti-inflammatory agents, as well as pesticides 3 .…”