Heterocyclic secondary enamines

Heterocyclic secondary enamines and dicarboxylic acid dichlorides undergo complex, ring-size-dependent annulation reactions that, in the case of ester 238 and phthaloyl chloride (Scheme 57), lead to lactone-containing derivative 239 (02T2821). 

Heterocyclic secondary 183-type enamines (exocyclic vinylogous urethanes) show ambident bisnucleophilicity their nucleophilic reaction... 

Irradiation of the secondary enamine 56 results in a mixture of five- and seven-membered heterocycles (equation 30)52. 

Heterocyclic ketene aminals have been found to be good aza-ene compounds which can undergo hetero-ene reactions readily with activated carbonyl compounds and enones " to provide novel and efficient synthetic routes to y-lactam-fused diaza-heterocycles and fused di- and tri-heterocycles, respectively. Such aminals bearing a secondary enamine moiety have been found to undergo an efficient aza-ene reaction with 4-phenyl-l,2,4-triazoline-3,5-dione under very mild conditions. The regio- and diastero-selectivity of the ene reaction of 4-phenyl-l,2,4-triazoline-3,5-dione with chiral allylic alcohols and their derivatives have been studied, " while Singleton and Hang have proposed a new mechanism for the ene reactions of triazolinediones which involves an open biradical as the key intermediate. This biradical is assumed either to form the ene product or to form reversibly an intermediate aziridinium imide which would be a shunt off the main ene mechanistic pathway. 

Type B (C—C—+ C—S) Syntheses.—Primary and secondary enamines and chlorocarbonyl sulphenyl chloride undergo a cycloacylation to thiazolones. Ethyl 3-aminoacrylate (7 X = OR ), for example, produces the 2-oxothiazole-5-carboxylic acid esters (8 X = COR ) in 60—80% yields. /3-Aminocrotonic nitriles (9) similarly afford the corresponding 5-cyano-heterocycles. ... 

The condensation of aldehydes or ketones with secondary amines leads to "encunines via N-hemiacetals and immonium hydroxides, when the water is removed. In these conjugated systems electron density and nudeophilicity are largely transferred from the nitrogen to the a-carbon atom, and thus enamines are useful electroneutral d -reagents (G.A. Cook, 1969 S.F. Dyke, 1973). A bulky heterocyclic substituent supports regio- and stereoselective reactions. 

Since tautomeric rearrangement is not possible when secondary amines react with acetylene, the intermediate enamines can be isolated.312,314 Vinylation with acetylene of heterocyclic nitrogen bases, such as pyrrole, indole, carbazole, was achieved in this way.312,315 However, when terminal alkynes react with secondary amines,... 

In streptocyanine dyes both ends of the methine chain are joined directly to nitrogen atoms, and a double enamine structure is thus present. The dyes are extremely susceptible to hydrolysis, particularly if they contain secondary nitrogen atoms. Stable dyes are obtained if the nitrogen is part of a heterocyclic ring system. Streptocyanine dyes are brilliant yellow dyes that dye polyacrylonitrile and acid-modified polyamide fibers with outstanding lightfastness [1],... 

Aminoquinolines 62 have been prepared in a two-step, one-pot, three-component reaction of 2-azidobenzophenones, secondary amines and arylac-etaldehydes [110]. The microwave-assisted reaction proceeded via the initial formation of enamines 59. Subsequent addition of 2-azidobenzophenones 60 afforded the triazoline intermediates 61, which underwent thermal rearrangement and cyclocondensation to furnish 2-aminoquinolines 62 (Scheme 41). Direct comparison with conventional thermal conditions demonstrated the superiority of microwave dielectric heating in terms of yields (73% vs. 31% of heterocycle 63 after 10 min at 180 °C). Furthermore, the formation of by-products due to decomposition of azide 60 was diminished in the microwave-assisted synthesis. Purification of the products was achieved using solid-phase extraction techniques. 

The typical behavior of enamines has been mainly observed for compounds possessing a tertiary nitrogen atom.1 The analogous derivatives with a secondary amino group (the a,j8-unsaturated secondary amines) could, in principle, possess either the imino or the tautomeric enamine structure, but the first possibility is preferred practically without exception. In the text, some examples of their properties are quoted for the sake of comparison with those of tertiary enamines on these occasions, the group designation imines is used. Nucleophilic reactions of a limited number of aromatic heterocyclic systems are also included when they are similar to the reactions of enamines and illustrate the specific character of the enamine grouping. 

If the amino group forms part of the ketone, as it does with y-87, 88 and 8-amino-ketones,89,90 heterocyclic enamines are obtained. 1,2-Dialkyl-J2-pyrrolines and 1,2-dialkyl-J2-piperideines (15) are formed from secondary amino groups, whereas primary amino groups 91 lead to 2-alkyl-J pyrrolines and 2-alkyl-J -piperideines. Gabriel90 used the suitably substituted phthalimidoketone for the synthesis of the alkaloid y-coniceine (15 R = H, R = n-Pr, n = 2). 

Compounds possessing reactive methylene groups condense with dimethylformamide diethyl acetal to give enamines, which may serve as precursors for heterocycles (cf. equations 48 and 66). Thus diethyl 2,6-dimethylpyridine-3,5-dicarboxylate (292) yields the enamine 293, which is converted into isolable secondary (Z)-enamines 294 by the action of primary aromatic amines. Thermal or base-catalysed cyclization then affords the naphthyridones 295 (equation 120)147. 

The first synthesis of the hexacyclic himandrine skeleton was achieved by L.N. Mander and co-workers. The last six-membered heterocycle was formed via an intramolecular Wacker-type oxidation in which the terminal alkene side-chain reacted with the secondary amine functionality. The oxidation was conducted in anhydrous acetonitrile to insure that the Pd-alkene complex was substituted exclusively by the internal nucleophile. The resulting six-membered enamine was then hydrogenated and the MOM protecting groups removed to give the desired final product. 

In the recent literature numerous reactions in which enamines are used for synthesis of enantiomerically pure compounds (EPC) can be found . Optically active enamines from substituted pyrrolidine (e.g. 27, R = CH20Me, CH20SiMe3, or 28, R = Me, CH20Me), or from piperidine , such as 29, (S)-phenylethylamine (30) " and stanna-N,0-heterocyclic amine (31) , are used. The cyclohexanenamines seem to be the preferred test compounds for this kind of reaction, whereas enamines of open-chain ketones and aldehydes have been investigated only rarely . Enamines from carbonyl compounds and secondary amines are obtained with azeotropic removal of water or by die Weingarten method with TiC. A titanium chloride-catalysed variation in which perfluorinated alkyl groups can be introduced is also known " . 

While most classical enamines and open-chain enamino esters2 are obtained by condensation, e.g., of a secondary amine with a keto compound, heterocyclic /3-enamino esters can be obtained only by special reactions as, e.g., rearrangement or direct syntheses. Some of these are depicted in this section. 

Enamines have most often been used as acetylene equivalents, the amine fragment being lost at a late stage to generate the aromatic heterocycle. Prior synthesis of the enamine is unnecessary these processes can also be achieved by heating together a ketone, a secondary amine and the heterocycle. 

The organolanthanide-catalyzed hydroamination of the aminoalkynes 276 gives the nitrogen-containing heterocycles 277 or 278 (in the case of R = H).158 The reaction of primary amines produces the cyclic imines 278, while the reaction of secondary amines gives the cyclic enamines 277 (Scheme 89). The organolan-... 

Fig. 1.2b) classes wherein an enolizable nucleophile (commonly an enamine, nitronate or 1,3-dicarbonyl) cyclizes onto an sp carbon. Enolexo-exo-tet cyclizations (Fig. 1.2c) are less common however, and tend to occur predominantly in cyclopropanation reactions. Indeed, alkylations using secondary amine catalysis are difficult under standard organocatalytic conditions owing to problems associated with the alkylation of the catalyst itself, although various methods have been adopted to address this. Finally, exo-trig cyclizations of heteroatoms onto sp centres (Fig. 1.2d) are a useful way of constructing enantiopnre heterocycles. 

The metal present can also catalyse other reactions, giving rise to tandem processes. If hydroformylation is carried out in the presence of a secondary amine, the aldehyde 4.136 produced by hydroformylation will condense to give an enamine 4.137, which will be hydrogenated (but not hydroformylated) under the reaction conditions to give a tertiary amine 4.138 (Scheme 4.52). This chemistry can be extended to dienes to give iV-heterocycles of various kinds (Schemes 4.53 and 4.54). ... 

Neutral nucleophiles are also alkenylated to give alkenylonium salts (Scheme 6). Examples include secondary amines (with concomitant deprotonation to afford enamines) and tertiary amines, acetic acid (with deprotonation to give alkenylacetates) formamides (that give alkenylformates), " sulphur-centred nucleophiles such as sulphides,thioamides (to give thioalkenes), thioureas and heterocyclic thiols group 15 nucleophiles triphenylphosphine, -arsine... 

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