Aldehydes continued heterocyclic

In a series of three papers, Noguchi and co-workers have reported their continuing studies on the formation of heterocycle-fused azepine systems <96X13081, 96X13097, 96X13111>. A typical example is the conversion of the aldehyde 15 into the azepines 16 and 17 (Scheme 3). Xhe reaction also proceeds with imines when the dihydroazepine prior to bridging can be isolated. Mechanistic and stereochemical aspects of the reaction have been explored. 

Introduction of heteroatoms, e. g. N, S, or O, into hydrocarbon molecules adds substantial value, and new routes for such reactions are of continuous interest to the chemical industry. The two main classes of aromatic N-containing hydrocarbons are the arylamines and the aromatic N-heterocyclic compounds. The aryl-amines, which are required industrially, are manufactured by nitration of aromatics to nitroaromatics, followed by hydrogenation to arylamines [1,2]. Because of the lower demand for aromatic heterocycles than for arylamines, coal tar is still an important source of pyridine and methylpyridines (picolines). Increasing demand for aromatic heterocyclic compounds has led to processes in which aldehydes and ketones are condensed with NH3 to furnish pyridine and alkylated pyridines [3,4]. 

Thiazolidones are another class of heterocycles that attract much attention because of their wide ranging biological activity [106], They are usually synthesized by three-component condensation of a primary amine, an aldehyde, and mercapto-acetic acid with removal, by azeotropic distillation, of the water formed [107]. The reaction is believed to proceed via imine formation then attack of sulfur on the imine carbon. Finally, an intramolecular cyclization with concomitant elimination of water occurs, generating the desired product. The general applicability of the reaction is limited, however, because it requires prolonged heating with continuous removal of water. To circumvent these difficulties and to speed up the synthesis, Miller et al. developed a microwave-accelerated three-component reaction for the synthesis of 4-thiazolidinones 63 [108]. In this one-pot procedure, a primary amine, an aldehyde, and mercaptoacetic acid were condensed in ethanol under MW conditions for 30 min at 120 °C (Scheme 17.44). The desired 4-thiazolidinones 63 were obtained in 55-91% yield. 

Arylcarboxylic acids. BaMn04 added to a stirred soln. of 4-methoxybenzaldehyde in methylene chloride at 36°, and stirring continued for 14 h - 4-methoxybenzoic acid. Y 77%. Aliphatic aldehydes gave a polymeric residue, a,p-ethylenealdehydes gave low yields, and heterocyclic aldehydes remained unoxidised. F.e.s. R.G. Srivastava, P.S. Venkataramani, Synth. Commun. 18, 2193-200 (1988). 

In continuation of our efforts in the development of new synthetic routes for the synthesis of heterocyclic compounds using nanocatalysts, we have recently reported a novel synthesis of 3,4,5-trisubstituted furan-2(5H)-one derivatives by the one-pot three-component condensation of aldehydes, amines, and dimethyl acetylenedicar-boxylate (DMAD) by nsing nanoparticulate ZnO as a catalyst in Et0H H20 (1 1) at 90°C (Scheme 9.30) (Tekale et al. 2013). Almost all the employed aldehydes and amines reacted smoothly to afford excellent yields of the prodncts, irrespective of the natnre of the snbstitnent present on the aldehyde or amine. The plausible mechanism for the synthesis of furan-2(5 f)-ones using nano-ZnO is depicted in Figure 9.3. The catalyst promotes the formation of enamines (99) from amines (97) and DMAD (96). ZnO polarizes the carbonyl group of aldehydes to form a polarized adduct (100) which reacts with the enamines, followed by cyclization with the elimination of methanol molecules to afford the corresponding trisubstituted furanone derivatives (98). 

The synthetic proposal in the same scheme suggests the two-step transformation of phthalanhydride to aldehyde TM 7.6b, first by standard hydride reduction and then by partial oxidation. Condensation with hydrazine passes over aldimine as a stable intermediate, and then the cyclization requires heating and continuous water elimination. Activation of the heterocyclic ring by chlorination of the enolic form is required before substitution by hydrazine to TM 7.6. 

NaBH4 added portionwise with stirring below 28° during 0.5 hr. to 2-cyclo-hexyl-3,4,4-trimethyl-stirring continued 4 hrs. at room temp., dil. with 2 N HGl, added to 2,4-dinitrophenylhydrazine reagent, and heated 1 hr. on a steam bath cyclohexanecarboxaldehyde 2,4-dinitro-phenylhydrazone. Y 78%. - Through this reaction, aldehydes can be obtained from carboxylic acids via zl -oxazolines. F. e. s. I. G. Nordin, J. Heterocyclic Ghem. 3, 531 (1966). 

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