Heterocyclic compounds, aromatic dihydropyridines

The Hantsch pyridine synthesis provides the final step in the preparation of all dihydrop-yridines. This reaction consists in essence in the condensation of an aromatic aldehyde with an excess of an acetoacetate ester and ammonia. Tlie need to produce unsymmetrically subsrituted dihydropyridines led to the development of modifications on the synthesis. (The chirality in unsymmetrical compounds leads to marked enhancement in potency.) Methyl acetoacetate foniis an aldol product (30) with aldehyde 29 conjugate addition of ethyl acetoacetate would complete assembly of the carbon skeleton. Ammonia would provide the heterocyclic atom. Thus, application of this modified reaction affords the mixed diester felodipine 31 [8]. 

Dihydro compounds are often useful synthetic intermediates showing different reactivity patterns to the parent, aromatic heterocycle. For example, indolines (2,3-dihydroindoles) can be used to prepare indoles with substituents in the carbocyclic ring, via electrophilic substitution then aromatisation (20.16.1.17), and similarly, electrophilic substitutions of dihydropyridines, very difficult in simple pyridines, followed by aromatisation, can give substituted pyridines. Dehydrogenation of tetra- and hexahydro-derivatives reqnires more vigorous conditions. 

A great variety of methods is available for the ring synthesis of pyridines the most obvious approach is to construct a 1,5-dicarbonyl compound, preferably also having further unsaturation and allow it to react with ammonia, addition of which at each carbonyl group, with losses of water, producing the pyridine. 1,4-Dihydropyridines, which can easily be dehydrogenated to the fully aromatic system, result from the interaction of aldehydes with two mol equivalents of 1,3-diketones (or 1,3-keto-esters, etc.) and ammonia aldol and Michael reactions and addition of ammonia at the termini, produces the heterocycle. 

Heterocyclic aromatic compounds can sometimes be reduced, particularly those which are electron-deficient. For example, reduction of pyridines gives 1,4-dihydropyridines (which are readily hydrolysed to 1,5-dicarbonyl compounds). Partial reduction of five-membered heteroaromatic compounds such as furans and pyrroles is also possible if these have electron-withdrawing substituents to stabilize the intermediate radical anion. For example, reduction of the furan 71 occurred with high selectivity to give the dihydrofuran 72, used in a synthesis of (-l-)-nemorensic acid (7.51).24... 

Certain heterocycles, e.g. pyridines or quinolines, bearing of an electron-withdrawing group such as oxazoline, undergo the Michael-type nucleophilic 1,4-addition accompanied with loss of aromaticity to give the new C-C bond. Thus formed dihydropyridine or benzodihydropyridine can be oxidatively aromatized with conservation of chirality, primary induced by an influence of chiral oxazoline moiety. In this manner, Meyers and coworkers [27] described the Michael-type addition of 1-naphthyllithium (609) to the oxazoline 610 at low temperature to form 611 in 90% yield. The latter was oxidatively aromatized to the naphthylquinoline 612 in 87% yield with 88 12 ratio of two diastereomers. Diastereoselectivity in this reaction remained on the same level as obtained by the nucleophilic addition of 609 to 610 indicating the virtually complete conservation of chirahty, from sp -type in the compound 611 to the axially chiral compound 612, Scheme 11. 

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