Pyridines, condensed aromatic

Basic nitrogen compounds such as condensed aromatic pyridines can be separated from neutral or slightly acidic types such as condensed... 

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]. 

Reaction of bisphenol with chloronitroaromatic compounds was generally performed in dimethylformamide (DMF) or dimethyl sulfoxide (DMSO) at reflux using K2C03 as a base.108 109 It is possible to achieve this condensation in Ullmann s conditions by using a cuprous chloride or iodide-pyridine system as a catalyst when this reaction is performed with deactivated aromatic compounds, it gives too poor yields110 ultrasounds can dramatically improve yields without solvent.111... 

A large range of aromatic and heteroaromatic aldehydes, for example benzalde-hyde 462a or pyridine-2-aldehyde 462b, condense with two equivalents of N-silyl-ated dimethylamine 463, piperidine, or morpholine 294 in the presence of... 

Aromatic azacrowns have also been synthesized. For example, condensation of o-hydroxyaniline with the appropriate dichloro polyether yields benzo-12-azacrown-4 or benzo-15-azacrown-5 (176) (Lockhart et al., 1973). Starting from 2,6-dibromopyridine, a number of pyridine-containing crowns such as (177) have also been obtained (Timko et al., 1974 Vogtle Weber, 1974). 

Tertiary bases (e.g. pyridine or dimethylaniline) are preferable as solvents to water (335, 336) for condensing certain aromatic amines and the parent, cyano-gnanidine. When the amine concerned lacks acidic substituents, an equivalent of a minerad acid is a useful catalyst (336) it is best introduced as a salt of the amine or a tertiary base, or as gaseous hydrogen chloride, to maintain anhydrous conditions. If the amine does contain acidic substituents an acid catalyst is unnecessary (335). 

Our own group is also involved in the development of domino multicomponent reactions for the synthesis of heterocycles of both pharmacologic and synthetic interest [156]. In particular, we recently reported a totally regioselective and metal-free Michael addition-initiated three-component substrate directed route to polysubstituted pyridines from 1,3-dicarbonyls. Thus, the direct condensation of 1,3-diketones, (3-ketoesters, or p-ketoamides with a,p-unsaturated aldehydes or ketones with a synthetic equivalent of ammonia, under heterogeneous catalysis by 4 A molecular sieves, provided the desired heterocycles after in situ oxidation (Scheme 56) [157]. A mechanistic study demonstrated that the first step of the sequence was a molecular sieves-promoted Michael addition between the 1,3-dicarbonyl and the cx,p-unsaturated carbonyl compound. The corresponding 1,5-dicarbonyl adduct then reacts with the ammonia source leading to a DHP derivative, which is spontaneously converted to the aromatized product. 

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