Pyridines Annelated with Heterocycles

Isoquinuclidine (2-azabicyclo[2,2,2]octane), catalytic synthesis of 88MI25. 

Perhydro azolopyridines with bridgehead N-atoms 90AHC(49)193. 

Praziqauntel, hexahydropyrazino[2, l-a]isoquinoline derivative with potent anthelmintic activity 90KFZ(9)60. 

Quinuclidine derivatives, synthetic chemistry, and pharmacology of 83MI4. 

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In the reactivity scale of Scheme 4.25 the reactivity of any of these heterocycles is substantially increased by annellation with a conjugated aromatic ring. Thus 2-quinolone is much more reactive than pyridine-2-one 245, which is the least reactive hydroxyheterocycle and requires reaction temperatures higher than 190-200 °C for silylation-amination [27]. To achieve these temperatures at normal pres-... 

The Diels-Alder methodology can also be applied in the synthesis of tricyclic heterocycles, as was demonstrated by reactions of 2-(2-trimethylsilylethynylphenyl-X)pyrimidines (X = 0, S, NCOMe, CHj, CO). They are converted in good yield on heating at 160°C into tricyclic annelated pyridines (89T6511) (Scheme 37). A similar reaction was found with the 2-(2-allylphenoxy)pyrimidines affording azaxanthenes (79H665) (Scheme 37). 

Since there are no extensive studies on the relative aromaticity of the heterocycles covered in this chapter, the relative order of aromaticity of these systems has been gleaned from disparate studies. A priori, the combined effects of the 7i-electron-deficient five-membered heterocycles annelated to a pyridine nucleus provides a series of bicyclic heterocycles with low reactivity towards electrophiles. In the presence of suitable leaving groups, they are prone to undergo nucleophilic substitution. Since these heterocycles are readily obtained from either appropriately substituted pyridines or five-membered heterocycles, methods for direct functionalization of the parent heterocycles are not frequently studied. Based on the diversity of reactions these heterocycles undergo, it can be inferred that the pyridofuroxans are the least aromatic. 

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