Heterocycles with Ring-Junction Nitrogen (Bridgehead Nitrogen) 145‘Azaindolizines’ – indolizines containing additional nitrogen(s) replacing carbons – are common. Compounds with
extra nitrogen(s) in the six-membered ring now contain imine systems and are much more susceptible to nucleophilic
attack in that ring. Compounds with extra nitrogens in the fi ve-membered ring show the expected relationships to the
other azoles – imidazole, pyrazole, triazoles and tetrazole.
Imidazo[1,2-a]pyridine undergoes electrophilic substitution, under mild conditions, at C-3 but if this position is
blocked, substitution at C-5 occurs.
Imidazo[1,5-a]pyridine undergoes electrophilic substitution at C-1 but, in contrast to its isomer, the alternative posi-
tion C-3 in the fi ve-membered ring is next most favoured. However, a variation allows direct C-3–benzoylation via the
intermediacy of an ylide formed by deprotonation of an N-benzoyl cation.
The preferred position for lithiation of both imidazopyridines is C-3, but when this is blocked, reaction occurs at either
C-5 or C-8. In the examples shown below, a methyl group in a peri-position hinders reaction at C-5 but a methoxy at
the same position directs the lithiation by coordination to the reagent (DoM).