144 Heterocycles with Ring-Junction Nitrogen (Bridgehead Nitrogen)
Indolizine
Indolizine is an electron-rich system with a reactivity similar to that of indole. However, it is signifi cantly more basic
than indole (pKaH –3.5). As for indole, protonation occurs on carbon – usually C-3 – not on the nitrogen because this
would produce a non-aromatic -system. The six-membered ring of indolizine is not very pyridine-like, because it
does not contain an imine so nucleophilic additions therefore are rare, however when protonated it has an iminium.
Standard electrophilic substitutions take place at C-3, but under strongly acidic conditions, reaction occurs at C-1,
presumably via attack on the indolizinium cation.
Lithiation occurs readily in the pyridine ring at C-5. Reduction in acidic solution can give either the dihydro or fully
saturated derivatives.
Despite its ten-electron aromatic -system, indolizine participates as an eight-electron -system in its reaction with die-
thyl acetylene dicarboxylate, although details of the mechanism are not clear. The reaction is carried out in the presence
of a catalyst to convert the unstable intermediate adduct into the stable, aromatic cyclazine product (see pages 148–149).
Azaindolizines
(Note: The numbering of azaindolizines is complex and varies with the number and disposition of nitrogens.)