Ring Synthesis of Indolizines

The traditional route to indolizines is the Chichibabin synthesis, which involves quatemisation of a 2-aUcyl-pyridine with an a-halo-ketone, followed by base-catalysed cyclisation via deprotonation of the pyridinium a-methyl, rendered easy by the quatemisation, then intramolecular attack on the carbonyl group.  

A variation of the classical procedure utilizes 2-methoxy-6-methylpyridine as a starting material and leads eventually to 5-aminoindolizines the intermediate oxazolo[3,2-fl]pyridinium salts are isolated as perchlorate salts (CAUTION).  

ArCOCH2Br, Me2CO, reflux then, H2SO4, HCIO4 

Another useful method involves the intermediacy of a pyridinium ylide as a 1,3-dipole in a cycloaddition.  

Aromatisation can alternatively occnr by loss of HX (HCN in the example shown) when a leaving group is present in one of the reactants.  

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