Heterocyclic Chemistry, Fifth Edition

28.1.2
 Ring Synthesis of Indolizines
 
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The traditional route to indolizines is the Chichibabin synthesis, 

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which involves quaternisation of a 
2 - alkyl - pyridine with an
α
- halo - ketone, followed by base - catalysed cyclisation via deprotonation of the 
pyridinium
α
- methyl, 
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rendered easy by the quaternisation, then intramolecular attack on the carbonyl 
group. 
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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 - a ]pyridinium salts are isolated as 
perchlorate salts ( CAUTION ). 
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Another useful method involves the intermediacy of a pyridinium ylide as a 1,3 
- 
dipole in a 
cycloaddition. 
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An important feature of this type of reaction (which can also be used in an analogous fashion to prepare 
aza - indolizines) is that although a dihydroindolizine is the logical product from a mechanistic viewpoint, 
the fully aromatic compound is usually obtained. The mechanism of aromatisation is not clear: it could be 
by air oxidation during work - up, or via hydride transfer to some other component in the reaction mixture. 
When dihydro compounds are isolated they can be easily aromatised using the usual reagents – palladium/
charcoal or quinones. An extension of this analysis is the production of aromatic indolizines from reaction 
of an ylide with an alkene (which would be expected to give the tetrahydro product) in the presence of a 
suitable oxidant such as the cobalt chromate complex 
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shown below. 
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542
 Heterocyclic 
Chemistry
Aromatisation can alternatively occur by loss of HX (HCN in the example shown) when a leaving group 
is present in one of the reactants. 
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In several variants, pyridines carrying either a 2 - alkynylmethyl or a 2 - alkenylmethyl substituent can be 
ring closed to indolizines. Iodine 
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and silver tetrafl uoroborate 
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have been used to close precursors avail-
able conveniently using the 2 
- 
lithiated pyridine. As in several situations in this chapter, comparably 
substituted imine units in other starting materials, can be ring closed by this route, for example 
2 - alkynylmethylquinoxalines 
give 
pyrrolo[1,2 - a ]quinoxalines 
and 
2 - alkynylmethylthiazoles 
give 
pyrrolo[2,1 - b ]thiazoles. 
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In a one - pot three - component sequence, a 2 - alkynylmethylpyridine intermediate is generated in situ , 
pyridine - 2 - carbaldehyde being the starting material and 1 - aminoindolizines the products. 
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Heterocycles Containing a Ring-Junction Nitrogen (Bridgehead Compounds) 543