Heterocyclic Chemistry, Fifth Edition

28.2
 Aza - Indolizines 
Note: as can be seen from the examples above, numbering sequences vary with the number and disposition 
of the nitrogen atoms. 
Seven monoaza - and many more polyaza - indolizines (some are shown above) are possible, indeed com-
pounds with up to six nitrogen atoms have been reported. Despite the rarity of such systems in nature, there 
is much interest in aza - indolizines stemming from their structural similarity to both indoles and purines. 
Apart from pyrrolo[1,2 - b ]pyridazine, all the monoaza - indolizines protonate on the second (non - ring -
junction) nitrogen, rather than on carbon. 
3,25
Alkylation similarly goes on nitrogen, however other electro-
philic reagents attack with regioselectivity similar to indolizine itself – they effect substitution of the 
fi ve - membered ring at positions 1 and 3 (where these are carbon). 
28.2.1
 Imidazo[1,2 - a]pyridines 
Electrophilic substitutions such as halogenation, nitration etc. go at C - 3, or at C - 5 if position 3 is blocked. 
26
Acylation does not require a catalyst. 
27
Of all the positional chloro isomers, nucleophilic displacement reactions are known only for the 5 - isomer; 
7 - chloroimidazolo[1,2 - a ]pyridine, where one might have anticipated similar activation, is not reactive in 
this sense, 
28
but, of course, transition - metal - catalysed replacement of halogen ( 4.2 ) can be carried out at 
any position. 
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Base - catalysed deuterium exchange proceeds at C - 3 and C - 5; 
30
preparative lithiation occurs at C - 3, or 
if C - 3 is blocked, at C - 5 or C - 8 depending on other substituents, 
31
but the 2,6 - dichloro compound reacts 
selectively at C - 5, even in the presence of hydrogen at C - 3. 
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544
 Heterocyclic 
Chemistry
Amino - imidazo[1,2 - a 
]pyridines exist as amino tautomers, but are even more unstable than amino 
-
indolizines. 2 - and 5 - oxo compounds are in the carbonyl tautomeric form and react with phosphoryl chloride 
yielding chloro compounds. 
20
The traditional ring synthesis of imidazo[1,2 - a ]pyridines is based on the Chichibabin route to indolizines 
( 28.1.2 ), but using 2 - aminopyridines instead of 2 - alkyl - pyridines. The initial reaction with the halo - ketone 
is regioselective for the ring nitrogen, so isomerically pure products are obtained. 
33,34
2 - Oxo - imidazo[1,2 - a ]
pyridines are the products when an
α
- bromo - ester is used instead of a ketone. 
35
The 1,2 
- 
bis 
- 
electrophiles generated from glyoxal, benzotriazole and an amine can be used to pro-
duce imidazo[1,2 - a ]pyridines as illustrated below, but also imidazo[1,2 - a ]pyrimidines, and imidazo[1,2 - c ]
pyrimidines. 
36
2 - Aminopyridines can be used in other ways: copper - catalysed interaction with diazo - ketones 
37
and 
three - component reactions 
38,39,40
involving an isonitrile and an aldehyde also give imidazo[1,2 - a ]pyridines; 
such condensations can be promoted using an ionic liquid 
41
or scandium trifl ate with microwave heating. 
42
In the former route, 2 - substituted products result and from the latter, 3 - aminoimidazo[1,2 - a ]pyridines are 
formed.
Here again other starting materials having an amidine sub - unit, as in 2 - aminopyridine, react comparably: 
2 - aminothiazoles give imidazo[2,1 - b ]thiazoles, 
40
2 - aminopyrazines generate imidazo[1,2 - a ]pyrazines, 
38
4 - aminopyrimidines lead to imidazo[1,2 - c ]pyrimidines 
43
and 2 - aminopyrimidines afford imidazo[1,2 - a ]
pyrimidines (illustrated below). 
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Heterocycles Containing a Ring-Junction Nitrogen (Bridgehead Compounds) 545