Heterocyclic Chemistry, Fifth Edition

 
2
 

The aromatic character of indolizine is expressed by three main mesomeric contributors, two of which 

incorporate a pyridinium moiety; other structures (not shown) incorporating neither a complete pyrrole nor 
a pyridinium are less important.

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540
 Heterocyclic 
Chemistry
28.1.1
 Reactions of Indolizines 
Indolizine is an electron - rich system and its reactions are mainly electrophilic substitutions, which occur 
about as readily as for indole, and go preferentially at C - 3, but may also take place at C - 1. Consistent with 
their similarity to pyrroles, rather than pyridines, indolizines are not attacked by nucleophiles, nor are there 
examples of nucleophilic displacement of halide. 
Indolizine, p K
aH
3.9, 
3
is much more basic than indole (p K
aH
−
3.5) and the implied relative stability of 
the cation makes it less reactive, and thus indolizines are resistant to acid - catalysed polymerisation (cf. 
20.1.1.9 ). Indolizine protonates at C - 3, but 3 - methylindolizine protonates mainly (79%) at C - 1; the delicacy 
of the balance is further illustrated by 1,2,3 - trimethyl - and 3,5 - dimethylindolizines, each of which protonate 
exclusively at C 
- 
3. Electrophilic substitutions such as acylation, 
4
Vilsmeier formylation 
5
and diazo 
- 
coupling 
6
all take place at C - 3.
Nitration of 2 - methylindolizine under mild conditions results in substitution at C - 3, 
7
but under strongly 
acidic conditions it takes place at C - 1, 
8
presumably via attack on the indolizinium cation.
Indolizine and its simple alkyl derivatives are sensitive to light and to aerial oxidation, which lead to 
destruction of the ring system. Catalytic reduction in acidic solution (reduction of the indolizinium cation) 
selectively saturates the pyrrole ring, giving a pyridinium salt; 
9
complete saturation, affording indolizidines, 
results from reductions over platinum. 
10
Despite its 10 - electron aromatic
π
- system, indolizine apparently participates as an 8 - electron system in 
its reaction with diethyl acetylenedicarboxylate, though the process may be stepwise and not concerted. By 
carrying out the reaction in the presence of a noble metal as catalyst, the initial adduct is converted into 
an aromatic cyclazine ( 28.5 ). 
11
Indolizines normally lithiate at C 
- 
5, 
4
but 5 
- 
methylindolizine undergoes lithiation at the side 
- 
chain 
methyl. 
12

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Heterocycles Containing a Ring-Junction Nitrogen (Bridgehead Compounds) 541
Of its functional derivatives, worth noting is the easy cleavage of carboxyl and acyl groups on heating 
with aqueous acid, and the instability of amino derivatives, which cannot be diazotised, but which can be 
converted into stable acetamides.