Heterocyclic Chemistry, Fifth Edition

27.2
 Reactions with Radicals 
Purines react readily with hydroxyl, alkyl, aryl and acyl radicals, usually at C - 6, 
36
or at C - 8 (or C - 2) if the 
6 - position is blocked. Both reactivity and selectivity for C - 8 are increased when the substitution is con-
ducted at lower pH. 
37
In nucleosides, a radical generated at C - 5 
′
cyclises rapidly onto C - 8, but can be 
trapped before cyclisation by using a large excess of acrylonitrile. 
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27.3
 Reactions with Oxidising Agents 
There are few signifi cant oxidations of purines apart from N - oxidations ( 27.1.1.4 ), but dimethyldioxirane 
gives good yields of 8 - oxo compounds, possibly via the intermediacy of a 9,8 - or 7,8 - oxaziridine. 
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C - 8 -
Oxidation 
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is an important process in vivo , for example with the oxomolybdoenzyme xanthine oxidase, 
where oxygen is introduced at C - 8 via a mechanism about which there is still debate.
27.4
 Reactions with Reducing Agents 
The reduction of substituted purines is very complex and ring - opened products are often obtained. 1,6 - 
Dihydropurine is formed by catalytic or electrochemical 
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reduction of purine, but this is unstable. Stable 
reduced compounds can be obtained by reduction in the presence of N - acylating agents. 
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7/9 - Quaternary 
salts are easily reduced by borohydride, in the fi ve - membered ring, producing 7,8 - dihydro derivatives. 
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27.5
 Reactions with Nucleophilic Reagents 
Nucleophilic displacement of leaving groups from C - 2, C - 6 and C - 8 is the most common means of prepara-
tion of substituted purines. Halides are the most popular leaving groups, particularly chlorides, but fl uorides 
are generally the most reactive, although slightly less accessible. Bromides and iodides can be used simi-
larly, but offer little advantage for simple nucleophilic substitutions. Sulfonates, sulfoxides, sulfones, 
quaternary ammonium, diphenylphosphonyloxy 
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and nitro 
33
are also highly reactive leaving groups. 
Although fl uoro is intrinsically more reactive than chloro, this does not overcome the natural bias of the 
purine ring, so 6 - chloro - 2 - fl uoro - purines react selectively at C - 6 with a number of nucleophiles. 
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Relatively easy nucleophilic displacement, via the usual addition/elimination sequence, takes place at all 
three positions with a wide range of nucleophiles, such as alkoxides, 
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sulfi des, amines, azide, cyanide 
and malonate and related carbanions. 
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522
 Heterocyclic 
Chemistry
In 9 - substituted purines, the relative reactivity of halides is 8
>
6
>
2, but strongly infl uenced by the 
presence of other substituents. In 9 H - purines this is modifi ed to 6
>
8
>
2, the demotion of the 8 - position 
being associated with anion formation in the fi ve - membered ring. Conversely, in acidic media the reactivity 
to nucleophilic displacement at C - 8 is enhanced: protonation of the fi ve - membered ring facilitates the 
nucleophilic addition step. 
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The relative reactivities of the 2 - and 6 - positions are nicely illustrated by the 
conditions required for the reaction of the respective chlorides with hydrazine, a relatively good nucleo-
phile. 
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It is worth noting the parallelism between the relative positional reactivity here with that in halo -
pyrimidines where it is 4
>
2.
In 2,6 - dichloropurine, reactivity at C - 6 is enhanced relative to 6 - chloropurine by the inductive effect of 
the second halogen, whereas the presence of electron - releasing substituents, such as amino, somewhat 
deactivates halogen to displacement, but, conversely, oxygenated purines, probably because of their car-
bonyl tautomeric structures, react easily. 
49
The generation of an N - anion by deprotonation in the fi ve - membered ring is given as the reason why 
8 - chloropurine reacts with sodamide to give adenine: inhibition of attack at C - 8 allows the alternative 
addition to C - 6 to lead eventually to the observed major product. 
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Direct conversion of inosines into 6 - amino derivatives, without the intermediacy of a halo - purine, can 
be achieved by heating with a mixture of phosphorus pentoxide and the amine hydrochloride 
51
or using the 
amine with
p 
- 
toluenesulfonic acid and a silylating agent (HMDS), 
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or the amine with iodine and 
triphenylphosphine. 
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Even where a nucleophilic displacement of halide is feasible, the use of transition - metal catalysis, such 
as with copper (for iodides) or palladium, generally offers much milder conditions ( 4.2.10 ). 
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Purines: Reactions and Synthesis 523
Other useful leaving groups in purine chemistry include sulfoxide, 
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trifl ate, 
56
and aryl - or alkylthio. 
57
Sulfones are highly reactive in some nucleophilic substitutions, and are also the reactive intermediates in 
sulfi nate - catalysed displacements of halide. 
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Displacement of halides can be catalysed by amines – trimethylamine, pyridine 
59
and DABCO 
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have 
been used. Mechanistically, the catalysis involves formation of an intermediate quaternary ammonium salt 
that is more reactive towards nucleophiles than the starting halide. The intermediate quaternary salts can 
be isolated, if required. Trimethylamine gives the most reactive quaternary salt, but DABCO can be more 
convenient. The relative reactivities for nucleophilic displacement at C - 6 are: trimethylamine : DABCO :
chlorine = 100 : 10 : 1. 
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Cyano 
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and fl uorine 
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are amongst the groups that have been introduced in 
this way.
Arylamines can be particularly unreactive as nucleophiles and for these, the use of fl uorine 
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or a sulfone 
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as a leaving group, or palladium - assisted displacement ( 4.2.10 ) of bromine 
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may be necessary. A 2 - 
chlorine, deactivated by the presence of a 6 - amino substituent, can be effi ciently displaced by arylamines 
with trimethylsilyl chloride in butanol. 
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The displacements of fl uorine, chlorine and butyl sulfone by ani-
lines are greatly accelerated by carrying out the reactions in 2,2,2 - trifl uoroethanol, with the addition of 
excess trifl uoroacetic acid. 
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Amino groups can be converted into good leaving groups by incorporation into a 1,2,4 - triazole. 
12,68
Imidazoles can be used similarly. 
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