108 1,2-Azoles and 1,3-Azoles
To understand the N-alkylation of imidazole and pyrazole, we need fi rstly to be aware of the tautomerism that rapidly
transfers the N-hydrogen between the two nitrogens but only becomes evident in unsymmetrically substituted com-
pounds. The two tautomers of an imidazole or pyrazole are in rapid equilibrium and are inseparable so we write, for
example, ‘4(5)-methylimidazole’ to designate the tautomerism in such molecules. So, in 4(5)-substituted imidazoles,
the alkylating electrophile reacts at a different rate with the two alternative imine nitrogens, on the basis of steric hin-
drance, and the mixture of salts produced refl ects that rate difference.
There is a further aspect of alkylations of imidazoles and pyrazoles that we illustrate with pyrazole: the fi rst formed salt
is an N-alkylpyrazolium salt but it is also the protonic salt of an N-alkylpyrazole. This salt can lose an N-proton in an
equilibrium with unreacted pyrazole, generating the protonic salt of the starting material, which cannot then alkylate,
and a neutral N-alkylpyrazole, which can alkylate but gives an N-1,N-2-dialkylpyrazolium salt. The consequence of
this interplay can be the formation of three-component mixtures of starting material with mono- and di-alkylated
products.
One way to avoid such diffi culties is to alkylate the N-anion of the heterocycles (pages 110–111). Another strategy is to
use an N-acyl or N-sulfonyl derivative from which, although the derivative is less nucleophilic, only one salt is obtained,
an easy hydrolysis of the N-blocking group then giving the desired mono-N-alkylated product. Note also, that in the
formation of an N-acylimidazole from a 4(5)-R-imidazole, a 1,4-disubstituted product is obtained (as a consequence
of reaction at the least hindered nitrogen), so after N-alkylation of this and hydrolysis of the N-acyl, the more hindered
1,5-disubstitution pattern is achieved.
N-Acylimidazoles are best prepared using the acylating agent together with a tertiary amine base that removes an
N-proton from the fi rst formed N-acylimidazolium salt. The carbonyl group in N-acylimidazoles is very easily attacked
by nucleophiles and advantage is taken of this property in the use of 1,1-carbonyldiimidazole (CDI) as a safe synthetic
equivalent for the highly toxic phosgene, that is, it is a synthetic equivalent for O=C^2 .