1,2-Azoles and 1,3-Azoles 111TheseN-anions provide the means for the controlled introduction of substituents onto the nitrogen of pyrazoles and
imidazoles by reaction with electrophiles. It is important to remember that, as the resonance structures imply, the anions
are ambident, that is, can react at either nitrogen, and the product or product mixture obtained from substituted pyrazoles
or imidazoles may refl ect a difference in steric hindrance to reaction at the two different nitrogen sites.
N-Arylation can be achieved; most often a copper-catalysed reaction is used and the aryl donor is either an aryl halide
or an aryl boronic acid. N-Alkenylation with vinyl halides similarly requires copper catalysis.
C-MetallatedN-substituted imidazoles and pyrazoles, and C-metallated
thiazoles and isothiazoles
Without the complication of an acidic N-hydrogen, strong base deprotonation of these azoles follows the principle
that the most acidic C-proton is on a carbon adjacent to the pyrrole/thiophene-like heteroatom. This is unambigu-
ously the 5-hydrogen in isothiazoles and N-substituted pyrazoles; two hydrogens fulfi l this criterion in thiazoles and
N-substituted imidazoles, but the 2-hydrogen is further acidifi ed by electron withdrawal by the imine unit and is the
most acidic. Various removable protecting groups have been used to mask the nitrogen of pyrazoles and imidazoles
prior to C-metallation (and may also provide assistance by coordination to the lithiating agent) and three are illus-
trated in the examples below.
When the 2-position is blocked, the 5-position is readily metallated, as the following sequence illustrates: lithiation of
N-SEM-imidazole, at C-2, is followed by the introduction of a substituent at that position. Now, lithiation proceeds
easily at C-5. Lithiated azoles react with the full range of electrophilic reagents: PhSSPh, DMF, an aldehyde and an
isocyanate are the examples in the following sequences.