Indoles 89-Alkylation of 3-alkyl-substituted indoles by cationic reagents involves a rearrangement of a fi rst-formed
3,3-dialkylated-3H-indolium cation, verifi ed in the formation of 1,2,3,4-tetrahydrocarbazole by boron trifl uoride
catalysed cyclisation of 4-(indol-3-yl)butan-1-ol using an isotopically labelled substrate. The consequence of the
rearrangement of the symmetrical spirocyclic intermediate, produced by initial preferred electrophilic attack at the
-position, is the equal distribution of the label between the C-1 and C-4 carbons of the product.
N-Deprotonation and N-metallated indoles
TheN-hydrogen of indole can be quantitatively removed with strong bases giving an indolyl anion. The pKa of 16.2
for this process is similar to that for pyrrole, 17.5, and much lower than that of an aromatic amine, such as aniline (pKa
30.7). Indolyl anions are still aromatic species, with two lone pairs associated with the nitrogen, one in the plane of
the ring, is available for reaction with electrophiles without disrupting the aromaticity, thus allowing N-substitution.
N-Substitution can also be achieved via small concentrations of the indolyl anion generated by weaker bases or in
phase-transfer situations.
The synthetically-important electrophilic trapping of indolyl anions is illustrated below by the preparation of
N-benzoylindole and N-methylindole, via the indolyl anion (produced quantitatively with a strong base – sodium
hydride), and N-phenylsulfonylindole and N-Boc-indole, via small concentrations of the anion.
N-Arylation of indoles can be carried out effi ciently using palladium or copper catalysis; various ligands have been
utilised and two sets of conditions, from several that are known, are shown below.