94 Indoles
Oxygen substituents
Indoles with a hydroxyl group on the benzene ring behave as normal phenols. ‘2-Hydroxyindole’ exists entirely in the
carbonyl tautomeric form and is known as oxindole. The properties of oxindole are generally those of a fi ve-membered
lactam but with somewhat enhanced acidity of the methylene at C-3. 3-Hydroxyindole is the minor component in
tautomeric equilibrium with the ketone form, and this mixture is usually known as indoxyl. It is easily oxidised and
transformed into the ancient dye, indigo. Isatin is best viewed simply as an -keto-amide. Isatins undergo straightfor-
ward electrophilic substitution in the benzene ring, at C-5, and this, coupled with reaction chemistry of the ketone and
amide groups, can be used to advantage for the synthesis of indoles and quinolines (see page 69).
Ring synthesis – disconnections
There are many, many ways to synthesise indoles but here we will discuss six important routes for the construction of
indoles from precursors without a pyrrole ring, based on the disconnections summarised below. Indoles can also be
obtained readily by dehydrogenation of indolines (2,3-dihydroindoles) with various oxidants.
Synthesis of indoles from arylhydrazones (1,2- and 3,3a-bonds made)
TheFischer synthesis, the classic route to indoles, was discovered by Emil Fischer in 1883. It is still one of most widely used
routes to indoles. In essence, an arylhydrazone of a ketone or aldehyde is heated with acid, ammonia is lost and an indole is
formed. Often it is convenient to make the arylhydrazone and carry out the ring synthesis in one pot without isolation of
the arylhydrazone, for example the reaction between cyclohexanone and phenylhydrazine producing tetrahydrocarbazole.
The scheme shows the sequence of steps for a general ketone with phenylhydrazine. The phenylhydrazone is in equilib-
rium with a small amount of its enamine tautomer, which is N-protonated, and it is this species that undergoes an irre-
versible electrocyclic rearrangement in which the 3–3a bond is made and the N–N bond is broken. Re-aromatisation
of the benzene ring, then intramolecular amine→iminium addition, and fi nally loss of ammonia produces the indole.