The Fischer indole synthesis is one of the most important classical methods for the preparation of indole and its substituted derivatives. It was developed by Emil Fischer and involves the acid-catalysed conversion of an arylhydrazone, usually a phenylhydrazone, into an indole derivative. The reaction is particularly useful because indoles are important structural units in many natural products, pharmaceuticals, dyes and biologically active compounds. The general reaction may be represented as: Aldehyde or ketone + phenylhydrazine → phenylhydrazone → indole derivative For example, acetone reacts with phenylhydrazine to form acetone phenylhydrazone, which on treatment with a strong acid and heating gives a substituted indole. Similarly, acetophenone phenylhydrazone gives a methyl-substituted indole derivative. The first step of the Fischer synthesis is the formation of an arylhydrazone. An aldehyde or ketone reacts with phenylhydrazine under mildly acidic conditions. The carbonyl oxygen is protonated, making the carbonyl carbon more electrophilic. Phenylhydrazine then attacks the carbonyl carbon, followed by proton transfers and elimination of water. The resulting compound is the corresponding phenylhydrazone. The second stage is acid-catalysed rearrangement of the hydrazone. Strong acids such as hydrochloric acid, sulphuric acid, polyphosphoric acid, zinc chloride or Lewis acids can be used depending upon the substrate. Heating is frequently required. The hydrazone undergoes protonation followed by tautomerisation to an enehydrazine form. This enehydrazine is the important intermediate in the Fischer indole synthesis. The enehydrazine undergoes a [3,3]-sigmatropic rearrangement, commonly called the Fischer rearrangement. This step produces a rearranged cyclohexadienyl imine-type intermediate. Subsequent proton transfers and cyclisation lead to formation of a cyclic intermediate. The nitrogen-containing ring is then formed, followed by cleavage of the N–N bond and loss of ammonia or an ammonia-derived species. Finally, aromatisation occurs to produce the indole system. The mechanism can therefore be broadly divided into the following stages: formation of phenylhydrazone, protonation and tautomerisation, formation of the enehydrazine, [3,3]-sigmatropic rearrangement, cyclisation, loss of ammonia, and aromatisation. The driving force for the final stages is the formation of the highly stable aromatic indole ring. The Fischer synthesis is especially significant because substitution in the starting carbonyl compound determines substitution in the final indole. For this reason, the reaction is widely employed in the synthesis of 2- and 3-substituted indoles. Substituted phenylhydrazines can also be employed