Ring Synthesis of Indoles

Indoles are usually prepared from non-heterocyclic precursors by cyclisation reactions on suitably substituted benzenes they can also be prepared from pyrroles by construction of the homocyclic aromatic ring, and from indolines by dehydrogenation. 

Because of the importance of indoles in natural product synthesis and pharmaceutical chemistry, reports of new routes to indoles and improvements to older reactions appear frequently. This section discusses the most important methods now available, often those that have been used most frequently and are the most adaptable. 

Still the most widely used route, heating an arylhydrazone, nsually with acid, sometimes in an inert solvent gives an indole with the loss of ammonia. 

The Fischer synthesis, hrst discovered in 1883, involves the acid- or Lewis-acid-catalysed rearrangement of an arylhydrazone with the elimination of ammonia. The preparation of 2-phenylindole illustrates the process in its simplest form.  

The mechanistic details of the mnlti-step Fischer sequence are best represented by the sequence shown below. Labelling stndies proved the loss of the non-aromatic nitrogen as ammonia, and in some cases intermediates have been detected by and NMR spectroscopy. The most important step - the one in which a carbon-carbon bond is made, marked A - is electrocyclic in character and analogous to the Claisen rearrangement of aryl allyl ethers. 

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