Fischer Indole Synthesis in the Absence of a Solvent

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The traditional Fischer synthesis of indoles has been investigated and it has been shown that the reaction proceeds in good yield in the absence of a solvent. Introduction In 1883, while studying the reactivity of arylhydrazines and arylhydrazones, Emil Fischer found that, under acidic conditions, enolizable arylhydrazones undergo rearrangement and loss of ammonia to provide indole products (1-3). Subsequent studies suggested a mechanism for the Fischer indole synthesis that proceeds through an initial acid-catalyzed tautomerization of an arylhydrazone to an ene-hydrazine. The ene-hydrazine then undergoes [3,3]-sigmatropic rearrangement to produce a bis-imine intermediate. Subsequent aromatization of the imlnocyclohexadlene ring followed by intramolecular nucleophilic attack produces an aminal, which after loss of ammonia affords the indole product (4). Over 100 years after the initial discovery, the Fischer indole synthesis remains the most commonly employed method for the preparation of Indoles (5,6) Since a novel entry into the Fischer indole synthesis via a palladium-catalyzed strategy for the preparation of hydrazones has recently been developed particularly by Buchwald (7,8), the scope of Fischer Indole synthesis has expanded. Recently combinatorial syntheses of indole derivatives have been reported (9). On the other hand, many advantages of solvent free reactions have been recognized such as reduced pollution, low costs, and simplicity in process and handling (10). We now report that the classical Fischer indole synthesis can be achieved in the absence of a solvent that is followed by a simple work up of the reaction products. Results and Discussion A mixture of Phenylhydrazine l a , 3-pentanone, and p-toluenesulfonic acid (molar ratio 1:1:3) was heated, with mixing, in a test tube, on a water bath, at around 100 °C for 5 mln. The crude product was collected by filtration, washed with water and dried to give 2-ethyl-3-methylindole In Vol. 9. No. 1, 2003 Fischer indole synthesis in the absence of a solvent 82 % yield. Other examples of the reaction products are summarized In Table 1. ρ -TsOH · H 2 0 (3 mmol) \ R2 JHNH2 (HCl) 1 ( 1 mmol) 2 ( 1 mmol) solvent-free 100 °C (250 °C)