What Is Fischer Indole Synthesis?
The Fischer indole synthesis method is to heat phenylhydrazone in the presence of Lewis acid or protonic acid to remove a molecule of nitrogen to obtain 2-substituted or 3-substituted indole derivatives. Fischer E.and Jourdan F. first reported this reaction in 1883. They cyclized N-methylphenylhydrazone of pyruvate to obtain 1-methyl-2-indolecarboxylic acid, but the yield was very low (5%).
Nowadays, this acid-catalyzed cyclization of arylhydrazines with aldehydes or ketones remains indispensable in synthesizing indole derivatives, which are pivotal in pharmaceuticals, agrochemicals, and natural product synthesis.
- Reagents: Catalysts [Brønsted acids, Lewis acids (ZnCl2, BF3), or polyphosphoric acid (PPA)]; Solvents [Polar aprotic solvents (e.g., DMSO, AcOH)].
- Reactants: Arylhydrazines (e.g., phenylhydrazine), aldehydes or ketones (excludes α,β-unsaturated ketones due to side reactions).
- Products: Indole derivatives.
- Reaction Type: Cyclization reaction.
- Related Reactions: Bartoli indole synthesis, Borsche-Drechsel cyclization.
Fig 1. Fischer indole synthesis and its mechanism. [1]
Mechanism of Fischer Indole Synthesis
The Fischer indole synthesis proceeds through a sequence of acid-mediated transformations:
Formation of the Hydrazone
The reaction begins with the condensation of an arylhydrazine (e.g., phenylhydrazine) with a carbonyl compound (aldehyde or ketone) to generate a hydrazone intermediate.
Tautomerization and [3,3]-σ Tropic Rearrangement
The hydrazone undergoes tautomerization to an enamine intermediate, followed by a [3,3]-σ tropic shift (analogous to the Cope rearrangement). This rearrangement forms a diimine structure, which subsequently aromatizes to yield a cyclic aminal.
Cyclization and Ammonia Elimination
Protonation of the aminal triggers ring closure and expulsion of ammonia, resulting in the aromatic indole core. The steric and electronic characteristics of the starting carbonyl compound control the regioselectivity between 2- and 3-substitution sites.
Experimental Tips for Fischer Indole Synthesis
- The most commonly used catalyst is zinc chloride, and there are many other catalysts available, such as boron trifluoride, polyphosphoric acid, metal halides, Lewis acids, protic acids, and certain transition metals. Microwave radiation can promote the reaction.
- Phenylhydrazone can be easily prepared by the reaction of phenylhydrazine with aldehydes or ketones. In actual operation, aldehydes or ketones are usually heated with an equal amount of aromatic hydrazine in acetic acid to undergo intermolecular condensation to obtain phenylhydrazone. The resulting benzene does not need to be separated, and is immediately heated under acid catalysis for rearrangement and deamination to obtain indole ring compounds.
- The α-carbon atom of the aldehyde or ketone used in the Fischer indole synthesis must contain at least two hydrogen atoms, that is, it must be a ketone with a RCOCH2R' (R or R' = alkyl, aryl or hydrogen) structure.
- If a ketone of the RCH2COCH2R' type is used in the reaction, a mixture of two products is obtained.
- Indole cannot be obtained by reacting the phenylhydrazone of acetaldehyde in a solution in the presence of zinc chloride, but indole can be obtained by loading the catalyst on glass beads and then passing acetaldehyde vapor under heating.
- Pyruvic acid phenylhydrazone is used to react to obtain 2-indolecarboxylic acid, which can also be obtained by heating and decarboxylation.
Application Examples of Fischer Indole Synthesis
- Example 1: Alexander Tuan-Huy Duong et al. used a continuous flow microfluidic reactor to react hydrazines with latent aldehydes through an interrupted Fischer indolization reaction, successfully generating fused indoline and azaindoline products. [2]
- Example 2: Xu Yang et al. reported an optimized Fischer indole cyclization process, using toluene as a co-solvent and extraction solvent, to achieve kilogram-scale synthesis of two key intermediates of MmpL3 inhibitors NITD-304 and NITD-349. [3]
Fig 2. Synthetic examples via Fischer indole synthesis.
Related Products
References
- Jie Jack Li. Name Reactions-A Collection of Detailed Mechanisms and Synthetic Applications, Sixth Edition, 2021, 197-199.
- Duong, Alexander Tuan-Huy, et al. Tetrahedron letters, 2019, 60(3), 322-326.
- Yang, Xu, et al. Organic Process Research & Development, 2018, 22(9), 1115-1118.
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