Fisher Indolization Reaction

We envisioned that improvement of the key Fisher indole reaction using diethyl 4-(N,N-dimethylamino)butanal (11) instead of diethyl 4-chlorobutanal (8) would lead to formation of the desired product directly. The approach would circumvent... 

When the objective is either to make a carful screening for finding a good candidate for future development, or to study whether a gradual change in the performance of the reaction could be traced to the properties of the reaction system, a design which affords a selection of test items which are uniformly spread in the score plot should be employed. An example of this principle is given in the study of the Fisher indole reaction below. 

One potential approach for the preparation of benzofuran derivatives involves the acid-catalyzed cyclization of O-aryl oximes 1193. 39 (equation 36). The transformation is analogous to well-known Fisher indole synthesis. The reaction proceeds through a [3,3]-sigmatropic rearrangement of enehydroxylamine 120 to compound 121 followed... 

A new synthetic method of benzofuran was reported (equation 39). The [3,31-sigma-tropic rearrangement of Af-trifluoroacetyl enehydroxylamines 136 obtained in situ by acylation of oxime ethers 135 in the presence of trifluoroacetic anhydride lead to the synthesis of cyclic or acyclic dihydrobenzofurans 138. The effects of base and temperature on the reaction products were studied. A similar pathway to that of Fisher indolization was proposed. The acylimine formed by the [3,3]-sigmatropic rearrangement of the V-trifluoroacetyl enehydroxylamine 136 gave the dihydrobenzofuran 137 by an intramolecular cyclization or the benzofuran 138 after elimination. 

Running the Fisher indole synthesis on an unsymmetrical phenyl hydrazone gives a mixture of 2,3-disubstituted indoles. For example, reaction of the phenyl hydrazone, 34, with acid can give both 35 and 36 (Eqn. 22.26). Soluble acids and Amberlyst-15 give these two products in a 75 25 ratio at 100% conversion. With an H-M catalyst they are formed in a 65 35 ratio but over a dealuminated H-beta zeolite, the selectivity is reversed and 36 is produced in an 82% yield at 100% conversion.62 n was proposed that the preferential formation of 36 over the H-beta catalyst was the result of a restricted transition state selectivity. ... 

A number of reactions relevant to fine chemicals manufacture can be catalyzed by superacids, for example, dehydration of carboxamides to nitriles, Friedel-Crafts alkylation and acylation, Fisher indole synthesis of coumarins, isomerization of limonene, condensation of hydroquinone with aniline, and esterification in general (Hino and Arata, 1980, 1985 Joshi and Rajadhyaksha, 1980 Rajadhyak-sha and Chaudhari, 1987 Kumbhar and Yadav, 1989 Rajadhyaksha and Joshi, 1991 Kumbhar et al., 1994). Two particularly important reactions are described here. 

The Buchwald-Hartwig amination reaction has also been applied to the synthesis of A -arylhydrazones, which can then be transformed into indoles via the Fisher indole synthesis. Since this reaction sequence does not use a Buchwald-Hartwig amination reaction directly in the synthesis of indoles, it will not be a focus of this chapter. 

Gassman indole synthesis provides a single regioisomer of 3-thioindole derivative 17 when ortho/para substituted anilines 1 are employed, the yields of which are moderate to good as is depicted in the scheme below. The reaction provides some advantages on the preparation of 7-substituted indoles compared to other methods (e.g.. Fisher-indole synthesis due to the sluggishness of the reaction and the low reported yields). 

Knight explored the C2-lithiation of indole-3-carboxylic acids [326, 327]. Similar to the reaction with alcohol 100, two equivalents of LDA were used to generate dianion intermediates which upon quenching with electrophiles gave 2-(substituted)indole-3-carboxylic acids. This strategy was later used by Fisher... 

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