Fischer indole synthesis applications

Buchwald parlayed the powerful Buchwald-Hartwig aryl amination technology [439-447] into a simple and versatile indoline synthesis [448-452], For example, indole 368, which has been employed in total syntheses of the marine alkaloids makaluvamine C and damirones A and B, was readily forged via the Pd-mediated cyclization shown below [448], This intramolecular amination is applicable to the synthesis of -substituted optically active indolines [450], and o-bromobenzylic bromides can be utilized in this methodology, as illustrated for the preparation of 369 [451]. Furthermore, this Pd-catalyzed amination reaction has been applied to the synthesis of arylhydrazones, which are substrates for the Fischer indole synthesis [453,454],... 

Superheated and supercritical water are used in several applications. Supercritical water is most often used in the destruction of organic wastes, including some chemical warfare agents, as an alternative to incineration (Katritzky et al., 1996 Sherman et al., 1998). Recent reports describe the use of both forms as a solvent and as a reactant in synthetic chemistry (Katritzky et al., 1996 An et al., 1997). Some of the reactions investigated include metal-mediated alkyne cyclizations, Pd-catalyzed al-kene arylations, aldol reactions, the Fischer indole synthesis, and hydrolysis reactions. Waterborne coatings and the destruction of wastes in supercritical water are fully... 

The Fischer indole synthesis has been extended to the synthesis of benzofurans as shown in a recent synthesis of 4,5, 8-trimethylpsoralen (Scheme 60) (79JOC2176). The availability of methods for the synthesis of the precursor O-aryloximes limits its application. 

The Fischer indole synthesis is a versatile method for preparing 2,3-substituted indoles. Indoles itself, in small concentrations, has a floral odour while many of 2,3-substituted indoles are biologically active and also find applications as pharmaceuticals and plant growth regulators. 

The first example of a "uniform spread" design in the study of solvent varation was applied to the Willgerodt-Kindler reaction.[3] It is not reproduced here, since it is very similar to the above example of amine variation. A very clear application of the principle of "uniform spread" is given in an example on the Fischer indole synthesis in the next chapter. 

Indoles are an important class of fine chemicals derivatives find application as fragrance chemicals. The indole nucleus is present in many biologically active molecules including plant-growth regulators, proteins and pharmaceuticals. The selective synthesis of indole derivatives constitutes an important area of drug research. The well-known Fischer indole synthesis provides a versatile method for synthesizing substituted indoles from the arylhydrazones of aldehydes or ketones... 

An early, non-shape-selective, application of zeolites in the Fischer indole synthesis was reported by Venuto and Landis [18]. They employed calcium-and rare-earth-exchanged zeolite X as catalysts under continuous-flow conditions at 150 °C. Good yields of indoles were obtained with both acetone and cyclohexanone phenylhydrazones a 72.5% yield of indole was obtained from the latter with CaX catalyst. 

Application of Fischer indole synthesis to ketone CXXI or its open chain precursor CXX resulted in the formation of 12If-indolo[2,3-a]-pyridocolinium salts substituted at the 2-position (CXXII) 53). 

This reaction has general application in the preparation of substituted styrene derivatives and aryl derivatives, especially for substituted indoles that are difficult to make by the traditional Fischer Indole Synthesis ... 

In addition to the general reviews of indole ring synthesis cited in Chapter 1, the Fischer indole synthesis per se has been extensively reviewed [6-10]. The excellent documentation (>3000 citations in reference 8) will not be repeated here. Rather in this chapter, I focus on recent applications in drug development, materials discovery, and natural-product synthesis. 

Sheradsky, T. 1966. Application of the Fischer indole synthesis to the preparation of benzofurans. Tetrahedron Lettl (43) 5225-5227. 

Compounds in which other heterocyclic rings (pyrazoles, isoxazoles, imidazoles ) are fused to thiopyrans have been described. The interesting thiazolium salts (56) were prepared by allowing the betaines (55) to react with 4-thioxothiazolidin-2-ones. Application of the Fischer indole synthesis and the Friedlander reaction to tetrahydrothiopyran-3-one led to the exported indolo-and quinolino-derivatives. Ring closure of (57) under acidic conditions afforded the rearranged product (58). Syntheses of benzothiopyrano[4,3,2-flfe]-quinazolines (59) from 1-amino-thioxanthones and of their S- and 7V-oxides have been described. ... 

Synthesis of carbazoles and related indoles fused to carbocyclic rings is yet another fruitful field for application of the Fischer indolization, which has for example resulted in routes to indeno[2,l- ]indoles <20040M344>, diaryl-carbazoles <1999HC451>, tetrahydrocarbazole derivatives <2000JOC3387, 2003BMC3413, 1999CAL93,... 

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