Fischer indole synthesis variations

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. 

The Fischer indole synthesis and its variations are prominently highlighted in the synthesis or partial synthesis of many natural products, many of which are summarized in Table 7 [288-311]. In addition to these examples, Fischer indolization was often applied to the synthesis of pyrrolo[2,3-( ]indole alkaloids in what Southwick in 1963 coined an arrested Fischer indole synthesis [312], later to be expanded by Garg as an interrupted Fischer indolization [313-317], as featured in his elegant syntheses of... 

Zheng et al. developed a variation of the Fischer indole synthesis whereby quinone 136 and aliphatic hydrazine 137 were combined to furnish fused indole 138. The newly disclosed reaction has much to recommend it the conditions are mild, the quinones are easily accessed by oxidation of commercially available phenols, and the hydrazines can be cyclic or acyclic (13AG(I)1753). 

Tryptophan is obtained industrially by a variation of the Fischer indole synthesis. Addition of hydrogen cyanide to acrolein gives 3-cyano-propanal which is converted to hydantoin through a Bucherer reaction. The nitrile group is then... 

A variation on the Fischer indole synthesis allows the formation of the 4-azaindole as shown below. The intermediate hydrazone undergoes a [3,3] sigmatropic shift to form the product indole [55], Write a mechanism for the reaction and identify the [3,3] shift. 

Lescot and co-workers (100) have described two routes to the 11//-pyrido[a]carbazoles. In the first (Scheme 36), a Fischer indole cyclization of the naphthylhydrazone 213, followed by dehydrogenation, gave the fully aromatic pyrido[a]carbazoles 215-217. Methylation or demethylation completed the preparation of the desired target compounds. A different route was used to synthesize the 5-methyl-2-aza derivatives 226 and 227 (Scheme 37) (100). Condensation of aldehyde 224 with 4-ethylpyridine gave the vinylindole 225. Deacylation and a variation of the Snieckus pyrido[c]carbazole synthesis (101) gave the desired compounds 226 and 227. 

A number of excellent variations on the classic Fischer indolization are known that fall outside of the previous three categories. Like solid-phase synthesis, multicomponent and domino reactions are of major interest to organic chemists. Ganem reported a three-component Fischer indole variation that embraces the union of nitriles or carboxylic acids with organometaUics followed by the addition of arylhydrazine. This exquisite method is summarized in Scheme 16 [117]. In both variations, in situ formation of the requisite arylhydrazones culminates in indolization. The presence of sufficient arylhydrazine hydrochloride... 

Much less commonly found are a few other Fischer-type variations that will be briefly mentioned. The Piloty-Robinson indole synthesis is a simple variation of the Piloty pyrrole synthesis, where the [3,3] sigmatropic event is triggered by acetic anhydride or methyl iodide (Scheme 26) [142,143]. An example is shown in equation 2 [143]. 

The Fischer indole ring synthesis, with all of its modifications and variations, may be the single most important method for constracting this heterocycle, but other methods exist, as we shall see. 

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