Fischer indole synthesis regioselectivity

Similar enamine cyclization processes occur in several other successful heterocycle syntheses, e.g. in the Fischer indole synthesis. In this case, however, a labile N—N bond of a l-aryl-2-vinylhydrazine is cleaved in a [3,3]-sigmatropic rearrangement, followed by cyclization and elimination of ammonia to yield the indole (B. Robinson, 1963, 1969 R. J. Sundberg, 1970). Regioselectivity is only observed if R2 contains no enolizable hydrogen, otherwise two structurally isomeric indoles are obtained. Other related cyclization reactions are found in the Pechmann synthesis of triazoles (T.L. Gilchrist, 1974) and in G. Bredereck s (1939) imidazole synthesis (M.R. Grimmett, 1970). 

Factors Controlling the Regioselectivity in the Fischer Indole Synthesis The Fischer indole reaction has been extensively used for the synthesis of indole derivatives [77]. A problem is that two isomeric indoles are possible when the reaction is applied to arylhydrazones from dissymmetric methylene ketones, see Scheme 10. 

Yamamoto and Maruoka found that organoaluminum amides are highly effective in the Fischer indole synthesis. In particular, DATMP is the reagent of choice for regioselective Fischer indole synthesis [120]. For instance, treatment of the E)-N-methyl-A-phenylhydrazone of 5-methyl-3-heptanone (123) with DATMP affords 3- ec-butyl-2-ethyl-l-methylindole (125) as the sole isolable product its (Z) isomer gives l,3-dimethyl-2-(2-methylbutyl)indole (124) with high regioselectivity under similar reaction conditions, as illustrated in Sch. 84. 

The total synthesis of (+)-deethylibophyllidine was accomplished by J. Bonjoch and co-workers, who applied a regioselective Fischer indole synthesis as one of the key steps to obtain octahydropyrrolo[3,2-c]carbazoles. The indole formation was followed by a tandem Pummerer rearrangement-thionium ion cyclization to generate the quaternary spiro stereocenter. 

Lacoume, B., Milcent, G., Olivier, A. Regioselectivity in the Fischer indole synthesis using 3-substituted cyclanones. Tetrahedron 1972, 28, 667-674. 

Pulici, M., Sello, G. Studies toward a model for the prediction of the regioselectivity in the Fischer indole synthesis. Part 2. Derivatives of cyclic ketones. THEOCHEM 993,107, 245-254. 

The reaction space linked to the response space, illustrated by a study on the Fischer indole synthesis. The objective of the study was to determine which properties of the reaction system are necessary to control with a view to obtaining regioselectivity in the reaction. 

Properties of the reaction system related to the selectivity of a reaction. Regioselectivity in the Fischer indole synthesis.[ll]... 

Table 12.16. Regioselectivity in the Fischer Indole Synthesis as a Function of Acid Concentration...

The Fischer indole synthesis using the phenylhydrazones and iV-methyl-phenylhydrazones of 5a- and 5j8-cholestan-3-ones, as well as some C-6-sub-stituted derivatives, gives mainly steroidal indoles of the types (393) and (394), respectively. These structures are predictable from the known regioselectivity of enolization of 3-oxo-steroids in the 5a- and 5/3-series. °... 

The Fischer indole synthesis has been a workhorse of medicinal chemistry. What has been needed is a procedure of comparable ease and efficiency for converting a ketone or aldehyde such as 12 to the corresponding pyridine, such as 13. Antonio Arcadi of the University of Milan has now developed (J. Org. Chem. 68 6959, 2003) just such a procedure, based on a gold-catalyzed condensation with propargylamine. The gold catalyst is commercially available. The regioselectivity of this procedure is noteworthy. 

Dihydrofuran was used as a ketone equivalent in a Fischer-type indole synthesis with an aryl hydrazine under strongly acidic conditions to give a tryptophol. As shown in Equation (129), 5-methyl-2,3-dihydrofuran gave rise to 2-methyltryptophol regioselectively <20040L79>. 

During the total synthesis of (+)-aspidospermidine by J. Aube et al., the final steps involved an efficient Fischer indolization of a complex tricyclic ketone." This ketone was unsymmetrical and the indole formation occurred regioselectively at the most substituted a-carbon in a weakly acidic medium (glacial AcOH). 

J.M. Cook et al. accomplished the enantiospecific total synthesis of the indole alkaloid tryprostatin A." The substituted indole nucleus was assembled at the beginning of the synthesis, and the necessary arylhydrazone was prepared via the Japp-Kiingemann reaction using the diazonium salt derived from m-anisidine and the anion of ethyl-a-ethylacetoacetate. The regioselectivity of the Fischer indoie synthesis favored the 6-methoxy-3-methylindole-2-carboxylate regioisomer in a 10 1 ratio. 

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