Fischer-indole reaction regioselectivity

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. 

For a recent example of a regioselective Fischer indole reaction mediated by organoaluminum amides, see Maruoka, K. Oishi, M. Yamamoto, H. J. Org. Chem. 1993, 58, 7638. 

There are several key aspects of the Fischer-indole reaction to consider when evaluating potential synthetic applications (1) the ease of preparing the iV-arylhydrazone starting materials (2) the energetic cost and regioselectivity associated with tautomerization of the... 

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). 

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 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]... 

The cyclization proceeds with reasonable regioselectivity. In ketone 303 there are two a-carbons, and two different enamine structures can be formed, as well as two bis(imine) intermediates. The final indole products were 304 and 305. Table 12.16 3 shows the changes in selectivity for this mixture of products in a Fischer indole syntheses under various conditions. As the concentration of acid catalyst increases, the yield decreases but the regioselectivity is about the same, (2 1 304/305). 3. 84 xhere is remarkably little change in this ratio until the acid concentration exceeds 45%. The stereochemical course of the reaction also depends on the stereochemistry of the hydrazone substrate. In another example, hydrazone 306 (with a cis ring juncture) was treated with ethereal HCl in dichloromethane at room temperature, a 61% yield of 307 was obtained. 3 Reaction of 306 with 85% sulfuric acid gave a 42% yield of the isomeric 308 and the course of the reaction... 

Several other metal-assisted Fischer indole syntheses are summarized in Scheme 12. Yamamoto employed organoalu-minum amides to effect regioselective Fischer indolizations [104]. For example, Z-hydrazone 10 affords l,3-dimethyl-2-(2-methylbutyl)indole (equation 1), whereas E-hydrazone 11 gives 3-5ec-butyl-2-ethyl-l-methylindole (equation 2). Both reactions are highly regioselective. The mechanism... 

The issue of regioselectivity arises with arylhydrazones of unsymmetrical ketones which can form two different enehydrazine intermediates. Under the conditions used most commonly for Fischer cyclizations, e g. ethanolic HCI, the major product is usually the one arising from the more highly substituted enehydrazine. Thus methyl ketones usually give 2-methy indoles and cycliz-ation occurs in a branched chain in preference to a straight chain. This regioselectivity is attributed to the greater stability of the more substituted enhydrazine and its dominance of the reaction path. 

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. 

The reaction of a,(3-unsaturated Fischer carbene complexes 42 with cyclic enamines 43 gives cyclopentannulation products 46 with complete regioselectivity by a formal [3-1-2] cycloaddition (Scheme 5.11) [20]. The formal [3-1-2] cycloaddition is assumed to occur in a stepwise manner via the 1,4-addition of cyclic enamines 43 to the alkynyl carbene complexes 42 (formation of iminium intermediate 44), the intramolecular cyclization to the formed iminium moiety from the carbene carbon (formation of intermediate 45), and the hydrolysis reaction. When (—)-8-phenylmenthyl derivatives of Fischer carbene complexes 42 are reacted with indoles 43, the corresponding indolinones 46 are obtained with >97% ee. 

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