Fischer’s indole synthesis

The pyridine-N-oxide 245 was converted into the cyanopyridine 246 and its isomer (Scheme 80). Grignard reaction, Fischer s indole synthesis, and N-protection gave a pyridinyl indole 247. Selenium dioxide selectively oxidized the methyl group to give the isonicotinic acid. The synthesis of Flavocarpine (244) was finally accomplished by a set of standard reactions as outlined in Scheme 80 (87TL5259). 

Experiment. E. Fischer s Indole Synthesis.—Mix 2 g. of phenylhydrazine with 2 c.c. of acetone in a test tube. Water is eliminated and a turbidity appears. Suspend the tube in the boiling water bath for forty-five minutes, then add 6 g. of dry zinc chloride and heat the mixture for a few minutes with stirring in an oil bath at 180°. Now wash the dark-coloured melt into a small round-bottomed flask with four volumes of dilute hydrochloric acid and separate the resultant a-methylindole by distillation with steam. The substance collects as an oil which soon solidifies. After drying crystallise it from a little petrol ether. Melting point 59°. 

Scheme 15.106 One-pot synthesis of indoles by Zr-catalyzed hydrohydrazination/Fischer s indole synthesis without a second Lewis acid.

Woodward s strychnine synthesis commences with a Fischer indole synthesis using phenylhydrazine (24) and acetoveratrone (25) as starting materials (see Scheme 2). In the presence of polyphosphor-ic acid, intermediates 24 and 25 combine to afford 2-veratrylindole (23) through the reaction processes illustrated in Scheme 2. With its a position suitably masked, 2-veratrylindole (23) reacts smoothly at the ft position with the Schiff base derived from the action of dimethylamine on formaldehyde to give intermediate 22 in 92% yield. TV-Methylation of the dimethylamino substituent in 22 with methyl iodide, followed by exposure of the resultant quaternary ammonium iodide to sodium cyanide in DMF, provides nitrile 26 in an overall yield of 97%. Condensation of 2-veratryl-tryptamine (20), the product of a lithium aluminum hydride reduction of nitrile 26, with ethyl glyoxylate (21) furnishes Schiff base 19 in a yield of 92%. 

Individual substitutions may not necessarily be true electrophilic aromatic substitution reactions. Usually it is assumed that they are, however, and with this assumption the furan nucleus can be compared with others. For tri-fluoroacetylation by trifluoroacetic anhydride at 75 C relative rates have been established, by means of competition experiments 149 thiophene, 1 selenophene, 6.5 furan, 1.4 x 102 2-methylfuran, 1.2 x 105 pyrrole, 5.3 x 107. While nitrogen is usually a better source of electrons for an incoming electrophile (as in pyrrole versus furan) there are exceptions. For example, the enamine 63 reacts with Eschenmoser s salt at the 5-position and not at the enamine grouping.150 Also amusing is an attempted Fischer indole synthesis in which a furan ring is near the reaction site and diverted the reaction into a pyrazole synthesis.151... 

Fermentation, 22, 53 Ferric nitrate, 23, 20 Fieser s solution, 21, 110 Filter fabric, Pyrex glass, 22, 33, 65 Vinyon, 22, 33, 67 Filter paper, hardened, 22, 45 Fischer indole synthesis, 22, 98 Flash distillation, 21, 85 Flask, modified Claisen, 22, 11 Fluorescence of 9-aminoacridine hydrochloride, 22, 7 Formaldehyde, 20, 60 Formalin, 22, 66 Formic acid, 20, 66, 102 23, 43 Formic acid, chloro-, benzyl ester, 23, 13... 

With conventional methods, the formation of indole derivatives from anilines proceeds at the expense of both unsubstituted ortho positions in the phenyl ring. This leads to undesirable by-products. Particularly, the formation of by-products takes place during Fischer s synthesis of benzohet-erocycles. In the previously described ion-radical variant of the synthesis, only one indole isomer is formed—the isomer that corresponds strictly to the structure of the starting haloaniline. 

Hutchins, S. M. Chapman, K. T. Fischer Indole Synthesis on a Solid Support, Tetrahedron Lett. 1996, 37,4869-4872. 

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). 

Shimizu, J., Murakami, S., Oishi, T., and Ban, Y. (1971) The Fischer indole synthesis with formic acid. II. The synthesis of hexahydrocyclopent(6) indoles. Chemical Ul Pharmaceutical Bulletin, 19, 2561-2566. 

The thermal conversion of arylhydrazones in the presence of a protic acid or a Lewis acid to form an indole ring. See OweUen, R.J., Fitzgerald, J.A., Fitzgerald, B.M. et al.. The cyclization phase of the Fischer indole synthesis. The structure and significance of Pleininger s intermediate. Tetrahedron Lett. 18, 1741-1746, 1967 Kim, R.M., Manna, M., Hutchins, S.M. et al., Dendrimer-supported combinatorial chemistry, Proc. Natl. Acad. Sci. USA 93, 10012-10017, 1996 Brase, S., Gil, C., and Knepper, K., The recent impact of solid-phase synthesis on medicinally relevant... 

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