Synthesis of the Indole Ring

Abstract

H A8 H R NH 2 A7arrangements. One line of effort has involved attempts to detect or trap the intermediates proposed for the various steps in the reaction. The hydrazonevinylhydrazine equilibrium in the first step of the reaction is analogous to ketone-enol and imine-enamine equilibria, but no firm physical evidence for the existence of measurable concentrations of the vinylhydrazine has been found to date (25a, 137a, 182, 183).Refluxing the phenylhydrazone of methyl ethyl ketone in acetic anhydride gives the diacylated vinylhydrazine A10. This can be considered to consti tute t r a p p i n g " of the first intermediate in the Fischer cyclization. Heating A9 /Et + Ac 2 0 H "Me H+ A10 A13 H NHAc A12 Me A14 H Ac 1 N / N v y A M e Ac I Me OH Me Ac H Me a V^M e NHAc NH 2 Me All D HI. SYNTHESIS OF THE INDOLE RINGA10 with dilute mineral acids gives 2,3-dimethylindole (259). These trans formations appear to constitute the closest analogy observed to date for the first step in the Robinson mechanism. Alkaline hydrolysis of A10 gave a substance formulated as A l l (259). This material gave 2,3-dimethylindole and acetamide on heating. Reexamination (72a) of the structure of this material has shown that it is actually A12. The formation of A l l can no longer be cited as an analogy for the second stage of the Robinson mechan ism. There are, however, products formed during Fischer reactions in certain cyclic systems which correspond to interruption of the reaction after the ortho substitution step. Plieninger (203,206) has reported the isolation of A16 by treatment of A15 with hydrochloric acid in acetic acid. Subsequent nmr spectral evi dence (185) has shown that the substance actually exists as the tautomer A17. It has been suggested that A17 is isolated because the enamine is very weakly basic and therefore the iminium species A18 is not generated in sufficient concentration to lead to indolization (185).Southwick and co-workers (238) have recorded isolation of compounds of structure A21. Structure A21 corresponds to interruption of the normal Fischer sequence at the aromatization stage. It has been suggested that ring A. THE FISCHER INDOLE SYNTHESIS □ 145 A20 N -I^< N R H ΝΗ 2^Ό A21 NH 3 R •N : NR A22 O strain effects are responsible for the failure of A21 to lose ammonia. Ring C of structure A22 contains three sp 2 atoms, representing considerable angle strain. Carlin and co-workers have examined the behavior of 2,6-disubstituted arylhydrazones under conditions of the Fischer synthesis (51, 54, 57, 59). Diortho substitution prevents the tautomerization A6 -> A7 in the Robinson mechanism. Heating the 2,6-dimethylphenylhydrazone of acetophenone in the presence of zinc chloride gives as the main product A24, as well as 4,7-dimethyl-2-phenylindole and cleavage products (54). The intermediate A26 can account for the formation of A24 and A25. / M e / V-NH-N < Ph Me Me A23The key step in the formation of the atomic skeleton of A24 is the trans formation A26 -> A29 which is analogous to a nucleophilic addition to a cyclohexadien...