Thioether-indole Function

Ox indole-derivatives. Hydrolysis of an indole 2-thioether in 20% acetic acid at 95-120° C in a sealed tube gives the corresponding oxindole. The reaction was studied with several indole 2-thioethers, the results of this study (420) can be summarized as follows. Various 2-sulfenyl 

A mechanism such as that shown below rationalizes the data. Protonation at the 3 position facilitates nucleophilic attack by the free amino group of the side chain on C-2 with concomitant displacement of the thioaryl-function and formation of a tetrahydropyrroloindole derivative (144), which is further hydrolyzed to an oxindole derivative. 

Conversion of (144) to (145) has been previously shown to occur on treatment of the hexahydropyrroloindole (147) obtained by peracetic acid oxidation of tryptophan (see Section III. 1.1.). (147) is converted by 2N HCl to the oxindole (145) in dilute acetic acid (147) can also add thiols giving 2-thioether indole compounds (141) 339). 

The above reaction offers a convenient synthetic pathway to oxindoles from parent indoles bearing an aminoethyl side chain at the 3-position. The yields are almost quantitative, as checked with tryptophan, 5-fluoro-tryptophan, tryptamine and serotonin (727). 

Thioxindole-derivatives. Upon reaction of tryptophan or another indole with the bifunctional sulfenyl halide, sulfur dichloride, in glacial acetic acid, dimers are obtained with a disulfide bridge at the 2-position (149). By reduction with excess mercaptan (mercaptoethanol. 

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Rainier devised a variant of the 5-exo-dig radical cyclization of 2-alkynylisocyanides 122 wherein thiols were utilized to both initiate the radical cascade as well as act as nucleophiles in the reaction with the indolenine intermediate 123 yielding the indoles 124 . When R = TMS, elimination of the C-10 thioether can be effected in a gramine-like fashion so as to add nucleophiles (e.g., malonate anion) in the presence of Bu3P allowing for the preparation of more highly functionalized indoles. 

Oxidation. Oxidation of an indole 2-thioether is of interest since this would increase the number of derivatives of tryptophan obtainable from the sulfenylation reaction, thus providing new permutations in the study of the structure-function relationships of tryptophan-containing peptides and proteins. In addition, the indole 2-sulfoxide function occurs naturally in the poisonous cyclic peptides amatoxins 114, 429). 

WiELAND and CO workers 64, 114, 429) independently reported oxidation of the indole-2-thioether function with H2O2 in acetic acid and applied the oxidative reaction to phalloidin. The isolation of the... 

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