Indoles Sommelet-Hauser rearrangement

Another indole/oxindole synthesis achieves the critical ortho-substitution by Sommelet-Hauser rearrangement of an anilinosiilfonium ion intermediate. Use of P-thioketones (G = R, an alkyl group) generates 2-substituted indoles, whereas P-thioesters (G = OR) lead to oxindoles. In each case, a 3-thio substituent must be removed by desulfuri2ation. 

The mechanism of the Gassman indole synthesis bears some resemblance to that of the Fischer indole reaction. An Sn2 displacement of the TV-chlorinated aniline with the a-keto sulfide gives rise to a sulfonium ion. After deprotonation, a [2,3]-sigmatropic rearrangement (Sommelet-Hauser rearrangement) takes place where the weak N-S bond is broken and a strong C-C bond is formed. Similar to the Fischer indole reaction, the resulting imine was transformed into indole after re-aromatization and cyclization. 

Sommelet-Hauser rearrangement in indole synthesis Gassman indole synthesis... 

Several variations exist for the classic Sommelet-Hauser rearrangement. The most important concern the use of base-free conditions for the [2,3]-sigmatropic rearrangement based on the fluoride anion induced desilylation of substituted benzyldialkyl-[(trimethylsilyl)methyl] ammonium halides" and the asymmetric versions of Sommelet-Hauser rearrangement that appeared recently in the literature. None of the above has ever been used in a modification of the Gassman indole synthesis. 

Although nitrogen ylides have been extensively used in organic transformations, especially those concerning the formation of nitrogen heterocycles,not many references are available for the use aza-sulfonium ylides and the Sommelet-Hauser rearrangement in the synthesis of indole derivatives. 

In 1981, Wierenga first introduced a modification of Gassman oxindole synthesis for the synthesis of indole derivative 34, part of the left-hand segment of the antitumor agent CC-1065. In accordance to that, addition of derivative 30 in a equimolar amount of the hindered base, [1,8-bis(dimethylamino)naphthylene (R3N), to the chloride complex of ethyl-a-(mercaptomethyl)propionate 31, followed by a triethylamine catalyzed Sommelet-Hauser rearrangement and an acid-induced cyclization gave oxindole 32. Treatment of 32 with excess BH3 SMei at room temperature afforded 33 in 95% yield. 

In 2003, Alper and co-workers, based on an earlier, reported the synthesis of substituted tosyl-indoles from substituted anilines and isopropylsulfides, introduced a practieal way for the elaboration of multigram scale of the otherwise difficult accessible methyl 7-chloroindole-4-carboxylate, based on the desulfurization and cyclization of a prior Sommelet-Hauser rearranged produet 41, derived from the reaction of methylsulfide 39 with o-chloroaniline derivative 40. 

In the course of this synthesis, the anilinosulfonium salts 53 are deprotonated by Et3N to give sulfonium ylides, which undergo a Sommelet-Hauser rearrangement (situation 54) to the (o-aminobenzyl) ketones 57. Subsequent (spontaneous) cyclization to 3-thiomethyhndoles 56 and reductive desulfurization lead to the 2- (or 1,2-) substituted indoles 55. 

The mechanism of the indolization of aniline 5 with methylthio-2-propanone 6 is illustrated below. Aniline 5 reacts with f-BuOCl to provide A-chloroaniline 9. This chloroaniline 9 reacts with sulfide 6 to yield azasulfonium salt 10. Deprotonation of the carbon atom adjacent to the sulfur provides the ylide 11. Intramolecular attack of the nucleophilic portion of the ylide 11 in a Sommelet-Hauser type rearrangement produces 12. Proton transfer and re-aromatization leads to 13 after which intramolecular addition of the amine to the carbonyl function generates the carbinolamine 14. Dehydration of 14 by prototropic rearrangement eventually furnishes the indole 8. 

The Gassman indole synthesis involves a one-pot process in which a hypohalite, a P-carbonyl sulfide derivative, and a base are added sequentially to an anihne or a substituted aniline to provide 3-thioalkoxyindoles. The mechanism of the Gassman indole synthesis involves a [2,3]-sigmatropic rearrangement (Sommelet-Hauser). The sulfur can be easily removed by hydrogenolysis or Raney nickel. 

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