Indoles sulfenylation

HCl or HBr (1-1.1 equiv), alcohols, 0-20 °C, 30 min 2-indole sulfenylation stable cleavage fairly stable (6301... 

Sulfenylation of indoles can be carried out with sulfenyl halides[7], disulfides[7-9] or with A -methylthiomorpholine[10]. With disulfides the indoles are converted to lithium[8] or zinc[9] salts prior to sulfenylation. Thiophenols and iodine convert indoles to 3-(arylthio)indoles[l 1]. 

Indole and carbazole, which can be regarded theoretically as derivatives of pyrrole through its anellation with one or two benzene rings, show variable behavior toward sulfenyl halides ... 

Alkylthio and arylthio derivatives of pyrroles and indoles are readily obtained from their reactions with the appropriate alkyl or aryl sulfenyl chlorides (e.g. B-77MI30502, B-77MI30506, 77CB67, 79HC(25-3)1>. 

A facile and efficient sulfenylation method using quinone mono-0,5 -acetals (793 or PhS-analog) under mild conditions was successfully applied to various pyrroles and indoles (Equations 193 and 194) <2001JOC2434>. The phenylsulfenyl analog of compound 793 reacted similarly to give regioselectively the corresponding sulfide in 43-99% yields. 

In the absence of efficient Nps-Q (92) capture, this intermediate reacts with the indole side chain of tryptophan residues to produce the related 2-Nps derivatives 96 (Scheme 48). Although reaction of sulfenyl hahdes with indoles was exploited by Wieland et al.t for the synthesis of phaUoidin, this side reaction leads to irreversible modification of Trp-containing peptides.This side reaction does not occur via an intramolecular electrophilic substitution as postulated previously,but by a direct attack of the Nps-Cl (92) in fact, it is efficiently suppressed by the addition of a large excess of an indole derivative as a scavenger.These scavengers serve also to decrease the proton activity of the acids vide supra). Due to the unpleasant odor of 2-methylindole the less volatile 1-acetyltryptophan butyl ester has been proposed as scavenger.f ... 

The preparation of sulfides by reaction of sulfenyl chlorides with compounds containing acidic hydrogen has been reported by Brintzinger and his coworkers in a series of papers.256 Sulfides of the indole series257 as well as (alkylthio)phenols and (alkylthio)phenyl ethers258 have been prepared by this method. 

Sulfonation of indole, at C-3, is achieved using the pyridine-sulfur trioxide complex in pyridine as solvent. Gramine is sulfonated in oleum to give 5- and 6-sulfonic acids, attack being on a diprotonated (C-3, side-chain-N) salt. Sulfenylation of indole also occurs readily, at C-3. The reversibility of this process has been demonstrated by desulfenylation in the presence of acid and a trap for the sulfenyl cation, and by the acid-catalysed isomerisation of 3-sulfides to 2-sulfides. Thiocyanation of indole can be achieved in virtually quantitative yield with a combination of thiocyanate and cerium(IV) ammonium nitrate. ... 

The formation of indole thioethers can be carried out at C-4 by a process involving migration from C-3. An intramolecular acylation of 2-(3-indolylthio)propionic acid undergoes reaction at C-3, with rearrangement of the sidfur moiety and substitution at C-4 via a sulfenyl chloride there is also good optical retention in a chiral substrate (Scheme 51) <92TL47I7>. 

Pyrrole and 1-methylpyrrole can be sulfinylated by sulfinyl chlorides or A-(phenyl-sulfinyl)succinimide. The products are prone to rearrange to the 3-isomers on contact with acid <80JOC5336>. A phenylsulfinyl group has been introduced at C3 of the indole ring by 3-sulfenylation of AT-lithioindole with diphenyl disulfide, followed by A-sulfonylation and oxidation to the sulfoxide <89JOCi782>. Sulfenylindoles can be oxidized to sulfones by MCPBA <93JMC1425>. 

Methylindole undergoes clean 3-sulfenylation with M-methylthiomorpholine in TFA. Indole itself gives mainly 3-methylthioindole (57%) with 1.5 equiv. of the reagent, but the 1,3- (61%) and 2,3- (22%) h s-sulfenyl derivatives are the main products with 2.5 equiv. [74]. 

Sulfonation of indole, at C-3, is achieved using the pyridine-sulfur trioxide complex in pyridine as solvent. Sulfenylation also occurs readily, at C-3. ... 

Indolyl sulfides 1 are easily prepared by sulfenylation of indoles with sulfenyl ehlorides. The mechanism of the sulfenylation is well known and follows the usual SfiAr-type substitution pathway depicted in Scheme 2.1. 

One drawback to the use of sulfenyl chlorides for the sulfenylation of indoles is their exeeptional reactivity. If the 2-position of the indole is unoccupied, the slightest excess of reagent leads to a seeond sulfenylation, and a full seeond equivalent leads to excellent yields of 2,3-indolyl bis-sulfides 2 (Seheme 2.2). 

The second sulfenylation of 3-(phenylthio)indole 3 with methanesulfenyl chloride yields a mixture of the bis-sulfides 4 and 5 (Scheme 2.3). 

For a start, the simplest option is to consider the mechanism of direct introduction of the sulfenyl group into the 2-position (Scheme 2.5). The nucleophilic attack of the indole nucleus to the sulfenyl chloride requires a temporary disruption of the aromaticity of the ring system leading to intermediate 8, which after aromatization leads to the final product 2. 

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