377-Indolium cation

Reaction of indole with excess of methyl iodide at 110°C gives a tetramethyl derivative (66). The intermediate 2,3-dimethylindole (65) is thought to arise by rearrangement of the 3,3-dimethyl-3Ff-indolium cation (64). 

Simple addition to carbonyl compounds occnrs nnder mild acidic conditions. Examples given illns-trate reaction with acetone, an aldol-like reaction, and conjngate addition to methyl vinyl ketone, a Michael-like reaction. The first-formed alcohol products in aldol-like reactions usually dehydrate to give a 3-alkylidene-3//-indolium cation. 

Protonation of indole has been shown to give the indoleninium (3H-indolium) cation, and this is presumably formed under the conditions commonly used for electrophilic substitution reactions in the benzene series. For indole these conditions are often unsatisfactory and, for example, nitration of indole with nitric acid gives polymers. On the other hand, A/ -alkylindoles can be nitrated with concentrated nitric acid and acetic anhydride at -70 °C to afford l-alkyl-3-nitroindoles. 

Pyridinium bromide perbromide efficiently brominates pyrroles already substituted by electron-withdrawing substituents and also gives a high yield of 3-bromoindole in its reaction with indole. In conjunction with sulfuryl chloride, it has been used in the synthesis of 3-bromo-2-chloro-, 2-bromo-3-chloro- and 2,3-dibromo-indole (81SC253). 3-Methylindole reacts with A-bromosuccinimide in acetic acid to give the 2-bromo derivative which reacts further with an excess of A-bromosuccinimide to yield 2,6-dibromo-3-methylindole (B-70MI30500, 72HC(25-2)127) whilst in aqueous or alcoholic media, 3-bromo-3-methylox-indole is produced (cf. Scheme 15). All of these reactions proceed via the 3-bromo-3A-indolium cation, but the course of the reaction depends not only upon the orientation or... 

Simple 2- and 3-halogenoindoles are generally stable in basic media but are readily converted into oxindoles by aqueous acids. Also, during the halogenation of indoles, 2-(3-indolyl)indoles are common by-products. The formation of both the oxindoles and the bisindoles involves protonation of the halogenoindole at the 3-position, followed by nucleophilic attack at the 2-position of the 3H-indolium cation and the subsequent elimination of the halogen acid (see Section 3.05.1.2.4). The formation of 2-(2-indolyl)indoles during the conversion of 3-substituted oxindoles into 3-substituted 2-chloroindoles has also been shown to result from the Lewis acid-catalyzed reaction of the 3-substituted 2-chloroindoles with 3-substituted indoles 81H(16)1441>. 

As a corollary to these results, it has been suggested (25) that the hydrogenation of eserethole (13, 14), in which the C2-Nb bond is broken, proceeds via ring opening to the indoleninium (i.e., 3//-indolium) cation, which then undergoes hydrogenation. [Both reductions (13, 14) were carried out in acidic media.]... 

Indolium cations are of conrse electrophilic species, in direct contrast with neutral indoles, and nnder favourable conditions will react as such. For example, the 3H-indolium cation itself will add bisnlhte at pH 4, under conditions that lead to the crystallisation of the product, the sodium salt of indoline-2-sulfonic acid (indoline is the widely used, trivial name for 2,3-dihydroindole). The salt reverts to indole on dissolution in water, however it can be M-acetylated and the resulting acetamide used for halogenation or nitration at C-5, final hydrolysis with loss of bisulfite affording the 5-substituted indole. ... 

When iVj-acyl-tryptophans are exposed to strong acid, the indolium cation is trapped by cyclisation involving the side-chain nitrogen. Comparable tricycles result from phenylselenylation of protected tryptophan or reaction with 4-methyl-l,2,4-triazoline-3,5-dione, ° or dimethyl(succinimido)sulfonium chloride (a CH2SMe group ends up at the indole C-3)." If M-bromosuccinimide is employed, the initially formed 3-bromo-tricycle loses hydrogen bromide to produce an aromatic indole. ... 

Indoles react with aldehydes and ketones under acid catalysis - with simple carbonyl compounds, the initial products, indol-3-yl-carbinols are never isolated, for in the acidic conditions they dehydrate to 3-alkylidene-37f-indolium cations those from aromatic aldehydes have been isolated in some cases reaction of... 

Alkylidene-3/f-indolium cations are themselves electrophiles and can react with more of the indole, as illustrated for reaction with formaldehyde. ... 

Alkylation of 2-alkyl- and 2-aryl-indoles can be achieved by trifluoracetic-acid-catalysed condensation with either aromatic aldehydes or aliphatic ketones in the presence of the triethylsilane, which reduces the intermediate 3-aIkylidene-3//-indolium cations. ... 

Both indole-3-carboxylic and indol-2-yl-acetic acids are easily decarboxylated in boiling water. In each case carbon dioxide is lost from a small concentration of P-protonated 3//-indolium cation, the loss being analogous to the decarboxylation of a P-keto-acid. Indole-l-carboxylic acid also decarboxylates very easily, but is sufficiently stable to allow isolation and use in acylation reactions. Indole-2-carboxylic acids can only be decarboxylated by heating in mineral acid or in the presence of copper salts. °... 

An attractive variant is to ntilise certain prodncts of reversible addition to 3//-indolium cations, such as the indole bisnlhte addnct, or where there has been an intramolecular nucleophilic addition (20.1.1.2) such compounds, thongh they are indolines, are still at the oxidation level of indoles, needing only mild acid treatment to regenerate the aromatic system. " ... 

The UV-mediated photolysis of the C-0 bond produced simultaneously two chromophores (see Fig. 6.4) phenolate anion (chromophore 1) and indolium cation (chromophore 2), which absorb in the same region of the visible spectrum resulting in an amplification (doubling) of the coloration efficiency. 

When 3-alkylindoles were electrolysed using Pt electrodes in MeCN solution in the presence of NaSCN, the major products isolated were 2-isothiocyanates with yields ranging from 41 to 79%. An explanation offered for this unexpected result is an ipso attack at the 3-position yielding a 3-thiocyano-3/f-indolium cation, which through a [3,5]-sigmatropic shift followed by [l,5]-hydrogen shift leads to the isothiocyanate. 

Indoles, like pyrroles, are very weak bases typical p a values are indole, -3.5 3-methylindole, -4.6 2-methylindole. -0.3. This means, for example, that in 6M sulfuric acid two molecules of indole are protonated for every one unprotonated, whereas 2-methylindole is almost completely protonated under the same conditions. By NMR and UV examination, only the 3-protonated cation (3//-indolium cation) is detectable it is the thermodynamically stablest cation, retaining full benzene aromaticity (in contrast to the 2-protonated cation) with delocalisation of charge over the nitrogen and o-carbon. The spectroscopically undetectable A -protonated cation must be formed, and formed very rapidly, for acid-catalysed deuterium exchange at nitrogen is 400 times faster than at C-3, indeed the A -hydrogen... 

When iV -acyl tryptophans are exposed to strong acid, the 3-protonated indolium cation is trapped by intramolecular cyclisation of the side-chain nitrogen. ... 

Indoles react with aldehydes and ketones under acid catalysis - with simple carbonyl compounds, the initial products, indol-3-ylcarbinols are never isolated, for in the acidic conditions they dehydrate to 3-alkylidene-3//-indolium cations those from aromatic aldehydes have been isolated in some cases reaction of 2-methylindole with acetone under anhydrous conditions gives the simplest isolable salt of this class. Only where dehydration is not possible have hydroxyalkylindoles been isolated, for example from reaction with diethyl mesoxalate. Reaction with 4-dimethylaminobenzaldehyde (the Ehrlich reaction, see section 13.1.7) gives a mesomeric and highly-coloured cation. 

Skatole is converted into an a,a -linked dimer in acid 2-methylindole, in contrast, is not susceptible to acid-catalysed dimerisation, reflecting the lower electrophilic character of the 3-protonated 2-substituted 377-indolium cation, much as ketones are less reactive than aldehydes. 

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