5-Substituted indoles protonation

The oxidation of 3-substituted indole to oxindoles can also be done with a mixture of DMSO and cone, hydrochloric acid[6-9]. This reaction probably involves a mechanism similar to the halogenation with a protonated DMSO molecule serving as the electrophile[10]. 

The pivotal step in this sequence is an electrophilic substitution on indole. Although the use of l,3-dithian-2-yl carbanions is well documented, it has been shown only recently that 1,3-dithian-2-yl carbenium ions can be used in a Priedel-Crafts type reaction. This was accomplished initially using 2-methoxy-l,3-dithiane [1,3-Dithiane, 2-methoxy-] or 2-metlioxy-l,3-dithiolane [1,3-Dithiolane, 2-methoxy-] and titanium tetrachloride [Titanate(l —), tetrachloro-] as the Lewis acid catalyst.9 2-Substituted lysergic acid derivatives and 3-substituted indoles have been prepared under these conditions, but the method is limited in scope by the difficulties of preparing substituted 2-methoxy-1,3-dithianes. l,3-Dithian-2-yl carbenium ions have also been prepared by protonation of ketene dithioacetals with trifluoroacetic acid,10 but this reaction cannot be used to introduce 1,3-dithiane moieties into indole. 

The formation of 2-(indolin-2-yl)indole dimers from indole-3-acetic acid and its propyl ester in trifluoroacetic acid and phosphoric acid has been studied." The reaction involves electrophilic attack of the protonated species (24) on the free substituted indole to give the trans stereochemistry at the C(2)-C(3) bond. 

The kinetics of reaction of four indoles with a number of benzhydryl cations has allowed the determination of the nucleophilicity parameters N and S for these reactions.49 Kinetic data from the reaction of a number of indoles with 4,6-dinitroben-zofuroxan then allow determination of their N values. Correlation of these data with those for protonation at C(3) of 5-substituted indoles and 5-substituted 2-methylindoles... 

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>. 

Nitration of indole by benzoyl nitrate gives 3-nitroindole (35%) [68JCS(C)2145]. Nitration of some alkyl-substituted indoles by nitric acid/ sulfuric acid (63JOC2262 79JOU528) takes place upon the protonated species, and in such cases the rates pass through a maximum at 90% sulfuric acid in the usual way. 2-Methyl-, 1,2-dimethyl-, 2-f-butyl-, and 2,3-dimethylindole are each nitrated at the 5-position, the former two compounds in 84 and 82% yield, respectively, the latter two compounds at similar rates. This rate similarity suggests that in the protonated species the 5-position is much the most reactive of the benzenoid ring positions. In the protonated species it is probably the 3-position that has become... 

One of the factors which affect the chemical shifts of protons is the solvent.18,21 Marked differences in chemical shift of the signal for the a-proton in indole and substituted indoles occur when spectra are obtained in nonpolar and polar solvents. In contrast, using polar and nonpolar solvents, only small differences are observed in the chemical shift of the signal for the /3-proton in indoles.28,33 Hence, solvent shift, or lack of it, may be used to determine whether there is a or /3 substitution. 

Recent studies33 of solvent and concentration effects on the NMR of indoles have established that, in addition to the 2-proton, the 7-proton resonance in certain substituted indoles also undergoes downfield shifts in more polar and more dilute solutions. The chemical shifts of protons of indole and several methylindoles in two solvents, carbon tetrachloride and tetrahydrofuran, are listed in Ref. 33. Proton chemical shifts of the... 

Comparison with the spectra of A7-substituted indoles also provides a means of detecting the N-H signals. Figure 4A and B illustrate23 the application of this device in the case of indole and iV-methylindole, wherein the triplets due to a- and /3-protons of indole are reduced to doublets in iV-methylindole, forming the simpler AB pattern. The N-H peak disappears in Fig. 4B and, hence, provides the location of the 1-proton signal in indole. 

It was observed that the 5- and 7-proton signals of 2-substituted indoles are shifted upheld on formation of the sodium salt.65... 

Quite different lines of approach to the synthesis of the aspidospermine nucleus have been reported recently. " In one route, " the product (96) of Mannich condensation (initial jS-protonation of the enamine system) at the indole -position of a jS-substituted indole was isolated. This approach has wide implications, both mechanistic and biogenetic, and succeeded because the indole a-substituent (CH2C02Me) provided, by isomerisation, a hydrogen-bonded enamino-acrylate unit to stabilise the substitution product (96). 

Nitroethene is sufficiently electrophilic to substitute indole without the need for acid catalysis. Despite this, it has been shown that siUca-gel-supported CeCl3.7H20/NaI brings about such reactions at room temperature under solvent-free conditions or, to take another solvent extreme, the reaction occurs in water with a catalytic amount of a heteropoly acid (H3PWi204o). The employment of 2-dimethylamino-l-nitroethene in trifluoroacetic acid leads to 2-(indol-3-yl)nitroethene - the reactive species is the protonated enamine and the process is similar to a Mannich condensation (20.1.1.9). The use of 3-trimethylsilyl-indoles, with tpxo-substitution of the silicon, is an alternative means for effecting alkylation, avoiding the need for acid catalysis. 

When protonated 3-bromoindole is employed as electrophile, a final elimination of hydrogen bromide gives rise to re-aromatised 2-substituted indoles pyrrole (illustrated) or indoles will take part in this type of process. ... 

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