Indole, aromaticity electrophilic substitution reaction

The Vilsmeier-Haack reaction (herein, Vilsmeier reaction ) provides an effective method for the formylation of aromatic systems. The combination of phosphoryl chloride with V-methylaniline or dimethylformamide generates an iminium phosphorus derivative or chloro-iminium cation that is the active electrophile in an electrophilic substitution reaction. The resulting substitution product is an iminium salt 1, which is hydrolyzed on workup with alkali to give the carbaldehyde product 2 (Scheme l).1,2 The method is particularly useful with activated arenes or electron-rich heterocycles, such as pyrroles, furans, thiophenes, and indoles. We had a special interest in the preparation of indole-7-carbal-dehydes, namely, their properties as isosteres of salicylaldehyde. Thus, we became involved in a wide-ranging investigation of 4,6-dimethoxy-... 

An aqueous Friedel-Crafts reaction has also been used in polymer synthesis. The acid-catalyzed polymerization of benzylic alcohol and fluoride functionality in monomeric and polymeric fluorenes was investigated in both organic and aqueous reaction media. Polymeric products are consistent with the generation of benzylic cations that participate in electrophilic aromatic substitution reactions. Similar reactions occurred in a water-insoluble Kraft pine lignin by treatment with aqueous acid. A Bisphenol A-type epoxy resin is readily emulsified in aqueous medium with an ethylene oxide adduct to a Friedel-Crafts reaction product of styrene and 4-(4-cumyl)phenol as emulsifier.Electrophilic substitution reaction of indoles with various aldehydes and ketones proceeded smoothly in water using the hexamethylenetetramine-bromine complex to afford the corresponding Z A(indolyl)methanes in excellent yields.InFs-catalyzed electrophilic substitution reactions of indoles with aldehydes and ketones are carried out in water.Enzymatic Friedel-Crafts-type electrophilic substitution reactions have been reported. ... 

Indoles are usually constructed from aromatic nitrogen compounds by formation of the pyrrole ring as has been the case for all of the synthetic methods discussed in the preceding chapters. Recently, methods for construction of the carbocyclic ring from pyrrole derivatives have received more attention. Scheme 8.1 illustrates some of the potential disconnections. In paths a and b, the syntheses involve construction of a mono-substituted pyrrole with a substituent at C2 or C3 which is capable of cyclization, usually by electrophilic substitution. Paths c and d involve Diels-Alder reactions of 2- or 3-vinyl-pyrroles. While such reactions lead to tetrahydro or dihydroindoles (the latter from acetylenic dienophiles) the adducts can be readily aromatized. Path e represents a category Iley cyclization based on 2 -I- 4 cycloadditions of pyrrole-2,3-quinodimcthane intermediates. 

Many of the common electrophilic aromatic substitution reactions can be conducted on indole. CompHcations normally arise either because of excessive reactivity or the relative instabiUty of the substitution product. This is the case with halogenation. 

Individual substitutions may not necessarily be true electrophilic aromatic substitution reactions. Usually it is assumed that they are, however, and with this assumption the furan nucleus can be compared with others. For tri-fluoroacetylation by trifluoroacetic anhydride at 75 C relative rates have been established, by means of competition experiments 149 thiophene, 1 selenophene, 6.5 furan, 1.4 x 102 2-methylfuran, 1.2 x 105 pyrrole, 5.3 x 107. While nitrogen is usually a better source of electrons for an incoming electrophile (as in pyrrole versus furan) there are exceptions. For example, the enamine 63 reacts with Eschenmoser s salt at the 5-position and not at the enamine grouping.150 Also amusing is an attempted Fischer indole synthesis in which a furan ring is near the reaction site and diverted the reaction into a pyrazole synthesis.151... 

Electrophilic aromatic substitution Electrophilic aromatic substitution of indole occurs on the five-membered pyrrole ring, because it is more reactive towards such reaction than a benzene ring. As an electron-rich heterocycle, indole undergoes electrophilic aromatic substitution primarily at C-3, for example bromination of indole. 

The fact that benzene derivatives are much more generally accessible than pyrroles has relegated pyrrole annelation to a relatively minor role in indole synthesis. Nevertheless the concept provides a viable synthetic approach and the existing methods serve as useful prototypes. One strategy is to build up an appropriately functionalized side-chain and complete indole formation by electrophilic substitution-aromatization. Reactions (135)-(137) illustrate this type of approach (79TL3477, 79JA257, 73JPR295). 

Alkylation of the C(2) or C(3) carbons of the pyrrole ring can be accomplished by electrophilic aromatic substitution. Such substitution reactions may be carried out on the neutral heterocycle or on a metal salt. The magnesium salts are of most synthetic importance for the alkylation of both pyrroles and indoles. As discussed in Section 3.05.1.2.7, there is a reversal of the preferred site of electrophilic substitution between pyrroles and indoles. Thus Friedel-Crafts-type substitution of pyrroles gives 2-aIkylpyrroles while similar reaction... 

Attack at C-3 gives a carbocation that is resonance-stabilized by a nonbonded pair of electrons on the adjacent nitrogen. Attack at C-2 gives a cation in which the positive charge is not adjacent to an atom bearing nonbonded electrons. Any additional resonance contributors disrupt the benzenoid structure in the left ring. Therefore, electrophilic aromatic substitution reactions of indole occur primarily at C-3. 

One of the most important condensed ring systems is indole. Whether the indole nitrogen is substituted or not, the favored site of attack is C-3 of the heterocyclic ring. Bonding of the electrophile at that position permits stabilization of the intermediate by the nitrogen without disruption of the benzene aromaticity. Indole can exist in two tautomeric forms, the more stable enam-ine and the 3-H-indole or imine forms. C-2 to C-3 pi-bond of indole is more capable of cycloaddition reactions then the other pi bonds of the molecule. Inter molecular cyclo additions are not favorable, whereas intramolecular variants are often high-yielding. 

Kinetics of reacting I R = H, OMe with nucleophiles such as the enol of pentan-2,4-dione aromatic amines , phosphorus derivatives and some reactive aromatic compounds , and relative rates with substituted (cyclohexadienyl)Fe(GO)3 cation have been examined. These behave as classically expected, but in contrast to 1-or 2-OMe, a 3-OMe increases rate through its inductive effect. The kinetics agree with electrophilic substitution with the possible intermediacy of n complexes " . Because aryl (N-diene)Fe(CO)3 complexes can rearrange by dissociation into C-aryl derivatives", intermediates could also involve reaction with an N of an indole or a MeO (oxonium cation) of MeO-aromatics. 

Pyrrole, furan, and thiophene are aromatic compounds that undergo electrophilic aromatic substitution reactions preferendally at C-2. These compounds are more reactive than benzene toward electrophiles. When pyrrole is protonated, its aromahcity is destroyed. Pyrrole polymerizes in strongly acidic solutions. Indole, benzofuran, and benzothiophene are aromatic compounds that contain a five-membered aromatic ring fused to a benzene ring. 

This reaction presumably proceeds by electrophilic substitution at C3 and dehydration of the resulting carbinol, followed by cycloaddition. The reaction also involves the decarboxylation of an indole-2-acetic acid, which is known to be facile. Similarly, reaction of indole, a carbonyl compound and 7V-phenylmaleimide generates tetrahydrocarbazoles of structure (68). The yields vary from 15-20% for simple aldehydes to 70% and above for cyclic ketones <93JHC8l>. The stereochemistry, which is predominantly all-cw, arises as the result of an endo addition followed by protonation from the less hindered side of the molecule in the step resulting in aromatization (Scheme 145). 

Electrophilic substitution of aromatic nuclei in tyrosine and tryptophan side chains has frequently been reported in connection with acidolytic removal of blocking groups. C-Benzylation and tert.butylation of the tyrosine side chain and N-alkylation of the indole nucleus in tryptophan are often attributed to the alkyl cations generated in the reaction. This common side reaction is caused, however, mainly by the alkylating agents formed in the process, such as benzyl bromide or tert.butyl trifluoroacetate. The same is true for the S-alkylation of the methionine side chain. Conversion of the thioether to a sulfonium salt can... 

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