Electrophilic Substitution of Indoles

The indole ring system appears in many naturally-oeeuring substances including the amino acid tryptophan and the drug reserpine. 

In addition to electrophilic attack on the pyrrole ring in indole, there is the possibility for additions to the fused benzene ring. First examine the highest-occupied molecular orbital (HOMO) of indole. Which atoms contribute the most What should be the favored position for electrophilic attack Next, compare the energies of the various protonated forms of indole (C protonated only). These serve as models for adducts formed upon electrophilic addition. Which carbon on the pyrrole ring (C2 or C3) is favored for protonation Is this the same as the preference in pyrrole itself (see Chapter 15, Problem 2)1 If not, try to explain why not. Which of the carbons on the benzene ring is most susceptible to protonation Rationalize your result based on what you know about the reactivity of substituted benzenes toward electrophiles. Are any of the benzene carbons as reactive as the most reactive pyrrole carbon Explain. 

Many heterocyclic compounds exist as mixtures of tautomers. For example, 2-hydroxypyridine exists in equilibrium with 2-pyridone. 

The equilibrium abundances of the tautomers is influenced by substituents and solvent among other factors. 

Examine the geometry and atomic charges of 2-pyridone to see if it is localized as indicated in the drawing above, or delocalized (as in 2-hydroxypyridine). If you need to, write alternative Lewis structures to that provided above. How many n electrons does 2-pyridone possess Is 2-pyridone aromatic  

---

Wang et al. investigated the catalytic behavior of cation exchange resin supported lanthanide(III) salts of the general structure (31) (Scheme 4.15), prepared from Dowex, Amberlite, Amberlyst and other resins [99]. It turned out that Am-berlyst XN-1010 and Amberlyst 15 complexed best with lanthanides(III). Thus, among others, electrophilic substitution of indole with hexanal and Mukayiama-type aldol reaction of benzaldehyde with ketene silyl acetal proceeded in excellent yields under catalytic conditions (Scheme 4.16). 

Electrophilic substitution of indole occurs preferentially at C3 metallation can activate C2. Complexation with Cr(CO)3 results in a marked preference for substitution at C4 steric factors can favor C7- over C4-substitution.3 Example ... 

An example of easy P-electrophilic substitution of indole with a weak electrophile... 

What is the of indole as a base and where does it protonate What is the pK of indole as an acid At what position is electrophilic substitution of indole fastest Cite two examples. 

Electrophilic substitution of indole. acidity of the LiC104-Et20 system. It can Diels-Alder reactions and cyclocond up to S stereocenters are created by this m action. Camphorsulfonic acid is also pm condensation involving an aldehyde and catalyzed. ... 

Electrophilic substitution of indole. This reaction strictly exploits the Lewis acidity of the LiClOa-Et system. It can be applied to a synthesis of yuehchukene. 

Grieco has applied the use of the unusual solvent system LiC104-Et20 to effect a Bronsted acid-catalyzed electrophilic substitution of indole by jS,jS-disubstituted allylic alcohols en route to YCK as shown in Scheme 5 (59). The synthesis commenced with the diol 89 (available in two steps from isophorone 84), which on treatment with indole in LiC104-Et20 containing 0.01 equivalent of acetic add furnished the substitution product 90 in 86% yield. In the face of the failure of standard methods, oxidation to the aldehyde required conversion to the alkoxymagnesium bromide, followed by treatment... 

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 double iron-mediated arylamine cyclization provides a highly convergent route to indolo[2,3-fc]carbazole (Scheme 16). Double electrophilic substitution of m-phenylenediamine 34 by reaction with the complex salt 6a affords the diiron complex 35, which on oxidative cyclization using iodine in pyridine leads to indolo[2,3-b]carbazole 36 [98].Thus,ithasbeen demonstrated that the bidirectional annulation of two indole rings can be applied to the synthesis of indolocarbazoles. 

Electrophilic substitutions of rings with a single N-nucleophilic site proceed smoothly. Thus, indolo benzazepine 36a, protected on the indole ring, and benzoxepine 36c are easily methylated on the benzazepine nitrogen (Scheme 79 (1991JHC379)). 

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. 

Although there appear to be no examples of the specific acid-catalyzed rearrangement of 3-substituted indoles to give the 2-substituted indoles, electrophilic substitution of 3-substituted indoles is known to proceed via the attack at the 3-position to give the... 

Acyl-pyrroles and -indoles have also been obtained from their dithioketals, which are produced by direct electrophilic substitution of the heterocyclic system using 2-substituted... 

In conjunction with their studies on electrophilic substitution in indoles, Jackson and co-workers [28] suggest that the initial protonation occurs at C-7 as in Mechanism 1, followed by hydride rearrangement of the indole P-hydrogen to the a-position. The epimerization reaction would then take place as depicted in Mechanism 2. Hence, Gaskell and Joule and Jackson et al. differ only in the matter of initial protonation. 

By theoretical calculations (B3LYP/6-31G ) four reaction pathways were investigated formation of endo or egzo product with initial bond formation to C2 or C3 in indole. For each mechanism theoretical 13C KIE were analysed and the best agreement of theoretical and experimental KIEs was found for the reaction involving the intermediacy of the radical cation 11, resulting from electrophilic aromatic substitution of indole at C3 by cyclohexadiene in the rate-limiting step ... 

Positional selectivity and possible role of relative stabilities of onium states of ring heteroatoms Electrophilic substitution of functionalyzed derivatives of five-membered heterocycles Positional selectivities in reactions of indole, benzofuran, benzothiophene and benzoselenophene with electrophiles... 

To further extend fhe substitution pattern of fhese building blocks, benzarmelated N-amino-N-heterocycles were prepared Electrophilic amination of indole, 2-mefhylindole, or carbazole using hydroxylamine-O-sulfonic acid [25] yielded fhe corresponding N-amino-indole 17, -2-methyhndole 18, and -carbazole 19, respectively. However, attempting the same reaction with 2,7-dimethyhndole or dibenza-zepine (iminostilbene) failed, most likely due to steric hindrance. 

Dihydro compounds are often useful synthetic intermediates showing different reactivity patterns to the parent, aromatic heterocycle. For example, indolines (2,3-dihydroindoles) can be used to prepare indoles with substituents in the carbocyclic ring, via electrophilic substitution then aromatisation (20.16.1.17), and similarly, electrophilic substitutions of dihydropyridines, very difficult in simple pyridines, followed by aromatisation, can give substituted pyridines. Dehydrogenation of tetra- and hexahydro-derivatives reqnires more vigorous conditions. 

---