Indoles electrophilic substitution, sites

There are a wide variety of methods for introduction of substituents at C3. Since this is the preferred site for electrophilic substitution, direct alkylation and acylation procedures are often effective. Even mild electrophiles such as alkenes with EW substituents can react at the 3-position of the indole ring. Techniques for preparation of 3-lithioindoles, usually by halogen-metal exchange, have been developed and this provides access not only to the lithium reagents but also to other organometallic reagents derived from them. The 3-position is also reactive toward electrophilic mercuration. 

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)). 

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... 

The position 3 is so much preferred in electrophilic substitution, that it is the site for primary attack even when it is already substituted. Jackson and co-workers255 have provided a considerable body of evidence that electrophilic substitution at the 2-position of 3-substituted indoles is an indirect process involving prior attack at the 3-position to give an indolenine derivative (30), which subsequently rearranges to a 2,3-disubstituted indole. 

A particularly striking example of the change from ground-state chemistry is provided by the electrophilic substitution in tryptamine 8.12, where the 4-position of the indole ring has overtaken both the 3- and the 2-position (seep. 174) as the most nucleophihc site, in line with the large LUMO coefficient at that site 8.11.1093... 

Regioselective substitution on indole is one of the most important goals in heterocyclic chemistry owing to the great importance of indoles in the preparation of biologically active products. The 2- and 3-positions of the ring are the normal sites of attack in the electrophilic substitution, including acylation because of their much more nucleophilic activity. ... 

By analogy with (37) <84KGS1219> and (38) <83KGS1086>, the )S-positions in dihydrobenzo[2,l-b 3,4-Z> ]dipyrrole (39) are the sites where electrophilic substitutions occur. The benzodipyrrole (39) afforded, upon treatment with dimethylamine hydrochloride and formaldehyde in methanol followed by addition of alkali, the Mannich bis-base (293) (Equation (2)). Benzodipyrrole (39) has been claimed to behave towards electrophilic reagents as a double indole rather than an a,a -bipyrryl <87CC1176>. 

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... 

The central diazepine ring of the condensed indole derivative in 5.19. was built up by the electrophilic attack of the pyridylpalladium intermediate on the indole system. Since the preferential site of the attack, the 2-position of indole was blocked through substitution, the ring closure was directed into the pen-position, giving rise to the formation of a seven membered ring.18... 

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. 

One explanation is that attack at C2 results in disruption of the aromaticity of the benzenoid ring, as in intermediate 7.25. This is therefore a high-energy intermediate, and this reaction pathway is slower because the first step is ratedetermining. Also the C3 selectivity is in accord with the electrophile attacking the site of highest electron density on the ring. In essence, indole tends to react like an enamine towards electrophiles, with substitution... 

For benzo[b]furan and indole no such precise data are available, but it is possible to adduce some information from the various reactions described below. The positional reactivity orders for these molecules and also for benzo[b]thiophene, which have been calculated by various methods, are given in Table 8.1. In principle the ab initio calculations should be the more reliable, but neither the tt nor the (a + it) order is correct for benzo[6]thiophene, suggesting that these are incorrect for the other molecules also. The calculations using the STO-3G basis set certainly wrongly predict the site of most rapid protonation. Notably, only the Hiickel calculations give the correct order for benzo[b]thiophene and indeed they are usually the most reliable indicators for electrophilic aromatic substitution. 

Amino acid residues, except hydrocarbon chains, may provide nucleophilic sites (electron-rich centers) or electrophilic sites (electron-deficient centers) for chemical modifications. Electron-rich centers include sulfur nucleophiles (thiol of Cys and thioether of Thr), nitrogen nucleophiles (e-amino of Lys, imidazole of His and Guanidyl of Arg), oxygen nucleophiles (phenolic of Tyr, carboxyl of Asp and Glu and hydroxyl of Ser and Thr), and carbon nucleophile (a-position of indole ring of Trp), with an increasing nucleophilicity in that order. They provide nucleophilic sites for alkylation (nncleophilic substitution), acylation, addition and oxidation at pH near or above their pK values. Electron-deficient centers include ammonium cation of Lys, guanidiiun cation of Arg and imidazolium cation of His. They provide electrophilic sites for metalation and reduction at pH near or below their pK values. 

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