Indole electrophilic additions

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. 

Since normal electrophilic addition to indoles occurs at the 3-position, the lithiation of compounds containing removable N-substituents has received a lot of attention over the years, because of its importance as a route to 2-substituted indoles. As a result, a variety of different protection systems are now available as shown in Table II. 

Indoles with 2-substituents such as methyl or benzyl are cyclized with enones to carbazoles in acetic acid in the presence of Pd/C. This reaction involves electrophilic addition at C-3 and subsequent aromatization (Scheme 2) (88T5215). 

Finally, in this category there must be included cyclisations of the benzylic anions derived from ortho-isocyano-toluenes the scheme shows this route in its simplest form. However, the synthesis is very flexible, for example the initial benzylic anion can be alkylated with halides or epoxides before the ring closure, thus providing 3-substituted indoles and, additionally, the final A -hthioindole can be A -alkylated by adding a suitable electrophile before work-up. ... 

Indole is a particularly interesting case, because the Cr(CO)3 unit selectively activates the six-membered ring (52) [104,117,118], while in free indole the five-membered ring dominates the (electrophilic addition) reactivity. The selectivity in addition to the Cr(CO)3 complexes of indole derivatives shows a preference for addition at C-4 (indole numbering) and C-7, with steric effects due to substituents at C-3 and N-1 as well as anion type influencing the selectivity [118]. 

Fused indoles 294 have been synthesized by photochemical and thermal cyclization of 293 via electrophilic addition of a nitrene and a rearrangement (Scheme 114) (11TL192). 

Based on this observation the authors proposed that both C2- and C3-arylation pathways proceed via electrophilic addition of Pd(II) at the more electron-rich C3 position. This C3-palladated indole may then either undergo deprotonation and reductive elimination to give the 3-arylindole, or experience a C3 to C2 Pd migration, which then would lead to the C2-... 

Pd(rV) intermediate. The alkylated Pd(II)-aryl thus generated performs an intramolecular C2-arylation on the indole. The authors suggest that this occurs via electrophilic addition at C3 followed by a C3-C2 Pd migration, as proposed by Sames and co-workers (05JA8050), although the possibility of a Heck-type carbopalladation cannot be excluded. 

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