Indole reactivity towards electrophiles

Donor substituents on the vinyl group further enhance reactivity towards electrophilic dienophiles. Equations 8.6 and 8.7 illustrate the use of such functionalized vinylpyrroles in indole synthesis[2,3]. In both of these examples, the use of acetyleneic dienophiles leads to fully aromatic products. Evidently this must occur as the result of oxidation by atmospheric oxygen. With vinylpyrrole 8.6A, adducts were also isolated from dienophiles such as methyl acrylate, dimethyl maleate, dimethyl fumarate, acrolein, acrylonitrile, maleic anhydride, W-methylmaleimide and naphthoquinone. These tetrahydroindole adducts could be aromatized with DDQ, although the overall yields were modest[3]. 

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. 

Indole is very reactive towards electrophiles, and it is usually necessary to employ reagents of low reactivity. Nitration with HNO3-H2SO4 is... 

Heteroaromatics have high reactivity toward electrophilic palladation and show good regioselectivity. Reactions with pyrrole,thiophene, furan, and indole have been reported (equation 3). The use of stoichiometric copper(II) ion gives a process catalytic in Pd. 

X-Ray studies of the system, using dimethyl 4-formyl-2,3-dihydro-1,4-benzothiazine-2,3-dicarboxylate,17 41/-1,4-benzothiazine 1,1-dioxide,18 and the 3-methyl derivative,19 showed these molecules to be essentially planar with only small distortions associated mainly with the heteroatoms in the thiazine ring. The various bond lengths and angles were related to those of indole in an attempt to rationalize their reactivity toward electrophiles, which has been reported20 to be similar to that of indole. Molecular mechanics calculations similarly indicated essentially planar rings for trans-2-dimethyl-4-acetyldihydrobenzo thiazine.21... 

Only alkyl groups at indole a-positions show any special reactions. Many related observations confirm that in a series of equilibria, P-protonation can lead to 2-aUcylidene-indolines, and hence reactivity towards electrophiles at an a-, but not a P-alkyl group, for example in DCl at 100 °C 2,3-dimethylindole exchanges H for D only at the 2-methyl. This same phenomenon is seen in Mannich condensation " and trifluoro-acetylation"" of 1,2,3-trimethylindole at the a-methyl. 

Reactions with electrophilic reagents takes place with substitution at C-3 or by addition at the pyridine nitrogen. All the azaindoles are much more stable to acid than indole (c/. section 17.1.1) no doubt due to the diversion of protonation onto the pyridine nitrogen, but the reactivity towards electrophiles at C-3 is only slightly lower than that of indoles. Bromination and nitration occur cleanly in all four parent systems and are more controllable than in the case of indole. Mannich and Vilsmeier reactions can be carried out in some cases, but when the latter fails, 3-aldehydes can be prepared by reaction with hexamine, possibly via the anion of the azaindole. Alkylation under neutral conditions results in quaternisation on the pyridine nitrogen and reaction with sodium salts allows A-1-alkylation. Acylation under mild conditions also occurs at N-1. The scheme below summarises these reactions for the most widely studied system - 7-azaindole. 

With ketone 271 in hand, focus turned to construction of the furoindole scaffold via a Fischer indolization. The lithium enolate of ketone 271 was generated in situ using lithium hexamethyldisilazide in a mixture of l,3-dimethyl-3,4,5,6-tetrahydro-2(lH)-pyrimidinone (DMPU) and THF (Scheme 36). Although this enolate is noted not to be very reactive toward electrophiles, treatment with allyl iodide affected a facile alkylation to provide ketone 272. 

The C-H/C-X coupling between electron-rich or -neutral heteroarenes such as indoles, thiazoles, furans, and 1,3-azoles with aryl hahdes have been described frequently in the literature (see earlier discussion). However, the couphng of electron-deficient heteroarenes such as pyridines has remained Hmited due to their low reactivity toward electrophilic metalation as well as CMD processes. Furthermore, 2-metallaazines are generally unstable and incompatible with the reaction conditions, although examples of such cross-coupling reactions (C-M/C-X coupling) exist. 

A second aspect of the chemistry of the indolic nucleus lies in taking advantage of its initial nucleophilic reactivity to realize transformations of synthetic and degradative usefulness. This reactivity towards electrophiles is sometimes a problem, e.g. the sensitivity of many Type II alkaloids towards autooxidation. The valuable transformations are sketched in Chart 3.5 for both condensations at the indolic a and /3 positions. a-Methyleneindoles turn out to be important intermediates in the formation and degradation of dimeric alkaloids, e.g., voacamine (p. 102) and vincaleukoblastine (p. 112). Although it is known that protonation, at least in simple indoles occurs predominantly on the j8 position we do not know in many cases whether the primary condensation... 

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. 

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 scope of this reaction is limited to electron-rich arenes and heteroarenes such as thiophenes, pyrroles, furans, indoles, and alkoxybenzenes as nucleophilic partners, corresponding to a Mayr ir-nucleophilicily parameter N>-1 [75-78], Electron-neutral to electron-deficient iodo(hetero)arenes are suitable electrophilic partners. Aryl halides or pseudohalides that are less reactive towards oxidative addition (Br, Cl, OTf) are not sufficiently reactive partners in this reaction. The reactivity of sterically hindered and/or ortho substituted iodoarenes has not been demonstrated. However biaryls bearing one ortho substituent of relatively small steric demand (e.g., from methoxybenzene or /V-mcthylindole) have been prepared. 

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. 

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