Reactivity of the Indole Ring

The reactivity of the indole ring of tryptophan60 has attracted much interest and attention. This aromatic, electron-rich nucleus is susceptible to oxidative cleavage and to substitutions by a number of reagents. It can react as an electron donor with aldehydes or carbocations. 

Another indication of the high reactivity of the indole ring toward acylation is its conversion to the 1,3-diacetyl derivative in refluxing acetic anhydride (24 h), and the isolation of 3-acetylindole in 40% yield after hydrolysis of the A-acetyl group [373]. A simple procedure for cyanoacetylation of indole and its 1-, 2-methyl and other derivatives has been reported. The indole is added to a warm (85°C) 10 1 solution of acetic anhydride cyanoacetic acid. The reaction presumably proceeds via the mixed anhydride and the enhanced reactivity of the cyano-substituted group leads to complete selectivity [374]. 

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. 

An important method for construction of functionalized 3-alkyl substituents involves introduction of a nucleophilic carbon synthon by displacement of an a-substituent. This corresponds to formation of a benzylic bond but the ability of the indole ring to act as an electron donor strongly influences the reaction pattern. Under many conditions displacement takes place by an elimination-addition sequence[l]. Substituents that are normally poor leaving groups, e.g. alkoxy or dialkylamino, exhibit a convenient level of reactivity. Conversely, the 3-(halomethyl)indoles are too reactive to be synthetically useful unless stabilized by a ring EW substituent. 3-(Dimethylaminomethyl)indoles (gramine derivatives) prepared by Mannich reactions or the derived quaternary salts are often the preferred starting material for the nucleophilic substitution reactions. 

The side chain on the fused five-membered ring can, interestingly, form part of a piperidine or piperazine ring. The scheme for preparing the first of these takes advantage of the reactivity of the indole 3 position. The relatively weak base, sodium hydroxide, thus catalyzes the addition of bromoindole (16-1) to the carbonyl group in 4-iV-methylpiperidone (16-2) to afford carbinol (16-3). This product dehydrates in the presence of acid catalytic reduction of the thus-produced olefin then affords the... 

The potential for transition metal complexes to provide new reactivity patterns continues to be explored by the preparation of complexes and the study of their reactivity patterns. The aminoalkyl substituents of gramine, tryptamine and methyl tryptophanate promoted metalation at C2 of the indole ring by Pt(DMSO)2Cl2. The crystal structure of the gramine product was determined. 

Nitration of indole by benzoyl nitrate gives 3-nitroindole (35%) [68JCS(C)2145]. Nitration of some alkyl-substituted indoles by nitric acid/ sulfuric acid (63JOC2262 79JOU528) takes place upon the protonated species, and in such cases the rates pass through a maximum at 90% sulfuric acid in the usual way. 2-Methyl-, 1,2-dimethyl-, 2-f-butyl-, and 2,3-dimethylindole are each nitrated at the 5-position, the former two compounds in 84 and 82% yield, respectively, the latter two compounds at similar rates. This rate similarity suggests that in the protonated species the 5-position is much the most reactive of the benzenoid ring positions. In the protonated species it is probably the 3-position that has become... 

The electronic character of the indole ring can be adjusted by introduction of substituents so as to become more reactive as a dienophile in inverse-electron-demand Diels-Alder reactions. For example, 2-ethoxy-1-methylindole reacts with the electrophilic heterocycle (56) (Equation (138)) <87ZN(B)1032>. 

These various synthetic methods have been applied to many syntheses of potential dmgs, alkaloids and other natural products. Ring-forming reactions are particularly valuable and the high reactivity of the indole 3-position can be used to induce nucleophilic addition at C-2. Depending on the electrophile, it may subsequently be eliminated, reestablishing aromaticity. 

Conjugate addition has also been carried out with l-(3-indolyl) enones. The reactivity of these compounds might be expected to be attenuated somewhat by the donor character of the indole ring, relative to the carbonyl group. Good results were obtained using InBrs-TMS-Cl, both at 10 mol % [261]. These conditions were also successful with A-protected (f-Boc, TIPS, PhS02) 3-indolyl enones. 

Indolylacylradical 203 exhibited similar reactivity, albeit in a less efficient manner with alkenes, such as methyl crotonate (32%), crotonitrile (20%), 1-octene (15%), and vinyl acetate (15%) to generate cyclopenta[h]indol-l-ones 204 after radical addition and cyclization onto the C-2 position of the indole ring [24]. These results contrasted nicely with the observed intermolecular reactions of 2- and 3-indolylacyl radicals generated using tributyltin hydride. 

Two new analogues of catharanthine, 753 and 754, differing from catharanthine in the fusion of the indole ring to the non-aromatic portion of the iboga skeleton have been synthesized in racemic form and their reactivity toward coupling with vindoline examined. The [2,1] fused analogues (e.g., 753) were found to give low... 

In a series of papers spanning 20 years, Natsume, Muratake, and coworkers reported a versatile synthesis of indoles exploiting the reactivity of the pyrrole ring toward intramolecular electrophilic attack at the C-2 or C-3 position [1-16], In their seminal paper, Natsume and... 

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