Indoles 2-alkylation, mechanism

Interactive mechanism for enantioselective organocatalytic indole alkylation... 

In their green catalytic method for the C—H alkylation of alkenes with alcohols, Yi and co-workers employed ruthenium complex 114 to alkylate Af-methylindole (113) in almost quantitative yields (116-117) whilst only generating water as the by-product (Scheme 10.38). Mechanistic experiments led the authors to propose a cationic Ru-indole-alkyl intermediate (115) that would arise from C2—H activation the exact mechanism of the C—O cleavage step is unknown. A related example with A-methoxycarbonyl-L-tryptophan methyl ester demonstrated that an indole protecting group was not necessary. 

Many 3-substituted indoles have also been prepared with the use of a-alkyl or a-aryl-p-keto sulfides. Thus indolization of aniline 5 with 3-methylthio-2-butanone 27 furnished indolenine 28, presumably via the same mechanism discussed earlier. The indolenine 28 was relatively unstable and reduced to the indole 29 without purification. Tetrahydrocarbazole 32 was prepared in 58% overall yield. Smith et al. made excellent use of the Gassman process in the total synthesis of (-i-)-paspalicine and (+)-paspalinine. ... 

In contrast, Cozzi and Umani-Ronchi found the (salen)Cr-Cl complex 2 to be very effective for the desymmetrization of meso-slilbene oxide with use of substituted indoles as nucleophiles (Scheme 7.25) [49]. The reaction is high-yielding, highly enantioselective, and takes place exclusively at sp2-hybridized C3, independently of the indole substitution pattern at positions 1 and 2. The successful use of N-alkyl substrates (Scheme 7.25, entries 2 and 4) suggests that nucleophile activation does not occur in this reaction, in stark contrast with the highly enantioselective cooperative bimetallic mechanism of the (salen)Cr-Cl-catalyzed asymmetric azidolysis reaction (Scheme 7.5). However, no kinetic studies on this reaction were reported. 

Alkylation reactions by the iminium methide species are well known in the mitomycin and mitosene literature 4,49,51-53 and are largely responsible for the cytotoxicity/antitumor activity of these compounds. As illustrated in Scheme 7.8, the electron-rich hydroquinone intermediate can also be attacked by the iminium ion resulting in either head-to-head or head-to-tail coupling. The head-to-head coupling illustrated in Scheme 7.8 is followed by a loss of formaldehyde to afford the coupled hydroquinone species that oxidizes to the head-to-head dimer upon aerobic workup. Analogous dimerization processes have been documented in the indole literature, 54-56 while the head-to-tail mechanism is unreported. In order to... 

It can be assumed that the azoles are deprotonated by the interfacial exchange mechanism, but it is noteworthy that it has been suggested that the rate of alkylation of indole under liquiddiquid two-phase conditions decreases with an increase in the concentration of the sodium hydroxide [8]. The choice of catalyst appears to have little effect on the reaction rate or on the overall yields of alkylated azole. Benzyltriethylammonium chloride, Aliquat, and tetra-n-butylammonium hydrogen sulphate or bromide have all been used at ca. 1-10% molar equivalents (relative to the concentration of the azole) for alkylation reactions, but N-arylation of indole with an activated aryl halide requires a stoichiometric amount of the catalyst [8]. 

Another example is the reaction of indoles with nitrosoarenes in the presence of acids. The redox potentials of the reactants cannot justify an outer-sphere ET process, thus the formation of the phenylaminoxyl detected for the reaction carried out in the ESR cavity, could be more likely justified by an inner-sphere ET mechanism95. In fact the reaction of quinoline N-oxide with primary alkyl Grignards for which an outer-sphere mechanism was earlier proposed, takes place through classical nucleophilic addition96. 

Reduction of the carbonyl groups at the 2-position of the pyrrole ring and at the 3-position of the indole ring with LAH or diborane generally leads to the formation of the corresponding alkyl derivatives, due to the facile nucleophilic displacement of the hydroxy group of the carbinols by the mechanism depicted in Scheme 69 (see Section 3.05.2.2). Predictably,... 

Most carbamates used as protective groups for amines are either acid-labile or base-labile. Deprotection proceeds by the mechanisms outlined in Figure 10.8. During the deprotection of acid-labile carbamates, carbocations are formed, which can alkylate electron-rich structural elements in a given substrate (e.g. phenols, thiols, indoles,... 

HF calculations with the 6-31G(d) basis set were used to study the mechanism of the Michael addition (or Friedel-Crafts alkylation) reaction of indole with dimethyl alkylidenemalonate. This reaction proceeds through two transition states, TSi and TS2 in the first step, assumed to be rate determining, the new C-C bond is formed, whereas in the second step, proton transfer from indole to malonate occurs with the formation of the new C-H bond. The calculations show that the transfer and interaction of the 7r-electrons in the reactant molecules may play an important role in the cleavage of the original C=C bond and the formation of the new bonds (C-C and C-H) the electron transfer is believed to be the driving force for the reaction to occur. 

Gramme is a common precursor for indol-3-ylmethylation of enolates and other nucleophiles. Such reactions normally occur by an elimination-addition mechanism. Following development of procedures for 4-substitution via directed lithiation with l-(tri-/w-propylsilyl)-gramine, Iwao and Motoi have developed conditions for tandem nucleophilic substitution of the dimethylamino group. Quatemization followed by reaction with a nucleophile in the presence of TBAF leads to alkylation. <95TL5929> The carbon nucleophiles which were successfully used include nitromethane, methyl acetoacetate, diethyl malonate and diethyl 2-(acetamido)malonate. Phthalimide, thiophenol, TMS-CN and TMS-Nj were also used as sources of nucleophiles. 

Indole was included with alkyl and arylamines in a study which demonstrated the potential of 2-pyridylsulfonyl as an /v -protecting group. The group is reductively removed using SmI,. <95JOC5969> A possible new means for indole debenzylation was uncovered l-Benzyl-2-phenylindole and several /V-benzylcarbazoles and tetrahydrocarbazoles were found to undergo debenzylation on reaction with methyllithium or LDA. An -elimination mechanism is proposed. <95TL1671>... 

Acyl-pyrroles, -furans, and -thiophenes in general have a similar pattern of reactivity to benzenoid ketones. Acyl groups in 2,5-disubstituted derivatives are sometimes displaced during the course of electrophilic substitution reactions. /V-Alkyl-2-acy I pyrroles are converted by strong anhydrous acid to A-alkyl-3-acylpyrroles. Similar treatment of N-unsubstituted 2- or 3-acylpyrroles yields an equilibrium mixture of 2- and 3-acylpyrroles pyrrolecarbaldehydes also afford isomeric mixtures. The probable mechanism of these rearrangements is shown in Scheme 133. A similar mechanism has been proposed for the isomerization of acetyl indoles. 

As with C-alkylation, the mechanism of amino group replacement can follow the elimination/addition or the nucleophilic replacement path. Both mechanisms are indeed mentioned in the literature and are cxrcasionally claimed to occur concurrently. The elimination/addition path is suggested in the reaction of p-aminoketones with uracils, and a four-centered transition state is proposed for the. same reaction with indole Mannich bases. ... 

Trifluoromethylation of pyrrole (and indole and imidazole) occurs on irradiation of a mixture of the compound with difluorodiiodomethane, again via a SET mechanism involving fragmentation of the radical anion (Scheme 31). The presence of the CF3 group in the final products, 45 and 46, is a result either of secondary decomposition of the initially formed—but not isolated—difluoroiodomethyl derivatives, or of formation of the CF3 anion or radical in situ [94], Perfluoroalkyla-tion of pyrroles can also be achieved by an SrnI mechanism—by reaction with perfluoroalkyl iodides in the presence of magnesium or zinc [95]. Indole, on the other hand, gives a mixture of the seven possible alkylated derivatives when irradiated in the presence of ethyl chloroacetate [96],... 

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