Protonation 2-methylindoles

Indole can be nitrated with benzoyl nitrate at low temperatures to give 3-nitroindole. More vigorous conditions can be used for the nitration of 2-methylindole because of its resistance to acid-catalyzed polymerization. In nitric acid alone it is converted into the 3-nitro derivative, but in a mixture of concentrated nitric and sulfuric acids 2-methyl-5-nitroindole (47) is formed. In sulfuric acid, 2-methylindole is completely protonated. Thus it is probable that it is the conjugate acid which is undergoing nitration. 3,3-Dialkyl-3H-indolium salts similarly nitrate at the 5-position. The para directing ability of the immonium group in a benzenoid context is illustrated by the para nitration of the conjugate acid of benzylideneaniline (48). 

The first proton to be removed from iV-methylpyrrole by w-butyllithium is from an a-position a second deprotonation occurs to give a mixture of 2,4- and 2,5-dilithiated derivatives. The formation of a 2,4-dilithio derivative is noteworthy since in the case of both furan and thiophene initial abstraction of a proton at C-2 is followed by proton abstraction from C-5 (77JCS(P1)887). iV-Methylindole, benzo[6]furan and benzo[6]thiophene are also deprotonated at C-2. Selenophene and benzo[6]selenophene and tellurophene and benzo[6]tellurophene similarly yield 2-lithio derivatives (77AHC(21)119). 

Competitive metallation experiments with IV-methylpyrrole and thiophene and with IV-methylindole and benzo[6]thiophene indicate that the sulfur-containing heterocycles react more rapidly with H-butyllithium in ether. The comparative reactivity of thiophene and furan with butyllithium depends on the metallation conditions. In hexane, furan reacts more rapidly than thiophene but in ether, in the presence of tetramethylethylenediamine (TMEDA), the order of reactivity is reversed (77JCS(P1)887). Competitive metallation experiments have established that dibenzofuran is more easily lithiated than dibenzothiophene, which in turn is more easily lithiated than A-ethylcarbazole. These compounds lose the proton bound to carbon 4 in dibenzofuran and dibenzothiophene and the equivalent proton (bound to carbon 1) in the carbazole (64JOM(2)304). 

Methylindole (skatole) [83-34-1] M 131.2, m 95 , pK -4.55 (C-3-protonation, aq H2SO4). Crystd from benzene. Purified by zone melting. 

In the presence of a catalytic amount of concentrated hydrochloric acid, dimethyl 1 -methyl-1 H-l-benzazepine-3,4-dicarboxylate (1) undergoes addition of 1-methylindole, probably via initial protonation of the enaminic 3-position of the benzazepine ring, to give the indolyldihydrobenz-azepine 2.21 In fact, adduct 2 is the major product from the reaction of 1-mcthylindole with dimethyl acetylenedicarboxylate in acetonitrile. Similar adducts are obtained with indole. 

Challis and Rzepa (1975) observed kinetic deuterium isotope effects in the azo coupling of 2-methyl-4,6-di-tert-butylindole (12.139) and its anion. The origin of this effect must also be attributed to steric hindrance of the proton transfer step in the substitution proper, since 2-deuterated methylindole and unsubstituted indole (Binks and Ridd, 1957) do not give isotope effects. 

Figure 5.1 The use of multiple catalysts encapsulated in star polymers to enable a one-pot cascade reaction containing interfering catalysts. Catalyst 11 is formed via the protonation of imidazolidinone (9) by immobilized PSTA (10), and is responsible for the nucleophilicaddition ofN-methylindole (14)...

The related reaction of 10 with ferrocenylmethylamine affords, in addition to the C3 adduct (as the minor product), a 2-ferrocenylethyl(dimethylamino)allenyli-dene complex as the major product, formed by migration of the resonance-stabilized [FcCH2] carbenium ion to the terminal carbon atom of the chain (Scheme 3.24) [46], The formation of pyrrolyl- and indolyl-substituted allenylidene complexes by reaction of complex 10 with various pyrroles and N-methylindole [47] has also been rationalized as involving initial attack of the electron-rich heterocyde on C3 of 10 followed by proton migration to the terminal =CH2 entity of the intermediate butenynyl-substituted a-complex (Scheme 3.25). 

Complexation of indoles with chromium hexacarbonyl, which reduces the electron density of the heterocyclic system, promotes nucleophilic attack at the 7-position and, to a lesser extent, also at the 4-position of the indole ring and provides a viable synthetic route to 7-formyl-l-methylindole (78CC1076). Curiously, although the benzenoid ring is rendered susceptible to nucleophilic attack, the reaction of the chromium complex with butyllithium results in abstraction of the proton from the 2-position. However, if this position is... 

The kinetics of reaction of four indoles with a number of benzhydryl cations has allowed the determination of the nucleophilicity parameters N and S for these reactions.49 Kinetic data from the reaction of a number of indoles with 4,6-dinitroben-zofuroxan then allow determination of their N values. Correlation of these data with those for protonation at C(3) of 5-substituted indoles and 5-substituted 2-methylindoles... 

Another anomalous orientation is observed in the nitration of 2-methylindole in sulfuric acid, which affords the 5-nitro derivative almost exclusively.257, 258 However, nitration in acetic acid yields the expected 3-nitro isomer. It has been shown258 that whereas nitration in acetic acid involves free indole, nitration in sulfuric acid proceeds through the protonated form (31). 

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