3- methylindoles

Unlike the intermolecular reaction, the intramolecular aminopalladation proceeds more easily[13,14,166], Methylindole (164) is obtained by the intramolecular exo amination of 2-allylaniline (163). If there is another olefinic bond in the same molecule, the aminopalladation product 165 undergoes intramolecular alkene insertion to give the tricyclic compound 166[178]. 2,2-Dimethyl-l,2-dihydroquinoline (168) is obtained by endo cyclization of 2-(3,3-dimethyiallyl)aniline (167). The oxidative amination proceeds smoothly... 

The cyclized products 393 can be prepared by the intramolecular coupling of diphenyl ether or diphenylamine(333,334]. The reaction has been applied to the synthesis of an alkaloid 394[335]. The intramolecular coupling of benzoyl-A-methylindole affords 5-methyl-5,10-dihydroindenol[l,2-b]indol-10-one (395) in 60% yield in AcOH[336]. Staurosporine aglycone (396) was prepared by the intramolecular coupling of an indole ring[337]. 

The classical conditions for the Madelung indole synthesis are illustrated by the Organic Syntheses preparation of 2-methylindole which involves heating o-methylacetanilide with sodium amide at 250 C[1]. 

A -(2 2-Diethoxyethyl)anilines are potential precursors of 2,3-unsubstituted indoles. A fair yield of 1-methylindole was obtained by cyclization of N-inethyl-M-(2,2-diethoxyethyl)aniline with BFj, but the procedure failed for indole itself[2], Nordlander and co-workers alkylated anilines with bromo-acetaldehyde diethyl acetal and then converted the products to N-trifliioro-acetyl derivatives[3]. These could be cyclized to l-(trifluoroacetyl)indoles in a mixture of trifluoroacetic acid and trifluoroacetic anhydride. Sundberg and... 

Indol-2-ylcopper reagents can also be prepared from 2-lithioindoles and they have some potential for the preparation of 2-substituted indoles. 1-Methyl-indol-2-ylcopper can be prepared by reaction of 2-lithio-l-methylindole with CuBr[10]. It reacts with aryl iodides to give 2-aryl-1-methylindoles. Mixed cyanocuprate reagents can be prepared using CuCN[ll], The cyan-ocuprate from 1-methylindole reacts with allyl bromide to give 2-allyl-l-methylindole. 

To a stirred ice-cooled solution of 2-(dimethylamino)-l-nitroethene (1.67 g, 14.4mmol) in TFA (7.2ml) was added 6-benzyloxy-l-methylindole (3.42g, 14.4 mmol). The solution was allowed to warm to room temperature and poured into ice water. The product was extracted using EtOAc to give 6-benzyloxy-l-methyl-3-(2-nitroethenyl)indoIe (4.2 g, 95%). 

A solution of 1.05 M diborane in THF (25 ml, 26 mraol) was added slowly to a stirred suspension of 3-acetyl-5-hydroxy-2-methylindole (1.0 g, 5.3 mmol) in THF (10 ml). After hydrogen evolution ceased, the mixture was heated at reflux for I h, cooled and poured into acetone (75 ml). The mixture was heated briefly to boiling and then evaporated in vacuo. The residue was heated with methanol (50ml) for 20min. The solution was concentrated and 3NHC1 (40ml) was added. The mixture was extracted with ether and the extracts dried (MgSO ) and evaporated to yield a yellow oil. Vacuum sublimation or recrystallization yielded pure product (0.76 g, 82%). 

The Madelung Synthesis and Related Base-Catalyzed Condensations. The Madelung cyclization involves an intramolecular condensation of an o-aLkylanilide. A classic example of the Madelung synthesis is the high temperature condensation of o-methylacetanihde [120-66-1] to 2-methylindole [95-20-5] by sodium amide. 

The reactivity sequence furan > tellurophene > selenophene > thiophene is thus the same for all three reactions and is in the reverse order of the aromaticities of the ring systems assessed by a number of different criteria. The relative rate for the trifluoroacetylation of pyrrole is 5.3 x lo . It is interesting to note that AT-methylpyrrole is approximately twice as reactive to trifluoroacetylation as pyrrole itself. The enhanced reactivity of pyrrole compared with the other monocyclic systems is also demonstrated by the relative rates of bromination of the 2-methoxycarbonyl derivatives, which gave the reactivity sequence pyrrole>furan > selenophene > thiophene, and by the rate data on the reaction of the iron tricarbonyl-complexed carbocation [C6H7Fe(CO)3] (35) with a further selection of heteroaromatic substrates (Scheme 5). The comparative rates of reaction from this substitution were 2-methylindole == AT-methylindole>indole > pyrrole > furan > thiophene (73CC540). 

Methylindole has a p/sTa of -4.6 and it is therefore a weaker base than indole itself this unusual effect has been ascribed in part to the decreased hyperconjugative stabilization of the conjugate acid (38) by the one hydrogen at position 3 compared with the two hydrogens at position 3 in the 3//-indolium ion (39). 

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). 

Benzo[Z)]thiophene reacts with dimethyl l,2,4,5-tetrazine-3,6-dicarboxylate in a cyclo-addition-fragmentation reaction to yield (143), whereas benzo[A]furan and N- methylindole yield products (144) arising from ring opening and recyclization (76AP679). 

The possibility of activating the indole nucleus to nucleophilic substitution has been realized by formation of chromium tricarbonyl complexes. For example, the complex from TV-methylindole (215) undergoes nucleophilic substitution with 2-lithio-l,3-dithiane to give a product (216) which can be transformed into l-methylindole-7-carbaldehyde (217) (78CC1076). 

The acid promoted cyclization of AT-(2-chloroallyl)enaminones (Scheme 35a) provides the expected 3-methyltetrahydroindoles, whereas similar treatment of iV-(2-chloroallyl)anilines yields unexpectedly 2-, rather than 3-, methylindoles (Scheme 35b) (75JCS(Pl)U46). The course of the latter cyclization is not resolved although various intermediates, such as those shown, have been considered. The ring closure in the furan synthesis shown in Scheme 35c is catalyzed by mercury(II) ion (79JCs(Pl)316l). 

Important synthetic paths to azirines and aziridines involve bond reorganization, or internal addition, of vinylnitrenes. Indeed, the vinylnitrene-azirine equilibrium has been demonstrated in the case of trans-2-methyl-3-phenyl-l-azirine, which at 110 °C racemizes 2000 times faster than it rearranges to 2-methylindole (80CC1252). Created in the Neber rearrangement or by decomposition of vinyl azides, the nitrene can cyclize to the p -carbon to give azirines (Scheme 4 Section 5.04.4.1). 

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. 

Essentially the present procedure converted 1-methylindole to l-methyl-3-(N,N-dimethylaminomethyl)indole and a-methyl-styrene to o -(N,N-dimethylaminoethyl)styrene. ... 

Methylindole has been prepared from the a5-methylphenyl-hydrazone of pyruvic acid, by the action of sodium amide or sodium hydride on indole followed by methyl iodide at elevated temperatures,by treatment of indole with methyl p-toluene-sulfonatc and anhydrous sodium carbonate in boiling xylene, and by the action of inelhyl sulfate on indole previously treated... 

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