N-methylindoles

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). 

In contrast to aziridine-2-carboxylic esters, treatment of aziridine lactone 166 (Scheme 3.60) with N-methylindole (167) in the presence of BF3 lil20 proceeded... 

Iminium-catalyzed nucleophilic addition of N-methylindole to 2-hexenal, followed by enamine-catalyzed formation of product Star polymer encapsulation... 

We chose the microwave-enhanced Raney Nickel catalyzed hydrogen isotope exchange of indole and N-methylindole as our substrates and D20, CD3COCD3, CD3OD and CDC13 as the solvents. The thermal reaction had already been the subject of a recent study [44], The microwave-enhanced method was some 500-fold faster than the corresponding thermal reaction (at 40 °C). Furthermore the pattern of labeling (Scheme 13.3) varied with the choice of solvent. Thus in the case of indole it-... 

The use of dimethyl sulphoxide as a dipolar aprotic solvent is well known,7 and the present method can be regarded as a model procedure and has been applied to the preparation of a number of N-w-alkyl-pyrroles and N-w-alkyl indoles.8 The yield of N-benzylindole is considerably higher than in previously reported preparations and is as good as that reported for the preparation of N-methylindole in liquid ammonia.4 The present method is, however, less laborious and quicker to carry out. Very high yields are obtained in reactions using w-alkyl halides and moderately good yields with secondary alkyl halides. The reactions should be compared with those recently reported for pyrryl-thallium.9... 

Electrochemical oxidation of indole [202] and N-methylindole [203] in acetonitrile gives rise to dimers and trimers. These are oxidised further to polymers. Oxidation of N-acetylindoles in acetic acid results in acetoxylation of the heterocyclic... 

As with pyrrole, the a-lithiation of N-substituted indoles occurs readily [790R1 84MI2], and reaction can also be performed in the presence of a number of reactive functional groups at C-3. Thus the 3-carboxylic acid, 3-diethylamide, and 3-aldehyde derivatives of N-methylindole (9,10, and 11) have all been a-lithiated (87JOC104 91M17), the latter via its a-(N-methylpiperazino) alkoxide 12. 

N-Methylindole-2-carboxaldehyde also undergoes /8-lithiation, after in situ conversion to its a-amino alkoxide with lithium A-methylpiperazide, and the resulting 3-lithio species has been successfully alkylated with methyl iodide (Scheme 22)(87JOC104). However, when the same reaction was repeated using N,A(,A -trimethylethylenediamine as the amine com-... 

Figure 6.50 (R)-bis-N-tosyl-BINAM-derivative 151 and axially chiral bis(thio)ureas 152-165 screened for catalytic efficiency in the asymmetric addition of indole and N-methylindole to nitroalkenes.

A screening of (R)-bis-N-tosyl-BlNAM 151 and axially chiral (thio)urea derivatives 152-162 (10mol% loading 0.36 M catalyst concentration incorporating the N-aryl(alkyl) structural motif was performed at various reaction temperatures in di-chloroform using the asymmetric FC addition of N-methylindole to trans-Ji-nitrostyrene as model reachon (product 1 Scheme 6.158). The structure of bis(3,5-bistrifluoromethyl) phenyl functionalized binaphthyl bisthiourea 158 was identified... 

Scheme 6.158 Product spectrum of the 158-catalyzed asymmetric FC addition of indole and N-methylindole to various nitroakenes. The product configurations were not determined.

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). 

To 10 mL of a stirred solution of LAH (1 M in THF under N2), there was added dropwise a solution of 0.57 4-acetoxyindol-3-yl-N-ethyl-N-methylglyoxylamide in 10 mL anhydrous THF. When the addition was complete, the reaction mixture was brought to a reflux for 15 min. After cooling to 40 °C, sufficient water was added to decompose both the reaction complex and the excess hydride. After filtration through Celite (under an N2 atmosphere), the solvent was removed under vacuum, and the solid residue recrystallized from /hexane to provide 0.18 g (41%) N-ethyl-4-hydroxy-N-methylindole (4-HO-MET) with a mp 118-119 °C. Anal C,H,N. 

All attempts to chromatograph epinochrome (in 2% aqueous acetic acid) yielded, in addition to the red epinochrome spot (Rf ca. 0.80), definite spots with Rf s of 0.44 and 0.25 due to the rearrangement product (5,6-dihydroxy-N-methylindole) and an unknown Ehrlich-positive substance, respectively. 

Iodoadrenochrome methyl ether I CHs H OCH3 5,6-diacetoxy- 3-methoxy - 7 -iodo-N-methylindole " I ch3 H OCH3 191-192... 

The first proton to be removed from /V-methylpyrrole by n-butyllithium is from an a-position a second deprotonation occurs to give a mixture of 2,4- and 2,5-dilithiated derivatives. In both furan and thiophene initial abstraction of a proton at C-2 is followed by proton abstraction from C-5 (77JCS(Pl)887). N-Methylindole, benzo[/j]furan, benzo[b thiophene, selenophene, benzo[b]selenophene, tellurophene and benzof/jjtellurophene similarly yield 2-lithio derivatives (77AHC(21)119). 

The possibility of activating the benzene ring of the indole nucleus to nucleophilic substitution has been realized by formation of chromium tricarbonyl complexes. For example, the complex from N-methylindole (294) undergoes nucleophilic substitution with 2-lithio-l,3-dithiane to give a product (295) which can be transformed into l-methylindole-7-carbaldehyde (296) (78CC1076). 

AS derivative indole n p.p.m. (CDCI3 Solvent). Calculated using the chemical shifts reported for N-methylindole in (77T1739). 

Lithiation of benzo[6]thiophene occurs exclusively at position 2, leading to good yields of 2-substituted products. 2-Methoxybenzo[6]thiophene is reported to be lithiated at position 3 this is the only known direct lithiation at the /3-position (70AHC(11)177). Competitive metallation of benzo[6]thiophene and N-methylindole affords only 2-benzo[6]thienyl-lithium. 

N-Methylindole acts like an enamine with sulfonyl azides and gives a diazoimino compound.443-445 So does dihydropyridine but only in the presence of 5% lithium hydroxide (Scheme 147).242 A triazole is postulated to be formed from the triazoline followed by a ring opening oxidation of diazoamino compounds to triazoles has been known to proceed via a diazoimino compound in equilibrium with the triazole (Scheme 1 19).285-3"-400... 

The first vinylpyrroles studied as diene systems in Diels-Alder reactions were the /3-nitrovinyl-A/-methylpyrroles because they are stable and readily available from condensation of the corresponding carboxaldehydes with nitromethane. The /3-nitro vinylpyrrole 117 added to MA and yielded the corresponding N-methylindole-4,5-dicarboxylic anhydride 118. The process is believed to follow the normal Diels-Alder [4 + 2]-cycloaddition pathway, with subsequent loss of nitrous acid to give the fully aromatized adduct [73JCS(P 1)2450]. 

Jorgensen and co-workers employed chiral bis-sulfonamide catalyst 27, a proven ligand for metal-based asymmetric catalysis, for the Friedel-Crafts alkylations of N-methylindoles (24) using -substituted nitroolefins [52]. Using optimized conditions, 2 mol% 27 gave the desired indole alkylation products of substituted aryl and heteroaryl nitroolefins in moderate to high yields (20-91%) and moderate enantiopurities (13-63% ee Scheme 6.3). Aliphatic -substitution... 

Competitive metallation experiments with iV-methylpyrrole and thiophene and with N-methylindole and benzo[6]thiophene indicate that the sulfur-containing heterocycles react more rapidly with n-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 iV-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). 

The relative reactivities of indole, 2- and N-methylindole, pyrrole, thiophene, and furan have been determined in alkylation by a benzenonium ion coordinated to iron tricarbonyl (73CC540). The effects of methyl substituents in pyrrole were determined in alkylation by 4-(7V,7V-dimethyl-amino)benzaldehyde [76JCS(P2)696]. In neither of these methods, nor in the alkylation of indole by aziridinium tetrafluoroborate [67AG(E)178], nor in self-alkylation of a X5-phosphorinyl tetrafluoroborate [73AG (E)753], is a catalyst required. 

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