5-Methylindole

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 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). 

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). 

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). 

Rauwolscine gives colour reactions like those of yohimbine and the absorption curves of the hydrochlorides of the two alkaloids are very similar. Heated to 300°/5 mm. rauwolscinic acid forms barman (p. 490) and 3-ethylindole and on fusion with potassium hydroxide decomposes into indole-2-carboxylic acid, isophthalic acid, barman and an unidentified indole derivative. Rauwolscine itself on distillation with zinc dust produces barman, 2-methylindole (scatole) and tsoquinoline. It is suggested that the alkaloid has the skeletal strueture suggested by Seholz (formula XIV, p. 508) for yohimbine, the positions of the hydroxyl and earbomethoxy grouf s being still imdetermined. 

The arylhydrazone 24 generally gives the 3-alkyl-2-methylindole 25 as major product. However, the indolization of ethyl methyl ketone has been reported to provide both 2,3-dimethyl indole and 2-ethyl indole. " ... 

In 1974, Gassman et al. reported a general method for the synthesis of indoles. For example, aniline 5 was reacted sequentially with r-BuOCl, methylthio-2-propanone 6 and triethylamine to yield methylthioindole 7 in 69% yield. The Raney-nickel mediated desulfurization of 7 then provided 2-methylindole 8 in 79% yield. The scope and mechanism of the process were discussed in the same report by Gassman and coworkers as well. 

Propenyl)aniline (1, 1.0 g, 7.52 mmol), PdCl2(CH3CN)2 (0.195 g, 0.75 mmol), benzoquinone (0.812 g, 7.52 mmol), and LiCl (3.158 g, 75.2 mmol) were combined in THF (95 mL). After 5 h at reflux, the solvent was removed and the residue was stirred with ether and decolorizing charcoal for approximately 20 min and filtered. The filtrate was washed five times with 50-mL portions of 1 M NaOH. The solvent was removed by vacuum, and the residue was placed on a silica gel column and eluted with 3 1 petroleum ether/ether. 2-Methylindole (2, 0.818 g, 86%) was collected as a white, crystalline solid, identical with authentic material. ... 

In 1912, Madelung reported that o-acetotoluidine 3 and o-benzotoluidine 5 provided the corresponding 2-methylindole 4 and 2-phenylindole 6 respectively when heated to 360-380 C with 2 molar equivalents of sodium ethoxide. ... 

In 1929, Nenitzescu reported that p-benzoquinone (4) was treated with ethyl 3-aminocrotonate (5) in boiling acetone to yield ethyl 5-hydroxy-2-methylindole-3-carboxylate (6). ... 

Methylindole and acetylenedicarboxylic acid is reported to give two unidentified products, but with the dimethyl ester the crs and trans (61) adducts were obtained. It was suggested that the major product had the trans configuration but this was not proved. Hydrogenation of both adducts gave the corresponding succinic ester, which was also obtained from 2-methylindole and maleic anhydride, followed by esterification. 

Methyl-3-re-propylindole (43) was obtained by hydrogenation of the intermediate 2-methyl-3-allylindole (44), obtained by the allylation of 2-methylindole magnesium iodide. There were no reports of isomeric products being formed in this reaction. ... 

Aeetyl-2-methylindole (116) can readily be obtained by the action of acetjd chloride on the 2-methylindole Grignard reagent in ether. ... 

Benzhydryl 2-methyl-3-indolyl ketone (201) has been prepared by the action of diphenylacetyl chloride on 2-methylindole magnesium iodide. ... 

Ethoxycarbonyl-2-methylindole (222) and l-ethoxycarbonyl-3-methylindole (223) were the main products said to be obtained by the action of ethyl chloroformate on the 2- and 3-methylindole Grignard... 

The related compounds bis(2-mothyl-3-indolyl)glyoxal (263) and bis(3-methyl-l-indolyl)glyoxai (264) - have been prepared by the action of oxalyl chloride on the Grignard reagents derived from 2-methylindole and 3-methylindole, respectively, Eis(l-methyl-3-indolyl)-glyoxal (265) was prepared by the action of oxalyl chloride on 1-methyIindole in ether. 

Sanna reported that l,3-di(3-indolyl)-l,3-dioxo-%-propanc (266) and l,4-di(3-indolyl)-l,4-dioxo-M-butane (267) were formed by the action of malonyl chloride and succinyl chloride, respectively, on the indole Grignard reagent in ether, and analogous products could be obtained from 2-methylindole. 

---