4-NITROINDOLE: INDOLE, 4-NITRO

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). 

It has been known that aromatic heterocycles such as furan, thiophene, and pyrrole undergo Diels-Alder reactions despite their aromaticity and hence expected inertness. Furans have been especially used efficiently as dienes due to their electron-rich properties. Thiophenes and pyrroles are less reactive as dienes than furans. But pyrroles with A-elecIron-withdrawing substituents are efficient dienes. There exists a limited number of examples of five-membered, aromatic heterocycles acting as dienophiles in Diels-Alder reactions. Some nitro heteroaromatics serve as dienophiles in the Diels-Alder reactions. Heating a mixture of l-(phenylsulfonyl)-3-nitropyrrole and isoprene at 175 °C followed by oxidation results in the formation of indoles (see Eq. 8.22).35a A-Tosyl-3-nitroindole undergoes high-yielding Diels-Alder reactions with... 

Nitro-l-(phenylsulfonyl)indole undergoes nucleophilic substitution reactions with enolates, for example, of diethyl malonate and cyclohexanone (Scheme 77), to afford the corresponding 3-substituted 2-nitroindoles <1997TL5603, 1999TL7615>. Similar S -type displacements of phenylsulfinate work very efficiently in an intramolecular sense (e.g., Scheme 78) <1999PHC45>. 

The 5-nitroindole (121), benzimidazole and 5-nitro- and 6-nitro-ben-zimidazole as their 5 -triphosphates are all incorporated opposite each of the natural nucleotides by DNA Pol a and Klenow fragment with efficiencies up to 4000-fold better than a natural mismatch.Pol a preferentially incorporated each opposite pyrimidines, whilst Klenow preferentially incorporated them opposite purines. Both polymerases incorporated the triphosphates opposite an abasic site up to 140-fold more efficiently than dATP, whilst T4 DNA polymerase incorporated (121) 1000-fold more efficiently than dATP. Incorporation of the 5 -triphosphate derivative of the related indole nucleoside opposite... 

Treatment of an imidate which is placed ortho to a reactive methylene group with sodium hydroxide-DMSO results in the formation of a new pyrrole ring. Good to xcelient yields of 4-nitroindoles are obtained when 3-nitro-2-methyl-anilines (or acetanilides) are treated with diethyl oxalate in the presence of a strong base (cf. Madelung synthesis of indoles, p. 68). 

Thermolysis of orffto-azido-styrenes gives nitrenes that insert into the side-chain to form indoles. Similar nitrenes have been generated by reaction of nitro-compounds with trialkyl phosphites. The azide thermolysis method can be used to prepare 2-nitroindoles. ... 

Pelkey and Gribble showed that the enolate of diethyl malonate adds to 3-nitro-l-(phenylsulfonyl)indole (6a) at C-2 to form the trani-3-nitro-2-substituted indo-line 7 [7, 8]. The stereochemistry is confirmed on the basis of coupling constants. Other enolates also add to 3-nitroindoles 6 to form the tran -indolines 7 in moderate to good yields [8] (Table 1). 

Some more recent examples of nucleophilic displacement of halide involve activation by nitro groups for example, 2-iodo-3-nitro-l-(phenylsulfonyl)indole 71 yields 2-amino-3-nitroindoles 72 in good yields when treated with secondary amines, but fails to undergo SnAt with sodium azide, phenol, and ammonia [36]. 

Pelkey ET, Barden TC, Gribble GW (1999) Nucleophilic addition reactions of 2-nitro-l-(phenylsulfonyl)indole. A new synthesis of 3-substituted-2-nitroindoles. Tetrahedron Lett 40 7615-7619... 

In the first route (Scheme 4), indoUne (5) is nitrated to 6-nitro-2,3-dUiydroindole (22, 92%). Apphcation of the tungstate method to 22 and subsequent methylation provide l-methoxy-6-nitroindole (9, 77%) via 8a. A Vilsmeier-Haack reaction (94%), followed by nitroaldol reaction (85%), leads 9 to l-methoxy-6-nitro-3-(2-nitrovinyl)indole (23) through 1-methoxy-6-nitroindole-3-carbaldehyde (10b). After selective reduction of the nitro-vinyl part of 23 with NaBH4, the resultant l-methoxy-6-nitro-3-(2-nitro-ethyl)indole (24,84%) is treated with Zn/HCl and then AC2O to give 21 (81%). Reduction of 24 with Zn/AcOH produces 6-amino-l-methoxytryptamine (25, 30%). 

Gribble used the Sundberg indole synthesis to make 2-nitroindole (30) by simply refluxing p-nitro-o-azidonitrostyrene (29) in xylene. This was the first synthesis of 2-nitroindole (30). 

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