Indole, nitration

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). 

The mechanistic foundations of indole nitration have been well established <72HC 25-2)539>. While the 3-position is the preferred site for electrophilic attack, nitration of indole itself is complicated by oxidation and dimerization. In strongly acidic solution, the 3-position is protonated and reaction takes place at the 5-position under the directing influence of the iminium moiety (Scheme 114). 

Baeyer confirmed his results by the total synthesis of oxindole, isatin and indole. Nitration ofphenylacetic acid, isolation of the o-nitro isomer, and reduction of the latter followed by ring closure gave oxindole. Reaction with nitrous acid ( .e. potassium nitrate and sulfuric acid) gave isatin oxime, from which by reduction, dehydrogenation with iron(lll) chloride and final hydrolysis, isatin itself was obtained. 

As regards reaetions other than nitration brought about by some of these systems, especially noteworthy are the addition processes undergone by eertain indole derivatives when treated with solutions of nitrie aeid in aeetie aeid. Produets inelude glycols, nitro-alcohols, and nitro-alcohol acetates. Such additions might well be encountered with some polynuclear aromatie eompounds, and with sueh eompounds the possibility of nitration by addition-elimination must always be borne in mind. 

A two-step synthesis of indoles from o-nitrobenzaldehydes proceeds by condensation with nitromcthanc followed by reductive cyclization. Like the Leim-gruber Batcho method, the principal application of the reaction is to indoles with only carbocyclic substituents. The forniation of the o,p-dinitrostyrenes is usually done under classical Henry condensation conditions but KF/18-crown-6 in propanol was found to be an advantageous reaction medium for acetoxy-substituted compounds[1]. The o,p-dinitrostyrenes can also be obtained by nitration of p-nitrostyrenes[2]. 

Nitration. Because nitration frequentiy generates nitrogen oxides which can participate in oxidative transformations, the nitration of indole itself is a complex reaction. In strongly acidic media, the nitration of 2-substituted indoles can proceed through the conjugate acid (8). Because the aromatic system is thereby transformed to an a2astyrene, the 5-position is the primary site of reaction. 

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). 

Jap-KIingermarm reactions, 4, 301 oxidation, 4, 299 reactions, 4, 299 synthesis, 4, 362 tautomerism, 4, 38, 200 Indole, 5-amino-synthesis, 4, 341 Indole, C-amino-oxidation, 4, 299 tautomerism, 4, 298 Indole, 3-(2-aminobutyl)-as antidepressant, 4, 371 Indole, (2-aminoethyl)-synthesis, 4, 278 Indole, 3-(2-aminoethyl)-synthesis, 4, 337 Indole, aminomethyl-reactions, 4, 71 Indole, 4-aminomethyl-synthesis, 4, 150 Indole, (aminovinyl)-synthesis, 4, 286 Indole, 1-aroyl-oxidation, 4, 57 oxidative dimerization catalysis by Pd(II) salts, 4, 252 Indole, 1-aroyloxy-rearrangement, 4, 244 Indole, 2-aryl-nitration, 4, 211 nitrosation, 4, 210 synthesis, 4, 324 Indole, 3-(arylazo)-rearrangement, 4, 301 Indole, 3-(arylthio)-synthesis, 4, 368 Indole, 3-azophenyl-nitration, 4, 49 Indole, 1-benzenesulfonyl-by lithiation, 4, 238 Indole, 1-benzoyl photosensitized reactions with methyl acrylate, 4, 268 Indole, 3-benzoyl-l,2-dimethyl-reactions... 

Vilsmeier-Haack formylation, 4, 222 Indole, dimethyl- C NMR, 4, 172 Indole, 1,2-dimethyl-bis-allylation, 4, 357 Indole, 1,3-dimethyl-nitration, 4, 211 reactions... 

Indole, l-methyl-2-sulfonamido-tautomerism, 4, 200 Indole, l-methyl-3-sulfonamido-tautomerism, 4, 200 Indole, (methylthio)-synthesis, 4, 368 Indole, 3-(methylthio)-synthesis, 4, 338, 368 Indole, l-methyl-3-vinyl-oxidation, 4, 280 Indole, nitro-rearrangement, 4, 297 Indole, 3-nitro-nitration, 4, 211, 213 reduction, 4, 362 synthesis, 4, 210, 363 Indole, 5-nitro-synthesis, 4, 211, 363 Indole, nitroso-rearrangement, 4, 297 Indole, 1-nitroso-reduction, 4, 362 Indole, 3-nitroso-reduction, 4, 362 Indole, nitrovinyl-... 

Indole, 4,5,6,7-tetrahydro-4,7-dioxo-structure, 4, 303 Indole, tetrahydro-3-methyl-synthesis, 4, 109 Indole, 2-(2-thienyl)-nitration, 4, 211 Indole, 3-thio-synthesis, 4, 368 Indole, 2-thioalkyl-synthesis, 4, 152 Indole, 3-thiocyano-synthesis, 4, 368 Indole, 1-tosyloxy-rearrangement, 4, 302 Indole, 1,2,3-trialkyl-Mannich reactions, 4, 228 Indole, 3-(tricyanovinyl)-nucleophilic addition reactions, 4, 281 reactions... 

EtOH). No methoxyl is present. It forms a series of crystalline double chlorides with cadmium, zinc or copper, does not give the thalleioquin reaction, and solutions of its sulphate are not fluorescent. It is diacidie and forms two series of salts of which the nitrate, B. HNOj, crystallises in minute prisms, m.p. 196°, insoluble in water. Cinchonamine hydrochloride, B. HCl, laminae or B. HCl. HjO, cubical crystals, has been suggested for use in the estimation of nitrates. When warmed with strong nitric acid the alkaloid furnishes dinitrocinchonamine. It gives an amorphous, monoacetyl derivative, and forms a methiodide, m.p. 208 , which with silver oxide yields an amorphous methylcinchonamine. Raymond-Hamet found that cinchonamine ves typical indole colour reactions and is probably an indole alkaloid. This seems to have been... 

The reaction of ethyl nitrate with the indole Grignard reagent is discussed... 

Most of the substitution reactions of di-, tetra, and hexa-hydro-carbolines and of their oxo derivatives are similar to those of the parent indole or indolenine derivatives. Nitration and bromination of harma-line (l-methyl-3,4-dihydro-j8-carbolme) are referred to in Section IV, A, 1. Sulfonation and azO COupling ° proceed as expected for indole derivatives. The preparation of chlorinated and iodinated derivatives of 6-nitroharmaline has been reported,but their structures have not been established. 

A neat synthesis of 4-nitroindole depends on an acyladon-deacyladon sequence from 2-methyl-3-nitroaniline, as shown in Eq. 10.53. On the other hand, treatment of iV-protected indoles v/ith acetyl nitrate generated in sini at bw temperanire gives the correspondmg... 

A paper concerned with the synthesis of pyridazino[3,4-fe]indoles 18 included a study of various conversions of 4,5-dichloro-2-methylpyridazin-3-one 17 including nucleophilic substitutions, Suzuki reactions and electrophilic substitution (nitration), combined with reductive dehalogenation, and usefully summarised previous work <06T121>. 

Fermentation, 22, 53 Ferric nitrate, 23, 20 Fieser s solution, 21, 110 Filter fabric, Pyrex glass, 22, 33, 65 Vinyon, 22, 33, 67 Filter paper, hardened, 22, 45 Fischer indole synthesis, 22, 98 Flash distillation, 21, 85 Flask, modified Claisen, 22, 11 Fluorescence of 9-aminoacridine hydrochloride, 22, 7 Formaldehyde, 20, 60 Formalin, 22, 66 Formic acid, 20, 66, 102 23, 43 Formic acid, chloro-, benzyl ester, 23, 13... 

Illustrated for 5,6,7-trimethoxyindole (for the trimethyl-indole see JOC 25,1542(1960)). 2-methoxy-beta-nitro-styrene, if nitrated at the 6 position and used in place of (I), should give 4-methoxy-indole. 

Indolizine is much more basic than indole (p Ta = 3.9 vs. —3.5), and the stability of the cation makes it less reactive and resistant to acid-catalyzed polymerization. Protonation occurs at C-3, although 3-methylindolizine protonates also at C-l. Introduction of methyl groups raises the basicity of indolizines. Electrophilic substitutions such as acylation, Vilsmeyer formylation, and diazo-coupling all take place at C-3. Nitration of 2-methylindolizine under mild conditions results in substitution at C-3, but under strongly acidic conditions it takes place at C-l, presumably via attack on the indolizinium cation. However, the nitration of indolizines often can provoke oxidation processes. 

---