Indolyl anions

Indolo[2,3-d][l,3]thiazine-2,4-dithione formation, 4, 299 Indolothiazines synthesis, 4, 519 Indoloyl azides Curtius rearrangement, 4, 288 Indolyl anions acylation, 4, 232 alkylation, 4, 235 Michael-type additions, 4, 236 Indomethacin... 

Interest in this reaction was revived when the relevance of a carbene mechanism was realized, particularly following the demonstration (cf. SectionI,B) of a similar ring expansion of indene to 2-chloro-naphthalene by dichlorocarbene via the cyclopropane adduct. Indeed, at this time Nakazaki suggested that these reactions occurred by the addition of dichlorocarbene to the indolyl anion and subsequent rearrangement to the indolenine and, with loss of chloride ion, to the quinoline [Eq. (12)]. The preference of dichlorocarbene for... 

The mechanism for the formations of 83, 85, and 93 can be explained as illustrated in Scheme 13. Initial deprotonation of the 1-methoxy group of 82 liberates formaldehyde and an indolyl anion 95, and then protonation of 95 affords 83. Following the reaction path a, 95 reacts with formaldehyde to produce indole-3-methanol 96. Unstable 96 collapses into 3-methyleneindolenine 97, which adds... 

Alkali metal borohydrides are frequently used for the reduction of rc-electron-deficient heteroaromatic systems, but reduction of jt-electron-excessive arenes is generally possible only after protonation of the systems [e.g. 35-37]. The use of tetra-n-butylammonium borohydride under neutral conditions for the conversion of alkylindoles into indolines [38] is therefore somewhat unusual. Reduction of indoles by diborane under strongly alkaline conditions involves the initial interaction of the indolyl anion with the diborane to form an amino-borane which, under the basic conditions, reacts with a second molecule of diborane to produce the indoline [39]. The reaction of tetra-n-butylammonium borohydride with indoles could also proceed via the intermediate formation of diborane. 

Many I- and 3-substituted indoles can be obtained from the indolyl anion however, in order to achieve selectivity, careful attention to the counter cation is necessary. 

More recently Franck et a/.331 prepared the pyrrolo[l,2-a]indolyl anion (247) by a similar method as part of a total synthesis of the mitomycin antibiotics (Section VI,A) Alkylation of (247) with methyl chloromethyl ether followed by photooxidation gave a product 248 with the basic mitomycin skeleton. 

Santaniello et al.125 have N-alkylated pyrrole and indole (71) in the presence of crown-ether catalysts. The indolyl anion also behaves as an ambident nucleophile alkylation occurs at nitrogen and at C-3.126... 

Aryl and alkyl nitriles also react with pyrrolyl and indolyl anions to yield the acylated heterocycles (see Section 3.05.1.2.9). 

Pyrroles, indoles, isoindoles and carbazoles having no substituent at the nitrogen atom are weakly acidic and, upon treatment with a strong base, form anions which are capable of subsequent reaction with electrophiles at the nitrogen atom and/or the 1-position of isoindoles, the 2-position of pyrroles and the 3-position of indoles. 1-Substituted pyrroles and indoles also react with butyllithium to give 1-substituted 2-pyrrolyl and 2-indolyl anions (see Section 3.05.1.2.9). 

Treatment of indole (pKa - 17) with strong bases such as butyl lithium, Grignard reagents, or metal hydrides produces the corresponding indolyl anion, which reacts with electrophiles either on nitrogen or at the C3 position. With lithium, sodium, or potassium as counterion the indolyl anion tends to react on nitrogen, as in the preparation of 7.35. However, with magnesium as the counterion the intermediate has an essentially covalent rather than ionic structure, and reaction tends to occur at the C3 position, as in the preparation of 7.36. 

As intended, C2 carbanion 7.47 attacked the nitrile giving 7.48, which unexpectedly attacked the adjacent sulphonyl group giving indolyl anion 7.49. During the acidic aqueous workup this anion is quenched and the reactive N-sulphonyl imine functionality is readily hydrolysed affording ketone 7.44 and sulphonamide 7.45. 

In the reaction of /7-chlorobenzonitrile and 4-chloropyridine with the indolyl anion under the same experimental conditions as with pyrrole anion, only the substitution product in position 3 was formed in 60% yield (equation 122)226. 

Despite the strong tendency for N-substitution of pyrrolyl and indolyl anions, 2-substituted pyrroles and 3-sub-stituted indoles can also result the following exemplify reactions of this type ... 

Indole with benzoyl nitrate at low temperatures gives 3-nitroindole this can also be obtained by reaction of the indolyl anion with ethyl nitrate. 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 is formed, by conjugate acid nitration (see Section 3.3.3.2.1). 

Gribble and Saulnier (79) have extended their ellipticine synthesis 43) to the synthesis of 9-methoxyellipticine (2) (Scheme 24). One of the key features of this approach is the regioselective nucleophilic addition to the C-4 carbonyl group of pyridine anhydride 28. The other noteworthy transformation is the conversion of keto lactam 142 to the diol 143 with methyllithium, a process that presumably involves cleavage of the initial adduct to a methyl ketone which undergoes cyclization at the C-3 position of the indolyl anion. Reduction of 143 with sodium borohydride completes the synthesis of 2, in 47% overall yield from 5-methoxyindole (139). Gribble and students 80) have also used this method to synthesize 8-methoxyellipticine (134), 9-fluoroellipticine (144), and the previously unknown 7,8,9,10-tetrafluorellipticine (145), each from the appropriate indole. 

Indoles react with epoxides and aziridines in the presence of Lewis acids (see 20.4.1 for reaction of indolyl anions with such reactants) with opening of the three-membered ring and consequent 3-(2-hydroxyethylation) and 3-(2-aminoethylation) of the heterocycle. Both ytterbium triflate and phenylboronic acid are good catalysts for reaction with epoxides under high pressure silica gel is also an effective catalyst, but reactions are slow at normal pressure and temperature. Reaction with aziridines can be catalysed by zinc triflate or boron trifluoride. °... 

Under neutral conditions and at 0 °C, indole reacts with a mixture of formaldehyde and dimethylamine by substitution at the indole nitrogen. This A-substitution may involve a low equilibrium concentration of the indolyl anion (20.4.1) or may be the result of reversible kinetic attack followed by loss of proton. In neutral solution at higher temperature or in acetic acid, conversion into the thermodynamically more stable... 

As in pyrroles, the A-hydrogen in indoles is much more acidic (pK 16.2) than that of an aromatic amine (aniline has pK 30.7). Any very strong base will effect complete conversion of an A-unsubstituted indole into the corresponding indolyl anion, amongst the most convenient being sodium hydride, n-butyUithium or an alkyl Grignard reagent. 

The indolyl anion has two main mesomeric structures showing the negative charge to reside mainly on nitrogen and the P-carbon. Electron-withdrawing substituents, particularly at the P-position, increase the acidity markedly, for example 3-formylindole is about five units more acidic than indole and 2-formylindole is some three units more acidic. ... 

In its reactions, the indolyl anion behaves as an ambident nucleophile the ratio of N- to P-substitution with electrophiles depends on the associated metal, the polarity of the solvent, and the nature of the electrophile. Generally, the more ionic sodio and potassio derivatives tend to react at nitrogen, whereas mag-nesio derivatives have a greater tendency to react at C-3 (see also 20.1.1.4), however, reaction of indolyl Grignards in HMPA leads to more attack at nitrogen. Complimentarily, more reactive electrophiles show a greater tendency to react at nitrogen than less electrophilic species. 

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