3//-Indole, tautomer

C-Aminoindoles autoxidize extremely rapidly. Consequently, comparatively few chemical reactions have been examined. The 2-amino derivative exists in the 3H-indole tautomeric form (473) and is protonated and alkylated on the annular nitrogen atom (72HC(25-2)179). The 1-methyl derivative (474) exits predominantly as such and not as the alternative 2-imino-3//-indole tautomer and is protonated at the 3-position to give a cation having the same electronic structure as that of the protonated (473). Acylation of (473) yields l-acetyl-2-acetylaminoindole, via the initial acylation of the annular nitrogen atom. Confirmation of this route has been established by the observation that 2-acetylaminoindole, obtained by hydrolysis of the diacetylated compound, is acetylated under identical conditions... 

Kostic el al. discovered that Pd11 complexes, when attached to tryptophan residues, can rapidly cleave peptides in acetone solutions to which a stoichiometric amount of water is added, for hydrolysis.436 The indole tautomer in which a hydrogen has moved from the nitrogen to C(3) is named indolenine. Its palladium(II) complexes that are coordinated via the nitrogen atom have been characterized by X-ray crystallography and spectroscopic methods.451 Binuclear dimeric complexes between palladium(II) and indole-3-acetate involve cyclopalladation.452 Bidentate coordination to palladium(II) through the N(l) and the C(2) atoms occurs in binuclear complexes.453 Reactions of palladium(II) complexes with indole-3-acetamide and its derivatives produced new complexes of unusual structure. Various NMR, UV, IR, and mass spectral analyses have revealed bidentate coordination via the indole carbon C(3) and the amide oxygen.437... 

Indole is a heteroaromatic compound consisting of a fused benzene and pyrrole ring, specifically ben2o[ ]pyrrole. The systematic name, IJT-indole (1) distinguishes it from the less stable tautomer 3JT-indole [271-26-1] (2). Iff-Indole [120-72-9] is also more stable than the isomeric ben2o[ ] pyrrole, which is called isoindole, (2H, (3) and IH (4)). A third isomer ben2o[i ]pyrrole is a stable compound called indoli2idine [274-40-8] (5). 

The Fischer Indole Synthesis and Related Sigmatropic Syntheses. In the Fischer indole synthesis (26) an Ai-aryUiydra2one is cyclized, usually under acidic conditions, to an indole. The key step is a [3,3] sigmatropic rearrangement of an enehydra2one tautomer of the hydra2one. 

The known 3-mercapto derivatives of furan, thiophene, selenophene (77ACS(B)198), ben-zothiophene (70JCS(Q243i) and indole (69TL4465) all exist as the 3-thiol tautomers. 

A large number of Brpnsted and Lewis acid catalysts have been employed in the Fischer indole synthesis. Only a few have been found to be sufficiently useful for general use. It is worth noting that some Fischer indolizations are unsuccessful simply due to the sensitivity of the reaction intermediates or products under acidic conditions. In many such cases the thermal indolization process may be of use if the reaction intermediates or products are thermally stable (vide infra). If the products (intermediates) are labile to either thermal or acidic conditions, the use of pyridine chloride in pyridine or biphasic conditions are employed. The general mechanism for the acid catalyzed reaction is believed to be facilitated by the equilibrium between the aryl-hydrazone 13 (R = FF or Lewis acid) and the ene-hydrazine tautomer 14, presumably stabilizing the latter intermediate 14 by either protonation or complex formation (i.e. Lewis acid) at the more basic nitrogen atom (i.e. the 2-nitrogen atom in the arylhydrazone) is important. 

It has been proposed that protonation or complex formation at the 2-nitrogen atom of 14 would enhance the polarization of the r,6 -7i system and facilitate the rearrangement leading to new C-C bond formation. The equilibrium between the arylhydrazone and its ene-hydrazine tautomer is continuously promoted to the right by the irreversible rearomatization in stage II of the process. The indolization of arylhydrazones on heating in the presence of (or absence of) solvent under non-catalytic conditions can be rationalized by the formation of the transient intermediate 14 (R = H). Under these thermal conditions, the equilibrium is continuously pushed to the right in favor of indole formation. Some commonly used catalysts in this process are summarized in Table 3.4.1. 

Photochemical oxidation of a mixture of 1,3,4,7-tctramethyliso-indole (51) and its tautomer (50) has been found to give the isoindolenine hydroperoxide (105). Conceivably, this hydroperoxide could disproportionate to give a hydroxyisoindolenine, since 106 is a major by-product when the condensation between 2,5-hexanedione and... 

A tautomeric equilibrium between quinone and quinone methide tautomers has been proposed to exist for the compounds which are obtained by oxidation of 5,6-dihydroxy indole (Scheme 18) (92TL3045). 

A derivative of 5-(indol-2 -yl)dihydropyridazine 44 (R = H) exists in DMSO-iig solution exclusively as tautomer 44a (within the limits of 400-MHz H NMR detection). However, the introduction of methyl groups both into the indole ring and into the pyridazine ring favors a shift of the tautomeric equilibrium... 

The Yao group has made use of a Ic type intramolecular Heck reaction to prepare the C2-symmetric dimeric indole core of chloptosin <06OL4919>. A solvent-free variation of the Bischler indole synthesis, electrophilic cyclization of a-arylamino imine tautomers prepared from aniline derived a-arylamino ketones, has been used by Menendez and co-workers for the preparation of 2-arylindoles <06SL91>. 

Tryptophan and its derivatives can be characterized as existing in three possible tautomers the indole form, the indolenine form (hydrogen atom at position 3), and the cyclic form. In neutral solvents only the indole form exists NMR studies indicate no evidence for the other two isomers (60JA2184). However, when dissolved in 85% phosphoric acid or TFA, N-methoxycarbonyltryptophan exists as a pyrrolo[2,3-i]indole derivative 119 (78JA5564 81T1487). Although the tricyclic compound is stable in the crystalline form, it reverts to the starting material when it dissolves in acetic acid or methanolic HCl. 

Diels-Alder reaction of 3-vinylindole 131 with aryne in the presence of air gives, besides primary Diels-Alder product 132, the methyl 12-methyl-12H-[3]-benzoxepino[l,2-l7]indole-5-carboxylate 135. This can be explained by the formation of 1,2-dioxetane 133, its cyclo reversion and final intramolecular cyclization of dienol 134 or its tautomers (Scheme 26 (1996JCS(P1)1767)). 

A way forward might be to form the imine 7.3 [and hence its enamine tautomer 7.4] by reacting the phenylamine 7.2 with cyclohexanone (Scheme 7.18). Then to generate the benzyne anion 7.5 by treating the tautomers with sodamide and sodium fcr/-buloxide in THF. Cydization to the required indole 7.1 occurs through nucleophilic addition to the benzyne, followed by protonation during work-up. 

The preparation and study of tautomers derived from 2-(2 -pyridyl)indole, 2-(2 -pyrrolo)[l,8]naphthyridine, and related heterocycles has been undertaken using ultraviolet (UV) and nuclear magnetic resonance (NMR) spectroscopy and also by molecular orbital (MO) calculations <1998JOC4055>. 

The important role that IR spectroscopy has played in the understanding of the tautomer-ism of pyrroles, indoles and their derivatives will be discussed in Section 3.04.6. 

In contrast with the hydroxy compounds, comparatively little is known of the tautomeric preferences of pyrrole- and indole-thiols. The compounds are readily oxidized to form the bis-heteroaryldisulfides and the available spectral data for the monomeric systems suggest that, in contrast with the oxygen analogues, the 2-pyrrole- and 3-indole-thiols exist predominantly as such, whereas the sulfur analogue of oxindole is the predominant tautomer for the 2-indolyl system <63AHC(2)1,76AHC(SuppI. 1)214). 

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