Indole sulfonation

A solution of trifluoroacetic acid in toluene was found to be advantageous for cydization of pyruvate hydrazoncs having nitro substituents[4]. p-Toluene-sulfonic acid or Amberlyst-15 in toluene has also been found to give excellent results in preparation of indole-2-carboxylale esters from pyruvate hydra-zoiies[5,6J. Acidic zeolite catalysts have been used with xylene as a solvent to convert phenylhydraziiies and ketones to indoles both in one-flask procedures and in a flow-through reactor[7]. 

Lithiation at C2 can also be the starting point for 2-arylatioii or vinylation. The lithiated indoles can be converted to stannanes or zinc reagents which can undergo Pd-catalysed coupling with aryl, vinyl, benzyl and allyl halides or sulfonates. The mechanism of the coupling reaction involves formation of a disubstituted palladium intermediate by a combination of ligand exchange and oxidative addition. Phosphine catalysts and salts are often important reaction components. 

A/-sulfonated ayiridines have also been used in Friedel-Crafts reactions (qv) (63). The successful C-alkylation of the heteroaromatic compounds indole (qv) [120-72-9] (64—66) and thiophene [110-02-1] (67) with a2itidines has also been reported ... 

Indole is sulfonated under similar conditions to pyrrole though in this case the 3-sulfonic acid is formed. Benzo[Z>]thiophene is also sulfonated in the 3-position (71AHC(13)235). 

Indigocarmine (2[l,3-dihydro-3-oxo-5-sulfo-2ff-indol-2-ylidene]-2,3-dihydro-3-oxo-lff-indole-5-sulfonic acid di-Na salt) [860-22-0] M 466.4, pK 2.8, pK2 12.3. Its... 

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. 

Treatment of l-ethylideneamino-3-methylindole 95 with p-toluene sulfonic acid in boiling benzene gave l,2-dihydro[l,2,4]triazino[l,6-a]indole 96 (75CPB2891). The reaction was said to be due to an initial formation of a Diels-Alder-type adduct followed by the liberation of 3-methylindole. Compound % was oxidized either on exposure to air or by the action of chloranil to give 97 (Scheme 24). 

In addition to the radical ipso-substitution of indolyl sulfones producing stannanes described earlier <96T11329>, Caddick has also reported an approach to fused [l,2-a]indoles based on the intramolecular cyclization of alkyl radicals. Thus, treatment of 112 with BuaSnH leads to the fused ring derivatives 113 (n = 1-4) <96JCS(P1)675>. 

Cyanine dyes also are used as labels for oligonucleotide probes. Unlike the hydrophilic cyanine dyes valuable for protein labeling, the use of dye-phosphoramidite compounds to synthesize DNA or RNA probes typically requires the use of more hydrophobic dye structures to make them compatible with the solvents and reactions of oligonucleotide synthesis. Thus, indol cyanines containing few or no sulfonates are used in these applications to label oligos for applications such as array detection, hybridization assays, and RT-PCR. 

A novel procedure for the synthesis of an indole skeleton 81 was developed by Mori s group (Scheme 13).16e,16f Enantioselective allylic amination of 78 with A-sulfonated < r/ < -bromoaniline 79 followed by Heck cyclization of 80 provided chiral indoline 81. The treatment of a cyclohexenol derivative 78 with 79 in the presence of Pd2(dba)3-GHGl3 and ( )-BINAPO gave compound 80 with 84% ee in 75% yield. Total syntheses of (—)-tubifoline, (—)-dehydrotubifoline, and (—)-strychnine were achieved from compound 80. 

An excellent synthesis of 5-bromo- (18) and 5-iodoindole (19) involves protecting the indole double bond as sulfonate 16, acetylation to 17, and halogenation [27]. Indoline itself undergoes bromination at C-4 and C-7 [28]. 

The corresponding reaction of diethyl 1,2-propadienyl phosphonates (sulfones or sulfoxides) with N-phenylhydroxylamine afforded a-anionic N-phenylvinyloxyamine 159, which upon [3,3]-sigmatropic rearrangement led to anionic 2-(2 -oxoalkyl)phe-nylamine 160. Further cyclization provides an efficient synthesis of indole derivatives 161 [84]. 

The indole chromophore of tryptophan is the most important tool in studies of intrinsic protein fluorescence. The position of the maximum in the tryptophan fluorescence spectra recorded for proteins varies widely, from 308 nm for azurin to 350-353 nm for peptides lacking an ordered structure and for denatured proteins. (1) This is because of an important property of the fluorescence spectra of tryptophan residues, namely, their high sensitivity to interactions with the environment. Among extrinsic fluorescence probes, aminonaphthalene sulfonates are the most similar to tryptophan in this respect, which accounts for their wide application in protein research.(5)... 

Anthracene-9-sulfonic acid, see Anthracene Anthranilic acid, see Azinnhos-methvl. Bentazone. Indole... 

The synthesis of 3- and 7-substituted indoles (184 and 185) by [3,3]-sigmatropic rearrangement of A-hydroxyindole derivatives (181) was reported (equation 54). A-hydroxyindole 181 in the presence of cyanogen bromide (182, R = Br, = N) and base afforded 183 that rearranged to the NCO substituted at position 3 and position 7, leading to two isomeric isocyanates, 184 and 185, respectively. Different behaviour was found when an acetylenic sulfone 182, R =11, R = CTos, was used where the 3-substituted indole 186 was the only rearrangement product identified. 

Hanaoka et al. reported a total synthesis of murrayaquinone A (107) based on an anionic [4+2] cycloaddition of the indole ester 864 with phenyl p-tiimethylsilylvinyl sulfone (865) (631). The reaction of the MOM-protected indole 864 with phenyl... 

Sulfonation of indole with pyridinium-A -sulfonate yields indolyl-3-sulfonic acid, and bromine in pyridine at 0 °C affords 3-bromoindole (Scheme 7.4). Acetylation with a heated mixture of acetic anhydride and acetic acid gives 1,3-diacetylindole. Methylation requires heating with methyl iodide in DMF (A,A-dimethylformamide) at 80-90 C and yields 3-methylindole. This compound reacts further, giving 2,3-dimethylindole and finally l,2,3,3-tetramethyl-3Ff-indoleninium iodide. 

In order to access the C-2 position, indirect methods of reaction are used, and a common procedure is to A-sulfonate indole with sodium hydride and benzenesulfonyl chloride and then to treat the derived sulfonate with butyllithium. C-2 deprotonation and lithiation occur (facilitated by chelation to the sulfonyl group) and the intermediate, without isolation, can then be reacted with a wide range of electrophiles at this site. Finally, the sulfonyl group can be hydrolysed off in a separate step to form the desired product (Scheme 7.10). 

The sulfones 367 (R = H and Me) obtained from 3-(indol-3-yl)propionate esters with the anion of dimethyl sulfoxide were cyclized, losing methylthiol, via 368 in the presence of p-toluenesulfonic acid in hot acetonitrile, ... 

In the first syntheses of CCK-related peptides that lack serine, threonine, or hydroxy-proline residues, sulfation of tyrosine residues was accomplished by treatment of the fully deprotected peptides with sulfuric acid. Under optimized conditions good separation between sulfated, sulfonated, and unreacted species (Scheme 2) was achieved using ion-ex-change chromatography. 3435 Sulfonation of the indole group, as observed in model studies/731 is apparently not a dominant side reaction. 

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