Indoles sensitivity

The reaction conditions applied are usually heating the amine with a slight excess of aldehyde and a considerable.excess of 2d-30hydrochloric acid at 100 °C for a few hours, but much milder ( physiological ) conditions can be used with good success. Diols, olefinic double bonds, enol ethers, and glycosidic bonds survive a Pictet-Spengler reaction very well, since phenol and indole systems are much more reactive than any of these acid sensitive functional groups (W.M. Whaley, 1951 J.E.D. Barton, 1965 A.R. Battersby, 1969). 

From the perspective of laboratory practice, the sensitivity of many indoles to acids, oxygen and light prescribes the use of an inert atmosphere for most reactions involving indoles and the avoidance of storage with exposure to light. This sensitivity is greatly attenuated by electron-withdrawing (EW) substituents. 

As illustrated in Scheme 8.1, both 2-vinylpyrroles and 3-vinylpyiroles are potential precursors of 4,5,6,7-tetrahydroindolcs via Diels-Alder cyclizations. Vinylpyrroles are relatively reactive dienes. However, they are also rather sensitive compounds and this has tended to restrict their synthetic application. While l-methyl-2-vinylpyrrole gives a good yield of an indole with dimethyl acetylenedicarboxylate, ot-substitiients on the vinyl group result in direct electrophilic attack at C5 of the pyrrole ring. This has been attributed to the stenc restriction on access to the necessary cisoid conformation of the 2-vinyl substituent[l]. 

A reaction of mixed molybdenum polyoxometalates (POMs) with cyanine dye has been used for highly selective and sensitive spectrophotometric determination of phosphorus(V) and arsenic(V). Color of the solution is considerably changed by reaction of Keggin POMs with styrene cyanine dyes. Derivatives of l,3,3-threemethyl-3//-indol - astrazone violet (AV 3R), astrazone rose, astrazone yellow, astrazone red were investigated. 

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. 

The isolated cr -adducts 57 undergo oxidation with KMn04 easily, resulting in the corresponding 5-indolyl-1,2,4-triazine 4-oxides 60 (98ZOR429). Separating the nucleophilic addition step from the oxidative aromatization of the intermediate (T -adducts allows the use of such oxidant-sensitive nucleophiles as indoles. 

Curiously, the ring expansion fails in sulfuric, trifluoroacetic, trichloroacetic, and orthophos-phoric acid. The reaction is sensitive to substituents both in the TV-aryl group and in the 2-and 3-positions of the indole nucleus. For example, 3-methyl-l-phenylindole yields a mixture of 10-methyl-5//-dibenz[/t,/]azepine (34% mp 129-131X) and 2-mcthyl-l-phenylindole (57%). In contrast, 2-methyl-l-phenylindole and 2,3-dimethyl-l-phcnylindole fail to ring expand. The reaction also fails with electron-withdrawing groups (N02 and CF3) in the TV-phenyl ring. 

Table 4.13 Photoinduced Diels-Alder reactions of indoles 64 and dienes 61-63 with sensitizers 59 and 65...

Dimethylamino)-benzaldehyde — hydrochloric acid reacts less sensitively than 4-(dimethylamino)-cinnamaldehyde — hydrochloric acid in the detection of indole derivatives, but the former is better for differentiation of substances on account of the multiplicity of different color shades produced. 

Evidently the reaction of the indoles investigated with fuming hydrochloric acid is less sensitive as is the case for the two other vanillin reagents. 

Bacteria which are almost always sensitive to the sulphonamides include Strep, pneumoniae, /3-haemolytic streptococci, Escherichia coli and Proteus mirabilis those almost always resistant include Enterococcus faecalis, Ps. aeruginosa, indole-positive Proteus and Klebsiella whereas bacteria showing a marked variation in response include Staph, aureus, gonococci, El. influenzae and hospital strains of E. coli and Pr. mirabilis. 

The reaction tolerates a variety of functional groups, especially the acid-sensitive acetal (81b), carbamate (81c) and the benzyl triazole (81d-f, and 81h, j). These intermediates, which are unstable under the conditions of the traditional Fischer indole reaction, were conveniently synthesized using this method. The structurally... 

Table 4 illustrates the use of the CAR technique to develop CL kinetic-based determinations for various analytes in different fields. As can be seen, the dynamic range, limit of detection, precision, and throughput (—80-100 samples/ h) are all quite good. All determinations are based on the use of the TCPO/ hydrogen peroxide system by exception, that for p-carboline alkaloids uses TCPO and DNPO. A comparison of the analytical figures of merit for these alkaloids reveals that DNPO results in better sensitivity and lower detection limits. However, it also leads to poorer precision as a result of its extremely fast reactions with the analytes. Finally, psychotropic indole derivatives with a chemical structure derived from tryptamines have also been determined, at very low concentrations, by CAR-CLS albeit following derivatization with dansyl chloride. 

Greenbeger LM, Annable T, Collins KI, Komm BS, Lyttle CR, Miller CP, et al. (2001) A new antiestrogen, 2-(4-hydroxy-phenyl)-3-methyl-l-[4-(2-piperidin-l-yl-ethoxy)-benzyl]-lH-indol-5-ol hydroclorhide (ERA-923), inhibits the growth of tamoxifen-sensitive and -resistant tumors and is devoid of uterotropic effects in mice and rats. Clin Cancer Res 7 3166-3177... 

Snyder and coworkers followed a completely different path to canthin-6-one (Fig. 23). Earlier they had shown that indole-substituted 1,24-triazine 66 could be heated in refluxing triisopropylbenzene (bp = 232 °C) to give /3-carboline 67 via an intramolecular cycloaddition/cycloreversion reaction [58]. Selective oxidation of 67 at C-6 was achieved through the use of triethylbenzylammonium permanganate [59]. Success of the reaction proved to be very sensitive to the solvent chosen. Heating 67 for 4 h at 70 °C in a 5 1 mixture of dichloromethane and acetic acid gave a 65% yield of 63, yet use of increasing amounts of dichloromethane slowed the reaction down (no reaction occurred in pure dichloromethane), while use of pure acetic acid led to an intractable mixture. 

Warbritton, J. D., Ill, Stewart, R. M., and Baldessarini, R. J. (1980) Increased sensitivity to intracerebroventricular infusion of serotonin and deaminated indoles after lesioning rat with dihydroxytryptamine. Brain Res., 183 355-366. 

The indole group of tryptophan is inert to activation and aminolysis reactions, so it does not have to be protected for constructing a peptide. It is sensitive, however, to... 

J. R. Lakowicz and S. Heating, Binding of an indole derivative to micelles as quantified by phase-sensitive detection of fluorescence,/. Biol. Chem. 5519-5524(1983). 

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)... 

Vaarman A, Kask A, Maeorg U. 2002. Novel and sensitive high-performance liquid chromatographic methods based on electrochemical coulometric assay detection for simultaneous determination of catecholamines, kynure-nine and indole derivatives of tryptophan. J Chrom B 769 145-153. 

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