Indoles acid-sensitive

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). 

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... 

As part of a programme of studies on the synthesis of mitomycins, the dione 1 was treated with sodium hydride in dry THF at room temperature. This gave an epimeric mixture of carbinolamines which was highly acid sensitive and which, on treatment with glacial acetic acid at room temperature for 5 minutes, underwent dehydration to the tricyclic indole derivative 2. 

The highly efficient Michael addition of acid sensitive substrates such as pyrrole and indoles to stmcturally diverse electron-deficient olefins in aqueous media at room temperature using aluminium dodecyl sulfate trihydrate, [A1(DS)3]-3H20, as a new Lewis acid surfactant catalyst affords 2-substituted pyrroles 442-445 (Scheme 95) and... 

Cyclization of indol-2-yl acyclo C-nucleosides that carry acid-sensitive... 

Amine Complexes. The pyridine —SO 3 complex has proved broadly applicable in the laboratory for the sulfonation of certain acid-sensitive ( acidophobic O compounds. This is in fact the preferred procedure for sulfonating five-membered heterocyclic compounds including furan, pyrrole, indole, thiophene, coumarone, and many of their derivatives. Yields are generally good (70-90 per cent), and the technique is simple (heating in a sealed tube at 80-140 C in the presence or absence of a solvent such as ethylene dichloride). The same method also works well in the sulfonation of alkadienes. Butadiene, for instance, yields the 1-sulfonic acid in fair yield. ... 

Cyclization of indol-2-yl acyclo C-nucleosides that carry acid-sensitive O-protective groups such as 11 has been successfully achieved without affecting these groups by dehydration with triphenylphosphine-diethyl azodicarboxylate-iodine a mixture of anomeric C-nucleosides (12) was usually produced [94CL265 95JAP(K)95/118268] (Scheme 4). 

Aminoalkylindoles are generally synthesized by following either Method A or Method B as depicted in Scheme 12(65,66). An appropriately functionalized indole was aroylated in the first step followed by A-alkylation (Method A). Alternatively, A-alkylation could be accomplished first, followed by aroylation of the resulting indole derivative at C3 (Method B). For acid-sensitive analogs, EtAlCl2 is used in place of AICI3 in Friedel-Crafts acylation. 

Amines or amine extracts (1-5 mg) are treated with 500 jA of acetonitrile and 50 y of anhydride for 5 minutes at room temperature. These conditions are best, particularly with indole compounds, which are acid-sensitive [68]. More usually, a 1 1 mixture of acetonitrile and anhydride is used at 60 °C for up to 20 minutes, depen-ing on the substances to be derivatized. It may be possible to use lower temperatures and shorter reaction times the best thing is to work out optimal reaction conditions with pure compounds first [67, 70]. Excess solvent and anhydride are completely removed in vacuo, or the reaction mixture is blown dry with nitrogen, and the dried residue is dissolved in ethyl acetate (if required, the solvent may contain an injection standard) for analysis [71, 72]. Removal of excess reagent is essential before injection into a GC with an ECD, because if reagent gets into the detector it will saturate it for a long... 

Indoleamines and indole alcohols, typically acid-sensitive compound, may be smoothly acylated with HFB-imidazole. The indolic compounds (1—2 mg) are dissolved in HFB-imidazole (100—200 fil) and heated in a reaction vial with a PTFE-lined screw-cap at 80 °C for 2-3 hours. After cooling, the products are extracted into hexane (3x5 ml). The hexane extracts are combined and chilled to —14 "C to precipitate residual reagent. The hexane layer is decanted, the precipitate is washed with hexane and the combined hexane solutions are concentrated to 500 1 for analysis by GC (113, 114]. Alternatively, excess reagent may be decomposed with water (1 ml) in the presence of toluene (2 ml), the aqueous layer being extracted with three further 2 ml portions of toluene. These extracts are washed once more with water, separated and filtered through filter paper before concentration for analysis [115,116). A novel way of separating the layers is to freeze the two layers in a solid COj/acetone bath and to withdraw the upper layer from the ice with a Pasteur pipette [117[. Phenolic acids, after esterification, may be acylated in a similar procedure, but here with 10% PFP-imidazole in ethyl acetate for 10 minutes at 70 °C [118]. 

Dimethyl sulfoxide containing cyclohexylcarbodiimide and an acid, such as phosphoric acid, is increasingly used as a mild selective oxidant . Also a mixture of dimethyl sulfoxide and an acid anhydride, e.g. acetic anhydride, has been found useful for the oxidation of sterically hindered hydroxyl groups and compounds, such ascertain indole akaloids, sensitive to non-selective oxidants . ... 

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. 

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. 

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. 

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. 

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. 

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