Indoles substitution with ethylene

A large number of pyridazines are synthetically available from [44-2] cycloaddition reactions. In one general method, azo or diazo compounds are used as dienophiles, and a second approach is based on the reaction between 1,2,4,5-tetrazines and various unsaturated compounds. The most useful azo dienophile is a dialkyl azodicarboxylate which reacts with appropriate dienes to give reduced pyridazines and cinnolines (Scheme 89). With highly substituted dienes the normal cycloaddition reaction is prevented, and, if the ethylenic group in styrenes is substituted with aryl groups, indoles are formed preferentially. The cycloadduct with 2,3-pentadienal acetal is a tetrahydropyridazine derivative which has been used for the preparation of 2,5-diamino-2,5-dideoxyribose (80LA1307). 

Substitution of indoles with ethylene derivatives G G GHGR... 

The vast majority of indole alkaloids contain a tryptamine unit in which Nb is linked to the j9-position of the indole nucleus by an ethylene chain. On biogenetic grounds and also from the mass spectral similarity with aspidospermine (II), it is reasonable to expect this feature in the aspidofractinine-type alkaloids. Furthermore, in kopsine lactam A (CLXXV), in which C-ll is substituted by the C-3 bridge and C-10 has been oxidized (five-membered lactam), the residual hydrogen atom on C-ll shows as a singlet (2.82 S) in the NMR-spectrum and C-12 is therefore quaternary. 

Diarylindoles, e.g. (7), classified as heterocombretastatins with respect to the ethylene bridged diaryl structure and the 3,4,5-trimethoxy substitution pattern, displayed cytotoxicity especially towards leukaemia, non-small cell lung and CNS cancers [33, 43]. A modification of the tubulin inhibitor (8) [44] led to the thiophene and indole analogue (9) with remaining high cytotoxicity (ICso-values in the range of 10 to 100 nM) [45]. The structure of (9) also represents a fragment of the tetracyclic tubulin inhibitor (10) [46] that showed similar activity. 

An aqueous Friedel-Crafts reaction has also been used in polymer synthesis. The acid-catalyzed polymerization of benzylic alcohol and fluoride functionality in monomeric and polymeric fluorenes was investigated in both organic and aqueous reaction media. Polymeric products are consistent with the generation of benzylic cations that participate in electrophilic aromatic substitution reactions. Similar reactions occurred in a water-insoluble Kraft pine lignin by treatment with aqueous acid. A Bisphenol A-type epoxy resin is readily emulsified in aqueous medium with an ethylene oxide adduct to a Friedel-Crafts reaction product of styrene and 4-(4-cumyl)phenol as emulsifier.Electrophilic substitution reaction of indoles with various aldehydes and ketones proceeded smoothly in water using the hexamethylenetetramine-bromine complex to afford the corresponding Z A(indolyl)methanes in excellent yields.InFs-catalyzed electrophilic substitution reactions of indoles with aldehydes and ketones are carried out in water.Enzymatic Friedel-Crafts-type electrophilic substitution reactions have been reported. ... 

The regio- and stereochemical course of the [2+2] cycloadditions between 1-benzoylindoles and different monosubstituted olefins were briefly investigated. Interestingly, both methyl acrylate and vinyl acetate produced 1-substituted cyclo-but[h]indoles regioselectively (Scheme 3). In contrast, a distinct difference was observed between the two olefins when the stereochemical outcome of the cycloadditions was considered While there was a significant preference for the 1-exo-isomer 14 in the case of methyl acrylate, there was no stereoselectivity (ca. 1 1 mixtures of the endo- and cxo-isomers 17 and 18) when vinyl acetate was used as the cycloaddition partner [16], For further investigation of the stereochemical course of this reaction with 1,2-disubstituted ethylenes as well as cyclic olefins, see [17]. 

Reaction of l,3-dihydro-3-(2-phenyl-2-oxoethylidene)indol-2(l//)-one (820) with 2-aminobenzenethiols (746) to give 8-substituted-2,5-dihydro-l,5-benzothiazepin-2-spiro-3 -3 /f-indol-2 -(l /7)-ones 821 in 49-65% yields was induced under MWI conditions. Ethylene glycol was used as the energy-transfer medium and the reaction required 7-15 min (Scheme 155). However, conventional heating of 820 and 746 in ethanol saturated with hydrogen chloride for 4-6 h gave 51-52% yields (98JCR(S)752). 

Palladium nanoparticles, stabilized in micelles formed by polystyrene-co-poly(ethylene oxide) copolymer (PS-PEO) and acetylpyridinium chloride (CPC) as a surfactant, have been used to catalyze heterocyclization of N-methylsulfonyl-o-iodoaniline with phenylacetylene leading to formation of a substituted indole. The activity of the colloidal palladium catalytic system is comparable to that of the low-molecular-we ht palladium complexes, whereas the stabUity of the colloidal palladium system is much h her. The reuse of the catalyst PS-PEO-CPC was demonstrated in experiments with fresh starts as well as by thermomorphous separation of the catalyst from products (20060M154). 

Aryl-lH-indol-3-carbaldehyde derivatives underwent Claisen-Schmidt condensation with different acetophenones in ethylene glycol and few drops of piperidine under microwave irradiation. The reaction proceeded within 3-10 min at 750 W to afford substituted 3-(2-aryl-lH-indol-3-yl)-prop-2-en-l-one derivatives, which react with phenylhydrazine in absolute ethanol and few drops of glacial acetic acid under microwave irradiation at 350 W in 1-2 min with successive periods of 30 sec to afford the corresponding indolylpyrazoline analogs (Zahran et al., 2010). On the other hand, the conventional method requires 9-12 h. 

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