Indoles regioselectivity

Still, there remain many open problems. It would be efficient to be able to prenylate or ferf-prenylate indole regioselectively at the benzene positions 4, 5 and 6 without having to rely on pre-functionalisation such as halogenation or hydroxylation. Here, deeper investigation of prenyl shifts and of CH functionalisation on indole is required. Enantioselective catalysis has to be explored further towards the synthesis of optically pure 3-prenylated or -tert-prenylated alkaloids. A chiral version of NBS would be helpful. In the case of conformationally flexible starting materials, the diastereoselectivity of oxidative cyclisations of tryptophan-derived diketopiperazines is still not convincing. In the area of chemoenzymatic synthesis, the number and availability of enzymes has to be enhanced and their substrate tolerance has to be elucidated in more detail. 

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]. 

The issue of regioselectivity arises with arylhydrazones of unsymmetrical ketones which can form two different enehydrazine intermediates. Under the conditions used most commonly for Fischer cyclizations, e g. ethanolic HCI, the major product is usually the one arising from the more highly substituted enehydrazine. Thus methyl ketones usually give 2-methy indoles and cycliz-ation occurs in a branched chain in preference to a straight chain. This regioselectivity is attributed to the greater stability of the more substituted enhydrazine and its dominance of the reaction path. 

Another issue of regioselectivity arises with meta-substituted arylhydrazones from which either 4- or 6-substitutcd indoles can be formed. Robinson has tabulated extensive data on this point[9]. A study comparing regioselectivity of cyclization as catalysed by HCl/EtOH and ZnClj was carried out for several m-substituted arylhydrazones of diethyl ketone[10]. The results given in Table 7.1 show some dependence on catalyst but mixtures are obtained under all conditions studied. 

As for regioselectivity in the electrophilic substitution reactions, we have assumed that introducing a methoxy group to the 1 position of indole nucleus might alter its positional reactivity. 

Acetylchloride is a trapping agent that allows the reaction to go completion, transforming the product into a less oxidizable compound.The results of other reactions between indole (57) and substituted cyclohexa-1,3-dienes show that the photo-induced Diels-Alder reaction is almost completely regioselective. In the absence of 59 the cycloaddition did not occur the presence of [2+2] adducts was never detected. Experimental data support the mechanism illustrated in Scheme 4.14. The intermediate 57a, originated from bond formation between the indole cation radical and 58, undergoes a back-electron transfer to form the adduct 60 trapped by acetyl chloride. 

The intramolecular Pummerer reaction has been applied to the synthesis of simple quinolizidine alkaloids like lupinine <2000JOC2368>, and also to arenoquinolizine alkaloids. Thus, the 2-(2-piperidyl)indole 284 was converted to indolo[2,3- ]quinolizidine 287 following a protocol that has as the key step the regioselective cyclization onto the indole 3-position of a thionium ion generated by Pummerer reaction from the appropriately substituted compound... 

Scheme 52 explains the [(Cp )Rh(MeCN)3]2+-assisted regioselective hydrogenation of pyridines, benzoquinolines, acridines as well as indoles and benzothiophene.258 The relative hydrogenation rates were attributed to both electronic and steric effects, the rate generally decreasing with increasing basicity and steric hindrance at the nitrogen atom. 

A type Ilac synthesis of functionalized pyrroles was developed that adapted the Larock indole synthesis <06OL5837>. For example, treatment of iodoacrylate 19 and trimethylsilylphenylacetylene 20 with palladium acetate led to the formation of pyrrole-2-carboxylate 21 with excellent regioselectivity. 19 was prepared by iodinating (N-iodosuccinimide) the corresponding commercially available dehydroamino ester. 

A versatile and regioselective synthesis of benzo[b]furans, naphthalenes, indoles and benzothiophenes was achieved by reaction of o-alkynylarene and heteroarene carboxaldehyde derivatives in the presence of iodonium ions. The reaction mechanism was also discussed <06CEJ5790>. 

Indolylborates 142 (Z = Me, Boc, OMe), available via regioselective C-2 lithiation of indoles 141, are capable of undergoing palladium-catalyzed carbonylative cross-coupling... 

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