Indoles radical attack

Radical reactions are facilitated by the fact that pyrroles and indoles can form reasonably stable radical cations in some cases. For instance, photoarylation of indole by 2-iodopyridine is controlled by a photochemical electron-transfer reaction leading to the combination of the indole radical cation and the 2-pyridyl radical. The direction of attack is controlled by the relative spin densities of the possible radical cations. In polar solvents, substitution is favored at positions 3,6, and 4, whilst in nonpolar solvents, there is a preference for substitution at positions 2 and 7 (Scheme 35) (88CPB940). 

Recently, Miranda and coworkers reported that tin hydride-mediated radical carbonylation can be applied to include the synthesis of ketones fused with heterocyclic rings, such as pyrroles and indoles. In the example given in run 10, an acyl radical attack at aromatic carbon and in situ oxidation leads to an indole-fused cyclopentanone in good yield [39]. On the other hand, an example shown in run 11 makes use of a methanesulfonyl group as a leaving radical [40]. When a related substrate which does not contain a sulfonyl substituent was used, a simple radical formylation took place. 

The catalytic mechanism for IDO and TDO is believed to proceed via the formation of a hydroperoxide at C-3 of the indole ring, followed either by dioxetane formation or Criegee rearrangement, as shown in Figure 26. Formation of the hydroperoxide could either take place via nucleophilic attack upon heme-bound dioxygen, or via the formation of an indole radical, followed by recombination with iron(III)-superoxide. The structure of human IDO was published in 2006. Site-directed mutagenesis of active site residues has established that Phe-226, Phe-227, and Arg-231 contribute toward catalysis. ... 

Wiest and co-workers have demonstrated that indole will participate in electron-transfer sensitized Diels-Alder reactions [14c, 41]. Irradiation of the electron-transfer sensitizer triphenylpyrylium tetrafluoroborate 21 in a methylene chloride solution containing indole, 1,3-cyclohexadiene and acetyl chloride yields the adduct 22 as an exo and endo mixture in a 1 3.3 ratio and a combined yield of 70% (Scheme 9) [14c,41a], Experiments are reported [14c, 41a] which demonstrate that the reaction proceeds by electron transfer from the indole to the excited sensitizer the indole radical cation produced then attacks the diene to give an intermediate 23 (Ri = = H) which, in conjunction with back-electron transfer from the... 

In the electron-transfer-sensitized reaction of the 2-vinylindole 27 with dienes it has been found that the indole rather than the diene usually [41c], although not always [41b], becomes the diene partner in the 2-1-4 cycloaddition reaction styrenes also add to 27 in this manner and the initial adducts are further oxidized to the carbazole 28 under the reaction conditions (Scheme 11) [41c]. Formation of the indole radical cation and its attack on the styrene to give intermediate 29 explains the regioselectivity observed. 

Photocarboxylation of the indole ring of N-methyl-2-phenylindole by carbon dioxide in the presence of amines to give N-methyl-2-phenylin-dole-3-carboxylic acid has been reported (Scheme 27), although the yield is very low [60], In this reaction, indole is thought to be the electron acceptor so that the product is formed by attack of the indole radical anion on carbon dioxide. 

The tetracyclic core of the berbane and alloyohimbane alkaloids has been accessed using xanthate-based radical chemistry [111]. The precursor xanthate 197 was prepared from tryptamine and then subjected to reflux conditions (1,2-dichloroethane or 2-propanol) in the presence of a catalytic amount of DLP. The resultant piperidones (198 and 200) generated via a 6-exo-trig cyclization were obtained in reasonable yields and accompanied by azepinone 199, the product of presumed radical attack on the 2-position of the indole. The alloyohimbane core was finally accessed through reductive Bischler-Napieralski conditions. 

Many compounds will undergo dimerization reactions those containing thiols (e.g., disulfide formation) olefins, alcohols, and carboxylic acids (or other carbonyl chemistry e.g., aldol condensation reactions). Indoles have been shown to dimerize under acidic conditions. The dimerization is presumed to occur as shown in Figure 120 via protonation at C3 and nucleophilic attack of a second indole on C2. Phenols have been shown to dimerize under free radical initiated oxidative conditions, usually to ortho phenols. Nalidixic acid API undergoes dimerization under thermolysis conditions to decarboxylate and produce a dimeric structure (Fig. 121) (172). 

As the azocinoindole 40 constitutes the tricyclic substructure of the indole alkaloid apparicine , we attempted to improve the cyclization yield. Satisfactorily, the regioselectivity was completely switched to the 8-endo mode when the alkene acceptor was substituted at the internal position by a bromine atom. Thus, cyclization of selenoester 43 led to the desired target 40 as the only reaction product in 75% yield. Clearly, the bromine atom not only sterically prevented the competitive 1-exo attack, but also benefited the cyclization by activation of the double bond. It should be noted that similar halogen-controlled 8-endo cyclizations are known in the literature, but involving amidyl-type radicals <06OL2647>. 

Chlorophenol is also reactive and irradiation in water leads to its conversion into resorcinoP" or in methanol to yield 3-methoxyphenol in 94% yield. Photoamidation with N-methylacetamide of 3-chlorophenol is also efficient and resnlts in the formation of the phenol 241 in a yield of 77%. Intramolecnlar amidation arises on irradiation of 242 in basic methanol. This resnlts in the formation of the indole derivative 243 as well as the methoxylated prodnct 244. More complex halophenols such as 245 are also photochemically reactive, but this yields a complex mixture of products including a benzofuran. The formation of this must be similar to the cychzations described earlier and involves the attack of a radical, produced by the C—I bond fission, on the other ring . 3-Nitrophenol is converted on irradiation in aqueous solution into a variety of products such as nitrocatechols, nitroresorcinol and resorcinol itself... 

Radicals such as benzyl and hydroxyl are unselective in their interaction with indoles, resulting in mixtures of products, so such reactions are of little synthetic use. On the other hand, benzoyloxylation of N-substituted indoles gives benzoates of indoxyl, i.e. it effectively oxidises the indole heterocyclic ring, via p-attack by the strongly electrophilic benzoyloxy-radical. In contrast, the weakly electrophilic radical derived from malonate reacts selectively at C-2, via an atom-transfer mechanism." "... 

BusSnH-mediated intramolecular arylations of various heteroarenes such as substituted pyrroles, indoles, pyridones and imidazoles have also been reported [51]. In addition, aryl bromides, chlorides and iodides have been used as substrates in electrochemically induced radical biaryl synthesis [52]. Curran introduced [4-1-1] annulations incorporating aromatic substitution reactions with vinyl radicals for the synthesis of the core structure of various camptothecin derivatives [53]. The vinyl radicals have been generated from alkynes by radical addition reactions [53, 54]. For example, aryl radical 27, generated from the corresponding iodide or bromide, was allowed to react with phenyl isonitrile to afford imidoyl radical 28, which further reacts in a 5-exo-dig process to vinyl radical 29 (Scheme 8) [53a,b]. The vinyl radical 29 then reacts in a 1,6-cyclization followed by oxidation to the tetracycle 30. There is some evidence [55] that the homolytic aromatic substitution can also occur via initial ipso attack to afford spiro radical 31, followed by opening of this cyclo-... 

Light-induced electron transfer from an indole to an alkyl, vinyl, or aryl halide would be expected to yield a radical anion which can ionize by loss of halide ion. This would give a radical that can attack an indole and so lead to products of substitution. Examples of this reaction for all three categories of halide have been observed. Photolysis of an aqueous methanol solution of indole with methyl chloroacetate gives a mixture of all the possible isomers of methyl indolylacetate in low yield. The 4-substituted isomer is formed in greatest amount (6.2%) and the yields of the six other isomers vary from 0.24 to 2.55% [62]. Photolysis... 

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