Indoles with radicals

Tryptophan and its derivatives such as the Hoechst compounds (Adhikary et al. 2000) have reduction potentials below that of G (tryptophan E7 = 1.0 V Jovanovic and Simic 1985) and thus are capable of repairing some of the DNA damage (for a review on indol free-radical chemistry see Candeias 1998 for the thermochemistry of N-centered radicals see Armstrong 1998). In these reactions, radical cations and N-centered radicals are formed. Similar to phenoxyl radicals, these radical react with 02- mainly by addition despite the large difference in the redox potential which would allow an ET as well (Fang et al. 1998). 

Figure 4 13C KIEs for the radical-cation catalysed Diels-Alder reaction of indole with cyclohexadiene.

Pyrroles, furans, and thiophenes react preferentially with radicals at the 2-position. Thus, reaction of pyrrole with benzyl radicals gives 2-benzylpyrrole. In rather better yields, pyrrole and indole treated with per(poly)fluoroalkyl chlorides (RfCI) in the presence of sodium dithionite in DMSO produce 2-perfluoroalkyl products <2001JFC(111) 107>. Furans trap aryl radicals, generated from the Mn(OAc)3 oxidation of arylboronic acids <2003JOC578> or... 

An explanation can be found in terms of the much lower reduction potential of the indole-type radical cations as compared to the phenylalkanoic acid ones, which results in a greater stabilization of the positive charge on the aromatic system thus opposing intramolecular electron transfer. In other words, a later transition state is expected in the decarboxylation of indole-type radical zwitterions as compared to the phenylalkanoic acid ones, with an increased importance of the stability of the carbon centered radical. 

Reactions of indoles with inorganic radical ions 79UK1968. Spiroindolenines as intermediates 78H(9)1O89. 

Fig. 4. Transient absorption spectra of indole cation radical produced by exciting the acetonitrile solution with the 4th harmonic of the ps Nd ...

The transient absorption spectra similar to that of the ion-pair state of indole cation radical and flavin anion radical were also observed in D-amino acid oxidase (5), although the spectra were not so clear as those of flavodoxin. In D-amino acid oxidase, the coenzyme, flavin adenine dinucleotide (FAD), is wealtly fluorescent. The fluorescence lifetime was reported to be 40 ps (16), which became drastically shorter (less than 5 ps) when benzoate, a competitive inhibitor, was combined with the enzyme at FAD binding site (17). The dissociation constant of FAD was also marlcedly decreased by the binding of benzoate (17). These results suggest that interaction between isoalloxazine and the quencher became stronger as the inhibitor combined with the enzyme. Absorbance of the transient spectra of D-amino acid oxidase-benzoate complex was remarkably decreased. In this case both rate constants of formation and decay of the CT state could become much faster than those in the case of D-amino acid oxidase free from benzoate. 

Reaction of 3-substituted indoles with halogens can be more complex initial 3-halogenation occurs generating a 3-halo-3//-indole, ° but the actual products obtained then depend upon the reaction conditions, solvent etc. Thus, nucleophiles can add at C-2 in the intermediate 3-halo-3//-indoles when, after loss of hydrogen halide, a 2-substituted indole is obtained as final product, for example in aqueous solvents, water addition produces oxindoles (20.13.1) comparable methanol addition gives 2-methoxyindoles. 2-Bromination of 3-substituted indoles can be carried ont nsing A -bromosuccinimide in the absence of radical initiators. 2-Bromo- and 2-iodo-indoles can be prepared very efficiently via a-lithiation (20.5.1). 2-Halo-indoles are also available from the reaction of oxindoles with phosphoryl halides. Some 2,3-diiodo-indoles can be obtained by iodination of the indol-2-ylcarboxyfic acid. ... 

Chlorination of indoles with CBT is a radical process with intermediate formation of indole radical cation followed by its reaction with chlorine radical (82JOC4895) or chloride anion [91JCS(P2)1779] (Scheme 49). 

Oxidation of the [Pd(tbu-iepp-cX l] and [Pd(p-iepp-c)Cl] complexes shown in Fig. 20 with 1 equiv of Ce(TV) afforded the corresponding one-electron oxidized species (76). (Htb-iepp = 3-[iV-2-pyridylmethyl-iV-2-hydroxy-3,5-di(-tcrt-butyl)benzylamina] ethylindole H p-iepp = 3-(iV-2-pyridylmethyl-iV-4-hy-droxybenzylamine] ethylindole H denotes a dissociable proton and tbu-iepp-c p-iepp-c and tbu-iepp-c denote p-iepp and tbu-iepp bound to Pd(ll) through a carbon atom respectively (76). The EPR spectroscopy (one sharp signal at g = 2.004) and absorption spectroscopy (peak at 550 nm) are consistent with an indole n radical rather than a Pd(lll) or a phenoxyl radical. 

The photochemical cyanoethylation of indoles has been the subject of two reports from the same group within the year. Irradiation of the heterocyclic compounds in the presence of acrylonitrile yields various substituted isomers, dependent upon the substitution pattern in the indole starting material.112 Indole and acrylonitrile in acetonitrile as solvent give 8% of l-(l-cyanoethyl)-indole and 12% 3-(l-cyanoethyl)indole.113 Reaction of indoles unsubstituted at the nitrogen occurs in both methanol or acetonitrile as solvent, but 7V-methyl-indoles are only labile in methanol thus proton transfer is suggested to be an important step.112 The intermediacy of an exciplex is proposed and the observed high reactivities of the 3- and 4-positions of the indoles correlate with the calculated spin densities of the indole cation-radical. 

Indoxyl reacts further by radical coupling followed by oxidation to give indigo. Other oxidizing agents, as well as air, cause such reactions. On oxidation, indoles with substituents in the 3-position are converted into indol-2(3//)-ones (oxindoles) ... 

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... 

Another kind of tandem cyclization was observed when 1-benzoyl indoles with 3-EW substituents reacted with dimethyl malonate and Mn(0Ac)j. Tetracyclic products are obtained in good yield. <94TL1283> It is presumed that the reaction involves initial attack by the b/s-carbomethoxymethyl radical on the indole ring at C2, followed by a second oxidation and cyclization. 

A study of the stereoselectivity of the radical-cation Diels-Alder reaction of indole with the diene 139 gave a mixture of both cis and trans adducts. This lack of stereospecificity is consistent with other evidence that the radical-cation cycloaddition is non-concerted. <93TL6391>... 

Following their investigation on the reactivity of 2-indolyl radicals, Jones (00TL4209) reported on their intramolecular addition reactions to benzene rings tethered to the nitrogen of the indole with various length chains (Scheme 28). 

In aqueous solutions and at room temperature, the hydrated electron e q is formed along with the Indole cation radical IH. ... 

Radical addition reactions were also recently added to the repertoire of 2-nitroin-dole (21), previously dominated by nucleophilic reactions [17]. Treatment of the indole with activated methylene compounds such as dimethyl malonate, malonitrile and pentane-2,4-dione in a refluxing solution of Mn(0Ac)3-2H20 in acetic acid gave mainly 2-oxo-indolin-ylidenes 22 after an in situ Nef reaction. The expected 3-subsitiuted 2-nitroinole 23, however, was only observed with the methine compounds 3-methylpentane-2,4-dione and 5-oxo-4-propionyUieptane-nitrile. 

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