Indole radical intermediate

As is broadly true for aromatic compounds, the a- or benzylic position of alkyl substituents exhibits special reactivity. This includes susceptibility to radical reactions, because of the. stabilization provided the radical intermediates. In indole derivatives, the reactivity of a-substituents towards nucleophilic substitution is greatly enhanced by participation of the indole nitrogen. This effect is strongest at C3, but is also present at C2 and to some extent in the carbocyclic ring. The effect is enhanced by N-deprotonation. 

Electron donating a-substituents favour the non-Kolbe reaction but the radical intermediates in these anodic processes can be trapped during co-electrolysis with an alkanoic acid. Anodic decarboxylation of sugar uronic acids leads to formation of the radical which is very rapidly oxidised to a carbonium ion, stabilised by the adjacent ether group. However, in the presence of a tenfold excess of an alkanoic acid, the radical intermediate is trapped as the unsymmetrical coupling product [101]. Highly functionalised nucleotide derivatives such as 20 will couple successfully in the mixed Kolbe reaction [102], Other examples include the co-electrolysis of 3-oxa-alkanoic acids with an alkanoic acid [103] and the formation of 3-alkylindoles from indole-3-propanoic acid [104], Anodic oxidation of indole-3-propanoic acid alone gives no Kolbe dimer [105],... 

As initially reported by Greci and coworkers83 and later by Greci, Eberson and coworkers84, l-methyl-2-phenylindole (22) treated with A-chlorobenzotriazole (BT-CI, 23) is monochlorinated to 24 and also yields dimeric structures, some of which themselves are chlorinated and dichlorinated (equation 56). Product 27 was mentioned only in the more recent paper. The mechanism in equation 57 was suggested in the initial paper. The formation of products 25-28 was ascribed to the interaction between various substituted indole-radical cations and adventitious water in the medium. The later study confirmed that the substituted indole-radical cation 22a is an intermediate and that the formation of... 

Indolines and indoles were prepared by a direct electrochemical reduction of arenediazonium salts. As a result, radical intermediates were generated from which 3,4-disubstituted tetrahydrofuran skeleta were constructed <02OL2735>. A short and stereoselective total synthesis of furano lignans was realized by radical cyclization of epoxides using a transition-metal radical source <02JOC3242>. Other preparations of tetrahydrofurans using radical cyclization include the synthesis of novel amino acids L-bis-... 

The reaction of indole (38) with copper(II) chloride also proceeds dirough a cation radical intermediate (39) to give mainly 2-chloroindole (40), together with a dimeric by-product (41), as shown in equation (15) ... 

Under the influence of UV light, 7V-methylindoles add dimethyl acetylenedicarboxylate, generating cyclobuteno-fused products,and even simple aUcenes add in an apparent 2 -t 2 fashion to A-acyl-indoles, but the mechanism probably involves radical intermediates Other photochemical additions to form N-benzoyl-indolines fused to four-membered rings include addition to the carbonyl group in benzophenone and the double bond in methyl acrylate "... 

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). 

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. 

It was noted above that the photolysis of indole and aldehydes in the solid state leads to diindolymethanes by a mechanism postulated to involve an oxetane intermediate (Scheme 14). The reaction also proceeds when aromatic aldehydes and indole or 2-methylindole are irradiated with UV light in acetonitrile solution (Scheme 28) [61]. Under these circumstances, it has been proposed that light-induced electron transfer from the indole to the aldehyde yields a ketyl radical anion and the indole radical cation. Proton transfers, coupling, and elimination of water can then yield an electrophilic alkylidene indolenine 65 which can react with indole thermally to give the observed product. 

Indole has been shown to undergo a Diels-Alder reaction with both endo- and exo-cyclic 1,3-dienes, in which electron transfer catalysis is provided using a triarylpyrylium cation as a sensitizer (Equation (83)) <90SL275,9UOC1405,93TL639l>. The adducts are generally mixtures of isomers, with endo predominating in the case of cyclohexadienes. The indole radical cation is postulated as an intermediate. 

The indole ring can act as a dienophile under the conditions of electron-transfer catalysis. In this mechanism, the indole radical cation is generated as a transient intermediate by single electron oxidation. Indole (58) and cyclohexadiene (59) react to give (60) in the presence of triarylpyrylium salts which act as photosensitizers. The reaction is carried out in the presence of acetyl chloride which traps and stabilizes the adduct (Equation (139)) <90SL275,91JOC1405>. 

Johnston demonstrated the applicability of a conceptually novel process for aryl amination using free radical intermediates for the preparation of indoles <010L1009>. In this approach, ketimines derived from o-bromophencthylamines 111 cyclize via a reductive 5-exo radical process to A -substituted indolines 112 when treated with n-BujSnH and a radical initiator. 

Matcha and Antonchick prepared a series of indoles, pyrazoles, and pyrid-azinones via the functionalization of alkenes in a cascade multicomponent process. An electrophilic trifluoromethyl radical added to the terminal position of olefin 119 to give radical intermediate 121. Then, in a Fischer indolization-like process, phenylhydrazone 122, through an ene-hydrazine, cyclized to aminoindoline 123. After elimination of ammonia, indole 120 was isolated in good yield (14AG(I)11960). 

In order to rationalize the mechanism of this reaction, firstly a CDC reaction involves the furane derivative, then a radical intermediate 30-A is produced and its addition to the first equiv. of indole leads to a radical species 30-B. A second SET process gives the substituted furane 30-C. Then, the double indolation can be explained by a Friedel-Crafts type allgrlation catalyzed by iron, which plays the role of a Lewis acid (Scheme 4.30). 

The reaction schemes shown in Figures 8, 9, 12 and 13 indicate that the oxidation chemistry of 5-HT and 5-HTPP is quite complex. Furthermore, radical intermediates and 4,5-dihydroxytryptamine derivatives are formed under very mild oxidizing conditions and such compounds are either expected to be or indeed are neurotoxic. Of all the other products of oxidation of 5-HT and 5-HTPP which have been thus far isolated only one, 5-hydroxytryptamine-4,7-dione (9), has been tested for its neurotoxic properties and it is clearly the most powerful indolic or catecholamine neurotoxin yet discovered. It does not, however, appear to exhibit any selective toxicity for particular neurons. Nevertheless, it seems probable that many other hydroxylated oxidation products of 5-HT, 5-HTPP and the other 5-hydroxyindoles found in the CNS might be neurotoxic. 

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