Radical-Based Arylation Methods

Santiago E. Vaillard, Birte SchuHe and Armido Studer 

Most radical reactions can be conducted under rruld conditions. In contrast to ionic reactions and many transition metal-mediated processes, most of the functional groups are tolerated under radical conditions. Moreover, radical reactions can be performed in various solvents even water is tolerated as a reaction medium. These facts, among others, make radical processes highly useful for arylations. Radical arylations can be performed using SsNl-type reactions, by homolytic aromatic substitutions, and by reactions of aryl radicals with various radical acceptors. In this chapter we first focus on SR Ttype reactions [1], and later concentrate on homolytic aromatic substitutions. Unfortunately, due to limitations of space, we cannot provide a comprehensive overview on this topic hence, for further information the reader is referred to some excellent reviews on this issue [2]. 

Modem Arylation Methods. Edited by Lutz Ackermann 

Copyright 2009 WILEY-VCH Verlag GmbH Co. KGaA, Weinheim 

Although some spontaneous or thermal SrnI reactions are known, in most of the cases initiation is necessary to trigger the process [4]. The most general method to initiate the chain reaction is the photoinduced ET from the nucleophile to the substrate (for a detailed discussion, see Chapter 14) (1). Other known methods of promoting SrnI reactions are the use of (i) alkali metals in liquid ammonia (ii) ferrous salts or (iii) electrochemistry. 

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Alkyl iodides have been widely used for selective alkylation of heteroaromatic bases. The method is based on rapid iodine abstraction by aryl radicals (obtained from benzoyl peroxide or diazonium salts) or by a methyl radical (obtained from MeCOOH, t-BuOH, t-BuOOH, (t-BuO)2, (MeCOO)2, MeS0Me/H202, or MeC0Me/H202) [2]. An example is depicted in Eq. (14) of Table 3. 

Aliphatic iodides, and especially secondary and tertiary representatives, are subject to hydride ehmination and are not generally useful substrates in transition metal catalysed coupling reactions. The last reaction in Scheme 14 [31], for instance, cannot be executed using current transition metal-based technology. In contrast, vinyl and aryl iodides, which are superb partners in many classical metal-induced couphng reactions, are very poor substrates in the present radical process because of the high energy of vinyl and aryl radicals. The two methods thus nicely complement each other. 

Another useful approach to styrenes via sp -sp -coupling reactions, which is beyond the scope of this section, is Meerwein-type arylations in which aryldiazonium salts undergo usually copper(I)- or palladium-catalyzed couplings with electron deficient alkenes, indicating a radical-based mechanism.The method is so useful for the synthesis of stilbenes from unsubstituted styrenes 92 or p>silylstyrenes. 93... 

Readily available Ifl-perfluoroalkanes can also be used for radical alkylation. This method employs, for example, thiazolyl iodide and 1/f-perfluoroalkane reagents, DMPU solvent, TMPjZn base, and a copper chloride/phenanthroline catalyst [8]. The reaction mechanism includes deprotonation of IH-perfluoroalkanes with TMPjZn to afford bis(perflnoroalkyl)zinc species. Subsequent transmetalla-tion with copper halide produces a mixture of anionic Cu species that reacts with aryl iodides (including thiazoles), either directly or via a neutral perfluoroalkyl compound, to give the coupling product. 

The production of aryl radicals from peroxides normally provides a cleaner method of arylation than the methods based on the decomposition of azo and diazo compounds, and, in the case of benzenoid compounds, better yields of arylated products are obtained. The... 

Cohen et al. (1977) recommend a new method for hydroxy-de-diazoniation. It is based upon an earlier observation (Lewin and Cohen, 1967) that aryl radicals, pro-... 

With the development of the cross coupling methodology, many 6-C-substituted purines have been prepared in the past decade. Thus, 6 halopurine derivatives react with arylmagnesium halides,25 alkyl(aryl)zinc or tin reagents,26 trialkylaluminum,27 or alkylcuprates28 to give the 6-alkylpurine derivatives. Also a reverse approach based on the reaction of purine-6-zinc iodide with aryl or vinyl halides has recently been described.29 For the synthesis of 6-arylpurines, an alternative approach makes use of radical photochemical reactions of adenine derivatives with aromatic compounds,30 but this method is very unselective and for substituted benzenes, mixtures of ortho-, meta-, and para substituted derivatives were obtained. 

Assessing on the whole the method of the production of alkyl- and aryl-chlorosilanes based on the interaction of alkyl- and arylchlorides with free silicon (i.e. direct synthesis), we should say that this method in comparison with metalorganic synthesis is more efficient, especially for the production of methyl- and phenylchlorosilanes. As for unsaturated chlorosi-lanes (vinyl- and allylchlorosilanes) and organochlorosilanes with higher radicals (hexyl-, heptyl-, octyl- and nonylchlorosilanes), no direct synthesis technique has yet been developed. 

In the original process using tin amides, transmetallation formed the amido intermediate. However, this synthetic method is outdated and the transfer of amides from tin to palladium will not be discussed. In the tin-free processes, reaction of palladium aryl halide complexes with amine and base generates palladium amide intermediates. One pathway for generation of the amido complex from amine and base would be reaction of the metal complex with the small concentration of amide that is present in the reaction mixtures. This pathway seems unlikely considering the two directly observed alternative pathways discussed below and the absence of benzyne and radical nucleophilic aromatic substitution products that would be generated from the reaction of alkali amide with aryl halides. 

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