Substitutions Involving Aryl Radicals

Substitution reactions involving aryl radicals have been quite important in synthesis. The reason, in part, is that the resistance of aryl halides and related compounds to nucleophilic substitution greatly restricts the utility of Sn2 processes for synthetic purposes. Radical substitution reactions can be carried out with any of the sources of aryl radicals mentioned in Section 12.1.4, but acylnitrosoanilines and aryl diazonium compounds have been most widely used in synthesis. The decomposition of acylnitrosoanilines is a relatively complex process. The principal points of evidence supporting the mechanism shown below have been briefly reviewed  

The radical-generating step is a special case of the decomposition of an azo compound. An important use for this reaction is in the synthesis of biphenyls, by reactions in which a second aromatic molecule is attacked by the aryl radical. Under these conditions, hydrogen abstraction from the intermediate arylcyc-lohexadienyl radical becomes part of the chain mechanism, with the aryl diazonium ion oxidizing the radical intermediate to give the biphenyl. Aryl diazonium ions generated in the usual way by diazotization of aryl amines can also serve as sources of aryl radicals. Substituted biphenyls can be synthesized by base-catalyzed decomposition of the diazonium salt, usually in the presence of an excess of the aromatic substrate  

The final product is either the substituted alkene or the halide which results from capture of the intermediate cation by chloride ion. 

Another convenient source of aryl radicals involves reaction of aromatic amines with an alkyl nitrite in organic solvent. The nitrosated aniline is the precursor of the radical  

The radicals generated in this way have been used to synthesize biphenyls. NH2 

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SECTION 7.3 SUBSTITUTIONS INVOLVING ARYL FREE RADICALS... 

Most of the subsequent work on this reagent was concerned with the formation of aryl radicals (see review by Cadogan, 1971). However, 2-terf-butyl-A-nitrosoacet-anilide was found to decompose in benzene to give, instead of 2-tert-butylbiphenyl, as expected for a substitution of benzene by a 2-tert-butylphenyl radical, a mixture of isomeric tert-butylphenyl acetates. A careful reexamination (Cadogan and Hib-bert, 1964) suggested that the ratio of 2- and 3-tert-butylphenyl acetates was consistent with the involvement of 2-tert-butylbenzyne, i.e., the product of an ionic dediazoniation, as an intermediate. This was later confirmed by trapping experiments designed to detect aryne intermediates. 

According to these conclusions, it is possible to propose a catalytic cycle (Fig. 20) involving no radical species, but a copper(I) complex with the classical oxidative addition, nucleophilic substitution and reductive elimination resulting lastly in the arylated nucleophile. 

In Entry 9, the initial reaction involves 5-exo addition of the aryl radical to the more-substituted end of the cyclohexene double bond, followed by a 6-endo addition to the phenylthiovinyl group. The reaction is completed by elimination of the phenylthio radical. The product is an intermediate in the synthesis of morphine. 

A more intriguing type of competition is due to radical processes, which usually involve the substrate radical anion. These can fragment, if they carry a suitable substituent, via anion expulsion.56 The resulting aryl radical, Ar, can form the reduced product, ArH, by hydrogen abstraction57 or the product of substitution via reaction with the nucleophile according to the SrnI mechanism, discussed in Chapter 2.2 of this volume. Examples of competition between SnAt and radical processes of this type have been reported.57-59... 

The use of hypervalent iodine reagents in carbon-carbon bond forming reactions is summarized with particular emphasis on applications in organic synthesis. The most important recent methods involve the radical decarboxylative alkylation of organic substrates with [bis(acyloxy)iodo]arenes, spirocyclization of para- and ortho-substituted phenols, the intramolecular oxidative coupling of phenol ethers, and the reactions of iodonium salts and ylides. A significant recent research activity is centered in the area of the transition metal-mediated coupling reactions of the alkenyl-, aryl-, and alkynyliodonium salts. 

A key step in a synthetic approach to 2-substituted 5-arylpiperidines has involved a radical 1,4-aryl transfer that proceeds by the mechanism depicted in Scheme 33.56... 

Ring closure reactions taking place by intramolecular addition of an aromatic radical to a double bond have been widely studied on both their regio- and stereochemical aspects [93]. Aryl halides and diazonium salts substituted at ortho- position with a 0-allyl or TV-allyl chain were used for the preparation of 2,3-dihydrobenzofuranes and 2,3-dihydro-1/7-indoles under different reaction conditions. The reaction pattern involves the generation of an aryl radical 20, which reacts with the double bond in a 5-exo trig fashion to afford the exocyclic radical 21, plausible of reduction by a hydrogen donor to obtain the reduced-cyclized product 22 (Sch. 23) [93d,94]. 

This is the generally accepted scheme but, according to a recent reexamination of various experimental results a reconsideration of the mechanism is possible. In certain cases at least, a nucleophilic substitution on the intermediate radical anion has also to be considered [100] and with another chain mechanism made of steps (11) and (12), the aryl radical intermediate no longer needs to be involved ... 

The best known PET bond cleavage reaction involves the substitution of aryl halides by the S l mechanism. This mechanism was first recognized by Bunnett and Rossi in 1970 [55]. The SRN1 mechanism [56,57] requires one-electron reduction of an aryl halide to initiate the substitution reaction. The anion-radical undergoes... 

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