Heteroatomic radicals addition reactions

Electron transfer from the alkene leads to a radical cation that can undergo coupling (Scheme la). The radical cation can also react with the nucleophilic heteroatom of a reagent to afford addition or substitution products (Scheme lb). Adducts can be likewise obtained by oxidation of the nucleophile to a radical that undergoes radical addition. Reactions between alkenes and nucleophiles can be realized too with chemical oxidants that are regenerated at the anode (mediators) (see Chapter 15). Finally, cycloadditions between alkenes can be initiated by a catalytic anodic electron transfer. These principal reaction modes are subsequently illustrated by selected conversions. 

This chapter begins with an introduction to the basic principles that are required to apply radical reactions in synthesis, with references to more detailed treatments. After a discussion of the effect of substituents on the rates of radical addition reactions, a new method to notate radical reactions in retrosynthetic analysis will be introduced. A summary of synthetically useful radical addition reactions will then follow. Emphasis will be placed on how the selection of an available method, either chain or non-chain, may affect the outcome of an addition reaction. The addition reactions of carbon radicals to multiple bonds and aromatic rings will be the major focus of the presentation, with a shorter section on the addition reactions of heteroatom-centered radicals. Intramolecular addition reactions, that is radical cyclizations, will be covered in the following chapter with a similar organizational pattern. This second chapter will also cover the use of sequential radical reactions. Reactions of diradicals (and related reactive intermediates) will not be discussed in either chapter. Photochemical [2 + 2] cycloadditions are covered in Volume 5, Chapter 3.1 and diyl cycloadditions are covered in Volume 5, Chapter 3.1. Related functional group transformations of radicals (that do not involve ir-bond additions) are treated in Volume 8, Chapter 4.2. 

Most synthetically useful radical addition reactions pair nucleophilic radicals with electron poor alkenes. In this pairing, the most important FMO interaction is that of the SOMO of the radical with the LUMO of the alkene.36 Thus, many radicals are nucleophilic (despite being electron deficient) because they have relatively high-lying SOMOs. Several important classes of nucleophilic radicals are shown in Scheme IS. These include heteroatom-substituted radicals, vinyl, aryl and acyl radicals, and most importantly, alkyl radicals. 

Early examples of intramolecular aryl radical addition reactions to heteroatom containing multiple bonds included cyclizations on N=N and C=S moieties [52, 53]. Recently, cyclizations to imines have been used as part of a new enantio-selective approach to indolines (Scheme 8). In the first step of the sequence, the required ketimines 19 were obtained by phase-transfer catalyzed alkylation of 2-bromobenzyl bromides 20 with glycinyl imines 21 in the presence of a cincho-nidinium salt [54], Due to the favorable substitution pattern on the imine moiety of 19, the tributyltin hydride mediated radical cyclization to 22 occurred exclusively in the 5-exo mode. The indoline synthesis can therefore also be classified as a radical amination. 

Atom transfer reactions encompass a broad range of radical addition reactions in which C-heteroatom or heteroatom-heteroatom bonds are added across alkenes, alkynes, or other multiply bonded functionality. Atom transfer processes were first proposed [1] to account for the low degree of polymerization of polystyrene in CCI4... 

Second, since radical reactions lead to no displacements of charge, the electronegativities of the atoms involved play no role. The ease of addition to a double bond depends solely on the strength of its n component. Since CC 71 bonds are weaker than those involving heteroatoms, radical addition takes place most readily to C=C bonds. 

Intermolecnlar Additions. The radical chain nature and the anti-Markovnikov regiochemistry of radical addition reactions were originally discovered by Kharasch in the 1930s. Since then, these reactions have been used extensively for the formation of carbon-carbon and carbon-heteroatom bonds. Substrates that are suitable for the former include polyhalomethanes, alcohols, ethers, esters, amides, and amines. The prototypical examples compiled in Table 1 are from reviews by Walling and Ghosez et al. ... 

The hydrogen abstraction addition ratio is generally greater in reactions of heteroatom-centered radicals than it is with carbon-centered radicals. One factor is the relative strengths of the bonds being formed and broken in the two reactions (Table 1.6). The difference in exothermicity (A) between abstraction and addition reactions is much greater for heteroatom-centered radicals than it is for carbon-centered radicals. For example, for an alkoxy as opposed to an alkyl radical, abstraction is favored over addition by ca 30 kJ mol"1. The extent to which this is reflected in the rates of addition and abstraction will, however, depend on the particular substrate and the other influences discussed above. 

The effects of heteroatoms on autoxidation reactions are reviewed and discussed in terms of six phenomena (1) the effect on reactivity of a-hydrogens in the hydroperoxide chain mechanism in terms of electron supply and withdrawal (2) the effect on a-hydrogen acidity in base-catalyzed oxidation (3) the effect on radical ion stability in base-catalyzed redox chains (4) the possibility of heteroatom hydrogen bond attack and subsequent reactions of the resulting heteroradical (5) the possibility of radical attack on higher row elements via valence expansion (6) the possibility of radical addition to electron-deficient II and III group... 

In a similar manner, many additions of heteroatom radicals to unsaturated positions have been studied. In many cases, addition reactions of heteroatom radicals to alkenes are reversible and thermodynamically disfavored, but their occurrence is apparent. For example, the rapid addition and elimination of thiyl radicals to unsaturated fatty acid methyl esters results in isomerization reactions from which kinetic parameters can be obtained. Additions of group 14 (IV A) metal-centered... 

Addition reactions of carbon radicals to C—O and C—N multiple bonds are much less-favored than additions to C—C bonds because of the higher ir-bond strengths of the carbon-heteroatom multiple bonds. This reduction in exothermicity (additions to carbonyls can even be endothermic) often reduces the rate below the useful level for bimolecular additions. Thus, acetonitrile and acetone are useful solvents because they are not subject to rapid radical additions. However, entropically favored cyclizations to C—N and C—O bonds are very useful, as are fragmentations (see Chapter 4.2, this volume). 

Addition and substitution reactions of heteroatom-centered radicals with multiple bonds have been extensively studied and are sometimes preparatively useful.11 This section will briefly consider the addition reactions of H—Y and X—Y reagents (Kharasch reactions) and substitution reactions (Scheme S6).245... 

The 02 -elimination reactions maybe divided into three groups. Those peroxyl radicals that have an -OH or -NH function in the a-position make up the first group. Such peroxyl radicals play a major role in nucleobase peroxyl radical chemistry [cf. reactions (12) and (13)]. Upon deprotonation at die heteroatom by OH" [reactions (10) and (12)], the peroxyl radical anion is formed (cf. the enhancement of the acidity of the functions a to the peroxyl group discussed above for the thermodynamics of the various equilibria that are involved in these reactions see Goldstein et al. 2002). As before, the driving force for the elimination reaction is the formation of a double bond [in addition to the energy gain by the formation of the stabilized 02- radical [cf. reactions (11) and (13)]. 

Intramolecular addition of heteroatom radicals to olefins constitutes a convenient method for the synthesis of heterocycles. The photochemical ring closure reaction of oxyl radical derived from 44 provides access to tetrahydrofuran 45 [95JOC6706]. The regioselectivity in this cyclization is excellent, however, the stereoselectivity is only modest. The stereoselectivity was dependent on the temperature of the reaction. 

Meerwein type arylations involving radical additions to carbon-heteroatom multiple bonds such as in isothiocyanates have been further extended to tandem reactions leading to heterocycles [117, 118]. 

Atom-transfer reactions encompass a broad range of radical addition processes in which carbon-heteroatom bonds are added across alkenes, alkynes, or other... 

Both intermolecular and intramolecular additions of carbon radicals to alkenes and alkynes continue to be a widely investigated method for carbon-carbon bond formation and has been the subject of a number of review articles. In particular, the inter- and intra-molecular additions of vinyl, heteroatomic and metal-centred radicals to alkynes have been reported and also the factors which influence the addition reactions of carbon radicals to unsaturated carbon-carbon bonds. The stereochemical outcome of such additions continues to attract interest. The generation and use of alkoxy radicals in both asymmetric cyclizations and skeletal rearrangements has been reviewed and the use of fi ee radical reactions in the stereoselective synthesis of a-amino acid derivatives has appeared in two reports." The stereochemical features and synthetic potential of the [1,2]-Wittig rearrangement has also been reviewed. In addition, a review of some recent applications of free radical chain reactions in organic and polymer synthesis has appeared. The effect of solvent upon the reactions of neutral fi ee radicals has also recently been reviewed. ... 

More recently, a radical-mediated variation of this addition-fragmentation has been explored. The reaction, summarized in Scheme 77 for a one-carbon expansion, involves the generation of a radical at the terminus of a chain by homolytic cleavage of a carbon-heteroatom bond. Addition of the radical to the carbonyl produces a bicyclic intermediate, which on cleavage of the alternate bond regenerates the ketone carbonyl group with formation of a new radical. The sequence is terminated by the reduction of the radical with the tributyltin hydride reagent. The near neutral conditions of the reaction avoid the reclo-... 

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