Hydrogen substitution reactions, radical-mediated

By far the most generally useful synthetic application of allyltributyltin is in the complementary set of transition metal- and radical-mediated substitution reactions. When the halide substrates are benzylic, allylic, aromatic or acyl, transition metal catalysis is usually the method of choice for allyl transfer from tin to carbon. When the halide (or halide equivalent) substrate is aliphatic or alicyclic, radical chain conditions are appropriate, as g-hydrogen elimination is generally not a problem in these cases. 

In this case, the intermediate vinyl radical (cf Scheme 9) underwent a remarkable [1,51-hydrogen abstraction from the non-activated C—H bond of the proximal isopropyl group. Furthermore, the resulting primary alkyl radical underwent a unique, stereoselective 5-endo-trig cyclization onto the adjacent double bond to generate a tertiary radical, which is a precursor of the highly substituted cyclopentanols 22 and 23. The reaction with Bu3SnH as radical mediator totally reversed the products ratio obtained in 88% yield, i.e. 22 23 = 19 81. 

To be effective as autoxidation inhibitors radical scavengers must react quickly with peroxyl or alkyl radicals and lead thereby to the formation of unreactive products. Phenols substituted with electron-donating substituents have relatively low O-H bond dissociation enthalpies (Table 3.1 even lower than arene-bound isopropyl groups [68]), and yield, on hydrogen abstraction, stable phenoxyl radicals which no longer sustain the radical chain reaction. The phenols should not be too electron-rich, however, because this could lead to excessive air-sensitivity of the phenol, i.e. to rapid oxidation of the phenol via SET to oxygen (see next section). Scheme 3.17 shows a selection of radical scavengers which have proved suitable for inhibition of autoxidation processes (and radical-mediated polymerization). 

The mechanism of photoinduced oxidation of aromatic compounds mediated by Ti02 in aqueous media is demonstrated by the reaction of 4-chlorophenol (601). Its degradation is principally based on oxidation by photocatalytically produced hydroxyl radicals, most likely adsorbed on the surface of a semiconductor catalyst.1554,1555 The initial reaction affords a 4-chlorodihydroxycyclodienyl radical 602, which releases the chlorine atom to form hydroquinone in a radical substitution reaction or loses the hydrogen atom via... 

Another interesting use of TEMPO has been in free-radical substitution of alkyl halides. In this reaction, halides react with tributyltin hydride and TEMPO to yield A-alkoxyamine substitution products [18. This reaction is especially attractive in cases where anionic nucleophiles are sterically prevented from carrying out substitution reactions. An example of this can be seen in Barrett s synthesis of sucrose [18b], in which a stereoselective iodoetherification reaction was used to produce neopentyl alkyl iodide 13 (Scheme 5). Free radical substitution mediated by tributyltin hydride and TEMPO yielded A-alkoxyamine 14. The mechanism [19] involves TEMPO abstraction of hydrogen from tributyltin hydride [20] the stannyl radical then abstracts iodide from the substrate, and a second equivalent of TEMPO traps the resulting carbon radical. 

However, their intermolecular addition reactions with alkynes are mostly aimed at synthesizing substituted aLkenes, ° and only very few cascade reactions that are initiated by P radical addition to C = C triple bonds have been reported. Renaud and coworkers developed a simple one-pot procedure for the cyclization of terminal alkynes mediated by dialkyl phosphites (Scheme 2.35). In this radical chain procedure, dialkyl phosphite radicals, (R0)2P =0, undergo addition to the C = C triple bond in 190, which triggers a radical translocation (l,5-HAT)/5-eAO cyclization cascade. The sequence is terminated by hydrogen transfer from dialkyl phosphite to the intermediate 194 and regeneration of P-centered radicals. 

The relative extent of dialkylation depends on the electrophilicity of RX (and the nucleophilicity of AR ) when a realtively fast SET (AE i/2 < 0.5 V) is the primary reaction. Other mechanisms may also satisfactorily explain the distribution of products. For instance, adduct formation between the alkyl radical and the mediator (acting as a radical trap) is possible and must be considered in such a case, further reduction of AR may take place, either by electron transfer or by abstraction of a hydrogen atom from the solvent. However, let us keep in mind that radical anions or dianions may act as nucleophiles, since a partial inversion of configuration of some optically active secondary RX compounds has been found [222] after workup under experimental conditions similar or identical to those of the electrolyses. Table 8 exemplifies alkylation reactions following a SET. The reaction scheme may be complicated by the fact that reduced forms of the mediator may act as a reducing nucleophile toward RX. The SET may then be assumed as the rate-determining step in aliphatic nucleophilic substitutions [223], and/or R generated in solution may be added to an electrophilic mediator, such as an activated ketone [224]. 

Electron Transfer. Neta and coworkers have worked extensively with halogen-substituted methyl peroxyl radicals (X H COO , where X = Cl, Br or F) in aqueous and non-aqueous media, using combinations of solvents in different ratios to change the polarity of the mixture. They describe the mechanism for the reaction of the water-soluble antioxidant Trolox with their peroxyl radicals as H-mediated electron transfer , having determined that the rate of the reaction increases with an increase in solvent polarity. They examined solvent polarity in terms of the dielectric constant of the solvent, e, and solvent basicity, reported as either the coordinate covalency parameter, f, which is a measure of solvent proton-transfer basicity, or the value, which is a measure of solvent hydrogen bond basicity . 

Manganese(III) can oxidize carbonyl compounds and nitroalkanes to carboxy-methyl and nitromethyl radicals [186]. With Mn(III) as mediator, a tandem reaction consisting of an intermolecular radical addition followed by an intramolecular electrophilic aromatic substitution can be accomplished [186, 187). Further Mn(III)-mediated anodic additions of 1,3-dicarbonyl and l-keto-3-nitroalkyl compounds to alkenes and alkynes are reported in [110, 111, 188). Sorbic acid precursors have been obtained in larger scale and high current efficiency by a Mn(III)-mediated oxidation of acetic acid acetic anhydride in the presence of butadiene [189]. Also the nitromethylation of benzene can be performed in 78% yield with Mn(III) as electrocatalyst [190]. A N03 radical, generated by oxidation of a nitrate anion, can induce the 1,4-addition of aldehydes to activated olefins. NOj abstracts a hydrogen from the aldehyde to form an acyl radical, which undergoes addition to the olefin to afford a 1,4-diketone in 34-58% yield [191]. 

A v ety of reactions are catalyzed by electrochemically generated Ni(0) (62). Electrochemical reduction of Ni(bipy)3Br2 affords a reagent that couples acid chlorides and alkyl or aryl halides to form unsymmetrical ketones (63). Symmetrical ketones are formed from alkyl halides and carbon dioxide (64). Reductive electrochemical carboxylation of terminal alkynes, enynes and diynes can be accomplished with 10% Ni(bipy)3(Bp4)2 in DMF (65-68). Terminal allies lead selectively to a-substituted acrylic acids. Electrocatalytic hydrogenation on hydrogen-active electrodes has been reviewed (69). Radical cyclizations of vinyl, alkyl and aryl radicals can be carried out by indirect electrochemical reduction with a Ni(II) complex as a mediator (70). 

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