Coupling radical-nucleophile

Asymmetric synthesis of amino acids.1 These lactones can serve as an optically active form of glycine for synthesis of either D- or L-amino acids. Thus (+ )-1 (or (—)-l) on radical bromination is converted into a single monobromide (2), which can be coupled with nucleophilic organometallic reagents, by either an SN1... 

While a large number of studies have been reported for conjugate addition and Sn2 alkylation reactions, the mechanisms of many important organocopper-promoted reactions have not been discussed. These include substitution on sp carbons, acylation with acyl halides [168], additions to carbonyl compounds, oxidative couplings [169], nucleophilic opening of electrophilic cyclopropanes [170], and the Kocienski reaction [171]. The chemistry of organocopper(II) species has rarely been studied experimentally [172-174], nor theoretically, save for some trapping experiments on the reaction of alkyl radicals with Cu(I) species in aqueous solution [175]. 

Substitutions by the SRn 1 mechanism (substitution, radical-nucleophilic, unimolecular) are a well-studied group of reactions which involve SET steps and radical anion intermediates (see Scheme 10.4). They have been elucidated for a range of precursors which include aryl, vinyl and bridgehead halides (i.e. halides which cannot undergo SN1 or SN2 mechanisms), and substituted nitro compounds. Studies of aryl halide reactions are discussed in Chapter 2. The methods used to determine the mechanisms of these reactions include inhibition and trapping studies, ESR spectroscopy, variation of the functional group and nucleophile reactivity coupled with product analysis, and the effect of solvent. We exemplify SRN1 mechanistic studies with the reactions of o -substituted nitroalkanes (Scheme 10.29) [23,24]. 

Support for a relatively slow C-C coupling for nucleophilic radicals also arises from observation of the NMR spectra of TTF reactions. Here, a few percent of the C-C coupled products are frequently seen, indicated by the very downfield signals of the dithiazolium ring protons. 

The radical nucleophilic substitution is perfectly suited for tandem reactions [180]. Recent examples have been reported by the Rossi group (Scheme 66). Dihydrobenzofuranes and dihydroindoles substituted at the 3-position were prepared from ortho-functionalized haloaromatic compounds in high yields [181]. The nucleophiles involved in the initial electron transfer and subsequent coupling are varied. In particular, starting form naphthyl derivative 210, phosphinyl anions lead to tricyclic phosphine oxide 211 (after oxidation) in 98% yield. 

Because both radical-nucleophile and radical-radical coupling (electropolymerization [316]) can occur under anodic conditions mechanistic differentiation is often difficult. Under chemical oxidation [279b] and PET conditions [279a], however, only radical-nucleophile coupling is encountered. Intermolecular [280] and intramolecular [281] C-C bond formation used for biomimetic atroposelective coupling [282] and for natural product synthesis [283] is nowadays a well-established synthetic tool. 

Intramolecular coupling or nucleophilic substitutions sometimes occur upon oxidation of the cation radical the new product frequently then undergoes an additional anodic electron-transfer reaction to yield a new cation radical. For example, tri-p-substituted triphenylamines form stable cation radicals upon oxidation at their first anodic wave. Reynolds et alt (1974) have shown, however, that further oxidation of the cation radicals leads to the appearance of a new reversible redox couple at potentials slightly positive with respect to the first anodic wave. This new couple was shown to occur at potentials where the corresponding carbazole is oxidized, so that the overall process involves conversion of the amine to the carbazole cation radical by reaction scheme (85). 

In the absence of suitable redox partners sulfide and disulfide radicals cations decay mainly by disproportionation or deprotonation. Considering their positive charge they are also prone for nucleophilic attack. Examples for the latter are the reaction of R2S with OH , leading to sulfuranyl radicals R2S (0H), or with halide ions, yielding sulfur-halide coupled radicals. Both these product radical species will be dealt with in more detail in separate sections. 

Photo-induced aromatic substitution reactions occur through an electron transfer process, which creates an aromatic radical anion or aromatic radical cation as intermediate. This intermediate couples with the electrophile or nucleophile radical to give the product. This mechanism is called Sr I (where the abbreviations stand for substitution, radical, nucleophilic, and first order). Photoirradiation of aromatic compounds in the presence of nucleophiles gives nucleophilic-substituted products different from those of thermal reaction. For example, 3,4-dimethoxynitrobenzene on UV irradiation in presence of hydroxide ion gives 3-hydroxy-substituted product, while on heating gives 4-hydroxy-substituted product [57]. 

A number of mechanisms have been proposed for the arylation of nucleophiles by diaryliodine(III) reagents including radical coupling processes, nucleophilic aromatic substitution (SArAr) and ligand coupling on iodine(III). It is now thought... 

Scheme 11.13 Copper(i) bromide-catal rzed coupling of nucleophiles involving radical and polar steps.

Electrochemical reduction of pentatluoronitrobenzene produces an intermediate radical anion that couples at position 4 to form the corresponding biphenyl along with hydroxy derivatives from subsequent nucleophilic substitution meta to the nitio groups [44] (equation 34) Similar reduction of halopyridines such as pen-tafluoropyridine leads mainly to 4,4 bipyridyls [45] (equation 35)... 

Similarly, when both the Cp and arene ligands are permethylated, the reaction of 02 with the Fe1 complex leads to C-H activation of the more acidic benzyl bond [57]. When no benzylic hydrogen is present, superoxide reacts as a nucleophile and adds onto the benzene ligand of the FeCp(arene)+ cation to give a peroxocyclohexadienyl radical which couples with a Fe Cp(arene) radical. A symmetrical bridging peroxo complex [(Fe"Cp)2(r 5-C6H60)2] is obtained. The C-H activation reactions of the 19e Fe1 radicals BH can be summarized as follows... 

The coupling reaction of arenediazonium ions with semidione radicals (12.84, obtainable by reduction of 1,2-diketones, 12.83) is also included here in the discussion of 1,3-dicarbonyl compounds, although it is a coupling with a nucleophilic radical and does not strictly belong in this context. The reaction (Scheme 12-43) was... 

Kolbe radicals can be added to olefins that are present in the electrolyte. The primary adduct, a new radical, can further react by coupling with the Kolbe radical to an additive monomer I (Eq. 9, path a), it can dimerize to an additive dimer II (path b), it can be further oxidized to a cation, that reacts with a nucleophile to III (path c), or it can disproportionate (path d). 

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