Arylation intramolecular homolytic

Formation of cyclized products, resulting from intramolecular attack of the intermediate aryl radical in the SrnI reaction on a second aromatic ring (i.e. intramolecular homolytic arylation) are rare and not synthetically useful.64-158-161... 

Beckwith and Storey have developed a tandem translocation and homolytic aromatic substitution sequence en route to spiro-oxindoles [95CC977]. Treatment of the bromoaniline derivative 122 with tin hydride at 160 °C generated the aryl radical 123 which underwent a 1,5-hydrogen atom transfer to give intermediate 124. Intramolecular homolytic aromatic substitution and aromatization gave the spiro-oxindole 125. Intramolecular aryl radical cyclization on to a pyrrole nucleus has been used to prepare spirocyclic heterocycles [95TL6743]. 

Exposure of the diazonium salt 1107 to iodide ion generates an aryl radical, which undergoes intramolecular homolytic substitution at sulfur to liberate the acyl radical intermediate 1108. An exo-mode cyclization with concomitant incorporation of iodide then occurs to afford the 3-disubstituted-chroman-4-one 1109 in excellent yield (Scheme 275) <1997JOC5982>. 

The first example of an intramolecular homolytic aromatic substitution was published by Pschorr more than a century ago [34], Biaryls were prepared by intramolecular homolytic substitution of arenes by aryl radicals which were generated by treatment of arenediazonium salts with copper(I) ions (Pschorr reaction). Later it has been shown that similar reactions can be conducted under basic conditions or by photochemical or thermal decomposition of the diazonium salts [35]. Electrochemical reduction [36], titanium (III) ions [37], Fe(II)-salts [38], tetrathiafulvalene... 

Furthermore, iminyl radicals, which are supposed to be intermediates in the annulations discussed above (see 32), have been directly generated from the corresponding oximes [56] or hydrazones [57] and applied in the intramolecular homolytic aromatic substitution. The intramolecular radical alkylation of arenes [58] and heteroarenes [59-62] was investigated by various research groups. As for the aryl radicals, the alkyl radicals used in these reactions are generally generated from the... 

S02-extrusion affords the electrophilic radical 49 (Scheme 10). Intramolecular homolytic substitution eventually gives tetrahydronaphthalene 50 (92%). Beckwith showed that the A-(o-bromophenyl)amide 51 can be transformed into the corresponding oxindole 54 (70%) at high temperatures using BusSnH via tandem radical translocation of the initially formed aryl radical 52 to form 53 with subsequent intramolecular homolytic substitution [77]. The nucleophilic a-aminomethyl radical 55 reacted in a tandem addition/homolytic aromatic substitution reaction via radical 56 to tetrahydroquinoline 57 [78]. Radical 55 can either be prepared by oxida-... 

Crich and co-worker report an attractive solution to this problem by a combination of efficient iodine abstraction by tributyltin or tris(trimethylsilyl)silyl radicals from an aryl iodide to form an aryl radical and successive intramolecular homolytic attack at sulfur by the aryl radicals to generate acyl radicals (Scheme 8) [60]. 

When Pschorr reported more than a century ago on the first intramolecular homolytic aromatic substitution [25], he showed that biaryls could be readily prepared by intramolecular homolytic aromatic substitution using reactive aryl radicals and arenes as radical acceptors. The aryl radicals were generated by treatment of arene-diazonium salts with copper(l) ions. Today, this reaction and related processes are referred to as Pschorr reactions. It was later found that radical biaryl synthesis could be conducted without copper salts by photochemical or thermal generation of the aryl radical from the corresponding diazonium salt [26], Moreover, the reduction of aryl diazonium salts offers another route to generate reactive aryl radicals. Hence, electrochemistry [27], titanium(lll) ions [28], Fe(II)-salts [29], tet-rathiafulvalene [30] and iodide [31] have each been used successfully for the reduction of diazonium salts to generate the corresponding aryl radicals [32]. As an example, the iodide-induced cycUzation of diazonium salt 6 to phenanthrene derivative 7 is presented in Scheme 13.3 [31]. For further information on the... 

Generation of Acyl Radicals. The generation of acyl radicals from simple thiol esters, either by photochemical methods or in conjunction with silanes and stannanes, is complicated by low quantum yields and lack of reactivity. This problem was circumvented by the inclusion of an additional propagation step, an intramolecular homolytic substitution (Sh2) of an aryl radical on the sulfur atom of a thiol ester carbonyl group (eq 2), in a radical chain sequence. 

Photolysis of methyl(L)cobaloxime as a methyl radical source, in the presence of the 4-chlorophenylester of thiolacetic acid (33) yields 4-chlorophenylmethyl-sulfane (34). The reaction (Scheme 12) is described by Tada et ai [33] as proceeding through sulfuranyl radical (35) as intermediate or transition state . No such intermediate is discussed in a corresponding intramolecular homolytic attack at a thiolester S atom by an aryl radical, with release of the acyl radical described in Scheme 13, wherein acyl radicals (36) are efficiently generated from aryl iodides (37) by two efficient free radical reactions, namely iodine... 

Intramolecular Addition/Homolytic Substitution Reactions. o-Bromo-A-methylanilides are converted into oxindoles in good to excellent yields upon treatment with Tri-n-Butylstannane and DTBP (eq 25). The reaction involves the initial formation of an aryl radical, translocation of the radical, and subsequent intramolecular homolytic aromatic substitution. 

Alkyl, vinyl and aryl radicals can give homolytic substitution at a heteroatom either inter- or intramolecularly thus forming C-heteroatom bonds. 

Although the two competing intermediates, the hypothetical ketyl-aryl radical pair (4) and the oxaspirooctadienyllithium (3), are not the rate-determining transition states, they should lie at almost the same energetic level. The rearrangement is in accord with the intramolecular nucleophilic addition/elimination mechanism rather than with homolytic cleavage/recombination. 

In intramolecular arylations, a new bond is created between two aromatic moieties of the same molecule or between an aromatic nucleus and an atom of a side-chain. Many intramolecular arylation reactions of homocyclic and heterocyclic aromatic halides have been studied mainly in view of their synthetic applications, and it is not always clear which mechanistic pathway is followed. The reaction may start with homolytic or heterolytic dissociation of the carbon-halogen bond and proceed by attack of the aryl radical or aryl cation on another part of the molecule. Electrocyclization followed by elimination of hydrogen halide is another possibility. Especially when heteroatoms such as nitrogen, sulphur or phosphorus are involved, the initial step may be a nucleophilic attack on the carbon atom bearing the halide atom. 

BusSnH-mediated intramolecular arylations of various heteroarenes such as substituted pyrroles, indoles, pyridones and imidazoles have also been reported [51]. In addition, aryl bromides, chlorides and iodides have been used as substrates in electrochemically induced radical biaryl synthesis [52]. Curran introduced [4-1-1] annulations incorporating aromatic substitution reactions with vinyl radicals for the synthesis of the core structure of various camptothecin derivatives [53]. The vinyl radicals have been generated from alkynes by radical addition reactions [53, 54]. For example, aryl radical 27, generated from the corresponding iodide or bromide, was allowed to react with phenyl isonitrile to afford imidoyl radical 28, which further reacts in a 5-exo-dig process to vinyl radical 29 (Scheme 8) [53a,b]. The vinyl radical 29 then reacts in a 1,6-cyclization followed by oxidation to the tetracycle 30. There is some evidence [55] that the homolytic aromatic substitution can also occur via initial ipso attack to afford spiro radical 31, followed by opening of this cyclo-... 

Though the almost unique catalytic effects of cuprous salts, or of metallic copper, in the Sandmeyer reaction have been contested by Hodgson (7), the careful kinetic work of Cowdrey and Davies (8) has established that the anion (CuCh)" does play a special role. These workers, however, suggested that an intramolecular decomposition of complex cuprous salts (At.N2, CuCh) produced the aryl halide. If this concept is correct, then the Sandmeyer reaction should not yield detectable free aryl radicals and should differ from many associated reactions of diazonium salts (9,10) for which the homolytic character is in less doubt. 

All of these tin hydride-mediated intramolecular arylations involve an initial radical generation by reaction of BusSn with precursor 25 to afford the corresponding Cintramolecular addition onto an arene to give a stable cyclohexadienyl radical 27 which is then oxidized ( ) to the product 28 (Scheme 13.7). It should be noted that this oxidation must occur under reducing tin hydride conditions. When debate centered on the mechanism of the homolytic aromatic substitution, a number of hypotheses was proposed. Thus, in... 

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