Intramolecular Homolytic Aromatic Substitutions

The same group recently disclosed a related free radical process, namely an efficient one-pot sequence comprising a homolytic aromatic substitution followed by an ionic Homer-Wadsworth-Emmons olefination, for the production of a small library of a,/3-unsaturated oxindoles (Scheme 6.164) [311]. Suitable TEMPO-derived alkoxy-amine precursors were exposed to microwave irradiation in N,N-dimethylformam-ide for 2 min to generate an oxindole intermediate via a radical reaction pathway (intramolecular homolytic aromatic substitution). After the addition of potassium tert-butoxide base (1.2 equivalents) and a suitable aromatic aldehyde (10-20 equivalents), the mixture was further exposed to microwave irradiation at 180 °C for 6 min to provide the a,jS-unsaturated oxindoles in moderate to high overall yields. A number of related oxindoles were also prepared via the same one-pot radical/ionic pathway (Scheme 6.164). 

Scheme 10.24 Dual role of AIBN in intramolecular homolytic aromatic substitution.

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]. 

Scheme 20 Intramolecular homolytic aromatic substitution mechanism...

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... 

Compared to the intramolecular aromatic alkylation with nucleophilic radicals, the analogous process with electrophilic radicals is far less common. Citterio carefully studied the Mn(OAc)3-mediated intramolecular homolytic aromatic substitution of various dialkyl malonates [71, 73]. He showed that the reaction is well suited for the formation of 5- (see 45), 6- (see 46) and 7-membered benzanellated rings (see 47). For cyclizations forming a 6-membered ring, high yields were obtained in the alkylation of electron-rich as well as electron-poor arenes. However, the formation of the 7-membered ring occurred only with electron-rich arenes. Cerium(IV) ammo-... 

Oxidation of diethyl a-benzylmalonate (25) by Mn(III) acetate in acetic acid at 70 °C in the presence of mono- or disubstituted alkynes leads to dihydronaphthalene derivatives (26) in moderate to good yields (equation 33). A mechanistic scheme involving the formation of the corresponding malonyl radical, its addition to a triple bond and intramolecular homolytic aromatic substitution of the vinyl radical adducts is discussed. Absolute rate constants, obtained from competitive studies, for the addition of a-benzylmalonyl radicals to a variety of alkynes cover few orders of magnitude e.g. the rate constants at 60 °C are 3x10 and 1 x 10 s for 4-octyne and phenylacetylene respectively. 

Isotope effects have also been applied to intramolecular homolytic aromatic substitution. Denney and Klemchuk (1958b) cyclized three biphenyl derivatives deuteriated in the 2 -position and substituted in the 2-position by a group suitable for homolytic intramolecular substitution. 2-(Phenyl-2 -d)-benzaldehyde heated with di-t-butyl peroxide gave a mixture of fluorenone and fluorenone-d (10) corresponding to an isotope... 

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... 

Furthermore, iminyl radicals have been used in intramolecular homolytic aromatic substitutions. The iminyl radicals can be generated in situ by C-radical addition onto nitriles [55] or they may be generated directly from the corresponding oximes [56] and hydrazones [57]. 

The best known intramolecular free radical reactions probably are the 1,5-hydrogen abstractions by alkoxyl or aminium radicals used in selective functionalization. The first, known as the Barton reaction, has been reviewed, " as has the second one, the Hofmann-Loffler-Freytag reaction. Synthetic uses and mechanistic aspects of intramolecular homolytic aromatic substitution have also been reviewed recently. " ... 

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. 

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