Radicals homolytic aromatic substitution

Leardini and Spagnolo have investigated the generation of iminyl radicals from azides via hydrogen atom transfer in the presence of tin hydride. Depending on the nature of the iminyl radicals, homolytic aromatic substitution was observed as well as conversion to the corresponding nitrile (Scheme 8.50, top). j8-Fragmentation of carbamoyl radicals has been observed as major reaction pathway with a-azidoamides (Scheme 8.50, bottom). 

Homolytic aromatic substitution often requires high temperatures, high concentrations of initiator, long reaction times and typically occurs in moderate yields.Such reactions are often conducted under reducing conditions with (TMSlsSiH, even though the reactions are not reductions and often finish with oxidative rearomatization. Reaction (68) shows an example where a solution containing silane (2 equiv) and AIBN (2 equiv) is slowly added (8h) in heated pyridine containing 2-bromopyridine (1 equiv) The synthesis of 2,3 -bipyridine 75 presumably occurs via the formation of cyclohexadienyl radicals 74 and its rearomatization by disproportionation with the alkyl radical from AIBN. ... 

Displacements such as this show all the usual characteristics of electrophilic aromatic substitution (substituent effects, etc., see below), but they are normally of much less preparative significance than the examples we have already considered. In face of all the foregoing discussion of polar intermediates it is pertinent to point out that homolytic aromatic substitution reactions, i.e. by radicals, are also known (p. 331) as too is attack by nucleophiles (p. 167). 

Attack on aromatic species can occur with radicals, as well as with the electrophiles (p. 131) and nucleophiles (p. 167) that we have already considered as with these polar species, homolytic aromatic substitution proceeds by an addition/elimination pathway ... 

Another very new radical/radical domino procedure was used in the total synthesis of the alkaloid lennoxamine by Ishibashi and coworkers. Here, a 7-endo cycliza-tion/homolytic aromatic substitution reaction cascade led to the target compound in 41% yield [75]. 

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). 

The addition of silyl radicals to double bonds in benzene or substituted benzenes (Reaction 5.2) is the key step in the mechanism of homolytic aromatic substitution with silanes [8,9]. The intermediate cyclohexadienyl radical 2 has been detected by both EPR and optical techniques [21,22]. Similar cyclohex-adienyl-type intermediates have also been detected with heteroaromatics like furan and thiophene [23]. 

Two steps must be considered in the mechanism of homolytic acylation, in addition to the formation of the acyl radical. The first fits in with the generally accepted mechanism of homolytic aromatic substitution, that is, the addition of the acyl radical to the aromatic nucleus to give an adduct in which the unpaired electron is delocalized over the residual heteroaromatic system (u-complex 6). 

G. H. Williams, Homolytic Aromatic Substitution. Pergamon, Oxford, 1960 D. H. Hey, Advan. Free Radical Chem. 2, 47 (1967). 

This awareness in a short time led to new homolytic aromatic substitutions, characterized by high selectivity and versatility. Further developments along these lines can be expected, especially as regards reactions of nucleophilic radicals with protonated heteroaromatic bases, owing to the intrinsic interest of these reactions and to the fact that classical direct ionic substitution (electrophilic and nucleophilic) has several limitations in this class of compound and does not always offer alternative synthetic solutions. Homolytic substitution in heterocyclic compounds can no longer be considered the Cinderella of substitution reactions. 

Homolytic substitution of thiophene as well as homolytic aromatic substitutions by thienyl radicals has been reviewed (73IJS295). In addition to this, a wider review on homolytic substitution of heteroaromatic compounds (74AHC(16)123) also briefly covers work done in the area of thiophenes. 

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]. 

Finally, the azido group would be expected to activate homolytic aromatic substitution by virtue of its ability to provide additional stabilization to free radical intermediates. No evidence in support of this prediction is available however and investigation in this area seems warranted. 

Homolytic aromatic substitution of pyrazines is a rare reaction. Early workers in the field have updated their work on radical addition of oxidized formamide to pyrazine (250). The new procedure affords pyrazine-2-car-boxamide (251) in 96% yield (85T4157). 

Radical cyclizations of nucleophilic N-alkyl radicals 96 onto the benzimidazole 2-position, mediated by tributyltin hydride and activated by quater-nizing the pyridine-like N-3 of imidazole with camphorsulfonic acid, have recently been reported (Scheme 20) [67]. These new five-, six- and seven-membered homolytic aromatic substitutions of nucleophilic N-alkyl radicals onto the benzimidazole-2-position occurred upon the use of large excesses of the azo-initiator, l,T-azobis(cyclohexanecarbonitrile), to supplement the non-chain reaction. The intermediate 97 aromatizes in high yields to the cy-clized benzimidazoles 98. 

Among the free radical reactions, homolytic aromatic substitution has an undoubted theoretical interest for the understanding of the reactivity of the aromatic compounds and of the free radicals. However it was considered till recent years a secondary aspect of the general problem of the aromatic substitution. It is difficult to find a modern text book of general organic chemistry in which this subject is only mentioned. 

Thus the arylation cannot be considered as a model of general validity for the homolytic aromatic substitution, not even for substitutions with carbon free radicals. 

Radical arylations can either be performed by SrnI reactions or by homolytic aromatic substitutions. The Srn 1 type reactions have recently been reviewed [1] and will not be included in the present article. Because of space limitations this review will focus on examples mostly from the recent literature. Especially for the older literature, we refer to several good review articles on homolytic aromatic substitutions which appeared in the 1960s, 1970s and 1980s [2]. 

The reaction of a nucleophilic alkyl radical R with benzene affords the a-complex 1, a fairly stable cyclohexadienyl radical, which under oxidizing conditions leads to cation 2 (Scheme 1). Depending on the stability of the attacking radical, the formation of 1 is a reversible process. Deprotonation eventually affords the homolytic aromatic substitution product 3. If the reaction is performed under non-oxidizing conditions, cyclohexadienyl radical 1 can dimerize (—> 4), disproportionate to form cyclohexadiene 5 and the arene 3, or further react by other pathways [3]. 

These reactivity trends clearly show that polar effects are involved in these radical substitution reactions. The transition state is thought to include a charge transfer 9) from the radical (electron donor) to the pyridinium ion (electron acceptor) [13], Frontier Molecular Orbital Theory (FMO) [14] has been applied to explain the reactivity differences which have been observed upon varying the substituents at the pyridinium ion and upon altering the nucleophilicity of the attacking radical. Moreover, FMO can be used to explain the regioselectivities obtained in these homolytic aromatic substitutions. The LUMO of the substituted pyridinium cation... 

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