Biaryls by radical substitution

Phenanthrene and anthracene are both much more reactive than benzene, and there is a preference for substitution to occur in the center ring. That this behavior would be expected is evident even from simple resonance considerations. The o--complexes that result from substitution in the center ring have two intact benzene rings. The total resonance stabilization of this intermediate is larger than that of the naphthalene system that results if substitution occurs in one of the terminal rings. 

Both phenanthrene and anthracene have a tendency to undergo addition reactions under the conditions involved in certain electrophilic substitutions. Halogenation and nitration may proceed in part via addition intermediates.For example, in the nitration of anthracene in the presence of hydrochloric acid an intermediate addition product is isolated. 

Cycloaddition reactions are also favorable for anthracene since the resonance stabilization of two benzene rings is comparable to that of the anthracene ring. 

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The Pschorr Reaction allows the preparation of biaryl tricyclics by intramolecular substitution of one arene by an aryl radical. This radical is generated in situ from an aryl diazonium salt by copper catalysis. Although excess copper salts are used, the yield is normally moderate. 

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-... 

By consideration of the intramolecular free radical / rn-substitution approach <1988TL2987> for the synthesis of biaryls, the direct [1,6]-addition product 184 was obtained in 63% yield from the corresponding -toluenesulfonyl derivative (Scheme 52) <1991CC877>. Under similar reaction conditions, the sultine 185 was available in 89% yield from the readily available substrate <2006AGE633>. 

Kita and Tohma found that exposure of p-substituted phenol ethers to [bis(tri-fluoroacetoxy)iodo]benzene 12 in the presence of some nucleophiles in polar, less nucleophilic solvents results in direct nucleophilic aromatic substitution [Eq. (84)] [156]. Involvement of a single-electron transfer (SET) from phenol ethers to A3-iodane 12 generating arene cation radicals was suggested by the detailed UV-vis and ESR studies. SET was involved in the oxidative biaryl coupling of phenol ethers by 12 in the presence of BF3-Et20 [157]. 

In the non-phenolic oxidative coupling reaction the electron-rich arene 19 undergoes electron transfer yielding the radical cation 20, which is preferably treated in chlorinated solvents or strongly acidic media. Attack of 20 on the electron-rich reaction partner 21 will proceed in the same way as an electrophilic aromatic substitution involving adduct 22 which extrudes a proton. The intermediate radical 23 is subsequently oxidized to the cationic species 24 which forms the biaryl 25 by rearomatization. In contrast with the mechanism outlined in Scheme 5, two different oxidation steps are required. 

Spirocycles can be obtained from intramolecular radical biaryl coupling reactions when suitable substituents are present for an alternative stabilization of the cyclohexadienyl intermediate (c.f. 69, Scheme 25). Otherwise, rearomatization can occur by cleavage of one substituent from the quaternary center of the spirocycle, such as the C-P bond in 69. First examples for an alternative reaction course have been reported in studies on the photochemically induced cyclization of iodoarenes [134]. Recently, ferf-butyldimethylsilyl ethers [135] and azides [136] were identified as well-suited substituents to lead the ipso substitution into the pathway towards spirocycles (Scheme 27). 

More recent studies, however, have proved that these anions, mainly di-7-butyl substituted phenoxides and 1- and 2-naphthoxide ions, are excellent nucleophiles under electrochemical or photostimulated conditions. These anions behave as bidentate nucleophiles and couple with radicals through the carbons of their aromatic ring. This has been proved to be a powerful route to biaryls unsymmetrically substituted by EWG and electron-acceptor groups, which are of interest in non-linear optics, as well as in the synthesis of cyclic compound (Section V.E.2). 

The biaryls are useful in rational designing functional molecules and materials. The large steric hindrance and the semirigid structure with restrict rotation provided various functional biaryls, such as arylporphyrins [162,170], molecular-scale motors rotate by chemical power or light [73,163], a photoswitchable electron transfer aromatic compounds for the design of molecular photonic devices [171,172],a stable thioaminyl radicals [173],phenylnitroxide-substitut-ed Zn(II) porphyrins [174], and polycyclic aromatic compounds [175-177]. 

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... 

ArPb(OzC-CF3)2 Ar+ + Pb(02C CF3)2]. The aryl cations have been trapped with aromatic compounds to give biaryls [with certain substrates, notably poly-methylbenzenes, high yields (up to 88 %) are obtained], but with reactive aromatic substrates aryl cations are not the precursors to the biaryls and in these cases it is proposed that reaction proceeds via preliminary complex formation between the substrate and a species which contains an aryl-lead bond. Oxidative coupling of methyl-substituted benzenes by the reagent Pb(0Ac)4-CFs C02H to give biaryls and diarylmethane is also considered to involve formation of a radical cation in the primary step. A study has also been made of the plumbylation of monohalogeno-benzenes with Pb(OAc)4-CF3 COsH. ... 

The major limitation of the all GBH reactions is that the arene has to be in the liquid form to serve as the solvent. All attempts to arylate solid arenes under the GBH reaction conditions were unsuccessful. Furthermore, the presence of radical-sensitive substituents in either diazonium salts or in arene results in lower yields, or the reaction fails completely. Generally, some alkyl, alkoxycarbonyl, formyl, or iodo-substituted arenes or diazonium salts are susceptible for hydrogen- or iodo-abstraction by free-radicals and are not common GBH reactants. For example, 2-tolyldiazonium tetrafluoroborate in the ptGBH reaction with benzene gives indazole in 74% yield, and only 2% of biaryl product [61]. 

When a monosubstituted benzene is attacked by aryl radical, a mixture of all three isomeric biphenyls is produced, as well as in the GBH reaction [105-107]. The nature of substituents apparently does not play any important role except those of bulky ort/jo-groups. The ortAo-substituted biaryl is always the main product followed by para- and meto-arylation product. The presence of a bulky ortho-tert-huXy group significantly decreases the amount of ort/io-arylation product, indicating the strong ort/io-steric effect. The typical isomer distribution and the yields of biaryls in the arylation of four mono-substituted benzenes with dibenzoyl peroxide are given in the Table 4. 

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... 

Scheme 13.3 Biaryl synthesis by homolytic aromatic substitution using reactive aryl radicals (AIBN = a,a -azobisisobutyrodinitrile).

A related approach used catalysis by FeCl, t-BuOOH (TBHP) as oxidant, and 1,8-diazabicycloundec-7-ene (DBU) as ligand. Several dialkyl ethers, sulfides, and amines have been used to generate alkyl radicals, which add to A-substituted A-phenylacrylamide [56]. This initiation methodology (M"+/ROOR) was also used in the synthesis of 6-arylated phenanthridines [57, 58], biaryls [59], fluorenones and xanthones [60], etc. 

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