Intermolecular Arylation of Phenols

Intermolecular arylation of carbocyclic arenes are rare. Exceptionally, phenols are easily arylated. As treated in Chapter 3.7.4, the aryl ether 48 is formed by reaction of aryl halides with hydroquinone monomethyl ether when bulky and electron-rich phosphines are used, which accelerate reductive elimination. Miura and co-workers found new completely different reactions of phenol with bromobenzene by using Pd(OAc)2, PPhs and CS2CO3 to give the unexpected pentaphenylated product 49 in 58% yield [lb, 15]. 

The first product of the interesting pentaphenylation is o-phenylphenol (50). It was found that o-phenylphenol (50) undergoes not only monophenylation, but also diphenylation on treatment with iodobenzene at the C-2 positions to give 51 and 52 by the use of PdCb and CS2CO3. The fact that the monoarylated product 51 (25 %) and the diarylated product 52 (62 %) were obtained by the treatment of 2-phenylphenol (50) with 4 equivalents of iodobenzene shows that the arylation of benzene ring is faster than the arylation of ortho carbon of phenol under these conditions [16]. Similarly, when the reaction of bromobenzene with 50 in xylene was stopped after a short time, 2-(biphenyl-2-yl)phenol (51) was obtained in high yield, but 2,6-diphenylphenol was not formed [15]. 

Formation of 50 may be understood in terms of arylation of phenol via the keto form 54 which is stabilized as the oxa-7r-allylpalladium 55 as one possibility. This reaction path is similar to arylation of cyclohexanone. Electrophilic attack of 53 at ortho carbon to give 56 and reductive elimination are another explanation. 

Formation of 2(biphenyl-2-yl)phenol (51) from 50 is explained by electrophilic attack of 57 to form 59 and its reductive elimination. As another explanation, oxidative addition of aromatic ortho C—H bond to 57 generates the palladacycle 58 and its reductive elimination affords 59. Domino arylations by a similar sequence of the reactions via 60 finally give rise to the pentaphenylated product 49 in 58 % yield. Certainly the reaction occurs by strong participation of OH group. It is surprising that efficient polyarylation of phenol with bromobenzene proceeds smoothly in the presence of CS2CO3 which is sparingly soluble in xylene and since it is difficult to abstract protons from phenol. 

Phenylation of o-(2-nitrophenyl)phenol (61) with iodobenzene occurred at C-6 of the electron-dehcient nitrobenzene to give 62 in 87 % yield, suggesting that the phenylation is not a simple electrophilic substitution [17]. 

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This adds to other reports of intra- and intermolecular arylations of phenolic derivatives (Equations (145)-( 147)). 124,124a 124c... 

Bedford RB, Limmert ME (2003) Catalytic intermolecular ortho-arylation of phenols. J Org Chem 68 8669-8682... 

At the beginning of the new millennium, Hashmi et al. presented a broad research study on both intramolecular and intermolecular nucleophilic addition to alkynes and olefins [18]. One of the areas covered by these authors was the isomerization of co-alkynylfuran to phenols [19]. After that, Echavarren and coworkers identified the involvement of gold-carbene species in this type of process, thus opening a new branch in gold chemistry [20]. And subsequently, Yang and He demonstrated the initial activation of aryl —H bonds in the intermolecular reaction of electron-rich arenes with O-nucleophiles [21, 22]. 

Intermolecular Arylation Reactions of Phenols and Aromatic Carbonyl Compounds... 

As described above, appropriately functionalized aromatic substrates such as phenols and aromatic carbonyl compounds undergo intermolecular arylation directly and regioselectively on treatment with aryl halides in the presence of palladium catalysts. As illustrated in Scheme 3, which is a proposed general... 

Regioselective synthesis of polysubstituted benzofurans from phenols and alkynes using a Cu(OTf)2 catalyst and ZnClj as Lewis acid in O2 atmosphere in a one-pot procedure has been reported by Jiang et al. (Scheme 8.79). The transformation consists of a sequential nucleophihc addition of phenols to alkynes and oxidative cyclization. A wide variety of phenols and alkynes can be used in this reaction. The reaction might proceed via a Cu-catalyzed intermolecular nucleophilic addition and intramolecular Cu-catalyzed aryl C(sp )-H functionahzation [149]. 

In 2006, Li and coworkers reported a Au-catalyzed aryl C(sp )-H functionalization of phenols and naphthols 3 with dienes toward the synthesis of benzofuran 4 (Scheme 12.2) [6]. This reaction proceeds via a Au(III)-catalyzed intermolecular addition of aryl C-H bond to dienes followed by the intramolecular addition of the phenol O-H bond to afford benzofuran 4. 

The Pd-catalyzed intermolecular C—O bond formation has also been achieved [105-108]. Novel electron-rich bulky phosphine ligands utilized by Buchwald et al. greatly facilitated the Pd-catalyzed diaryl ether formation [109], When 2-(di-tert-butylphosphino)biphenyl (95) was used as the ligand, the reaction of triflate 93 and phenol 94 elaborated diaryl ether 96 in the presence of Pd(OAc)2 and K3PO4. The methodology also worked for electron-poor, neutral and electron-rich aryl halides. 

The consecutive formation of o-hydroxybenzophenone (Figure 3) occurred by Fries transposition over phenylbenzoate. In the Fries reaction catalyzed by Lewis-type systems, aimed at the synthesis of hydroxyarylketones starting from aryl esters, the mechanism can be either (i) intermolecular, in which the benzoyl cation acylates phenylbenzoate with formation of benzoylphenylbenzoate, while the Ph-O-AfCL complex generates phenol (in this case, hydroxybenzophenone is a consecutive product of phenylbenzoate transformation), or (ii) intramolecular, in which phenylbenzoate directly transforms into hydroxybenzophenone, or (iii) again intermolecular, in which however the benzoyl cation acylates the Ph-O-AfCL complex, with formation of another complex which then decomposes to yield hydroxybenzophenone (mechanism of monomolecular deacylation-acylation). Mechanisms (i) and (iii) lead preferentially to the formation of p-hydroxybenzophenone (especially at low temperature), while mechanism (ii) to the ortho isomer. In the case of the Bronsted-type catalysis with zeolites, shape-selectivity effects may favor the formation of the para isomer with respect to the ortho one (11,12). 

Phenols do not undergo intermolecular dehydration. Although aryl halides cannot be used as substrates in typical Williamson syntheses, they do undergo a modified Williamson-type synthesis at higher temperature in the presence of Cu. 

Values of molar Kerr constants and dipole moments of nitrogen azoles and their complexes with phenols have been obtained. " These complexes are formed by an intermolecular hydrogen bond between the pyridine-type nitrogen of the azole and the phenolic proton. " The use of dipole moments in conformational studies has shown that A-aryl- and C-aryl- and A-furyl- and C-furyl imidazoles (and benzimidazoles) are nonplanar, but l-(a-furyl)-4,5-diphenylimidazoles do have a planar bicyclic fragment. The dipole moments and conformations of azolides (A-acylazoles) have been studied. In the 1-arylimidazoles the dipole is toward the aryl group. In 4,5-di-t-butylimidazole the molecule is essentially planar, but the C-4—C-5 bond is slightly stretched. Among other imidazole derivatives which have been studied by X-ray are histidine hydrochloride, 4-acetyl-amino - 2 - bromo - 5 - isopropyl -1 - methylimidazole, 4- acetyl - 5 - methyl - 2 -phenylimidazole, and imidazole-4-acetic acid hydrochloride. 

Values of molar Kerr constants and dipole moments of nitrogen azoles and their complexes with phenols have been obtained. " These complexes are formed by an intermolecular hydrogen bond between the pyridine-type nitrogen of the azole and the phenolic proton. The use of dipole moments in conformational studies has shown that N-aryl- and C-aryl- and iV-furyl- and C-furyl imidazoles (and benzimidazoles) are nonplanar, but... 

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