Phenol ethers biaryls

In connection with another project being developed we needed large quantities of a biaryl phenol or biaryl aryl methyl ether which was being prepared by a Suzuki coupling reaction (Scheme 6). 

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 intermolecular mode, this reaction has been utilized for the preparation of products 28 from various nucleophiles, including C-nucleophiles (e. g. (3-dicarbonyl compounds). A similar reaction in the intramolecular mode provides a powerful synthetic tool for the preparation of various polycyclic compounds via oxidative biaryl coupling [21,27 - 30]. Several examples of these C-C bond forming reactions are shown in Schemes 13-15. Specifically, various dibenzoheterocyclic compounds 30 have been prepared by the oxidation of phenol ether derivatives 29 with [bis(trifluoroacetoxy)iodo]benzene in the presence of BF3-etherate in dichloromethane (Scheme 13) [27-29]. 

Oxidation of Phenol Ether Derivatives to Biaryls, Quinone-Imine... 

One-electron oxidation of an aryl ether, for example at the anode, gives rise to a radical cation whose fate may be radical coupling (shown as dimerization) or substitution into a neutral phenol ether both paths are shown in Scheme 6 and converge to a biaryl product. Other products are possible if coupling at a quaternary center takes place. Mechanisms of this type must operate for the important couplings of phenol ethers with phenol ethers, and phenols with phenol ethers possibly they should not be neglected for phenol-phenol coupling also, in certain cases. 

This section covers the union of two aryl moieties, one of which is a fully alkylated phenol, and the other is either a free phenol or a phenol ether. Clearly, radical dimerization is not operative in such reactions. An early example is to be found in the work of Pitcher and Dietrich (1924) ° who showed that 3,3, 4,4 -tetramethoxybiphenyl was among the products of electrolytic oxidation of veratrole in sulfuric acid using a lead dioxide anode the biaryl was formed in about 20% yield based on reacted veratrole. 

Electrooxidation is also viable for phenol ether-phenol ether coupling and has been thoroughly investigated. For example a range of compounds (65) with R = H or Me, Z = CH2 or O, = 1 or 2, reacted at the anode to give fair yields of the corresponding biaryls (66), together with spirodienone products (see Section 2.9.3.2). 

The use of air-sensitive TTFA was later replaced by its in situ preparation from thallium(III) oxide and TFA [121]. This method represented a new and effective route to biaryls. Conversions were significantly improved, the formation of overoxidized by-products could be decreased and in most cases yields were better than those in classical phenolic couplings or in other previously known methods [122]. Phenolic ethers could also be transformed to biaryls in this way [123] (Scheme 53). The TTFA/ TFA system was occasionally used for the regioselective formation of aryl-aryl bonds [124]. 

Additional examples of intramolecular oxidative coupling of phenolic ethers include the oxidative biaryl coupling of various N-substituted 1-benzyltetrahydroisoquinolines 313 to the corresponding aporphines 314 [374], the oxidative cyclization of 3,4-dimethoxyphenyl 3,4-dimethoxyphenylacetate (315) leading to the seven-membered lactone 316 [375] and the conversion of phenol ether derivatives 317 into the products of... 

Popular two-electron oxidant lead(IV) acetate (LTA) [88-92], in the presence of BFyEt20 in dichloromethane, smoothly couples phenols and phenol-ethers to the respective biaryls in good to excellent yields [93]. Once again, at certain electron-poor substrates, the aromatic substitution - acetoxylation, became the major process. 

Transmetallation of aiyl halide (VIII) with n-butyl lithium and treating it with readily available and inexpensive 3-ethoxycyclohexen-l-one followed by acid work-up would provide enone (XI) (Scheme 8). Enone (XI) can be then aromatized to phenol (X) or any other biaryl alkyl ether. By using this protocol, 3-ethoxycyclohexen-l-one is a synthon for 3-hydroxyphenyl boronic acid. The bulk price of 3-ethoxycyclohexen-l-one is 85/kg compared to 3500 for the boronic acid, thereby significantly reducing the cost to prepare biaryl (X). 

Ortho- and para-rearrangement and phenol formation on uv-irradiation of aryl esters are accompanied in several cases by decarboxylation,37,60,62,64,80,81 represented for 3,5-di-t-butylphenyl benzoate by the equation 118 -> 119-122. It was shown that this reaction cannot be sensitized,64 but the dramatic differences in product distribution could be observed by changing of the solvent.60,84 The results in Table VI indicate that in polar solvents the decarboxylation process is minimized while the formation of the photo-Fries rearrangement 119 is enhanced. The reverse appears to be true when nonpolar ethereal solvents are used. A considerable amount of biaryls are formed, and hence this reaction may prove useful for the preparation of biaryls and alkylary Is. 

The reaction of pentafluoroiodobenzene with aromatic compounds such as anilines, pyrroles, indoles, imidazoles, aromatic ethers and phenols leads to aryl—aryl coupling477. The reactions proceed via pentafluorophenyl radicals which are generated by photoin-duced electron transfer (PET) and loss of iodide ion. Coupling between the pentafluorophenyl radical and the radical cation of the donor gives biaryl cations (138,139) which lose a proton. The reaction is illustrated for N, A-dimethylaniline (equation 125). 

Finally, reactions with O-protected phenol 40 were studied, but only silyl ethers (40s-u, R = TMS, TBDMS) afforded the cyclohexadienone product 41 in good yield. Other protecting groups primarily yielded the biaryl coupling product 42 (Table 9). 

Macrocyclic diarylheptanoids can be derived from their open chain congeners by oxidative phenol coupling resulting in macrocyclic biaiyls or biaryl ethers. Usually they were named after the plant source and can be conveniently classified according to the plant families in which they occur. 

In the laboratory of K.C. Nicolaou, a novel mild method for the preparation of biaryl ethers was developed. The di-ort/70-halogenated aromatic triazenes underwent efficient coupling with phenols in the presence of CuBr. This mild modified Ullmann condensation was utilized in the synthesis of the DOE and COD model ring systems of vancomycin. 

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