Biaryls nucleophilic substitution

Nucleophile substitution of the T1 resin synthesis of phenols, biaryls, alkyl arenes, azides, aromatic hydrazines, halides, ester, azo compounds cinnolines, benzotriazoles [129-137, 140, 141]... 

Couplings can also be carried out by simple nucleophilic substitution reactions of arenechromium tricarbonyls . For example, in the synthesis of biaryl 469, asymmetric lithiation of 463 using in situ silylation provides the complex 466 via 464 and 465. Nucleophilic substitution by the tolyl Grignard 467 yields 468 as a single atropisomer in 68% yield, and decomplexation gives the biaryl 469 in 92% yield (Scheme 184). 

Finally, by introducing the aryl halide into the isocyanide component, as in 96, various macrocyclic peptidomimetics containing a nonsymmetrical endo biaryl ether bridge have been synthesized [89-91]. Aryl nucleophilic substitution also takes place in this case under standard base-promoted conditions. The synthesis was also carried out on solid phase. Selected examples are shown in Fig. 19, but also a... 

Similar types of nucleophilic substitutions have also been carried out when PIFA is activated by two equivalents of Lewis acids such as trimethylsilyl triflu-oromethanesulfonate (TMSOTf) and BF3 Et20 or heteropolyacid in standard solvents such as CH2C12 and MeCN. These reactions were applied to intramolecular reactions by the same authors leading to biaryls (49) [54-57], quinone imine derivatives (50) [58], and dihydrobenzothiophens (51) [59], which are important structures of bioactive natural products [Eqs. (7)-(9)]. Dominguez and co-workers have expanded the above biaryl coupling reaction to the syntheses of benzo[c]phenanthridine system (52) [60] and heterobiaryl compounds (53) [61] [Eqs. (10,11)]. 

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). 

In aromatic systems, oxazolines can have three different functions (Fig. 4). Firstly, they can be used as protecting groups for carboxylic acids. Secondly, they activate even electron-rich aromatic systems for nucleophilic substitution. Fluorine or alkoxy groups in the ortho position can be substituted by strong nucleophiles such as Grignard reagents. Thirdly, when biaryl compounds with axial chirality are synthesized in these reactions, oxazolines can induce the formation of only one atropisomer with excellent selectivity. These three qualities were all used in the synthesis of 20, a precursor of the natural product isochizandrine [10]. 

Axially chiral biaryls can be also prepared by nucleophilic substitution of tri-carbonylchromium complexes of 2-methoxy-benzoates with aryl Grignard reagents [65]. 

Proline analogs, biaryl-substituted, fluorous synthesis 112 PS-anthracene, dienophiles 151 PS-carbodiimide 136 Pimine C-2, nucleophilic displacement 119... 

Substituted unsymmetrical biaryls can be readily obtained from 6-aryl-3-cyanopyran-2-ones on treatment with acetone and a base. Initial nucleophilic attack at C-2 is followed by a C-C cyclisation (Scheme 38) <00JCS(P1)37I9>. 

Constitutionally Unsymmetrical Biaryls by Nucleophilic Aromatic Substitution... 

Cycloamidation has been used extensively to prepare 17-membered cycloisodityrosines. The acyclic biaryl ether precursors were prepared by methods including the Ullmann reaction 2-5 and nucleophilic aromatic substitution (SNAr)J6 7 Since these methods have all been used intramolecularly in cyclization reactions, they will be discussed in Sections 9.5.3 and 9.5.4. Evans and co-workers employed the pentafluorophenyl ester method of macrolactamization 8] to prepare 11, an intermediate in their total synthesis of OF4949-III (7) (Scheme 2)J3 In this case, the acidic removal of a Boc group was employed to release the cyclization substrate, although hydrogenolysis of a Z group is also effective 3 ... 

Diastereo- and enantio-selectivity in nucleophilic aromatic substitution is limited to atropisomerism in binaphthyl- and biaryl-forming reactions.21-42... 

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]. 

The 2,6- and 2,4-di-t-butyl phenoxide ions were shown to be more reactive than PhO ions. The reaction of these nucleophiles, mainly of 2,6-di-/-butylphenoxide ion (185), was studied with a considerable variety of compounds in order to achieve the synthesis of biaryls of importance in non-linear optics249,250. In these nucleophiles, the r-butyl groups substitute two of the possible coupling positions in order to perform a selective synthesis of either the o- or the /7-isomer. The substituents can be easily removed later251,252. 

Fluorinated biaryl derivatives were obtained by substitution of p-F,p-CF3 and p-CF30 bromobenzenes with 2,4- and 2,6-di-r-butylphenoxide ion and / -MeO and p-CF30 phe-noxide ions as well as with 198 under photostimulation264. Depending on the nucleophile and the substrate, 6>-disubstitution and 4-addition products were obtained. 

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