Biaryls, unsymmetrically substituted

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 same system is further applied to various dibromobiaryls and resulted in the successful production of unsymmetrically substituted biaryls [65],... 

Nagaki A, Takabayashi N, Tomida Y et al (2009) Synthesis of unsymmetrically substituted biaryls via sequential lithiation of dibromobiaryls using integrated microflow systems. Beilstein J Org Chem 5 11... 

Tab. 10. Regiochemical control in the PI FA-mediated oxidative coupling of unsymmetrically substituted biaryl substrates.

A related reaction is the coupling of two molecules of aryl halide by metallic copper at temperatures above 100° (Ullmann). Activated copper bronze or freshly precipitated copper is used. The order of activity of the aryl halides is I > Br > Cl. Both symmetrically and unsymmetrically substituted biaryls may be prepared in fair yields. An excellent review of the literature to 1945 has been made. Most functional groups do not interfere hydroxyl, carboxyl, amino, and acetamino groups are exceptions. ... 

The Suzuki reaction of arylboronic acid derivatives with aryl halides is one of the most powerful methods for construction of an unsymmetrically substituted biaryl derivative [11, 23, 85]. Due to the importance of substituted biaryls as building blocks for pharmaceuticals, there is currently a great deal of interest in the coupling of economically attractive aryl halides with arylboronic acids [86-98]. 

Recently, the formation of unsymmetrically substituted biaryls from simple arenes was achieved with a catalytic system consisting of [Pd(0Ac)2]-CF3C02H and K2S2Og under mild reaction conditions (Scheme 9.50) [128], The chemo- and regioselec-tivities of these reactions were controlled by the use of an excess of the less reactive coupling partner as solvent [129]. 

In analogous fashion, aryl Grignard reagents can be used in place of the vinyl Grignard reagent, to synthesize unsymmetrically substituted biaryls 494 (yields mainly 60-70% for 10 examples). ... 

Nishii et al. reported metal-mediated benzannulation reaction of diaryl(gm-dichlorocyclopropyl)methanols to synthesize unsymmetrically substituted a-arylnaphthalenes [61]. In particular. The reaction of optically active alcohol 145 in the presence of 1 equiv of HCU at —78 °C afforded chiral biaryl 146 with an excellent level of stereo induction (Scheme 27.48) [62]. It should be noted that chi-raUty exchange from sp central chiraUty to axial chirality takes place in this process. This methodology has been employed successfully for total synthesis of natural lignin lactones, justicidin B, and dehydrodesoxypodophyllotoxin (Scheme 27.49) [63]. 

This reaction is straightforward with benzene or symmetrical alkyl or methoxy arenes. Unsymmetrically substituted arenes give rise to regioisomers. The mechanistic proposal for this transformation includes activation of the aryl-halogen bond by Fe(II) via one-electron oxidation of the metal center. The aryl radical species thus formed adds to the arene. Subsequent loss of hydrogen halogenide releases the biaryl under formation of the active Fe(II) catalyst. 

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... 

Gomberg-Bachmann biphenyl synthesis. Reaction of stable arenediazonium tet-rafluoroborates or hexafluorophosphates in an aromatic solvent with potassium acetate (2 equiv.) and a phase-transfer catalyst results in biar Is in high yield. Crown ethers, Aliquat 336, and tetrabutylammonium hydrogen sulfate arc all effective catalysts. The reaction is useful for synthesis of unsymmetrical biaryls. The ortho-isomer predominates in reactions with a monosubstituted benzene. The most selective method is to couple a substituted arenediazonium salt with a symmetrical arene. 

In the presence of a catalytic amount of PdCh, Ar>,BiX2 (X=C1, OAc) couples with arylstannanes to give biaryls (Scheme 14.155) or, under a CO atmosphere, diaryl ketones (Scheme 14.156) [316]. Unsymmetrical biaryls are also prepared by Pd-catalyzed reaction of diaryliodonium salts with Ar3BiX2 [317]. Terminal acetylenes are phenylated by Ph3BiF2 under CuCl catalysis to afford phenyl-substituted acetylenes [318]. 

By the same procedure differently substituted aryl halides can also be coupled to biaryls and heterobiaryls but the method is rather impractical because the desired unsymmetrical product is always accompanied by the symmetrical ones. 

One of the most recent developments in the area of biaryl coupling is the use of higher order mixed diarylcyanocuprates these kinetically prepared higher-order cuprates function well at very low temperatures to yield unsymmetrical coupling products (Scheme 135) <94TL815>. Two dissimilarly substituted thiophenes have also been coupled by this procedure. 

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