Unsymmetrical biaryl synthesis

The Stille reaction has developed as a popular protocol for the formation of C-C bonds due to the air- and moisture-stability as well as functional group compatibility of organotin compounds. Together with the Suzuki-Miyaura coupling it is one of the most powerful methods for the synthesis of molecules containing unsymmetrical biaryl moieties. However, despite its efficiency, this versatile reaction has slowly been displaced by other procedures that avoid the use of highly toxic organostannanes. 

The direct preparation of arylboronic esters from aryl halides or triflates now allows a one-pot, two-step procedure for the synthesis of unsymmetrical biaryls (Scheme 1-41) [147]. The synthesis of biaryls is readily carried out in the same flask when the first coupling of the triflate with diboron 82 is followed by the next reaction with another triflate. The synthesis of naturally occurring biflavanoids and the couphng of N-(phenylfluorenyl)amino carbonyl compounds to polymeric supports are reported [154]. 

SYNTHESIS OF UNSYMMETRICAL BIARYLS USING A MODIFIED SUZUKI CROSS-COUPLING 4-BIPHENYLCARBOXALDEHYDE ([1,1 -Biphenyl]-4-carboxaldehyde)... 

So far a high selectivity in the electrochemical synthesis of unsymmetrical biaryls has only been obtained in two-step processes. 

Unsymmetrical biaryls.14 The Pd(0)- or Ni(0)-catalyzed coupling of arylzinc derivatives with aryl halides appears to be the method of choice for synthesis of unsymmetrical biaryls (equation I). Both Pd[P(C6H5)3]4 and Ni[P(C6H5)3]4 are usually equally effective with aryl iodides, but only activated aryl bromides can be coupled with Pd(0). 

The coupling of Grignard reagents with alkyl, vinyl or aryl halides under Ni-catalysis provides an economic transformation, but the reaction is limited to halide partners that do not react with organomagnesium compounds. One example is in the industrial-scale production of styrene derivatives, and the Kumada Coupling is the method of choice for the low-cost synthesis of unsymmetrical biaryls. 

Nitrosoacetylamine Reaction. In this synthesis of unsymmetrical biaryls, developed by Grieve and Hey 7 and Heilbron8 and collaborators, three steps are involved (illustrated by the preparation of 3-nitrobi-phenyl). 

Hart, H., Harada, K. and Frank Du, C.-J. (1985) Synthetically useful aryl-aryl bond formation via Grignard generation and trapping of arynes. A one-step synthesis of p-terphenyl and unsymmetrical biaryls. The Journal of Organic Chemistry, 50, 3104-10. 

The Ullmann reaction (Figure 16.5) represents another synthesis of biaryls that reliably leads to the formation of symmetric biaryls (upper and middle reaction examples), but, in particular cases, is also suitable for the synthesis of unsymmetrical biaryls (lower reaction example). To prepare a symmetric biaryl in the traditional way, an aryl iodide is heated with Cu powder in order to prepare the parent compound of biaryls, i.e., biphenyl, one starts with iodobenzene. The metal reduces 50% of the substrate to phenylcopper in situ. The latter... 

The mixed Ullman reaction in which two haloarenes couple in the presence of copper powder is still commonplace in industrial process, but the catalyzed cross-coupling reactions appear to be more productive and provide reliable results in synthesis of unsymmetrical biaryls (Scheme 30). The isomeric michel-... 

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. 

The synthesis of unsymmetrical biaryls 8 from two monoaryl species involves the coupling of a metallated aromatic molecule 6 with an aryl halide or triflate 4 under the action of palladium(O) catalysis. The reaction involves a catalytic cycle in which palladium(O) inserts into the C-halogen bond via an oxidative addition to generate an arylpalladium(II) species 5 (Scheme 10.18). This undergoes a trans-metallation with the metallated component, producing a biarylpalladi-um(II) complex 7. The biaryl product is formed by reductive elimination. In the process, Pd(0) is regenerated and this can then react with a second molecule of aryl halide. Pd(0) is therefore a catalyst for the reaction. 

The ready availability of ort/io-functionalized arylboronic acids by a direct ortho-metallation-boronation sequence (Scheme 2-45) provides a very useful synthetic link to the cross-coupling protocol. Snieckus has amply demonstrated that the sequence has considerable scope for the synthesis of unsymmetrical biaryls, heterobiaryls, and terphenyls [120]. 

Negishi, E., King, A. O., Okukado, N. Selective carbon-carbon bond formation via transition metal catalysis. 3. A highly selective synthesis of unsymmetrical biaryls and diarylmethanes by the nickel- or palladium-catalyzed reaction of aryl- and benzylzinc derivatives with aryl halides. J. Org. Chem. 1977,42, 1821-1823. 

Aryllead tricarboxylates have been shown to react in trifluoroacetic acid with a range of aromatic compounds to give biaryls [31c]. With aromatic compounds that are more electron-rich than toluene the yields are generally good and the method is a useful synthesis of unsymmetrical biaryls (Scheme 13.18). It has been reported that a cationic intermediate generated from aryllead tricarboxylates was probably involved. 

Scheme 39 Synthesis of unsymmetrical biaryls via ort/ro-arylation/hydrogenolysis reaction...

In 2006, the synthesis of unsymmetrical biaryls from simple arenes was achieved successfully in a catalytic system of Pd(OAc)2/TFA/K2S2Og by tuning the concentrations of arenes and TFA, reported by Lu and coworkers (Scheme 15) [61]. Although the yield of cross-coupling reaction is not practical (11-50% based on the limiting arene), it provides valuable information on the Pd-catalyzed crosscoupling reaction via double aromatic C-H activation. 

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