Biaryl cross-coupling

Biaryls, Cross-Coupling and the Promise of C-H Functionalization Methods.. 232... 

Aldous and co-workers also reported extensive results on palladium-catalyzed coupling reactions. They introduced the utility of electron-deficient pyridazinyl triflate 136 in Stille and Suzuki biaryl cross-couplings with electron rich aryl stannanes and aryl boronales 137 <01SL150>. Electron deficient aryl stannanes resulted in more sluggish reactions and poor yields. In general, Suzuki reactions were found to be better than the corresponding Stille couplings. 

Scheme 3.7 Cu-catal3 ed asymmetric oxidative biaryl cross-coupling reactions reported by Habaue.

In 2012, Itami and Yamaguchi discovered the bisoxazoHne-Pd catalysts such as 173 and 174 that enable the synthesis of hindered heterobiaryls by direct C-H coupling. Moreover, they demonstrated the first enantioselective C-H biaryl cross-coupling (Scheme 17.49) [227]. For example, when an n-PrOH solution of thiophene 175 and arylboronic acid 176 was treated with a Pd(OAc)2/biox 174 catalyst and TEMPO at 70 °C under air, (S)-177 was obtained in 41% ee (63% yield). When a more hindered arylboronic add 178 was used, the enantiometric excess of product (S)-179 was increased to 72% at the expense of lower yield. 

The transition metal catalyzed cross coupling of an organohalide with a boronic acid derivative, the Suzuki-Miyaura coupling, has become one of the most popular ways of preparing biaryls.3 The reaction is very robust and can easily be scaled to provide multigrams of material.4... 

Microwave and fluorous technologies have been combined in the solution phase parallel synthesis of 3-aminoimidazo[l,2-a]pyridines and -pyrazines [63]. The three-component condensation of a perfluorooctane-sulfonyl (Rfs = CgFiy) substituted benzaldehyde by microwave irradiation in a single-mode instrument at 150 °C for 10 min in CH2CI2 - MeOH in the presence of Sc(OTf)3 gave the imidazo-annulated heterocycles that could be purified by fluorous solid phase extraction (Scheme 9). Subsequent Pd-catalyzed cross-coupling reactions of the fluorous sulfonates with arylboronic acids or thiols gave biaryls or aryl sulfides, respectively, albeit it in relatively low yields. 

A drawback of the Heck-type reaction is that it is not strictly regioselective [119]. Depending on the substituents >1% of 1,1-diarylation is observed. Soluble 2,5-dialkoxy-PPVs 63 or 2-phenyl-PPV PPPV 93, without 1,1-diarylated moieties, were synthesized by Heitz et al. in a Suzuki-type cross coupling of substituted 1,4-phenylenediboronic acids and fran5-l,2-dibromoethylene, catalyzed by Pd(0) compounds [120]. However, about 3% of biaryl defect structures are observed in the coupling products (M up to 12,000), resulting from homocoupling of boronic acid functions. 

It was not until Cazin and co-workers introduced the well-defined dimer complex [Pd( J,-Cl)(Cl)(SIPr)]2 that the Kumada-Tamao-Corriu cross-coupling between severely sterically hindered partners was pursued, allowing the synthesis of tri- and tetra-orf/io substituted biaryls [81] (Scheme 6.20). 

Chamoin S, Houldsworth S, Kruse CG, Bakker WI, Snieckus V. The Suzuki-Miyaura cross coupling reactions on solid support. Link to solution phase directed ortho metalation. The Leznoff acetal linker approach to biaryl and heterobiaryl aldehydes. Tetrahedron Lett 1998 39 4179-4182. 

If the stannane bears substituents at the position geminal to tin, the reaction requires activation by Cu1 (Section 9.6.3.2.1). The cross-coupling of aryl (or heteroaryl) stannanes with aryl (or heteroaryl) halides or triflates is a general route to various biaryls and their analogues, particularly useful in those cases when the Suzuki-Miyaura reaction is less effective for... 

A general method for the Pd-catalyzed cross-couplings of alkyl- and arylzinc chlorides with aryl, heteroaryl, and vinyl chlorides was reported by Dai and Fu.420 They determined that the commercially available and air stable complex Pd(PBut3)2 catalyzed these reactions leading to the formation of an sp2)C - sp2)C bond (Scheme 164). Remarkably, bulky biaryls with two, three, or even four 0/7/fo-substituents (e.g., 323) were obtained in very high yields (76-96%). 

Several microwave-assisted protocols for soluble polymer-supported syntheses have been described. Among the first examples of so-called liquid-phase synthesis were aqueous Suzuki couplings. Schotten and coworkers presented the use of polyethylene glycol (PEG)-bound aryl halides and sulfonates in these palladium-catalyzed cross-couplings [70]. The authors demonstrated that no additional phase-transfer catalyst (PTC) is needed when the PEG-bound electrophiles are coupled with appropriate aryl boronic acids. The polymer-bound substrates were coupled with 1.2 equivalents of the boronic acids in water under short-term microwave irradiation in sealed vessels in a domestic microwave oven (Scheme 7.62). Work-up involved precipitation of the polymer-bound biaryl from a suitable organic solvent with diethyl ether. Water and insoluble impurities need to be removed prior to precipitation in order to achieve high recoveries of the products. 

The Table lists the results of applying these modified conditions to a number of biaryl derivatives, including recent examples from the literature. With the exception of entry 6, that employs a non-reactive aromatic chloride, all the cross-couplings result in excellent yields and are indicative of the generality of this procedure. 

Preparation o< Biaryls via Pd(0) Catalyzed Cross-Coupling of Boronic Acids with Aryl Halides3... 

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

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