The importance of biaryls

Biaryl structures are wide-spread in many of naturally occuring products including alkaloids, lignans, terpenes, flavonoids, tannins, as well as polyketides, coumarins, peptides, glycopeptides, etc. For example, vancomycin (1) is a basic structure of several related glycopeptide antibiotics [1] balhimycin, actinoidin A, ristocetin A, teicoplanin A2-2, complestatin, etc which are important in medicinal chemistry or as a HPLC chiral stationary phases (vancomycin) [2]. 

A lot of natural pigments are biaryls as gossypol (2), a major constituent of cottonseed pigment, is a binaphthyl structured polyphenol, having also a male antifertility action 

Recently, in the medicinal chemistry, biphenyl motif became an important spacer within the structure of several modern antihypertenzive agents, so-called sartanes. For example, losartan (7) is one of the most prescribed block-buster drugs of today. 

The aryl-aryl bond formation is the most important reaction in the synthesis of various polyaryl materials which possess valuable conducting properties. The polyaryls such as poly-p-phenylene (PPP), which by various doping procedures reach a conductive state, are in focus as a potential for use as electrode materials in light-weight rechargeable batteries, electrochemical cells, semi-conductor devices, solar cells, and in the several other possible electrochemical uses. Very comprehensive polyarene-chemistry and its practical applications are excellently rewieved by Takakazu Yamamoto [6]. 

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Figure 3.1 Examples Illustrating the importance of biaryl compounds [1,2]. ...

The importance of biaryl units as components of many kinds of compounds, such as pharmaceuticals, herbicides, and natural products, as well as engineering materials such as conducting polymers, molecular wires, and liquid crystals, has attracted enormous interest from the chemical community. Palladium-catalyzed Suzuki coupling is the most important and efficient strategy for the construction of symmetrical and un-symmetrical biaryl compounds,... 

From the point of view of the synthetic organic chemist, the importance of aromatic thallation, and the remarkable degree of orientation control which can be exercised over this process, lies in the ease with which the resulting ArTlXj compounds can be converted into substituted aromatic derivatives in which the new substituent group has entered the ring at the position to which thallium was originally attached. Syntheses of phenols, nitroso compounds, biaryls, aromatic nitriles, thiophenols, and deuterated aromatic compounds have all been achieved these results are summarized briefly below. 

Mechanistic studies carried out by the Buchwald group97,98 on the key C-O bond formation step in these reactions have reinforced the importance of the properties of the ligand, and have led to the adoption of a variety of more sterically hindered ligands (e.g., 23, 24, 27, 29, and 30), which have given improved results for the preparation of biaryl ethers (Equation (15)),89 /-butyl aryl ethers,99 and aryl ethers of primary alcohols.100... 

Transition metal-catalyzed cross-coupling is now recognized to be one of the most powerful carbon-carbon bond-formation reactions [1], The palladium-catalyzed coupling of aryl halides or their synthetic equivalents, for example aryl triflates, with arylmetals is very often employed in the synthesis of biaryl molecules, whose skeletons are found in a wide range of important compounds including natural products and organic functional materials [1-3]. 

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. 

A novel macrocyclization reaction was developed based on a domino Miyaura boration intramolecular Suzuki crosscoupling sequence in the laboratory of J. Zhu. " This strategy was applied in the synthesis of biaryl-containing macrocycles. The diiodide substrate was dissolved in degassed DMSO, and then the catalyst and the base were added. Successful macrocyclization required extensive experimentation, and the authors determined that the concentration and the nature of the base were the two most important factors. Interestingly, potassium carbonate is not suitable as a base in the Miyaura boration, since it tends to give biaryl by-products, but in this particular macrocyclization reaction it proved to be completely ineffective because the reaction failed to take place. 

Ullmann reaction. During a study of the synthesis of biaryls with nickel catalysts (4, 33 6, 654), Tsou and Kochi2 found that nickcl(II) complexes such as 1 readily yield biaryls on treatment with an aryl halide and that they are important intermediates in the radical-chain process of nickel-catalyzed Ullmann reactions. 

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]. 

When a monosubstituted benzene is attacked by aryl radical, a mixture of all three isomeric biphenyls is produced, as well as in the GBH reaction [105-107]. The nature of substituents apparently does not play any important role except those of bulky ort/jo-groups. The ortAo-substituted biaryl is always the main product followed by para- and meto-arylation product. The presence of a bulky ortho-tert-huXy group significantly decreases the amount of ort/io-arylation product, indicating the strong ort/io-steric effect. The typical isomer distribution and the yields of biaryls in the arylation of four mono-substituted benzenes with dibenzoyl peroxide are given in the Table 4. 

However, the copper- and manganese-catalysed Stille reactions with aryl iodides have become the most important approaches to the synthesis of biaryls involving organostannanes. The efficacy of Cu- and Mn-catalysed Stille reactions can be seen from the examples in the Table 7. 

Despite the prevalence and importance of atropisomerism in organic structures, the field of asymmetric catalysis has not yet recorded extensive success in the development of catalysts, which control this stereochemical feature. Indeed, catalytic reactions of this nature are presently rare and only modest atropi-somer selectivity has been observed. In this context. Miller s group recently developed the DKR of biaryl atropisomers via peptide-catalysed asymmetric bromination. The reaction proceeded via an atropisomer-selective electrophilic aromatic substitution reaction using a simple bromination reagent such as A7-bromophthtalimide. As shown in Scheme 5.27, a series of chiral bromi-nated biaryl compounds could be prepared with excellent enantioselectivities of... 

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