Highly substituted biaryls

Oxidative dimerization of A,A-dialkyl-<9-(8-lithio-7-quinolyl)carbamates with anhydrous ferric chloride has been shown to be efficient for the preparation 1,1 -dioxygenated 8,8 -biquinolyls (Scheme 61) and it is anticipated that this tandem halogen-dance oxidative dimerization reaction will find further applications for the synthesis of other highly substituted biaryl molecules.96... 

This anionic remote Fries rearrangement provides a general route to highly substituted biaryls 146 which, due to steric effects, may be difficult to prepare directly by Suzuki-Miyaura cross-coupling, as evidenced in the comparison with the synthesis of dibenzopyr-anones 147 (Scheme 39) [66]. The efficient acid-catalyzed cyclization to dibenzopyranones shows broad scope both for unusually substituted (148-150, Scheme 40) and various heterocyclic analogues (151-153, Scheme 40) [65, 67]. 

Ni complexes are used in place of copper metal and 2) for the preparation of highly substituted biaryls the use of preformed aryl copper species has been successful (Ziegler modification). °... 

Method X is a modification of the method F where barium hydroxide was used as the base in 96% ethanol to affect efficient SM reactions of aryl bromides at room temperature with excellent yields. In this manner, boronic acid 280 and 3,4-methylene dioxybromobenzene (281) were converted under very mild reaction conditions to the highly substituted biaryl 282 in 96% yield [10], respectively. Scheme 22. 

Wang, W. (1991) Directed ortho and remote aromatic metalation synthesis of highly substituted biaryls, dibenzo(b,d)pyranones and 3,3 -substituted-l,l -bi-2-naphthols. M.Sc. Thesis. University of Waterloo, Canada. 

The present method of preparation of 4,4 -dimethyl-l,l -biphenyl is that described by McKillop, Elsom, and Taylor 15 It has the particular advantages of high yield and manipulative simplicity and is, moreover, applicable to the synthesis of a variety of symmetrically substituted biaryls 3,3 - and 4,4 -Disubstituted and 3,3, 4,4 -tetrasubstituted 1,1 -biphenyls are readily piepared, but the reaction fails when applied to the synthesis of 2,2 -disubstituted-l,T biphenyls The submitters have effected the following conversions by the above procedure (starting aromatic bromide, product biphenyl, % yield) bromobenzene, biphenyl, 85,1 -bromo-4-methoxybenzene, 4,4 -dimethoxy-l, 1 -biphenyl, 99, 1 bromo 3 methylbenzene, 3,3 dimethyl-1,l -biphenyl, 85 4-bromo-l,2-dimethylbenzene, 3,3, 4,4 -tetramethyl-l,l -biphenyl, 76, l-bromo-4-chlorobenzene, 4,4 -dichloro-l,l -biphenyl, 73, l-bromo-4-fluorobenzene, 4,4 -difluoro-l,l -biphenyl, 73... 

Very recently another highly active and well-defined Pd-NHC based pre-catalyst containing a cyclopentadienyl (Cp) ligand 18 has been successfully applied in this transformation. Cp was chosen as stabilising ligand due to its well-known tendency to reductively be removed from Cp-Pd complexes that may help in the transformation of the pre-catalyst into the desired catalytic active species (NHC)Pd(O) [107]. Di- and tii-ortho substituted biaryls were obtained in good to excellent yields however, when the formation of tetra-orf/to substituted compounds was attempted very poor yields were obtained, even using aryl bromide or iodide substrates (Scheme 6.28). 

Restricted rotation about the biaryl axis as a result of bulky substituents leads to the existence of atropisomers. Depending upon the degree of steric hindrance due to the ortho substituents, three or four substituents are needed to produce a sufficient barrier to rotation at room temperature. This particular form of axial chirality is not generally resistant to heat. To produce acceptable yields of hindered biaryls under Suzuki conditions, high temperatures (60-110 °C) [78, 85] and reaction times of several hours are required. In atropisomer-selective reactions, these conditions would be deleterious to the discrimination between dia-stereomeric transition states and could racemize the biaryls formed. As a consequence, it is necessary to carry out such Suzuki reactions at ambient temperature. Recently, conditions employing Pd(OAc)2 and 95 % ethanol were used to generate mono-ortho-substituted biaryls at 20 °C (Eq. (54)) [86],... 

The polymer-assisted solution-phase (PASP) synthesis of a 192-member group of 1,5-biaryl pyrazoles from 1,3-diketones and 4-hydrazinobenzoic acid as precursors has been reported <2004JC0332>. Condensation of aromatic or aliphatic esters with resin-supported sulfonamides 527, followed by cyclization with hydrazines, activation with trimethylsilyldiazomethane, and cleavage using amines, provided highly substituted, isomeric pyrazoles 528 and 529 (Scheme 63) <20000L2789>. 

The highly substituted biphenyls [99-106], phenylpyridines [99,100], phenylthiazoles [99], terphenyls [101], and some natural products [102] containing the biaryl structures have been successfully obtained using this strategy. 

Several hindered ortho-di-, tri- and tetra-substituted biaryls were successfully obtained by this method in 58-98% yields [114]. Recently, the great breakthrough has been achieved since several very active palladacycle catalysts were developed [120-131]. The first report by Beller and coworkers [120] has shown very high activity of the palladacycle complex 89 (see Chapter 3) with TON S up to 74 000 in the SM reactions of aryl bromides and activated chlorides. Najera s group [121,122] has developed... 

Somewhat different approach to the synthesis of orf/jo-substituted biaryls was reported by Julia and coworkers [48]. They found that tert-butylsulfonyl group can be replaced by aryl-carbanions originated from Grignard reagents in Ni(acac)2-catalysed process with formation of biaryls in moderate to high yields. Aryl-tert-butylsulfones are readily obtained by quenching the aryllithiums with di-tert-butyl disulfide, followed... 

Other groups have followed the investigations of Nolan and Herrmann with novel NHC-based palladium catalysts. Carbenes derived from bisoxazolines are suitable for the synthesis of highly hindered tetra-ortho-substituted biaryls (Equation 2.36) [65]. 

Furthermore, the Tedicyp/fPdClfCjHjljj system efficiently catalyzes the Suzuki coupling of sterically hindered substrates. Very high turnover numbers can be obtained for the coupling of sterically hindered aryl bromides with benzeneboronic acid or for the coupling of bromobenzene with sterically hindered arylboronic acids. Conversely, the formation of tri-ortho-substituted biaryl adducts requires a high catalyst loading (Equation 65) [87]. 

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