Biaryls highly hindered

Yet, despite a broad spectrum of classical and more modern procedures for the chemical connection of aromatic moieties2-4, the development of efficient aryl coupling methods that allow the directed, namely regio- and especially stereoselective, construction of even sterically highly hindered biaryls, has only recently begun these stereoselective reactions will be dealt with in this section. 

Directed remote metalation (DreM) of biaryl amides and O-carbamates, conceptually based on the complex-induced proximity effect (CIPE) [15] provides, especially in view of their link to transition metal-catalyzed cross coupling regimens [16], general and versatile routes to fluorenones (16 —> 15, Scheme 4) [5,17] and biaryl amides (16 —> 17) [18] whose features are overriding Friedel-Crafts reactivity and yield enhancement in comparison to Suzuki-Miyaura coupling routes for highly hindered biaryls, respectively. Additional features of the O-carbamate DreM result is potential further DoM of 17 with appropriate phenol protection and cyclization to dibenzopyranones [18]. 

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]. 

Yin, J. Rainka, M. P. Zhang, X.-X. Buchwald, S. L. A highly active Suzuki catalyst for the synthesis of sterically hindered biaryls novel ligand coordination. J. Am. Chem. Soc. 2002, 124, 1162-1163. 

Variation in electronic effects within the biaryl backbone has produced the P-Phos family of ligands, which contain a hindered dipyridinyl backbone. These ligands have demonstrated high catalytic activities and enantioselectivities with JST catalysts. 

The palladium(0)-catalyzed borylation/Suzuki coupling protocol was developed by Baudoin and co-workers in order to synthesize sterically hindered 2,2 -disubstituted biaryl compounds such as 170 in high yield and in a convenient manner [162,163], Indeed, the catalytic borylation of 2-bromoaniline 167 (R=H) gave the corresponding pinacolboronic ester 168 which was reacted in a one-pot fashion with phenyl iodide 169 in the presence of barium hydroxide to give the functionalized biphenyl 170 in 78% yield. Cleavage of the MOM group and cyclization in the presence... 

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],... 

Caused by the high rotational barrier of the biaryl linkage, an element of axial chirality emerges. In addition, the rotation of the aryl residues of the amino acids 6 and 2 (Scheme I) around their longitudinal axes is hindered, resulting in two elements of planar chirality. The unu-... 

Biaryls. Nickel complexes of the type NiCl2L2 catalyze the cross-coupling of sterically hindered aryl Grignard reagents with an aryl bromide to give biaryls in high yield as shown in the example. Thus 2-phenylmesitylene can be... 

Sulfur-containing palladacycle XVIII-13 is a precursor of an effective catalyst in the presence of Bu4NBr [36]. Palladacycle XVIII-1 is an efficient catalyst, and high TON (74 000) was obtained in the coupling of electron-deficient aryl bromide 27 [37]. Preparation of sterically hindered biaryl 28 was carried out with bulky phenanthrene-based phosphine V-5 [38]. 

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... 

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