Suzuki hindered biaryls

The aforementioned PEPPSI-IPr pre-catalyst 16 has also been used in the Suzuki-Miyaura reaction. This pre-catalyst allowed the easy preparation of hindered biaryls and drug-like heteroaromatic compounds in good to excellent yields (Scheme 6.27). 

Watanabe, T. Miyaura, N. Suzuki, A. Synthesis of sterically hindered biaryls via the Pd-cat-alyzed cross-coupling reaction of arylboronic acids or their esters with haloarenes. Synlett 1992, 207-210. 

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. 

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]. 

Another total synthesis of michellamines A-C, korupensamines A-D, and ancistrobrevine B has been developed by Hoye et al. [32], who emphasized that Suzuki coupling of the boronic acid derived from the naphthalene moiety with a THIQ-iodide proved to be the most generally effective method for forming the hindered biaryl bond. A racemic isochromane analogue of michellamines has been synthesized by a similar procedure [33]. 

Leadbeater and Griffiths developed palladium catalysts for the Suzuki cross-coupling of aryl halides bearing two ortho substituents with phenylboronic acid, and used them in the synthesis of sterically hindered biaryls [83]. 

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],... 

Genet et al. have reported recently that Suzuki cross-coupling reactions between a range of aryl bromides and boronic acids using a water-soluble Pd/TPPTS (sodium triphenylphosphinometatrisulfonate) catalyst occur under mild conditions with high efficiency. The process tolerates both electron-rich and electron-poor substituents and provides an efficient access to sterically hindered biaryls. Good turnovers are observed and the catalyst can be recycled three times without loss of activity (Equation 48) [57]. 

Buchwald et al. have reported a number of bulky phosphine ligand PR 2R which give high activity in Suzuki— Miyaura catalysis for the synthesis of sterically hindered biaryls.The conditions used in the catalysis involved the in situ preparation of the Pd(0) catalyst from Pd2(dba)3 and the phosphine. Two ligands which proved superior to the others had in common the same polyaromatic R (R = Cy, Ph) as a difference from the rest. A Pd(0) complex could be prepared by mixing Pd2(dba)s and PR 2R in toluene, which has the X-ray structure 40 sketched in the upper reaction of Scheme 25. The key structural feature of the complex is the short distance of Pd to one double bond of the phenanthrene moiety (distances to the two carbons are 2.298 and 2.323 A) supporting an 77 -phenanthrene... 

A new synthetic approach to fluorescent 4-amino-4 -boryl biaryls by a boronate selective Suzuki-coupling of / -(dimesitylboryl)phenylboronates with haloarenes under the employed reaction conditions has been reported. The triarylboryl unity is not attacked whereas non-sterically hindered triarylboranes like tri-l-naphthylborane gave coupling products in good yields 207.120... 

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... 

Deprotonation of 3-fluorotoluene 53 with n-BuLi-KOr-Bu or, better, r-BuLi-KOr-Bu follows the selectivity expected with these superbases and leads to metallation at the least hindered position ortho to the fluoro substituent. Trapping the metallated intermediate 54 with dimethylfluoroboronate gave, after hydrolysis, a boronic acid whose Suzuki arylation provided the biaryl 55. These four steps may be carried out in a single pot, giving 55 in 79% overall yield from 53. 

When IBioxl2 HOTf was employed as the ligand precursor for the Suzuki-Miyaura coupling of sterically hindered aryl chlorides and aryl boronic acids, excellent to good yields were obtained in refluxing toluene for a variety of starting materials (Table 6). Notably, this work represents the first report of tetra-orf/zo-substitulcd biaryl compounds achieved from aryl chlorides [143]. 

Suzuki and co-workers found that aryl triflates react with arylboronic acids [ArB(OH)2], in the presence of a palladium catalyst, to give biaryls in a reaction that is now known as Suzuki coupling.269 Even hindered boronic acids give good yields of the coupled product.2 0 Organoboranes, react with aryl triflates under these conditions as well. In a simple example, boronic acid 426 reacted with 3-bromopyridine in the presence of Pd(PPh3)4 to give a 90% yield of the biaryl 427.2 2... 

Due to the growing importance of asymmetrically substituted biaryl derivates used as drug intermediates, the Suzuki coupling reaction is increasingly important. Mostly, however, large amoimts of catalyst are used and the catalyst recycling is often hindered by precipitation of palladium black. 

The enantioselective Suzuki-Miyaura reaction (SM) can be accomplished by using the chiral ligands 213 [37] or 631 [38], whose palladium complexes catalysed the crosscoupling reaction of sterically hindered iodides and bromides with also quite encumbered arylboronic acids furnishing the axially chiral, sterically demanded biaryls in moderate to good yields with low to moderate enantioselectivity. 

Phosphine 23 proved in general to be an excellent ligand for Suzuki coupling reactions to form stericaUy hindered tetra-ortho-substituted biaryls in good yields. Ortho substituents such as methyl, primary alkyl, phenyl, and alkoxy groups are accommodated. It was necessary to use 2.0 equiv of the boronic acid to effect complete consumption of the aryl bromide in some cases, presumably due to competitive pro-todeboronation. Crystallographic analysis of 23/Pd(dba) revealed an unusual rc-coor-dination of the phenanthrene moiety - the first of its type for a Pd(0) complex (Equation 50) [61]. 

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]. 

The biaryl moiety of proteasome inhibitor TMC-95 has been prepared via a ligandless Pd(OAc)2-catalyzed Suzuki-coupling reaction of 7-iodoisatin with steri-cally hindered tyrosine-derived aryl boronic acid using potassium fluoride as a... 

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