Biaryl synthesis ortho substituents

B. SYNTHESIS OF BIARYLS WITHOUT ORTHO SUBSTITUENTS VIA Pd- OR Ni-CATALYZED ARYL-ARYL COUPLING... 

It is especially noteworthy that this reaction sequence to ( + )-ancistrocladisine (8) offers the unique possibility of synthesizing a natural biaryl compound with two identical ortho-substituents, e.g, methoxy groups, next to the biaryl linkage (see also the nonstereoselective synthesis of ancistrocladisine as a mixture of all four possible stereoisomers13). 

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]. 

The main difficulties associated with constructing the biaryl moiety as a single atropisomer early in the synthesis lies within the arene substitution pattern. The thermal isomerization barrier for a steganone precursor that carries only three ortho substituents is extremely sensitive to the exact identity of those substituents. Specifically, when one of the three groups (e.g., a formyl moiety) adds only a small amount to the inversion barrier and a second substituent (e.g., a methoxy group) is also relatively small, the barrier to inversion renders the biaryl stereochemically labile even at 0 For example, at least one of... 

Synthesis of biaryls without an ortho substituent (Sect B). 

Synthesis of biaryls containing one or two ortho substituents (Sect. C). 

Synthesis of chiral atropisomeric biaryls containing three or four ortho substituents (Sect. D). 

D. SYNTHESIS OF BIARYLS CONTAINING THREE OR FOUR ORTHO SUBSTITUENTS... 

Some representative examples of the synthesis of biaryls containing just one ortho substituent are shown in Table 8. The product yields are generally in the range of 70-100%, and Mg, Zn, B, and Sn are commonly used. Thus, one ortho substituent does not generally exert significant steric effects detrimental to the desired CTOSS-coupling. Somewhat surprisingly, even those substituents that can chelate metals, such as COOMe " and have been... 

An alternative to the Meyers or Cram oxazoline methods is the use of 2-menthoxybenzoates for the synthesis of axially chiral biaryls. Treatment of the ester 34 with Grignard reagent 35 provides the (M)-biphenyl 36 in 94% e.e (ref. 23). However, poor enantioselectivities were observed in cases where an ortho chelating substituent on the Grignard reagent was absent. 

In a handful of cases, two CCXIH groups have been activated for the synthesis of biaryls. Larrosa and coworkers reported for the first time the decarboxylative homocoupling of aromatic acids mediated by Pd and Ag [62a]. The reaction makes use of Pd(TFA)j as a catalyst and Ag CO as an additive to afford the desired biaryls in 76-95% yields. The only by-products observed were due to the proto-decarboxylation of the aryl carboxylic acid. Both metals are essential for the reaction, and the role of the Ag salt is not only as the terminal oxidant but also as a mediator of the decarboxylation process. The method is subject to some limitations on the substituents on the benzoic acids. Thus, m- and p-nitrobenzoic acids as well as benzoic acids ortho substituted with F, Br, or MeO failed to give decarboxylative homocoupling products. In all cases, protodecarboxylations to the corresponding arenes were the main products observed. The same problem was reported in the protocol developed by Deng and coworkers, where the best results were obtained with PdCl and PPhj in the presence of Ag COj [62b]. 

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