Palladium mediated biaryl coupling

If the enhancement of enantiomeric excess did not impress you much (though it should, 99.96% is very difficult to achieve in one go ) perhaps an example where the ee is a bit lower after the first round will make the point more effectively. The bistriflate 82 contains a biaryl bond with restricted rotation so that replacing one of the triflates with something else will give us a chiral molecule (83a and 83b are enantiomers). As above, the first reaction is a desymmetrisation and the second reaction a kinetic resolution upon the products from the first. Both reactions are palladium mediated cross-couplings of an aryl triflate and phenyl Grignard. 

Palladium-catalyzed Functionalization at N-/. Palladium-mediated cross-coupling of variedly substituted indazoles using dialkylphosphino biaryl ligands delivers excellent yields for N- arylation products. The reaction conditions are tolerant toward the presence of electron-withdrawing nitro and cyano substituents at the 6-position of benzopyrazole. Importantly, the use of aryl chlorides and bromides in these coupling reactions expands the available scope of aryl halides available for coupling at the A -1 position (eqs 6-8). 

Palladium chemistry has rapidly become an indispensable tool for synthetic organic chemists. Palladium-catalyzed coupling is now the method of choice for the synthesis of a wide range of biaryls and heterobiaryls. The number of applications of palladium chemistry to the syntheses of heterocycles has grown exponentially. In this book important palladium-mediated reactions involving heterocycles are highlighted with emphasis on the unique characteristics of individual heterocycles. 

Aryltrimethyl- or tri- -butylstaimanes as common Stille reagents are also successfully homo-coupled under palladium catalysed reactions in the presence of ethyl 2,3-dibromophenylpropionate (443) [26], or more conveniently by oxidation with copper(I) salts, e.g. CuCl [27], or copper(II) salts, e.g. Cu(N03)2 3H20 [28,29], which proceed smoothly at room temperature in tetrahydrofuran or DMF to afford symmetrical biaryls in excellent 3uelds. The Cu(N03)2-mediated homo-coupling works well also with diaryldimethyl(or -butyl)stannanes [30]. Moreover, the reaction can be accomplished with a catalytic amount of copper(II) chloride or manganese(II) bromide (10 mol%) in the presence of iodine as stoichiometric oxidant [31]. For example, compound 443, acting as an oxidant, converts the phenyltri-n-butylstannane (184) to biphenyl (8) in 86% yield [26], Scheme 11. 

Following interesting and valuable method for synthesis of polyaromatics, including well known cancerogenic structures, is the trichlorosilane-mediated palladium-catalysed homo-coupling reaction of 1,4-epoxy-1,4-dihydroarenes to biaryls [100]. For example, the reaction of 7-oxabenzonorbomadiene (536) with trichlorosilane in the... 

The phenanthrene nucleus required for ( )-hasubanonine 79 (Scheme 17.16) was also assembled using RCM [35], in a similar way to that illustrated by luliano [26]. Initially, the biaryl compound 83 had to be assembled. This was done by synthesizing the aromatic iodide 84 and the aromatic pinacol ester 85. These compounds were then subjected to a palladium-mediated coupling, followed by conversion of the aldehydes to aUcenes, which proceeded smoothly to furnish 83. Compound 83 was then subjected to 2-Ru catalyst affording the required phenanthrene 86, which was then converted into ( )-hasubanonine 79 over a number of further steps. 

Pd-Catalyzed Reactions in the Presence of Ag Salts A bimetallic system containing a Pd catalyst has been used in some cases to achieve Ar-Ar bond formation. Palladium-mediated decarboxylative cross-coupling of aromatic acids and aryl iodides takes place efficiently under microwave heating (MW), affording the corresponding biaryls, as shown in Scheme 22.40 (path a) [55]. 

The Suzuki-Miyaura coupling has traditionally been carried out using palladium as the metal catalyst however, there have been several reports that employ alternative metals as catalysts for the coupling reaction. In fact a rather controversial report even disclosed the use of no metal catalyst however, on careful examination of the reaction conditions it was found that palladium contaminants down to a level of 50 ppb found in commercially available sodium carbonate were responsible for the generation of the biaryl rather than an alternative non-palladium-mediated reaction. ... 

Carbon Nucleophiles. Palladium-mediated homocoupling of substituted arenes generally yields mixtures of all possible coupling products. If the reaction is carried out with a catalytic amount of palladium diacetate and with thallium(III) trifluoroacetate as stoichiometric oxidant (eq 67), aryls carrying substituents such as alkyl or halide afford mainly the 4,4 -biaryls in yields ranging from 60% (R = ethyl) to 98% (R = H). Biaryls can also be formed without the palladium catalyst. 

In 1990, while working on the total synthesis of pradimicin, Kelly discovered that the treatment of a biaryl halide (46) or triflate in presence of hexaalkyldistannane (47) and a catalytic amount of Pd(PPh3)4 led to the clean intramolecular biaryl coupling to produce 48 in 80% isolated yield. This reaction can be regarded as the transmetalation with the distannane mediated by palladium to afford the intermediate organostannane 49 which then... 

As for the biaryl ether containing macrocycles, an array of bioactive macrocycles with an endo aryl-aryl bond exist in nature. A new palladium catalyzed reaction has been recently developed in which bis(pinacolato)diborane(4) mediated the process to reach such a structural motif. The reaction consists of a domino process involving a Miyaura s arylboronic ester synthesis and an intramolecular Suzuki-coupling. Synthesis of a bicyclic A-B-O-C ring system of RP-66453 273, a neurotensine receptor antagonist, with an endo aryl-aryl and an endo aryl-aryl ether bond was described (Scheme 53).141... 

Direct arylations of arenes are, however, not restricted to palladium-catalyzed transformations, but were also accomplished with, inter alia, iridium complexes. Thus, the direct coupling of various aryl iodides with an excess of benzene in the presence of [Cp IrHCl]2 afforded the corresponding biaryl products, but usually in moderate yields only (Scheme 9.30) [69]. The reaction is believed to proceed via a radical-based mechanism with initial base-mediated reduction of iridium(III) followed by electron transfer from iridium(II) to the aryl iodide. Rather high catalyst loadings were required and the phenylation of toluene (90) under these reaction conditions provided a mixture of regioisomers 91, 92, and 93 in an overall low yield (Scheme 9.30) [69]. 

The coupling reaction of arylsilanes with aryl iodides is also mediated by a palladium catalyst and a fluoride ion.f " Optimized reaction conditions are as follows (i) two fluorine atoms on silicon are required (ii) an ethyl or propyl group as a dummy alkyl ligand is preferred, because a methyl group competitively participates in the crosscoupling reaction and (iii) TBAF, a highly effective fluoride ion source, can be replaced by inexpensive KF. Various unsymmetrical biaryls are synthesized under the conditions (Scheme 10). 

---