Palladium acetate biaryl couplings

The procedure described here incorporates a number of modifications to the Suzuki coupling that result in a sound, efficient and scaleable means of synthesizing biaryls. First, the catalytic use of palladium acetate and triphenylphosphine to generate palladium(O) eliminates the need for the expensive air and light sensitive tetrakis(triphenylphosphine)palladium(0). No purification of reagents is necessary, no special apparatus is required, and rigorous exclusion of air from the reaction mixture is not necessary. Furthermore, homo-coupled products are not present in significant levels (as determined by 500 MHz 1H NMR). 

As an alternative to the Ullmann reaction, haloarenes are coupled to form the biaryls using palladium acetate in the presence of abase and tetra-n-butylammonium bromide [24], Yields are generally high (>70%) but dehalogenation of the haloarene may also occur as a side reaction. 

Researchers from Merck elaborated a convergent synthesis for the AT II antagonist losartan 30 with the key biaryl coupling step in the final stage of the protocol [100]. The two reaction partners 28 and 29 were coupled very efficiently (99% yield) utilizing 1 mol% of palladium(II) acetate and 4 mol% triphenylphosphine. As the solvent, a 1 4 mixture of THF and diethoxymethane containing a defined amount of water was crucial for the high reaction rates and yields. 

Palladium acetate is better than PdCl2(dppf) in terms of cost and catalyst removal and effectively catalyzes the cross-coupling of a wide variety of aryl halides with bis(pinaco-lato)diboron to form the corresponding boronates. These boronates can be conveniently isolated or used in situ for Suzuki cross-coupling reactions with aryl halides to provide biaryls [189b]. 

Other oxidants like thallium(III) oxide, vanadium(V) oxyfluoride, palladium ) acetate, and ruthenium(IV) tetrakis(trifluoracetate) have been developed as powerful tools for the intramolecular biaryl coupling reaction [7,93,113]. Nevertheless, DDQ is still one of the most versatile reagents in oxidative coupling reactions (see Scheme 14 and 29 [82,114]). The highly strained dioxa[8](2,7)pyrenophane (65), portraying an overall curvature of nearly 90° for the pyrene subunit, was finally obtained from the mefa-cyclophanediene (66) by dehydrogenation with DDQ in refluxing benzene in 67% yield [114]. 

Leadbeater et al. recently showed that the PTC procedure with MW irradiation can be used to prepare of biaryls using water, palladium acetate, and TBAB as solvent, catalyst, and phase-transfer agent, respectively [117]. The desired coupling products were obtained in good yield (60 to 90%). The reaction can, however, be performed equally well using MW and conventional heating methods. Although it... 

In general it is not advisable to have the palladium-catalysed coupling reaction as last or penultimate step in view of the need to reduce palladium levels in the final product to below 10 ppm. Based on this reasoning, Taiwanese chemists patented an alternative route towards Lapatinib in which the furan ring is coupled to the quinazoline moiety before attachment of the substimted aniline (Scheme 23) [69]. Thus, coupling between the furfural-boronic acid 99 and aryl halide 103 catalysed by a catalyst prepared in situ from palladium acetate and one equivalent of tri-t-butylphosphine (2 mol%) gave the biaryl compound 104 in 98% HPLC yield. 

The total synthesis of the proteasome inhibitor cyclic peptide TMC-95A was accomplished by. S.J. Danishefsky and co-workers. The biaryl linkage in the natural product was constructed by a Suzuki cross-coupling between an aryl iodide and an arylboronic ester derived from L-tyrosine. The required arylboronic pinacolate substrate was prepared using the Miyaura boration. The aryl iodide was exposed to b/s(pinacolato)diboron in the presence of a palladium catalyst and potassium acetate in DMSO. The coupling proceeded in high yield and no symmetrical biaryl by-product was observed. 

Palladium, in the form of palladium(II) acetate, has also been used to catalyze biaryl formation directly from aryl iodides (R3N 100 °C), especially P-NO2 and p-Cl derivatives. As usual, ortho substituents severely hinder this type of coupling. Related reductive couplings of aryl halides have been achieved using hydrazine and a Pd-Hg catalyst, electrochemically generated Pd° catalysts, or a palladium on carbon catalyst in the presence of aqueous sodium formate, sodium hydroxide and, crucially, a catalytic amount of a surfactant. The first two procedures look to be particularly selective and efficient, while the latter, rather different, method is not so efficient but does look amenable to large scale work. 

The intermolecular examples of synthetic value are self-couplings, e.g. formation of the dimer (43) from benzylsesamol, in 85% yield using vanadium oxytrifluoride preparation of the biaryl (44 95%), from 4-methylveratrole, employing iron(III) chloride supported on silica and synthesis of 4,4 -dimeth-oxybiphenyl (69%) fr om anisole by oxidation with thallium(III) trifluoroacetate in the presence of catalytic palladium(II) acetate. This approach has been used in a natural product synthesis. The dimers (45) and (46) were prepared from appropriate derivatives of gallic acid, and transformed into schizandrin C (47) and an isomer respectively. ... 

In early 1970 s Norman and coworkers [4] reported the first coupling reactions of aryl halides using palladium(ll) acetate under reaction conditions typical for the Heck reaction. They found that aryl iodides readily couple when they are treated with the catalytic quantity of palladium(Il) acetate in refluxing triethylamine or tri- -butyl amine to produce biaryls in moderate to good yields, Table 7. 

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