Palladium-catalyzed reactions coupling

Palladium-catalyzed coupling reactions of organic halides with olefins or dienes (R. F. Heck, 1979) are broad in scope and simple to carry out. Anhydrous conditions or any special technique are not required and most functional groups are tolerated. 

Due to their successful synthesis of 2-(4 -chlorophenyl)-4-iodoquinoline from the corresponding precursor acetylene, Arcadi et al. (99T13233) developed a one-step synthesis of 2,4-disubstituted quinolines via palladium-catalyzed coupling reactions. An example is the Heck reaction of 4-iodoquinoline (131) with a-acetamidoacrylate (132). This one-pot synthesis yielded adduct 133 in 50% overall yield after purification via flash chromatography. 

The synthesis of 1-alkenylboronic acids from l-alkenylmagnesiums or -lithiums suffers from difficulty in retaining the stereochemistry of 1-aikenyl halides, but the palladium-catalyzed coupling reaction of diboron 82 with 1-aikenyl halides or tri-flates directly provides 1-alkenylboronic esters (Scheme 1-43) [157, 158]. Although the reaction conditions applied to the aryl coupling resulted in the formation of an... 

At the same time, Schmidtchen et al. compared cationic phosphine ligands containing the hydrophilic guanidinium (4.3, 4.4) and the anionic phosphine ligand TPPTS for this palladium-catalyzed coupling reaction. They found that the cationic ligands were effective for the coupling reaction but less efficient than TPPTS 43... 

Diazonium salts react with various nucleophiles in water (Eq. 11.62).106 In acidic aqueous solution, p-pheny I e ncbis di azo ni um ion reacts with alcohols more rapidly than it does with water.107 In the presence of nucelophiles such as halides, the substitution products are obtained. Furthermore, diazonium salts of aromatic compounds are excellent substrates for palladium-catalyzed coupling reactions such as the Heck-type reactions in water. 

Another palladium-catalyzed coupling reaction that has been successfully performed on soluble polymers is the Sonogashira coupling. Xia and Wang have presented an approach in which the PEG 4000 utilized simultaneously serves as polymeric support, solvent, and phase-transfer catalyst (PTC) in both the coupling and... 

The Fukuyama indole synthesis involving radical cyclization of 2-alkenylisocyanides was extended by the author to allow preparation of2,3-disubstituted derivatives <00S429>. In this process, radical cyclization of 2-isocyanocinnamate (119) yields the 2-stannylindole 120, which upon treatment with iodine is converted into the 2-iodoindole 121. These N-unprotected 2-iodoindoles can then undergo a variety of palladium-catalyzed coupling reactions such as reaction with terminal acetylenes, terminal olefins, carbonylation and Suzuki coupling with phenyl borate to furnish the corresponding 2,3-disubstituted indoles. 

Recent developments in palladium-catalyzed coupling reactions have arisen in the pyrimidine field as well. The Sonogashira coupling of bromopyrimidine 85 with alkynes 86 produced pyrimidines 87, important intermediates reported by Hart and co-workers in their approach to the cylindrospermopsin substructure . 

Scheme 2. Selected examples of palladium-catalyzed coupling reactions...

With regard to application in the pharmaceutical industry, palladium-catalyzed coupling reactions offer the opportunity of shorter and more selective routes for a number of currently marketed and future drugs. Therefore, it is not surprising that since the early 1990s more and more palladium-catalyzed reactions are transferred from academic protocols to the industrial context (Beller et al. 2001 Beller and Zapf 2002 de Vries 2001). Selected examples of processes that are used nowadays or have been used in the pharmaceutical industry are shown in Scheme 3. In order to see more realizations of this type of chemistry, more active and productive palladium catalysts have to be developed because of the high price of palladium and most often the ligand system. 

Scheme 4. Palladium-catalyzed coupling reactions of aryl chlorides...

In the palladium-catalyzed coupling reactions of arenes with alkenes, the cr-arylpalladium complexes react with CO to give aromatic acids in AcOH, as shown in Scheme u 97>97a 97c This carboxylation reaction of arenes with CO proceeds catalytically with respect to Pd at room temperature under atmospheric pressure of CO, when K2S2O8 is added as an oxidant and TFA is employed as a solvent. 

The 2,3-substituted indols are formed via a palladium-catalyzed coupling reaction of aryl halide, o-alkenylphenyl isocyanide, and amine (Equation (122)).481 Oxidative addition of an aryl halide, insertion of both the isonitrile and alkene moieties of o-alkenylphenyl isocyanide, and 1,3-hydrogen migration may form a 7r-allylpalladium species, which is then attacked by an amine to afford an indol. 

A separate, quite thorough study of terminal alkyne hydrosilylation with platinum arrived at a similar set of conditions.39 This work utilized a one-pot hydrosilylation with the preformed platinum(O) complex (>Bu3P)Pt[(CH2=CH)Me2Si]20 ([(CH2=CH)Me2Si]20 = DVDS) and subsequent palladium-catalyzed coupling reaction to demonstrate that the platinum catalyst is compatible with cross-coupling conditions, providing a convenient hydrocarbation of terminal alkynes (Table 2). 

Secondary phosphine oxides are known to be excellent ligands in palladium-catalyzed coupling reactions and platinum-catalyzed nitrile hydrolysis. A series of chiral enantiopure secondary phosphine oxides 49 and 50 has been prepared and studied in the iridium-catalyzed enantioselective hydrogenation of imines [48] and in the rhodium- and iridium-catalyzed hydrogenation functionalized olefins [86]. Especially in benzyl substituted imine-hydrogenation, 49a ranks among the best ligands available in terms of ex. 

Of all the palladium-catalyzed coupling reactions, the Kumada coupling has been applied least often in indole chemistry. However, this Grignard-Pd cross-coupling methodology has been used to couple l-methyl-2-indolylmagnesium bromide with iodobenzene and a-bromovinyltrimethylsilane to form l-methyl-2-phenylindole and l-methyl-2-(l-trimethyl-... 

Scheme 5 Palladium-catalyzed coupling reactions of C-l stannylated glycals with organic halides.

Reetz,M.T. and Westermann, E., Phosphane-free palladium-catalyzed coupling reactions thedecisive role of Pd nanoparticles, Angew. Chem. Int. Ed., 39, 165, 2000. 

Allylstannanes for use in palladium-catalyzed coupling reactions can readily be made from Lappert s stannylene, [(MesSi N Sn , with an ally 1 bromide or iodide. The reaction is immediate at room temperature, and the product can be used without further purification (Equation (92)).258... 

Palladium-Catalyzed Coupling Reactions of Propargyl Electrophiles with Hard Carbon Nucleophiles... 

Palladium-catalyzed coupling reactions are very efficient for the introduction of new carbon- carbon bonds onto molecules attached to solid support. The mild reaction conditions and compatibility with a broad range of functionalities and high reaction yields, have made this kind of transformation a very common tool for the combinatorial synthesis of small organic molecules. The literature for synthetic methods of palladium-catalyzed reactions on solid supports has recently been reviewed [237-239]. 

In the second series of experiments, O. Nuyken et al. investigated the Heck reaction of iodobenzene with styrene as a model for the numerous palladium-catalyzed coupling reactions (Scheme 6.6) [54]. In the literature only a few Heck coupling reactions of hydrophobic substrates in aqueous solution are known. The most detailed study has been performed by Jeffery et al. on the model reaction of iodobenzene with methylacrylate in the presence of tetrabutylammonia salts. Product yield was at least 95% after 2 h reaction time at 50 °C in pure aqueous solution [55], however more... 

The ratio of trimethylvinyltin to tetrahydrofuran is determined by NMR. The trimethylvinyltin/THF solution may be used in palladium-catalyzed coupling reactions without further purification. 

A kinetically controlled Negishi palladium-catalyzed coupling reaction was used in a highly stereospecific synthesis of (E)- or (Z)-a-fluoro-a,/(-unsaturated ketone (29), an intermediate to the above described depsipeptides [54], Reaction of E/Z gem-bromofluoroolefin (30) and alkoxyvinylzinc species (31) yielded (Z)-29 in 70-99% yields. When the unreacted (Z) bromo, fluoroolefin was allowed to react in tetrahydrofuran (THF) under reflux, (E)-29 was formed in up to 98% yield (Scheme 9). 

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