Copper cocatalysts

Although the Sonogashira reaction is normally performed with a copper cocatalyst, a copper-free, one-pot procedure for direct coupling with l-aryl-2-trimethylsilylacetylenes has been developed <2005T2697>. The procedure uses a mixture of palladium acetate and tri(o-tolyl)phosphine as catalyst in the presence of tetra- -butylammonium chloride... 

The Wacker process (Eq. 1) was developed nearly 50 years ago [1-3] and represents one of the most successful examples of homogeneous catalysis in industry [4-9]. This palladium-catalyzed method for the oxidation of ethylene to acetaldehyde in aqueous solution employs a copper cocatalyst to facilitate aerobic oxidation of Pd° (Scheme 1). Despite the success of this process, certain features of the reaction have Umited the development of related aerobic oxidation reactions. Many organic molecules are only sparingly sol-... 

In a subsequent study of oxygen heterocychzation, Andersson et al. investigated various catalyst reoxidation conditions with the Pd(OAc)2/DMSO catalyst system (Eq. 27, Table 3) [ 150]. Several conditions result in high substrate conversion to the product, including the use of BQ, BQ with methanesulfonic acid, and molecular oxygen, with and without copper(II) salts as a cooxidant. Only the aerobic methods enable formation of the product 37 with high regio-selectivity. The presence of a copper cocatalyst enhances the rate but is not necessary for catalysis. 

Gouverneur and coworkers showed that a,b-unsaturated esters can be cy-clized in good to excellent yields (Eq. 31) [156]. Optimization of the reaction conditions revealed that four equivalents of BQ were necessary to achieve good yields (73%). Aerobic conditions, without a copper cocatalyst, proved to be superior, resulting in 89% yield over extended reaction times. No cycli-zation product was observed with the Pd/pyridine catalyst system described above. 

Hosokawa, Murahashi, and coworkers demonstrated the ability of Pd" to catalyze the oxidative conjugate addition of amide and carbamate nucleophiles to electron-deficient alkenes (Eq. 42) [177]. Approximately 10 years later, Stahl and coworkers discovered that Pd-catalyzed oxidative amination of styrene proceeds with either Markovnikov or anti-Markovnikov regioselectivity. The preferred isomer is dictated by the presence or absence of a Bronsted base (e.g., triethylamine or acetate), respectively (Scheme 12) [178,179]. Both of these reaction classes employ O2 as the stoichiometric oxidant, but optimal conditions include a copper cocatalyst. More recently, Stahl and coworkers found that the oxidative amination of unactivated alkyl olefins proceeds most effectively in the absence of a copper cocatalyst (Eq. 43) [180]. In the presence of 5mol% CUCI2, significant alkene amination is observed, but the product consists of a complicated isomeric mixture arising from migration of the double bond into thermodynamically more stable internal positions. 

The well-known Wacker oxidation of terminal alkenes to methylketones has been used for many years on a large scale. It requires a catalytic amount of Pd(II) together with stoichiometric CuCl2 under aerobic conditions. But it is hmited by palladiiun decomposition and chlorinated byproducts. Therefore, a lot of research has been devoted to modifying the reaction, but most of the time copper cocatalysts were necessary. Another problem is the often observed cleavage of the double bond and the production of aldehydes. 

Good yields of carbonyl compounds have also been obtained from the vapor-phase oxidation of alkenes by steam and air over palladium catalysts supported on charcoal.413 In this case, no copper cocatalyst is needed, presumably because palladium(II) is not reduced to palladium(O), but remains in the form of a stabilized palladium(Il) hydride which can react with 02 to give the hydroperoxidic species. 

Gelman, D. Buchwald, S. Efficient palladium-catalyzed coupling of aryl chlorides and tosylates with terminal alkynes use of a copper cocatalyst inhibits the reaction. Angew. Chem., Int. Ed. 2003, 42, 5993-5996. 

The metal-catalyzed coupling of terminal acetylenes with aryl halides remains one of the most powerful ways to make aryl-acetylene linkages. While most protocols require the use of an organic solvent for a successful reaction, a recent report outlined a solvent-free palladium-catalyzed protocol using microwave heating (Scheme 2.6). The authors were able to remove the traditional copper cocatalyst from the reaction... 

Aryl halides carrying electron-withdrawing groups ortho or para to the hahde will more readily undergo oxidative addition. The reaction does proceed without the copper cocatalyst but only under more forcing conditions and not with less active substrates, such as aryl bromides or chlorides. 

Some of the optimized procedures for Stille and Sonogashira reactions involve the addition of copper cocatalysts to accelerate the cross-coupling procedures. A word of caution should be provided on the role of these additives in Pd-catalyzed amination procedures. Beletskaya and Davydov have reported the arylation of benzotriazole and of diary-lamines in polar organic or aqueous organic solvents using a combination of palladium and copper as catalyst.The arylation of amino acids has been reported under similar conditions.However, these reaction conditions are similar to classic Ullmann procedures for the synthesis of arylamines, except for the addition of palladium to the reaction mixture. In one case, subsequent work showed that the palladium species was not an essential component and that copper alone was the true catalyst in their reactions. An unusual accelerating effect of amino acid coordination to copper was used to explain the low-temperature Ullmann conditions. Beletskaya, however, showed that lower yields and a mixture of N1 and N2 arylation products were observed from the reactions of benzotriazole in the absence of copper and no reaction was observed in the absence of palladium. The conditions for this chemistry are, however, distinct enough from those of the majority of the aryl halide aminations to support the idea that a different mechanism may operate. 

While the industrial Wacker reaction is run with CuClj as a catalyst for re-oxidation of the Pd(0) by Oj, other oxidants have been used in the laboratory without the need for copper cocatalysts. These oxidants include benzoquinone, heteropolyphosphates, many metal ions, and oxygen alone. The rate of the oxidation of ethylene (and other olefins) is... 

This method has successfully been applied for the arylation of amino acidsJ lodonium salts can be used for the arylation of heterocycles such as benzotriazole. The reaction can be run in neat water, in which both substrates are soluble in the presence of base, and does not require copper cocatalyst (Scheme 59). ° ... 

The applicability of the decarboxylative biaryl synthesis was rapidly extended to a broad range of aryl electrophiles with the help of new catalyst generations, including not only aryl iodides, bromides, and triflates but also the inexpensive but unreactive aryl chlorides and tosylates [46, 47]. Its preparative utility was demonstrated, e.g., in the synthesis of telmisartan and valsartan [48, 49]. The key factor in these advances was the identification of ligands that strongly activate the palladium catalysts toward oxidative addition steps while not interfering with the decarboxylation activity of the copper cocatalysts (Scheme 14). 

The reaction was first developed by D. M. Fenton [75] in the presence of oxygen (or air) and copper cocatalysts unfortunately it was slow and scarcely selective. 

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