Palladium chemistry high-activity ligands

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. 

In general, highly activated aryl chlorides (e.g. 4-chlorobenzonitrile or 4-chlorobenzo-phenone) react similarly to bromobenzene in the oxidative addition step. Thus the standard arylphosphine ligands are suitable for palladium-catalyzed chemistry with these substrates77. ... 

Af-Heterocyclic carbenes and phosphine ligands can bind metal centers in a somewhat similar feshion via dative coordination using a lone pair of electrons. Therefore, phosphines are often considered to be the closest neighbors to NHCs in terms of organometallic chemistry. However, the properties of these two classes of compounds can be quite different, and can yield, for example, catalysts with quite different reactivity. The use of NHCs in olefin metathesis [25] and in palladium catalysis [26], for example, has allowed the preparation of highly active and stable species that are now at the forefront of their fields. Various studies have been conducted to explore the nature of bonding between NHCs and metal centers. Diez-Gonzalez and Nolan reviewed some aspects of NHC coordination to metal centers in 2007 [27]. 

Modem cross coupling chemistry is heavily dominated by the use of palladium and nickel complexes as the catalysts, which show an impressively wide scope and an excellent compatibility with many functional groups.2 This favorable application profile usually overcompensates the disadvantages resulting from the high price of the palladium precursors, the concerns about the toxicity of nickel salts, the need for ancillary ligands to render the complexes sufficiently active and stable, and the extended reaction times that are necessary in certain cases. 

In the quest for additional active catalysts for the Mizoroki-Heck reaction, the advent of N-heterocychc carbene (NHC) ligands was warmly welcomed [32], Transition metal-transition metal-phosphine complexes, and have therefore attracted considerable interest as competitive alternatives in Mizoroki-Heck chemistry, which requires high reaction temperatures. Since the seminal application of NHC ligands in Mizoroki-Heck arylations by Herrmann et al. [33], several research groups have introduced novel palladium catalyst-NHC ligand combinations. These were tested and assessed in standard couplings of simple iodo- or bro-moarenes 60 and activated acceptors such as acrylates 61 or styrene (63) [32], and a selection of impressive examples is summarized in Scheme 7.14. 

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