Palladium-catalyzed C-C cross-coupling reactions, which were acknowledged by the award of the Nobel Prize in chemistry in December 2010, nowadays belong to an indispensable tool for the target oriented synthesis of complex organic molecules across all research fields and industrial segments. The Mizoroki-Heck reaction for example, allows the coupling of olefins with aryl halides in the presence of a base and is nowadays the most popular method for the preparation of vinylbenzenes (Figure 1). The Heck reaction has been demonstrated to find wide utility in both, total syntheses of natural products in academia and synthesis in pharmaceutical and agrochemical industry1-10.



Figure 1. General Heck cross-coupling reaction between an aryl bromide and an olefin. Click here to view larger image.

Taxol, a mitotic inhibitor used in cancer chemotherapy, Singulair, an asthma drug and the herbicide prosulfuron as well as Cyclotene, a monomer for high performance electronic resins are examples that have been successfully prepared including a Heck-Mizoroki cross-coupling step in their syntheses (Figure 2)11-14.



Figure 2. Examples of industrially relevant organic compounds involving a palladium-catalyzed Heck cross-coupling reaction as key step in their synthesis. Click here to view larger image.

Even though recent developments have considerably increased the activity of Heck catalysts15-29, a typical reaction protocol with aryl bromides as substrates still requires high reaction temperatures (140 °C), catalyst loadings in the range of 1 mol% and reaction times of up to 24 hr. Moreover, modified reaction conditions, including the reaction temperature, catalyst loadings, bases, solvents, and additives, e.g. are often reported, implying that these protocols will rarely find their application in organic syntheses due to lack of generality. Furthermore, most catalysts require multiple reaction steps for their synthesis and hence, are time-consuming and low-yielding. Additionally, inert-atmosphere techniques and expensive starting materials of poor stability are often used for their preparation. This refers to the need of new and improved, cheap and easy accessible, stable and green but reactive and general applicable Heck catalysts with high functional group tolerance that efficiently and reliably operates at low catalyst loadings with general applicable reaction protocols.

Dichloro-bis(aminophosphine) complexes of palladium were recently introduced as easy accessible, cheap and air stable but highly active C-C cross-coupling catalysts with excellent functional group tolerance30-34, of which dichloro{bis[1,1',1''-(phosphinetriyl)tripiperidine]}palladium [(P(NC 5 H 10 ) 3 ) 2 Pd(Cl) 2 ] (1) proved to be a highly efficient, reliable, and versatile Heck catalyst that efficiently operates at 100 °C35. 1 was quantitatively prepared within only a few minutes by treatment of THF suspensions of [Pd(Cl) 2 (cod)] (cod = cycloocta-1,5-diene) with 1,1',1''-(phosphinetriyl)tripiperidine under air atmosphere at 25 °C. 1,1',1''-(phosphinetriyl)tripiperidine, the respective ligand system was achieved in one step by the dropwise addition of an excess of piperidine to cooled diethyl ether solutions of PCl 3 . The substrate costs for the preparation of 1,1',1''-(phosphinetriyl)tripiperidine for 1 g of palladium precursor is less than 1€ (estimated from catalogue prices of a chemical supplier) and hence, very cheap.



Figure 3. Synthesis of dichloro{bis[1,1',1''-(phosphinetriyl)tripiperidine]}palladium [(P(NC 5 H 10 ) 3 ) 2 Pd(Cl) 2 ] (1). Click here to view larger image.

Moreover, despite the simple and cheap synthesis of 1 and its excellent catalytic performance, the addition of aqueous hydrochloric acid (work-up conditions), lead to a rapid and complete catalyst degradation, accompanied by the formation of phosphonate, piperidinium salt, and insoluble palladium-containing decomposition products, which are easily separated from the coupling products. This is an often ignored, but very important issue to be considered (from ecologic and economic points of view) and is of particular importance for the preparation of pharmaceutically relevant compounds.