Pd(II)/Pd(IV) Catalytic Cycles involving Pseudohalides in Cross-Coupling Processes: Mechanistic Studies and Synthetic Applications

Lead Research Organisation: University of York
Department Name: Chemistry


Transition metals can act as catalysts, effecting the reactions of many types of substrates to provide important products that display extraordinary complexity and structural diversity. Such enhanced reactions often proceed rapidly, are higher yielding and give fewer by-products than the related non-catalysed reaction. Indeed, there are many cases where reactions do not occur at all in the absence of a catalyst and it is this what makes transition metal-catalysed reactions important. The metal centre is essentially the active site for catalysis, the activity of which can be modulated using ligands that are capable of binding metals to varying degrees, depending on their size and electronic properties. One can envisage changing the catalytic properties just like a tunable dial on a radio receiver. The precise property required, whether that is high activity, selectivity or catalyst lifetime, can be tuned by alteration of these ligands, to each specific reaction of interest. One of the most versatile transition metals available to synthetic chemists is palladium. It has attracted significant interest for use in many reactions applied to the preparation of valuable synthetic targets such as natural products and therapeutic agents, that possess unique medicinal and biological properties (anti-cancer etc.), and advanced materials.In this proposal, we wish to study the mechanism of an important palladium-catalysed reaction known as Stille cross-coupling, employing the catalyst (PPh3)2Pd(N-Succ)Br, recently developed by our research groups. Many palladium catalysts have been found for this reaction, although the majority of researchers have focussed on preparing catalysts that are more active, something accomplished through alteration of the type of donor neutral ligand for palladium. However, alteration of anionic ligands e.g. halides and pseudohalides, is an area that has been relatively neglected, which is surprising given that these ligands are likely to involve the global catalyst reactivity arguably more so than neutral donor ligands. We have found that an unusual pseudohalide, succinimide and related pseudohalides, exerts intriguing substrate selectivity effects in Stille coupling (for allylic and benzylic substrates); effects that are unprecedented for any other known palladium catalyst. Generally, product selectivity is something which has been overlooked in this field, particularly when two outcomes are possible (from two reactive centres). Being able to direct one outcome is an important goal, as the second reactive centre can be used for other synthetic transformations, making overall synthetic routes more efficient. The selectivity origin is likely to derive from an unusual mechanistic pathway. We wish to gather insights and understanding into the precise mechanism by which (PPh3)2Pd(N-Succ)Br operates by using classical and state-of-the-art tools to assist mechanism elucidation. The identification of clear reaction pathways allows us to exploit this knowledge in the rational design of more efficient, selective and environmentally friendly catalysts, as well as taking advantage of novel mechanistic implications that have been established. The latter point is important, as this often facilitates the development of new synthetic transformations. The substrate scope and reaction types, using our catalyst and related derivatives, will be significantly expanded.We plan to identify and develop new synthetic transformations using the proposed technology. An efficient synthetic route to an exciting target, phacelocarpus-pyrone A, using (PPh3)2Pd(N-Succ)Br in Stille cross-coupling and related cross-coupling processes, is outlined. The overall aim is to demonstrate the versatility of this and related catalysts in a target compound containing a fascinating arrangement of functionality as part of a macrocyclic ring.


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Description We developed a palladium precatalyst for use in the synthesis of high value chemicals. Reactions such as Suzuki-Miyaura cross-coupling are industrially relevant and important transformations in both agrochemical and pharmaceutical sectors. Sigma-Aldrich has commercialized one of our Pd precatalysts, for the synthetic chemistry community to use, broadly in cross-coupling reactions.

We collaborated with Organon Ltd. (now Merck) on the development of the Pd precatalysts and their use in the synthesis of biologically relevant chemical structures.

We went on to develop new gold catalysts for organic transformations in collaboration with GlaxoSmithKline.

The Taylor group were able to utilise the palladium precatalyst studied in this project in other natural product syntheses and synthetic methodologies.
Exploitation Route The application of the new palladium and gold catalysts in various synthetic transformations (especially cross-coupling processes).
Sectors Chemicals,Pharmaceuticals and Medical Biotechnology

URL http://www.sigmaaldrich.com/catalog/papers/13678197
Description Our findings are being used to aid the design and synthesis of new palladium catalysts for use in organic synthesis / target-orientated synthesis. Our mechanistic work has allowed us to understand the complex interplay of the ligands for palladium with the reaction conditions. Part of our work was in collaboration with Organon Laboratories Ltd. (now Merck). New gold catalysts have been developed in follow-on work from this study, which involved collaboration with GlaxoSmithKline.
First Year Of Impact 2007
Sector Chemicals,Pharmaceuticals and Medical Biotechnology