SOME IMPORTANT PALLADIUM CATALYZED COUPLING REACTIONS AND THEIR APPLICATIONS Dr. S N MURTHY BODDAPATI, M. Sc., Ph.D., Associate Professor, Department of Chemistry Sir C R Reddy College, PG courses, Eluru, A.P-534007. Affiliated to Adikavi Nannaya University, Rajamahendravaram, Andhra Pradesh, India-533296 SOME IMPORTANT PALLADIUM CATALYZED COUPLING REACTIONS AND THEIR APPLICATIONS Introduction Organic synthesis has a great impact on every aspect of human life. For example, organic chemists design and produced the newest pharmaceuticals. One more example is the high-performance polymers which are affecting human lives in so many ways. Everything, ranging from automobile parts to the most advanced sports equipment had their roots in organic synthesis. Organic synthesis deals with the construction of molecules ranging from complex, biologically active natural products to new materials. Since synthesis is allowing a chemist to build entirely novel structures, it allows synthetic chemists to investigate the world around them in creative and innovative ways. Among the various method of organic synthesis Cross coupling reactions are an important category of reactions playing a vital role towards the synthesis of biologically potent molecules. The power of cross-coupling reactions can be illustrated through two observations. First, the advent of these methods has enabled the development of expedient synthetic routes for the preparation of molecules with valuable industrial applications. Second, and perhaps even more significantly, cross-coupling reactions have inspired novel designs for molecules that would not otherwise have been imagined. For instance, the synthesis of the losartan.2 Many different types of electrophiles and metal complexes have been successfully employed in these reactions, resulting in a plethora of synthetic methods for molecular assemblies ranging from polymers and liquid crystals to pharmaceuticals and natural products. A major factor in the widespread use of cross-coupling reactions is their reliability and reproducibility compared with many other synthetic methods.3 In particular, the high success rates of Suzuki−Miyaura reactions are remarkable.4 Undoubtedly, our detailed understanding of the mechanism of cross coupling reactions, including knowledge about the nature of the organometallic intermediates and catalyst decomposition pathways, has contributed to the dependability of these reactions.1 Generally, all these reactions need a transition metal catalyst to proceed at a synthetically useful rate. Types of Coupling Reactions Coupling reactions can be classified into two types based on the chemical species that are combined by them: 1) Homo-coupling reactions: Here, two identical chemical species are combined to yield a single product. The best example for homo coupling reaction is a) Ullman coupling reaction b) Glacer-Hay coupling a) Ullmann coupling is a useful technique for the formation of a new C–C bond between two aryls by the condensation of two molecules of aromatic halide (Scheme 1). This is the first transition metal mediated coupling reaction for the formation of aryl–aryl bond. Scheme 1: Ullman reaction. b) The Hay coupling is another version of the Glaser coupling with the TMEDA complex of copper(I) chloride (Scheme 2).It was first reported in 1962. 5 mol % CuCl 5 mol% TMEDA, O Ph H 2 Ph Ph + H O o 2 Acetone, 28 C Scheme 2. Glacer-Hay coupling reaction. 2) Hetero-coupling reactions (cross-coupling reactions): In these reactions two dissimilar chemical species are joined together to afford a single product. Few examples for cross coupling reaction are a) Suzuki coupling.; b) Stille coupling reaction; c) Sonagashira cross-coupling; d)Heck coupling reaction; d) The Buchwald-Hartwig reaction etc…. Overview of transition metal catalysis The transition metal-catalyzed reactions achieved extreme importance in organic synthesis in the past decades, these reactions were contributing extremely in progress of chemical science & technology by the discovery and development of novel chemical compounds and powerful new synthetic methodologies.5 Generally, the transition metal catalysts are obtained from metals such as palladium,6 nickel,7 copper,8 cobalt,9 iron,10 gold,11 manganese,12 rhodium13 and ruthenium.14 The three Nobel Prizes in Chemistry by Richard F. Heck, Ei-ichi Negishi, and Akira Suzuki for their revolutionary work on the palladium- catalyzed cross couplings (in the year 2010) further emphasized the importance of transition metal chemistry. Before that also, Nobel Prizes in Chemistry (in the year 2001, 2005 and 2007) were won by seven other researchers for their pivotal contributions in the area of catalysis. Until now, various bond-breaking/forming reactions are well established with the aid of transition metal catalysts, though, many important and often unpredicted achievements continue to persist. Apart from the continuous development and application of traditional noble metals, such as palladium,15 rhodium16 and ruthenium,17 other inexpensive metal catalysts have also attracted cumulative attention recently because of their simple handling and absolute affordability in price. A general catalytic cycle for cross-coupling reactions is presented in Figure 1. In general the cross coupling reactions (with the exception of the Heck reaction) occurs by a sequence of three stages (1) oxidative addition (2) transmetallation (+isomerization) (3) reductive elimination. The oxidative addition and reductive elimination are multi-step as they involve ligand association and dissociation respectively. Transmetalation involves the exchange of ligands between two metal centers. The characteristics of both the transition metal and the main group metal reagent, in addition to effects associated with other reaction conditions, will affect the catalytic performance. The oxidative addition step is often regarded as the rate-determining step in the catalytic cycle, and the strength of the C–X bond (X=halide or pseudohalide) is determinant. The relative reactivity decreases then in the order I> OTf > Br » Cl.18 1 R1 R R X Ln[M] Reductive Oxidative Elimination addition R1 R1 L [M] n [M] R Ln X Transmetalation M= Fe, Ni, Pd, Rh .... m= Li, Mg. B, Si, Zn, Cu, Zr, Sn... L= Ligand m-X R-m Figure 1. General catalytic cycle for cross-coupling reactions. Palladium catalysis: Over the past 30–40 years, organopalladium chemistry has found widespread use in organic synthesis, and has been described in detail in a number of useful and informative books.19 Although several metal centers are in principle capable of catalyzing the various steps of these reactions, there is no doubt that catalysts based on Pd dominate the scene to the point that, beside their synthetic application at the laboratory and industrial scale, these reactions have also become standard methods to evaluate the reactivity of Pd species as potential catalysts. Palladium catalysts facilitate unique transformations that cannot be readily achieved using classical techniques, and in many cases palladium-catalyzed reactions proceed under mild reaction conditions and tolerate a broad array of functional groups. Out of variable oxidation states of Palladium Pd0, PdII and PdIV are most common. As such, the use of palladium catalysts for the synthesis of important, biologically active heterocyclic compounds has been the focus of a considerable amount of research.20 Pd-catalyzed cross- coupling reactions have become essential tools for the construction of carbon−carbon and carbon−heteroatom bonds. Over the last three decades, great efforts have been made with cross-coupling chemistry in the discovery, development, and commercialization of innovative new pharmaceuticals and agrochemicals (mainly herbicides, fungicides, and insecticides). Some of the important palladium catalyzed coupling reactions of synthetic importance and their applications industrial and medicinal sectors were presented here under. Some of the widely used Palladium catalysts in organic synthesis are Pd(OAc)2 - Palladium(II) acetate Pd(PPh3)4 - Tetrakis(triphenylphosphine)palladium(0 )Pd(PPh3)4Cl2 - Bis(triphenylphosphine)palladium(II) dichloride Pd(dba)3 - Tris(dibenzylideneacetone)dipalladium(0) PdCl2 - Palladium(II) chloride Whenever the reactions involving Pd(0) are encountered the general procedure is as shown below. All organic reactions involving Pd complexes are generally “two electron transfer oxidation, reduction reactions.” 2e II 2e 0 Pd0 Pd Pd 2e 2e PdII PdIV PdII 1) Suzuki coupling reaction In 1979, Suzuki, Miyaura, and Yamada reported21 the palladium-catalyzed cross- coupling reaction of organohalide with borinic and boronic acid derivatives. This reaction is referred to as the Suzuki–Miyaura reaction. Later, Akira Suzuki shared the 2010 Nobel Prize in Chemistry with Richard F. Heck and Ei-ichiNegishi for their effort for discovery and development of palladium-catalyzed cross couplings in organic synthesis.2 It is widely used to synthesize poly-olefins, styrenes and substituted biphenyls. Several reviews have been published describing advancements and the development of the Suzuki Reaction. The general scheme for the Suzuki reaction is shown in below Scheme 3. The coupling of organoboran reagents has become the most regularly used cross-coupling process. Pd(0) catalyst, B(OH)2 + X Base, Solvent, R R New C-C single bond Scheme 3. Suzuki coupling reaction The advantages of Suzuki coupling over other similar reactions include more availability of common boronic acids, mild reaction