Palladium-Catalyzed Coupling Reactions

Practical Aspects and Future Developments

Árpád Molnár

• Publisher: Wiley-VCH
• Year: 2013
• Print ISBN: 9783527332540
• eBook ISBN: 9783527648306
• Edition: 1
• Topic: Physical Sciences
• Subtopic: Physical & Theoretical Chemistry

This handbook and ready reference brings together all significant issues of practical importance in selected topics discussing recent
significant achievements for interested readers in one single volume. While covering homogeneous and heterogeneous catalysis, the text is unique in focusing on such important aspects as using different reaction media, microwave techniques or catalyst recycling. It also provides a comprehensive treatment of key issues of modern-day coupling reactions having emerged and matured in recent years and emphasizes those topics that show potential for future development, such as continuous flow systems, water as a reaction medium, and catalyst immobilization, among others. With its inclusion of large-scale applications in the pharmaceutical industry, this will equally be of great interest to industrial chemists. From the contents
* Palladium-Catalyzed Cross-Coupling Reactions - A General Introduction
* High-turnover Heterogeneous Palladium Catalysts in Coupling Reactions: the Case of Pd Loaded on Dealuminated Y Zeolites
Palladium-Catalyzed Coupling Reactions with Magnetically Separable Nanocatalysts
* The Use of Ordered Porous Solids as Support Materials in Palladium-Catalyzed Cross-Coupling Reactions
* Coupling Reactions Induced by Polymer-Supported Catalysts
* Coupling Reactions in Ionic Liquids
* Cross-Coupling Reactions in Aqueous Media
* Microwave-Assisted Synthesis in C-C and C-Heteroatom Coupling Reactions
* Catalyst Recycling in Palladium-Catalyzed Carbon-Carbon Coupling Reactions
* Nature of the True Catalytic Species in Carbon-Carbon Coupling Reactions with
* Heterogeneous Palladium Precatalysts
* Coupling Reactions in Continuous Flow Systems
* Large-Scale Applications of Palladium-Catalyzed Couplings in the Pharmaceutical Industry

1

Palladium-Catalyzed Cross-Coupling Reactions – A General Introduction

Klaus Köhler, Katharina Wussow, and Andreas Sebastian Wirth

1.1 Introduction

1.1.1 Historical Reflection

Fifty years ago, when palladium began to make its way into organic chemistry, carbon–carbon bond formation in organic synthesis was mainly achieved by stoichiometric reactions of, for example, reactive nucleophiles with electrophiles. The introduction of palladium to this chemistry by Richard Heck, who developed coupling reactions of aryl compounds in the presence of either stoichiometric or catalytic amounts of palladium(II) in the late 1960s, designates a breakthrough toward the fascinating area of palladium-catalyzed carbon–carbon bond forming reactions. A number of new C–C coupling reactions mediated by palladium have been published in the following years. Today, palladium-catalyzed coupling reactions provide extraordinarily useful and widely applied tools for organic synthesis. Famous representatives are the Heck, Negishi, and Suzuki reactions [1] whose importance and excellence in organic chemistry were acknowledged by awarding the Nobel Prize in Chemistry in 2010 [2]. The pioneering work in the 1960s and 1970s of the three Nobel Prize winners has led to cross-coupling reactions nowadays becoming extremely valuable and reliable transformations in complex natural product syntheses, and even more importantly for numerous pharmaceutical and agrochemical applications, as well as for the production of new materials. In addition, there are several other named palladium-catalyzed cross-coupling reactions to be mentioned and presented in this introductory chapter. The most important ones are the Sonogashira reaction, the Stille coupling, and the Tsuji–Trost reaction, while less common ones such as the Hiyama coupling, the Kumada reaction, and carbon–nitrogen coupling reactions according to Buchwald and Hartwig are established as well.

Since their discovery, palladium-catalyzed cross-coupling reactions have come a long way and there are several reasons for their continuing popularity and success. Carbon–carbon bond formation was mainly performed using Grignard reagents and organoalkali metal compounds before the introduction of Pd into this area. While these reactions are applicable for sterically undemanding alkyl halides, conversion of unsaturated substrates such as alkenyl, alkynyl, and aryl electrophiles is dissatisfactory [3]. On the contrary, Pd-catalyzed reactions favor sp²-hybridized reactants. Exemplary taking into account that organometallic complexes with alkyl groups tend to perform β-hydride elimination, saturated educts are not suitable for transition metal-mediated cross-couplings. Such an intermediate state would clearly reduce the selectivity to the coupling products.

1.1.2 Characteristics, Recent Developments, and Progress

The application of Pd is characterized by additional striking features and synthetic advantages. Mild reaction conditions minimize the formation of unwanted side products and, consequently, high selectivities can be achieved. Furthermore, the Pd catalysis shows tolerance toward a large number of functional groups on both coupling partners. Hence, it is possible to construct complex organic building blocks efficiently in fewer steps than by traditional stoichiometric reactions. In addition, the development of ligands and cocatalysts allows fine-tuning of reactivity. High stability of organopalladium compounds to water and air (except some phosphane complexes) enables easy processing and lower costs. It is not surprising that these reactions are widely employed for various applications. General disadvantages of the Pd-mediated reactions are rooted in high noble metal prices and toxicity of the metal residue that can become problematic in pharmaceutical products. Thanks to excellent activities of palladium catalysts, these problems can be minimized, because only very small amounts are required for high conversions and yields. Not surprisingly, the development of alternative Pd catalysts (separation, reuse) is a flourishing field. In fact, in addition to palladium complexes in homogeneous solution, a series of new, highly active, and effective heterogeneous (supported) palladium catalysts has been developed in recent years. They can be repeatedly used and thus contribute to efficient and economic application of coupling reactions (see also Ref. [4]). Clearly, numerous cross-coupling reactions are sufficiently efficient to be run in industry on a ton scale. Thus, this palladium-catalyzed approach has very often made the transfer from gram-scale synthesis in academic laboratories to ton-scale production in the pharmaceutical, agrochemical, and fine chemical industries in the past two decades.

In conclusion, during the past decade very important advances have taken place in the development of highly active catalysts to carry out the coupling of unreactive and sterically hindered substrates. This progress is likewise due to development from the point of view of (i) organic synthesis, (ii) improved mechanistic understanding, and (iii) “engineering” aspects (separation and catalyst reuse). Thus, (i) tailor-made, for example, bulky electron-rich, ligands that have been developed have contributed greatly to the diversity and utility of cross-coupling chemistry. Various protocols have been developed that are of practical use to the organic chemist. The majority of functional groups can be tolerated, which certainly simplifies the construction of complex heterocyclic structures. The success of the described systems provides a good basis for a more rational approach to the design and development of new catalytic systems for cross-coupling reactions. (ii) Important structure–activity relationships have been established that open possibilities for even more active and universal catalytic systems that are becoming an increasingly more powerful tool in synthetic organic chemistry. (iii) Separation and reuse of the palladium catalyst have been demonstrated numerous times in the past few years in particular using supported Pd catalysts. No expensive ligands, for example, phosphanes, are required and the “ligand-free” systems are not sensitive to air and moisture. At least for reactive substrates, coupling products can be obtained in high yields after short reaction times. In several cases, reactions can be carried out in water or even solventless. These catalyst systems are valuable alternatives to homogeneous complexes, but also new ways to separate dissolved palladium from reaction mixtures have been proven to be successful: use of ionic liquids or solvent mixtures composed of an ionic liquid and an organic solvent or water offers additional advantages.

1.1.3 Literature Reviews and Organization of the Chapter

Because of the extensive developments in particular of the past 10 years, the task to comprehensively review carbon–carbon cross-coupling reactions is a hopeless adventure, even for a single reaction type only. Also, a book like this cannot provide it; rather, a multivolume series would be required. According to the academic interest and practical importance of the coupling reactions under consideration, books [5] and a remarkable number of review articles are available. Some reviews address the topic in general [6]. Other reviews focus on specific subjects such as the use of cross-coupling reactions in total synthesis [7] or coupling reactions performed in ionic liquids [8] (see Chapter 6). A series of reviews focus on particularly heterogeneous systems [4, 9], for example, the use of silica-supported [10] and polymer-supported catalysts [11], Pd/C [12], or palladium nanoparticles (NPs) [13] in coupling reactions. There are a number of reviews dealing with the nature of the active species [14] and particular high-turnover palladium catalysts [15] (see Chapter 7). Coupling catalysis in pure water has been extensively reviewed too [16]. Particular approaches to convert unreactive substrates such as aryl chlorides [17], Pd-catalyzed C–C coupling for the synthesis of polymers [18], and theoretical approaches to understand carbon–carbon cross-coupling reactions [19] are other more specific subjects addressed in review articles. Not surprisingly, a number of review articles deal with the synthetic importance of C–C couplings [20], the use of selected groups of ligands and Pd complexes [21], and industrial applications in the production of fine chemicals [22]. The majority of the results treat the three most important coupling reactions, that is, the Heck, Suzuki–Miyaura, and Sonogashira couplings. Other reaction types such as the Stille reaction, a few examples of coupling reactions studied less frequently (Kumada, Hiyama, and Negishi reactions), allylations including the Tsuji–Trost reaction, and relevant homocoupling processes are also covered. The main emphasis, naturally, is on palladium with a few additional examples for the ...

Table of contents

• Cover
• Related Titles
• Title Page
• Copyright
• Foreword
• Preface
• List of Contributors
• Chapter 1: Palladium-Catalyzed Cross-Coupling Reactions – A General Introduction
• Chapter 2: High-Turnover Heterogeneous Palladium Catalysts in Coupling Reactions: the Case of Pd Loaded on Dealuminated Y Zeolites
• Chapter 3: Palladium-Catalyzed Coupling Reactions with Magnetically Separable Nanocatalysts
• Chapter 4: The Use of Ordered Porous Solids as Support Materials in Palladium-Catalyzed Cross-Coupling Reactions
• Chapter 5: Coupling Reactions Induced by Polymer-Supported Catalysts
• Chapter 6: Coupling Reactions in Ionic Liquids
• Chapter 7: Cross-Coupling Reactions in Aqueous Media
• Chapter 8: Microwave-Assisted Synthesis in C–C and Carbon–Heteroatom Coupling Reactions
• Chapter 9: Catalyst Recycling in Palladium-Catalyzed Carbon–Carbon Coupling Reactions
• Chapter 10: Nature of the True Catalytic Species in Carbon–Carbon Coupling Reactions with Heterogeneous Palladium Precatalysts
• Chapter 11: Coupling Reactions in Continuous-Flow Systems
• Chapter 12: Palladium-Catalyzed Cross-Coupling Reactions – Industrial Applications
• Index