Solid-Phase Organic Syntheses, Volume 2

Solid-Phase Palladium Chemistry

Peter J. H. Scott

• Publisher: Wiley
• Year: 2012
• Print ISBN:
  9780470566657
• eBook ISBN:
  9781118336700
• Edition: 1
• Topic: Physical Sciences
• Subtopic: Physical & Theoretical Chemistry

Integrates solid-phase organic synthesis with palladium chemistry

The Wiley Series on Solid-Phase Organic Syntheses keeps researchers current with major accomplishments in solid-phase organic synthesis, providing full experimental details. Following the validated, tested, and proven experimental procedures, readers can easily perform a broad range of complex syntheses needed for their own experiments and industrial applications. The series is conveniently organized into themed volumes according to the specific type of synthesis.

This second volume in the series focuses on palladium chemistry in solid-phase synthesis, exploring palladium catalysts and reactions, procedures for preparation and utilization, ligands, and linker reactions. The first part of the volume offers a comprehensive overview of the field. Next, the chapters are organized into three parts:

• Part Two: Palladium-Mediated Solid-Phase Organic Syntheses
• Part Three: Immobilized Catalysts and Ligands
• Part Four: Palladium-Mediated Multifunctional Cleavage

Each chapter is written by one or more leading international experts in palladium chemistry. Their contributions reflect a thorough examination and review of the current literature as well as their own first-hand laboratory experience. References at the end of each chapter serve as a gateway to the field's literature.

The introduction of palladium-mediated, cross-coupling reactions more than thirty years ago revolutionized the science of carbon-carbon bond formation. It has now become a cornerstone of today's synthetic organic chemistry laboratory. With this volume, researchers in organic and medicinal chemistry have access to a single resource that explains the fundamentals of palladium chemistry in solid-phase synthesis and sets forth clear, step-by-step instructions for conducting their own syntheses.

Part I

Introduction

Chapter 1

An Introduction to Solid-Phase Palladium Chemistry

Carmen Gil

1 Introduction

Palladium chemistry has a central position in organic chemistry because of its ability to selectively form carbon–carbon and carbon–heteroatom bonds between organic fragments [1].

Palladium-catalyzed reactions represent one of the most powerful and versatile tools in organic synthesis for the preparation of fine chemicals, pharmaceutical intermediates, active pharmaceutical ingredients, and also bioactive drugs [2].

In recent years, the synthesis of combinatorial libraries has emerged as a valuable tool in the search for novel lead structures. The success of combinatorial chemistry in drug discovery is dependent, in part, on further advances in solid-phase organic synthesis (SPOS). The generation of molecular diversity to create libraries for drug discovery was originally focused on the synthesis of peptide and nucleotide libraries. However, the limitation of such libraries is the pharmacokinetic properties of large polymeric and often hydrophilic structures that make these molecules less suitable as leads in drug discovery [3]. It is therefore desirable to develop methods to prepare small, nonpolymeric molecules with sufficient diversity [4]. The rapid generation of such small-molecule libraries can be executed effectively by employing combinatorial or simultaneous parallel synthesis on solid supports [5–7]. Considerable work has been carried out to optimize many of the useful reactions from the organic chemists' arsenal for solid-phase conditions and to design versatile linkers [8, 9]. In this respect, palladium chemistry is a powerful synthetic methodology for the preparation of libraries of small organic compounds by multiparallel synthesis schemes on solid supports [10]. In particular, the development of reliable procedures with a wide scope for the formation of carbon–carbon bonds is of great importance together with the new solid-supported reagents, ligands, and catalysts [11, 12].

Some of the commonly employed palladium-catalyzed organic couplings that lead to the formation of carbon–carbon or carbon–heteroatom bonds have been named by prominent researchers in this field, such as Stille, Heck, Suzuki, Sonogashira, Kumada, Negishi, Nozaki–Hiyama, Buchwald–Hartwig, and Tsuji–Trost [13]. These reactions are usually very efficient, although the main drawback is that palladium is often retained by the isolated product. This is, however, a serious drawback because pharmaceutical ingredients official guidelines place exacting limits on the permissible levels of heavy-metal contaminants. In this sense, the use of resin-bound catalyst systems is particularly beneficial in reducing metallic contamination of the final products [14].

Numerous research groups have developed new metal complexes and ligands, expanding the scope of these transformations to give access to more complex molecules [15, 16]. The development of solid-phase palladium chemistry is also another approach to access such molecules, offering straightforward syntheses, without tedious and time-consuming purifications.

2 Palladium-Catalyzed Reactions

Palladium-catalyzed coupling reactions are very efficient for the introduction of new carbon–carbon bonds onto molecules attached to solid supports. The mild reaction conditions, the compatibility with a broad range of functionalities, and high reaction yields have made this kind of transformation a very common tool for the combinatorial synthesis of small organic molecules.

2.1 Heck Reactions

This reaction has become one of the most powerful tools to bring up complex structural changes, in particular when conducted intramolecularly. Owing to the mild conditions employed and the toleration of many functional groups, the Heck reaction has been successfully adapted in a broad scope to organic synthesis in the solid phase [11, 17]. This reaction between terminal olefins and alkyl/aryl halides has been widely employed in various intra- and intermolecular versions in solid phase, taking advantage of the ready accessibility of starting materials. The Heck reaction involves immobilized aryl or alkenyl halides with soluble alkenes as well as vice versa (Scheme 1.1) [18, 19].

Figure 1.1 Heck reactions in solid-phase synthesis [18].

One of the most interesting applications of this cross coupling on solid phase has been the application in the preparation of medicinally relevant heterocycles [20]. For example, the synthesis of 2-oxindole derivatives on solid support was published by Arumugam et al. [21]. As shown in Scheme 1.2, the synthesis starts with reductive alkylation of the corresponding immobilized aniline 5. After construction of the tertiary amide 7, an intramolecular Heck reaction affords the oxindoles 9 as a mixture of (E)- and (Z)-isomers.

Figure 1.2 Synthesis of 2-oxindole 9 derivatives by Arumugam et al. [21].

Bolton and Hodges [22] described the synthesis of benzazepines via intramolecular Heck cyclization as shown in Scheme 1.3. Deprotection of immobilized allylglycine ester 10, followed by reductive amination with benzaldehyde cleanly produces the secondary amine 11. Subsequent acylation with 2-iodobenzoyl chloride provides 12, which undergoes efficient Heck cyclization to bicyclic lactam 13. Acidic cleavage and esterification of this compound afforded 14 as a bicyclic aminoacid scaffold, which can be efficiently functionalized at various sites.

Figure 1.3 Synthesis of benzazepines 14 via intramolecular Heck cyclization by Bolton and Hodges [22].

Cyclization of immobilized enaminoesters to indolecarboxylates was described by Yamazaki et al. via palladium-catalyzed reactions (Scheme 1.4) [23]. They described successfully the intramolecular palladium-catalyzed cyclization of the α- or β-(2-halophenyl)amino-substituted α,β-unsaturated esters employing in the solid-phase synthesis of indole 2- and 3-carboxylates with various functional groups on the benzene ring.

Figure 1.4 Palladium-assisted indole synthesis by Yamazaki et al. [23].

Zhang and Maryanoff reported the construction of benzofurans on a solid phase via palladium-mediated cyclizations [24], when different ortho-iodo phenols 19 were immobilized on functionalized Rink amide resin, followed by an intramolecular Heck-type reaction and cleavage with trifluoroacetic acid (TFA) to yield the benzofurans 21 in excellent purities and yields (Scheme 1.5).

Figure 1.5 Solid-supported benzofuran synthesis by Zhang and Maryanoff [24].

A key step in SPOS is the development of a new kind of versatile linkers, which expand the possibilities of synthetic transformations. In this sense, Bräse et al. developed a traceless linker system of the triazene type to immobilize aryl halides 22, with application to the Heck reaction with different olefins (Scheme 1.6) [25, 26].

Figure 1.6 Heck reaction on T1 triazene resins 22 [26].

Another solid-phase approach to N-heterocycles was described by using a sulfur linker cleaved in a traceless fashion by reduction with samarium(II) iodide. The route to tetrahydroquinolones 26 involves a microwave-assisted Heck reaction followed by a Michael cyclization (Scheme 1.7) [27]. This route shows the compatibility of the linker system with a number of important reaction types and its utility for library synthesis.

Figure 1.7 Solid-phase approach to tetrahydroquinolones 27 by using a sulfur linker [27].

2.2 Suzuki Reactions

The palladium-catalyzed coupling of boronic acids with aryl and alkenyl halides, known as Suzuki reaction, is one of the most efficient carbon–carbon cross-coupling processes used in reactions on polymeric support. The mild reaction conditions have made this reaction a powerful and widely used tool in organic synthesis. These coupling reactions require only gentle heating to 60–80°C, and the boronic acids employed are nontoxic and stable toward air and water. When the Suzuki reaction is transferred to a solid support, the boronic acid can be immobilized or used as a liquid reactant (Scheme 1.8) [28].

Figure 1.8 Solid-supported boronic acids as reagents for Suzuki couplings [29].

Solid-phase Suzuki reaction was first utilized in biaryls synthesis [30]. Since then, several examples for the synthesis of biologically active biaryl compounds have been described. Functionalized biaryl α-k...

Table of contents

• Cover
• Solid-Phase Organic Syntheses
• Title Page
• Copyright
• Contributors
• Preface
• Abbreviations
• Part I: Introduction
• Part II: Palladium-Mediated SPOS
• Part III: Immobilized Catalysts and Ligands
• Part IV: Palladium-Mediated Multifunctional Cleavage
• Index