Palladium in Heterocyclic Chemistry

A Guide for the Synthetic Chemist

Jie Jack Li, Gordon Gribble, Gordon W. Gribble

• Publisher: Elsevier Science
• Year: 2006
• Print ISBN:
  9780080451176
• eBook ISBN:
  9780080914411
• Edition: 2
• Topic: Physical Sciences
• Subtopic: Organic Chemistry

Palladium chemistry, despite its immaturity, has rapidly become an indispensable tool for synthetic organic chemists. Heterocycles are of paramount importance in the pharmaceutical industry and palladium chemistry is one of the most novel and efficient ways of making heterocycles. Today, palladium-catalyzed coupling is the method of choice for the synthesis of a wide range of biaryls and heterobiaryls. The number of applications of palladium chemistry to the syntheses of heterocycles has grown exponentially. These developments highlight the need for a monograph dedicated solely to the palladium chemistry in heterocycles and this book provides a comprehensive explanation of the subject. The principal aim of Palladium in Heterocyclic Chemistry is to highlight important palladium-mediated reactions of heterocycles with emphasis on the unique characteristics of individual heterocycles. 1. Palladium chemistry of heterocycles has its "idiosyncrasies" stemming from their different structural properties from the corresponding carbocyclic aryl compounds. Even activated chloroheterocycles are sufficiently reactive to undergo Pd-catalyzed reactions. As a consequence of &agr and &bgr activation of heteroaryl halides, Pd-catalyzed chemistry may take place regioselectively at the activated positions, a phenomenon rarely seen in carbocyclic aryl halides. In addition, another salient peculiarity in palladium chemistry of heterocycles is the so-called "heteroaryl Heck reaction". For instance, while intermolecular palladium-catalyzed arylations of carbocyclic arenes are rare, palladium-catalyzed arylations of azoles and many other heterocycles readily take place. Therefore, the principal aim of this book is to highlight important palladium-mediated reactions of heterocycles with emphasis on the unique characteristics of individual heterocycles. 2. A myriad of heterocycles are biologically active and therefore of paramount importance to medicinal and agricultural chemists. Many heterocycle-containing natural products (they are highlighted in boxes throughout the text) have elicited great interest from both academic and industrial research groups. Recognizing the similarities between the palladium chemistry of arenes and heteroarenes, a critical survey of the accomplishments in heterocyclic chemistry will keep readers abreast of such a fast-growing field. We also hope this book will spur more interest and inspire ideas in such an extremely useful area. This book comprises a compilation of important preparations of heteroaryl halides, boranes and stannanes for each heterocycle. The large body of data regarding palladium-mediated polymerization of heterocycles in material chemistry is not focused here; neither is coordination chemistry involving palladium and heterocycles. Many heterocycle-containing natural products (highlighted throughout the text) have elicited great interest from both academic and industrial research groups. Recognizing the similarities between the palladium chemistry of arenes and heteroarenes, a critical survey of the accomplishments in heterocyclic chemistry keeps readers abreast of this fast-growing field. It is also hoped that this book will stimulate more interest and inspire new ideas in this exciting field. - Contains the most up-to-date developments in this fast-moving field - Includes 3 new chapters - Contains material from selected well-respected authors on heterocyclic chemistry

Chapter 1

An introduction to palladium catalysis

John P. Wolfe; Jie Jack Li

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 [1]. 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. 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 [2].

This chapter describes the fundamentals of palladium catalysis in the context of heterocyclic chemistry, including the basic mechanisms of many useful transformations along with a number of new synthetic and mechanistic developments. The majority of the Pd-catalyzed reactions described in this book proceed via catalytic cycles that are comprised of eight fundamental organopalladium transformations shown below [1]. Most of these transformations can occur via more than one mechanistic pathway, and in some instances the precise mechanisms have not been fully elucidated.

The basic reactions are

(1) oxidative addition, in which a Pd(0) complex undergoes insertion into a (usually) polarized σ-bond to afford a Pd(II) complex;

(2) reductive elimination, which is the microscopic reverse of oxidative addition, and leads to formation of a σ-bond with concomitant formal reduction of Pd(II) to Pd(0);

(3) migratory insertion, which involves the syn-addition of a palladium–carbon or palladium-heteroatom bond across an alkene with no change in metal oxidation state;

(4) β-hydride elimination, which is the syn-elimination of a hydrogen atom and Pd(II) from a palladium alkyl complex with no change in oxidation state;

(5) Wacker-type addition, which is the anti-addition of (most commonly) a heteroatom and a Pd(II) species across a C–C double bond;

(6) electrophilic palladation, in which a C–H σ-bond is exchanged for a C–Pd bond with loss of one equivalent of acid;

(7) transmetalation, which involves the exchange of an R–M bond with a Pd–X bond to form Pd–R and M–X;

(8) formation and trapping of π-allylpalladium species (formally a type of oxidative addition/reductive elimination sequence). The linking of these individual steps together in synthetically useful catalytic cycles is described throughout the course of this chapter.

In most of the mechanistic schemes described below, the ligands on palladium have been omitted for the sake of clarity and simplicity. However, the nature of the ligands is often crucial for the reactivity and selectivity of palladium catalysts. For example, in many instances Pd-catalyzed amination reactions of aryl halides provide low yields with PPh₃-ligated palladium complexes but proceed in excellent yields when catalysts bearing bulky electron-rich ligands are employed (see Section 1.7.1 below). Thus, the choice of the appropriate catalyst/ligand is often crucial for success in these reactions.

Palladium chemistry involving heterocycles has many unique characteristics stemming from the inherently different structural and electronic properties of heterocyclic molecules in comparison to the corresponding aromatic carbocycles. One salient feature of heterocycles is the marked activation at positions α and γ to the heteroatom. For N-containing heterocycles, the presence of the N-atom polarizes the aromatic ring, thereby activating the α and γ positions, making them more prone to nucleophilic attack. For example, the order of S_NAr displacement of heteroaryl halides with EtO⁻ is [3]:

$\begin{array}{ccccccc}\hfill \mathrm{chloropyrimidine}\hfill & \hfill >\hfill & \hfill \mathrm{chloroquinoline}\hfill & \hfill >\hfill & \hfill \mathrm{chloropyridine}\hfill & \hfill \gg \hfill & \hfill \mathrm{chlorobenzene}\hfill \\ \hfill 7\times {10}^5\hfill & \hfill \hfill & \hfill 3\times {10}^2\hfill & \hfill \hfill & \hfill 1\hfill & \hfill \hfill & \hfill \mathrm{no}\mathrm{reaction}\hfill \end{array}$

The order of reactivities observed in S_NAr displacement reactions often parallels the order of reactivity of aryl halides in oxidative additions to Pd(0). Likewise, the ease with which the oxidative addition occurs for heteroaryl halides can often be predicted on the basis of S_NAr reactivity of a given substrate. In addition, α- and γ-chloroheteroarenes are sufficiently activated for use in Pd-catalyzed reactions with a variety of different catalysts, whereas Pd-catalyzed reactions of unactivated aryl chlorides (e.g. chlorobenzene) typically require large, electron-rich phosphine or N-heterocyclic carbene ligands [4].

The α- and γ-position activation has a remarkable impact on the regiochemical outcome for the Pd-catalyzed reaction of heterocycles. For example, Pd-catalyzed reactions of 2,5-dibromopyridine take place regioselectively at the C(2) position [5], whereas lithium-halogen exchange takes place at C(5) [6]. Palladium-catalyzed reactions of 2,4- or 2,6-dichloropyrimidines take place at C(4) and C(6) more readily than at C(2) [7].

1.1 Oxidative coupling/cyclization

The oxidative coupling/cyclization reaction is the intramolecular union of two arenes with formal loss of H₂ promoted by a Pd(II) species (typically Pd(OAc)₂). In an early example of this transformation, treatment of diphenylamines 1 with Pd(OAc)₂ in acetic ac...

Table of contents

• Cover image
• Title page
• Table of Contents
• Copyright page
• Contributing authors
• Preface to the first edition
• Preface to the second edition
• Abbreviations
• Chapter 1: An introduction to palladium catalysis
• Chapter 2: Pyrroles
• Chapter 3: Indoles
• Chapter 4: Pyridines
• Chapter 5: Thiophenes and benzo[b]thiophenes
• Chapter 6: Furans and benzo[b]furans
• Chapter 7: Thiazoles and benzothiazoles
• Chapter 8: Oxazoles and benzoxazoles
• Chapter 9: Imidazoles
• Chapter 10: Pyrazines and quinoxalines
• Chapter 11: Pyrimidines
• Chapter 12: Quinolines
• Chapter 13: Pyridazines
• Chapter 14: Industrial scale palladium chemistry
• Index