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 SNAr displacement of heteroaryl halides with EtO− is [3]:

>chloroquinoline>chloropyridine≫chlorobenzene7×1053×1021noreaction

The order of reactivities observed in SNAr 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 SNAr 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 acid yielded carbazoles 2 [8]. The role of acetic acid in such oxidative cyclization processes is to protonate one of the acetate ligands, which affords a more electrophilic cationic Pd(II) species, thereby promoting the initial electrophilic palladation of the aromatic ring.

Presumably, the oxidative cyclization of 1 commences with direct palladation at the ortho-position, forming σ-arylpalladium(II) complex 3 in a fashion analogous to a typical electrophilic aromatic substitution (this notion is useful in predicting the regiochemistry of oxidative cyclizations). The mechanism of the second formal C–H bond functionalization step is not fully elucidated, but may occur either via (a) an intramolecular carbopalladation reaction (migratory insertion) followed by anti-β-hydride elimination from 4 (Path A); (b) by σ-bond metathesis (through a four-centered transition state) followed by reductive elimination (Path B); (c) by electrophilic aromatic substitution followed by C–C bond-forming reductive elimination (Path C) [9].

Overall, this transformation leads to the conversion of Pd(II) to Pd(0), which consumes one equivalent of expensive Pd(OAc)2 in most cases. However, progress has been made towards the development of catalytic versions of this transformation, in which catalytic turnover is effected by employing a second oxidant that serves to convert Pd(0) back to Pd(II). For example, Knölker described the oxidative cyclization of 5 using catalytic Pd(OAc)2 to afford indole derivative 6 [10]. The reoxidation of Pd(0) to Pd(II) was accomplished using excess cupric acetate in a manner analogous to the Pd-catalyzed Wacker reaction (see Section 1.9) [11].

1.2 Cross-coupling reactions with organometallic reagents

One of the most frequently employed methods for the construction of Csp2–Csp2 bonds is the Pd-catalyzed cross-coupling of aryl or vinyl halides with main-group organometallic reagents. These reactions generally proceed with retention of regiochemistry and/or olefin geometry, and can be effected with a broad range of substrates. A simplified mechanism for these transformations (shown below) typically commences with oxidative addition of the aryl/vinyl halide to a Pd(0) complex to afford intermediate 9. The organopalladium halide complex 9 can then undergo transmetalation with the main-group coupling partner (R1M, 10) to afford the diorganopalladium species 12. Carbon–carbon bond-forming reductive elimination from 12 affords the desired cross-coupling product 13 and regenerates the Pd(0) catalyst [12].

The turnover-limiting step in this catalytic cycle depends on the steric and electronic properties of both the organohalide and the organometallic reagent as well as the nature of the main-group metal, and can also be affected by the structure of the metal catalyst. The order of halide reactivity in oxidative addition processes is: I > Br ≈ OTf > Cl, and as noted above, the relative rate of oxidative addition of various aromatic halides is roughly proportional to the relative rates of SNAr transformations of these substrates. The transmetalation step [13] is often faster with more nucleophilic/electron-rich organic fragments (R1), and is inhibited by the steric bulk of both coupling partners. When there is more than one group attached to metal M, the order of transmetalation for different substituents...