Suzuki–Miyaura Coupling

DAVID BLAKEMORE

Pfizer World Wide Medicinal Chemistry, The Portway Building, Granta Park, Cambridge CB21 6GS, UK Email: david.blakemore@pfizer.com

1.1 Introduction

In this book, we will focus on reactions that are of importance to the pharmaceutical industry and the synthesis of drug-like molecules or motifs. It therefore seems highly appropriate to start this book and our coupling section with a true work-horse of the pharmaceutical industry. The Suzuki–Miyaura coupling (SMC) is the most frequently used carbon–carbon bond forming reaction in drug discovery; more specifically, it is the most frequently used reaction for carrying out C(sp2)–C(sp2) couplings and, in the context of drug synthesis, this translates to the synthesis of biaryl motifs (Scheme 1.1).

At its simplest, the biaryl SMC is the reaction of an aryl boronic acid, boronate ester (also referred to as boronic esters) or other boronate species (for simplicity we will refer to all these species as aryl boronates) with an aryl halide in the presence of a palladium(0) catalyst (which may have been generated from a palladium(II) source and is likely partnered with a ligand that stabilises the species and facilitates reaction) and aqueous base in a suitable solvent. The success of the reaction is due to the fact that it works across a wide range of aryl and heteroaryl substrates and has a high degree of functional group tolerance. A large number of boronic acids and boronate esters are now commercially available and the majority of aryl halides, including the traditionally challenging aryl chlorides, can be coupled with aryl boronates by the appropriate choice of palladium species and accompanying ligand. From a pharmaceutical industry perspective, in comparison with other common coupling protocols, the SMC reaction has a number of advantages including (1) the reagents used in SMC reactions are typically non-toxic (unlike the Stille coupling where the toxic tin reagents and residues left at the end of the reaction pose a huge issue for any scale-up work), and (2) the fact that boronic acids or esters are generally relatively stable intermediates (although, as we will see in the protodeboronation section, this is not always the case) means that they can be isolated rather than having to be generated and used in situ (in comparison, organozinc species or Grignard species need to be generated in situ in the reaction as they are highly reactive species).

The impact of the SMC reaction on the pharmaceutical industry has been profound: an analysis of the types of molecules synthesised within the pharmaceutical industry noted that there had been an increase in the "flatness" of molecules since the 1970s and that this correlates with the availability of chemistry facilitating sp2–sp2 couplings. Indeed, one of the key challenges currently for carbon–carbon coupling reactions is to access motifs with increased three-dimensional shape. With the success of the SMC reaction in generating biaryl motifs, it is clear that a variant of the SMC allowing aryl–alkyl couplings in a chiral manner is both highly desirable and could fundamentally change the motifs being generated. This topic will be discussed further in Volume 2, Chapter 16.

This issue of the ubiquity of biaryl motifs has cast the SMC reaction in a negative light in recent years but there can be little doubt that the reaction is a key work-horse in drug discovery programs. Ultimately, the importance of the reaction and coupling chemistry itself is evidenced in the award of the 2010 Nobel Prize in Chemistry to Heck, Negishi and Suzuki.

In this chapter, we will look in detail at the SMC highlighting optimal conditions but also, and very importantly, detailing the limitations of the reaction. For a reaction that is used routinely in a drug discovery environment, typically attaching elaborated fragments to one another, and that results in a significant increase in molecular complexity, it is important to know which reactions will work and which are likely to be challenging. For example, we could envisage a situation where we are coupling one aryl bromide with a range of aryl boronic acids to make a library of molecules to be screened for biological activity against a target. If a number of the boronic acids used fail to give desired product, it is important to understand why they have failed to react and whether there is a subset of the chemical space we defined at the outset that we have failed to screen against our target.

1.2 The Catalytic Cycle of the SMC

To understand the SMC, we need to start by examining the catalytic cycle (Figure 1.1). The cycle starts with the active catalytic LnPd(0) species where L represents the ligand stabilising the Pd(0) species. The Pd(0) species can be added directly to the reaction with examples being Pd(PPh3)4, Pd(dba)2 and Pd(tBu3P)2. An alternative to the use of a Pd(0) species is to use a Pd(II) species which is then reduced in situ. The advantage here is that the Pd(II) species is more stable than the Pd(0) species but typically it is also less reactive as it does require the reduction to generate the active species. Representative examples of Pd(II) species are Pd(OAc)2, Pd(dppf)Cl2 and PdCl2(PPh3)2. Reduction of the Pd(II) species is typically effected by the...