Foreword.- Abbreviations - Background: Introduction to catalysis.- General.- Considerations.- The elementary steps of catalytic reactions.- Classification of the catalytic processes on the basis of the electronic character of the reagents.- References.- Overview of common carbon-carbon and carbon-heteroatom bond forming reactions: Cross-coupling reactions.- Heck reaction.- Buchwald-Hartwig reaction.- Reactions proceeding with Co insertion.- Copper catalyzed processes.- References.- Late transition metal catalysis in the synthesis of heterocycles: the synthesis of five membered rings.- Introduction to catalysis: Transmetalation route.- Insertion route.- Carbon-heteroatom bond formation.- Other processes.- References.- The synthesis of six membered rings: Transmetalation route.- Insertion route.- Carbon-heteroatom bond formation.- Other processes.- References.- The synthesis of other ring systems.- Transmetalation route.- Insertion route.- Carbon-heteroatom bond formation.- Other processes.- References.- Late transition metal catalysis in the functionalization of heterocycles: The functionalization of five membered rings: Transmetalation route.- Insertion route.- Carbon-heteroatom bond formation.- Other processes.- References.- The functionalization of six membered rings.- Transmetalation route.- Insertion route.- Carbon-heteroatom bond formation.- Other processes.- References.- The functionalization of other ring systems: Transmetalation route.- Insertion route.- Carbon-heteroatom bond formation.- Other processes.- References.- Introduction to catalysis.- Subject index.
Chapter 7
THE FUNCTIONALIZATION OF SIX MEMBERED RINGS (p. 137-138)
The transition metal catalyzed functionalization of six membered heterocycles constitutes a major chapter of this book. The abundance of examples might be tracked down to two reasons: i) the large number of available haloazines, ii) the marked reactivity of haloazines in catalytic reactions, which originates in their electron deficient nature. In general the reactivity of a 2-chloropyridine derivative is comparable to a bromoarene, while a bromopyridine behaves more like an iodobenzene derivative. The increasing number of nitrogen atoms in the ring makes chlopyridazines or chloropyrimidines reactive enough to participate in transition metal catalyzed processes. The potential biological activity of six membered heterocyclic systems and their abundance as structural motif in natural products drove synthetic chemists to exploit their transformations. This chapter is mainly dedicated to the reactions of monocyclic six membered heterocycles and their benzologues. The chemistry of other condensed systems of importance, such as purines and pyrons, is discussed in Chapter 8.
7.1 TRANSMETALATION ROUTE
Probably the most thoroughly studied transition metal catalyzed transformation of six membered systems is their participation in crosscoupling reactions. Due to the vastness of this field we present only some representative examples for the different reaction types. In this chapter reactions where a haloazine is used to introduce the six membered ring on the palladium in the oxidative addition and processes, where the azine moiety is transferred onto the catalyst in a transmetalation step will be discussed parallel. The featured reactions were divided into subclasses along the commonly used name reactions.
Suzuki coupling
The availability of reagents and their functional group tolerance led to the emergence of Suzuki coupling as the most utilized cross-coupling reaction of the recent years.1 Either haloazines are coupled with an organoboron reagent, or the azines are converted into boronate esters, boronic acids or boranes and react with aryl halides, the reaction usually proceeds equally well. The examples presented below will focus more on the latter case, the coupling of hetarylboron compounds.2 The coupling of pyrone derivatives is discussed in Chapter 8.1.
In equation 7.1. a 4-chloropyridine was coupled with diethyl(3- pyridyl)borane.3 The reaction was run in aqueous THF in the presence of potassium carbonate. The role of the base is to facilitate the transmetalation step through the formation of a borate ion, as organoboranes are usually not nucleophilic enough to transfer their organic moiety onto the palladium. An alternate function of the base is to increase the electrophilicity of the palladium through exchange of the halide to carbonate.
