Transition Metal-Catalyzed Aromatic Substitution Reactions

Transition Metal-Catalyzed Aromatic Substitution Reactions 

As noted in Section 11.2.2, nucleophilic substitution of aromatic halides lacking activating substituents is generally difficult. It has been known for a long time that the nucleophilic substitution of aromatic halides can be catalyzed by the presence of copper metal or copper salts.137 Synthetic procedures based on this observation are used to prepare aryl nitriles by reaction of aryl bromides with Cu(I)CN. The reactions are usually carried out at elevated temperature in DMF or a similar solvent. 

A general mechanistic description of the copper-promoted nucleophilic substitution involves an oxidative addition of the aryl halide to Cu(I) followed by collapse of the arylcopper intermediate with a ligand transfer (reductive elimination).140 

Some reactions of this type are accelerated further by use of naphthoic acid as an additive. This effect is believed to result from formation of a mixed anionic cuprate 

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Transition Metal-Catalyzed Aromatic Substitution Reactions... 

Direct aromatic substitution of unactivated aryl halides is slow and generally requires a catalyst to become a useful synthetic method. Copper reagents have been used in some cases in classical procedures for the formation of products from aromatic substitution. In many cases these copper-mediated reactions occur at high temperatures and are substrate dependent. Since the 1970s, transition metal catalysts have been developed for aromatic substitution. Most of the early effort toward developing metal-catalyzed aromatic substitution focused on the formation of... 

Chapter 11 focuses on aromatic substitution, including electrophilic aromatic substitution, reactions of diazonium ions, and palladium-catalyzed nucleophilic aromatic substitution. Chapter 12 discusses oxidation reactions and is organized on the basis of functional group transformations. Oxidants are subdivided as transition metals, oxygen and peroxides, and other oxidants. 

Substitution of halopurines at C-2 and C-6 has become a well-developed synthetic process, with a wide variety of nucleophilic aromatic substitution and palladium-catalyzed C-N or C-O hond formations exemplified in the literature. The use of selective, sequential substitution reactions on polyhalopurine scaffolds is the basis of an increasing number of combinatorial syntheses of polysubstituted purines, both in solution and on solid phase. The introduction of N-, 0-, or S-substituents has often been combined with transition metal-catalyzed C-C bond-forming reactions (see Section 10.11.7.4.2) and selective N-alkylation (see Section 10.11.5.2.1) to provide versatile routes to purines with multiple, diverse substituents. 

The introduction of nucleophiles onto five membered heterocycles through non-catalyzed aromatic nucleophilic substitution is of little synthetic value, since the comparatively high electron density of the aromatic ring makes the nucleophilic attack unfavourable. The introduction of transition metal catalyzed carbon-heteroatom bond forming reactions overcame this difficulty and led to a rapid increase in the number of such transformations. 

Aryl- and heteroaryl halides can undergo thermal or transition metal catalyzed substitution reactions with amines. These reactions proceed on insoluble supports under conditions similar to those used in solution. Not only halides, but also thiolates [76], nitro groups [76], sulfinates [77,78], and alcoholates [79] can serve as leaving groups for aromatic nucleophilic substitution. 

The author believes that students are well aware of the basic reaction pathways such as substitutions, additions, eliminations, aromatic substitutions, aliphatic nucleophilic substitutions and electrophilic substitutions. Students may follow undergraduate books on reaction mechanisms for basic knowledge of reactive intermediates and oxidation and reduction processes. Reaction Mechanisms in Organic Synthesis provides extensive coverage of various carbon-carbon bond forming reactions such as transition metal catalyzed reactions use of stabilized carbanions, ylides and enamines for the carbon-carbon bond forming reactions and advance level use of oxidation and reduction reagents in synthesis. 

Substituted styrenes and vinylic compounds are versatile intermediates in organic synthesis, so various methods have been published in the literature [33, 34]. Among them, the Heck reaction is one of the best-studied methods for preparing these compounds [34]. However, for this reaction, the use of the halogen-carbon bond is essential for making C-C bonds. If direct addition of otherwise unreactive C-H bond to acetylenes takes place, this method will become one of the simplest methods for preparing substituted styrenes and vinylic compounds. In this section, we will describe the transition metal-catalyzed vinyla-tion of aromatic compounds by using acetylenes. 

The introduction or replacement of substituents on aromatic rings by substitution reactions is one of the most fundamental transformations in organic chemistry. On the basis of the reaction mechanism, these substitution reactions can be divided into (a) electrophilic, (b) nucleophilic, (c) radical, and (d) transition metal catalyzed. In this chapter we consider the electrophilic and nucleophilic substitution mechanisms. Radical substitutions are dealt with in Chapter 11 and transition metal-catalyzed reactions are discussed in Chapter 9 of Part B. 

Consequently, pyridine has a reduced susceptibility to electrophilic substitution compared to benzene, while being more susceptible to nucleophilic attack. One unique aspect of pyridine is the protonation, alkylation, and acylation of its nitrogen atom. The resultant salts are still aromatic, however, and they are much more polarized. Details for reactivity of pyridine derivatives, in particular, reactions on the pyridine nitrogen and the Zincke reaction, as well as C-metallated pyridines, halogen pyridines, and their uses in the transition metal-catalyzed C-C and C-N cross-coupling reactions in drug synthesis, will be discussed in Section 10.2. 

For reviews on the Fujiwara-Moritani reaction, see (a) Fujiwara, Y. (2002) Palladium-promoted alkene-arene coupling via C—H activation, in Handbook of Organopalladium Chemistry in Organic Synthesis, Vol. 2 (eds E.-i. Negishi and A. de Meijere), John Wiley Sons, Inc., New York, pp. 2863-71 (b) Jia, C., Kitamura, T. and Fujiwara, Y. (2001) Catalytic functionalization of arenes and alkanes via C—H bond activation. Acc. Chem. Res., 34, 633-9 (c) Fujiwara, Y. and Jia, C. (2001) New developments in transition metal-catalyzed synthetic reactions viaC—H bond activation. PureAppl. Chem., 73,319-24 (d) Moritani, I. and Fujiwara, Y. (1973) Aromatic substitution of olefins by palladium salts. Synthesis, 524-33. 

Oxidative addition of substrates possessing C-X or H-X bonds of medium polarity and of substrates possessing Ar-X bonds that cannot undergo S 2 pathways often occur by concerted pathways involving three-centered transition states more like those of the oxidative additions of nonpolar substrates. The clearest cases in which reactions occiu by concerted pathways are the oxidative additions of aryl halides and sulfonates to paUadium(0) complexes. These reactions have been studied extensively because they are the first step of transition-metal-catalyzed nucleophilic aromatic substitution reactions called cross couplings. The oxidative additions of the O-H and N-H bonds in water, alcohols, and amines also appear to occur by concerted three-centered transition states in many cases. 

The possibilities for the formation of carbon-carbon bonds involving arenes have been dramatically increased in recent years by the use of transition metal catalysis. Copper-mediated reactions to couple aryl halides in Ulknann-type reactions [12, 13] have been known for many years, and copper still remains an important catalyst [14, 15]. However, the use of metals such as palladium [16,17] to effect substitution has led to such an explosion of research that in 2011 transition metal-catalyzed processes comprised more than half of the reactions classified as aromatic substitutions in Organic Reaction Mechanisms [18]. The reactions often involve a sequence outlined in Scheme 6.6 where Ln represents ligand(s) for the palladium. Oxidative addition of the aryl halide to the paiiadium catalyst is followed by transmetalation with an aryl or alkyl derivative and by reductive elimination to give the coupled product and legeuCTate the catalyst. Part 6 of this book elaborates these and related processes. 

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