Palladium catalysis aromatic substitution

The development of methods for aromatic substitution based on catalysis by transition metals, especially palladium, has led to several new methods for indole synthesis. One is based on an intramolecular Heck reaction in which an... 

As in the Skraup quinoline synthesis, loss of two hydrogen atoms is necessary to reach the fully aromatic system. However, this is usually accomplished in a separate step, utilising palladium catalysis to give generalised isoquinoline 6.14. This is known as the Bischler-Napieralski synthesis. The mechanism probably involves conversion of amide 6.12 to protonated imidoyl chloride 6.15 followed by electrophilic aromatic substitution to give 6.13. (For a similar activation of an amide to an electrophilic species see the Vilsmeier reaction, Chapter 2.)... 

While the major use for palladium catalysis is to make carbon-carbon bonds, which are difficult to make using conventional reactions, the success of this approach has recently led to its application to forming carbon-heteroatom bonds as well. The Overall result is a nucleophilic substitution at a vinylic or aromatic centre, which would not normally be possible. A range of aromatic amines can be prepared direcdy from the corresponding bromides, iodides, or triflates and the required amine in the presence of palladium(O) and a strong alkoxide base. Similarly, lithium thiolates couple with vinylic triflates to give vinyl sulfides provided lithium chloride is present. 

The direct coupling of aromatic systems has been achieved in the generation of 2-arylpyridines. These frameworks have been of importance in material and medicinal chemistry. The Pd-catalyzed Ullmann reaction afforded 2-nitrophenylpyridine derivatives that served as precursors to 2-substituted-phenylpyridines, which are found to have antiarrhythmic activity [152], To this end, 3-iodopyridine 152 could be directly coupled to 429 by palladium-catalysis to afford 430. 

With palladium catalysis, refluxing in nitrobenzene or xylene dehydrogenates 3-substituted 5,6,7,8-tetrahydropyrido[4,3-rf]pyrimidin-4(3//)-ones to yield the corresponding aromatic compounds. Thus, the 3-phenyl compound is dehydrogenated by heating in nitrobenzene with palladium on carbon at 125 130°C for 17 hours.509... 

A tandem Suzuki-Miyaura coupling/nucleophilic aromatic substitution to carba-zoles was developed by St. Jean et al. (Scheme 51) [210]. Reaction of A -sulfonyl-protected 2-aminophenylboronates 216 with l-bromo-2-fluorobenzenes 217 under palladium(0)-catalysis provides the Af-sulfonyl-protected carbazoles 218. This annulation is compatible with a variety of electron-withdrawing groups (e.g., aldehydes, esters, and sulfones) and has been applied to an efficient synthesis of glycosinine (147) (four steps, 50% overall yield). 

Nucleophilic aromatic substitution and palladium catalysis compared... 

There is a wide range of methods available to construct aromatic heterocydes. Nevertheless, many of these rely upon relatively involved multistep processes, especially for the assembly of highly substituted products. In addition, these can sometimes suffer from harsh reaction conditions, or display limited product diversity. As such, there has been intense recent interest in the design of new and more efficient routes to these products. In this regard, metal catalysis, and in particular palladium catalysis, has played a central role. 

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. 

Direct nucleophilic displacement of halide and sulfonate groups from aromatic rings is difficult, although the reaction can be useful in specific cases. These reactions can occur by either addition-elimination (Section 11.2.2) or elimination-addition (Section 11.2.3). Recently, there has been rapid development of metal ion catalysis, and old methods involving copper salts have been greatly improved. Palladium catalysts for nucleophilic substitutions have been developed and have led to better procedures. These reactions are discussed in Section 11.3. 

Several reports have been made of a successful catalyzed addition/ substitution reaction resulting in direct attachment of phosphorus to aromatic rings. The preparation of mixed triarylphosphines has been accomplished by the reaction of tin- or silicon-substituted diphe-nylphosphines with aryl halides catalyzed by palladium reagents.74 A similar transformation has also been reported using nickel catalysis.75 The addition/substitution of diphenylphosphine to triflate functionalized phenolic linkages has been of use for the preparation of substances as analogues of tyrosine-related amino acid derivatives, accomplished with catalysis by palladium acetate (Equation 4.29).76... 

Benzylic oxidation of aromatic side-chains is also a well established technology in the bulk chemicals arena, e. g. toluene to benzoic acid and p-xylene to ter-ephthalic acid [1,2]. These processes involve homogeneous catalysis by, e. g., cobalt compounds, however, and also fall outside the scope of this book. Ammoxi-dation of methyl-substituted aromatic and heteroaromatic compounds is performed over heterogeneous catalysts in the gas phase but this reaction is treated elsewhere (Section 9.5). Transition metal-substituted molecular sieves have been widely studied as heterogeneous catalysts for oxidation of aromatic side-chains in the liquid phase, but there are serious doubts about their heterogeneity [5,6]. Here again, a cursory examination of the literature reveals that supported palladium seems to be the only heterogeneous catalyst with synthetic utility [4]. 

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