Nucleophilic aromatic substitution palladium

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. 

A mild and efficient a-heteroarylation of simple esters and amides via nucleophilic aromatic substitution has been described <06OL1447>. Treatment of 2-chloro-benzo[//Jthiazole 99 with tert-butyl propionate in the presence of NaHMDS under nitrogen furnishes tert-butyl 2-(benzo[c(jthiazol-2-yl)propanoate 100. When the same reaction is preformed initially under nitrogen and then exposed to air, the hydroxylation product 101 is obtained. This method offers two desirable features that are either complementary or improvements to the palladium-catalyzed a-arylation reactions. First, heteroaryl chlorides... 

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. 

An extensive series of neutral macrocyclic complexes, mainly of nickel(II), copper(II), platinum(II) and palladium(II), has been developed by Dziomko and coworkers. The cyclization step in the template reaction is a nucleophilic aromatic substitution of an arylamine on to a haloaryl azo compound. A variety of aryl and heteroaryl rings can be incorporated in different combinations. For instance, a diaminoazo compound can be combined with a dihaloazo compound (Scheme 58).246 247 Another synthetic strategy involves the dimerization of an aminohaloazo compound and leads to more symmetrical macrocyclic complexes (Scheme 59).248 249 Most recently, dihalodiazo compounds have been synthesized from dihydrazines and pyrazolinediones and undergo template reactions with simple 1,2-diamines (Scheme 60).249 250... 

As mentioned earlier, Ding et al.15 captured a number of dichlorohetero-cyclic scaffolds where one chloro atom is prone to nucleophilic aromatic substitution onto resin-bound amine nucleophiles (Fig. 1). Even though it was demonstrated that in many cases the second chlorine may be substituted with SNAr reactions, it was pointed out that palladium-catalyzed reactions offer the most versatility in terms of substrate structure. When introducing amino, aryloxy, and aryl groups, Ding et al.15 reported Pd-catalyzed reactions as a way to overcome the lack of reactivity of chlorine at the purine C2 position and poorly reactive halides on other heterocycles (Fig. 10). 

Substituted imidazole 1-oxides 228 are predicted to be activated toward electrophilic aromatic substitution, nucleophilic aromatic substitution, and metallation as described in Section 1. Nevertheless little information about the reactivity of imidazole 1-oxides in these processes exists. The reason for this lack may be the high polarity of the imidazole 1-oxides, which makes it difficult to find suitable reaction solvents. Another obstacle is that no method for complete drying of imidazole 1-oxides exists and dry starting material is instrumental for successful metallation. Well documented and useful is the reaction of imidazole 1-oxide 228 with alkylation and acylation reagents, their function as 1,3-dipoles in cycloadditions, and their palladium-catalyzed direct arylation. 

In the original process using tin amides, transmetallation formed the amido intermediate. However, this synthetic method is outdated and the transfer of amides from tin to palladium will not be discussed. In the tin-free processes, reaction of palladium aryl halide complexes with amine and base generates palladium amide intermediates. One pathway for generation of the amido complex from amine and base would be reaction of the metal complex with the small concentration of amide that is present in the reaction mixtures. This pathway seems unlikely considering the two directly observed alternative pathways discussed below and the absence of benzyne and radical nucleophilic aromatic substitution products that would be generated from the reaction of alkali amide with aryl halides. 

The facility of arene reductive elimination underpins numerous C-C, C-O and C-N bond-forming reactions, which may be catalysed by late transition metals, in particular palladium (Figure 4.10). Although there are many variants, the general reaction scheme involves introduction of the aryl in electrophilic form via oxidative addition of an aryl halide (or sulfonate), substitution of the palladium halide by a nucleophile (which may also be carbon based) followed by reductive elimination. It is noteworthy that nucleophilic aromatic substitution in the absence of such catalysts can be difficult. 

For heteroaromatic systems, this reaction complements nucleophilic aromatic substitutions. The Pd-catalyzed reaction of 19 with 69 afforded 410 in excellent yield [145]. The use of bis-chelating ligands in this chemistry prevented ligand exchange with the pyridine substrate, thereby preventing formation of a bis(pyridyl)palladium species that would terminate the catalytic cycle. As a result of these specific catalytic conditions, this represented the first example of amination of a heteroaromatic halide. 

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... 

The mechanism of the reactions of aryl halides cannot occur by the common S 2 patii for the oxidative addition of methyl halides, and most aryl halides lack substituents that would make them sufficiently electrophilic to react by nucleophilic aromatic substitution pathways. As presented in the section on radical pathways for oxidative addition, aryl halides react with metal complexes that readUy imdergo one-electron oxidation by radical mechanisms. However, metal complexes that do not readily undergo one-electron processes tend to react by two-electron mechanisms. Thus, aryl halides typically react with tP" palladium(O) complexes by concerted pathways through three-centered transition states. No strong data for a radical pathway has been gained during the many studies on the oxidative addition of aryl halides to Pd(0). In contrast, evidence that oxidative addition of aryl halides to P, iridium, Vaska-t)q)e complexes occurs by a radical pathway has been published. ... 

Nucleophilic aromatic substitution can also be promoted by jr-complex formation but chromium complexes are particularly useful for realizing this type of activation as palladium or nickel do not lead to stable JT-complexes with arenes. For example, Jt-arenechromium tricarbonyl complexes react easily with nucleophiles, even when electrodonating substituents are present on the aromatic ring. This reaction has been used in two steps for the synthesis of carenone B (a sesquiterpene), one of these steps being an mrm-molecular nucleophilic attack with formation of a spirobicyclic system [22]. 

The scope and value of the benzannulation reaction is further increased by the substitution pattern of the arene ring, which can be modified by the incorporation of allcynes bearing additional functional groups such as silyl, stannyl, or boryl substituents. These functional groups have been used in various palladium-catalyzed (cross)-coupling reactions [63, 64]. Further structural elaboration may be based on benzannulation followed by nucleophilic aromatic addition [63b]. 

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