Catalyzed Nucleophilic Aromatic Substitution

One group of nucleophilic aromatic substitution processes does not fit mechanistically into the previous categories. This group is a series of copper-catalyzed displacements of aromatic halogen compounds. 

There are several closely related processes involving other nucleophiles that, at least to date, have found less synthetic application. For example, heating aryl halides with cuprous benzoate produces aryl benzoates  

Another example is the rapid displacement of iodine by ammonia in the presence of cuprous trifluoromethylsulfonate  

The scope of these two types of reactions is not yet well documented. All, however, are believed to proceed through an organocopper species formed from the aryl halide.  

Perhaps the most useful application of aromatic substitution reactions that proceed by way of free radicals is for the synthesis of biphenyls. An aryl radical is 

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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. 

Benzyne is considered to be the intermediate in strong base-catalyzed nucleophilic aromatic substitution. 

Phase transfer was used to catalyze nucleophilic aromatic substitutions by Makosza et al. in 1974.201 202 Zoltewicz203 has given a good early review of various methods and has compared other techniques that make use of polar solvents, transition metals, and monoelectron transfers. 

Fluorinated nitrobenzenes are highly activated electrophiles, and have been used in PTC-catalyzed nucleophilic aromatic substitution by Jorgensen and colleagues [44,45]. The arylation ratio at C- or O- is heavily dependent on the catalyst structure, counter anion and reaction temperature, and the reaction of ketoesters... 

Copper-mordenite catalyzed nucleophilic aromatic substitution reactions. 

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. 

Development Center achieved this in the late 1970s [10], An important feature of this invention was the development of a process to make dianhydrides, specifically dianhydrides based on bisphenol-A. This was achieved by phase-transfer-catalyzed nucleophilic aromatic substitution, as shown in Eq. (8.4). Anitro group was displaced from a phthal-imide by a bisphenol salt to yield a difunctional imide compound, which, in turn, was converted to the bisphenol-A dianhydride (BPADA). Sodium nitrite is made as a by-product. 

In discussing base catalysis it will prove convenient to adopt, at the outset, a distinction first proposed by Bunnett and Garst22, who noted that the observed cases of catalysis in nucleophilic aromatic substitution could be broadly divided into two categories. The classification was in terms of the relative rates of the catalyzed and uncatalyzed reactions. Since all of the systems could be accommodated empirically by eqn. (4),... 

Bifunctional catalysis in nucleophilic aromatic substitution was first observed by Bitter and Zollinger34, who studied the reaction of cyanuric chloride with aniline in benzene. This reaction was not accelerated by phenols or y-pyridone but was catalyzed by triethylamine and pyridine and by bifunctional catalysts such as a-pyridone and carboxylic acids. The carboxylic acids did not function as purely electrophilic reagents, since there was no relationship between catalytic efficiency and acid strength, acetic acid being more effective than chloracetic acid, which in turn was a more efficient catalyst than trichloroacetic acid. For catalysis by the carboxylic acids Bitter and Zollinger proposed the transition state depicted by H. 

It has been well known since the pioneering work of Bunnett59 that some nucleophilic aromatic substitutions can be catalyzed by single electron transfer. Electrochemistry was shown60,61 to be an efficient technique both for inducing reactions and for determining mechanisms and thermodynamic data concerning equilibria in the overall process. 

The general approaches for the synthesis of poly(arylene ether)s include electrophilic aromatic substitution, nucleophilic aromatic substitution, and metal-catalyzed coupling reactions. Poly(arylene ether sulfone)s and poly(arylene ether ketone)s have quite similar structures and properties, and the synthesis approaches are quite similar in many respects. However, most of the poly(arylene ether sul-fone)s are amorphous while some of the poly(arylene ether)s are semicrystalline, which requires different reaction conditions and approaches to the synthesis of these two polymer families in many cases. In the following sections, the methods for the synthesis of these two families will be reviewed. 

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... 

In more recent work by other researchers, sealed-vessel microwave technology has been utilized to access valuable medicinally relevant heterocyclic scaffolds or intermediates (Scheme 6.120) [240-245]. Additional examples not shown in Scheme 6.120 can be found in the most recent literature (see also Scheme 6.20) [246-249]. Examples of nucleophilic aromatic substitutions in the preparation of chiral ligands for transition metal-catalyzed transformations are displayed in Scheme 6.121 [106,108]. 

The utilization of polar polymers and novel N-alkyl-4-(N, N -dialklamino)pyridinium sedts as stable phase transfer catalysts for nucleophilic aromatic substitution are reported. Polar polymers such as poly (ethylene glycol) or polyvinylpyrrolidone are thermally stable, but provide only slow rates. The dialkylaminopyridininium salts are very active catalysts, and are up to 100 times more stable than tetrabutylammonium bromide, allowing recovery and reuse of catalyst. The utilization of b is-dialkylaminopypridinium salts for phase-transfer catalyzed nucleophilic substitution by bisphenoxides leads to enhanced rates, and the requirement of less catalyst. Experimental details are provided. 

Miscellaneous PTC Reactions The field of PTC is constantly expanding toward the discovery of new enantioselective transformations. Indeed, more recent applications have demonstrated the capacity of chiral quaternary ammonium salts to catalyze a number of transformations, including the Neber rearrangement (Scheme 11.19a), ° the trifluoromethylation of carbonyl compounds (Scheme 11.19b), ° the Mannich reaction (Scheme 11.19c), and the nucleophilic aromatic substitution (SnAt)... 

Monoalkylation of a-isocyano esters by using tert-butyl isocyano acetate (R = fBu) has been reported by Schollkopf [28, 33]. Besides successful examples using primary halides, 2-iodopropane has been reported to produce the a-alkylated product (1) as well by this method (KOfBu in THF). In the years 1987-1991, Ito reported several methods for the monoalkylation of isocyano esters, including the Michael reaction under TBAF catalysis as described earlier [31], Claisen rearrangements [34], and asymmetric Pd-catalyzed allylation [35]. Finally, Zhu recently reported the first example of the introduction of an aromatic substituent by means of a nucleophilic aromatic substitution (Cs0H-H20, MeCN, 0°C) in the synthesis of methyl ot-isocyano p-nitrophenylacetate [36]. 

Similarly, 3-oxo-6-nitrobenzoxazine, which is also a lactam, has been N-arylated using sodium hydride and 4-nitrochlorobenzene in dimethylformamide (DMF) <1985IJB1263>. The reaction is a nucleophilic aromatic substitution assisted by the 4-nitro group and is therefore not general to all aryl halides. However, there is a route to N-arylated benzoxazines 148-151 through a catalyzed tandem cyclization-arylation reaction of 147, shown in Scheme 9 <2004S2527>. 

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 absence of nitro groups in these substrates is noteworthy. The observed adducts are exclusively stabilized by the electron-withdrawing capacity of the aza groups present in the fused ring system of purine. Accordingly, all ring protons in the adducts are more shielded than the corresponding protons in the substrates. Adducts 19 and 20 can be taken as models for intermediates in nucleophilic aromatic substitution at the C-6 position of purine. Moreover, their formation support the view that a tetrahedral carbon at C-6 is involved in the mechanism of the adenosine deaminase-catalyzed hydrolysis of 6-substituted purine ribonucleosides.43... 

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. 

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