Nucleophilic Aromatic Substitution SNAr Reactions

Smith, Jason A., 431 Sn2+ compounds, 233 Sn4+ compounds, 232 SNAr reaction. See also Nucleophilic aromatic substitution reaction poly(arylene ether sulfone) synthesis via, 336-340... 

Aromatic nitro compounds undergo nucleophilic aromatic substitutions with various nucleophiles. In 1991 Terrier s book covered (1) SNAr reactions, mechanistic aspects (2) structure and reactivity of anionic o-complexes (3) synthetic aspects of intermolecular SNAr substitutions (4) intramolecular SNAr reactions (5) vicarious nucleophilic substitutions of hydrogen (VNS) (6) nucleophilic aromatic photo-substitutions and (7) radical nucleophilic aromatic substitutions. This chapter describes the recent development in synthetic application of SNAr and especially VNS. The environmentally friendly chemical processes are highly required in modem chemical industry. VNS reaction is an ideal process to introduce functional groups into aromatic rings because hydrogen can be substituted by nucleophiles without the need of metal catalysts. 

In recent years, the importance of aliphatic nitro compounds has greatly increased, due to the discovery of new selective transformations. These topics are discussed in the following chapters Stereoselective Henry reaction (chapter 3.3), Asymmetric Micheal additions (chapter 4.4), use of nitroalkenes as heterodienes in tandem [4+2]/[3+2] cycloadditions (chapter 8) and radical denitration (chapter 7.2). These reactions discovered in recent years constitute important tools in organic synthesis. They are discussed in more detail than the conventional reactions such as the Nef reaction, reduction to amines, synthesis of nitro sugars, alkylation and acylation (chapter 5). Concerning aromatic nitro chemistry, the preparation of substituted aromatic compounds via the SNAr reaction and nucleophilic aromatic substitution of hydrogen (VNS) are discussed (chapter 9). Preparation of heterocycles such as indoles, are covered (chapter 10). 

Cycloamidation has been used extensively to prepare 17-membered cycloisodityrosines. The acyclic biaryl ether precursors were prepared by methods including the Ullmann reaction 2-5 and nucleophilic aromatic substitution (SNAr)J6 7 Since these methods have all been used intramolecularly in cyclization reactions, they will be discussed in Sections 9.5.3 and 9.5.4. Evans and co-workers employed the pentafluorophenyl ester method of macrolactamization 8] to prepare 11, an intermediate in their total synthesis of OF4949-III (7) (Scheme 2)J3 In this case, the acidic removal of a Boc group was employed to release the cyclization substrate, although hydrogenolysis of a Z group is also effective 3 ... 

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). 

Nucleophilic aromatic substitution (SnAr) reactions are not, in general, facile and usually require the presence of at least one strongly electron-withdrawing group, such as a nitro group, or otherwise a very good leav-... 

Pseudobase formation by nucleophilic addition to heteroaromatic cations is closely related to the long-known Meisenheimer complex formation by nucleophilic addition to an electron-deficient neutral aromatic molecule.20-25 In both cases nucleophilic attack on an electron-deficient aromatic ring produces a c-complex—an anionic Meisenheimer complex or a neutral pseudobase molecule. Despite the intense interest over the past few years in Meisenheimer complexes as models for er-complex intermediates in nucleophilic aromatic substitution reactions, there has been little overt recognition of the relationship between Meisenheimer complexes and pseudobases derived from heteroaromatic cations. In this regard, it is interesting that the pseudobase 165, which can be regarded as the complex intermediate that would be expected for an SNAr reaction between the l-methyl-4-iodoquinolinium cation and hydroxide ion, has been spectroscopically characterized.89... 

The rate enhancements observed in these nucleophilic aromatic substitution reactions when using crown-complexed ions and tetraalkylam-monium ions are indeed not surprising. Many examples are known of increased reactivity in nucleophilic substitutions due to complexation with crown compounds (24), also in SNAr reactions (25, 26). In our system, however, this normal effect is accompanied by an inhibiting effect on the competing reduction path, which is discussed under Reduction Channel. 

Furthermore, the stronger C-F bonds, compared with other C-halogen bonds such as the C-Cl, are the actual thermodynamic driving force for Halex reactions towards the fluoroaromatics [57]. The Halex reaction is a nucleophilic aromatic substitution (SNAr) in which chlorine atoms activated by an electron-withdrawing group are displaced by fluorine upon reaction with a metal fluoride under polar aprotic conditions [58]. 

As is the case with nucleophilic aliphatic substitution, nucleophilic aromatic substitution (SNAr) can occur by processes that exhibit either first- or second-order kinetics. In contrast to the aliphatic reactions, however, the first-and second-order aromatic reactions are quite different in character. 

Just as the benzyne mechanism was proposed in order to explain apparent anomalies in reactions considered initially to be SNAr reactions, another mechanism for nucleophilic aromatic substitution was developed because of results of studies under conditions in which the benzyne mechanism was expected. Kim and Burmett investigated the reaction of halogen-substituted isomers of pseudocumene (1,2,4-trimethylbenzene, 94) with KNH2 in liquid NH3. ° As shown in Figure 8.68, ehmination of HX from both the 5-halo-pseudocumenes (95a,b,c) and the 6-halopseudociunenes (96a,b,c) should produce the same aryne intermediate, 97. Therefore, the distribution of... 

In addition to the SNAr mechanism, several other mechanisms are known for nucleophilic aromatic substitutions. For example, an SnI mechanism is relevant for nucleophilic substitution reactions which encounter aromatic diazonium salts. Radical-nucleophilic aromatic substitutions (SrnI) are known in reactions where no electron-withdrawing group is available, whereas a mechanism via a benzyne intermediate is of relevance for substitutions employing NHJ as a nucleophile. 

In spite of the faet that the nucleophilic aromatic substitution in electron-deficient aromatic rings (SNAr) is one of the most venerable organic reactions, it is still a subject of debate. The generally accepted meehanism for this reaction is the classical addition-elimination sequence that involves the formation of a Meisenhei-mer-type intermediate 1 (Scheme 33.1). 

We have recently reported ( ) several synthetic studies of weak nucleophile SnAr reactions. In the latter cases (26f-1), new synthetic methodology was reported for the direct introduction of fluoroalkoxy groups into a variety of aromatic systems. These reports represent synthetically useful procedures for obtaining some otherwise inaccessible fluoroalkoxy materials but, unfortunately, they require the use of a dipolar, aprotic solvent (usually hexamethylphosphoramide, HMPA) and, in some cases, elevated temperatures. However, because of their diverse and important applications ( ), the syntheses of these and other organofluoro compounds continue to be of interest. For example, two recent reports of useful fluoroalkoxy materials include the insecticide activity exhibited by fluoroalkoxy substituted 1,3,4-oxadiazoles... 

While the greatest percentage of PTC-aided anionic substitutions involve non-aromatic systems (7-10), a number of liquid-liquid and solid-liquid, PTC-aided SnAr reactions have been reported (32-38). These reports involve a variety of substrates [unactivated (32,33), slightly activated (M), activated (35-37), and transition metal complexed 32,38)1, nucleophiles OMe (32,38), CN ( ), SR (34) SCN (36), SO (36), OR (37)] and PTCs... 

Secondary steric effects could become significant in aromatic nucleophilic substitution in activated halogenoben-zenes. This can be ascribed to steric inhibition of resonance. In contrast, secondary steric effects are not important in SNAr reactions of thiophene derivatives this is due to the geometry of five-membered ring derivatives, which strongly lowers the steric interactions between the substituents on the thiophene ring. This has been reconfirmed by kinetic data in methanol on SNAr reactions of the two pairs of substrates 210 and 211 with different nucleophiles (piperidine and sodium benzenethiolate) <1997J(P2)309>. 

Now you have three basic mechanisms for aromatic rings — electrophilic aromatic substitution, SNAr, and elimination/addition. How do you choose among these The first consideration is what types of other reagents are present. If the reagents include an electrophile, then the reaction will be electrophilic aromatic substitution. The presence of a nucleophile may lead to either SNAr or elimination/addition. If the system meets the three requirements for SNAr, then the reaction will follow that mechanism. If not, it will be an elimination/addition. 

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