SNAr substitution

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. 

SNAr substitutions of activated aromatic halides, especially aromatic fluorides, provide useful means for the construction of aromatic diethers or amines. Primary and secondary amines react with l, 2-dihalo-4,5-dinitrobenzene to give nitro group substitution at room temperature. The halogen substituents on the ring remain unsubstituted and can be used in further transformation (Eq. 9.5).8... 

This mechanism is sometimes called SNAr (substitution-nucleophilic-aromatic). 

Extensive use of Pd-catalyzed reactions was included in the synthesis of 2,6,8-trisubstituted purines (Fig. II).33 The synthesis started by anchoring dichloropurine to Rink resin via N9 linkage. Polymer-bound 2,6-dichloropurine (63) was selectively substituted at C6 via acid-catalyzed SNAr substitutions. In the absence of Pd catalysis, the substitution on C2 could be performed only with strongly nucleophilic amines. To expand the scope of C2 substitution, catalytic amounts of Pd were used. Under these reaction conditions arylboronic acids and amines successfully substituted the chloro atom on C2 to afford C2-C and C2-N bonds. Subsequently, the C8 position was brominated with a bromine-lutidine complex33 (66) to give resin 67. 

Ammonia can react with the C2 position of oxazoles resulting in ring cleavage and formation of an imidazole ring. Ring cleavage by this mechanism occurs more frequently than SNAr substitution. 

Piccionello and co-workers have also developed a versatile and efficient Boulton-Katritzky rearrangement involving a N-N-C side-chain. Installation of the side chain was effected by SNAr substitution with methylhydrazine and subsequent imine formation with 4-trifluoromethyl-benzaldehyde (19), to provide 20. Solvent free thermolysis gave 21 in nearly quantitative yield. 

Compared with the aromatic electrophilic substitution approach, the SNAr approach general requires higher reaction temperatures. The polymers generally have well-defined structures. Therefore, it is more facile to control the structures of die products. In addition, it is more tolerable to some reactive functional groups, which makes it possible to synthesize reactive-group end-capped prepolymers and functional copolymers using functional monomers. 

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... 

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). 

A one-pot three-step conversion of aryl fluorides to phenols based on a consecutive nucleophilic aromatic substitution/isomerization/hydrolysis sequence has been reported by Levin and Du (Scheme 6.126) [256], The authors discovered that 2-butyn-l-ol can function as a hydroxyl synthon through consecutive SNAr displacement, in situ isomerization to the allenyl ether, and subsequent hydrolysis, to afford phenols rapidly and in good yields. In most cases, excesses of 2-butyn-l-ol (1-2 equivalents) and potassium tert-butoxidc (2-4 equivalents) were required in order to achieve optimum yields. 

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... 

Nucleophilic substitutions with [ F]fluoride have been largely developed both in aromatic (SNAr) and aliphatic (generally SN2) series. Nucleophilic additions remain rare. F-Nucleophilic radiofluorinations usually do not require any carrier and thus enable the synthesis of products with high specific radioactivity. The SN can be performed either directly on a suitable and generally complex precursor of the target molecule or indirectly via a small labelled precursor. Both approaches present drawbacks the first one generally leads to poor yields and the second requires multistep synthesis and more sophisticated automation processes. 

Two other important modes of substitution require mention here. They are the SNAr and elimination-addition reactions. Actually, it is sometimes difficult to distinguish between true aromatic nucleophilic substitutions and addition-elimination processes. The second group involves pyridyne intermediates (Scheme 53). Both of these reaction types are discussed fully under substituent reactions (Chapter 2.06). 

Die nukleophile aromatische Substitution verlauft entweder wie bei der Nitro-Dehaloge-nierung von aktivierten Halogen-arenen iiber einen Meisenheimer-Komplex (SNAr-Mechanismus) oder wie bei der Nitro-Dediazotierung iiber einen gewohnlichen SN1-Me-chanismus bzw. in Gegenwart von Kupfer(II)-Ionen iiber einen Radikal-ionischen Mechanismus ... 

The reaction labelled IPSO substitution is only applicable to species like OH - and NH2" and corresponds to a special case of the SNAr mechanism. 

---