Nucleophilic aromatic substitution asymmetric

Anne-Sophie Castanet, Anne Boussonniere, and Jacques Mortier 

Institut des Molecules et Matiriaux du Mans, Faculte des Sciences et Techniques, 

UMR CNRS 6283, Universiti du Maine and CNRS, Le Mans Cedex, France 

Although the nucleophilic aromatic substitution of electron-deficient arenas with nucleophiles has been known for more than 100 years, to the best of our knowledge, there is no review on the asymmetric version of this reaction [1,2], Within the context of this chapter, we have classified the main approaches involving asymmetric nucleophihc aromatic substitution reactions (Sj Ar ). We detail the current mechanistic understanding based on experimental and computational studies, and we summarize a selection of representative synthetic apphcations. 

In an Sj Ar process, a nucleophile reacts stereoselectively with an electron-deficient arene activated by one or more EWGs located ortho and/or para to a leaving group (L), creating a new C—C, C—O, or C—N bond (Fig. 8.1). The reaction provides access to a variety of aromatic derivatives with axial, central, and planar chirality. 

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In 2005 and 2006, Jorgensen and coworkers reported the development of the first catalytic asymmetric nucleophilic aromatic substitution reaction of 2-(carboethoxyjcyclopentanone (80) with highly activated aromatic electrophiles... 

AUXILIARY- AND SUBSTRATE-CONTROLLED ASYMMETRIC NUCLEOPHILIC AROMATIC SUBSTITUTION... 

Recently, asymmetric PTC using chiral quaternary ammonium salt 110 has proven to be an effective method for the enantioselective a-arylation of a-imino acid derivatives 108 via asymmetric nucleophilic aromatic substitution, to give a,a-disubstituted a-amino acids 111 in good to high enantiomeric purity (Scheme 8.22) [86]. 

SCHEME 8.24 Absolute asymmetric nucleophilic aromatic substitution. 

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). 

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]. 

Enolase type activity is displayed in the efficient supramolecular catalysis of H/D exchange in malonate and pyruvate bound to macrocyclic polyamines [5.32]. Other processes that have been studied comprise for instance the catalysis of nucleophilic aromatic substitution by macrotricyclic quaternary ammonium receptors of type 21 [5.33], the asymmetric catalysis of Michael additions [5.34], the selective functionalization of doubly bound dicarboxylic acids [5.35] or the activation of reactions on substituted crown ethers by complexed metal ions [5.36]. 

A radical cyclization approach to spiro-oxindoles was revealed <05OL151>. Treatment of p-trityloxybenzamide 125 with triethylborane and tris(trimethylsilyl)silane gave cyclohexadienone 126 via an ipso cyclization. The nucleophilic aromatic substitution of aryl fluorides was utilized in an asymmetric approach to spiro-pyrrolidone oxindoles <05JA3670>. 

Tomioka documented the use of organolithium reagents in enantioselec-tive conjugate additions to conjugated imines (Equation 31) [136]. The readily available chiral diether 173 served to mediate such additions with high asymmetric induction for example, the addition of PhLi to 172 furnished aldehyde 174 in 94% ee after hydrolysis of the imine adduct. In subsequent developments, Tomioka reported the enantioselective preparation of biaryls in which a naphthyllithium participates in a nucleophilic aromatic substitution catalyzed by only 5mol% of 173 (see insert on the left) and delivers the product in 82% ee [137]. 

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