SNAr chemistry

Schultz and co-workers31 also described the preparation of a 2,6,9-trisubstituted purine library. A preformed 2-fluoro-6-(4-aminobenzylamino) purine was reductively aminated onto the BAL linker 12. Mitsunobu chemistry was employed to alkylate the C9 position on the support-bound intermediate (Scheme 4). Subsequently, SNAr chemistry was used to incorporate amines at C6. The newly introduced primary and secondary amines bear diverse functional groups and the Mitsunobu reaction allows for incorporation of primary and secondary alcohols lacking acidic hydrogens. The support-bound product 13 was cleaved with 90% TFA/10% H20 to give a library with HPLC purities ranging between 51 and 85%. 

In addition to the ruthenium SNAr chemistry discussed in Section 11.7.2, an analogous copper-assisted S Ar cyclization reaction of a boronic acid and a phenol has been reported to construct biaryl ethers 146 (Scheme 11.19). Specifically, this functionality was then incorporated into MMP inhibitors. The mild conditions were shown to tolerate amides and esters in the substrate, although the presence of an additional phenol resulted in only trace product. Some other transformations involving copper mediation are presented in Section 11.8. 

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). 

There is certain similarity in the order of reactivities between SNAr displacement reactions and oxidative additions in palladium chemistry. Therefore, the ease with which the oxidative addition occurs for these he ter o aryl chlorides has a comparable trend. Even a- and y-chloroheterocycles are sufficiently activated for Pd-catalyzed reactions, whereas chlorobenzene requires sterically hindered, electron-rich phosphine ligands. 

Benzotriazoles, for example, are accessible from o-aminoaryl-substituted triazenes after a two-step reaction sequence a nucleophilic displacement followed by cleavage/heterocyclization.35 The nucleophilic halide displacement of activated haloarenes is an indispensable tool for the synthesis of highly substituted arenes. Fluoronitroarenes in particular have served as excellent precursors in this transformation. Thus, it was appealing to combine this SNAr reaction with the flexibility of diazonium chemistry. In this case, an immobilized fluoronitrophenyl triazene would be the equivalent of the Sanger reagent. 

The basic concepts of nucleophilic substitution reactions appeared in the first semester of organic chemistry. These reactions follow SN1 or SN2 mechanisms. (In aromatic nucleophilic substitution mechanism, we use the designation SNAr.) In SN1 and SN2 mechanisms, a nucleophile attacks the organic species and substitutes for a leaving group. In aromatic systems, the same concepts remain applicable, but with some differences that result from the inherent stability of aromatic systems. 

A recent and important new development in the application of [Fe(arene)Gp] chemistry is that iron-assisted SnAr reactions have, for the first time, been performed in the solid phase. A library of 36 unsymetrically substituted phenylpiperazines and phenyl-1,4-diazepanes was synthesized using this novel strategy. Scheme 29 shows some of the iron complexes 114a-d that were prepared. Decomplexation of resin-bound iron complexes was achieved with 1,10-phenanthroline under irradiation. ... 

As stated previously, arylhalides do not typically participate in Arbuzov-type chemistry due to their sluggish behavior in nucleophilic substitution reactions. Typically, metal salts are added to promote the reaction. However, suitably activated systems are known to participate in SNAr reactions using phosphorus nucleophiles. To this end, the pyrazinones have been phosphorylated through a metal-free Arbuzov reaction (Scheme 4.213) [352]. This approach to the functionalization of these heterocycles was attractive since it is operationally straightforward and was successful under solvent-free conditions. A focused microwave... 

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