Acidic conditions SNAr reactions

In conclusion, SNAr reactions are often facihtated by polar protic solvents such as butanol or by polar solvents in the presence of Brpnsted or Lewis acids. When displacements of halides with amines are used, both polar and protic solvents can solubilize the ammonium halides resulting from the reactions, and lead to the formation of Brpnsted acids. Fluoride or chloride ions are preferred leaving groups for this reaction. Suliinyl and sulfenyl groups require somewhat harsher conditions. 

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. 

SnAr reactions like nitration (with HNO3/H2SO4) or sulfonation (with H2SO4 or oleum) proceed very slowly, since in strongly acidic medium imidazolium ions are the participants in the SnAr processes. Thus, nitration of imidazole leads to 4-nitroimidazole (11), and under more drastic conditions to 4,5-dinitroimidazole (12). Sulfonation of imidazole in oleum at 160 °C yields imidazole-4-sulfonic acid ... 

SnAr reactions of pyridine proceed much more slowly than those of benzene they usually require drastic conditions and occur exclusively at the 3-position [80]. The relative reactivity of pyridine is comparable to that of nitrobenzene ( 10 rel. to benzene) in SnAr reactions operating in strongly acidic medium (nitration, sulfonation), the... 

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. 

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