Development and Application of Nucleophilic Aromatic Substitution Reaction Mediated by Unclassical Activating Groups

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Although nucleophilic aromatic substitution reaction (S_NAr) is an important process in organic synthesis, it generally requires severe reaction conditions and/or the presence of highly electron-withdrawing, so-called "activating" groups on the aromatic nucleus, which limits its applicability. We have investigated the chelation-assisted S_NAr reaction mediated by unclassical activating groups and obtained the following results. 1.The reactions of 2,6-di-tert-butyl-4-methoxyphenyl 2-methoxybenzoate with several organometallics were found to give the methoxy-substitution products and/or the conjugate addition products to the benzoate ring, preferring the latter products at the expense of the former with the increase of the electron-donating ability of the carbanion species. 2.The S_NAr reactions were found to be accelerated by introducing a substituent which could ligate to the metal center of the nucleophiles into the 3-position of the benzoate ring. 3.Facile synthesis of O-methylhamati … More ne was achieved by the asymmetric biaryl coupling reaction of a chiral 1-menthoxy-2-naphthoate with an aryl Grignard reagent as the key step. 4.Chiral cyclophanes and an acetal were employed as the substrate of the S_NAr reaction and highly efficient conversions of chiral elements among C-centro-, planar and axial chirality were attained. 5.Triarylamines were conveniently prepared by the reaction of a 2- or 4-fluorobenzoate with lithium diarylamides. 6.Novel chiral alcohols, 1,8-disubstituted fluorenols and 7-substituted 2,2-dimethyl-1-indanols were synthesized via the S_NAr reaction and resolved. The latter were proved to be highly resistant to racemization and could effectively be utilized as chiral auxiliaries. 7.2-Sulfonyl-as well as 2-sulfinyl-substituted 1-methoxynaphthalenes were found to undergo the S_NAr reaction. Factors affecting the activating power of the 2-substituents were elucidated. 8.Chiral aminophosphines were prepared via the S_NAr reaction of 2-diphenylphosphinoyl-1-methoxynaphthalene with chiral lithium amides, followed by reduction of the phosphinoyl function. They could effectively be utilized as the ligands for palladium-catalyzed allylic substitution reaction. Less