Development and Application of Ester-Mediated Nucleophilic Aromatic Substitution Reaction

Nucleophilic aromatic substitution (S_NAr) reactions of ortho-alkoxyarylcarboxylic esters by C-, N-, and O-nucleophiles, developed in our laboratory, are reviewed. Aryl Grignard reagents efficiently displaced the 1-methoxy group of 1-methoxy-2-naphthoates to afford the corresponding biaryls in excellent yields ; isopropyl ester is bulky enough to prevent the Grignard addition to the ester carbonyl function. 2-Methoxybenzoic esters derived from 2,6-dialkylphenols also underwent the S_NAr reaction by proper choice of the bulk of the 2,6-dialkyl-substituents. High levels of asymmetric induction were achieved in these reactions by use of an enantiomeric menthoxy leaving group. As the electrondonating ability of the carbanion species increased, 1,4- or 1,6-conjugate addition of the nucleophiles to the 2-methoxybenzoates was found to compete with the S_NAr reaction. Triarylamines were conveniently prepared by the reaction of a 2- or 4-fluorobenzoate with lithium diarylamides in THF-HMPA. 2-Sulfonyl- as well as 2-phosphinoyl-substituted 1-methoxynaphthalenes also underwent the S_NAr reaction. Factors affecting the activating power of the 2-substituents are discussed.