Regioselective Syntheses of Multisubstituted Aromatic Compounds via Ester-Mediated Nucleophilic Alkylation

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We have investigated regioselective syntheses of multisubstituted aromatic compounds via the ester-mediated nucleophilic aromatic substitution(S_NAr)and the conjugate addition to benzoate rings. 1.The S_NAr reaction of 2-methoxybenzoates with Grignard reagents was found to be accelerated by introduction of a methoxy or halo substituent at the 3-position of the benzoate ring. The ligating ability of the 3-methoxy group was found to play a crucial role in enhancing the reactivity of the 2-methoxy moiety, while the electron-withdrawing ability was more important in the case of the halogens. 2.A stepwise S_NAr reaction of 2, 6-dimethoxybenzoates with two kinds of Grignard reagents was achieved by controlling the molar equivalence of the Grignard reagents to the substrates, giving the corresponding benzoic esters with different substituents at the 2- and 6-positions. Novel chiral alcohols, 1, 8-disubstituted fluorenols and 7-substituted 2, 2-dimethyl-1-indanols were conveniently synthesized … More by using the process and evaluated for their chiral induction abilities. 3.Novel ternaphthalenes were synthesized by the S_NAr reaction between 1, 5-(or 1, 4-)dialkoxynaphthalen-2, 6-(or 2, 3-)dicarboxylic esters and 1-naphthyl Grignard reagents or 1-alkoxy-2-naphthoic esters and naphthalen-1, 4-di-Grignard reagents. 4.A regioselective allylation of 3-bromo-2, 6-dimethoxybenzonic ester at the 2-position was achieved and utilized for a facile preparation of 5-bromo-8-methoxy-3-methylnaphthalen-1-ol, which is a key compound for the syntheses of michellamines. 5.A combination of the estermediated S_NAr reaction and the conjugate addition to benzoate rings made it possible to introduce three different substituents at the 2-, 4- and 6-positions of a 3-bromo-2, 6-dimethoxybenzoate, which was utilized for the synthesis of a larreantin analog. 6.A biphenyl-2-carboxylic ester, which had been prepared by the S_NAr reaction, was successfully utilized as a key synthetic intermediate for blestriarene C.7.Calix[4]arenes comprised of four aniline units were synthesized for the first time via the S_NAr reaction of tetramethyl ether of sulfinyl- or sulfonylcalix[4]arene with lithium benzylamide. Less