Article: First General, Direct, and Regioselective Synthesis of Substituted Methoxybenzoic Acids by Ortho Metalation

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First General, Direct, and Regioselective Synthesis of Substituted Methoxybenzoic Acids by Ortho Metalation

Thi-Huu Nguyen, Nguyet Trang Thanh Chau, Anne-Sophie Castanet, Kim Phi Phung Nguyen, and Jacques Mortier

J. Org. Chem., 72 (9), 3419 -3429, 2007

Abstract:

New general methodology of value in aromatic chemistry based on ortho-metalation sites in o-, m-, and p-anisic acids (1-3) (Scheme 1) is described. The metalation can be selectively directed to either of the ortho positions by varying the base, metalation temperature, and exposure times. Metalation of o-anisic acid (1) with s-BuLi/TMEDA in THF at -78 C occurs exclusively in the position adjacente to the carboxylate. On the other hand, a reversal of regioselectivity is observed with n-BuLi/t-BuOK. With LTMP at 0 C, the two directors of m-anisic acid (2) function in concert to direct introduction of the metal between them while n-BuLi/t-BuOK removes preferentially the proton located ortho to the methoxy and para to the carboxylate (H-4). s-BuLi/TMEDA reacts with p-anisic acid (3) exclusively in the vicinity of the carboxylate. According to these methodologies, routes to very simple methoxybenzoic acids with a variety of functionalities that are not easily accessible by other means have been developed.

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