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

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 degrees 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 degrees 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 (Table 1).

C3-triiodocyclotriveratrylene as a key intermediate to fluorescent probes: application to selective choline recognition

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Combined Metalation–Cross Coupling Strategies: A Synthesis of Schumanniophytine by a Key Biaryl O‐Carbamate Remote Anionic Fries Rearrangement

“…In view of the connections to D o M11 and cross‐coupling strategies,6 the route provides opportunity for incorporation of functionality in the aromatic, pyridyl, and pyranyl moieties for potential SAR profiling studies. This and related contributions from our20 and other laboratories21 further demonstrate the increasing value of carbanionic chemistry for the regioselective construction of aromatics and heteroaromatics.…”

Axially Chiral 1,1'‐Binaphthyl‐2‐Carboxylic Acid (BINA‐Cox) as Ligands for Titanium‐Catalyzed Asymmetric Hydroalkoxylation

“…According to Metz et al, H‐3 of MeO‐BINA‐Cox ( L1 ) was regioselectively lithiated with sec ‐BuLi–TMEDA and then alkylated with MeI to give L13 (Scheme , h, i) . An analogous metalation followed by quenching with iodine gave L11 , whose direct Suzuki coupling with phenyl boronic acid to L12 failed, but was realized at the stage of its methyl ester.…”