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 theortho positions by varying the base, metalation temperature, and exposure times. Metalation of
o-anisicacid (
1) with
s-BuLi/TMEDA in THF at -78
C occurs exclusively in the position adjacente to thecarboxylate. On the other hand, a reversal of regioselectivity is observed with
n-BuLi/
t-BuOK. WithLTMP at 0
C, the two directors of
m-anisic acid (
2) function in concert to direct introduction of themetal between them while
n-BuLi/
t-BuOK removes preferentially the proton
located ortho to the methoxyand para to the carboxylate (H-4).
s-BuLi/TMEDA reacts with
p-anisic acid (
3) exclusively in the vicinityof the carboxylate. According to these methodologies, routes to very simple methoxybenzoic acids witha variety of functionalities that are not easily accessible by other means have been developed (Table 1).