A. Daniewski, Wen Liu, Kurt Püntener
Feb 22, 2002
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Influential Citations
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Journal
Organic Process Research & Development
Abstract
Two efficient methods for the preparation of 2-chloro-6-methylbenzoic acid were developed: one based on nucleophilic aromatic substitution and the other based on carbonylation. In the first approach, 2-chloro-6-fluorobenzaldehyde was converted to its n-butylimine, then treated with 2 equiv of methylmagnesium chloride in THF to give, after hydrolysis, 2-chloro-6-methylbenzaldehyde. Subsequent oxidation of this compound gave the title compound in 85% overall yield. In the second approach, 3-chloro-2-iodotoluene was efficiently carbonylated in methanol to give methyl 2-chloro-6-methylbenzoate, which after hydrolysis afforded the title compound in 94% yield (84% yield after recrystallization). The carbomethoxylation proceeded smoothly even at a high substrate-to-Pd ratio of 10 000. Both methods do not require isolation of intermediates and are suitable for the preparation of kilogram quantities of 2-chloro-6-methylbenzoic acid.