Regioselective Dealkylation of 2-Alkoxybenzoic Acid and Its Amide Derivatives with Aliphatic Amines

Abstract

The methoxy group of o-anisic acid was cleaved with aliphatic amines in aprotic dipolar solvents. This cleavage reaction was especially smooth when piperazine in dimethylacetamide was used. This method was applicable to a variety of dealkylations of o-alkoxybenzoic acid and ist amide derivatives with high regioselectivity.For the demethylation of o-anisic acid (o-methoxybenzoic acid) and amide derivatives, dealkylation methods used for the O-alkyl protective group of phenols 1 can generally be applied. A number of methods have been reported using reagents such as Brønsted acid, 2 Lewis acid, 3-7 alkali metals or organic metals. 8-12 However, the use of aliphatic amines as a nucleophile has not been reported in the dealkylation of the O-alkyl protective group of phenols.Buchanan and coworkers have succeeded in the specific demethylation of o-anisic acid using lithium iodide or pyridinium hydroiodide in boiling pyridine. 14,15 The reaction was explained in terms of nucleophilic attack of the iodide ion on the methyl group with activation of the ether oxygen by intramolecular hydrogen bonding. 16,17 In a preliminary investigation, we found that heating o-anisic acid and hexylamine in 2-methoxyethyl ether at 150°C led to a 30% of salicylic acid accompanied by 28% of N-hexyl-o-anisamide. In order to systematically investigate this interesting cleavage of the methoxy group, we attempted to find the optimal reaction conditions and to clarify the scope and limitations of this useful method for the dealkylation of o-alkoxybenzoic acid and amide derivatives. Table 1 shows the results of the reaction of o-anisic acid with various amines and solvents. In using hexylamine, the cleavage reaction proceeded predominantly in DMSO, DMF and dimethylacetamide (DMA) (Entries 1-3) although the amide formation was only observed in cumene (Entry 4). The results of various amines in DMA revealed that the use of secondary or tertiary amines was superior to that of primary amines in terms of yield and reaction time (Entries 3,8,9). Furthermore, diacidic bases (ethylenediamines) shortened the reaction time (Entries 13, 14) and cyclic amines (piperidine, morpholine) gave higher yields (Entries 15, 16). Consequently, the optimal condition was obtained using piperazine as a diacidic cyclic base in DMA at 150°C (Entry 17). Table 2 shows the results of the reaction of various alkoxybenzoic acids and amides with piperazine in DMA. The amide derivatives required a longer time for completion of this demethylation in comparison with acids. The benzyloxy, methoxymethoxy or even ethoxy group was cleaved at the ortho position, but the isopropoxy group was inactive (Entries 8-11). In addition, o-anisic acid or amide derivatives including a meta-or para-alkoxy group underwent the selective cleavage of the ortho-alkoxy group without affecting other substituents (17)(18)(19)(20). However, 2,6-dimethoxybenzoic acid failed to demethylate, and 6-methyl-o-anisic acid required a longer reaction time for completion (Entries 15, 16). Scheme 1 Scheme 2Ethyl ester ...

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