The reaction of safrole derivatives with aluminum chloride: improved procedures for the preparation of catechols or their mono-O-Methylated Derivatives and a mechanistic interpretation

Journal of the Brazilian Chemical Society

Silva, Alcides J. M. da¹  Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil¹  Costa, Paulo R. R.¹  Amorim, Mauro B. de¹ 

关键词: aluminum chloride;    1;    3-benzodioxole;    safrole;    molecular orbitals;    MNDO;   

DOI  :  10.1590/S0103-50532001000300005

学科分类：化学（综合）

来源: SciELO

【 摘 要 】

The 3,4-dihydroxyphenyl group 1 and its O-substituted analogues 2 and 3 (Figure 1) are commonly found in numerous naturally occurring products1 and pharmaceutical compounds2. For the preparation of these compounds, the availability of starting materials with appropriate patterns of substitution is commonly required. Safrole (4a, Figure 1), an abundant phenylpropanoid bearing a methylenedioxy ring, and its easily available derivatives 4b and 4c have been used for this aim1, 2. As the cleavage of the methylenedioxy ring is a necessary step to be carried out sometime during the processes of conversion of 4 into products having the structural pattern present in 1, 2 and 3, several methods with this purpose have been developed3. Most of them have been used only for preparations of free catechols (1-type products), as exemplified by almost all of the methods mediated by electrophilic reagents3. On the other hand, when the aromatic ring in derivatives of 4 contains electron-withdrawing groups (as in 4b, c), the methylenedioxy ring can be regioselectively cleaved by nucleophilic reagents (RO- or ArO-) leading either to p-alkoxy products (2-type; resulting form ipso attack of RO) or to m-aryloxymethoxy derivatives (3-type, resulting form attack of ArO- at the methylene carbon)3,4. Similar results have also been reported for some electrophilic reagents, as ether free Grignard reagents3,5, but low regioselectivity has resulted5. Furthermore, AlCl3 reacts with piperonal derivatives 4c and 4d, in CH2Cl2 at room temperature, followed by treatment with refluxing aqueous HCl/THF/NaI or KI, leading to the corresponding catechols6.  In this paper we describe our results on the reaction of safrole derivatives 4a-h (Schemes 1 and 2) with AlCl3: (i) an improved procedure to obtain the corresponding catechols 11b, e in a one-pot procedure and mild conditions (Scheme 1), (ii) the use of the chloro ether intermediates 5b-d and 6e in the regioselective synthesis of mono-O-methylated phenols 9b-d and 10e (Scheme 2), and (iii) a theoretical study of the reaction course by semi-empirical (MNDO)7 molecular orbital calculations. Based on these new experimental and theoretical data, we were able to propose a mechanistic rationalization for the observed results. Results and DiscussionCompounds 4c-h were prepared from 4a and 4b as previously described8. Substrates (4a-h) were reacted with AlCl3 in CH2Cl2 at room temperature and the reaction mixtures were quenched in two different ways: (a) with cold water, followed by overnight stirring at room temperature (Scheme 1) and (b) with glacial AcOH (Scheme 2). When H2O was used to quench the reaction, the resulting biphase mixture was stirred overnight at room temperature and the catechols 11b, e were isolated as pure compounds (> 95% by 1H NMR) simply by extraction of the aqueous layer with EtOAc (Scheme 1). This constitutes a one-pot procedure for the preparation of these catechols from 4b, e under mild conditions6 and high degree of purity, precluding the isolation of the chloro methyl ether intermediates6a,b.When glacial AcOH was used (Scheme 2), the relatively unstable chloro methyl ether intermediates (5 and/or 6) were isolated. In the

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