Abstract
An improved procedure for the one-pot preparation of cathecols from methylenedioxy-ring cleavage reaction of safrole derivatives with aluminum chloride is described. In substrates substituted by conjugated electron-withdrawing groups (carboxyaldehyde or nitro groups) the regioselective formation of the easily isolable chloromethyl ether intermediates was observed. From these intermediates the syntheses of mono-O-methylated phenols (3-hydroxy-4-methoxybenzaldehyde, 2-bromo-4-methoxy-5-hydroxybenzaldehyde, 2-nitro-4-methoxy-5-hydroxybenzaldehyde and 2-methoxy-4-(2-oxoprop-1-yl)-5-nitrophenol) were accomplished. Based on these experimental data and semi-empirical (MNDO) molecular orbital calculations, a mechanistic rationale that explains the observed regioselectivities was also proposed.
Highlights
The 3,4-dihydroxyphenyl group 1 and its O-substituted analogues 2 and 3 (Figure 1) are commonly found in numerous naturally occurring products[1] and pharmaceutical compounds[2]
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
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) 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 conditions[6] and high degree of purity, precluding the isolation of the chloro methyl ether intermediates6a,b
Summary
The 3,4-dihydroxyphenyl group 1 and its O-substituted analogues 2 and 3 (Figure 1) are commonly found in numerous naturally occurring products[1] and pharmaceutical compounds[2]. 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
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