英语原文
Highly Efficient One-Pot Three-Component Mannich Reaction in Water Catalyzed by Heteropoly Acids
NajmodinAzizi, LallehTorkiyan, and Mohammad R. Saidi*
Department of Chemistry, Sharif University of Technology, P.O. Box 11465-9516, Tehran 11365, Iran
Org. Lett., 2006, 8 (10), pp 2079–2082
DOI: 10.1021/ol060498v
Publication Date (Web): April 20, 2006
Copyright © 2006 American Chemical Society
Abstract
Heteropoly acids efficiently catalyzed the one-pot, three-component Mannich reaction of ketones with aromatic aldehydes and different amines in water at ambient temperature and afforded the corresponding β-amino carbonyl compounds in good to excellent yields and with moderate diastereoselectivity. This method provides a novel and improved modification of the three-component Mannich reaction in terms of mild reaction conditions and clean reaction profiles, using very a small quantity of catalyst and a simple workup procedure.
Carrying out organic reactions in water has become highly desirable in recent years to meet environmental considerations.1 The use of water as a sole medium for organic reactions would greatly contribute to the development of environmentally friendly processes. Indeed, industry prefers to use water as a solvent rather than toxic organic solvents. In this context, in recent years, much attention has been focused on Lewis acid catalyzed organic reactions in water.
Heteropoly acids (HPAs) are environmentally benign and economically feasible solid cataly
sts that offer several advantages.2 Therefore, organic reactions that exploit heteropoly acid catalysts in water could prove ideal for industrial synthetic organic chemistry applications, provided that the catalysts show high catalytic activity in water.
Mannich reactions are among the most important carbon−carbon bond forming reactions in organic synthesis.3They provide β−amino carbonyl compounds, which are important synthetic intermediates for various pharmaceuticals and natural products.4 The increasing popularity of the Mannich reaction has been fueled by the ubiquitous nature of nitrogen-containing compounds in drugs and natural products.5
However, the classical Mannich reaction is plagued by a number of serious disadvantages and has limited applications. Therefore, numerous modern versions of the Mannich reaction have been developed to overcome the drawbacks of the classical method. In general, the improved methodology relies on the two-component system using preformed electrophiles, such as imines, and stable nucleophiles, such as enolates, enol ethers, and enamines.6But the preferable route is the use of a one-pot three-component strategy that a
llows for a wide range of structural variations. In this context, recent developments of asymmetric synthesis, using a three-component protocol, have made the Mannich reaction very valuable.7 However, despite the diverse synthetic routes so far developed for the asymmetric Mannich reaction, only a few one-pot procedures on the use of unmodified aldehydes or ketones in water have been reported in the literature. Furthermore, most of the reported Mannich reactions in water have been carried out in the presence of surfactants such as SDS. Unfortunately, normal-phase separation is difficult during workup due to the formation of emulsions because of the SDS.
There is increasing interest in developing environmentally benign reactions and atom-economic catalytic processes that employ unmodified ketones, amines, and aldehydes for Mannich-type reaction in recent years. In continuation of our studies on the new variants, of one-pot, three-component Mannich-type reactions for aminoalkylation of aldehydes with different nucleophiles,9 and our ongoing green organic chemistry program that uses water as a reaction medium, performs organic transformations under solvent-free conditions,10 h
erein we describe a mild, convenient, and simple procedure for effecting the one-pot, three-component reaction of an aldehyde, an amine, and a ketone for the preparation of β-amino carbonyl compounds in water using a heteropoly acid catalyst.
Initially, the three-component Mannich reaction of 4-chlorobenzaldehyde (3.0 mmol), aniline (3.1 mmol), and the cyclohexanone (5 mmol) was examined (Scheme 1).
Scheme 1. reactive翻译 Direct Mannich Reaction Catalyzed by Heteropoly Acids in Different Solvents
As a preliminary study, several Lewis acids and solvents were screened in the model reaction. The results of extensive Lewis acid and solvent screening and optimization are shown in a table in the Supporting Information. Heteropolyacids (HPAs) catalyze Mannich reactions in organic solvents such as acetonitrile, 1,2-dichloroethane, methanol, ethanol, toluene and mixtures of toluene/water and gave the desired products in low yield with the foramtion of aldol side products. Among the screened solvent systems, water was the solvent of choice, since in this solvent the Mannich-type reactions proceeded smoothly and
afforded the desired adducts in high yields at room temperature. Consequently, we conclude that the HPAs are much more reactive in water than in other organic solvents. At room temperature, the Mannich reaction proceeded to completion affording the Mannich adduct in good to excellent yield and relatively good diastereoselectivity. Addition of surfactants such as sodium dodecyl sulfate (SDS) or cetyltrimethylammonium bromide (CTAB) was not effective, and they did not improve diastereoselectivity. The reaction in pure water without using any catalyst gave a low yield of the product. Furthermore, we were excited to find that only 0.12 mol % of the catalyst gave good yields at room temperature. In the some cases, even 0.06 mol % of HPA was sufficient for the completion of the reaction. Furthermore, simple workup in water opened the route for an entirely green highly efficient one-pot Mannich reaction in water. In addition, H3PMo12O40 has been compared with H3PW12O40, and we found the same results for both heteropoly acids in this reaction in water.

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