Highly Efficient One-Pot Three-Component Mannich Reaction in Water Catalyzed by Heteropoly AcidsNajmodin Azizi, Lalleh Torkiyan, and Mohammad R. SaidiDepartment of Chemistry, Sharif University of Technology, P.O. Box 11465-9516, Tehran 11365, Iran Org. Lett., 2006, 8 (10), pp 20792082DOI: 10.1021/ol060498vPublication Date (Web): April 20, 2006Copyright 2006 American Chemical SocietyAbstractHeteropoly 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 -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.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 catalysts that offer several advantages.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 carboncarbon bond forming reactions in organic synthesis.They provide amino carbonyl compounds, which are important synthetic intermediates for various pharmaceuticals and natural products.The increasing popularity of the Mannich reaction has been fueled by the ubiquitous nature of nitrogen-containing compounds in drugs and natural products.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.But the preferable route is the use of a one-pot three-component strategy that allows 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. 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, and our ongoing green organic chemistry program that uses water as a reaction medium, performs organic transformations under solvent-free conditions, herein 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 -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. 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. Heteropoly acids (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. Encouraged by the remarkable results obtained with the above reaction conditions, and in order to show the generality and scope of this new protocol, we used various aldehydes and amines and the results. Table 2 clearly demonstrates that HPAs are excellent catalysts for Mannich reactions in water. Thus, a variety of aromatic aldehydes, including electron-withdrawing and electron-donating groups, were tested using our new method in water in the presence of H3PW12O40 or H3PMo12O40. The results are shown in Table 2. Generally, excellent yields of -amino ketones were obtained for a variety of aldehydes including those bearing an electron-withdrawing group. Furthermore, several electron-rich aromatic aldehydes led to the desired products in good yield. However, under the same reaction conditions aliphatic aldehydes, such as isobutyaldehyde, gave a mixture, due to enamine formation; the desired product was obtained in low yield (Table 2, entry 22). The scope of our method was extended to other amines. In the case of amines having an electron-donating group, such as 4-isopropylaniline, the corresponding amino ketones were obtained in good yields. Furthermore, amines with electron-withdrawing groups, such as 4-chloroaniline and 3,4-dichloroaniline, gave the desired product in good yields. The high yield, simple reaction protocol, and originality of this novel process prompted us to use other ketones under these conditions (Table 1). Thus, the three-component coupling reactions were carried out with acyclic ketones such as 2-butanone and acetophenone. The expected products were obtained in moderate yields under these conditions. Acyclic ketones were less reactive than cyclohexanone and needed much more catalyst to afford the desired products (Table 1). Table 1. HPA-Catalyzed Three-Component Mannich Reactiona(5mmol), acetophenone (3 mmol), and H3PW12O40 (0.02 g).bYield of isolated aReaction conditions: aldehyde (3 mmol), amine (3.1 mmol), 2-butanone products.cSyn/anti ratio.dSyn/anti ratio was determined by 1H NMR analysis of crude products.Table 2. One-Pot, Three-Component Direct Mannich Reactiona aReaction conditions: aldehyde (3 mmol), amine (3.1 mmol), and cyclohexanone (5 mmol) were successively added to a solution of catalyst (10 mg) in water (5 mL) placed in a test tube, and the reaction mixture was vigorous stirred at room temperature for 316 h.bYields of isolated products.cDiastereomeric ratio mearsured by 1H NMR spectroscopy analysis of the crude reaction mixture.The regioselectivity was determined by 1H and 13C NMR spectroscopy and by comparison with known compounds reported in the literature.8 In general, anti selectivity was observed in the reaction of cyclohexanone and 2-butanone. Despite of the low solubility of aldehydes, ketones, and amines in water, the heteropoly acid-catalyzed Mannich reactions still proceed efficiently at ambient temperature. The reaction might take place at the interface of organic materials with water in the heterogeneous system. It was found that vigorous stirring was required for the success of these reactions. The possibility of recycling the catalyst was examined. For this reason, the reaction of 4-chlorobenzaldehyde, aniline and cyclohexanone in water at room temperature in the presence of H3PW12O40 was studied. When the reaction was complete, ethyl acetate was added and organic materials were extracted and the aqueous solution was saved for the next reaction. When the same reaction was carried out in this solution, containing the used catalyst, low yields (ca. 60%) of the product were obtained. Another characteristic feature of the present protocol is the high chemoselectivity of cyclohexanone toward aldimines, prepared in situ from the reaction of aldehydes and amines, in preference to aldehydes as shown in Scheme 2. Although conventional Lewis acids activate aldehydes preferentially, in this media, aldehydes do not undergo aldol reaction by means of HPAs in water. The high chemoselectivity is rationalized by considering the higher basicity of nitrogen over oxygen. A related phenomenon was recently reported in the reactivity between aldimines and aldehydes by the use of proline, HBF4, and dibutyltin dimethoxide.11 Scheme 2. Aldole and Mannich Reaction in Water In conclusion, this procedure offers several advantages including low loading of catalyst, improved yields, clean reaction, use of unmodified ketones, which make it a useful and attractive strategy for the multicomponent reactions of combinational chemistry. In addition, a very easy workup has been realized that does not require organic solvents. When the products are solid and insoluble in water, the pure products can be obtained directly by filtration and washing the filtrate with water and by crystallization from ethanol or diethyl ether. No extraction or separation by column chromatography is necessary in some cases. Current efforts in our research group are attempting to expand the application of heteropoly acids in water for other reactions. AcknowledgmentWe are grateful to the Research Council of Sharif University of Technology for financial support. We thank “Volkswagen-Stiftung, Federal Republic of Germany” for financial support toward the purchase of chemicals. We also thank Professor J. Ipaktschi (University of Giessen) for his valuable advice and suggestions. 翻譯稿雜多酸高效催化三組分共混曼尼希反應(yīng)Najmodin艾則孜， Lalleh Torkiyan ，穆罕默德R 賽迪*謝里夫理工大學(xué)化學(xué)系，PO 11465-9516箱，伊朗，德黑蘭11365ORG 。 Lett ， 2006年， 8（10） ，PP 2079-2082DOI ： 10.1021/ol060498v出版日期（網(wǎng)絡(luò)） ： 2006年4月20日版權(quán)所有 2006年美國化學(xué)學(xué)會摘要 雜多酸能高效催化酮，芳香醛與不同胺類在環(huán)境溫度下水中的三組分共混曼尼希反應(yīng)，并且給予相應(yīng)的 -氨基羰基化合物以優(yōu)良的產(chǎn)量和溫和的非對映選擇性。這種方法使用非常少量的催化劑和一個簡單的檢驗所程序，給三組分的曼尼希反應(yīng)在反應(yīng)條件的溫和性和反應(yīng)型材的干凈性上提供了一個新的和改進的修改。為滿足對環(huán)境的考慮，開展在水中的有機反應(yīng)在近年來已變得非?？扇　Ｋ鳛橛袡C反應(yīng)的唯一媒介的使用，將大大推動環(huán)保進程的發(fā)展。事實上，業(yè)內(nèi)人士更傾向于使用水作為溶劑，而不是有毒的有機溶劑。在此背景下，近年來，路易斯酸催化水中的有機反應(yīng)受到了更多的關(guān)注。雜多酸（ HPAs）提供了多種優(yōu)勢，是對環(huán)境無害的和經(jīng)濟上可行的固體催化劑。因此，利用雜多酸催化劑在水中進行的有機反應(yīng)證明了工業(yè)有機合成化學(xué)應(yīng)用的理想選擇，提供了催化劑在水中的高催化活性。曼尼希反應(yīng)是有機合成反應(yīng)中最重要的碳-碳鍵形成的反應(yīng)的一種。它們?yōu)楦鞣N藥品和天然產(chǎn)品提供了重要的合成中間體，即 -氨基羰基化合物。曼尼希反應(yīng)的日益普及推動了普遍存在的含氮化合物在藥物和天然產(chǎn)物的性質(zhì)。然而，經(jīng)典的曼尼希反應(yīng)被一系列嚴(yán)重的弊端所困擾，并且只有有限的應(yīng)用。因此，眾多的現(xiàn)代版本的曼尼希反應(yīng)已開發(fā)，以克服傳統(tǒng)方法的弊端。在一般情況下，改進的方法依賴于使用預(yù)制的親電試劑，如亞胺和穩(wěn)定的親核試劑，如烯醇，烯醚，烯胺的雙組分系統(tǒng)。但更好的途徑是使用三組分共混的戰(zhàn)略，它允許廣泛的結(jié)構(gòu)性的變化。在此背景下，使用三組分不對稱合成最近的發(fā)展已經(jīng)使曼尼希反應(yīng)非常寶貴。然而，盡管不對稱的曼尼希反應(yīng)到目前為止已開發(fā)了各種不同的合成路線，但只有為數(shù)不多的使用未修改的醛或酮在水中的共混程序已被文獻報道。此外，大部分的被報道的在水中進行的曼尼希反應(yīng)已被證實了表面活性劑如SDS的存在。不幸的是，由于SDS導(dǎo)致乳劑的形成，正常的相分離在工作中非常困難。在開發(fā)環(huán)境的良性反應(yīng)和原子經(jīng)濟的催化過程中用未修改的酮，胺和醛的曼尼希型反應(yīng)近年來有越來越多的利益。作為我們研究的新變種，即醛和不同的親核試劑反應(yīng)生成氨烷基化物的三組分共混反應(yīng)和我們正在進行的使用水作為反應(yīng)介質(zhì)的綠色有機化學(xué)程序的延續(xù)，在無溶劑條件下進行有機轉(zhuǎn)換，這里我們描述一個溫和，方便，程序簡單的以雜多酸作為催化劑在水中進行的醛，胺，酮制備 -氨基羰基化合物的三組分共混反應(yīng)。4 - 氯苯甲醛（3.0mmol），苯胺（3.1mmol）和環(huán)己酮（5mmol）進行的三組分反應(yīng)首先被研究。方案1 直接在不同溶劑中進行的雜多酸催化的曼尼希反應(yīng)作為一個初步的研究，在模擬反應(yīng)中對幾種路易斯酸和溶劑進行了篩選。廣泛的路易斯酸和溶劑的篩選和優(yōu)化的結(jié)果顯示在一個表格中。雜多酸催化在有機溶劑如乙腈， 1,2 - 二氯乙烷，甲醇，乙醇，甲苯，甲苯/水的混合物中進行的曼尼希反應(yīng)，由于副產(chǎn)品的生成使所要產(chǎn)品產(chǎn)量低。在篩選溶劑體系中，水是被選擇的溶劑，因為在此溶劑下曼尼希反應(yīng)能順利地進行，并且在室溫下使所需的產(chǎn)物有一個高的產(chǎn)量。因此我們得出的結(jié)論是比起其它有機溶劑，雜多酸在水中更具有活性。在室溫下，曼尼希反應(yīng)能不斷給予曼尼希加合物以良好的產(chǎn)量和相對較好的非對映選擇性。添加表面活性劑，如十二烷基硫酸鈉（ SDS ）或十六烷基三甲基溴化銨（CTAB）不是有效的，他們并沒有提高非對映選擇性。在不使用任何催化劑的純水中進行的反應(yīng)的產(chǎn)品產(chǎn)量比較低。此外，我們高興地發(fā)現(xiàn)，在室溫下只有0.12 mol的催化劑就給了良好的收益。在某些情況下，甚至0.06 mol %的雜多酸催化劑就能使反應(yīng)非常有效地完成。此外，僅僅是研究水中的反應(yīng)為一個在水中進行的完全綠色高效共混曼尼希反應(yīng)已找到了反應(yīng)路線。此外，H3PMo12O40已與H3PW12O40作了對比，并且對于在水中進行的這個反應(yīng)，我們發(fā)現(xiàn)這兩種雜多酸有相同的結(jié)果。在上述反應(yīng)條件下取得了顯著的成果感到鼓舞，并以顯示這一新協(xié)議的通用性和范圍，我們使用了各種醛，胺和