一篇化学文献的翻译

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 catalysts 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

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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 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.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 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 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.  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.

2

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.

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 α-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

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products (Table 1).

 Table 1.  HPA-Catalyzed Three-Component MannichReactiona

a Reaction conditions:  aldehyde (3 mmol), amine (3.1 mmol), 2-butanone (5

mmol), acetophenone (3 mmol), and Hd3PW12O40 (0.02 g).b Yield of isolated

products.c Syn/anti ratio. Syn/anti ratio was determined by

1H NMR analysis

of crude products.

 Table 2.  One-Pot, Three-Component Direct MannichReactiona

entry R1 R2 catalyst anti/synb yieldsc (%)

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1 Ph 4-ClC6H4

A

63:37 81

2 Ph 4-ClC6H4

B

62:38 80

3 Ph Ph

A

63:37 84

4 4-ClC6H4 Ph

B

64:35 80

5 4-ClC6H4 4-ClC6H4

A

64:36 84

6 4-ClC6H4 4-ClC6H4

B

65:35 83

7 3-NO2C6H4 4-ClC6H4

B

47:53 95

8 3-NO2C6H4 4-ClC6H4

A

46:54 95

9 3-NO2C6H4 Ph

B

58:42 90

10 3-NO2C6H4 Ph

A

55:45 94

5

11 4-NO2C6H4 4-ClC6H4

B

56:44 90

12 4-NO2C6H4 4-ClC6H4

A

57:43 88

13 2,4-Cl2C6H3 3,4-Cl2C6H3

B

41:59 80

14 2,4-Cl2C6H3 3,4- Cl2C6H3

A

39:61 93

15 2,4-Cl2C6H3 4-ClC6H4

B

66:34 80

16 2,4-Cl2C6H3 Ph

B

68:32 83

17 2-MeOC6H4 Ph

B

65:33 60

18 4-MeOC6H4 4-ClC6H4

B

54:46 70

19 4-OMeC6H4 4-ClC6H4

B

50:50 72

20 4-MeO2CC6H4 Ph

B

72:28 88

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21 4-ClC6H4 4-(i-Pr)C6H4

B

62:38 80

22 (CH3)2CH Ph

B

- 25

23 2-naphthyl 4-ClC6H4

B

43:57 85

24 2-thienyl 4-ClC6H4

B

62:38 87

a Reaction 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 3−16 h.b Yields of isolated

products.c Diastereomeric 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

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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.

Acknowledgment

We 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.

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翻译稿

杂多酸高效催化三组分共混曼尼希反应

Najmodin艾则孜，LallehTorkiyan，穆罕默德R •赛迪*

谢里夫理工大学化学系，PO 11465-9516箱，伊朗，德黑兰11365

ORG 。Lett， 2006年， 8（10），PP 2079-2082

DOI ： 10.1021/ol060498v

出版日期（网络）： 2006年4月20日

版权所有© 2006年美国化学学会

摘要

杂多酸能高效催化酮，芳香醛与不同胺类在环境温度下水中的三组分共混曼尼希反应，并且给予相应的β -氨基羰基化合物以优良的产量和温和的非对映选择性。这种方法使用非常少量的催化剂和一个简单的检验所程序，给三组分的曼尼希反应在反应条件的温和性和反应型材的干净性上提供了一个新的和改进的修改。

为满足对环境的考虑，开展在水中的有机反应在近年来已变得非常可取。水作为有机反应的唯一媒介的使用，将大大推动环保进程的发展。事实上，业内人士更倾向于使用水作为溶剂，而不是有毒的有机溶剂。在此背景下，近年来，路易斯酸催化水中的有机反应受到了更多的关注。

杂多酸（ HPAs）提供了多种优势，是对环境无害的和经济上可行的固体催化剂。因此，利用杂多酸催化剂在水中进行的有机反应证明了工业有机合成化学应用的理想选择，提供了催化剂在水中的高催化活性。曼尼希反应是有机合成反应中最重要的碳-碳键形成的反应的一种。它们为各种药品和天然产品提供了重要的合成中间体，即β -氨基羰基化合物。曼尼希反应的日益普及推动了普遍存在的含氮化合物在药物和天然产物的性质。

然而，经典的曼尼希反应被一系列严重的弊端所困扰，并且只有有限的应用。因此，众多的现代版本的曼尼希反应已开发，以克服传统方法的弊端。在一般情况下，改进的方法依赖于使用预制的亲电试剂，如亚胺和稳定的亲核试剂，如烯醇，烯醚，烯胺的双组分系统。但更好的途径是使用三组分共混的战略，它允许广泛的结构性的变化。在此背景下，使用三组分不对称合成最近的发展已经使曼尼希反应非常宝贵。然而，尽管不对称的曼尼希反应到目前为止已开发了各种不同的合成路线，但只有为数不多的使用未修改的醛或酮在水中的共混程序已被文献报道。此外，大部分的被报道的在水中进行的曼尼希反应已被证实了表面活性剂如SDS的存在。不幸的是，由于SDS导致乳剂的形成，正常的相分离在工作中非常困难。在开发环境的良性反应和原子经济的催化过程中用未修改的酮，胺和醛的曼尼希型反应近年来有越来越多的利益。作为我们研究的新变种，即醛和不同的亲核试剂反应生成氨烷基化物的三组分共混反应和我们正在进行的使用水作为反应介质的绿色有机化学程序的延续，在无溶剂条件下进行有机转换，这里我们描述一个温和，方便，程序简单的以杂多酸作为催化剂在水中进行的醛，胺，酮制备β -氨基羰基化合物的三组分共混反应。

4 - 氯苯甲醛（3.0mmol），苯胺（3.1mmol）和环己酮（5mmol）进行的三组分反应首先被研究。

方案1 直接在不同溶剂中进行的杂多酸催化的曼尼希反应

作为一个初步的研究，在模拟反应中对几种路易斯酸和溶剂进行了筛选。广泛的路易斯酸和溶剂的筛选和优化的结果显示在一个表格中。杂多酸催化在有机溶剂如乙腈， 1,2 - 二氯乙烷，甲醇，乙醇，甲苯，甲苯/水的混合物中进行的曼尼希反应，由于副产品的生成使所要

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产品产量低。在筛选溶剂体系中，水是被选择的溶剂，因为在此溶剂下曼尼希反应能顺利地进行，并且在室温下使所需的产物有一个高的产量。因此我们得出的结论是比起其它有机溶剂，杂多酸在水中更具有活性。在室温下，曼尼希反应能不断给予曼尼希加合物以良好的产量和相对较好的非对映选择性。添加表面活性剂，如十二烷基硫酸钠（ SDS ）或十六烷基三甲基溴化铵（CTAB）不是有效的，他们并没有提高非对映选择性。在不使用任何催化剂的纯水中进行的反应的产品产量比较低。此外，我们高兴地发现，在室温下只有0.12 mol％的催化剂就给了良好的收益。在某些情况下，甚至0.06 mol %的杂多酸催化剂就能使反应非常有效地完成。此外，仅仅是研究水中的反应为一个在水中进行的完全绿色高效共混曼尼希反应已找到了反应路线。此外，H3PMo12O40已与H3PW12O40作了对比，并且对于在水中进行的这个反应，我们发现这两种杂多酸有相同的结果。

在上述反应条件下取得了显着的成果感到鼓舞，并以显示这一新协议的通用性和范围，我们使用了各种醛，胺和结果。表2清楚地表明，杂多酸是在水中的曼尼希反应的优良催化剂。因此，在水中存在 H3PW12O40 或 H3PMo12O40的情况下，使用我们的新方法对各种芳香醛，包括吸电子和推电子基团进行了测试。结果如表2所示。一般来说，α -氨基酮的优良产量是由包括承担一个吸电子基团的各种醛得到的。此外，一些含电子多的芳香醛也能使所需的产品得到良好的收益。然而，在相同的反应条件下脂肪醛得到了一种混合物，是由于来烯胺的形成导致所需要的产品产量低（见表2， 22项）。我们的方法范围扩展到其他胺。在含有一个推电子集团的胺，如4 -异丙基胺的情况下，相应的氨基酮能获得良好收益。此外，带有吸电子基团的胺，如4 - 氯苯胺和3,4 - 二氯苯胺给所需的产品带来良好的收益。

高的产量，简单的反应原理和独创性的反应过程促使我们在这些条件下使用其他酮。（见表1）因此，三组分偶联反应使用无环酮，例如2 - 丁酮和苯乙酮。在这些条件下，预期的产品得到了良好的收益。无环酮的反应活性低于环己酮，需要更多的催化剂来得到所需的产品。（见表1）

表1 杂多酸催化三组分曼尼希反应

反应条件为：醛（3mmol），胺（ 3.1 mmol）， 2 - 丁酮（ 5 mmol），苯乙酮（ 3mmol），和H3PW12O40（ 0.02g）。经1H 核磁共振分析确定产品产量 SYN /反ratio的比例。

表2 三组分直接共混的曼尼希反应

entry R1 R2 catalyst anti/synb yieldsc (%)

1 Ph 4-ClC6H4 A 63:37 81

2 Ph 4-ClC6H4 B 62:38 80

3 Ph Ph A 63:37 84

4 4-ClC6H4 Ph B 64:35 80

5 4-ClC6H4 4-ClC6H4 A 64:36 84

6 4-ClC6H4 4-ClC6H4 B 65:35 83

7 3-NO2C6H4 4-ClC6H4 B 47:53 95

8 3-NO2C6H4 4-ClC6H4 A 46:54 95

9 3-NO2C6H4 Ph B 58:42 90

10 3-NO2C6H4 Ph A 55:45 94

11 4-NO2C6H4 4-ClC6H4 B 56:44 90

12 4-NO2C6H4 4-ClC6H4 A 57:43 88

10

13 2,4-Cl2C6H3 3,4-Cl2C6H3 B 41:59 80

14 2,4-Cl2C6H3 3,4- Cl2C6H3 A 39:61 93

15 2,4-Cl2C6H3 4-ClC6H4 B 66:34 80

16 2,4-Cl2C6H3 Ph B 68:32 83

17 2-MeOC6H4 Ph B 65:33 60

18 4-MeOC6H4 4-ClC6H4 B 54:46 70

19 4-OMeC6H4 4-ClC6H4 B 50:50 72

20 4-MeO2CC6H4 Ph B 72:28 88

21 4-ClC6H4 4-(i-Pr)C6H4 B 62:38 80

22 (CH3)2CH Ph B - 25

23 2-naphthyl 4-ClC6H4 B 43:57 85

24 2-thienyl 4-ClC6H4 B 62:38 87

反应条件:醛（3mmol）,胺（3.1mmol）,并且环己酮（5mmol）被不断地加到盛有10mg催化剂的5ml水的试管中，并且在室温下大力搅拌反应混合物3-16小时。隔离产品的产量，经1H核磁共振谱分析反应混合物的非对映体的比例确定。

区域选择性是由1H和13C核磁共振光谱与文献报道的已知化合物比较来确定。在一般情况下，反选择性在环己酮和2 - 丁酮的反应中观察。

尽管醛，酮，胺的水溶解度低，杂多酸催化的曼尼希反应室温下仍继续有效。这个反应可能在异构系统中有机材料的界面发生。结果发现，这些反应的成功需要剧烈搅拌。

对回收催化剂的可能性进行了检查。出于这个原因，对 4 - 氯苯甲醛，苯胺，环己酮在室温下H3PW12O40存在的水中的反应进行了研究。当反应完成后，乙酸乙酯被提取而有机材料和水溶液被保存来进行下一个反应。在此解决方案下，当同样的反应进行，包含所使用的催化剂，获得了产量低的产品（约60％）。

本反应的另一个特点是如表2所示环己酮极大的化学选择性对其中在原位进行反应的醛亚胺要优先于醛。虽然传统的路易斯酸要优先激活醛，在这种介质下，醛类不接受在水中通过杂多酸催化的羟醛缩合反应。考虑到氮气比氧气有更高的碱度，高化学选择性是合理的。最近报道了一个相关的现象，即使用脯氨酸， HBF4 和二壬酸二丁锡得到的醛和醛亚胺之间的反应性。

方案2 水中的Aldole和Mannich反应

总之，本程序提供了几个优点，包括低负载的催化剂，提高了产量，清洁反应，使用未修改酮，这使得它成为多元组合化学反应的一个有益的和有吸引力的战略。此外，一个非常简单的方法已经实现，而不需要有机溶剂。当产品是固体并且不溶于水时，纯净的产品可通过过滤，洗涤滤液和用乙醇或乙醚重结晶得到。无柱层析分离提取在某些情况下是必要的。我们的研究小组目前正在努力试图扩大杂多酸在水中的反应的应用范围。

声明

我们非常感谢谢里夫的财政支持科技大学的研究会。我们感谢“大众汽车基金会，德意志联邦共和国”对化学品购买的金融支持。我们也感谢J. Ipaktschi（吉森大学）教授的宝贵意见和建议。

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