多组分反应研究现状
第02期多组分反应研究现状
1 · ·
综述专论
多组分反应研究现状
刘丽华
（中国矿业大学化工学院，江苏徐州 221008）
摘要：多组分反应（Multicomponent Coupling Reactions,）,即“一锅法”，是将三种或三种以上的反应物原料投到反应器中给以一定的反应条件让其反应。由于其反应操作简单，原料简单易得，不经中间体的分离等优点而被有机合成以及药物合成方面的学者们所关注，多组分发展至今，已成功应用到多个领域，尤其在药物合成的方面起到很重要的作用，近些年多组分合成方法的应用不断被报道，本文就综述了多组分反应的发展史以及其他优势，对多组分在合成杂环化合物方面的应用加以概述，其中以液相和固相在这方面的应用的研究进展加以概括总结。
关键词：合成；多组分；研究现状
中图分类号：TQ463 文献标识码：A 文章编号: T1672-8114(2012)02-01-05
0 多组分简介
多组分反应（Multicomponent Coupling Reactions, 简称：MCRs），就是将三种或三种以上的相对简单易得的原料加入到反应中，用一锅煮的方法，不经中间体的分离，直接获得结构复杂的分子，在终产物的结构中含有所有加入的原料片断的合成方法。MCRs被认为是合成分子多样性和复杂性的有效手段[1-9]。
第一次多组分反应是由Strecker在1850年合成α-氨基酸报道的[10]，其方法是醛、氨和氢氰酸的三组分反应；但直到1921年才由Passerini用基于异氰化合物的多组分反应[11-15]提出多组分这个概念；1961年 ugl 用四组分法合成了第一个化合物库，之后的很少有人对此产生兴趣[16-20]；20世纪70年代，Divnafid等利用四组分法合成了一些生物碱[21]； 1993年，Domling和Ugi发表了将两个四组分反应联合起来的七组分反应[22]，提出了将两个MCR联合起来建立新的更多组分的MCRs; 1995年，Keating等[23]和weber等[24]第一次使用ugl的四组分法方法建立化合物库中的化合物，将其应用到医学药物的产业中。之后，多组分反应的关注度急速上升，发表的相关论文也随之迅速增多。
多组分反应中的多步反应可以从相对简单易的的原料出发，不经中间体的分离，直接获得结构复杂的分子‘而传统的有机合成是分步进行的，一个复杂天然产物的合成要20步以上的反应。这样的反应显然经济上和环境友好上较为有利。多组分合成法具有以下特点:高效性、高选择性、反应条件温和, 操作简洁方便。这种方法能够容易地合成常规方法难以合成的目标分子。正由于多组分反应的诸上特点及优点，其很快成为有机合成的瞩目焦点。
多组分反应有利于药物发现过程中先导物的发现和优化，MCRs与药效和生物活性的虚拟筛选和体外筛选结合起来，成为一个新的新药研究工具 [25-29]。在合成复杂结构的天然化合中时，MCRs可以一步就得到其关键的中间体或基子骨架[30]。1 多组分反应的国内外研究现状
多组分反多组分反应的国内外研究现状多组分反应已经发展至今，已有液相和固相的多组分合成之分，并且已成功应用到嘧啶酮、吡唑、吡啶、吡喃、咪唑啉、吩嗪、喹唑啉、呋喃等衍生物的合成，而这些化合物或是具有多种药理活性或是重要的合成中间体。现将多组分反应概括如下。1.1 液相多组分法合成应用
2008年，Chennan Ramalingan和Young-WooKwak用
作者简介：姜磊，中国矿业大学化工系读硕士，研究方向有机合成。
10 mol%的四氯化硅催化多组分一步方法合成具有药物
化工中间体
2 · ·
Chenmical Intermediate2012年第02期
功能的杂环嘧啶酮，其溶剂为DMF[31]。
O
H2NH
+
O
Me
NH2
Me
O
NHHN
Ambient temp,4h
O
MeO
Me
的纳米四氧化三铁为催化剂来合成喹唑啉的方法[37]。
ONH
+RNH2+R12NNH
RR1
2008年，刘海玲等人在液相条件下，分别用两种不同的溶剂和催化剂成功合成了吡唑化合物[32]。
O+
Ph
王红娟等报道了五组分的多组分来合成四氢异喹啉，由芳香醛、脂肪胺、β-酮酯及硝酸铈铵和甲腈在常温下的缩合即可得到预想产物[38]。
1 PdCl2(PPh3)2/CuINH2NH2.H2O
O
NNH
Ph
OR3
CAN (15 mol %)1
R2R1
N
R3李明等用离子液体研究了Biginelli反应，以芳香醛、5-氨基-1H-吡唑和丙二腈为原料, 三组分“一锅煮”合成4,5-二氢吡唑并[1,5-a]嘧啶类化合物[33]。
R
1
2R1CHO+2R2NH2+
1.2 固相多组分法合成应用
NHR2
荣良策等人提出无溶剂合成2-嘧啶酮的简便方
R1N
NH2NNH
acetic acid
R法，其反应物采用的是芳香醛、芳芳香酮和丙二腈，在NaOH存在的条件下，研磨充分，加热到75oC,反应速度快产率高，环境友好[39]。
RCHO+NCCH2CN+
2
Ar1CHO+
Ar2COCH3+CH2(CN)2
75C
Ar2
1
CNNH
吴晓金等人在以醋酸为溶剂的条件下，2-氰基取代吡啶、醛和醋酸铵反应成功合成了咪唑啉化合物[34]。
N
+
R
1
OH
+NH4OAc
170C, 10 h
o
RR
NNH
N
将醛、1,3-二羰基化合物、尿素或硫脲用Fe(CF3CO2)3 或Fe(CF3SO3)3催化，无溶剂条件下，在70
℃反应30分钟，可以方便的发生Biginelli 缩合[40]。
R1CHO+
R2
O
O
+R3
H2N
NH2Fe(CF3CO2)3orFe(CF3SO3)3
R3
solvent-free70
R2
N
X=O,SO
R1
NHX
赵丽琴等研究了以碱性季铵盐(2-二甲氨乙基苄基二甲基氯化铵)为催化剂进行的“一锅法”合成四氢苯并[b]吡喃的水相反应,其反应快，操作简单，环境友好
[35]
。
CN+
+O
[PhCH2Me2NCH2CH2NMe2]Cr
2+
Kantevari等报道了无溶剂条件下，以HClO4·SiO2
O
Ar
CNO
NH2
ArCHO
作为催化剂，胺、醛、二苯乙二酮和醋酸氨的反应，一锅法高产率合成了咪唑衍生物[41]。
NH2
+
+
CHO
HClO4·SiO2
NN
王树良等研究了一锅两步法合成吩嗪衍生物的方法，先在常温下以醋酸溶剂，然后再在微波条件下以苯甲醛为溶剂合成目次产物[36]。
O
Mohammad A. 等学者研究了固相合成法让硫氰酸胺、酰氯和萘酚在室温条件下反应，反应得到预想产
物[42]。
N
R
OH
O
NH4SCN+
R
Cl
+
NSolvent-Free, r.t.
张展慧等报道了用一锅法三组分反应以N-羧基邻氨基苯甲酸酸酐、胺、芳醛在水相环境中，用可回收
韩红霞等人报道了合成嘧啶的新方法，他们将固相多组分合成方法应用到嘧啶酮的合成，芳香醛、丙二睛以及碳酸胍和NaOH研磨后在70oC温度下加热，其
第02期多组分反应研究现状
3 · ·
方法较以往的方法简便而产率高[43-44]。
合成嘧啶衍生物的方法[49]。
NNAr
H2N
NHNH2
H2CO3+
2
O
H2N
O
NH2
R
O
CHO
6
ArCHO+
R
R2
N
NH21
R+
3
Organocatalyst 1 hr
+
R1R2
NR
3
R6
NH
ArCHO+
H2N
NH2
H2CO3
2
+
R4
R5
ArCHO+
+
H2N
Ar
NHNH2
H2CO3
2
蒋虹等人提出用3,4-二氢-1-萘酮和查尔酮，在
R5
R4
H2N
NN
CNNH2
K2CO3-NaOH 存在下,室温研磨, 使其反应, 得到2-[3-氧代-1,3-二(未)取代苯基丙基]-1,2,3,4-四氢萘-1-酮[50]。
姚昌盛等人在无溶剂，无催化剂的条件下，查尔酮、1,3-二酮和醋酸铵反应得到高产率的1,4,5,6,7,8-六氢喹啉-5-酮衍生物。
O
Ar1
2
[45]
+
Ar
1
O
O
CCAr2HH
KCO-NaOHGrinding
Ar1
OAr2
O
NHOAcRAr
1
2 结论
2
+
RR
NH
本文总结了多组分反应的发展史和诸多优点，并将多组分反应的应用分为固相和液相应用两部分进行总结概括，为多组分反应的后续研究提供参考。参考文献
[1] Bhar, S.S., Ramana, M. M. V. Novel domino reactions for diterpene synthesis[J]. Organic Chemistry, 2004, 69, 8935-8937.
[2] Nordmann, G., Bchwald, S. L. A Domino Copper-Catalyzed C-O Coupling-Claisen . Rearrangement Process[J]. Journal of the American Chemical Society, 2003, 125, 4978- 4979.
[3] Tietze, L. F. Domino reactions in organic synthesis[J]. Chemical reviews, 1996, 96, 115- 136.
[4] Zeng, Y., Reddy, D. S., Hirt, E. Domino Reactions That Combine an
庄启亚等学者使用无溶剂研磨法研磨芳醛、丙二睛、和N-甲基哌啶-4-酮，成功的合成了一系列的6-氨基-8-芳基-2-甲基-5,7,7(1H)-三腈基-2,3,8,8a-四氢异喹啉衍生物[46]。
ArCHO
+
CN
+CN
N3
Grinding
H3C
N
CNCNNH2
荣良策等学者利用无溶剂研磨法提出一种合成喹唑啉的新方法，方法简单易操作，反应时间短，条件温和[47-48]。
NH
Ar
NNH2
Azido-Schmidt Ring Expansion with the Diels-Alder Reaction[J]. Organic Letters. 2004, 6, 4993-4995.
[5] Tejedor, D., Gonzalez, C. D., Garcia, T. F., Marrero, T. J. J., Rodriguez, M. L. A diversity-oriented strategy for the construction of tetrasubstituted
NH2NArCHO
+
H2NNH2
H2CO3
2
N
pyrroles via coupled domino processes[J]. Journal of the American Chemical Society, 2004, 126, 8390- 8391.
[6] Kraus, G. A., Kim. Tandem Diels-Alder/Ene Reactions[J]. Organic Letters, 2004, 6, 3115-3117.
ArCHO
+
[7] Bear, B. R., Shea, K. J. Tandem Hetero Diels-Alder Reaction: Synthesis of Oxygenated Macrocycles[J]. Organic Letters, 2001, 3, 723-726.[8] Shindo, M., Sato, Y., Shishido, K. A Novel Tandem [2+2] Cycloaddition-Dieckmann Condensation: Facile One-Pot Process To Obtain 2, 3-Disubstituted-2-cycloalkenones from Ynolates[J]. Journal of the American Chemical Society, 1999, 121, 6507-6508.
Atul Kumar 和 Ram Awatar Maury报道了一种无溶剂
[9] Eibracht, P., Barfacker, L., Buss, C. etal. Tandem reaction sequences
化工中间体
4 · ·
Chenmical Intermediate2012年第02期
under hydroformyla- tion conditions: New synthetic applications of transition metal catalysis[J]. Chemical Reviews, 1999, 99, 3329-3366.[10] A. Strecker. Strecker amino acid synthesis[J]. Justus liebigs Annalen
der chemie 1850, 75, 27-45.
[11] Bienayme, H., Hulme,C., Oddon, G., Schmitt, P. Maximizing synthetic
efficiency: Multi-component transformations lead the way[J]. Chemidtr -A European Journal, 2000, 6, 3321-3329.
[12] Döming, A. The discovery of new isocyanide-based multicomponent
reactions[J]. Current opinion in chemical biology, 2000, 4, 318-323.[13] Döming, A., Ugi, I. Multicomponent Reactions with Isocyanides[J].
Angewandte Chemie International Edition, 2000, 39, 3168-3210.[14] Döming, A. Recent advances in isocyanide-based multicomponent
chemistry[J]. Current opinion in chemical biology. 2002, 6, 306-313.[15] J. Zhu. Recent Developments in the Isonitrile-Based Multicomponent
Synthesis of Heterocycles[J]. European Journal of Organic Chemistry, 2003, 1133-1144.
[16] Domingo, L. R. Why do Electron-Deficient Dienes React Rapidly
in Diels-Alder Reactions with Electron-Deficient Ethylenes: A Density Functional Theory Analysis[J]. European Journal of Organic Chemistry, 2004, 4788-4793.
[17] Appukkuttan, P., Dehaen, W., Fokin, V. V., Vander Eycken, E. A
microwave-assisted click chemistry synthesis of 1, 4-disubstituted 1, 2, 3-triazoles via a copper(I)-catalyzed three-component reaction[J]. Organic Letters, 2004, 6, 4223-4225.
[18] Hayes, J. F., Shipman, M., Twin, H. Multicomponent reactions involving
2-methyleneaziridines: rapid synthesis of 1, 3-disubstituted propanones[J]. Organic Chemistry, 2002, 67, 935- 942.
[19] Byk, G., Kabahn, E. Anomalous regioselective four-member
multicomponent Biginelli reaction II: one-pot parallel synthesis of spiro heterobicyclic aliphatic rings[J]. Combinatorial Chemistry, 2004, 6, 596- 603.
[20] Marcaccini, S., Miguel, D., Torroba, T., Garcia-Valverge, M. 1,
4-Thiazepines, 1, 4-benzothiazepin-5-ones, and 1, 4-benzothioxepin orthoamides via multicomponent reactions of isocyanides[J]. Organic Chemistry, 2003, 68, 3315-3318.
[21] Divanfard, H. R., Lysenko, Z., Wang, P. C.,et al. Novel γ-Ketoester
Synthesis[J]. Synthetic Communications, 1978, 8, 279- 283.
[22] Döming, A., Ugi, I. The Seven-Component Reaction[J]. Angewandte
Chemie International Edition in English, 1993, 32, 563-564.
[23] Keating, T. A., Armstrong, R. W. Molecular Diversity via a Convertible
Isocyanide in the Ugi Four-Component Condensation[J]. Journal of the American Chemical Society, 1995, 117, 7842- 7843.
[24] Weber, L., Wallbaum, S., Broger, C., et al. Optimization of the Biological
Activity of Combinatorial Compound Libraries by a Genetic Algorithm[J]. Angewandte Chemie International Edition in English, 1995, 34, 2280-2282.
[25] Döming, A., Ugi, I. Multicomponent reactions with isocyanides[J].
Angewandte Chemie International Edition, 2000, 39, 3168－3210. [26] Weber, L. The application of multi-component reactions in drug
discovery[J]. Current medicinal chemistry, 2002, 9, 2085-2086.[27] Döming, A. Recent advances in isocyanide-based multicomponent
chemistry[J].Current Opinion in Chemical Biology, 2002, 6, 306-313.[28] Hulme, C., Gore, V. Multi-component Reactions: Emerging Chemistry
in Drug Discovery"'From Xylocain to Crixivan[J]. Current medicinal chemistry, 2003, 10, 51- 80.
[29] Weber, L. Multi-component reactions and evolutionary chemistry[J].
Drug discovery today, 2002, 7, 143-147.
[30] Ugi, I., Heck, S. The multicomponent reactions and their libraries for
natural and preparative chemistry[J]. Combinatorial Chemistry ＆ High Throughput Screening, 2001, 4, 1-34.
[31] Chennan Ramalingan, Young-Woo Kwak. Tetrachlorosilane catalyzed
multicomponent one-step fusion of biopertinent pyrimidine heterocycles[J]. Tetrahedron, 2008, 54, 5023-5031.
[32] Hailing Liu, Huanfeng Jiang, Min Zhang, Wenjuan Yao, Qiuhua Zhu,
Zhou Tang. One-pot three-component synthesis of pyrazoles through a tanden coupling-cyclocondensation sequence[J]. Tetrahedron, 2008, 49, 3805-3809.
[33] 李明, 郭维斯, 文丽荣, 左正泉. 三组分“一锅煮”合成 4,5-二氢吡
唑并[1,5-a]嘧啶[J], 有机化学, 2008, 28 , 472-475.
[34] Xiaojin Wu, Ran Jiang, Xiaoping Xu, Xiaoming Su, Weihong Lu,
Shunjun Ji. Practical multi-component Synthesis of Di- or Tri-Aryl (Heteraryl) Substituted 2-(Pyridin-2-yl)imidazoles from Simple Building Blocks[J]. Combinatorial Chemistry, 2010, 12 (6): 829-835.[35] 赵丽琴, 李毅群, 陈路, 周波. 碱性季铵盐“一锅法”催化合成四氢
苯并[b]吡喃的水相反应研究[J]. 有机化学. 2010, 30, 124-127.[36] ShuLiang Wang, FeiYue Wu, Chuang Cheng, Ge Zhang, YinPing Liu,
Bo Jiang, Feng Shi, and ShuJiang Tu. Multicomponent Synthesis of Poly-Substituted Benzo[a]pyrano[2,3-c]phenazine Derivatives under Microwave Heating[J]. Combinatorial Science, 2010, 13, 135-139. [37] Zhanhui Zhang, Hongyan Lv, Shuhong Yang, Jianwu Gao. Synthesis
of 2,3-Dihydroquinazolin-4(1H)-ones by Three-Component Coupling of Isatoic Anhydride, Amines, and Aldehydes Catalyzed by Magnetic Fe3O4 Nanoparticles in Water[J]. Combinatorial Chemistry, 2010, 12, 643-646.
第02期多组分反应研究现状
5 · ·
[38] HongJuan Wang, LiPing Mo, ZhanHui Zhang. Cerium Ammonium Nitrate-Catalyzed Multicomponent Reaction for Efficient Synthesis of
Functionalized Tetrahydropyridines[J]. Combinatorial Science, 2010, 13, 181-185.
[39] Liangce Rong , Haiying Wang, Jingwen Shi, Fang Yang, Hao Yao,
Shuajiang Tuand Daqing Shi.An Efficient and Facile Procedure for the Synthesis of 4,6-Diaryl-2(1H)-pyridones under Solvent-free Conditions[J]. Heterocyclic Chemistry, 2006, 44, 1505-1508.
[40] Adibi H, Samimi H A, Beygzadeh M. Iron(III) trifluoroacetate and
trifluoro- methanesulfonate: Recyclable Lewis acid catalysts for one-pot synthesis of 3,4-di hydropyrimidinones or their sulfur analogues and 1,4-dihydropyridines via solvent- free Biginelli and Hantzsch condensation protocols[J]. Catalysis Communications, 2007, 8, 2119-2124.
[41] Kantevari S, Srinivasu V N. Highly efficient, one-pot, solvent-free
synthesis of tetrasubstituted imidazoles using HClO4-SiO2 as novel heterogeneous catalyst[J]. Journal of Molecular Catalysis A: Chemical, 2007, 266, 109-113.
[42] Mohammad A. Khalilzadeh , Issa Yavari, Zinatossadat Hossaini,
Hasan Sadeghifar. N-Methylimidazole-promoted efficient synthesis of 1,3-oxazine-4-thiones under solvent-free conditions[J]. Monatsh Chemistry. 2009, 140, 467-471.
[43] Liangce Rongab, Hongxia Hana, Lijiu Gao, Yisi Dai, Minxia
Cao, Shujiang Tu. Efficient and Facile Synthesis of 2,4-Diamino-6-arylpyrimidine-5-carbonitrile Under Solvent-Free Conditions[J]. Synthetic Communications, 2010, 40, 504-509.
[44] Liangce Rong, Hongxia Han, Haiying Wang, Hong Jiang, Shuajiang Tu,
and Daqing Shi. An Efficient and Facile Synthesis of Pyrimidine and Quinazoline Derivatives via One-Pot Three-Component Reaction under Solvent-Free Conditions[J]. Heterocyclic Chemistry, 2009, 46, 152-157.
[45] 荣良策, 韩红霞, 姜 虹, 庄启亚, 姚昌盛, 屠树江. 无溶剂、无催化
剂条件下合成1,4,5,6,7,8-六氢喹啉-5-酮衍生物[J]. 有机化学, 2008, 28(5): 837-840.
[46] 荣良策, 韩红霞, 姜 虹,庄启亚, 王苏惠, 屠树江. 无溶剂研磨合成6-氨基-8-芳基-2-甲基-5,7,7(1H)-三腈基-2,3,8,8a-四氢异喹啉衍生物[J]. 有机化学, 2009, 29, 962-965.
[47] Liangce Rong, Hongxia Han, Haiying Wang, Hong Jiang, Shuajiang Tu,
and Daqing Shi. An Efficient and Facile Synthesis of Pyrimidine and Quinazoline Derivatives via One-Pot Three-Component Reaction under Solvent-Free Conditions[J]. Heterocyclic Chemistry, 2009, 46, 152-157.
[48] Lijiu Gao, Honglou Ji, Liangce Rong, Hongxia Han, Yanhui Shi, and
Shujiang Tu. An Efficient Synthesis of 5,6-Dihydrobenzo[h]quinazoline Derivatives under Solvent-Free Conditions[J]. Heterocyclic Chemistry, 2010, 47, 358-362.
[49] Atul Kumar, Ram Awatar Maury. Organocatalysed three-component
domino synthesis of 1,4-dihydropyridines under solvent free conditions[J]. Tetrahedron, 2008, 64, 3477-3482.
[50] 荣良策, 韩红霞, 蒋 虹, 李小跃, 姚昌盛, 屠树江. 无溶剂条件下合
成2-[3-氧代-1,3-二(未)取代苯基丙基]-1,2,3,4-四氢,萘-1-酮[J]. 有机化学，2008, 28 (4): 746-749.
Study on the current situation of MCRs
Liu Li Hua
Abstract: Multicomponent Coupling Reactions ("one-pot" synthesis), that is to say, put three or more reactants in a reactor and give it some conditions to react. As its simple operation , easy-getting stuff, short reaction time and without seperating the intermediate, has been caused schoolar's attentions currently. As far, MCRs has been used in many fields, especially playde an important role in the pharmaceuticals synthesis. Recently, many methods have been reported. In this paper, the Multicomponent Coupling Reactions' development history, many other advantages and application in heterocycle compounds have been summarized. Particularly sum up the liquid and solid applications in the fi elds.
Key words: Synthesis; Multicomponent Coupling Reactions; Current development.