以β-邻氯芳基杂环烯酮缩胺为合成子的多组分串联反应研究
|
摘要
β-邻氯芳基杂环烯酮缩胺有着极高的反应活性,是有机化学中碳-碳键和碳-氮键形成的一种优秀合成子。而新型的合成方法多组分反应(MCR)和串联反应不仅能快速大量地合成具有结构多样性和复杂性的化合物和化合库,而且具有环保,操作简便等优势,已经成为有机合成中强有力的手段。本论文基于β-邻氯芳基杂环烯酮缩胺独特结构和突出的反应性能,采用新型的有机合成方法,构筑和发展新型1, 8-二氮杂萘类杂环体系的合成方法。从多样性导向合成来看,该方法灵活,富有变换,具有高化学选择性,能显著提高键形成的效率。
论文研究了以β-邻氯芳基杂环烯酮缩胺,芳醛和乙酰乙酸乙酯在三乙胺和K2CO3催化下进行多组分串联反应,构建新型1, 8-二氮杂萘类化合物骨架。研究了溶剂,催化剂,原料摩尔比等条件对反应的影响,确定了最佳反应条件为:0.4当量Et3N做催化剂,β-邻氯芳基杂环烯酮缩胺,芳醛和乙酰乙酸乙酯的摩尔比为1:1.2:1.2,乙腈为溶剂回流反应。反应完成后,不分离中间体,在DMF溶剂中使用K2CO3为催化剂进行串联反应,高产率的得到目标产物。反应条件温和,操作简便,产品易于纯化。这种方法合成苯并二氮杂萘类化合物迄今未见文献报道,是一种环境友好的方法。合成中间体(4c)1个,目标化合物(5a-o)15个。
论文探讨了β-邻氯芳基杂环烯酮缩,芳醛和麦氏酸进行多组分串联反应,生成了一类新型的1, 8-二氮杂萘类化合物。合成中间体(7c)1个,目标化合物(8a-l)12个。
在反应中,有7个不同活性位点参与反应,经历了一系列Knoevenagel缩合、氮杂烯反应、环化和分子内亲核取代反应,生成了两个新环、三个新键,充分体现了“原子经济性”。所合成的化合物均经IR、1H NMR、13C NMR和高分辨质谱分析表征。其中对化合物5c进行了X-单晶衍射分析,确定了其精确的空间结构。并提出了可能的反应机理。
β- (2-Chloroaryl)-heterocyclic ketene aminals are good synthons in the form of C-C bond and C-N bond because of its high reactivity. They play a significant role in organic synthesis and much attention has been given to them. New strategy of organic synthesis-multicomponent reaction and tandem reaction-can synthesize libraries of compounds with structural complexity and diversity rapidly, by virtue of their convergence, productivity, ease of execution, and generally high yields of products, have become the most enabling synthetic tools in organic synthesis. This thesis focus on building new framework of [1, 8]naphthyridine from high functionalβ- (2-Chloroaryl)-heterocyclic ketene aminals. This method is flexible, which includs the advantages of high chemo- and regioselectivity and high bond-forming efficiency.
In this thesis, Tetrahydroimidazo[3,2,1-ij]bezeno[1,8]naphthyridine derivatives unreported in the literatures have been synthesised withβ- (2-chloroaryl)- heterocyclic ketene aminals by the multicomponent and tandem reactions in the presence of Et3N and K2CO3 as catalyst. The reaction conditions including solvent, catalyst and molar ratio were also investigated. The optimal condition was Et3N as catalyst, molar ratio ofβ- (2-chloroaryl) - heterocyclic ketene aminals, ethyl acetoacetate and aldehyde with1: 1.2: 1.2 and acetonitrile as solvent. The intermediate was not separated, and then proceeded intramolecular cyclization reactions in the presence of K2CO3 in DMF to obtain the target compounds in high yields. These reactions were very mild, convenient and effective. One intermediate (4c) and 15 target compounds (5a-o) were synthesized.
Then,β- (2-Chloroaryl)-heterocyclic ketene aminals react with aldehyde and Meldrum’s acid to get a new skeleton of 1, 8- naphthyridine. One intermediate (7c) and 12 target compounds (8a-l) were synthesized.
In this reaction, seven different active sites were involved; three new bonds and two new rings were constructed with all reactants which efficiently utilized via a sequence of Knoevenagel condensation, aza-ene reaction, cyclization and intramolecular nucleophilic substitution reactions. It fully reflects the“atom economy”in this reaction
The structures of all the target compounds were confirmed by IR, 1 H NMR, 13 C NMR, and HRMS, and the plausible mechanism was also presented. The unambiguous molecular structure of 5c was determined by X-ray diffraction analysis.
论文研究了以β-邻氯芳基杂环烯酮缩胺,芳醛和乙酰乙酸乙酯在三乙胺和K2CO3催化下进行多组分串联反应,构建新型1, 8-二氮杂萘类化合物骨架。研究了溶剂,催化剂,原料摩尔比等条件对反应的影响,确定了最佳反应条件为:0.4当量Et3N做催化剂,β-邻氯芳基杂环烯酮缩胺,芳醛和乙酰乙酸乙酯的摩尔比为1:1.2:1.2,乙腈为溶剂回流反应。反应完成后,不分离中间体,在DMF溶剂中使用K2CO3为催化剂进行串联反应,高产率的得到目标产物。反应条件温和,操作简便,产品易于纯化。这种方法合成苯并二氮杂萘类化合物迄今未见文献报道,是一种环境友好的方法。合成中间体(4c)1个,目标化合物(5a-o)15个。
论文探讨了β-邻氯芳基杂环烯酮缩,芳醛和麦氏酸进行多组分串联反应,生成了一类新型的1, 8-二氮杂萘类化合物。合成中间体(7c)1个,目标化合物(8a-l)12个。
在反应中,有7个不同活性位点参与反应,经历了一系列Knoevenagel缩合、氮杂烯反应、环化和分子内亲核取代反应,生成了两个新环、三个新键,充分体现了“原子经济性”。所合成的化合物均经IR、1H NMR、13C NMR和高分辨质谱分析表征。其中对化合物5c进行了X-单晶衍射分析,确定了其精确的空间结构。并提出了可能的反应机理。
β- (2-Chloroaryl)-heterocyclic ketene aminals are good synthons in the form of C-C bond and C-N bond because of its high reactivity. They play a significant role in organic synthesis and much attention has been given to them. New strategy of organic synthesis-multicomponent reaction and tandem reaction-can synthesize libraries of compounds with structural complexity and diversity rapidly, by virtue of their convergence, productivity, ease of execution, and generally high yields of products, have become the most enabling synthetic tools in organic synthesis. This thesis focus on building new framework of [1, 8]naphthyridine from high functionalβ- (2-Chloroaryl)-heterocyclic ketene aminals. This method is flexible, which includs the advantages of high chemo- and regioselectivity and high bond-forming efficiency.
In this thesis, Tetrahydroimidazo[3,2,1-ij]bezeno[1,8]naphthyridine derivatives unreported in the literatures have been synthesised withβ- (2-chloroaryl)- heterocyclic ketene aminals by the multicomponent and tandem reactions in the presence of Et3N and K2CO3 as catalyst. The reaction conditions including solvent, catalyst and molar ratio were also investigated. The optimal condition was Et3N as catalyst, molar ratio ofβ- (2-chloroaryl) - heterocyclic ketene aminals, ethyl acetoacetate and aldehyde with1: 1.2: 1.2 and acetonitrile as solvent. The intermediate was not separated, and then proceeded intramolecular cyclization reactions in the presence of K2CO3 in DMF to obtain the target compounds in high yields. These reactions were very mild, convenient and effective. One intermediate (4c) and 15 target compounds (5a-o) were synthesized.
Then,β- (2-Chloroaryl)-heterocyclic ketene aminals react with aldehyde and Meldrum’s acid to get a new skeleton of 1, 8- naphthyridine. One intermediate (7c) and 12 target compounds (8a-l) were synthesized.
In this reaction, seven different active sites were involved; three new bonds and two new rings were constructed with all reactants which efficiently utilized via a sequence of Knoevenagel condensation, aza-ene reaction, cyclization and intramolecular nucleophilic substitution reactions. It fully reflects the“atom economy”in this reaction
The structures of all the target compounds were confirmed by IR, 1 H NMR, 13 C NMR, and HRMS, and the plausible mechanism was also presented. The unambiguous molecular structure of 5c was determined by X-ray diffraction analysis.
引文
[1] Huang, Z. T., Wang, M. X., Heterocyclic ketene aminals. Heterocycles, 1994, 37, 1233-1262.
[2] Wang, M. X., Liang, J. M., Huang, Z. T., Spectral and structural properties of heterocyclic ketene aminals. J. Chem. Res., 1994: 1001-1004.
[3] Huang, Z. T., Liu, Z. R., Alkylation of heterocyclic ketene aminals with benzyl chloride and ethyl bromoacetate, Synthesis of heterobicycles containingγ-lactam-fused diazaheterocycles. Chem. Ber., 1989, 122, 95-100.
[4] Wang, L. B., Yu, C. Y., Huang, Z. T., The regiospecific N-alkylation of heterocyclic ketene aminals ethyl bromoacetate: a facile route to 3-pyrrolidinone fused diazaheterocycles. Synthesis, 1994: 1441-1444.
[5] Huang, Z. T., Wang, J. C., Wang, L. B., Acylation of heterocyclic ketene aminals with propionyl chloride. Synth. Commun., 1996, 26, 2285-2295.
[6] Yu, C. Y., Wang, L. B., Huang, Z. T., Reactions of heterocyclic ketene aminals with dimethyl oxalate: a facile synthesis ofγ-lactam-fused 1, 3-diazaheterocycles. Synthesis, 1996, 8, 959-962.
[7] Li, Z. J., Wang, L. B., Huang, Z. T., Synthesis of O-glycopyranosyl heterocyclic ketene aminals and their use as glycosyl donors. Carbohydr. Res., 1996, 295, 77-89.
[8] Ren, Z. X., Wang, L. B., Li. Z. J., el a1., Stereoselective synthesis of O- galactosides of benzoyl- substituted heterocyclic ketene aminals. Carbohydr. Res., 1998, 309, 251-259.
[9] Huang, Z. T.,Wang, M. X., Huang, Z. T., The reaction of benzoyl substituted heterocyclic ketene aminsls with aryl azides .A facile approach to synthesize 1,5-diaryl- 4-(2-imidazolinyl)- 1,2,3- triazoles. Chinese Chem. Lett., 1990, 1, 5-11.
[10] Huang, Z. T., Wang, M. X.,Huang, Z. T., The reaction of benzoyl substituted heterocyclic ketene aminsls with 4-nitrobenzhydroximic acid chooride. Synth. Commun., 1991, 21, 1167- 1176.
[11] Huang, Z. T., Wang, M. X., Huang, Z. T., The reaction of benzoyl substituted heterocyclic ketene aminsls with 2,4,6-trimelhylbenzonitrile oxide. Synth. Commun., 1991, 21, 1909-1921.
[12] Huang, Z. T., Wang, M. X., Huang, Z. T., The reaction of benzoyl substituted heterocyclic ketene aminsls with aryl azides. J. Org. Chem., 1992, 57, 184-190.
[13]黄志镗,李占江.陈晓闽.等.中国发明专利CNl188771A.1996, 07, 12.
[14]黄志镗.李占江.任忠旭,等.中国发明专利CN170727A.1996, 07, 12.
[15] Raymond C. F., Pravin P., Simon C H., Annulation of imidazolines with bis-electrophiles: Synthesis of imidazo[1,2-a]pyridines. Tetrahedron, 1998, 54, 6191-6200.
[16] Hoffmann H. M. R. The Ene Reaction. Angew. Chem. Int. Ed. Engl., 1969, 8, 556-577.
[17] Alder K., Pascher F., Schmitz A.,über die Anlagerung von Maleins?ure- anhydrid und Azodicarbons?ure-ester an einfach unges?ttigte Koh an einfach unges?ttigte Kohlenwasserstoffe. Zur Kenntnis von Substitutionsvorg?ngen in der Allyl-Stellung. Chem. Ber., 1943, 76, 27-53.
[18] Barry B. S., Lewis-acid catalyzed ene reactions. Acc. Chem. Res., 1980, 13(11), 426-432.
[19] Koichi M., Masaki S., Asymmetric ene reactions in organic synthesis. Chem. Rev., 1992, 92, 1021-1050.
[20] Barry M. T., Ian F., Comprehensive Organic Synthesis Selectivity, Strategy & Efficiency in Modern Organic Chemistry, Pergamon, Oxford, 1991, Vol. 2, 527-528.
[21] Sasaki I. Daran J. C., Balavoine G. G. A., An Effective Route to Polysubstituted Symmetric Terpyridines. Synthesis, 1999, 5, 815-820.
[22] Prein M., Adam W. The Schenck Ene Reaction: Diastereoselective Oxyfunctionalization with Singlet Oxygen in Synthetic Applications. Angew. Chem. Int. Ed. Engl., 1996, 35, 477-494.
[23] Bernard T. G., Francis A. D., The Reaction of Azodicarboxylic Acid Esters with Aldehyde Monosubstituted Hydrazones. J. Org. Chem., 1962, 27, 4001-4003.
[24] Fahr E., Rupp H. D. The Structure of the“Tetrazanes”Produced from Alkoxycarbonylazo Compounds and Aldehyde Phenylhydrazones. Angew. Chem. Int. Ed. Engl., 1964, 3, 693.
[25] Shmizu T., Hayashi Y., Kitora Y., Intramolecular 1,3-Dipolar Cycloadditions and Intramolecular Ene Reactions of 2-(Alkenyloxy) benzaldehyde Arylhydrazones. Bul1. Chem. Soc. Jpn., 1982, 55, 2450-2455.
[26] Novak M., Novak J., Salemink C.A., New type of intramolecular imino-ene cyclization during pyrolysis of (?)-cocaine. Tetrahedron Lett., 1991, 32, 4405-4408.
[27] Laschat S., Grehl M., Diastereoselective Synthesis of Amino-Substituted Indolizidines and Quinolizidines by the Intramolecular Hetero-Ene Reaction of Prolinal Imine and 2-Piperidine Carbaldimine. Angew. Chem. Int. Ed. Engl., 1994, 33, 458-461.
[28] Laschat S., Grehl M., Diastereoselective Synthesis ofα-Hydroxy- andα- Aminoindolizidines and -quinolizidines. Evidence for a Novel Cyclization/Hydride Migration Mechanism in the TiCl4-Induced Reaction of Prolinal Benzylimines by Deuterium Labeling Studies. Chem. Ber., 1994, 127, 2023-2034.
[29] Lasehat S., Grehl M., Wibbeling B., Preparation of 2, 3, 4-Trisubstituted Piperidines by a Formal Hetero-Ene Reaction of Amino Acid Derivatives. J. Org. Chem., 1996, 61, 2829-2838.
[30] D'Angelo J., Desma?le D., Dumas F., The asymmetric Michael addition reactions using chiral imines. Tetrahedron: Asymmetry, 1992, 3, 459-505.
[31] Sevin A., Tortajada J., Pfau M., Toward a transition-state model in the asymmetric alkylation of chiral ketone secondary enamines by electron-deficient alkenes. A theoretical MO study. J. Org. Chem., 1986, 51, 2671-2675.
[32] Pfau M., Tomas A., Lim S., et. al, Diastereoselectivity in the Michael-Type Addition of Imines Reacting as Their Secondary Enamine Tautomers. J. Org. Chem., 1995, 60, 1143-1147.
[33] D'Angelo J., Guingant A., Riche C., et al. The asymmetric Michael addition process involving chiral imines: stereochemical data in support of a cyclic-like transition state. Tetrahedron Lett., 1988, 29, 2667-2670.
[34] Cossy J., Bouzide A., Pfau M., Asymmetric intramolecular Ene-reaction. Tetrahedron Lett., 1992, 33, 4883-4884.
[35] Cossy J., Bouzide A., Pfau M., Intramolecular Ene Reactions. Stereo- and Enantioselective Synthesis of Spirolactams through Thermolysis of Enamino Carboxamides. J. Org. Chem., 1997, 62, 7106-7113.
[36] Huang Z. T., Wang X. J., A facile ring cleavage of cyclic ketones. Synthesis of 9- (alkoxycarbonylalkyl) pyrido[1,2-a] pyrimidines. Tetrahedron Lett., 1987, 28, 1527-1528.
[37] Huang Z. T., Wang X. J., Synthesis of Cycloalkanone-Substituted Ketene Aminals and their Reaction with Ethyl Propiolate. Chem. Ber., 1987, 120, 1803-1807.
[38] Zhao M. X., Wang X. J., Huang Z. T., The aza-ene or the Michael addition? Examination of an unusual substituent effect on the reaction of heterocyclic keten aminals with ethyl propiolate. Tetrahedron, 2002, 58, 1309-1316.
[39] Huang Z. T., Wang M. X., Further investigation on the reaction of heterocyclic ketene aminals with ethyl propiolate: ene-type reaction of enamines and an unusual substituent effect. J. Chem. Soc., Perkin Trans., 1, 1993, 1085-1090.
[40] Zhang J. H., Wang M. X., Huang Z. T., The aza-ene reaction of heterocyclic ketene aminals with enones: an e?cient and simple synthetic route to fused di- and tri-heterocycles. J. Chem. Soc., Perkin Trans., 1, 1999, 2087–2094.
[41] Weber L., The application of multi-component reactions in drug discovery. Curr. Med. Chem., 2002, 9, 2085-2093.
[42] Dǒmling A., Ugi I., Multicomponent reactions with isocyanides. Angew Chem. Int. Ed., 2000, 39, 3168-3210.
[43] Dǒmling A. Recent advances in isocyanide-based multicomponent chemistry. Curr. Opin. Chem. Biol., 2002, 6, 306-313.
[44] Hulme C., Gore V., Multi-component reactions: emerging chemistry in drug discovery from Xylocain to Crixivan. Curr. Med. Chem., 2003, 10, 51 -80.
[45] Weber L., Multi-component reactions and evolutionary chemistry. Drug Discovery Today, 2002, 7, 143-147.
[46] Ugi I., Heck S., The multicomponent reactions and their libraries for natural and preparative chemistry. Combinatorial Chemistry & High Throughput Screening, 2001, 4, 1-34.
[47] Strecker, A., Ueber die künstliche Bildung der Milchs?ure und einen neuen, dem Glycocoll homologen K?rper. Justus Liebigs Ann. Chem., 1850, 75, 27-45.
[48] Dǒmling A., Ugi I., The seven-component reaction. Angew. Chem. Int. Ed., 1993, 32, 563-564.
[49] Bossio R., Marcaccini S., Pepino R., Studies on isocyanides and related compounds. Synthesis of oxazole derivatives via the Passerini reaction. Liebigs Ann. Chem., 1991, 1107-1108.
[50] Heck S., Dǒmling A., A Versatile multi-component one-pot thiazole synthesis. Synlett., 2000, 3, 424-426.
[51] Schreiber S. T., Target-Oriented and Diversity-Oriented Organic Synthesis in Drug Discovery. Science, 2000, 28, 1964-1969.
[52] Lee D., Sello J. K., Schreiber S., Pairwise Use of Complexity-Generating Reactions in Diversity-Oriented Organic Synthesis. Org. Lett., 2000, 2, 709-712.
[53] Denmark S. E., Thorarensen A., Tandem [4+2]/ [3+2] Cycloadditions of Nitroalkenes. Chem. Rev., 1996, 96, 137-166.
[54]王建武,贾炯,候殿杰,等,一个新的制备咪唑并[1,5-a]吡啶衍生物的串联反应.有机化学,2003,23,173-177.
[55] Stelmakh A., Stellfeld T., Kalesse M., Tandem Intramolecular Michael-Aldol Reaction as a Tool for the Construction of the C-Ring of Hexacyclinic Acid. Org. Lett., 2006, 8, 3485-3488.
[56] Paulvannan K., An Atom-Economical Approach to Conformationally Constrained Tricyclic Nitrogen Heterocycles via Sequential and Tandem Ugi/Intramolecular Diels?Alder Reaction of Pyrrole. J. Org. Chem., 2004, 69, 1207-1214.
[57] Pirali T., Tron G. C., Zhu J. P., One-Pot Synthesis of Macrocycles by a TandemThree-Component Reaction and Intramolecular [3+2] Cycloaddition. Org. Lett., 2006, 8, 4145-4148.
[58]许加喜,[3,3]σ迁移反应过渡态立体化学过程的新观点.大学化学, 2006, 21, 40-44.
[59] Corey E. J., Lee D.H., The E/Z geometry of the enolate component determines face selection of the aldehyde component in chiral diazaborolidine-directed enantioselective aldol coupling. Tetrahedron Lett., 1993, 38, 1737-1740.
[60] Alajarín M., Ortín M. M., Pilar S. A., et al. Tandem Pseudopericyclic Reactions: [1,5]-X Sigmatropic Shift/6π-Electrocyclic Ring Closure Converting N-(2-X-Carbonyl)phenyl Ketenimines into 2-X-Quinolin-4(3H)-ones. J. Org. Chem., 2006, 71, 8126-8139.
[61] Handa S., Pattenden G., A new approach to steroid ring construction based on a novel radical cascade sequence. Chem. Comm., 1998, 3, 311-312.
[62] Ueda M., Miyabe H., Nishimura A., Indium-Mediated Tandem Radical Addition- Cyclization-Trap Reactions in Aqueous Media. Org. Lett., 2003, 5, 3835-3838.
[63] Leardini R., Nanni D., Tundo A., Novel [3+2] radical annulations of cyano-substituted aryl radicals with alkynes. Tetrahedron Lett., 1998, 39, 2441-2442.
[64] Trost B. M., Shi Y., Diastereoselective cycloisomerizations of enediynes via palladium catalysis. J. Am. Chem. Soc., 1993, l15, 12491-12509.
[65] Yu C. Y., Yang P. H., Zhao M. X., et al. A Novel One-Pot Reaction of Heterocyclic Ketene Aminals: Synthesis of a Small Library of Tetrahydropyridinone-Fused 1, 3- Diazaheterocycles. Synlett., 2006, 12, 1835-1840.
[66] Sheldrick G. M., SHELXS97, Program for Crystal Structure Solution, University of G?ttingen, Germany, 1997.
[67] Sheldrick G. M., SHELXS97, Program for Crystal Structure Refinement, University of G?ttingen, Germany, 1997.
[68] Gaber, A. E. M., McNab, H., Synthetic applications of the pyrolysis of meldrum’s acid derivatives. Synthesis, 2001, 2059-2074.
[69] Sabitha, G., Fatima, N., Reddy, E. V., et al. First examples of praline-catalyzed domino knoevenagel/hetero-diels-alder/elimination reactions. Adv. Synth. Catal., 2005, 347, 1353-1355.
[70] Yu, C. Y., Yang, P. H., Zhao, M. X., et al. A novel one-pot reaction of heterocyclic ketene aminals: synthesis of a small library of tetrahydropyridinone-fused-1,3-diazaheteroccycles. Synlett, 2006, 1835-1840.
[71]王常清,任仲皎,曹卫国等,无溶剂研磨条件下芳基亚甲基麦氏酸的合成.有机化学,2006, 26, 107-109.
[72] Rodríguez, H., Suarez, M., Pérez, R., et al. Solvent-free synthesis of 4-aryl substituted 5-alkoxycarbonyl-6-methyl-3,4-dihydropyridones und microwave irradiation. Tetrahedron Lett., 2003, 44, 3709-3712.
[73] Huang, X., Xie, L., One pot synthesis of 5-monosubstituted Meldrum’s acid. Synth. Commun., 1988, 18, 1701-1707.
[74] Huang, X., Chen, C. C., Wu, Q. L., Copper-catalyzed conjugate addition of grignard reagents to isopropylidene alkylidenemalonates. Tetrahedron Lett., 1982, 23, 75-76.
[75]Seefeld M. A., Miller W. H., Newlander K. A., Indole Naphthyridinones as Inhibitors of Bacterial Enoyl-ACP Reductases FabI and FabK. J. Med. Chem., 2003, 46, 1627-1635
[76] Ye G. Z., Zhou A.H, Henry W. P., et al. Tandem Reactions of 1, 3-Diacid Chlorides with 2-Methylimidazoline and 2-Methyl-1, 4, 5, 6-tetrahydropyrimidine: One-Pot Synthesis of 1, 8- Naphthyridinetetraones. J. Org. Chem., 2008, 73, 5170-5172.
[2] Wang, M. X., Liang, J. M., Huang, Z. T., Spectral and structural properties of heterocyclic ketene aminals. J. Chem. Res., 1994: 1001-1004.
[3] Huang, Z. T., Liu, Z. R., Alkylation of heterocyclic ketene aminals with benzyl chloride and ethyl bromoacetate, Synthesis of heterobicycles containingγ-lactam-fused diazaheterocycles. Chem. Ber., 1989, 122, 95-100.
[4] Wang, L. B., Yu, C. Y., Huang, Z. T., The regiospecific N-alkylation of heterocyclic ketene aminals ethyl bromoacetate: a facile route to 3-pyrrolidinone fused diazaheterocycles. Synthesis, 1994: 1441-1444.
[5] Huang, Z. T., Wang, J. C., Wang, L. B., Acylation of heterocyclic ketene aminals with propionyl chloride. Synth. Commun., 1996, 26, 2285-2295.
[6] Yu, C. Y., Wang, L. B., Huang, Z. T., Reactions of heterocyclic ketene aminals with dimethyl oxalate: a facile synthesis ofγ-lactam-fused 1, 3-diazaheterocycles. Synthesis, 1996, 8, 959-962.
[7] Li, Z. J., Wang, L. B., Huang, Z. T., Synthesis of O-glycopyranosyl heterocyclic ketene aminals and their use as glycosyl donors. Carbohydr. Res., 1996, 295, 77-89.
[8] Ren, Z. X., Wang, L. B., Li. Z. J., el a1., Stereoselective synthesis of O- galactosides of benzoyl- substituted heterocyclic ketene aminals. Carbohydr. Res., 1998, 309, 251-259.
[9] Huang, Z. T.,Wang, M. X., Huang, Z. T., The reaction of benzoyl substituted heterocyclic ketene aminsls with aryl azides .A facile approach to synthesize 1,5-diaryl- 4-(2-imidazolinyl)- 1,2,3- triazoles. Chinese Chem. Lett., 1990, 1, 5-11.
[10] Huang, Z. T., Wang, M. X.,Huang, Z. T., The reaction of benzoyl substituted heterocyclic ketene aminsls with 4-nitrobenzhydroximic acid chooride. Synth. Commun., 1991, 21, 1167- 1176.
[11] Huang, Z. T., Wang, M. X., Huang, Z. T., The reaction of benzoyl substituted heterocyclic ketene aminsls with 2,4,6-trimelhylbenzonitrile oxide. Synth. Commun., 1991, 21, 1909-1921.
[12] Huang, Z. T., Wang, M. X., Huang, Z. T., The reaction of benzoyl substituted heterocyclic ketene aminsls with aryl azides. J. Org. Chem., 1992, 57, 184-190.
[13]黄志镗,李占江.陈晓闽.等.中国发明专利CNl188771A.1996, 07, 12.
[14]黄志镗.李占江.任忠旭,等.中国发明专利CN170727A.1996, 07, 12.
[15] Raymond C. F., Pravin P., Simon C H., Annulation of imidazolines with bis-electrophiles: Synthesis of imidazo[1,2-a]pyridines. Tetrahedron, 1998, 54, 6191-6200.
[16] Hoffmann H. M. R. The Ene Reaction. Angew. Chem. Int. Ed. Engl., 1969, 8, 556-577.
[17] Alder K., Pascher F., Schmitz A.,über die Anlagerung von Maleins?ure- anhydrid und Azodicarbons?ure-ester an einfach unges?ttigte Koh an einfach unges?ttigte Kohlenwasserstoffe. Zur Kenntnis von Substitutionsvorg?ngen in der Allyl-Stellung. Chem. Ber., 1943, 76, 27-53.
[18] Barry B. S., Lewis-acid catalyzed ene reactions. Acc. Chem. Res., 1980, 13(11), 426-432.
[19] Koichi M., Masaki S., Asymmetric ene reactions in organic synthesis. Chem. Rev., 1992, 92, 1021-1050.
[20] Barry M. T., Ian F., Comprehensive Organic Synthesis Selectivity, Strategy & Efficiency in Modern Organic Chemistry, Pergamon, Oxford, 1991, Vol. 2, 527-528.
[21] Sasaki I. Daran J. C., Balavoine G. G. A., An Effective Route to Polysubstituted Symmetric Terpyridines. Synthesis, 1999, 5, 815-820.
[22] Prein M., Adam W. The Schenck Ene Reaction: Diastereoselective Oxyfunctionalization with Singlet Oxygen in Synthetic Applications. Angew. Chem. Int. Ed. Engl., 1996, 35, 477-494.
[23] Bernard T. G., Francis A. D., The Reaction of Azodicarboxylic Acid Esters with Aldehyde Monosubstituted Hydrazones. J. Org. Chem., 1962, 27, 4001-4003.
[24] Fahr E., Rupp H. D. The Structure of the“Tetrazanes”Produced from Alkoxycarbonylazo Compounds and Aldehyde Phenylhydrazones. Angew. Chem. Int. Ed. Engl., 1964, 3, 693.
[25] Shmizu T., Hayashi Y., Kitora Y., Intramolecular 1,3-Dipolar Cycloadditions and Intramolecular Ene Reactions of 2-(Alkenyloxy) benzaldehyde Arylhydrazones. Bul1. Chem. Soc. Jpn., 1982, 55, 2450-2455.
[26] Novak M., Novak J., Salemink C.A., New type of intramolecular imino-ene cyclization during pyrolysis of (?)-cocaine. Tetrahedron Lett., 1991, 32, 4405-4408.
[27] Laschat S., Grehl M., Diastereoselective Synthesis of Amino-Substituted Indolizidines and Quinolizidines by the Intramolecular Hetero-Ene Reaction of Prolinal Imine and 2-Piperidine Carbaldimine. Angew. Chem. Int. Ed. Engl., 1994, 33, 458-461.
[28] Laschat S., Grehl M., Diastereoselective Synthesis ofα-Hydroxy- andα- Aminoindolizidines and -quinolizidines. Evidence for a Novel Cyclization/Hydride Migration Mechanism in the TiCl4-Induced Reaction of Prolinal Benzylimines by Deuterium Labeling Studies. Chem. Ber., 1994, 127, 2023-2034.
[29] Lasehat S., Grehl M., Wibbeling B., Preparation of 2, 3, 4-Trisubstituted Piperidines by a Formal Hetero-Ene Reaction of Amino Acid Derivatives. J. Org. Chem., 1996, 61, 2829-2838.
[30] D'Angelo J., Desma?le D., Dumas F., The asymmetric Michael addition reactions using chiral imines. Tetrahedron: Asymmetry, 1992, 3, 459-505.
[31] Sevin A., Tortajada J., Pfau M., Toward a transition-state model in the asymmetric alkylation of chiral ketone secondary enamines by electron-deficient alkenes. A theoretical MO study. J. Org. Chem., 1986, 51, 2671-2675.
[32] Pfau M., Tomas A., Lim S., et. al, Diastereoselectivity in the Michael-Type Addition of Imines Reacting as Their Secondary Enamine Tautomers. J. Org. Chem., 1995, 60, 1143-1147.
[33] D'Angelo J., Guingant A., Riche C., et al. The asymmetric Michael addition process involving chiral imines: stereochemical data in support of a cyclic-like transition state. Tetrahedron Lett., 1988, 29, 2667-2670.
[34] Cossy J., Bouzide A., Pfau M., Asymmetric intramolecular Ene-reaction. Tetrahedron Lett., 1992, 33, 4883-4884.
[35] Cossy J., Bouzide A., Pfau M., Intramolecular Ene Reactions. Stereo- and Enantioselective Synthesis of Spirolactams through Thermolysis of Enamino Carboxamides. J. Org. Chem., 1997, 62, 7106-7113.
[36] Huang Z. T., Wang X. J., A facile ring cleavage of cyclic ketones. Synthesis of 9- (alkoxycarbonylalkyl) pyrido[1,2-a] pyrimidines. Tetrahedron Lett., 1987, 28, 1527-1528.
[37] Huang Z. T., Wang X. J., Synthesis of Cycloalkanone-Substituted Ketene Aminals and their Reaction with Ethyl Propiolate. Chem. Ber., 1987, 120, 1803-1807.
[38] Zhao M. X., Wang X. J., Huang Z. T., The aza-ene or the Michael addition? Examination of an unusual substituent effect on the reaction of heterocyclic keten aminals with ethyl propiolate. Tetrahedron, 2002, 58, 1309-1316.
[39] Huang Z. T., Wang M. X., Further investigation on the reaction of heterocyclic ketene aminals with ethyl propiolate: ene-type reaction of enamines and an unusual substituent effect. J. Chem. Soc., Perkin Trans., 1, 1993, 1085-1090.
[40] Zhang J. H., Wang M. X., Huang Z. T., The aza-ene reaction of heterocyclic ketene aminals with enones: an e?cient and simple synthetic route to fused di- and tri-heterocycles. J. Chem. Soc., Perkin Trans., 1, 1999, 2087–2094.
[41] Weber L., The application of multi-component reactions in drug discovery. Curr. Med. Chem., 2002, 9, 2085-2093.
[42] Dǒmling A., Ugi I., Multicomponent reactions with isocyanides. Angew Chem. Int. Ed., 2000, 39, 3168-3210.
[43] Dǒmling A. Recent advances in isocyanide-based multicomponent chemistry. Curr. Opin. Chem. Biol., 2002, 6, 306-313.
[44] Hulme C., Gore V., Multi-component reactions: emerging chemistry in drug discovery from Xylocain to Crixivan. Curr. Med. Chem., 2003, 10, 51 -80.
[45] Weber L., Multi-component reactions and evolutionary chemistry. Drug Discovery Today, 2002, 7, 143-147.
[46] Ugi I., Heck S., The multicomponent reactions and their libraries for natural and preparative chemistry. Combinatorial Chemistry & High Throughput Screening, 2001, 4, 1-34.
[47] Strecker, A., Ueber die künstliche Bildung der Milchs?ure und einen neuen, dem Glycocoll homologen K?rper. Justus Liebigs Ann. Chem., 1850, 75, 27-45.
[48] Dǒmling A., Ugi I., The seven-component reaction. Angew. Chem. Int. Ed., 1993, 32, 563-564.
[49] Bossio R., Marcaccini S., Pepino R., Studies on isocyanides and related compounds. Synthesis of oxazole derivatives via the Passerini reaction. Liebigs Ann. Chem., 1991, 1107-1108.
[50] Heck S., Dǒmling A., A Versatile multi-component one-pot thiazole synthesis. Synlett., 2000, 3, 424-426.
[51] Schreiber S. T., Target-Oriented and Diversity-Oriented Organic Synthesis in Drug Discovery. Science, 2000, 28, 1964-1969.
[52] Lee D., Sello J. K., Schreiber S., Pairwise Use of Complexity-Generating Reactions in Diversity-Oriented Organic Synthesis. Org. Lett., 2000, 2, 709-712.
[53] Denmark S. E., Thorarensen A., Tandem [4+2]/ [3+2] Cycloadditions of Nitroalkenes. Chem. Rev., 1996, 96, 137-166.
[54]王建武,贾炯,候殿杰,等,一个新的制备咪唑并[1,5-a]吡啶衍生物的串联反应.有机化学,2003,23,173-177.
[55] Stelmakh A., Stellfeld T., Kalesse M., Tandem Intramolecular Michael-Aldol Reaction as a Tool for the Construction of the C-Ring of Hexacyclinic Acid. Org. Lett., 2006, 8, 3485-3488.
[56] Paulvannan K., An Atom-Economical Approach to Conformationally Constrained Tricyclic Nitrogen Heterocycles via Sequential and Tandem Ugi/Intramolecular Diels?Alder Reaction of Pyrrole. J. Org. Chem., 2004, 69, 1207-1214.
[57] Pirali T., Tron G. C., Zhu J. P., One-Pot Synthesis of Macrocycles by a TandemThree-Component Reaction and Intramolecular [3+2] Cycloaddition. Org. Lett., 2006, 8, 4145-4148.
[58]许加喜,[3,3]σ迁移反应过渡态立体化学过程的新观点.大学化学, 2006, 21, 40-44.
[59] Corey E. J., Lee D.H., The E/Z geometry of the enolate component determines face selection of the aldehyde component in chiral diazaborolidine-directed enantioselective aldol coupling. Tetrahedron Lett., 1993, 38, 1737-1740.
[60] Alajarín M., Ortín M. M., Pilar S. A., et al. Tandem Pseudopericyclic Reactions: [1,5]-X Sigmatropic Shift/6π-Electrocyclic Ring Closure Converting N-(2-X-Carbonyl)phenyl Ketenimines into 2-X-Quinolin-4(3H)-ones. J. Org. Chem., 2006, 71, 8126-8139.
[61] Handa S., Pattenden G., A new approach to steroid ring construction based on a novel radical cascade sequence. Chem. Comm., 1998, 3, 311-312.
[62] Ueda M., Miyabe H., Nishimura A., Indium-Mediated Tandem Radical Addition- Cyclization-Trap Reactions in Aqueous Media. Org. Lett., 2003, 5, 3835-3838.
[63] Leardini R., Nanni D., Tundo A., Novel [3+2] radical annulations of cyano-substituted aryl radicals with alkynes. Tetrahedron Lett., 1998, 39, 2441-2442.
[64] Trost B. M., Shi Y., Diastereoselective cycloisomerizations of enediynes via palladium catalysis. J. Am. Chem. Soc., 1993, l15, 12491-12509.
[65] Yu C. Y., Yang P. H., Zhao M. X., et al. A Novel One-Pot Reaction of Heterocyclic Ketene Aminals: Synthesis of a Small Library of Tetrahydropyridinone-Fused 1, 3- Diazaheterocycles. Synlett., 2006, 12, 1835-1840.
[66] Sheldrick G. M., SHELXS97, Program for Crystal Structure Solution, University of G?ttingen, Germany, 1997.
[67] Sheldrick G. M., SHELXS97, Program for Crystal Structure Refinement, University of G?ttingen, Germany, 1997.
[68] Gaber, A. E. M., McNab, H., Synthetic applications of the pyrolysis of meldrum’s acid derivatives. Synthesis, 2001, 2059-2074.
[69] Sabitha, G., Fatima, N., Reddy, E. V., et al. First examples of praline-catalyzed domino knoevenagel/hetero-diels-alder/elimination reactions. Adv. Synth. Catal., 2005, 347, 1353-1355.
[70] Yu, C. Y., Yang, P. H., Zhao, M. X., et al. A novel one-pot reaction of heterocyclic ketene aminals: synthesis of a small library of tetrahydropyridinone-fused-1,3-diazaheteroccycles. Synlett, 2006, 1835-1840.
[71]王常清,任仲皎,曹卫国等,无溶剂研磨条件下芳基亚甲基麦氏酸的合成.有机化学,2006, 26, 107-109.
[72] Rodríguez, H., Suarez, M., Pérez, R., et al. Solvent-free synthesis of 4-aryl substituted 5-alkoxycarbonyl-6-methyl-3,4-dihydropyridones und microwave irradiation. Tetrahedron Lett., 2003, 44, 3709-3712.
[73] Huang, X., Xie, L., One pot synthesis of 5-monosubstituted Meldrum’s acid. Synth. Commun., 1988, 18, 1701-1707.
[74] Huang, X., Chen, C. C., Wu, Q. L., Copper-catalyzed conjugate addition of grignard reagents to isopropylidene alkylidenemalonates. Tetrahedron Lett., 1982, 23, 75-76.
[75]Seefeld M. A., Miller W. H., Newlander K. A., Indole Naphthyridinones as Inhibitors of Bacterial Enoyl-ACP Reductases FabI and FabK. J. Med. Chem., 2003, 46, 1627-1635
[76] Ye G. Z., Zhou A.H, Henry W. P., et al. Tandem Reactions of 1, 3-Diacid Chlorides with 2-Methylimidazoline and 2-Methyl-1, 4, 5, 6-tetrahydropyrimidine: One-Pot Synthesis of 1, 8- Naphthyridinetetraones. J. Org. Chem., 2008, 73, 5170-5172.