牛血清白蛋白:一种催化四组分反应合成吡喃[2,3-c]并吡唑类化合物的高效和绿色生物催化剂

多组分反应(MCRs)是通过一锅法同时或先后加入3种或3种以上起始原料合成目标产物的过程,具有原子经济性高、化学键构造效率高和反应选择性高等优点,而且可以避免中间体分离和纯化,从而减少废物产生,节省时间,简化分离纯化过程.MCRs由于其灵活性和高效性超过了传统多步合成方法,已成为构建结构新颖的多样性有机分子的新兴工具,尤其是在新药开发中具有广泛应用.吡喃[2,3-c]并吡唑是一类重要杂环化合物,是许多重要新兴药物的关键内核,这些药物具有抑制人类Chk1激酶活性、抗肿瘤活性、止痛镇痛活性、抗菌活性和抗炎活性等.目前已有通过三组分反应(3CRs)、四组分反应(4CRs)乃至五组分反应(5CRs)合成吡喃[2,3-c]并吡唑的文献报道.所用催化剂大多为无机或有机碱性催化剂,所报道的多组分反应或多或少存在一些不足,如反应条件苛刻、所使用试剂昂贵和不易获得、使用定量的催化剂、产率不理想及操作繁琐等.牛血清白蛋白(BSA)是一种来源于牛,在生物体系中没有天然催化功能的廉价易得的非酶转运蛋白.由于生物催化剂如蛋白质、酶及完整细胞等具有催化效率高、选择性高和操作简单等优点,将生物催化剂用于催化有机反应已成为化学领域的研究热点.在这些生物催化剂中,BSA能催化一系列有机反应,包括还原反应、Knoevenagel缩合、aldol缩合、Morita-Baylis-Hillman反应和Biginelli反应等.考虑到吡喃[2,3-c]并吡唑衍生物的重要性以及BSA催化有机反应的多样性,我们设想利用生物催化剂BSA催化4CRs合成吡喃[2,3-c]并吡唑衍生物,即在45℃下,于90％乙醇水溶液中,催化量BSA催化乙酰乙酸乙酯、水合肼、丙二腈和羰基化合物反应.反应完成后,产物经乙醇重结晶纯化,BSA可回收重复使用,重复使用5次,催化活性基本保持不变.在优化条件下,合成了22个吡喃[2,3-c]并吡唑衍生物或及其螺环衍生物.迄今为止,该法尚未见文献报道.总之,我们发展了一种新颖和有效的BSA催化构建结构多样性吡喃[2,3-c]并吡唑衍生物的绿色方法.该法具有环境友好、反应条件温和、反应时间短、产率高和操作简单等优点.同时,该法底物适应范围广,可以使用各种羰基化合物为起始原料,这使它成为一种高效实用的合成结构多样性吡喃[2,3-c]并吡唑衍生物的方法.     

Convenient synthesis of spiro[indoline-3,4'-pyrano[2,3-c]pyrazole] and spiro[acenaphthyl-3,4'-pyrano[2,3-c]pyrazoles] via fourcomponent reaction

The base promoted four-component reaction of hydrated hydrazine, dimethyl acetylenedicarboxylate, isatines and malononitrile (ethyl cycanoacetate) in ethanol afforded polysubstituted spiro[indoline-3,4‘-pyrano[2,3-c]pyrazoles] and spiro[acenaphthyl-3,4-pyrano[2,3-c]pyrazoles]     

Polyethylene glycol-promoted synthesis of pyrimido[1,2-a]benzimidazole and pyrano[2,3-c]pyrazole derivatives in water

Synthesis of pyrimido[1,2-a]benzimidazole and pyrano[2,3-c]pyrazole derivatives were achieved using polyethylene glycol (PEG-400) as promoting reaction medium in water under catalyst-free conditions at reflux and room temperature, respectively. The structure of pyrimido[1,2-a]benzimidazole was confirmed using ¹H NMR, ¹³C NMR, DEPT, and HMBC experiments. The promising points for the present methodology are efficiency, generality, high yield, short reaction time, cleaner reaction profile, ease of product isolation, simplicity, potential of recycling reaction medium, and finally agreement with green chemistry protocols.     

Synthesis of New Benzopyrano[2,3-c]pyrazoles and 3-triazolonyliminocoumarins From 3-cyano Iminocoumarin Derivatives

Synthesis of benzopyrano[2,3-c]pyrazoles and 3-triazolonyliminocoumarins was successfully performed using heterocyclization of 3-cyano iminocoumarin or their N-ethoxycarbonylated derivatives with semicarbazide reagents. Elemental analysis, infrared, and ¹H NMR spectral data confirmed the molecular structure of the newly synthesized compounds.     

One-pot multicomponent diastereoselective synthesis of novel dihydro-1H-furo[2,3-c]pyrazoles

An efficient method was developed for the diastereoselective synthesis of novel fused dihydro-1H-furo[2,3-c]pyrazole by a one-pot, four-component reaction of β-keto ester, hydrazine, aromatic aldehyde, and pyridinium ylide in the presence of triethylamine under microwave irradiation in solvent-free conditions in good yields. The merits of this cascade Knoevenagel condensation/Michael addition/cyclization sequence include its high atom economy, good yields, and efficiency of producing three new bonds (two C–C and one C–O) and two stereocenters in a single operation.     

Morpholine triflate promoted one-pot,four-component synthesis of dihydropyrano[2,3-c] pyrazoles

A one-pot,four-component reaction of ethyl acetoacetate,hydrazine hydrate,aldehydes,and malononitrile was discussed using Lewis acid catalyst morpholine triflate (MorT) to afford a series of dihydropyrano[2,3-c] pyrazoles,which were generally catalyzed by organic alkalis.Moderate to excellent yields,no chromatographic purification,and evasion of environmentally hazardous solvents in the reaction process make this protocol very useful for academia and industry.     

四组分一锅法合成多取代吡喃[2,3-c]吡唑-5-腈

在三乙胺催化下,以乙酰乙酸甲酯、苯肼、芳醛和丙二腈等4组分为原料,经一锅法合成了一系列多取代的吡喃并[2,3-c]吡唑衍生物(5a～5j),反应在10～15 min内即可完成.所有产物由IR、1HNMR和MS确证.该方法具有产率高、操作简单等优点.     

Theophylline as a new and green catalyst for the one-pot synthesis of spiro[benzo[a]pyrano[2,3-c]phenazine] and benzo[a]pyrano[2,3-c]phenazine derivatives under solvent-free conditions

A green, convenient, high yielding and one-pot procedure for the synthesis of novel spiro[benzo[a]pyrano[2,3-c]phenazine] derivatives by domino multi-component condensation reaction between 2-hydroxynaphthalene-1,4-dione, benzene-1,2-diamines, ninhydrine, and malononitrile in the presence of a catalytic amount of 1,3-dimethyl-7H-purine-2,6-dione (theophylline) as an expedient, eco-friendly and reusable solid base catalyst under thermal, microwave irradiation and solvent-free conditions. This procedure has also been applied successfully for the synthesis of benzo[a]pyrano[2,3-c]phenazines.     

Novel Synthesis of Thieno[2,3-c]Pyridazine and Pyrimido[4',5':4,5]thieno[2,3-c]pyridazine Derivatives

Abstract

Novel series of thieno[2,3-c]pyridazines and pyrimido[4′,5′:4,5] thieno-[2,3-c]pyridazines have been synthesized from the readily accessible 4-cyano-5,6-dimethylpyridazin-3(2H)-thione 3b.     

Efficient atom-economic one-pot multicomponent synthesis of benzylpyrazolyl coumarins and novel pyrano[2,3-c]pyrazoles catalysed by 2-aminoethanesulfonic acid (taurine) as a bio-organic catalyst

The present work describes eco-friendly multicomponent protocol for the synthesis in excellent yields of structurally diverse benzylpyrazolyl coumarin 5 (a–s) involving the reaction of 4-hydroxycoumarin, ethyl acetoacetate, hydrazine hydrate/phenyl hydrazine hydrate and aldehydes, also novel pyrano[2,3-c]pyrazole derivatives 8 (a–k) integrated by isonicotinic acid hydrazide from reaction of aldehyde, ethyl acetoacetate, malononitrile with isoniazid, employing water as a reaction medium and 2-aminoethanesulfonic acid (taurine) as the catalyst. This new methodology endowed the advantages such as short reaction time, recovery of catalysts after catalytic reaction and reusing them without losing their activity and alleviate of operation.     

碱性离子液体催化“一锅法”合成1,4-二氢吡喃并[2,3-c]吡唑

在碱性离子液体氢氧化1-丁基-3-甲基咪唑([bmim]OH)催化作用下,由芳香醛、丙二腈、苯甲酰乙酸乙酯和肼或苯肼"一锅法"合成了一系列1,4-二氢吡喃并[2,3-c]吡唑化合物.实验中考察了催化剂、反应温度、催化剂用量、溶剂对反应的影响,确定了最优反应条件,给出了可能的反应机理.此外催化剂可以方便地收回,且循环使用四次其催化活性并没有显著降低.目标产物经过了1H NMR,IR,MS和元素分析确证.合成方法条件温和、反应时间短、产率高且对环境友好.     

Zn(ANA)2Cl2 complex as efficient catalyst for the synthesis of dihydropyrano[2,3-c]pyrazoles in aqueous medium via one-pot multicomponent reaction: a green approach

Abstract

The first example of recyclable Zn(ANA)₂Cl₂ catalyzed tandem one-pot three-component protocol reaction between aromatic aldehydes, malononitrile, and phenylmethylpyrazolone to furnish 4-substituted-1,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile (4a–l) in a short reaction time (～10?min) in aqueous media at room temperature is described.     

Synthesis of furo[3,2-c]- and pyrano[3,2-c]quinolines by lanthanide triflate catalyzed imino-Diels-Alder reaction

Imino Diels-Alder reaction of imines with 2,3-dihydrofuran or 3,4-dihydro-2H-pyran proceeded smoothly in the presence of a catalytic amount (0.5 mol %) of ytterbium triflate to afford furo[3,2-c]- and pyrano[3,2-c] quinolines conveniently in high yield.     

A novel one-pot two-component synthesis of tricyclic pyrano[2,3-b]quinoxalines

A one-pot two-component synthesis of tricyclic pyrano[2,3-b]quinoxalines with a pendant hydroxymethyl fuction at the 2-position relevant to molybtopterin is described by the reaction of o-phenylenediamine and phenylhydrazone derivatives of sugars in good yields.     

Thieno[2,3-c]pyridazine Derivatives: Synthesis and Antimicrobial Activity

Thieno[2,3-c]pyridazine 2 was selected as the starting material for the synthesis of some novel 5-arylidene amino and 5-thiazolidine derivatives. The structures of the synthesized compounds were elucidated by elemental analyses and spectral data. The antimicrobial and antifungal activities of the newly synthesized products were measured against some microorganisms.     

An Efficient Four-Component Synthesis of Multisubstituted Pyrano[2,3-c]pyrazole

A series of substituted pyrano[2,3-c]pyrazole derivatives were synthesized by a one-pot reaction of methyl 4-methyl-3-oxovalerate, phenylhydrazine, aromatic aldehyde, and malononitrile in ethanol with catalysis by triethylamine. The title compounds were obtained in good to excellent yields. A possible mechanism for this reaction was proposed.     

Convenient DABCO-catalyzed one-pot synthesis of multi-substituted pyrano[2,3-c]pyrazole dicarboxylates

We developed an efficient and simple one-pot synthesis of functionalized multi-substituted 2,4-dihydro-pyrano[2,3-c]pyrazole dicarboxylates from β-ketoesters, hydrazine, dimethyl acetylenedicarboxylate and malononitrile in EtOH. This four-component one-pot reaction carried out in the presence of DABCO catalyst showed advantages over a one-pot three-component method in its simple procedure, high yield and low toxicity.     

A concise synthesis of functionalized 2,3-dihydrofuro[3,2-b], [3,2-c], and [2,3-b]pyridines

A strategy for the efficient and rapid one-pot synthesis of 2-aryl-2,3-dihydrofuro[3,2-b], [3,2-c], and [2,3-b]pyridines from readily available o-nitropicolines and aromatic aldehydes is described. The key transformation involves reaction of o-nitropicolines with aromatic aldehydes in the presence of TBAF and Hünig's base giving rise to functionalized products having molecular complexity suitable for further manipulation.     

Synthesis of 6-Amino-2,4-dihydropyrano[2,3-c]pyrazol-5-carbonitriles Catalyzed by Silica-Supported Tetramethylguanidine Under Solvent-Free Conditions

An efficient, high-yielding, and rapid protocol has been developed for the synthesis of diversity-oriented 6-amino-2,4-dihydropyrano[2,3-c]pyrazol-5-carbonitriles derivatives via a four-component, one-pot cyclocondensation reaction of ethyl acetoacetate, hydrazine hydrate, aldehydes, and malononitrile using silica-supported tetramethylguanidine as a heterogeneous catalyst for the first time. The protocol proves to be efficient and environmentally benign in terms of very easy workup, good yields, and ease of recovery of catalyst. In addition, the present method is superior in terms of green media, the amount of catalyst, and reaction time.