3,4-二氢嘧啶-2 -酮衍生物合成研究进展

报道了最近6年来3,4二氢嘧啶酮衍生物合成研究进展,包括催化合成法、绿色合成法以及天然产物合成中的一些研究进展,为该类化合物的合成提供了详尽的文献综述。有望在药物合成、不对称合成和天然产物合成方面提供有意义的指导。     

Heteropoly acid catalyzed synthesis of 3,4-dihydropyrimidin-2(1H)-ones

Simple and improved conditions have been found to carry out the Biginelli reaction for the synthesis of 3,4-dihydropyrimidin-2(1H)-one derivatives. This synthesis was performed using 11-molybdo-1-vanadophosphoric acid (H₄PMo₁₁VO₄₀) in ethanol solution. Compared with the classical Biginelli reaction conditions, this new method has the advantage of excellent yields (85–95%).     

HBF4-catalyzed Biginelli reaction: One-pot synthesis of dihydropyrimidin-2(1H)-ones under solvent-free conditions

An efficient synthesis of dihydropyrimidinones from the aldehyde, 1,3-dicarbonyl compound and urea (thiourea) under solvent-free conditions, using fluoroboric acid as the catalyst, is described. Compared with the classical Biginelli reaction conditions, this new protocol has the advantage of high yields, short reaction time and simplicity in the experimental procedure.     

Synthesis of Dihydropyrimidinones Using Large Pore Zeolites

Abstract  

A series of dihydropyrimidin-2(1H)-one (DHPM) belongs to one of the important class of therapeutic and pharmacological active compound, were synthesized through the multicomponent reactions (MCRs) of aldehydes, ethyl acetoacetate and urea, followed by the heterogeneous catalyzed Biginelli reaction. In the present endeavour, medium (ZSM-5) and large pore zeolites (Y, BEA and MOR) as well as dealuminated zeolites BEA, were studied as catalysts. An excellent activity for DHPMs synthesis is achieved by optimizing accessibility of the reactants to the active sites and the surface polarity of zeolite catalysts. Moreover, the mechanism of Biginelli reaction was studied by means of GAUSSVIEW energy calculations of adsorbed acylimine intermediate on zeolite by using the density functional method (DFT).     

Trichloroisocyanuric acid,a new and efficient catalyst for the synthesis of dihydropyrimidinones

An efficient three-component synthesis of 3,4-dihydropyrimidinones using trichloroisocyanuric acid (TCCA) as a mild, homogeneous and neutral catalyst for Biginelli reaction in ethanol or DMF under reflux condition and microwave irradiation is described. Yields are excellent in either of the two conditions.     

NH4Cl催化微波照射合成3,4-二氢嘧啶-2-酮衍生物

经典的Biginelli反应用HCl作催化剂,通常产率较低(20%～50%).本文用NH4Cl作为催化剂,反应中用元水乙醇作溶剂,在微波辐射下反应.此改进方法具有催化剂廉价易得、反应时间短、收率高、操作简便等优点.本文所制得的9种3,4-二氢嘧啶-2-酮类化合物,收率较经典的Biginelli反应收率有较大的提高.该方法的使用为3,4-二氢嘧啶-2-酮衍生物的制备提供了一条方便、快捷、有效的合成方法.     

CuI as reusable catalyst for the Biginelli reaction

An improved protocol for the Biginelli reaction using CuI as a reusable catalyst is described. The synthesis of 3,4-dihydropyrimidin-2(1H)-ones was achieved in acetonitrile, water and under solvent-free condition. After separation of product from the reaction mixture, the mother liquor (acetonitrile or water) containing the catalyst was reused two times without any loss of activity.     

Synthesis of Cu@CF@SBA15: A Versatile catalysts for (i) reduction of dyes,trifluralin, Synthesis of (ii) DHPMs by Biginelli reaction and (iii) 1,2,3-triazole derivatives by ‘Click reaction’

Herein, we are reporting a facile route to synthesize magnetically separable Cu nanoparticle loaded CoFe₂O₄@SBA15 catalysts, which exhibits high catalytic activity towards (i) reduction of various synthetic dyes, trifluralin, (ii) synthesis of DHPMs via Biginelli reaction pathway in solventless condition and (iii) 1,2,3-triazole derivatives by ‘Click reaction’ in aqueous medium. To the best of our knowledge, this is the first time one single catalyst is reported which shows its high activity for these three important reactions.     

Recyclable Amberlyst-70 as a Catalyst for Biginelli Reaction: An Efficient One-Pot Green Protocol for the Synthesis of 3,4-Dihydropyrimidin-2(1H)-ones

An environmentally benign aqueous protocol for the synthesis of 3,4-dihydropyrimidin-2(1H)-ones using Amberlyst-70 as a recyclable catalyst has been developed. The use of resinous, nontoxic, thermally stable and inexpensive Amberlyst-70, as a recyclable heterogeneous catalyst, makes the process simple with negligible chemical waste. Thus renders this method an environmentally acceptable synthetic tool for Biginelli reaction.     

Sulfated tungstate: An alternative,eco-friendly catalyst for Biginelli reaction

Sulfated tungstate catalyzed simple, one pot, solvent free and environmentally benign process for synthesis of dihydropyrimidinones via Biginelli reaction is described. It was found that the catalyst is reusable and exhibited remarkable activity.     

微波促进下的Biginelli反应:5-(4-甲基苯甲酰基)-3,4-二氢嘧啶-2酮(硫酮)类衍生物的无溶剂合成

微波无溶剂条件下,通过醛、对甲基苯甲酰丙酮、尿素(硫脲)在对甲苯磺酸催化下进行的Biginelli反应来合成5-(4-甲基苯甲酰基)-3,4-二氢嘧啶-2酮(硫酮)类衍生物,易得到且收率高。     

Biginelli反应的研究新进展

1893年,意大利化学家Pietro.Biginelli首次利用苯甲醛、乙酰乙酸乙酯和尿素三种原料＂一锅法＂合成了3,4-二氢嘧啶-2（1H）-酮（DHPMS）。后来,经过大量研究证明该类化合物具有良好的药理活性和生物反应活性,是抗癌药物及海洋生物碱的重要中间体。因此本文对Biginelli衍生化反应的机理和Biginelli反应的影响因素两个方面进行了详细阐述.     

三聚氯氰高效催化一锅法合成3,4-二氢嘧啶-2(1H)-酮衍生物

3,4-二氢嘧啶酮衍生物具有重要生理活性,因此该类化合物的合成受到广泛关注。以廉价的三聚氯氰催化芳醛、尿素和乙酰乙酸乙酯或环戊酮的“一锅法”Biginelli反应,在无溶剂和无保护的条件下合成了一系列芳亚甲基稠环嘧啶酮化合物,其中代表性化合物结构经NMR、IR和熔点等表征手段确定。该方法所用催化剂经济易得,且催化剂用量较少,反应条件温和,产率较高,为3,4-二氢嘧啶-2(1H)-酮衍生物的合成提供了新的方法。     

Design and synthesis of new classes of heterocyclic C-glycoconjugates and carbon-linked sugar and heterocyclic amino acids by asymmetric multicomponent reactions (AMCRs)

While chemical efficiency relies on several factors, the multicomponent reaction (MCR) approach was considered as a powerful synthetic tool for preparing target molecules of biological relevance in an efficient manner. Four classes of new bioactive molecules were designed and synthesized by asymmetric MCRs, in some cases with the cooperation of polymer-assisted solution-phase (PASP) technique. These include (a) C-glycosyl dihydropyrimidines and dihydropyridines via Biginelli and Hantzsch cyclocondensations, (b) C-glycosyl beta-amino acids via Mannich- and Reformatsky-type reactions, (c) C-glycosyl beta-lactams via Staudinger reaction, and (d) heterocyclic alpha-amino acids (glycine and alanine) via the Biginelli and Hantzsch reactions.     

Greener,solvent free three component Biginelli reaction over different recyclable solid acid catalysts

Solid acids comprising 12-tungstophosphoric acid and 12-tungstosilicic acid anchored on to metal oxide (ZrO₂), zeolites (Hβ and HZSM-5), and mesoporous material (MCM-41) were synthesized, characterized and used as the catalysts. A solvent free green route to carry out the Biginelli cyclocondensation reaction is described over synthesized catalysts. The method provides an efficient and much improved protocol of Biginelli reaction in terms of solvent free conditions, high yields up to 98 %, very short reaction time of 15 min, and simple work-up procedure. Based on the above study a best catalyst among all is proposed and is recycled up to four times without any significant change in % yields of the product. Another important feature of this method is survival of a variety of functional groups under the reaction conditions.     

瑞舒伐他汀中间体的合成工艺改进

采用B iginelli嘧啶酮缩合反应,以4-氟苯甲醛、异丁酰乙酸甲脂和硫脲为原料,在质子酸存在下经缩合、甲基化、氧化、亲核取代、还原和氧化反应,合成了降血脂药物瑞舒伐他汀(Rosuvastatin)的中间体嘧啶醛化合物(Ⅶ),总收率为32.5%,与H irai K所申请的专利(US 5 260 440,1993)的方法相比,不仅缩短了反应步骤,而且收率提高了14.5%。化合物的结构经1HNMR,IR和MS进行了确证。     

Comparative study using different infrared zones of the solventless activation of organic reactions

In this work, the results of a study comparing the use of irradiation from different regions of the infrared spectrum for the promotion of several organic reactions, are presented and discussed. This use of eco-conditions provides a green approach to chemical synthesis. A set of ten different organic reactions were evaluated, including the Knoevenagel, Hantzsch, Biginelli and Meldrum reactions. It is important to highlight the use of a commercial device that produces infrared irradiation in the near infrared region and its distribution by convection providing heating uniformity, significantly reducing reaction times, achieving good yields and proceeding in the absence of solvent. It is also worth noting that a variety of different reactions may be performed at the same time. Finally, the products obtained were identified using TLC, together with corresponding MS-data, complementarily in comparison of NMR (1)H and (13)C data with literature information.     

“一锅煮”制备Biginelli和Hantzsch两种产物及其结构分析

苯甲醛、尿素和乙酰乙酸乙酯三组分“一锅煮”可以同时制备Biginelli和Hantzsch两种产物。教学中通过改变催化剂种类、反应物料比、反应溶剂等条件,引导学生探讨反应条件的改变对总产率及两种异构体比例的影响。实验中通过薄层色谱来跟踪反应进程,通过柱色谱分离混合物,最后通过熔点、红外光谱对合成的化合物进行结构表征。本实验集无机化学、有机化学、基础分析化学和仪器分析于一体,具有很强的实用性和可操作性,可作为有机化学实验中的综合性、设计性实验开设。     

Microwave assisted solvent-free synthesis of dihydropyrimidinones by Biginelli reaction over Si-MCM-41 supported FeCl3 catalyst

Among the Si-MCM-41 or montmorillonite K 10 clay supported ZnCl₂, AlCl₃, GaCl₃, InCl₃ and FeCl₃ catalysts, FeCl₃/Si-MCM-41 shows best performance for the microwave-assisted synthesis of dihydropyrimidinones by the Biginelli reaction involving multicomponent condensation of aromatic aldehyde, ethyl acetoacetate and urea in the absence of any solvent. It is a promising catalyst for the microwave-assisted reaction providing high product yield in a short period (3.0–5.0 min).     

Urease: A highly biocompatible catalyst for switchable Biginelli reaction and synthesis of 1,4-dihydropyridines from the in situ formed ammonia

Urease is a superior biocompatible catalyst for switching from the Biginelli reaction to urea-based synthesis of 1,4-dihydropyridines in water, where 100% switching occurs at 0.02 g/mL of enzyme. Hantzsch reaction with ammonium acetate (NH₄OAc) is inefficiently catalyzed by urease (70%, 4 h), and heavy metal ions inhibit the urease-catalyzed reactions with urea or NH₄OAc. Promotion of the urea-based Hantzsch reaction by urease and its inhibition with Hg^2 + supports specificity of urease for in situ generation of ammonia, whereas the role of urease in further transformations is not so specific. The features of this enzymatic method are reusability, mild reaction conditions, biocompatibility, generality, and high yield of products.