Three-component Biginelli Condensation Research Articles

Effect of Different Solvents on Biginelli Reaction Using Layered Double Hyroxide (LDH) As an Ecofriendly Catalyst

A simple and efficient method of the 3,4- dihydropyrimidin-2(1H)-ones/thiones synthesis in good to high yield is described. It consists in a one-pot three-component Biginelli condensation using Layered double hydroxide (LDH) as catalyst. The effect of different solvents on the yields of final product also been studied. Highly polar solvent as well as highly non-polar gives less yields in presence of LDH catalyst.

Fast and Efficient One-Pot Three-Component Synthesis of Some 1,2,3,4- Tetrahydro-6-methyl-N-phenyl-5-pyrimidinecarboxamide Derivatives via Biginelli Condensation Reaction

Tetrahydropyrimidine (THPM) synthesis has an enormous importance in organic chemistry and especially in pharmaceutical applications. Pyrimidines are the most active class of N-containing heterocyclic compounds and have different biological properties. The heterocyclic ring system with a thio group occupy a unique position in medicinal chemistry. This type of compounds play an important role in synthetic drugs and in biological processes. Dihydropyrimidinethione derivatives occur widely in nature. Several modifications of THPM-5-carboxamides have attracted considerable interest of medicinal chemists due to their pharmacological and therapeutic properties. A series of 1,2,3,4-tetrahydro- 2-pyrimidinone/thione derivatives bearing a phenylcarbamoyl group at C-5 position were synthesized by one-pot three-component Biginelli condensation reaction. The reaction of acetoacetanilide as the 1,3-dicarbonyl component with various aromatic aldehydes and urea/thiourea in the presence of a catalytic amount of p-toluenesulfonic acid monohydrate (PTSA·H2O) or concentrated HCl as an efficient catalyst leads to Biginelli compounds. We have prepared eight THPM 5-carboxamide derivatives, four of them are new compounds. Their structures were confirmed by spectroscopic techniques and elemental analysis. These compounds have potential applications in organic synthesis and medicinal chemistry. We have synthesized a series of THPM-5-carboxamides by simple and efficient threecomponent Biginelli condensation reaction. Significant benefits of the present procedure include: a) application of inexpensive, non-toxic, environmentally friendly and easily available catalysts, b) the reactions are easy to carry out without high temperature and the workup is very simple, c) the required reaction times are relatively short (30-80 min with HCl and 8-24 h with PTSA·H2O), d) compatibility with various functional groups, e) the products are isolated in good to excellent yields (50-95%).

Mg-Doped ZnO and Zn-Doped MgO Semiconductor Nanoparticles; Synthesis and Catalytic, Optical and Electro-Optical Characterization

A series of MgxZn1 –xO and ZnxMg1 –xO (mol %) were synthesized by the sol–gel method. All the synthesized nanoparticles were investigated as catalyst in the one-pot, three-component Biginelli condensation reaction of benzaldehyde, ethyl acetoacetate and urea under heterogeneous conditions. Findings revealed Mg0.007Zn0.093O (Zn7) as the best in the mentioned condensation reaction. Zn7 was characterized by FT-IR, SEM, CHN, and XRD. In addition, linear and nonlinear optical properties of MgxZn1 –xO and ZnxMg1 –xO thin films and their colloidal solutions were studied. Using an exact numerical method, some photo-physical properties of the prepared films such as dispersion curve, absorption spectrum, optical permittivity and optical band gap were attained and compared. Finally, using z-scan method at low laser irradiation, thermo-optical effect has also studied and a nonlinear refractive index due to this effect was attained. Doping effect on the optical properties was also investigated physically. It was found in both the particles groups, increasing the doping percent reduces the band gap and it suggests new optoelectronic materials with a spectrum of optical properties.

Antioxidant properties of amide derivatives of 3,4-dihydropyrimidin-2-one with phenolic substituent in heterocycle

The antioxidant properties of 4-[3,5-di(tert-butyl)-4-hydroxyphenyl]-5-aminocarbonyl-6-methyl-3,4-dihydropyrimidin-2-one were researched by volumetric analysis and decomposition of hydroperoxide. The reactant was obtained by three-component Biginelli condensation using urea, 3,5-di (tert-butyl) -4-hydroxybenzaldehyde and acetoacetic acid amide as reactants. The decomposition of cumene hydroperoxide in dimethylformamide under these conditions is described by a first-order kinetics equation. As the concentration of hydroperoxide increases, the rate of its decomposition decreases, apparently due to the formation of dimethylformamide dimer stabilized by molecules. 4- [3,5-Di (tert-butyl) -4-hydroxyphenyl] -5-aminocarbonyl-6-methyl-3,4-dihydropyrimidin-2-one inhibits the decomposition of hydroperoxide by slowing induced and homolytic cleavage. The inhibitory effect rises with the increase of the concentration of the inhibitor. An equation, which describes the inhibitory action of the analyzed compound on the hydroperoxide decomposition, was proposed, and the coefficients of this equation were calculated. The initiated oxidation of cumene was carried out at a temperature of 343 K in the presence of the initiator azodiisobutyronitrile. The concentration of 4- [3,5-di (tert-butyl) -4-hydroxyphenyl] -5-aminocarbonyl-6-methyl-3,4-dihydropyrimidin-2-one varied from 1,5×10-4 до 5,0×10-3 mol / l. In the concentration interval of the analyzed substance (1,25¸5,0)×10-3 mol / l the duration of the induction period exceeds 60 min. At lower concentrations, a linear change in the duration of the induction period is observed. The inhibitory action of 4- [3,5-di (tert-butyl) -4-hydroxyphenyl] -5-aminocarbonyl-6-methyl-3,4-dihydropyrimidin-2-one is higher than that of ionol. The basic kinetic parameters of the processes of initiated oxidation of cumene and decomposition of cumene hydroperoxide are calculated. Therefore, the analyzed compound has an antioxidant effect both during the decomposition of hydroperoxide and during the initiation of cumene oxidation. The phenolic group and the urea moiety of the dihydropyrimidinone cycle have an inhibitory effect.

Facile and Rapid Synthesis of 3,4-Dihydropyrimidin-2(1H)-one Derivatives Using [Et3NH][HSO4] as Environmentally Benign and Green Catalyst

5-acetyl-6-methyl-4-aryl-3,4-dihydropyrimidin-2(1H)-ones were synthesized in good to excellent by one-pot three-component Biginelli condensation in the presence of ammonium salt [Et3NH][HSO4] as an inexpensive and green catalyst under solvent-free conditions. High yields, short reaction time, easy work-up, a green environment which requires no toxic organic solvents and reusability of the catalyst are the advantages of this procedure. A broad range of structurally diverse aldehydes (aromatic aldehydes bearing electron withdrawing and electron releasing groups) was applied successfully, and corresponding products were obtained in good to excellent yields without any by-product. In addition, this catalyst was stable during the reaction process and could also be reused several times with consistent activity.

Unexpected transformations of 11-acetyl-8-bromo-2-methyl-5,6-dihydro-2H-2,6-methano-1,3,5-benzoxadiazocin-4(3H)-one(thione)

11-Acetyl-8-bromo-2-methyl-5,6-dihydro-2H-2,6-methano-1,3,5-benzoxadiazocin-4(3H)-one and -4(3H)-thione are prepared via the three-component Biginelli condensation as the only diastereomers. For the first time we observed that these compounds in DMSO solution undergo a slow isomerization with formation of mixtures with the respective 4-(5-bromo-2-hydroxyphenyl)-3,4-dihydropyrimidin-2(1Н)-one(thione). The same methanobenzoxadiazocines underwent deacetylation in boiling ethanol in the presence of HCl.

Ascorbic acid-Catalyzed One-Pot Three-Component Biginelli Reaction: A Practical and Green Approach towards Synthesis of 3,4-dihydropyrimidin- 2(1H)-ones/thiones

An efficient one-pot synthesis of 3,4-dihydropyrimidin-2(1H)-ones/thiones via a three-component Biginelli condensation of aldehyde, ethyl acetoacetate, and urea or thiourea in the presence of a catalytic amount of ascorbic acid (5 mol %) is described. The reaction proceeded efficiently under solvent-free conditions at 80 °C to afford the desired products in moderate to good yields.

First application of hexaaquaaluminium(III) tetrafluoroborate as a mild, recyclable, non-hygroscopic acid catalyst in organic synthesis: a simple and efficient protocol for the multigram scale synthesis of 3,4-dihydropyrimidinones by Biginelli reaction

Abstract For the first time hexaaquaaluminium(III) tetrafluoroborate has been used as a mild acid catalyst in organic synthesis. A simple method of its preparation based on the reaction of aluminium triisopropoxide and tetrafluoroboric acid in isopropanol afforded catalyst of high purity and activity. The three-component Biginelli condensation of acetoacetate esters, urea and aldehydes catalyzed by 10 mol % of [Al(H2O)6](BF4)3 in refluxing acetonitrile afforded 3,4-dihydropyrimidonones in good to high yields on multigram scales. The tolerance to acid sensitive reactants such as thienyl and furyl carbaldehydes, applicability to sterically hindered β-ketoesters and simple recyclability without losing catalytic activity make this catalyst as good replacement to literature methods. The mechanism of the reaction includes formation of the so called ‘ureido-crotonate’ rather than corresponding acylimino intermediate as found with Bronsted type catalysts.

Synthesis of new thiazolopyrimidines proceeding from 4-aryl-substituted 3,4-dihydropyrimidine-2(1H)-thiones

S _MeOH O Et3N Recently a number of publications grew considerably in the field of the chemistry of 4-aryl-3,4-dihydropyrimidin-2-ones and 4-aryl-3,4-dihydropyrimidine-2thione obtained by the three-component Biginelli condensation. It is not only due to their preparative accessibility but also to their wide range of pharmacological action (analgesic, antibacterial, antihypertension etc.) [1– 3]. The presence of several reactive nucleophilic centers also attracts attention to, e.g., 4-aryl-3,4-dihydropyrimidine-2-thiones for it makes possible carry out both versatile monoand dialkylation and acetylation [4, 5] and also very promising cyclizations. For instance, a method was described of a cyclization of 4-phenyl-3,4dihydropyrimidine-2(1H)-thione into 3,5-dihydro-2Hthiazolo[3,2-a]pyrimidine by boiling in DMF with chloroacetic acid [6]. Aiming to preparation from 4-aryl-substituted 3,4dihydropyrimidine-2(1H)-thiones of new 3,5-dihydro-2Hthiazolo[3,2-a]pyrimidines derivatives we developed a new preparatively more accessible method consisting in the boiling of toluene solutions of 4-aryl-substituted 3,4-dihydropyrimidine-2(1H)-thiones with a slight excess of methyl chloroacetate in the presence of triethylamine. It was expected that the reaction would stop at the formation of one of intermediate products of Sor N-alkylation whose formation depended on the solvents and acceptors used affecting apparently the process of thione-thiol transition [5]. However in 86–90% yield the target cyclization products IIa–IId were isolated. The formation of 3,5-dihydro-2H-thiazolo[3,2-a]pyrimidines IIa–IId was proved by the lack in the IR spectra of the absorption bands of amino groups and also the absence in the 1H NMR spectra of the signals of ester methoxy group and of N3H protons observed in the initial compounds and in their monoalkylated products as doublets in the region 9.2 ppm. The methylene protons CH2 of the thiazole ring turned out to be nonequivalent and thus appeared as a doublet of doublets with a coupling constant of 17.7 Hz.

N-Substituted benzoxazolyl ureas and thioureas in Biginelli reaction promoted by trifluoromethane sulfonic acid: An efficient and convenient synthesis of substituted benzoxazolyl 3,4-dihydropyrimidine (1 H)-(thio)-ones

Abstract An efficient synthesis of 3,4-dihydropyrimidine 2 (1 H )-ones and thiones (3,4-DHPMs) core was prepared by one-pot three-component Biginelli condensation and which was catalyzed by trifluoromethane sulfonic acid. The classical Bignelli reaction has been extended by the use of N-substituted benzoxazolyl semicarbazides and thiosemicarbazides and this method has the advantage of excellent yields and short reaction times.

Ionic liquid phase organic synthesis (IoLiPOS) methodology applied to the preparation of new 3,4-dihydropyrimidine-2(1H)-ones bearing bioisostere group in N-3 position

Abstract The ionic liquid phase organic synthesis (IoLiPOS) methodology has been used for the preparation of new 3,4-dihydropyrimidine-2(1H)-ones (DHPMs) bearing bioisostere group in N-3 position. For the 3,4-DHPMs substituted with various thiazole rings, the strategy involved a three-component Biginelli condensation in the second step with good yields (93–96%) from ILP bound acetoacetate, aromatic aldehyde (93–97% yield), and N-methyl urea followed by N-3 alkylation with chloroacetonitrile on the ILP bound 3,4-DHPM. Quantitative thionation of the nitrile group grafted on the ILP bound 3,4-DHPM was realized in MeOH with a 40–48% solution of ammonium sulfide and subsequent addition of α-bromoketone produced the thiazole ring appended on the 3,4-DHPM core. After cleavage by transesterification, the target compounds were obtained in good overall yields (47–50%). The efficiency of the IoLiPOS methodology was also demonstrated by the preparation of new 3,4-DHPMs with a tetrazole ring in N-3 position in 5 steps (53–61% overall yield) via the ILP bound 3-cyanomethyl 3,4-DHPM as key intermediate.

Rapid preparation of the mitotic kinesin Eg5 inhibitor monastrol using controlled microwave-assisted synthesis

We present here a protocol for the synthesis of the dihydropyrimidine (DHPM) derivative monastrol, which is known to be a specific mitotic kinesin Eg5 inhibitor. By applying controlled microwave heating under sealed-vessel conditions, the synthesis via the one-pot three-component Biginelli condensation can be performed in a shorter reaction time (30 min) compared with conventional heating methods that normally require several hours of reflux heating. For the purification of the crude target compound, two different methods are presented. The first protocol includes a simple precipitation/filtration step to provide monastrol in 76% isolated yield and high purity so that no recrystallization step is necessary. This can be ascribed to the microwave heating technology in which less side-product formation is typically one of the advantages. In an alternative purification step, column chromatography is performed, which provides the product in a slightly higher yield (86%). Monastrol synthesis can be conducted in approximately 2 h by employing the precipitation/filtration purification method.

A new approach to N-3 functionalized 3,4-dihydropyrimidine-2(1 H)-ones with 1,2,4-oxadiazole group as amide isostere via ionic liquid-phase technology

New N-3 functionalized 3,4-dihydropyrimidine-2(1H)-ones with 1,2,4-oxadiazole group as amide isostere were synthesized in six steps by ionic liquid-phase organic synthesis (IoLiPOS) methodology from ILP bound acetoacetate. The 3,4-dihydropyrimidine-2(1H)-one (3,4-DHPM) core was prepared in the first step by one-pot three-component Biginelli condensation followed by N-alkylation with chloroacetonitrile. Then the nitrile group appended on the 3,4-DHPM heterocycle was quantitatively transformed into amidoxime. Addition of aliphatic carboxylic anhydride or aromatic carboxylic acid to the amidoxime produced the expected 1,2,4-oxadiazole via the O-acylamidoxime intermediate grafted on the ILP bound 3,4-DHPM using two convergent methods. After cleavage by transesterification under mild conditions, the target compounds were obtained in good overall yields. The structures and the purities of the reaction intermediates in each step were verified easily by routine spectroscopic analysis.

An efficient synthesis of 4-substituted pyrazolyl-3,4-dihydropyrimidin-2(1H)-(thio)ones catalyzed by Mg(ClO 4) 2 under ultrasound irradiation

Abstract A simple method for the one-pot, three-component Biginelli condensation reaction of 5-chloro/phenoxyl-3-methyl-1-phenyl-4-formylpyrazole, a 1,3-dicarbonyl compound and urea or thiourea is described, employing Magnesium perchlorate [Mg(ClO 4 ) 2 ] as an efficient catalyst under ultrasound irradiation. A novel series of 4-substituted pyrazolyl-3,4-dihydropyrimidin-2(1H)-(thio)ones have been synthesized in moderate yields. The catalyst exhibited remarkable reactivity and can be recycled.

Highly Enantioseletive Biginelli Reaction Using a New Chiral Ytterbium Catalyst: Asymmetric Synthesis of Dihydropyrimidines

The highly enantioselective three-component Biginelli condensation catalyzed by a recyclable chiral ytterbium triflate with a novel hexadentate amine phenol ligand containing a pyridyl group has been developed. A wide range of optically active dihydropyrimidines with remarkable pharmacological interest was obtained in high yields with good to excellent enantioselectivities under mild conditions.

A Novel Cu-catalysed Three-component One-pot Synthesis of Dihydro­pyrimidin-2(1H)-ones Using Microwaves under Solvent-free Conditions

Cupric chloride dihydrate catalyzes the three-component Biginelli condensation between an aldehyde, a b-ketoester and urea or thiourea under microwave irradiation in the absence of solvent to yield various substituted 3,4-dihydropyrimidin-2(1H)-ones. The reaction is also effective when performed at room temperature in acetonitrile or at 100 °C in a solvent free approach, without any side reactions as observed by Biginelli and others.

Ionic liquids catalyzed Biginelli reaction under solvent-free conditions

Abstract 3,4-Dihydropyrimidin-2(1 H )-ones were synthesised in high yields by one-pot three-component Biginelli condensation in the presence of room temperature ionic liquids such as 1- n -butyl-3-methylimidazolium tetrafluoroborate (BMImBF 4 ) or hexafluorophosphorate (BMImPF 6 ) as catalysts under solvent-free and neutral conditions.

4-Aryldihydropyrimidines via the Biginelli Condensation: Aza-Analogs of Nifedipine-Type Calcium Channel Modulators

Recent results from the author's laboratory in the area of dihydropyrimidine chemistry are summarized.