A new approach to N-3 functionalized 3,4-dihydropyrimidine-2(1H)-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.     

Diketene as an alternative substrate for a new Biginelli-like multicomponent reaction: one-pot synthesis of 5-carboxamide substituted 3,4-dihydropyrimidine-2(1H)ones

5-Carboxamide substituted 3,4-dihydropyrimidine-2(1H)one derivatives were synthesized in a simple and efficient method from the one-pot four-component reactions of an aliphatic or aromatic amine, diketene, an aromatic aldehyde and urea or thiourea in the presence of p-toluenesulfonic acid as a catalyst under mild reaction conditions at ambient temperature.     

Synthesis of 3,4-dihydropyrimidin-2(1H)-ones and 1,4-dihydropyridines using ammonium carbonate in water

Various known and new 3,4-dihydropyrimidin-2(1H)-ones and 1,4-dihydropyridines are prepared efficiently via Biginelli and Hantzsch reactions using ammonium carbonate in water. Competition between Biginelli and Hantzsch reactions is observed with pyridine carbaldehydes. Using this methodology, Hantzsch esters are synthesized in higher yields and purities than with other procedures without the use of a catalyst or an organic solvent.     

Synthesis of 3,4-dihydrobenzo[g]isoquinoline-1(2H)-ones and 3,4-dihydroisoquinoline-1(2H)-ones skeleton via intramolecular electrophilic cyclization

An original alternative approach to isoquinolines based on the installation of a benzene nucleus on a performed heterocyclic ring. Synthesis of 3,4-dihydrobenzo[g]isoquinoline-1(2H)-ones and 3,4-dihydroisoquinoline-1(2H)-ones via intramolecular electrophilic cyclization of 3,4-disubstituted lactams is reported.     

Propane phosphonic acid anhydride: a new promoter for the one-pot Biginelli synthesis of 3,4-dihydropyrimidin-2(1H)-ones

Propane phosphonic acid anhydride has been found to promote the Biginelli synthesis of 3,4-dihydropyrimidin-2(1H)-ones. The use of this agent is characterized by moderate costs, low toxicity and simple workup conditions.     

N1,N3-Diacyl-3,4-dihydropyrimidin-2(1H)-ones: neutral acyl group transfer reagents

Readily available N1,N3-diacyl-3,4-dihydropyrimidin-2(1H)-ones efficiently acylate ammonia, primary and secondary amines to furnish primary, secondary and tertiary amides in good to excellent yields. The wide applicability of the procedure is demonstrated by running the reactions in a neutral medium, easy isolation of products, recycling of the innocuous by-product and chemoselectivity of the transformation.     

An efficient bakers’ yeast catalyzed synthesis of 3,4-dihydropyrimidin-2-(1H)-ones

Bakers’ yeast (Saccharomyces cerevisiae) efficiently catalyzes the three-component Biginelli reaction of aldehydes, β-keto esters, and urea/thiourea to form 3,4-dihydropyrimidin-2-(1H)-ones in good to excellent yields.     

p-Sulfonic acid calixarenes as efficient and reusable organocatalysts for the synthesis of 3,4-dihydropyrimidin-2(1H)-ones/-thiones

A new and efficient methodology is proposed for obtaining 3,4-dihydropyrimidin-2(1H)-ones/-thiones through Biginelli reactions. It is based on the use of less than the stoichiometric amount of p-sulfonic acid calixarenes as organocatalysts. A number of aromatic aldehydes as well as urea or thiourea can be employed for successfully synthesizing the corresponding Biginelli adducts. The described methodology is devoid of metal-containing catalysts, which in turn is very attractive for safely producing 3,4-dihydropyrimidin-2-(1H)-ones/-thiones of pharmacological interest. In addition, the catalyst efficiency is not compromised after its successive use in reactions. This is the first report about the application of calixarenes as catalysts in the multicomponent Biginelli reaction.     

Palladium-catalyzed synthesis of 4-alkoxycarbonyl-3,4-dihydroisoquinolin-1(2H)-ones

Palladium-catalyzed intermolecular cyclocarbonylation of diethyl (2-iodoaryl)malonates with N-tosylimines produces 4-ethoxycarbonyl-3,4-dihydroisoquinolin-1(2H)-ones in moderate to good yields. This reaction is highly stereoselective. This protocol involves Mannich addition, and subsequent cyclocarbonylation.     

Cu(OTf)2: a reusable catalyst for high-yield synthesis of 3,4-dihydropyrimidin-2(1H)-ones

Copper(II) triflate catalyzes efficiently the three-component condensation reaction of an aldehyde, β-ketoester and urea in acetonitrile to afford the corresponding 3,4-dihydropyrimidin-2(1H)-ones in high yields. The catalyst exhibited remarkable reusable activity.     

New three-component cyclocondensation reaction: microwave-assisted one-pot synthesis of 5-unsubstituted-3,4-dihydropyrimidin-2(1H)-ones under solvent-free conditions

Sixteen 5-unsubstituted-3,4-dihydropyrimidin-2(1H)-ones have been synthesized by microwave-assisted Biginelli reactions in a short and concise manner employing ZnI₂ as a catalyst under solvent-free conditions. All products were identified by IR, NMR, elemental analysis and HRMS. The advantages of this novel protocol include the excellent yield, operational simplicity, short time and the avoidance of the use of organic solvents and expensive catalysts.     

Regioselective dehydrogenation of 3,4-dihydropyrimidin-2(1H)-ones mediated by ceric ammonium nitrate

Ceric ammonium nitrate (CAN) has been explored for the regioselective oxidation of 3,4-dihydropyrimidin-2(1H)-ones (DHPMs). Interestingly, we obtained ethyl 2,4-dioxo-6-phenyl-tetrahydropyrimidin-5-carboxylates as the major products during the oxidation of DHPMs by CAN/AcOH at 80 °C. The reaction afforded a mixture of products while employing CAN in organic solvents without additives. However, the regioselective dehydrogenated product, ethyl 6-methyl-4-aryl(alkyl)-pyrimidin-2(1H)-one-5-carboxylate was obtained by performing the reaction with NaHCO₃. The single crystal X-ray crystallography of ethyl 6-methyl-4-(2-phenyl)-pyrimidin-2(1H)-one-5-carboxylate revealed that the oxidized product existed in amidic form rather than aromatized enol form of pyrimidines. The efficiency of the present protocol enabled the synthesis of structurally diverse pyrimidines in moderate to good yields under milder reaction conditions.     

Access to 4-substituted 3,4-dihydroquinolin-2(1H)-ones by an unusual radical cyclisation of a secondary amide

A novel route to 3,4-dihydroquinolin-2(1H)-ones involving two radical addition steps is reported, starting from readily accessible xanthates and N-aryl-3-butenamides.     

Ionic liquid phase organic synthesis (IoLiPOS) methodology applied to the three component preparation of 2-thioxo tetrahydropyrimidin-4-(1H)-ones under microwave dielectric heating

An ionic liquid phase organic synthesis (IoLiPOS) has been developed for the preparation of 2-thioxo tetrahydropyrimidin-4(1H)-ones. Treatment of the starting poly(ethyleneglycol)ionic liquid phases (PEG_n-ILPs) 1 with acryloyl chloride 2 afforded a serie of (PEG_n)-ILPs bound acrylate 3 in quantitative yields. Michael addition of aliphatic primary amines 5 to the PEG₁-ILPs 3(a,d) allowed the preparation of β-aminoesters 6 in high yields. Addition of alkyl isothiocyanates 7 to 6 gave the corresponding thioureido esters 8 in the third step. The final cyclization-cleavage under microwave/solventless strategy provides, under basic conditions, the expected 2-thioxo tetrahydropyrimidin-4(1H)-ones 9 in high purity after flash chromatography. According to the IoLiPOS methodology, the NMR method was used to establish loading of all the PEG-ionic liquid phases intermediates.     

Synthesis of C2-functionalized pyrimidines from 3,4-dihydropyrimidin-2(1H)-ones by the Mitsunobu coupling reaction

The Biginelli 3,4-dihydropyrimidin-2(1H)-one was converted to various C2-multifunctionalized pyrimidines via the dehydrogenation and Mitsunobu reaction using amines, alcohols, phenols and carboxylic acids as nucleophiles. A possible mechanism was also proposed to rationalize the formation of products.     

Biginelli reaction in aqueous medium: a greener and sustainable approach to substituted 3,4-dihydropyrimidin-2(1H)-ones

An environmentally benign aqueous Biginelli protocol for the synthesis of substituted 3,4-dihydropyrimidin-2(1H)-ones using polystyrenesulfonic acid (PSSA) as a catalyst has been achieved. These microwave-assisted reactions proceed efficiently in water in the absence of organic solvent, with simple filtration as the product isolation step.     

Gallium(III) triflate-catalyzed one-pot selective synthesis of 2,3-dihydroquinazolin-4(1H)-ones and quinazolin-4(3H)-ones

A series of 2,3-dihydroquinazolin-4(1H)-ones and quinazolin-4(3H)-ones have been synthesized in good to excellent yields and high selectivity by one-pot reaction using isatoic anhydride, ammonium acetate (or amines), and aldehydes in ethanol or in DMSO under mild conditions, respectively. The reaction was efficiently promoted by 1 mol % Ga(OTf)₃ and the catalyst could be recovered easily after the reactions and reused without evident loss of reactivity.     

Efficient synthesis and fluorescence properties of highly functionalized 2-aryl-quinazolin-4(3H)-ones

Three different methodologies for the preparation of highly substituted 2-aryl-quinazolin-4(3H)-ones including short and high-yielding reaction sequences are described. The 2-aryl-substituent of most of the target compounds bears three functional groups. The fluorescence properties of these compounds are presented and potential correlations between structure and optical properties are discussed.     

Solvent-free microwave synthesis of 4-hydroxy-3-phenylquinolin-2(1H)-ones and variants using activated arylmalonates

The disclosure herein describes the rapid synthesis of 4-hydroxy-3-phenylquinolin-2(1H)-ones and variants via a solvent-free microwave cyclocondensation reaction using di-(2,4,6-trichlorophenyl)-2-phenylmalonate, which improves the general scope of this reaction.