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.     

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.     

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.     

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.     

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.     

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.     

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.     

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.     

TaBr5-catalyzed Biginelli reaction: one-pot synthesis of 3,4-dihydropyrimidin-2-(1H)-ones/thiones under solvent-free conditions

An efficient TaBr₅ (5-10 mol %)-catalyzed Biginelli reaction under solvent-free conditions for one-pot syntheses of 3,4-dihydropyrimidin-2-(1H)-ones (DHPMs) and their thione analogs is reported. The catalyst is stable at room temperature and employed under mild and environmentally friendly conditions.     

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.     

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.     

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.     

Rapid access to 3-(N-substituted)-aminoquinolin-2(1H)-ones using palladium-catalyzed C-N bond coupling reaction

A series of 3-(N-substituted)-aminoquinolin-2(1H)-ones have been synthesized by the palladium-catalyzed C-N coupling reaction starting from 3-bromoquinolin-2-(1H)-ones. Various nucleophiles including amines, amides, sulfonamides, carbamates and ureas have been used successfully. In all the cases, the reactions take place rapidly in 1,4-dioxane and proceed in good to excellent yield using palladium acetate as a catalyst, Xantphos as a ligand and Cs₂CO₃ as a base.     

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.     

Preparation of 2-aminosubstituted 3H-imidazo[4,5-c]quinolin-4(5H)-ones by palladium-assisted internal biaryl coupling reaction

Representatives of the 3H-imidazo[4,5-c]quinolin-4(5H)-ones have shown interesting biological activity. We have found 2-aminosubstituted 3H-imidazo[4,5-c]quinolin-4(5H)-one as a potent dipeptidyl peptidase 4 inhibitor. However effective synthesis of this nucleus with various substituents at the 6-9-positions has not been reported. We report herein the development of a novel and efficient synthesis of 2-aminosubstituted 3H-imidazo[4,5-c]quinolin-4(5H)-ones by palladium-assisted internal biaryl coupling reaction. Our optimization of the reaction conditions revealed that the most important factors for this reaction are use of silver carbonate as a base and high reaction temperature.     

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.     

Synthesis of 1H-indol-2-yl-(4-aryl)-quinolin-2(1H)-ones via Pd-catalyzed regioselective cross-coupling reaction and cyclization

An efficient and novel route for the synthesis of 1H-indol-2-yl-(4-aryl)-quinolin-2(1H)-one 1 via palladium-catalyzed site-selective cross-coupling reaction and cyclization process was described. Reaction of 3-bromo-4-trifloxy-quinolin-2(1H)-one 3 with arylboronic acid catalyzed by PdCl₂(PPh₃)₂ afforded 3-bromo-4-aryl-quinolin-2(1H)-one 4, which then reacted with 2-ethynylaniline 5 via Pd-catalyzed Sonogashira coupling and CuI-mediated cyclization leading to the desired 1H-indol-2-yl-(4-aryl)-quinolin-2(1H)-one 1 in good yields.     

The Thorpe-Ziegler-type reaction of 3-cyanopyridine-2(1H)-thiones with Biginelli 6-bromomethyl-3,4-dihydropyrimidin-2(1H)-ones: cascade assembling of tetra- and pentacyclic heterocyclic scaffolds

3-Cyanopyridine-2(1H)-thiones have been shown to react with Biginelli-type ethyl 4-aryl-6-(bromomethyl)-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylates upon heating in DMF giving rise to ethyl 4-aryl-6-{[(3-cyanopyridin-2-yl)thio]methyl}-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylates. The latter upon treatment with an excess of NaH or t-BuOK in boiling DMF undergo a tandem Thorpe-Ziegler-type heterocyclization to give pyrido[3″,2″:4′,5′]thieno[2′,3′:5,6]pyrido[4,3-d]pyrimidine derivatives in good yields. Selected compounds were tested for antibacterial and antifungal activity.     

Isoquinolin-1(2H)-ones and 1,6-naphthyridin-5(6H)-ones by an N-acylation-SNAr sequence

A new synthesis of 2,3-dialkyl-4-carbomethoxyisoquinolin-1(2H)-ones and 6,7-dialkyl-8-carbomethoxy-1,6-naphthyridin-5(6H)-ones is reported. The process involves treatment of a β-enaminoester with 2-fluoro-5-nitrobenzoyl chloride, 2-fluorobenzoyl chloride or 2-chloronicotinoyl chloride followed by heating in the presence of base. The conversion, which proceeds by an N-acylation-S_NAr reaction sequence, affords 50–86% yields when R¹ is n-alkyl but ≤30% yields when R¹ is α-branched.