Applying density functional theory on tautomerism in 3,4-dihydropyrimidin-2(1H)-ones

In the present study, the density functional theory (DFT) and Gibbs free energy calculations were performed to investigate the stability and tautomerism of C4-substituted-3,4-dihydropyrimidin-2(1H)-ones. Three different forms are possible for the ethyl 3,4-dihydropyrimidinones (ethyl 4-aryl-6-methyl-3,4-dihydropyrimidin-2(1H)-one-5-carboxylates, ethyl 4-aryl-2-hydroxy-6-methyl-1,4-dihydropyrimidine-5-carboxylates and ethyl 4-aryl-2-hydroxy-6-methyl-3,4-dihydropyrimidine-5-carboxylates) forms that the most stable form is ethyl 4-aryl-6-methyl-3,4-dihydropyrimidin-2 (1H)-one-5-carboxylates (keto-form). The obtained data showed that the substitution on the C4-substitut position can be effective on the equilibrium constant (K _eq).     

Synthesis of 2-(Pyrazol-1-yl)pyrimidine Derivatives by Cyclocondensation of Ethyl Acetoacetate (6-Methyl-4-oxo-3,4-dihydropyrimidin-2-yl)hydrazone with Aromatic Aldehydes

2-(4-Arylidene-3-methyl-5-oxo-4,5-dihydropyrazol-1-yl)-6-methylpyrimidin-4(3H)-ones were obtained by reaction of ethyl acetoacetate (6-methyl-4-oxo-3,4-dihydropyrimidin-2-yl)hydrazone with aromatic aldehydes. Successful cyclization occurs with aldehydes containing an auxochromic substituent in the para position.     

An unusual oxidation-dealkylation of 3,4-dihydropyrimidin-2(1H)-ones mediated by Co(NO3)2·6H2O/K2S2O8 in aqueous acetonitrile

4-Aryl-6-methyl-3,4-dihydropyrimidin-2(1H)-one (DHPM) scaffolds of Biginelli type were oxidized using Co(II)/S₂O₈²⁻ and the reaction afforded 6-unsubstituted pyrimidin-2(1H)-ones through an unprecedented dealkylation process. 4-Alkyl DHPMs under similar conditions afforded yet another unusual product, ethyl tetrahydropyrimidin-2,4(1H,3H)-dione-5-carboxylate.     

Synthesis and properties of ethyl 1-aryl-5-methyl-4-[1-(phenylhydrazinylidene)ethyl]-1<Emphasis Type="Italic">H</Emphasis>-pyrazole-3-carboxylates

Ethyl 1-aryl-4-acetyl-5-methyl-1H-pyrazole-3-carboxylates reacted with phenylhydrazine to give the corresponding hydrazones, ethyl 1-aryl-5-methyl-4-[1-(phenylhydrazinylidene)ethyl]-1H-pyrazole-3-carboxylates, which were converted to ethyl 1′-aryl-4-formyl-5′-methyl-1-phenyl-1H,1′H-3,4′-bipyrazole-3′-carboxylates by treatment with the Vilsmeier–Haack reagent. No indole derivatives were formed from the same hydrazones under the Fischer reaction conditions, but cyclization to 2-aryl-3,4-dimethyl-6-phenyl-2,6-dihydro-7H-pyrazolo[3,4-d]pyridazin-7-ones was observed.     

Reaction of sulfene and dichloroketene with open-chain N,N-disubstituted α-aminomethyleneketones. Synthesis of N,N-disubstituted 4-amino-3,4-dihydro-(5-methyl-6-phenyl)(5,6-diphenyl)-1,2-oxathiin 2,2-dioxides and of 4-amino-3-chloro-5-methyl-6-phenyl-2H-pyran-2-ones

Cycloaddition of sulfene to N,N-disubstituted 3-amino-2-methyl-1-phenyl-2-propen-1-ones (I) and 3-amino-1,2-diphenyl-2-propen-1-ones (II) occurred in good to moderate yield only in the case of aliphatic N-substitution to give 4-dialkylamino-3,4-dihydro-(5-methyl-6-phenyl)(5,6-diphenyl)-1,2-oxathiin 2,2-dioxides. Polar 1,4-cycloaddition of dichloroketene to I and II occurred only in the former case, giving in good to moderate yield N,N-disubstituted 4-amino-3,3-dichloro-3,4-dihydro-5-methyl-6-phenyl-2H-pyran-2-ones which were dehydrochlorinated with DBN to N,N-disubstituted 4-amino-3-chloro-5-methyl-6-phenyl-2H-pyran-2-ones. In the reaction of 2-methyl-1-phenyl-3-diphenylamino-2-propen-1-one with dichloroketene, a product was isolated which was proven by uv, ir, nmr and chemical evidence to be the dipolar ion VI, the supposed intermediate of the polar 1,4-cycloaddition of dichloroketene to N,N-disubstituted enaminones.     

Novel Biginelli-like three-component cyclocondensation reaction: efficient synthesis of 5-unsubstituted 3,4-dihydropyrimidin-2(1H)-ones

Iron (III) catalyzed the three-component Biginelli-like cyclocondensation reaction efficiently in acetonitrile to afford the corresponding 5-unsubstituted 3,4-dihydropyrimidin-2-(1H)-ones in high yields. The first Biginelli-like reactions of urea, aldehydes and ketones were furnished important new 3,4-dihydropyrimidin-2-(1H)-ones derivatives suitable for further study.     

Biginelli reaction starting directly from alcohols

An efficient of one-pot oxidative access to 3,4-dihydropyrimidin-2-(1H)-ones directly from aromatic alcohols under mild conditions is reported. The protocol involves 1-methylimidazolium hydrogen sulphate [Hmim]HSO₄ catalyzed oxidation of aromatic alcohols to aromatic aldehydes with NaNO₃ followed by their cyclocondensation with 1,3-dicarbonyl compounds and urea in the same reaction vessel at 80 °C within 2-4 h to afford 3,4-dihydropyrimidin-2-(1H)-ones in 55-97% overall yields. Thus, the present work utilizing alcohols instead of aldehyde in Biginelli reaction is a valid and green alternative to the classical synthesis of 3,4-dihydropyrimidin-2-(1H)-ones.     

Catalytic Potential of Pyrazolone Based Dioxidomolybdenum(VI) Complexes for Multicomponent Biginelli Reactions,Epoxidation of Olefins and Oxidative Bromination of Phenol Derivatives

Three different types of dioxidomolybdenum(VI) complexes of 4-acetyl-3-methyl-1-phenyl-5-pyrazolone (Hmp, I )), 3-methyl-1-phenyl-4-propionyl-5-pyrazolone (Hpp, II ), 4-butyryl-3-methyl-1-phenyl-5-pyrazolone (Hbutp, III ), and 4-isobutyryl-3-methyl-1-phenyl-5-pyrazolone (isobutp, IV ) have been isolated and characterized by various spectroscopic (FT-IR, UV/Vis, ¹H and ¹³C NMR) techniques, thermal analysis and single crystal X-ray analysis. These complexes adopt a distorted six-coordinate octahedral geometry where ligands act as bidentate, coordinating through the two O atoms. These complexes have been used as catalysts to explore a single pot multicomponent (benzaldehyde or its derivatives, urea/thiourea and ethyl acetoacetate/phenyl acetoacatate) Biginelli reaction producing biologically active 3,4-dihydropyrimidin-2-(1H)-one and 3,4-dihydropyrimidin-2-(1H)-thione based biomolecules under solvent-free conditions. Presence of H₂O₂ improves the yield of dihydropyrimidin-2-(1H)-one but it acts as poison for the later molecule. Epoxidation of internal and terminal alkenes mainly resulted in the formation of the corresponding epoxide. The catalytic oxidative bromination of thymol, a reaction facilitated by vanadium dependent haloperoxidases, resulted in the formation of three product namely 2-bromothymol, 4-bromothymol and 2,4-bromothymol. Other phenol derivatives have also been brominated effectively.     

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.     

ZrCl4 or ZrOCl2 under neat conditions: optimized green alternatives for the Biginelli reaction

Biginelli reactions were performed using either ZrCl₄ or ZrOCl₂·8H₂O as catalysts under neat conditions. Shorter reaction time than most of the classical methods was required when ZrCl₄ was used. In general, 3,4-dihydropyrimidin-2(1H)-ones and thioxo-3,4-dihydropyrimidin-2(1H)-ones were obtained under neat conditions in moderate to good yields and good purity without using harmful solvents in the work up.     

Synthesis and intramolecular transformations of 8-substituted 11-nitro-2-phenyl-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one diastereomers

The Biginelli reaction between 5-R-salicylic aldehyde (R = H, Me, and Br), α-nitroacetophenone, and urea affords 8-R-11-nitro-2-phenyl-5,6-dihydro-2H-2,6-methanobenzo-[g][1,3,5]oxadiazocin-4(3Н)-ones as mixtures of two diastereomers. The ratio of diastereomers depends on the catalyst (HCl) concentration in the reaction medium. In DMSO and DMF, the resulting compounds undergo oxadiazocine ring opening with establishment of a three-component equilibrium between 4-(2-hydroxy-5-R-phenyl)-5-nitro-6-phenyl-3,4-dihydropyrimidin-2(1Н)-one as the major component and diastereomeric methanobenzoxadiazocines as two minor components. Dilution of these solutions with water favors the oxa-Michael reaction resulting in the reverse transformation of dihydropyrimidinones into the corresponding starting diastereomers.     

Synthesis and tuberculocidic activity of some 4-arylaminomethylene-3-methyl-1-(pyrimidin-2-yl)pyrazol-5(4H)-ones

4-Arylaminomethylene-3-methyl-1-(6-methyl-4-oxo-1,4-dihydropyrimidin-2-yl)pyrazol-5(4H)-ones were synthesized by a three-component reaction between the 6-methyl-2-(3-methyl-5-oxo-2,5-dihydropyrazol-1-yl)pyrimidin-4(1H)-one, triethoxymethane, and an aromatic amine. These compounds were found to exist as aminomethyleneketones regardless of the electronic effects of substituents in the aromatic fragments. The resulting compounds showed pronounced tuberculocidic activity.     

Reaction of sulfene and dichloroketene with open-chain N,N-disubstituted α-aminomethyleneketones. Synthesis of 4-dialkylamino-3,4-dihydro-6-methyl-5-phenyl-1,2-oxathiin 2,2-dioxides and of N,N-disubstituted 4-amino-3-chloro-(6-methyl-5-phenyl)(6-benzyl)-2H-pyran-2-ones

Cycloaddition of sulfene to N,N-disubstituted 4-amino-3-phenyl-3-buten-2-ones (III) occurred in good yield only in the case of aliphatic N-substitution to give 4-dialkylamino-3,4-dihydro-6-methyl-5-phenyl-1,2-oxathiin 2,2-dioxides, whereas N,N-disubstituted 4-amino-1-phenyl-3-buten-2-ones (IV) did not react at all. Polar 1,4-cycloaddition of dichloroketene to III and IV occurred partly in the case of aromatic N-substitution, with the exception of the morpholino derivative IVd, giving in low yield N,N-disubstituted 4-amino-3,3-dichloro-3,4-dihydro-(6-methyl-5-phenyl)(6-benzyl)-2H-pyran-2-ones, which were dehydrochlorinated with DBN to the corresponding 4-amino-3-chloro-(6-methyl-5-phenyl)(6-benzyl)-2H-pyran-2-ones (VII) in good yield. In some cases of aliphatic N,N-disubstitution of III and IV, cycloaddition led directly to N,N-dialkyl derivatives VII in low yield.     

A simple and efficient synthesis of 3,4-dihydropyrimidin-2-(1H)-ones via Biginelli reaction catalyzed by nanomagnetic-supported sulfonic acid

Nanomagnetic-supported sulfonic acid is found to be a new, powerful, and reusable heterogeneous catalyst for the rapid synthesis of 3,4-dihydropyrimidin-2-(1H)-ones under conventional heating and microwave irradiation. This is the first example of combination of magnetic iron nanoparticles and microwave technique for the multicomponent reaction. The optical behaviors of the 3,4-dihydropyrimidin-2-(1H)-ones have been investigated by UV–vis spectroscopy.     

Substituent dependent regioselective synthesis of pyranopyrandiones and 1,2-teraryls from 2H-pyran-2-ones

The one-pot substituent-directed regioselective synthesis of 1,7-diaryl-2-methyl-4H,5H-pyrano[3,4-c]pyran-4,5-diones 3 as the major and 3,4-diaryl-2-methyl-6-methylsulfanylbenzonitriles 4 as the minor products has been delineated through ring transformation of suitably functionalized 2H-pyran-2-ones 1 with aryl acetones 2. Under similar reaction conditions, 6-aryl-4-sec-amino-2H-pyran-2-ones 5 led, regioselectively, to 3,4-diaryl-2-methyl-6-sec-aminobenzonitriles 6.     

Three-component condensation of α-nitroacetophenone,aromatic aldehydes,and methylurea

The three-component condensation of aromatic aldehydes, methylurea, and α-nitroacetophenone affords both N(1)-and N(3)-methyl-substituted 4,6-diaryl-5-nitro-3,4-dihydropyrimidin-2(1H)-ones depending on the structure of aldehyde. Intermediate 4,6-diaryl-4-hydroxy-3-methyl-5-nitrohexahydropyrimidin-2-ones and trisubstituted urea, which is the transformation product of the 4-hydroxy-3-methyl derivative in an acidic medium (retro-Henry reaction), were identified in the reaction mixtures. Dedicated to the memory of Academician N. N. Vorozhtsov on the 100th anniversary of his birth. Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 6, pp. 1141–1145, June, 2007.     

Synthesis of new polydentate tweezers ligands of amido-amine type

A series of new tweezers amido-amine ligands containing pyrrole, bipyrrole, and dipyrrolylmethane fragments were synthesized by reaction of 2-thioxothiazolidin-3-yl derivatives of α-pyrrolecarboxylic acids {5-[1-(5-carboxy-3-methyl-4-phenyl-1H-pyrrol-2-yl)-1-methylethyl]-4-methyl-3-phenyl-1H-pyrrole-2-carboxylic acid, 5-[(5-carboxy-3-methyl-4-phenyl-1H-pyrrol-2-yl)phenylmethyl]-4-methyl-3-phenyl-1H-pyrrole-2-carboxylic acid, 5-(5-carboxy-3-methyl-4-phenyl-1H-pyrrol-2-yl)-4-methyl-3-phenyl-1H-pyrrole-2-carboxylic acid, and 3,4-dimethyl-pyrrole-2,5-dicarboxylic acid} with o-phenylenediamine. All compounds obtained were characterized by elemental analysis, NMR and mass spectra.     

Über die Einwirkung von Ammoniak auf 5-Chlor-2-(N-methyl-jodmethansulfonamido)-benzophenon

Zusammenfassung 5-Chlor-2-(N-methyl-jodmethansulfonamido)-benzophenon (6 b) reagiert mit flüss. NH₃ zu 6-Chlor-4-hydroxy-1-methyl-4-phenyl-3,4-dihydro-1H-2,1-benzothiazin-2,2-dioxid (7), mit NH₃ in absol. Alkohol zu 6-Chlor-4-hydroxy-3-jod-1-methyl-4-phenyl-3,4-dihydro-1H-2,1-benzothiazin-2,2-dioxid (9). Der Mechanismus dieser Reaktionen wird diskutiert.

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The reaction of ammonia with 5-Chloro-2-(N-methyl-iodo-methanesulfonamido)-benzophenone

The reaction of 5-chloro-2-(N-methyl-jodomethanesulfon-amido)-benzophenone (6b) with liquid or absol. alcoholic ammonia leads to 6-chloro-4-hydroxy-1-methyl-4-phenyl-3,4-dihydro-1H-2,1-benzothiazine-2,2-dioxid (7) and 6-chloro-4-hydroxy-3-jodo-1-methyl-4-phenyl-3,4-dihydro-1H-2,1-benzothiazine-2,2-dioxid (9) resp. The mechanism of these reactions is discussed.

     

Cyanamide: a convenient building block to synthesize 4-aryl-2-cyanoimino-3,4-dihydro-1H-pyrimidine systems via a multicomponent reaction

4-Aryl-2-cyanoimino-3,4-dihydro-1H-pyrimidine derivatives were prepared using a multicomponent reaction by reacting a mixture of arene or heteroarenecarbaldehyde, 1,3-dicarbonyl compounds, and cyanamide under acidic conditions. The novelty of this approach derives from its use of cyanamide as a building block in a four-component Biginelli-type reaction. Varying the reaction conditions led to the formation of either N-(2-imino-6-phenyl-1,3,5-oxadiazinan-4-ylidene) cyanamide or 3,4-dihydropyrimidin-2(1H)-one. The type of heterocycle skeleton synthesized depends on the nature of the acid catalyst as well as the reaction conditions employed.     

Synthesis of new imidazo[1,2-a]pyrazolo[4,3-e]pyrimidin-4(6H)-one derivatives by iodocyclization of 6-alkenyl(alkynyl)-aminopyrazolo[3,4-d]pyrimidin-4(5H)-ones

6-Allyl(diallyl, prop-2-yn-1-yl)amino-1-R-pyrazolo[3,4-d]pyrimidin-4(5H)-ones reacted with iodine to give angularly fused 8-iodomethyl-7,8-dihydro-1-R-imidazo[1,2-a]pyrazolo[4,3-e]pyrimidin-4(6H)-ones which were treated with sodium acetate to obtain 8-methylidene-1-R-7,8-dihydroimidazo[1,2-a]pyrazolo-[4,3-e]pyrimidin-4(6H)-ones as a result of elimination of hydrogen iodide. 8-Methylidene-1-R-7,8-dihydroimidazo[1,2-a]pyrazolo[4,3-e]pyrimidin-4(6H)-ones were converted into 8-methyl-1-R-imidazo[1,2-a]pyrazolo-[4,3-e]pyrimidin-4(5H)-ones on heating to the melting point. 8-Methylidene-1-phenyl-7,8-dihydroimidazo-[1,2-a]pyrazolo[4,3-e]pyrimidin-4(6H)-one underwent isomerization into linearly fused 6-methyl-1-phenyl-1,8-dihydro-4H-imidazo[1,2-a]pyrazolo[3,4-d]pyrimidin-4-one on heating in sulfuric acid.