Synthesis of 4-unsubstituted dihydropyrimidines having acyl and alkoxycarbonyl groups at 5- and 6-positions by cyclization–elimination reactions using 1,3-diaza-1,3-butadienes

A synthetic method for novel 4-unsubstituted 2-phenyldihydropyrimidines having acyl and alkoxycarbonyl groups at the 5- and 6-positions was developed. The cyclization of 4-dimethylamino-1,3-diaza-1,3-butadiene having N-protecting groups (Boc, Cbz) with 1,2-disubstituted ethylenes, such as diethyl maleate, diethyl fumarate, (Z)-hex-3-ene-2,5-dione, (E)-1,4-diphenylbut-2-ene-1,4-dione, and unsymmetrical (E)-ethyl 4-oxo-4-phenylbut-2-enoate, following the elimination of a dimethylamino group proceeded smoothly, producing the corresponding dihydropyrimidines in good overall yield. The N-protecting group (Boc) could be easily removed to obtain N-unsubstituted dihydropyrimidines as a mixture of tautomers, and their tautomeric behavior was analyzed by ¹H NMR spectroscopy.     

Synthesis of coruscanones A and B,metabolites of <Emphasis Type="Italic">Piper coruscans</Emphasis>, and related compounds

Base-catalyzed rearrangements of both individual 4-(acylmethylidene)butenolides and their mixtures prepared by condensation of citraconic anhydride with various phosphoranes occur successfully only in the presence of 5.2% MeONa in MeOH (molar ratio MeONa: substrate ≤ 10: 1, room temperature, 1–2 h). Under these conditions, the yields of 2-cinnamoyl-4-methylcyclopent-4-ene-1,3-dione (coruscanone B) and 2-acetyl-4-methylcyclopent-4-ene-1,3-dione are 56 and 65%, respectively. With a considerable increase in the reaction temperature or the molar ratio MeONa: substrate, formal addition of MeOH to the C(4)=C(5) double bond of these triketones becomes an appreciable (or predominant) process. A reaction of coruscanone B with CH₂N₂ in ether gives coruscanone A as a ~3: 2 mixture of (Z)- and (E)-methyl enolates (43%); other products (10%) result from the expansion and aromatization of the five-membered ring of the triketone. The simplest analog of coruscanone B, 2-acetyl-4-methylcyclopent-4-ene-1,3-dione, reacts with CH₂N₂ in a similar way.     

Synthesis and photolysis of N-phthalimidoaziridines with electron-withdrawing substituents

Mono-, bi-, tetra-, and pentacyclic N-phthalimidoaziridines with electron-withdrawing substituents in the three-membered ring have been obtained by the oxidative addition of N-aminophthalimide to dimethyl fumarate, ethyl cinnamate, N-phenyl-and N-benzylmaleimide, and endotricyclo[6.2.1.0^2,7]undeca-4,9-diene-3,6-dione. Photolysis of 3-benzyl-6-phthalimido-3,6-diazabicyclo-[3.1.0]hexane-2,4-dione obtained in this way in the presence of dimethyl acetylenedicarboxylic acid (DMAD) gives in low yield the dimethyl ester of 3-benzyl-2,4-dioxo-8-phthalimido-3,8-diazabicyclo[3.2.1]oct-6-ene-6,7-dicarboxylic acid, the product of 1,3-dipolar cycloaddition to the N-phthalimidoazomethinylide formed as intermediate. However photolysis of this phthalimidoaziridine in the presence of other 1,3-dipolarophiles, like photolysis in the presence of DMAD of the remaining phalimidoaziridines, does not lead to a 1,3-dipolar cycloaddition product. __________ Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 9, pp. 1320–1328, September, 2006.     

Convenient synthesis of 5-benzyl-2,3,5-trichloro-4,4-dimethoxycyclopent-2-en-1-one and some its reactions

5-Benzyl-2,3,5-trichloro-4,4-dimethoxycyclopent-2-en-1-one was synthesized by reaction of 1,2,3,4-tetrachloro-5,5-dimethoxycyclopentadiene with benzyl alcohol in methylene chloride in the presence of powdered sodium hydroxide and benzyltrimethylammonium chloride as phase-transfer catalyst. Deprotection of the title compound gave 2-benzyl-2,4,5-trichlorocyclopent-4-ene-1,3-dione which was subjected to unusual intramolecular carbocyclization initiated by molecular iodine.     

Five-Membered 2,3-dioxoheterocycles: XCV. Recyclization of 4-benzoyl-5-phenylfuran-2,3-dione at the action of substituted 1,3,3-trimethyl-2-azaspiro[4.5]dec-1-enes. Crystal and molecular structure of substituted 5-(2-azaspiro[4.5]dec-1-ylidene)cyclopent-3-ene-1,2-dione

4-Benzoyl-5-phenylfuran-2,3-dione reacts with 2′,5′,5′-trimethyl-4′,5′-dihydro-4H-spiro[naphthalene-1,3′-pyrrol]-4-one and 8-(2-methoxy-5-methylphenyl)-1,3,3,9-tetramethyl-2-azaspiro[4.5]deca-1,7-dien-6-one with the formation of (Z)-3-benzoyl-5-(5′,5′-dimethyl-4-oxo-4H-spiro[naphthalene-1,3′-pyrrolidin]-2′-ylidene)-4-phenylcyclopent-3-ene-1,2-dione, whose structure was proved by XRD analysis, and of (Z)-3-benzoyl-5-{8-(2-methoxy-5-methylphenyl)-3,3,9-trimethyl-6-oxo-2-azaspiro[4.5]dec-7-en-1-ylidene}-4-phenylcyclopent-3-ene-1,2-dione.     

Cytotoxicity of novel cross-conjugated arylated cyclopentene-1,3-diones

Novel 2,4-dichloro-5-phenylcyclopent-4-ene-1,3-dione and 5-aryl-4-chlorocyclopent-4-ene-1,3-dione were synthesized by the Suzuki–Miyaura or Friedel–Crafts reactions of the di- and trichlorocyclopentenone monoketals and subsequent hydrolysis of the ketal function. Condensation of these diones with (hetero)aromatic aldehydes afforded multifunctional 1,3-cyclopentenediones that showed anticancer activity.Keywords: organochlorine compounds, cyclopentenones, ketals, Suzuki–Miyaura reaction, Friedel–Crafts reaction, Knoevenagel condensation, aldehydes, cross-conjugated cyclopentene-1,3-diones, cytotoxicity.     

Reactivity of 5-<Emphasis Type="Italic">endo</Emphasis>-hydroxy-4-azatricyclo[5.2.1.0<Superscript>2,6</Superscript>]dec-8-en-3-ones and their isomerization initiated by acids and bases

Study of isomerization of 5-endo-hydroxy-4-azatricyclo[5.2.1.0^2,6]dec-8-en-3-ones under the action of Lewis acids (MgBr₂, AlCl₃), CF₃COOH, and NaH showed that the optimum catalyst of the process was trifluoroacetic acid. In reaction of 4-benzyl-5-endo-hydroxy-4-azatricyclo-[5.2.1.0^2,6]dec-8-en-3-one with anhydrous AlCl₃ in benzene was unexpectedly isolated N-benzyl-3-(diphenylmethyl)bicyclo[2.2.1]hept-5-ene-2-carboxamide. A convenient method was developed for the preparation of 5-exo-alkoxy-4-alkyl(aryl)-4-azatricyclo[5.2.1.0^2,6]dec- 8-en-3-ones.     

Isomeric pyrazolo­[3,4-d]­pyrimidine-based mol­ecules: disappearance of dimerization due to interchanged substitutions

In 5-benzyl-1,7-di­methyl-4,5,6,7-tetra­hydro-1H-pyrazolo­[3,4-d]­pyrimidine-4,6-dione, C₁₄H₁₄N₄O₂, which crystallizes in space group P, weak intermolecular C—H⋯O hydrogen bonds generate dimers. The isomeric compound 1-benzyl-5,7-di­methyl-4,5,6,7-tetra­hydro-1H-pyrazolo­[3,4-d]­pyrimidine-4,6-dione, C₁₄H₁₄N₄O₂, crystallizes in space group P2₁/n, and shows no such dimerization. Instead, it exhibits C—H⋯π interactions with the phenyl ring. In both structures, the mol­ecules are linked by aromatic π–π-stacking interactions.     

Rigid Scaffolds: Synthesis of 2,6-Bridged Piperazines with Functional Groups in all three Bridges

The activity of pharmacologically active compounds can be increased by presenting a drug in a defined conformation, which fits exactly into the binding pocket of its target. Herein, the piperazine scaffold was conformationally restricted by substituted C₂- or C₃-bridges across the 2- and 6-position. At first, a three-step, one-pot procedure was developed to obtain reproducibly piperazine-2,6-diones with various substituents at the N-atoms in high yields. Three strategies for bridging of piperazine-2,6-diones were pursued: 1. The bicyclic mixed ketals 8-benzyl-6-ethoxy-3-(4-methoxybenzyl)-6-(trimethylsilyloxy)-3,8-diazabicyclo[3.2.1]octane-2,4-diones were prepared by Dieckmann analogous cyclization of 2-(3,5-dioxopiperazin-2-yl)acetates. 2. Stepwise allylation, hydroboration and oxidation of piperazine-2,6-diones led to 3-(3,5-dioxopiperazin-2-yl)propionaldehydes. Whereas reaction of such an aldehyde with base provided the bicyclic alcohol 9-benzyl-6-hydroxy-3-(4-methoxybenzyl)-3,9-diazabicyclo[3.3.1]nonane-2,4-dione in only 10 % yield, the corresponding sulfinylimines reacted with base to give N-(2,4-dioxo-3,9-diazabicyclo[3.3.1]nonan-6-yl)-2-methylpropane-2-sulfinamides in >66 % yield. 3. Transformation of a piperazine-2,6-dione with 1,4-dibromobut-2-ene and 3-halo-2-halomethylprop-1-enes provided 3,8-diazabicyclo[3.2.1]octane-2,4-dione and 3,9-diazabicyclo[3.3.1]nonane-2,4-dione with a vinyl group at the C₂- or a methylene group at the C₃-bridge, respectively. Since bridging via sulfinylimines and the one-pot bridging with 3-bromo-2-bromomethylprop-1-ene gave promising yields, these strategies will be exploited for the synthesis of novel receptor ligands bearing various substituents in a defined orientation at the carbon bridge     

Reduction of (1,3-diformylindenyl)cyclopentadienylruthenium derivatives

The reduction of the (1,3-diformylindenyl)cyclopentadienylruthenium derivatives {η⁵-1,3-(CHO)₂C₉H₅}RuCp (Cp = C₅H₅), {η⁵-1,3-(CHO)₂C₉H₅}RuCp* (Cp* = C₅Me₅), and {η⁵-1,3-(CHO)₂C₉H₅}RuCpF (Cp^F = C₅Me₄CF₃) with NaBH₄ or LiAlH₄ under mild conditions affords the [1,3-bis(hydroxymethyl)indenyl]cyclopentadienylruthenium complexes {η⁵-1,3-(CH₂OH)₂C₉H₅}RuCp, {η⁵-1,3-(CH₂OH)₂C₉H₅}RuCp*, and {η⁵-1,3-(CH₂OH)₂C₉H₅}-RuCp^F, respectively, in good yields.     

Molecular and polymeric uranyl and thorium hybrid materials featuring methyl substituted pyrazole dicarboxylates and heterocyclic 1,3-diketones

A series of seven novel f-element bearing hybrid materials have been prepared from either methyl substituted 3,4 and 4,5-pyrazoledicarboxylic acids, or heterocyclic 1,3- diketonate ligands using hydrothermal conditions. Compounds 1, [UO₂(C₆H₄N₂O₄)₂(H₂O)], and 3, [Th(C₆H₄N₂O₄)₄(H₂O)₅]·H₂O feature 1-Methyl-1H-pyrazole-3,4-dicarboxylate ligands (SVI-COOH 3,4), whereas 2, [UO₂(C₆H₄N₂O₄)₂(H₂O)], and 4, [Th(C₆H₅N₂O₄)(OH)(H₂O)₆]₂·2(C₆H₅N₂O₄)·3H₂O feature 1-Methyl-1H-pyrazole-4,5-dicarboxylate moieties (SVI-COOH 4,5). Compounds 5, [UO₂(C₁₃H₁₅N₄O₂)₂(H₂O)]·2H₂O and 6, [UO₂(C₁₁H₁₁N₄O₂)₂(H₂O)]·4.5H₂O feature 1,3-bis(4-N¹-methyl-pyrazolyl)propane-1,3-dione and 1,3-bis(4-N¹,3-dimethyl-pyrazolyl)propane-1,3-dione respectively, whereas the heterometallic 7, [UO₂(C₁₁H₁₁N₄O₂)₂(CuCl₂)(H₂O)]·2H₂O is formed by using 6 as a metalloligand starting material. Single crystal X-ray diffraction indicates that all coordination to either [UO₂]²⁺ or Th(IV) metal centers is through O-donation as anticipated. Room temperature, solid-state luminescence studies indicate characteristic uranyl emissive behavior for 1 and 2, whereas those for 5 and 6 are weak and poorly resolved.     

Condensation of 2-naphthylamine with aromatic aldehydes and substituted cyclohexane-1,3-diones

New 12-aryl(or hetaryl)-9-methyl(or 4-butoxyphenyl)-8,9,10,12-tetrahydro-7H-benzo[a]acridin-11-ones possessing two asymmetric carbon atoms (C⁹ and C¹²) were synthesized by condensation of 5-methyl-or 5-(4-butoxyphenyl)cyclohexane-1,3-dione with 2-naphthylamine and aromatic or heteroaromatic aldehydes. According to the ¹H NMR data, the products were isolated as mixtures of diastereoisomers.     

Synthese des 4α et 4β-deuterio 3β, 17β-dihydroxy androsta-5-ene

The synthesis of 4β and 4α-deuterio 3β, 17β-dihydroxyandrost-5-ene, based on the reduction of 6β-bromo-17β-hydroxyandrost-4-ene-3 one benzoate and of its deuterated homologue by LiAlH₄, is reported. This S_N2' reaction requires a syn relationship of entering and departing groups. The conditions for the synthesis of androst-5-ene-3,17-dione sterospecifically labelled at the 4 position are discussed.     

Reaction of Long-Chain Vanillyl Esters with CH-Acids and 2-Naphthylamine

The previously unknown 4-(alkyl-11-oxo-7,8,9,10,11,12-hexahydrobenzo[a]acridin-12-yl)- and 4-(alkyl-1,8-dioxo-2,3,4,5,6,7,8,9-octahydro-1H-xanthen-9-yl)-2-methoxyphenyl esters of aliphatic (C₅-C₇, C₁₂) carboxylic acids were synthesized via cascade heterocyclization of cyclohexane-1,3-dione and dimedone with 2-naphthylamine and long-chain vanillyl esters.     

Cyclization of vicinally substituted heterocyclic analogs of 3,4-bis(indol-1-yl)maleimide under the action of protic acids: a quantum chemical study

B3LYP/6-31G(d) density functional quantum chemical calculations of vicinally substituted bis(indol-1-yl)derivatives of 1,5-dihydropyrrol-2-one, furan-2,5-dione, cyclopent-4-ene-1,3-dione, cyclobut-3-ene-1,2-dione, and pyrrolidine-2,5-dione were carried out to study the effect of modification of the maleimide moiety in 3,4-bis(indol-1-yl)maleimides on the direction of intramolecular cyclization under the action of protic acids. Geometric parameters, charge distributions, energy characteristics, and frontier orbital energies of these compounds and the corresponding indoleninium cations were determined. Alternative protonation routes of 3,4-bis(indol-1-yl)-1,5-dihydropyrrol-2-one have been studied. Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 7, pp. 1348–1352, July, 2008.     

Five-membered 2,3-dioxo heterocycles: LXXV. Reaction of methyl 1-aryl-3-aroyl-4,5-dioxo-4,5-dihydro-1H-pyrrole-2-carboxylates with 1,3-diphenylguanidine. Crystalline and molecular structure of 9-Benzoyl-8-hydroxy-2-imino-6-(4-methylphenyl)-1,3-diphenyl-1,3,6-triazaspiro-[4.4]non-8-ene-4,7-dione

Methyl 1-aryl-3-aroyl-4,5-dioxo-4,5-dihydro-1H-pyrrole-2-carboxylates reacted with 1,3-diphenylguanidine to give the corresponding 6-aryl-9-aroyl-8-hydroxy-2-imino-1,3-diphenyl-1,3,6-triazaspiro[4.4]non-8-ene-4,7-diones. The molecular and crystalline structures of 9-benzoyl-8-hydroxy-2-imino-6-(4-methylphenyl)-1,3-diphenyl-1,3,6-triazaspiro[4.4]non-8-ene-4,7-dione were determined by X-ray analysis.     

Metal complexes of 2-aza-2-benzyl-5,10,15,20-tetraphenyl-21-carbaporphyrin: M(2-NCH2C6H5NCTPP) (M = Ni, Pd) and Mn(2-NCH2C6H5NCTPP)Br (NCTPP = N-confused 5,10,15,20-tetraphenyl porphyrinate)

The crystal structures of (2-aza-2-benzyl-5,10,15,20-tetraphenyl-21-carbaporphyrinato-N,N′,N″) nickel(II) methylene chloride solvate [Ni(2-NCH₂C₆H₅NCTPP); 4], (2-aza-2-benzyl-5,10,15,20-tetraphenyl-21-carbaporphyrinato-N,N′,N″) palladium(II) [Pd(2-NCH₂C₆H₅NCTPP); 5] and bromo(2-aza-2-benzyl-5,10,15,20-tetraphenyl-21-carbaporphyrinato-N,N′,N″) manganese(III) toluene solvate [Mn(2-NCH₂C₆H₅NCTPP)Br·C₆H₅CH₃; 3·C₆H₅CH₃] have been established. The coordination sphere around the Ni²⁺ ion in 4 (or Pd²⁺ ion in 5) is distorted square planar (DSP), whereas for Mn³⁺ in 3·C₆H₅CH₃, it is a square-based pyramid with the Br atom lying in the axial site. The g value of 11.34, measured from parallel polarization of the X-band EPR spectra at 4 K, is consistent with a high spin mononuclear manganese(III) centre (S = 2) in 3. The magnitude of the axial (D) zero-field splitting (ZFS) for the mononuclear Mn(III) centre in 3 was determined approximately to be 1.4 cm⁻¹ by paramagnetic susceptibility measurements and conventional EPR spectroscopy.     

Fast atom bombardment mass spectrometry of reaction products between C3O2 and stabilized phosphorus ylides

A fast atom bombardment (FAB) mass spectrometric study on the open-chain compound 1,3-bis(cyanomethylenetriphenylphosphorane)propane-1,3-dione and on the cyclic zwitterionic compounds 4-oxy-5-triphenylphosphonium-6-methyl-2-pyrone and 4-oxy-5-triphenylphosphonium-6-phenyl-2-pyrone, obtained by reaction of carbon suboxide, C₃O₂, with stabilized phosphorus ylides, Ph₃PCHX (X?CN, COMe, COPh), is described. The FAB mass spectrometric behaviour of these compounds is compared with that shown by tri-phenylphosphoranilideneketene, Ph₃P ? C ? C ? O, and by 4-hydroxy-6-methyl-2-pyrone, with the aid of metastable ion data and collision spectroscopy.     

Thermodynamics of Dissociation of <Emphasis Type="Italic">ortho</Emphasis>-Hydroxyphenylhydrazo-<Emphasis Type="Italic">β</Emphasis>-diketones and of Their Complexation with Copper(II) in Aqueous–Ethanol Solutions

The thermodynamics of dissociation of 3-(2-hydroxyphenylhydrazo)pentane-2,4-dione (H ₂ L ¹ ), 5,5-dimethyl-2-(2-hydroxyphenylhydrazo)cyclohexane-1,3-dione (H ₂ L ² ), 5,5-dimethyl-2-(2-hydroxy-4-nitrophenylhydrazo)cyclohexane-1,3-dione (H ₂ L ³ ), 1-ethoxy-2-(2-hydroxyphenylhydrazo)butane-1,3-dione (H ₂ L ⁴ ) and 1-ethoxy-2-(2-hydroxy-4-nitrophenylhydrazo)butane-1,3-dione (H ₂ L ⁵ ) and of their complexation with copper(II) was studied in aqueous–ethanol solutions by potentiometry and UV–vis spectrophotometry. It was found that the thermodynamic parameters of the proton dissociation in H₂L^1–5 and of their complexation with copper(II) depend on the substituents in the aromatic and β-diketone fragments of the molecules. Thus, the acidic properties of H₂L increase from H₂L¹ to H₂L⁵, reflecting the electron-acceptor character of the substituents, whereas all of the thermodynamic functions tend to decrease with increasing electron-withdrawing capacity of the substituents. The complexation of Cu(II) with H₂L^1–5 is exothermic, which is connected with the formation of two stable chelating cycles.     

(1,3-Diformylindenyl)cyclopentadienyl ruthenium derivatives

The reaction of [CpRu(CH₃CN)₃][PF₆], [Cp*RuCl] _n , and [Cp^FRuCl]n with 1,3-diformylindene results in the predominant formation of zwitter-ionic arene-cyclopentadienyl complexes {η⁶-1,3-(CHO)₂C₉H₅}RuCp (Cp = C₅H₅), {η⁶-1,3-(CHO)₂C₉H₅}RuCp* (Cp* = C₅Me₅), and {η⁶-1,3-(CHO)₂C₉H₅}RuCp^F (Cp^F = C₅Me₄CF₃), respectively. The ruthenocenes {η⁵-1,3-(CHO)₂C₉H₅}RuCp, {η⁵-1,3-(CHO)₂C₉H₅}RuCp*, and {η⁵-1,3-(CHO)₂C₉H₅}RuCpF were synthesized by the reaction of 1,3-diformylindenyl potassium with [CpRu(CH₃CN)₃][PF₆], [Cp*RuCl] _n , and [Cp^FRuCl] _n .