Diels-Alder reactions of pyridinone o-quinodimethanes generated from substituted sulfolene[3,4-c]pyridin-4(1H)-ones

1-Benzyl-3-(bromomethyl)-2(1H)-pyrazinone was converted to [3,4-c] sulfolene pyridinone 8a and further (1- or 3-) substituted derivatives having a dienophilic side chain on the sulfolene ring. Thermolytic extrusion of sulfur dioxide from o-QDM precursor 8 led to generation of 3,4-dimethylene-2(1H)-pyrazinone 9, which was reacted in situ with various dienophiles. Thermolysis of the substituted precursors resulted in intramolecular cycloaddition of the corresponding o-QDM intermediates     

Interaction of polyhedral boron hydride anions [B10H10] and [B12H12] with cyclic copper and silver 3,5-bis(trifluoromethyl)pyrazolate complexes

The interactions of cyclic trinuclear copper {[3,5-(CF₃)₂Pz]Cu}₃ and silver {[3,5-(CF₃)₂Pz]Ag}₃ complexes with polyhedral borate anions [B₁₀H₁₀]²⁻ and [B₁₂H₁₂]²⁻ in solvents of low-polarity were studied using IR spectroscopy (190-290 K). Two types of complexes were found in solution: {[((3,5-CF₃)₂PzM)₃][B_nH_n]}²⁻ and {[((3,5-CF₃)₂PzM)₃]₂[B_nH_n]}²⁻ (M = Ag, Cu; n = 10, 12). The stability constants of these complexes were determined from IR-spectra.     

Amide-based atropisomers in tachykinin NK1-receptor antagonists: synthesis and antagonistic activity of axially chiral N-benzylcarboxamide derivatives of 2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocin-6-one

A series of novel N-benzylcarboxamide derivatives of bicyclic compounds, 3,4-dihydropyrido[3,2-f][1,4]oxazepin-5(2H)-one and 2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocin-6-one, were synthesized by cyclization of N-benzyl-2-chloro-N-(2-hydroxyethyl)- [and -(3-hydroxypropyl)-] nicotinamides, respectively. Atropisomerism was observed in 5-[3,5-bis(trifluoromethyl)benzyl]-7-phenyl-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocin-6-ones due to steric hindrance of the carboxamide moiety and restriction of its rotation. Cyclization of N-[3,5-bis(trifluoromethyl)benzyl]-2-chloro-N-[(2S)-3-hydroxy-2-methylpropyl]-5-methyl-4-phenylnicotinamide gave (3S)-5-[3,5-bis(trifluoromethyl)benzyl]-3,8-dimethyl-7-phenyl-2,3,4,5-tetrahydro-6H-pyrido[2,3b][1,5]oxazocin-6-one, which exists predominantly in the thermodynamically stable aR-conformer in CDCl₃. This compound showed excellent NK₁-antagonistic activity with IC₅₀ value (in vitro inhibition of [¹²⁵I]-Bolton-Hunter-substance P binding in human IM-9 cells) of 0.47 nM, which is ca. 200-fold more potent than that of its enantiomer, indicating that the atropisomer chirality affects NK₁-receptor recognition.     

Synthesis of highly functionalized 2(1H)-pyrazinone 3-carboxamide scaffolds

Synthesis of highly functionalized 2(1H)-pyrazinone 3-carboxamide derivatives is reported. A one-pot, two-step process including the base-mediated reaction of N,N-disubstituted aminoacetonitrile derivatives 18 with 3,5-dihalo-2(1H)-pyrazinones 1 afforded substituted aminoacetonitrile pyrazinone derivative 19, which on subsequent oxidation followed by transamidation of the resulting intermediate with primary or secondary amines gave the corresponding highly functionalized 2(1H)-pyrazinone 3-carboxamide derivatives 21.     

Fluorination of alcohols and diols with a novel fluorous deoxy-fluorination reagent

We prepared a novel fluorous deoxy-fluorination reagent N,N-diethyl-α,α-difluoro-[3,5-bis(1H,1H,2H,2H-perfluorodecyl)benzyl]amine (1b) from 3,5-diiodobenzoic acid (3b) via N,N-diethyl-3,5-bis(1H,1H,2H,2H-perfluorodecyl)benzamide (2b) in four steps and used it for the fluorination of alcohols and diols. After the fluorination reactions, the isolation of the products and recovery of 2b was performed by extraction with a fluorous/organic solvent system.     

Studies on pyrazines. 13 . Chlorination of 1-hydroxy-2(1H)-pyrazinones with phosphoryl chloride. Formation of 2,5-dichloro-3-phenylpyrazine from 1-hydroxy-3-phenyl-2(1H)-pyrazinone

The chlorination of 1-hydroxy-3-phenyl-2(1H)-pyrazinone with phosphoryl chloride proceeded to 5-chloro-3-phenyl-2(H)-pyrazinone or 2,5-dichloro-3-phenylpyrazine on heating to elevated temperatures. To define the mechanism of the novel formation, reactions of the parent or methyl-substituted 1-hydroxy-2(1H)-pyraz-inones with the same reagent were investigated.     

Synthesis and Structures of Silver(I) and Copper(I) 3,5-Dipentyl-1,2,4-Triazolates

The Ag(I) and Cu(I) complexes of 4-amino-3,5-dipentyl-4H-1,2,4-triazole (4-NH₂-3,5-(C₅H₁₁)₂tz) and 3,5-dipentyl-1H-1,2,4-triazole (3,5-(C₅H₁₁)₂tzH) have been synthesized and characterized. X-Ray analysis shows that {Ag₄[4-NH₂-3,5-(C₅H₁₁)₂tz]₆}(BF₄)₄ is a tetranuclear complex featuring an Ag₄tz₆ cluster; {Ag[3,5-(C₅H₁₁)₂tz]}_n exhibits a 3D structure of lvt-a topology; and {Cu₂[3,5-(C₅H₁₁)₂tz]Br}_n is a Cu₄Br₄-cluster based 3D complex with the dia topology.     

New routes for the synthesis of 3- and 5-substituted 2(1H)-pyrazinones

Various 3-(hetero)aryl, 3-alkyl and 3-alkenyl-2(1H)-pyrazinones were prepared by applying the Suzuki and Heck reaction methodology to 3,5-dichloro-2(1H)-pyrazinones. Furthermore, following hydrogenolysis of the 5-chloro substituent and regioselective 5-bromination, this palladium-catalysed cross-coupling approach could be extended to the synthesis of the analogous 5-substituted 2(1H)-pyrazinones.     

Electronic and steric effects of ligands as control elements for rhodium-catalyzed asymmetric hydrogenation

Electronic and steric effects in the rhodium diphosphinite catalyzed asymmetric hydrogenation were investigated. A series of electronically and sterically modified (S)-BINOL and (S)-H₈-BINOL ligands was synthesized and effects on the catalytic performance were studied. Phosphinite basicity was varied by using p-CH₃O, p-CH₃, p-H, p-CF₃, 3,5-(CH₃)₂, 3,5-(CF₃)₂ substituents on the diphenylphosphine moieties. In the hydrogenation of dimethyl itaconate and methyl (Z)-α-acetamido cinnamate an increase in enantioselectivity and activity was observed with increasing phosphine basicity.     

Alkylation of 3,5-dichloro-2(1H)-pyrazinones using malonate esters

An efficient base-promoted 3-alkylation of 3,5-dichloro-2(1H)-pyrazinones with various malonate esters is described. The method constitutes a simple example of a C-C bond forming process at the 3-position of the pyrazinone core allowing to attain 3-substituted pyrazinones in good to high yields. 3-Alkylation of 3,5-dichloro-2(1H)-pyrazinones with acetoacetic ester was accompanied by further retro-Claisen fragmentation.     

Insertion vs. site epimerization with singly-bridged and doubly-bridged metallocene polymerization catalysts

A statistical model has been employed to determine the unidirectional site epimerization probability, ε, during propylene polymerization with the following C₁-symmetric metallocene precatalysts activated with MAO (MAO = methylaluminoxane): doubly-bridged rac-(1,2-SiMe₂)₂{η⁵-C₅H₂-4-(CHMe(CMe₃))}{η⁵-C₅H-3,5-(CHMe₂)₂}ZrCl₂ (1) and (1,2-SiMe₂)₂{η⁵-C₅H₂-4-(1R,2S,5R-menthyl)}{η⁵-C₅H-3,5-(CHMe₂)₂}ZrCl₂ (2); and singly-bridged Me₂C(3-(2-adamantyl)-C₅H₃)(C₁₃H₈)ZrCl₂ (3) and Me₂Si(3-(2-adamantyl)-C₅H₃)(C₁₃H₈)ZrCl₂ (4). For 1/MAO a steep tacticity dependence on monomer concentration was found, as ε increased from 0.114 to 0.909 as [C₃H₆] decreased from 12.5 M to 0.5 M; similarly, ε increased for 2/MAO from 0.177 to 0.709. For 3/MAO, ε was moderately responsive to an increase in polymerization temperature, as ε increased from 0.000 to 0.485 from T_p = 0-90 °C ([C₃H₆] = 1.1 M). Similarly, ε increased for 4/MAO from 0.709 to 0.913 from T_p = 0-40 °C; at higher temperatures, bidirectional site epimerization was implicated.     

Chemistry of diphenyltetrafluorophosphazene: Reactions with dilithiated diols

Reaction of gem-diphenyltetrafluorophosphazene, [1,1-(C₆H₅)₂]P₃N₃F₄ (1) with LiO(CH₂)₃OLi resulted in the formation of four products, spiro-{3,3-[O(CH₂)₃O]}[1,1-(C₆H₅)₂]P₃N₃F₂ (2), ansa-{3,5-[O(CH₂)₃O]}[1,1-(C₆H₅)₂P₃N₃F₂] (3), bridged-[1,1-(C₆H₅)₂N₃P₃F₃][O(CH₂)₃O][1,1-(C₆H₅)₂N₃P₃F₃] (4) and dangling-[HO(CH₂)₃O][1,1-(C₆H₅)₂P₃N₃F₃] (5) derivatives of 1, among which compound 5 was found to be the major product. Reaction of 1 with the dilithiated ferrocene derived diol, FcCH₂P(S)(CH₂OLi)₂ resulted in the formation of two isomers of ansa substituted fluorophosphazenes namely endo-[1,1-(C₆H₅)₂]{3,5-[FcCH₂P(S)(CH₂O)₂]}P₃N₃F₂ (6) and exo-[1,1-(C₆H₅)₂]{3,5-[FcCH₂P(S)(CH₂O)₂]}P₃N₃F₂ (7). These were formed along with the spiro isomer [1,1-(C₆H₅)₂]{3,3-[FcCH₂P(S)(CH₂O)₂]}P₃N₃F₂ (8) the dangling derivative [1,1-(C₆H₅)₂P₃N₃F₃][OCH₂(FcCH₂)P(S)CH₂OH] (9) and the bridged compound [1,1-(C₆H₅)₂P₃N₃F₃][OCH₂(FcCH₂)P(S)CH₂O][1,1-(C₆H₅)₂P₃N₃F₃] (10). All compounds were separated by column chromatography and characterized by ¹H, ³¹P{¹H}, ¹⁹F NMR, mass spectra and elemental analysis. The spirocyclic compound 8 was also characterized by X-ray crystallography.     

Synthesis of imidazolidin-4-one and 1H-imidazo[2,1-a]isoindole-2,5(3H,9bH)-dione derivatives of primaquine: scope and limitations

The synthesis of imidazolidin-4-one derivatives of primaquine as potential antimalarial agents is described. The target compounds were synthesized in three steps: (i) condensation of (±)-primaquine with N^α-protected amino acids, (ii) removal of the N^α-protecting group, and (iii) reaction of the N-acylprimaquine with a carbonyl compound: acetone, three cyclic ketones and veratraldehyde. Using 2-formylbenzoic acid in the third step afforded 1H-imidazo[2,1-a]isoindole-2,5(3H,9bH)-diones. All products were isolated in good to excellent yields. Whereas imidazolidin-4-ones were formed as mixtures of all possible diastereomers in equal amounts, 1H-imidazo[2,1-a]isoindole-2,5(3H,9bH)-diones were produced in a stereoselective fashion. The compounds hydrolyse very slowly (t_1/2 5-30 d) in pH 7.4 buffer to release primaquine. These primaquine derivatives are being submitted to biological assays, and preliminary results of their antimalarial activity are quite encouraging.     

N-arylammonio- and N-pyridinium-substituted derivatives of dodecahydro-closo-dodecaborate(2-)

We report two methods for preparing N-arylammonio, N-pyridyl and N-arylamino dodecaborates: heating of the tetrabutylammonium salt of dodecahydro-closo-dodecaborate(2-) with aryl and pyridyl amines, or nucleophilic attack of [closo-B₁₂H₁₁NH₂]²⁻ on a strongly deactivated aromatic system. With aryl amines we obtained [1-closo-B₁₂H₁₁N(R¹)₂C₆H₅]⁻ (R¹ = H, CH₃). With 4-(dimethylamino)pyridine, [1-closo-(B₁₂H₁₁NC₅H₄)-4-N(CH₃)₂]⁻, with a bond between the boron and the pyridinium nitrogen, was obtained. A presumable mechanism for this kind of reactions is reported. By nucleophilic substitution, two products, [1-closo-(B₁₂H₁₁NHC₆H₃)-3,4-(CN)₂]²⁻ and [1-closo-(B₁₂H₁₁NHC₆H₂)-2-(NO₂)-4,5-(CN)₂]²⁻, were formed with 4-nitrophthalonitrile and 1-chloro-2,4-dinitrobenzene gave [1-closo-(B₁₂H₁₁NHC₆H₃)-2,4-(NO₂)₂]²⁻. For [1-closo-B₁₂H₁₁N(CH₃)₂C₆H₅]⁻ and [1-closo-(B₁₂H₁₁NHC₆H₃)-2,4-(NO₂)₂]²⁻ single crystal X-ray structures were obtained.     

Exploring the reactivity of an N-pyrazole, P-phosphine hybrid ligand with Cu(I), Ag(I) and Au(I) precursors

The reactivity of (3,5-dimethyl-1H-pyrazol-1-yl)ethyldiphenylphosphine (L) hybrid ligand against Cu(I), Ag(I) and Au(I) has been assayed and compounds [Cu(L)₂](PF₆) (1), [Ag(L)]₂(PF₆)₂·2C₂H₄Cl₂·2C₄H₁₀O (2) and [AuCl(L)]₂ (3) have been isolated and fully characterised. A fully characterisation by analytical and spectroscopic methods of 1-3 are presented and X-ray crystal structures of 1 and 2 are also reported. The similar data obtained between 2 and 3 permits to do a serious purpose of the structure of 3 in solid and solution.     

Tautomerism of aza cycles: I. Structure of 3(5)-butylsulfanyl-5(3)-methyl(phenyl)-1H-1,2,4-triazole tautomers in crystal. Preference of the 3-RA-5-RD-1H-tautomer of 3(5)-mono-and 3,5-disubstituted 1,2,4-triazoles

The X-ray diffraction study of potentially tautomeric 3(5)-butylsulfanyl-5(3)-methyl-1H-1,2,4-triazole and its 5(3)-phenyl-substituted analog showed that these compounds in crystal have the structure of 3-butylsulfanyl-5-methyl(phenyl)-1H-tautomers. Analysis of our experimental and published data indicated that 3(5)-monosubstituted 1,2,4-triazoles and 3,5-disubstituted derivatives having nonequivalent substituents in crystal as exist as a tautomer in which the electron-acceptor substituent (R_A) occupies the 3 position, while the electron-donor substituent (R_D) resides in the 5 position, i.e., as 3-R_A-5-R_D-1H-1,2,4-triazoles. Symmetric 3,5-disubstituted 1,2,4-triazoles could give rise to tautomeric equilibrium between the 1H-and 2H-structures even in crystal.     

4(And 5)-cyclopropylamino-5(and 4)halo-3(2H)pyridazinones. Formation and characterization of isomers

The reactions of 4,5-dihalo-3(2H)pyridazinones with ammonia and amines gave mixtures of 5-amino-4-halo- and 4-amino-5-halo-3(2H)pyridazinones separated by chromatography. Structures were elucidated by means of retention values (R_f) and confirmed by independent synthesis.     

Utilization of DmbNHNH2 in the synthesis of amino-substituted 4-((3,5-diamino-1H-pyrazol-4-yl)diazenyl)phenols

(2,4-Dimethoxybenzyl)hydrazine (DmbNHNH₂) was utilized in the synthesis of Dmb-protected 4-((3,5-diamino-1H-pyrazol-4-yl)diazenyl)phenols. This unambiguous protection of the pyrazole endocyclic nitrogen atom enabled the preparation of amino-substituted 4-((3,5-diamino-1H-pyrazol-4yl)diazenyl)phenols that were inaccessible through direct substitution. The Boc group could be selectively cleaved in the presence of the Dmb group.     

Reactivity studies of (η-arene)ruthenium dimeric complexes towards pyrazoles: isolation of amidines, bis pyrazoles and chloro bridged pyrazole complexes

The complex [(η⁶-p-cymene)Ru(μ-Cl)Cl]₂1 reacts with pyrazole ligands (3a-g) in acetonitrile to afford the amidine derivatives of the type [(η⁶-p-cymene)Ru(L)(3,5-HRR′pz)](BF4)₂ (4a-f), where L = {HNC(Me)3,5-RR′pz}; R, R′ = H (4a); H, CH₃ (4b); C₆H₅ (4c); CH₃, C₆H₅ (4d) OCH₃ (4e); and OC₂H₅ (4f), respectively. The ligand L is generated in situ through the condensation of 3,5-HRR′pz with acetonitrile under the influence of [(η⁶-p-cymene)RuCl₂]₂. The complex [(η⁶-C₆Me₆)Ru(μ-Cl)Cl]₂2 reacts with pyrazole ligands in acetonitrile to yield bis-pyrazole derivatives such as [(η⁶-C₆Me₆)Ru (3,5-HRR′pz)₂Cl](BF₄) (5a-b), where R, R′ = H (5a); H, CH₃ (5b), as well as dimeric complexes of pyrazole substituted chloro bridged derivatives [{(η⁶-C₆Me₆)Ru(μ-Cl) (3,5-HRR′pz)}₂](BF₄)₂ (5c-g), where R, R′ = CH₃ (5c); C₆H₅ (5d); CH₃, C₆H₅ (5e); OCH₃ (5f); and OC₂H₅ (5g), respectively. These complexes were characterized by FT-IR and FT-NMR spectroscopy as well as analytical data. The molecular structures¹ of representative complexes [(η⁶-C₆Me₆)Ru{3(5)-Hmpz}₂Cl]⁺5b, [(η⁶-C₆Me₆)Ru(μ-Cl)(3,5-Hdmpz)]₂²⁺5c and [(η⁶-C₆Me₆)Ru(μ-Cl){3(5)Me,5(3)Ph-Hpz}]₂²⁺5e were established by single crystal X-ray diffraction studies.     

Synthesis and characterization of copper(II) and cobalt(II) complexes with two new potentially hexadentate Schiff base ligands. X-ray crystal structure determination of one copper(II) complex

Two new potentially hexadentate N₂O₄ Schiff base ligands 2-((z)-(2-(2-(2-((z)-3,5-di-tert-butyl-2-hydroxybenzylideneamino) phenoxy) phenoxy) phenylimino) methyl)-4,6-di-tert-butylphenol [H₂L¹] and 2-((z)-(2-(2-(2-((z)-3,5-di-tert-butyl-2-hydroxybenzylideneamino) phenoxy)-5-tert-butylphenoxy) phenylimino) methyl)-4,6-di-tert-butylphenol [H₂L²] were prepared from the reaction of 3,5-di-tert-butyl-2-hydroxy benzaldehyde with 1,2-bis(2′-aminophenoxy)benzene or 1,2-bis(2′-aminophenoxy)-4-t-butylbenzene, respectively. From the direct reaction of ligands [H₂L¹] and [H₂L²] with copper(II) and cobalt(II) salts in methanolic solution and in the presence of N(Et)₃ the neutral [CuL¹], [CuL²], [CoL¹] and [CoL²] complexes were prepared. All complexes were characterized by IR spectra, elemental analysis, magnetic susceptibility, mass spectra, molar conductance (Λ_m), UV-Vis spectra and in the case of [CuL²] with X-ray diffraction. X-ray crystal structure of [CuL²] showed that the complex contains copper(II) in a distorted square planar environment of N₂O₂ donors. Three CH/π interactions were observed in the molecular structure of latter complex.