Dimethyl Maleate Research Articles

Synthesis and design of supramolecular systems on the basis of tetrapyrrole macrocycles

Three new cyclophane-like calixarene-bis-porphyrins were synthesized, and their spectral properties were studied. Zinc complex of meso-(aminophenyl)-substituted calixarene-bis-porphyrin was found to form a stable 1:1 complex with dimethyl maleate in toluene. Its stability constant was determined by spectrophotometric titration.

Versatile Reactivity of the Germene Mes2GeCR2 toward Esters and Related Carbonyl Derivatives

Dimesitylfluorenylidenegermane, Mes2GeCR2 (1; Mes = 2,4,6-trimethylphenyl, CR2 = fluorenylidene), undergoes a [2 + 4] cycloaddition with the CCCO system of α-ethylenic esters such as methyl acrylate, dimethyl maleate and dimethyl fumarate, and diethyl fumarate, leading to the 1,2-oxagerma-5-cyclohexenes 2 and 3a,b, respectively. With diethyl oxalate, maleic anhydride, and cyclopent-2-ene-1,3-dione [2 + 2] cycloadditions are observed between the GeC double bond and the carbonyl function, with formation of 1,2-oxagermetanes 4−6, respectively. In the last case, a double [2 + 2] cycloaddition on both CO groups to form a tricyclic compound occurs with excess germene. Germene 1 reacts exclusively by an ene reaction with 2-methyl-1,3-pentadione to give the corresponding (germyloxy)cyclopentenone 8.

Synthesis of 4′-thionucleosides by 1,3-dipolar cycloadditions of the simplest thiocarbonyl ylide with alkenes bearing electron-withdrawing groups

Reactions of the simplest thiocarbonyl ylide with a variety of appropriate alkenes bearing electron-withdrawing substituents afforded the corresponding tetrahydrothiophenes, which could be easily elaborated into hydroxy and hydroxymethyl derivatives and then coupled with nucleobases to produce different 4′-thionucleosides. Particularly, α- and β-anomers of 1-[3,4-bis(hydroxymethyl)tetrahydro-2-thienyl]-thymine, -cytosine, -uracil and -fluorouracil were prepared with dimethyl fumarate and maleate, while 1-[4-(hydroxymethyl)tetrahydro-2-thienyl]- and 1-[4-(hydroxymethyl)tetrahydro-3-thienyl]-thymine, -cytosine, -uracil and -fluorouracil were prepared with a chiral α,β-unsaturated amide. These processes, simple in the experimental conditions and large availability of the starting materials, affording moderate to good yields of 4′-thionucleosides, represent an optimum alternative to those, already known, based on sugars, which often have the drawbacks of a higher number of steps and lower yields.

Easy and Stereoselective Synthesis of Cyclopropyl-Substituted Phosphonates via α-Chlorophosphonates

A facile stereoselective synthesis of cyclopropylphosphonates from the reaction of inexpensive α-chlorophosphonates with alkyl acrylates in the presence of sodium hydride is reported. Reaction with dimethyl maleate or fumarate also leads to cyclopropyl-substituted phosphonates. These reactions take place via Michael addition of acrylate, dimethyl maleate, or fumarate to the phosphonate carbanion, followed by expulsion of the chloride ion.

Effect of dimethylmaleate and phorone on glutathione content of Setaria cervi (Nematoda: Filarioidea) during in vitro incubation

Abstract Glutathione metabolism represents a prospective target for antifilarial drug design, and therefore, the alterations in glutathione (GSH) content of filarial worms by known mammalian GSH depletors i.e. dimethylmaleate (DMM) and phorone were first thought for investigation in model filarial worms Setaria cervi. The dose dependent GSH depletion was achieved when these worms were incubated at 37°C for 6 h in Hanks balanced salt solution with varying concentrations (10–250 μM) of DMM or phorone. During the short incubation period of 6 h, 250 μM of DMM and phorone declined more than 90 % of the GSH content of filarial worms.

Monofluoro-substituted azomethine ylides in fluorocarbene reactions with imines. Synthesis and transformations of monofluoroaziridines

N-Arylmethylene and N-benzhydrylideneamines react with fluorocarbene yielding fluoro-substituted azomethine ylides that undergo 1,3-π-cyclization into aziridines. Generation of fluoroylides in the presence of dipolarophiles (dimethyl maleate or dimethyl acetylenedicarboxylate) led to the reaction of 1,3-dipolar cycloaddition resulting in substituted 2-pyrrolines or pyrroles. 2-Fluoroaziridines, products of N-alkyl-N-benzhydrylideneamines 1,3-π-cyclization, in the presence of acid catalysts suffer isomerization into α-fluoroimines and 1,3-disubstituted indoles.

Asymmetric nitrone cycloadditions and their application to the synthesis of enantiopure pyrrolidine and pyrrolizidine derivatives

The cycloaddition reactions of a pair of chiral pyrroline- N-oxides derived from d-ribose with some typical mono and disubstituted alkenes are reported. In all these reactions with monosubstituted alkenes as well as with dimethyl maleate the preferred stereochemical outcome of the cycloaddition step comes from a 5- exo- anti transition state whereas stereoisomers from the 5- exo- syn transition state are also present as minor adducts. In the reaction with dimethyl fumarate the major adduct comes from a 4- exo- 5- endo- syn transition state. The further behavior of the obtained isoxazolidines upon reductive ring opening conditions depends on the kind and the geometry of the preexisting substituents and they are transformed to enantiomerically pure pyrrolidine or pyrrolizidinone derivatives.

1,3‐Dipolar Cycloaddition of Difluoro‐Substituted Azomethine Ylides. Synthesis and Transformations of 2‐Fluoro‐4,5‐dihydropyrroles.

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Cross-metathesis of dimethyl maleate and ethylene catalyzed by second generation ruthenium carbene complexes: B3LYP and MPW1K comparison study

The cross-metathesis of methyl maleate ( 2) and ethylene ( 10) using second generation Grubbs catalyst; (1,3-dimesityl-4,5-dihydroimidazol-2-ylidene) (PCy 3)CI 2Ru CHPh has been modeled at B3LYP/LACVP ∗ and MPW1K/LACVP ∗ levels of theory. Both models predict the metathesis of 2 to be viable kinetically and thermodynamically. The low reactivity of 2 in the metathesis reaction can be explained by the non-productive complex formation between carbonyl oxygen and Ru center that impedes the metathesis. Calculations show that the metathesis of ethylene is slightly endothermic process reflecting the relative stability of (1,3-dimesityl-4,5-dihydroimidazol-2-ylidene)CI 2Ru CHCOOMe catalyst due to additional stabilization of Ru center by sp 2 or sp 3 oxygen atoms. Although both models; B3LYP and MPW1K predict qualitatively similar picture of the metathesis; MPW1K functional seems to be superior to B3LYP in predicting the reaction energetics.

Effects of Ethanol and Acetaldehyde on Reactive Oxygen Species Production in Rat Hepatic Stellate Cells

Alcoholism is a common cause of cirrhosis. Hepatic stellate cells are the main source of collagen that ultimately leads to hepatic fibrosis and cirrhosis. Reactive oxygen species (ROS) enhance stellate cell activation and stimulate fibrogenesis. In this study, the acute effects of ethanol (ET) and acetaldehyde (AC) were determined on the production of ROS in isolated rat hepatic stellate cells. Rat stellate cells were isolated in situ by perfusion of the portal vein and cultured. Hydrogen peroxide (H(2)O(2)) was determined by luminol-derived chemiluminescence (CL), while superoxide anion (O(2*-)) production was assessed by the fluorescent probe hydroethidine. AC increased the formation of H(2)O(2) and O(2*-), and these effects were first detectable at AC concentrations of 5 and 10 microM, respectively, reaching a maximum at 50 to 75 microM. Reduction of glutathione (GSH) synthesis by 1-buthionine sulfoximide (BSO) or by GSH conjugation with dimethylmaleate (DEM) further enhanced the effects of AC on H(2)O(2) and O(2*-) formation, while N-acetylcysteine (NAC) decreased H(2)O(2) and eliminated the enhanced generation of O(2*-) caused by AC. Raloxifene, which inhibits O(2*-) production by NAD(P)H oxidase, reduced the effects of AC on H(2)O(2) and O(2*-) production. ET increased H(2)O(2) or O(2*-) only in the presence of BSO or DEM. This study shows that concentrations of AC, which occur in vivo after the ingestion of alcoholic beverages, result in the formation of ROS in rat hepatic stellate cells. The increases in ROS are known to activate stellate cells promoting fibrogenesis.

One-step hydrogenolysis of dimethyl maleate to tetrahydrofuran over chromium-modified Cu–B/γ-Al 2O 3 catalysts

The one-step gas-phase hydrogenolysis of dimethyl maleate to tetrahydrofuran has been investigated over a series of chromium-modified Cu–B/γ-Al 2O 3 catalysts prepared by the wetness impregnation–chemical reduction method. The characterizations reveal that copper in the Cu–B/γ-Al 2O 3 and chromium-modified Cu–B/γ-Al 2O 3 catalysts is solely in the metallic state, while chromium and boron are in the oxidized state. The addition of chromium not only reduces the crystallite size of metallic copper and increases the dispersion, but also promotes the intrinsic activity of the Cu–B/γ-Al 2O 3 catalyst. With the aid of the acidity of γ-Al 2O 3, a tetrahydrofuran yield of 94% is achieved over the 30% Cr–Cu–B/γ-Al 2O 3 catalyst under optimized reaction condition.

Diels–Alder reaction in protic ionic liquids

Protic imidazolium ionic liquids have been tested as reaction media in the Diels–Alder reaction between cyclopentadiene and two dienophiles (dimethyl maleate and methyl acrylate). Good conversions and endo/exo selectivities were achieved. The activation of the dienophile by hydrogen bonding with protic imidazolium ILs was demonstrated.

Reactions of three [c]annelated 2-aminothiophenes with electron poor olefins

A series of electron poor alkenes (maleic acid derivatives 3a-d, dimethyl maleate (4), ethyl acrylate (5a), phenyl vinyl sulfone (5b)) undergo (4+2)-cycloaddition to the thiophene moiety of benzopyrano(3,4-c)annelated 2-aminothiophenes 1a,b and 2. The primary adducts tend to release hydrogen sulfide, in this way the fused thiophene ring is replaced by a fused benzene ring bearing the amino group and any new substituents introduced by the dienophile. With maleic anhydride (3a) and dichloromaleic anhydride (3b) acylation of the amino group competes with the (4+2)-cycloaddition to the thiophene ring. The cycloaddition of the monosubstituted alkenes 5a,b follows a head-to-head regioselectivity as predicted from FMO-considerations.

Palladium-Assisted Regioselective Olefin Insertion into and β-Hydrogen Elimination of Hydrogen−Molybdenum and −Tungsten Bonds. Synthesis and Reactions of Heterodinuclear Hydrido Complexes of Palladium and Platinum with Molybdenum and Tungsten

Smooth reversible olefin insertion of ethyl acrylate, acrylonitrile, ethylene, dimethyl fumarate, and dimethyl maleate into MHCp(CO)3 (M = Mo (1a), W (1b)) has been catalyzed by Pd(PPh3)4 (4) or Pd(ethyl acrylate)(dppe) (8) at room temperature.

Biocatalytic Synthesis and Characterization of Copolymers Based on Poly(Ethylene Glycol) and Unsaturated Methyl Esters

Biocatalytic organic synthesis has proved to be a significant breakthrough in the area of polymer synthesis. Environmentally benign methodology and the use of mild reaction conditions are a hallmark of this approach. We have studied the biocatalytic synthesis of unsaturated polyesters under solvent‐less conditions by the condensation copolymerization of dimethyl fumarate and dimethyl maleate with polyethylene glycol (PEG) catalyzed by Novozyme‐435 (immobilized Candida antarctica lipase B). The structures of the resulting polymers, poly(ethylene glycol)‐co‐dimethyl fumarate and poly(ethylene glycol)‐co‐dimethyl maleate were studied from their 1H and 13C‐NMR spectra. The molecular weights of polymers were determined by size exclusion chromatography.

Domino 6π‐Electrocyclization/Diels–Alder Reactions on 1,6‐Disubstituted (E,Z,E)‐1,3,5‐Hexatrienes: Versatile Access to Highly Substituted Tri‐ and Tetracyclic Systems

The (E,Z,E)-1,3,5-hexatrienes 1a, 2a,b and 3b undergo 6pi-electrocyclization within 15-30 min upon heating to 200-215 degrees C. While the cyclohexene-annelated products 8a,b were stable, the analogous cyclopentene- and cycloheptene-annelated derivatives 7a and 9b easily underwent dehydrogenation to the corresponding aromatic compounds 10a and 12b during the work-up. The cyclohexadiene derivatives 8a,b were employed in thermal Diels-Alder reactions with 4-phenyl-3H-1,2,4-triazoline-3,5-dione (PTAD) and tetracyanoethylene (TCNE) to give the expected [4+2] cycloadducts 13a and 14a in good yields (60 and 78%). The initially formed cycloadduct of 8a and dimethyl acetylenedicarboxylate (DMAD) underwent a subsequent retro-Diels-Alder reaction to give the tetrahydronaphthalene 11b (47%). Under high pressure (10 kbar), the cycloadduct 15a was formed at room temperature and could be isolated in 44% yield. TCNE and N-phenylmaleimide with 8a under high pressure also led to the [4+2] cycloadducts 14a and 16a in good yields (60 and 77%). The 6pi-electrocyclization and subsequent Diels-Alder reaction, when performed as a one-pot domino process, provided direct access to Diels-Alder products of intermediately formed 6pi-electrocyclization products, for example from the 1,3,5-hexatrienes 1a,b, 2a,b, 3b and TCNE to the corresponding tricyclic products 17a,b, 14a,b, 18b in moderate to good yields (27-80%) depending on the nature of the alkoxycarbonyl group. Such sequential reactions with N-phenylmaleimide, maleic anhydride, dimethyl maleate and fumarodinitrile, the latter two under high pressure (10 kbar), worked as well to yield 16b (70%), 19a,b (19, 32%) and 20b (39%) and 21b (76%), respectively. With PTAD, however, the hexatrienes 2a,b reacted at ambient temperature without 6pi-electrocyclization to give the formal [4+2] cycloadducts 27a,b (48 and 46%), most probably via zwitterionic intermediates 23a,b and 25a,b.

The first example of the generation of azomethine ylides from a fluorocarbene: 1,3-cyclization and 1,3-dipolar cycloaddition

The reaction of Schiff bases with fluorocarbene, generated by reduction of dibromofluoromethane with active lead in the presence of Bu 4NBr under ultrasound irradiation, involves the formation of fluoro-substituted azomethine ylides which undergo cyclization into aziridines. 1,3-Cyclization of ylides, generated from N-arylimines of benzaldehyde, proceeds stereoselectively. When carrying out the reaction of Schiff bases with fluorocarbene in the presence of dimethyl maleate or dimethyl acetylenedicarboxylate, the products of dehydrofluorination of the primary adducts of the 1,3-dipolar cycloaddition of fluoro-substituted azomethine ylides to multiple bonds of dipolarophiles were obtained. In the case of the reaction of N-alkylimines of benzaldehyde the cycloaddition of ylides to dimethyl maleate completely suppressed the cyclization to aziridines.

1,3-Dipolar Cycloaddition of Difluoro-Substituted Azomethine Ylides. Synthesis and Transformations of 2-Fluoro-4,5-dihydropyrroles

2-Fluoro-4,5-dihydropyrrole-3,4-dicarboxylic acid derivatives were obtained by reaction of difluorocarbene with N-substituted ketone imines in the presence of fumaronitrile, maleonitrile, or dimethyl maleate. The reaction involves intermediate formation of azomethine ylides and their subsequent cycloaddition at the double bond. 11H-Dibenz[b,e]azepine and 3,4-dihydroisoquinolines react with difluorocarbene in the presence of fumaronitrile to give fluoro-substituted dibenzo[c,f]pyrrolo[1,2-a]azepine and pyrrolo[2,1-a]-isoquinoline derivatives. Treatment of 2-fluoro-4,5-dihydropyrrole-3,4-dicarbonitrile with amines and alkoxides affords the corresponding 2-amino- and 2-alkoxy derivatives, while its reactions with hydrazine hydrate and benzimidamide lead to formation of substituted pyrrolo[2,3-c]pyrazole and pyrrolo[2,3-d]-pyrimidine derivatives.

A Series of Hydrido(vinyl)iridium(III) Complexes That Are Thermodynamically More Stable than Their Olefin Iridium(I) Isomers

The reaction of the in situ generated cyclooctene iridium(I) derivative trans-[IrCl(C8H14)(PiPr3)2] with methyl vinyl ketone and other Michael systems RCHC(R‘)C(O)R‘ ‘ (R = H, Me, Ph, OMe; R‘ = H, Me, iPr; R‘ ‘ = H, Me, OMe, NH2, NMe2) resulted in the formation of the octahedral hydrido(vinyl)iridium(III) complexes [IrH(Cl){κ2(C,O)-C(R)C(R‘)C(R‘ ‘)O}(PiPr3)2] (2−13) with the vinyl ligand coordinated in a bidentate fashion. Treatment of trans-[IrCl(C8H14)(PiPr3)2] with methyl acrylate and either dimethyl fumarate or dimethyl maleate afforded the iridium(I) compounds trans-[IrCl(η2-RCHCHCO2Me)(PiPr3)2] (15, 16), which thermally or photochemically rearrange to the thermodynamically more stable iridium(III) isomers [IrH(Cl){κ2(C,O)-C(R)CHC(OMe)O}(PiPr3)2] (17, 18) by intramolecular C−H activation. The reaction of trans-[IrCl(C8H14)(PiPr3)2] with PhCHCHC(O)Ph gave a 1:1 mixture of the isomeric iridium(III) complexes [IrH(Cl){κ2(C,O)-C(Ph)CHC(Ph)O}(PiPr3)2] (19) and [IrH(Cl){κ2(C,O)-C6H4C(CHCHPh)O}(PiPr3)2] (20), which were separated by column chromatography. From trans-[IrCl(C8H14)(PiPr3)2] and acrylic acid both [IrH(Cl)-{κ2(C,O)-CHCHC(OH)O}(PiPr3)2] (21) and [IrH(Cl){κ2(O,O)-O2CCHCH2}(PiPr3)2] (22) were obtained. While the attempted hydrogenation of [IrH(Cl){κ2(C,O)-CHCHC(Me)O}(PiPr3)2] (2) with Pd/C as the catalyst led to the formation of [IrH2(Cl)(PiPr3)2] (24) and ethyl methyl ketone, the same starting material reacted with a solution of Cl2 in chloroform to give the dichloro vinyl complex [IrCl2{κ2(C,O)-CHC(Cl)C(Me)O}(PiPr3)2] (27) in virtually quantitative yield. The reaction of both 2 and [IrH(I){κ2(C,O)-CHCHC(Me)O}(PiPr3)2] (29) with CO afforded the carbonyl compounds [IrH(X){η1-(Z)-CHCHC(O)Me}(CO)(PiPr3)2] (31, 32) by partial opening of the chelate bond. Similarly to the Ir(PiPr3)2 counterparts, a series of (olefin)iridium(I) and hydrido(vinyl)iridium(III) compounds with Ir(PMetBu2)2 as a molecular unit were also prepared. Most remarkably, treatment of trans-[IrCl(η2-CH2CHC(O)H)(PMetBu2)2] (43) with in situ generated trans-[IrCl(C8H14)(PMetBu2)2] led to a clean cleavage of coordinated acrolein to CO and ethene and afforded a 1:1 mixture of trans-[IrCl(CO)(PMetBu2)2] (44) and trans-[IrCl(C2H4)(PMetBu2)2] (45), respectively.

Benzo[a]heptalenes from Heptaleno[1,2‐c]furans. Part I

AbstractIt is shown that heptaleno[1,2‐c]furans 1, which are available in two steps from heptalene‐4,5‐dicarboxylates by reduction and oxidative dehydrogenation of the corresponding vicinal dimethanols 2 with MnO2 or IBX (Scheme 4), react thermally in a Diels–Alder‐type [4+2] cycloaddition at the furan ring with a number of electron‐deficient dipolarophiles to yield the corresponding 1,4‐epoxybenzo[d]heptalenes (cf. Schemes 6, 15, 17, and 19). The thermal reaction between dimethyl acetylenedicarboxylate (ADM) and 1 leads, kinetically controlled, via a sterically less‐congested transition state (Fig. 4) to the formation of the (M*)‐configured 1,4‐dihydro‐1,4‐epoxybenzo[a]heptalenes, which undergo a cyclic double‐bond shift to the energetically more‐relaxed benzo[d]heptalenes 4 (Schemes 6 and 7). Most of the latter ones exhibit under thermal conditions epimerization at the axis of chirality, so that the (M*)‐ and (P*)‐stereoisomers are found in reaction mixtures. The (P*)‐configured forms of 4 are favored in thermal equilibration experiments, in agreement with AM1 calculations (Table 1). The relative (P*,1S*,4R*)‐ and (M*,1S*,4R*)‐configuration of the crystalline main stereoisomers of the benzo[d]heptalene‐2,3‐dicarboxylates 4a and 4f, respectively, was unequivocally established by an X‐ray crystal‐structure determination (Figs. 1 and 2). Acid‐induced rearrangement of 4 led to the formation of the corresponding 4‐hydroxybenzo[a]heptalene‐2,3‐dicarboxylates 5 in moderate‐to‐good yields (Schemes 8, 13, and 14). When the aromatization reaction is performed in the presence of trifluoroacetic acid (TFA), trifluoroacetates of type 6 and 13 (Schemes 8, 12, and 13) are also formed via deprotonation of the intermediate tropylium ions of type 7 (Scheme 11). Thermal reaction of 1 with dimethyl maleate gave the 2,3‐exo‐ and 2,3‐endo‐configured dicarboxylates 14 as mixtures of their (P*)‐ and (M*)‐epimers (Scheme 15). Treatment of these forms with lithium di(isopropyl)amide (LDA) at −70° gave the expected benzo[a]heptalene‐2,3‐dicarboxylates 15 in good yields (Scheme 16). Fumaronitrile reacted thermally also with 1 to the corresponding 2‐exo,3‐endo‐ and 2‐endo,3‐exo‐configured adducts 17, again as mixtures of their (P*)‐ and (M*)‐epimers (Scheme 17), which smoothly rearranged on heating in dimethoxyethane (DME) in the presence of Cs2CO3 to the benzo[a]heptalene‐2,3‐dicarbonitriles 18 (Scheme 18). Some cursory experiments demonstrated that hex‐3‐yne‐2,5‐dione and (E)/(Z)‐hexa‐3‐ene‐2,5‐dione undergo also the Diels–Alder‐type cycloaddition reaction with 1 (Scheme 19). The mixtures of the stereoisomers of the 2,3‐diacetyl‐1,4‐epoxytetrahydrobenzo[d]heptalenes 22 gave, on treatment with Cs2CO3 in DME at 80°, only mixtures of the regioisomeric inner aldol products 24 and 25 of the intermediately formed benzo[a]heptalenes 23 (Scheme 20).