2-氨基-4H-咪唑啉-4-酮衍生物的快速平行合成法

咪唑啉酮衍生物是一类具有良好生物活性和药理活性的杂环化合物 [1,2 ] ,尤其是一些 2 -氨基咪唑啉酮表现出良好的杀菌、抗炎及抗癌活性 [3 ,4 ] .从自然界如一些海洋生物中可分离得到含 2 -氨基咪唑啉酮结构的生物碱 [5,6] .最近 ,组合化学方法广泛地应用于有机合成 ,它包括固相合成法和液相合成法[7～ 9] .我们曾应用氮杂 Wittig反应制得 2 -氨基取代咪唑啉酮衍生物 ,部分化合物表现出一定的抑菌活性 [10 ,11] .本文进一步报道应用液相平行反应法快速合成 2 -氨基 - 4H-咪唑啉 - 4-酮衍生物 (4) .该方法应用烯基膦亚胺 1与苯基异氰酸酯的…     

A New Solution-phase Parallel Synthesis of 2-Alkylamino-3-aryl-5-phenylmethylene-3,5-dihydro-4H-imidazol-4-ones

IntroductionImidazolonesareimportantheterocyclesbearingfungici dal,anti inflammotoryandangiotensinIIantagonisticalactiv ities.1 4 Someof 2 alkylaminoimidazolonesexhibitgoodan tibacterialactivities,5whereasothersshowpotentialantiviralandantitumoractivities.6 Untilnow ,manyofthenewderiva tivesofimidazoloneshavebeensynthesizedtoevaluatetheirbiologicalandpharmaceuticalactivities .Recently ,combinatorialsynthesisoflibrariescontainingsmallorganicmoleculeshasbecomearapidevolvingareaofresearch .7,8…     

A Solution-Phase Parallel Synthesis of 5-Substituted 3,6-Dihydro-7H-1,2,3-triazolo[4,5-d]pyrimidin-7-ones

5‐Substituted 7H‐1,2,3‐triazolo[4,5‐d]pyrimidin‐7‐ones ( 4 ) were rapidly prepared by a solution‐phase parallel synthetic method, which includes aza‐Wittig reaction of iminophosphorane ( 1 ) with phenyl isocynate to give carbodiimide ( 2 ) and subsequent reaction of 2 with various amine and alcohols in the presence of catalytic amount of sodium alkoxide in a parallel fashion.     

A New Solution—phase Parallel Synthesis of 2—Alkyamino—3—aryl—5—phenylmethylene—3,5—dihydro—4H—imidazol—4—ones

Thirteen new 2-alkylaminoimidazolones(4) wre rapidly synthesized by a new solution-phase parallel synthetic method,which includes aza-Wittig reaction of iminophosphorane(1) with aromatic isocyanate to give carbodi-imide(2) and subsequent reaction of 2 with various aliphatic primary amine in a parallel fashion.The products were confirmed by ^1H NMR,MS,IR and X-ray crystallographic analysis.The unusual selectivity of the cyclization was probably due to the deometry of the guanidine intermediate.     

Syntheses of 1,3-Imidazoline-2-thione and 2-Phenylimino-1,3-thiazoline combinatorial libraries through different sequences of the same components

We have developed combinatorial libraries of new 1,3-imidazoline-2-thiones 5 and 2-phenylimino-1,3-thiazolines 7 by way of different reaction sequences of the same three components, gamma-chloroacetoacetanilides 1, amines 2, and isothiocyanates 3 in a parallel synthetic fashion. One of the building blocks, the gamma-chloroacetoacetanilides 1, was prepared by the sequential reaction of 4-methylene-oxetan-2-one (ketene dimer) with chlorine and various anilines. The condensation of 1 with amines gave dihydrofuran 4 intermediates that when reacted with 3 afforded the 1,3-imidazoline-2-thiones 5. On the other hand, reaction of 3 with 2 provided substituted thioureas 6 that were reacted with 1 to yield 2-phenylimino-1,3-thiazolines 7.     

Parallel solid-phase synthesis of 2-imino-4-oxo-1,3,5-triazino[1,2-a]benzimidazoles via tandem aza-Wittig/heterocumulene-mediated annulation reaction

The parallel synthesis of a large number of 2-imino-4-oxo-1,3,5-triazino[1,2-a]benzimidazole derivatives via a solid-phase 1,3,5-triazino-annulation reaction is described. The solid-phase approach involves the in situ generation of iminophosphorane derivatives derived from resin-bound 2-aminobenzimidazoles employing Mitsunobu conditions. The subsequent Aza-Wittig reaction of the iminophosphoranes with isocyanates leads to highly reactive carbodiimides, which undergo an intramolecular heterocyclization reaction to form tetrasubstituted 2-imino-4-oxo-1,3,5-triazino[1,2-a]benzimidazoles in high yields (74-94%) and good purity (>80%).     

Reaction path determination for quantum mechanical/molecular mechanical modeling of enzyme reactions by combining first order and second order "chain-of-replicas" methods

A two-step procedure for the determination of reaction paths in enzyme systems is presented. This procedure combines two chain-of-states methods: a quantum mechanical/molecular mechanical (QM/MM) implementation of the nudged elastic band (NEB) method and a second order parallel path optimizer method both recently developed in our laboratory. In the first step, a reaction path determination is performed with the NEB method, along with a restrained minimization procedure for the MM environment to obtain a first approximation to the reaction path. In the second step, the calculated path is refined with the parallel path optimizer method. By combining these two methods the reaction paths are determined accurately, and in addition, the number of path optimization iterations are significantly reduced. This procedure is tested by calculating both steps of the isomerization of 2-oxo-4-hexenedioate by 4-oxalocrotonate tautomerase, which have been previously determined by our group. The calculated paths agree with the previously reported results and we obtain a reduction of 45%-55% in the number of path optimization cycles.     

Substituent effects on the rate constants for the photo-Claisen rearrangement of allyl aryl ethers

The photochemistry of 11 substituted allyl 4-X- and 3-X-aryl ethers 3 (ArOCH2-CH=CH2) has been examined in both methanol and cyclohexane as solvents. The ethers react by the photo-Claisen rearrangement to give allyl substituted phenols as the major primary photoproducts, as expected from the well-established radical pair mechanism. The excited singlet state properties (absorption spectra, fluorescence spectra, fluorescence quantum yields, and singlet lifetimes) were compared with a parallel set of unreactive 4-X- and 3-X-anisoles 4. The excited-state properties of three substituted 4-X-aryl 4-(1-butenyl) ethers 14 (ArOCH2CH2-CH=CH2) were also examined. The model compounds 4 and the reactive allyl ethers 3 have essentially identical rate constants for the excited-state processes with the exception of, the rate constant for homolytic cleavage from S(1) of the allyl ethers to give the radical pair. The difference between the fluorescence quantum yields and/or singlet lifetimes for 3 and 4 were used to obtain values of for all of the allyl ethers. These values exhibit a large substituent effect, spanning almost 2 orders of magnitude with electron-donating groups (CH3O, CH3) accelerating the reaction and electron-withdrawing ones (CN, CF3) slowing it down. The parallel range of rate constants observed in both methanol and cyclohexane indicates that ion pairs are not important intermediates in these rearrangements. Quantum yields of reaction (Phi(r)) for several of the more reactive ethers demonstrate that neither these values nor rate constants of reaction derived from them are reliable measures of the actual excited-state process. In fact, the values are significantly lower than the ones, indicating that the radical pairs undergo recombination to generate starting material. Finally, the rate constants were found to parallel a trend for the change in bond dissociation energy (deltaBDE) for the O-C (allyl) bond of the allyl ethers, indicating that other possible substituent effects are of minor importance.     

Expedient parallel synthesis of 2-amino-4-heteroarylpyrimidines

[reaction: see text] An expedient synthesis of diverse 2-amino-4-heteroarylpyrimidines via a 2-chloropyrimidine intermediate is described. A series of potentially biologically active analogues have been synthesized in two parallel steps to afford focused arrays.     

Solution-phase parallel synthesis of a pyridinium pyrazol-3-olate inner salt library using a three-component reaction

We present here the discovery of a novel, versatile, multicomponent reaction leading to various 4-[4-(pyridinium-1-yl)-2,5-dioxo-2,5-dihydro-1H-pyrrol-3-yl]-2H-pyrazol-3-olate inner salts. The structure of the unusual zwitterionic inner salts was elucidated, and the scope of the novel reaction was investigated. After rapid optimization, the reaction was adapted to parallel synthesis, and an 800-membered compound library was produced.     

Liquid-phase combinatorial synthesis of alicyclic beta-lactams via Ugi four-component reaction

[reaction: see text] Alicyclic beta-lactams were successfully synthesized via a parallel liquid-phase Ugi four-center three-component reaction (U-4C-3CR), starting from alicyclic beta-amino acids such as cis-2-aminocyclohexanecarboxylic acid, cis-2-aminocyclopentanecarboxylic acid, 2,3-diexo-3-aminobicyclo[2.2.1]heptane-2-carboxylic acid and some of their partially unsaturated analogues. A six-membered mixture-based combinatorial library of beta-lactams was also generated.     

Reaction d'elimination-1,3 : Aciton du n-butyl lithium sur les iodométhyl-2 tosyloxy-1 cyclohexanes (ènes) cis et trans. Stéréochimie et mécanisme

The reaction of cis and rans 2-iodomethyl 1-tosyloxycyclohexanes and 4-enes with nBuLi was studied and found to be stereospecific, the products being respectively bicyclo(4.1.0)hexane (ene) cis and methylene cyclohexane (ène). A parallel is drawn between this reaction and alkaline deshydrohalogenation of cyclic 1,2-halohydrins; a reaction pathway is proposed.     

Base-pairing, tautomerism, and mismatch discrimination of 7-halogenated 7-deaza-2'-deoxyisoguanosine: oligonucleotide duplexes with parallel and antiparallel chain orientation

Oligonucleotides containing 2'-deoxyisoguanosine (1, iG(d)), 7-deaza-2'-deoxyisoguanosine (2, c(7)iG(d)), and its 7-halogenated derivatives 3 and 4 were synthesized on solid phase using the phosphoramidite building blocks 5-7. The hybridization properties of oligonucleotides were studied on duplexes with parallel and antiparallel chain orientation. It was found that the 7-halogenated nucleoside analogues 3 and 4 enhance the duplex stability significantly in both parallel (ps) and antiparallel (aps) DNA. Moreover, the halogenated nucleosides shift the tautomeric keto-enol equilibrium strongly toward the keto form, with K(TAUT) [keto]/[enol] approximately 10(4) coming close to that of 2'-deoxyguanosine (10(4)-10(5)), while the nonhalogenated 7-deaza-2'-deoxyisoguanosine 2 shows a K(TAUT) of around 2000 and the enol concentration of 1 is 10% in aqueous solution. Consequently, nucleosides 3 and 4 show a much better mismatch discrimination against dT than compound 1 or 2 in antiparallel as well as in parallel DNA. 3 and 4 are expected to increase the selectivity of base incorporation opposite to isoC(d) in the form of triphosphates or in the polymerase-catalyzed reaction in comparison to 1 or 2.     

A practical synthesis of 2,4(5)-diarylimidazoles from simple building blocks

A simple and efficient approach to selectively obtain 2,4(5)-diarylimidazoles suppressing formation of 2-aroyl-4(5)-arylimidazoles is described. The yield of each of the two products strongly depends on the reaction conditions employed. This reaction provides a simple method to prepare small libraries of biologically active compounds by parallel synthesis.     

Synthesis and structures of cooligo(lactone) macromonomers

Cooligo(lactone) macromonomers were prepared by cooligomerisation of (S,S)-3,6-dimethyl-1,4-dioxane-2,5-dione (L-lactide), 1-oxacyclohexane-2-one (δ-valerolactone) or 1-oxacycloheptane-2-one (ε-caprolactone), initiated by 2,2-bis[4-(2-hydroxy-3-methacryloyloxypropoxy)phenyl]-propane (BisGMA). Two different reaction ways were used for the synthesis: parallel reaction and step reaction of lactones and L-lactide. The macromonomers were characterised by differential scanning calorimetry (DSC), size exclusion chromatography (SEC), ¹H- and ¹³C-NMR spectroscopy and MALDI-TOF mass spectrometry. Cooligo(lactone) macromonomers prepared by parallel and by step reaction show different molecular structures resulting in different properties. Their glass transition temperatures depend on the molar ratio of lactide and lactone as well as on the degree of oligomerisation. Macromonomers with high amounts of L-lactide units are partially crystalline.     

Guest-dependent flexible coordination networks with fluorinated ligands

Guest-dependent flexible coordination networks are formed from 1,4-bis(4-pyridylmethyl)tetrafluorobenzene (bpf), 4,4'-bis(4-pyridylmethyl)octafluorobiphenyl (bpfb), 2,6-bis(4-pyridylmethyl)hexafluoronaphthalene (2,6-bpfn), and 2,7-bis(4-pyridylmethyl)hexafluoronaphthalene (2,7-bpfn) with Cd(NO3)2 in the presence of various organic compounds. The reaction of bpf affords one-dimensional cyclic chains, two-dimensional rhombus grid sheets, and three-dimensional diamond frameworks with threefold interpenetration. The reaction of bpfb mainly affords two-dimensional rhombus grid sheets with twofold parallel interpenetration. The reaction of 2,6-bpfn affords a one-dimensional ladder and two-dimensional rhombus grid, twisted grid, and herringbone sheets. The reaction of 2,7-bpfn affords two-dimensional rhombus grid sheets and grid sheets with dumbbell-shaped cavities. This diversity of network topologies is induced by interactions between the guest molecules and the flexible ligand frameworks.     

Parallel liquid-phase synthesis of N-substituted 6-aminosulfonyl-2-oxo-1,2-dihydroquinoline-4-carboxamide and 6-aminosulfonylquinoline-4-carboxamide derivatives

Two efficient strategies for solution-phase parallel synthesis of libraries of quinoline derivatives are described. The first synthetic pathway features the Pfitzinger reaction of isatin with diethyl malonate and sulfochlorination of the resulting 2-oxo-1,2-dihydroquinoline-4-carboxylate followed by generation of sulfonamide library. The second strategy employs the unusual behavior of 5-sulfamoylisatins in Pfitzinger reactions, which results in formation of 6-sulfamoyl-4-carboxyquinolines instead of the anticipated 2-oxo-1,2-dihydroquinoline structures. The obtained carboxylates appeared to be convenient synthetic intermediates for the generation of the corresponding carboxamide libraries. Using these reagents, the parallel solution-phase synthesis of more than 500 substituted quinoline and 2-oxo-1,2-dihydroquinoline derivatives has been accomplished on the 50-100-mg scale. Simple manual techniques for parallel reactions using special CombiSyn synthesizers were coupled with easy purification procedures to give high-purity final products. The scope and limitations of the developed approaches are discussed.     

Study of aromatic nucleophilic substitution with amines on nitrothiophenes in room-temperature ionic liquids: are the different effects on the behavior of para-like and ortho-like isomers on going from conventional solvents to room-temperature ionic liquids related to solvation effects?

The kinetics of the nucleophilic aromatic substitution of some 2-L-5-nitrothiophenes (para-like isomers) with three different amines (pyrrolidine, piperidine, and morpholine) were studied in three room-temperature ionic liquids ([bmim][BF4], [bmim][PF6], and [bm(2)im][BF4], where bmim = 1-butyl-3-methylimidazolium and bm(2)im = 1-butyl-2,3-dimethylimidazolium). To calculate thermodynamic parameters, a useful instrument to gain information concerning reagent-solvent interactions, the reaction was carried out over the temperature range 293-313 K. The reaction occurs faster in ionic liquids than in conventional solvents (methanol, benzene), a dependence of rate constants on amine concentration similar to that observed in methanol, suggesting a parallel behavior. The above reaction also was studied with 2-bromo-3-nitrothiophene, an ortho-like derivative able to give peculiar intramolecular interactions in the transition state, which are strongly affected by the reaction medium.     

Hammett analysis of photodecarbonylation in crystalline 1,3-diarylacetones

[reaction: see text] The relative quantum yields and chemical efficiencies of crystalline p,p'-disubstituted 1,3-diphenyl-2-propanones with 4-MeO, 4-Me, 4-F, 4-CF3, and 3,4-diMeO groups were determined by parallel irradiation of polycrystalline samples. Variations in quantum yields that span a factor of 4 are analyzed in terms of the effects of substituents on the stability of the benzylic radical. All solid-state reactions proceeded with 100% chemoselectivity and in >95% chemical yield.     

Synthesis of substituted thienopyrimidine-4-ones

The parallel solution-phase synthesis of more than 3000 substituted thienopyrimidin-4-ones has been accomplished. Key reactions include assembly of the 2-thioxopyrimidin-4-one ring by condensation of isomeric aminothiophenecarboxylates or their appropriate reactive derivatives (isothiocyanates or dithiocarbamates) with the corresponding isothiocyanates or amines. The libraries from libraries were then obtained in good yields and purities using solution-phase alkylation and acylation methodologies. Simple manual techniques for parallel reactions using special CombiSyn synthesizers were coupled with easy purification procedures (crystallization from the reaction mixtures) to give high-purity final products. The scope and limitations of the developed approach are discussed.