A Novel Conversion of 2, 4‐Diaryl‐2, 3‐dihydro‐1 H‐1, 5‐benzodiazepines into 2, 4‐Diaryl‐3 H‐1, 5‐benzodiazepines

A novel conversion of 2, 4‐diaryl‐2, 3‐dihydro‐1 H‐1, 5‐benzodiazepins into 2, 4‐diaryl‐3 H‐1, 5‐benzodiazepines by the reaction with m‐chloroperbenzoic acid (MCPBA) was reported.     

Isocyanide‐Based Three‐Component Synthesis of Highly Substituted 1,6‐Dihydro‐6,6‐dimethylpyrazine‐2,3‐dicarbonitrile, 3,4‐Dihydrobenzo[g]quinoxalin‐2‐amine,and 3,4‐Dihydro‐3,3‐dimethyl‐quinoxalin‐2‐amine Derivatives

A novel and efficient isocyanide‐based multicomponent reaction between alkyl or aryl isocyanides 1 , 2,3‐diaminomaleonitrile ( 2 ), naphthalene‐2,3‐diamines ( 6 ) or benzene‐1,2‐diamine ( 9 ), and 3‐oxopentanedioic acid ( 3 ) or Meldrum's acid ( 4 ) or ketones 7 was developed for the ecologic synthesis, at room temperature under mild conditions, of 1,6‐dihydropyrazine‐2,3‐dicarbonitriles 5a – 5f in H₂O without using any catalyst, and of 3,4‐dihydrobenzo[g]quinoxalin‐2‐amine and 3,4‐dihydro‐3,3‐dimethyl‐quinoxalin‐2‐amine derivatives 8a – 8g and 10a – 10e , respectively, in the presence of a catalytic amount of p‐toluenesulfonic acid (TsOH) in EtOH, in good to excellent yields (Scheme 1).     

Synthesis of 2‐Thioxohydropyridine‐3‐Carbonitrile, 2‐Alkylthiopyridine,Thienopyridine, Pyrazolopyridine Derivatives and Their Theoretical Calculations

Cyanothioacetamide ( 1 ) reacted with but‐2‐enal ( 2 ) to give the corresponding 4‐methyl‐2‐sulfanylpyridine‐3‐carbonitrile ( 7 ) which was used as a good starting material for the synthesis of 1‐(3‐amino‐4‐methylthieno[2,3‐b]pyridin‐2‐yl)ethan‐1‐one ( 10 ), 3‐amino‐4‐methylthieno[2,3‐b]pyridine‐2‐carboxamide ( 15 ), 3‐amino‐4‐methylthieno[2,3‐b]pyridine‐2‐carboxylate ( 18 ) and 3‐amino‐4‐methylthieno[2,3‐b]pyridin‐2‐ylarylketone 25a‐c through its reactions with each of (1‐chloroacetone ( 8 ), 3‐chloropentane‐2,4‐dione ( 11 ) or ethyl 2‐chloro‐3‐oxo‐butanoate ( 19 )), 2‐chloroacetamide ( 13 ), ethyl 2‐chloroacetate ( 16 ) and 2‐bromo‐1‐arylethan‐ 1 ‐one 23a‐c , respectively. Considering the data of elemental analyses, IR, ¹HNMR, mass spectra and theoretical calculations, structures of the newly synthesized heterocyclic compounds were elucidated.     

Trans‐3,5‐dihydroperoxy‐3,5‐dimethyl‐1,2‐dioxalane/HBr System as New,Effective, Mild and Non‐toxic Reagent for Synthesis of 2‐Aryl‐1H‐benzothiazoles and 2‐Aryl‐1‐arylmethyl‐1H‐benzimidazoles

Ttrans‐3,5‐dihydroperoxy‐3,5‐dimethyl‐1,2‐dioxalane has been used as new, effective, solid, inexpensive and nontoxic oxidant for in situ generation of Br⁺ from HBr. This system has been applied as catalyst for synthesis of 2‐aryl‐1H‐benzothiazoles and 2‐aryl‐1‐arylmethyl‐1H‐benzimidazoles at room temperature in excellent yields and high purity.     

The First One‐Pot,Solvent‐Free,Microwave‐Accelerated,Three‐Component Synthesis of Spirothiazolidin‐4‐ones via Staudinger/Aza‐Wittig Coupling/Cyclization

An efficient and rapid, solvent‐free, microwave‐accelerated, one‐pot, three‐component protocol for the synthesis of spirothiazolidin‐4‐ones from organic azides is reported for the first time via Staudinger/aza‐Wittig coupling/cyclization. The solvent‐free approach overcomes the limitations associated with the prevailing solution‐phase methodologies in the case of amines. In particular, its novelty is that it eradicates the vital limitation, i.e., the accumulation of H₂O (by‐product), which is known to affect the yield and rate of the reaction, thus affording the spirothiazolidin‐4‐ones in short reaction times in excellent yields.     

Three‐component One‐pot Synthetic Route to Functionalized N‐Phenyl‐ and N,N‐(1,4‐phenylene)‐2‐alkylimino‐2,3‐dihydrothiazoles under Mild,Solvent‐ and Catalyst‐free Conditions

A simple and efficient one‐pot synthesis of alkyl‐2‐(alkylimino)‐4‐methyl‐3‐phenyl‐2,3‐dihydrothiazole‐5‐carboxylate and dialkyl 3,3′‐(1,4‐phenylene)‐bis‐[2‐(alkylimino)‐4‐methyl‐2,3‐dihydrothiazole‐5‐carboxylate] derivatives from the reaction of phenylisothiocyanate (and also 1,4‐phenylene diisothiocyanate) and primary alkylamines in the presence of 2‐chloro‐1,3‐dicarbonyl compounds is described. This new protocol has several advantages such as lack of necessity of the catalyst and solvent, good yields,mild conditions and short times for reaction.     

Synthesis of 4‐fluoroalkyl‐2H‐pyrido [1, 2‐a] pyrimidin‐2‐ones from 2, 2‐dihydropolyfluoroalkanoic acids

In the presence of N, N′‐dicyclohexylcarbodiimide, 2‐aminopyridine and its derivatives (2) condensed with 2, 2‐di‐hydropolyfluoroalkanoic adds (1) to give the corresponding amides. Subsequent intramolecular Micheal addition‐elimination reactions of the fluorine‐containing amides under basic conditions gave 4‐fluoroalkyl‐2H‐pyrido[1,2‐a]pyrimidin‐2‐ones (3) in good yields.     

UPLC‐HR‐MS/MS‐based determination study on the metabolism of four synthetic cannabinoids,ADB‐FUBICA,AB‐FUBICA,AB‐BICA and ADB‐BICA,by human liver microsomes

Since 2012, several cannabimimetic indazole and indole derivatives with valine amino acid amide residue have emerged in the illicit drug market, and have gradually replaced the old generations of synthetic cannabinoids (SCs) with naphthyl or adamantine groups. Among them, ADB‐FUBICA [N‐(1‐amino‐3,3‐dimethyl‐1‐oxobutan‐2‐yl)‐1‐(4‐fluorobenzyl)‐1H–indole‐3‐carboxamide], AB‐FUBICA [N‐(1‐amino‐3‐methyl‐1‐oxobutan‐2‐yl)‐1‐(4‐fluorobenzyl)‐1H–indole‐3‐carboxamide], AB‐BICA [N‐(1‐amino‐3‐methyl‐1‐oxobutan‐2‐yl)‐1‐benzyl‐1H‐indole‐3‐carboxamide] and ADB‐BICA [N‐(1‐amino‐3,3‐dimethyl‐1‐oxobutan‐2‐yl)‐1‐benzyl‐1H‐indole‐3‐carboxamide] were detected in China recently, but unfortunately no information about their in vitro human metabolism is available. Therefore, biomonitoring studies to screen their consumption lack any information about the potential biomarkers (e.g. metabolites) to target. To bridge this gap, we investigated their phase I metabolism by incubating with human liver microsomes, and the metabolites were identified by ultra‐performance liquid chromatography–high resolution–tandem mass spectrometry. Metabolites generated by N‐dealkylation and hydroxylation on the 1‐amino‐alkyl moiety were found to be predominant for all these four substances, and others which underwent hydroxylation, amide hydrolysis and dehydrogenation were also observed in our investigation. Based on our research, we recommend that the N‐dealkylation and hydroxylation metabolites are suitable and appropriate analytical markers for monitoring their intake.     

7‐Iodo‐5‐aza‐7‐deazaguanine ribonucleoside: crystal structure,physical properties,base‐pair stability and functionalization

The positional change of nitrogen‐7 of the RNA constituent guanosine to the bridgehead position‐5 leads to the base‐modified nucleoside 5‐aza‐7‐deazaguanosine. Contrary to guanosine, this molecule cannot form Hoogsteen base pairs and the Watson–Crick proton donor site N3—H becomes a proton‐acceptor site. This causes changes in nucleobase recognition in nucleic acids and has been used to construct stable `all‐purine' DNA and DNA with silver‐mediated base pairs. The present work reports the single‐crystal X‐ray structure of 7‐iodo‐5‐aza‐7‐deazaguanosine, C<sub>10</sub>H<sub>12</sub>IN<sub>5</sub>O<sub>5</sub> ( 1 ). The iodinated nucleoside shows an anti conformation at the glycosylic bond and an N conformation (O4′‐endo) for the ribose moiety, with an antiperiplanar orientation of the 5′‐hydroxy group. Crystal packing is controlled by interactions between nucleobase and sugar moieties. The 7‐iodo substituent forms a contact to oxygen‐2′ of the ribose moiety. Self‐pairing of the nucleobases does not take place. A Hirshfeld surface analysis of 1 highlights the contacts of the nucleobase and sugar moiety (O—H…O and N—H…O). The concept of pK‐value differences to evaluate base‐pair stability was applied to purine–purine base pairing and stable base pairs were predicted for the construction of `all‐purine' RNA. Furthermore, the 7‐iodo substituent of 1 was functionalized with benzofuran to detect motional constraints by fluorescence spectroscopy.     

Syntheses,antitumor activities,and antiangiogenesis of exo‐3,6‐epoxy‐1,2,3,6‐tetrahydrophthalimidoethanoyl‐ 5‐fluorouracil and its polymers

A new monomer, exo‐3,6‐epoxy‐1,2,3,6‐tetrahydrophthalimidoethanoyl‐5‐fluorouracil (ETFU), was synthesized by the reaction of exo‐3,6‐epoxy‐1,2,3,6‐tetrahydrophthalimidoethanoyl chloride (ETPC) and 5‐fluorouracil (5‐FU). The homopolymer of ETFU and its copolymers with acrylic acid (AA) and vinyl acetate (VAc) were prepared via photopolymerizations with 2,2‐dimethoxy‐2‐phenylacetophenone at 25 °C for 48 h. The structures of the synthesized monomer and polymers were identified by Fourier transform infrared, ¹H NMR, and ¹³C NMR spectroscopy and elemental analysis. The ETFU contents in poly(ETFU‐co‐AA) and poly(ETFU‐co‐VAc) were 26 mol % and 26 mol %, respectively. The number‐average molecular weights of the polymers, as determined by gel permeation chromatography, ranged from 5600 to 17,000. The in vitro cytotoxicities of 5‐FU and the synthesized samples against mouse mammary carcinoma and human histiocytic lymphoma cancer cell lines increased in the following order: ETFU > 5‐FU > poly(ETFU‐co‐AA) > poly(ETFU) > poly(ETFU‐co‐VAc). The in vivo antitumor activities of the polymers against Balb/C mice bearing the sarcoma 180 tumor cells were greater than those of 5‐FU at all doses tested. The inhibitions of the samples for SV40 DNA replication and antiangiogenesis were much greater than the inhibition of the control. © 2000 John Wiley & Sons, Inc. J Polym Sci A: Polym Chem 38: 4272–4281, 2000     

A Three‐Component One‐Pot Synthesis of Functionalized 5,5‐Dicyanocyclopenta‐1,3‐dienes from Arylidene­malononitriles,Activated Acetylenes,and KCN or KSCN

The reaction of dialkyl acetylenedicarboxylates with arylidenemalononitriles in the presence of KSCN in MeCN led to a mixture of dialkyl (3E)‐4‐aryl‐3‐(arylideneamino)‐5,5‐dicyanocyclopenta‐1,3‐diene‐1,2‐dicarboxylates and dialkyl 4‐aryl‐5‐cyanothiophene‐2,3‐dicarboxylates. When these reactions were performed in the presence of KCN, only the functionalized 5,5‐dicyanocyclopenta‐1,3‐dienes were obtained.     

Synthesis,Anticancer Evaluation,and Molecular Docking Studies of Novel (4‐Hydroxy‐2‐Thioxo‐3,4‐Dihydro‐2H‐[1,3]Thiazin‐6‐Yl)‐Chromen‐2‐Ones via a Multicomponent Approach

A series of coumarin‐substituted 1,3‐thiazine‐2‐thione derivatives ( 4a–m ) were synthesized via the multicomponent reaction of 3‐chloro‐3‐(2‐oxo‐2H‐chromen‐3‐yl)acrylaldehyde ( 1 ) carbon disulfide ( 2 ), and various primary amines ( 3 ), in presence of triethylamine and acetonitrile under stirring with good yields. The structures of all the synthesized compounds were characterized by analytical and spectral studies. Further, the synthesized compounds were screened for their in vitro antiproliferative activities against different cancer cell lines (A549, MDA‐MB‐231, MCF7, HeLa, and B16F10). Studies on the molecular interactions to recognize the hypothetical binding motif of the title compounds with the target Hsp 100 were carried out employing the Schrodinger software. Compounds 4a , 4c and 4m showed activity against all the five cell lines compared with the reference drug, and 4a exhibited the least IC₅₀ concentration of 7.56 ± 1.07 μg/mL against MCF7. This in vitro anticancer result was supported by in silico docking and in silico ADME (absorption, distribution, metabolism, and excretion) studies as well.     

Synthesis,Characterization and Crystal Structure of Some Novel 1‐Aryl‐2‐Thioxo‐2,3‐Dihydro‐1H‐Quinazolin‐4‐Ones

The base catalyzed intramolecular nucleophilic cyclization of 1‐(2‐haloaroyl)‐3‐aryl thioureas ( 1a‐i ), in the presence of DMF afforded the 1‐aryl‐2‐thioxo‐2,3‐dihydro‐1H‐quinazolin‐4‐ones ( 2a‐i ). The structures were confirmed by spectroscopic data, elemental analyses and in case of the 2c by single crystal X‐ray diffraction data. The mechanistic studies support an intramolecular nucleophilic substitution (S_NAr mechanism) rather than intramolecular aromatic substitution (S_RN1 mechanism).     

Simple,Efficient, and Catalyst‐Free Synthesis of (2‐Amino‐4H‐1‐benzopyran‐4‐yl)phosphonates in Polyethylene Glycol

Several (2‐amino‐4H‐1‐benzopyran‐4‐yl)phosphonates were efficiently synthesized by employing a multicomponent protocol involving a salicylaldehyde, malononitrile or ethyl cyanoacetate, and a trialkyl phosphite in polyethylene glycol. The latter could be recovered and re‐used. No additional solvent or catalyst was required. To the best of our knowledge, this is the first report of the one‐pot preparation of (2‐amino‐4H‐1‐benzopyran‐4‐yl)phosphonic acid dimethyl esters.     

1,2,3-三唑取代的1,4-二氢-4-氧代-1,5-二氮杂萘-3-羧酸衍生物的设计、合成与HIV整合酶抑制活性评价

一价铜催化端炔与叠氮化物的1, 3-环加成反应是一种快速构建小分子库并筛选其可能性质的的主要方法。本文报道了1,2,3-三唑取代的1,4-二氢-4-氧代-1,5-二氮杂萘-3-羧酸衍生物的设计与合成。在该类化合物中,疏水性与亲水性片段通过Click反应有效地连接。所设计化合物8和12的结构通过光谱手段进行了表征;其可能的HIV整合酶抑制活性也进行了筛选。     

Syntheses,Structures, and Electrochemical Properties of Two Bis‐triazole‐bis‐amide‐based Copper(II) Pyridine‐2,3‐dicarboxylate Coordination Polymers

Abstract. Two bis‐triazole‐bis‐amide‐based copper(II) pyridine‐2,3‐dicarboxylate coordination polymers (CPs), [Cu(2,3‐pydc)(dtb)_0.5(DMF)] · 2H₂O ( 1 ) and [Cu(2,3‐pydc)(dth)_0.5(DMF)] · 2H₂O ( 2 ) (2,3‐H₂pydc = pyridine‐2,3‐dicarboxylic acid, dtb = N,N′‐bis(4H‐1,2,4‐triazole)butanamide, and dth = N,N′‐bis(4H‐1,2,4‐triazole)hexanamide), were synthesized under solvothermal conditions. CPs 1 and 2 show similar two‐dimensional (2D) structures. In 1 , the 2,3‐pydc anions bridge the Cu^II ions into a one‐dimensional (1D) chain. Such 1D chains are linked by the dtb ligands to form a 2D layer. The adjacent 2D layers are extended into a three‐dimensional (3D) supramolecular architecture by hydrogen‐bonding interactions. The electrochemical properties of 1 and 2 were investigated.     

New Substituted 1‐Aryl‐4,4,6‐Trimethyl‐3,4‐Dihydropyrimidine‐2‐(1H)Thiones; A Metal‐Free and Solvent‐Free Synthesis,Characterization, and Lymphoid Tyrosine Phosphatase Inhibition Studies

A series of fourteen 3,4‐dihydropyrimidine‐2‐thiones ( 3a–n ) were synthesized by a green protocol, and their structures were characterized by spectroanalytical data. The compounds were obtained in high yields by efficient annulation of mesityl oxide (4‐methylpent‐3‐en‐2‐one) with anilines in the presence of potassium thiocyanate. The reaction is essentially metal‐catalyst‐ and solvent‐free, as mesityl oxide itself is the solvent as well as the reactant. The compounds were tested for their ability to inhibit the lymphoid tyrosine phosphatase PTPN22, and 5 of the 14 compounds exhibited IC₅₀ values in the mid‐micromolar range, with the most potent hit being the compound 3d , having a methoxy substituent at the 2‐position of the phenyl ring with an IC₅₀ = 18 ± 1 μM, and second most potent compound ( 3c ) with an IC₅₀ value of 45 ± 3 μM, having methyl substituents at both 2‐ and 4‐position of the phenyl ring.     

Synthesis of Endo,Endo‐2.9‐Dihydroxypentacyclo‐[8.4.0.03,8.04,14.07,11]Tetradeca‐5,12‐Diene

The title compound 30 was synthesized starting from the endo,syn,endo Diels‐Alder adduct 3a of hexahydro‐5,6,7,8‐tetrachloro‐9,9‐dimethoxy‐5,8‐methanonaphthalene‐1,4‐diol diacetate 6 and 1,2,3,4‐tetrachloro‐5,5‐dimethoxycyclopentadiene (TDCp) in six steps, keyed upon a symmetry‐allowed [4+4] photocyclization of decahydro‐11,12‐dioxo‐[1,4;5,8]dimethanoanthracene‐9,10‐diol diacetate 22. The epimeric monoacetate 26 related to 22 was also synthesized and their thermolysis and photolysis were investigated. Oxidation of diol 30 afforded hexacyclic bridged hemiacetal 31 as a result of transannular reaction. The structure of hemiacetal 31 was analyzed by single‐crystal X‐ray crystallography.     

The effect of temperature on the stability of compounds used as UV‐MALDI‐MS matrix: 2,5‐dihydroxybenzoic acid, 2,4,6‐trihydroxyacetophenone, α‐cyano‐4‐hydroxycinnamic acid, 3,5‐dimethoxy‐4‐hydroxycinnamic acid,nor‐harmane and harmane

The thermal stability of several commonly used crystalline matrix‐assisted ultraviolet laser desorption/ionization mass spectrometry (UV‐MALDI‐MS) matrices, 2,5‐dihydroxybenzoic acid (gentisic acid; GA), 2,4,6‐trihydroxyacetophenone (THA), α‐cyano‐4‐hydroxycinnamic acid (CHC), 3,5‐dimethoxy‐4‐hydroxycinnamic acid (sinapinic acid; SA), 9H‐pirido[3,4‐b]indole (nor‐harmane; nor‐Ho), 1‐methyl‐9H‐pirido[3,4‐b]indole (harmane; Ho), perchlorate of nor‐harmanonium ([nor‐Ho + H]⁺) and perchlorate of harmanonium ([Ho + H]⁺) was studied by heating them at their melting point and characterizing the remaining material by using different MS techniques [electron ionization mass spectrometry (EI‐MS), ultraviolet laserdesorption/ionization‐time‐of‐flight‐mass spectrometry (UV‐LDI‐TOF‐MS) and electrospray ionization‐time‐of‐flight‐mass spectrometry (ESI‐TOF‐MS)] as well as by thin layer chromatography analysis (TLC), electronic spectroscopy (UV‐absorption, fluorescence emission and excitation spectroscopy) and ¹H nuclear magnetic resonance spectroscopy (¹H‐NMR). In general, all compounds, except for CHC and SA, remained unchanged after fusion. CHC showed loss of CO₂, yielding the trans‐/cis‐4‐hydroxyphenylacrilonitrile mixture. This mixture was unambiguously characterized by MS and ¹H‐NMR spectroscopy, and its sublimation capability was demonstrated. These results explain the well‐known cluster formation, fading (vanishing) and further recovering of CHC when used as a matrix in UV‐MALDI‐MS. Commercial SA (SA 98%; trans‐SA/cis‐SA 5 : 1) showed mainly cis‐ to‐trans thermal isomerization and, with very poor yield, loss of CO₂, yielding (3′,5′‐dimethoxy‐4′‐hydroxyphenyl)‐1‐ethene as the decarboxilated product. These thermal conversions would not drastically affect its behavior as a UV‐MALDI matrix as happens in the case of CHC. Complementary studies of the photochemical stability of these matrices in solid state were also conducted. Copyright © 2008 John Wiley & Sons, Ltd.     

Synthesis,psychotropic and anticancer activity of 2,2‐dimethyl‐5‐[5′‐trialkylgermyl(silyl)‐2′‐hetarylidene]‐1,3‐dioxane‐4,6‐diones and their analogues

A series of 2,2‐dimethyl‐5‐(5′‐R‐hetarylidene)‐1,3‐dioxane‐4,6‐diones has been synthesized for examing a structure–activity relationship. Furyl and thienyl derivatives of Meldrum's acid possess neurotropic activity comprising both depriming and activating components. Comparison of acute toxicity of carbon, silicon and germanium analogues in the furan series of the compounds has demonstrated that the germanium derivative is 11.5 times less toxic than the carbon analogue and four times less toxic than the silicon derivative. 2,2‐Dimethyl‐5‐(5′‐triethylsilyl‐2′‐thenylidene)‐1,3‐dioxane‐4,6‐dione has moderate toxicity with the highest neurotropic and cytotoxic activity Copyright © 2003 John Wiley & Sons, Ltd.