Synthesis and stereochemical studies of 2‐substituted thiazolidine‐4‐carboxamide derivatives

A series of new 2‐substituted thiazolidine‐4‐carboxamide derivatives which have potentially useful immunological properties, have been synthesized in a stereoselective manner by coupling 2‐subsituted thiazolidine‐4‐carboxylic acids with amines or amino esters. The structure of these compounds was established by combination of NMR methods and by X‐ray analysis.     

Microwave induced synthesis of the thiazolidine‐2,4‐dione motif and the efficient solvent free‐solid phase parallel syntheses of 5‐benzylidene‐thiazolidine‐2,4‐dione and 5‐benzylidene‐2‐thioxo‐thiazolidine‐4‐one compounds

Novel microwave induced method for the synthesis of thiazolidine‐2,4‐dione motif under solvent phase conditions is developed. Further we report an efficient, microwave assisted method for the parallel syntheses of biologically important 5‐benzylidene‐thiazolidine‐2,4‐dione and 5‐benzylidene‐2‐thioxothiazolidine‐4‐one compounds under solid‐phase and solvent‐free conditions. A comparative study between the developed microwave methods and the conventional methods is described. We have also illustrated the possible mechanism behind to address the reason why piperidine, acetic acid and silica gel enhanced the Knoevenagel condensation reaction.     

2-(对烷氧基苯甲酸酯基或对烷氧基苯丙烯酸酯基)-5-氧-2,5-二氢呋喃化合物的合成与液晶性质研究

Two series of p-alkoxybenzoates Ia-If and p-alkoxycinnamates IIa-IIf, each species beating one terminal furanone, have been synthesized and characterized by IR, ^13C NMR, ^1H NMR, MS spectra and elemental analysis. The mesogenic properties of both series of furanones have been studied by polarizing optical microscopy and differential scanning calorimetry （DSC）. The relationship between structures and mesogenic properties was discussed. The results show that the increased alkoxy chain length （C7-C12） and the bridging groups between the benzene ring and the furanone ring affected the mesomorphic properties greatly, and the two series of furanones might display monotropic or enantiotropic nematic （N） or semetic C （SmC） mesophases and different mesomorpic phase temperature ranges corresponding to different carbon chain length.     

Synthesis of an 4‐oxo‐1,4‐dihydropyridinomethylidene substituted 2‐indolinone

The (Z)‐3‐substituted 2‐indolinone 6 was prepared using the aldehydes 4 and 8 unknown up to now and 2‐indolinone.     

Synthesis and Antiproliferative Evaluation of 2′‐Arenesulfonyloxy‐5‐benzylidene‐thiazolidine‐2,4‐diones

A series of 2′‐arenesulfonyloxy‐5‐benzylidene‐thiazolidine‐2,4‐diones (TZDs) were synthesized and examined for their antiproliferative effects on a panel of carcinoma cell lines. Our results indicated that initial synthesis of 5‐[2′‐hydroxybenzylidene]‐2,4‐thiazolidinone (9) by Knoevenagel condensation followed by nucleophilic substitution with arylsulfonyl chlorides exhibited superior efficiency to the alternative synthetic route. Among tested compounds, only 8c and 8e showed significant antiproliferative activity against PC‐3 and BT474 cells with GI₅₀ values of 8.4 and 20.6 μM, respectively. SKHep cells displayed interesting structure‐activity relationships in response to TZD derivatives treatment. Alkyl group‐substituted TZD analogs such as 8a (4‐Me, GI₅₀, 9.4 μM) and 8k (4‐iso‐propyl, GI₅₀, 9.8 μM) revealed better antiproliferative activity than those with bulkier alkyl groups. On the other hand, halogen‐substituted TZD analogs 8c, 8h, and 8i showed better antiproliferative activity against H460 cell line. Together, the new synthesized TZD derivatives 8a , 8b , 8c , 8d , 8e , 8f , 8g , 8h , 8i , 8j , 8k , 8l , 8m , 8n , 8o , 8p exhibited appreciable antiproliferative activity worth for further study.     

Synthesis and Biological Screening of 2‐Substituted 5,6‐Dihydro‐5‐oxo‐ 4H‐1,3,4‐oxadiazine‐4‐propanenitriles and of Their Intermediates

To evaluate the effect of substituents on biological activities of electron‐rich N‐containing heterocycles, the variably 2‐substituted 5,6‐dihydro‐5‐oxo‐4H‐1,3,4‐oxadiazine‐4‐propanenitriles 26 – 33 were synthesized and evaluated for antibacterial, antifungal, and enzyme‐inhibition activities. The target compounds were obtained from alkyl 4‐ or 3‐hydroxy benzoates 1 and 2 , respectively, and from methyl indoleacetate 3 . The phenolic OH group of benzoates 1 and 2 were substituted with p‐toluenesulfonyl (→ 4 and 5 ), benzoyl (→ 6 and 7 ), and benzyl groups (→ 8 and 9 ) and then converted to 5,6‐dihydro‐5‐oxo‐4H‐1,3,4‐oxadiazine‐4‐propanenitriles. To establish structure‐activity relationships (SAR), a pharmacological screening of the intervening intermediates was also conducted, which revealed that the intermediate hydrazide 11 possesses significant antimicrobial and MAO‐A inhibiting properties and intermediates 12, 24, 28 , and 29 appreciable antifungal activities. Compound 7 inhibits α‐chymotrypsin.     

Synthesis and Crystal Structure of 4,7‐Diaryl‐5‐oxo‐4H‐benzo[b]pyran Derivatives

A green and convenient approach to the synthesis of a series of 4,7‐diaryl‐5‐oxo‐4H‐benzo[b]pyran derivatives from appropriate aromatic aldehydes and 5‐aryl‐1,3‐cyclohexanedione with malononitrile in the presence of dilute HCl as catalyst (30 mmol/L) is described. This method provides several advantages such as environmental friendliness, low cost, high yields, and simple work up procedure. The structures of all compounds were characterized by infrared (IR), mass spectrometry (MS), ¹H NMR, and elemental analysis. The crystal structure of trans/cis‐2‐amino‐3‐cyano‐7‐(4′‐methoxo‐phenyl)‐4‐phenyl‐5‐oxo‐4H‐benzo[b]pyran, g , was determined by single crystal X‐ray diffraction analysis. The crystal of compound g belongs to monoclinic with space group P 21/c, a = 8.477(3) nm, b = 18.948(6) nm, c = 24.915(7) nm, α = 90.00°, β = 107.388(11)°, γ= 90.00°, Z = 8, V = 3.819(2) nm³, R₁ = 0.0754, wR₂ = 0.2042.     

Synthesis of new 5‐acetyl(arylmethyliden)‐4‐thiazolidones

A new approach to the synthesis of new heterocyclic compounds with triazine and 4‐thiazolidone fragments in one molecule is developed. The synthesis methods comprise [2+3]‐cyclocondensation reactions essential in the preparative synthesis of 4‐thiazolidone derivatives. The reactions of S,N‐nucleophiles with C₂‐cyclization agents for the synthesis of a number of biologically active 2‐triazin‐4‐thiazolidones were investigated. The interaction of thiosemicarbazone of sym‐triazine with derivatives of α‐halogencarboxylic acids and maleic anhydride resulted in correspondent (2‐[2‐(4,6‐dichloro‐1,3,5‐triazin‐2‐yl)hydrazino]‐5‐(3,4,5‐ R‐p‐phenyl‐methyliden)‐1,3‐thiazol‐4‐ones obtained in the one‐step synthesis. © 2010 Wiley Periodicals, Inc. Heteroatom Chem 21:392–396, 2010; View this article online at wileyonlinelibrary.com . DOI 10.1002/hc.20631     

Synthesis and Antimicrobial Activity of Some New N‐substituted‐5‐arylidene‐thiazolidine‐2,4‐diones

A total of 17 new N‐substituted derivatives ( 2b , 2c , 2d , 2e , 2f , 2g , 2h , 2i , 2j , 2k and 3b , 3c , 3d , 3e , 3f , 3g , 3h ) of 5‐((2‐phenylthiazol‐4‐yl)methylene) thiazolidine‐2,4‐dione ( 2a ) and 5‐(2,6‐dichloro‐ benzylidene)thiazolidine‐2,4‐dione ( 3a ) were synthesized. The structural elucidation of the newly synthesized compounds was based on elemental analysis and spectroscopic data (MS, ¹H NMR, ¹³C NMR), and their antimicrobial activities were assessed in vitro against several strains of Gram‐positive and Gram‐negative bacteria and one fungal strain (Candida albicans) as growth inhibition diameter. Some of them showed modest to good antibacterial activity against Gram‐negative Escherichia coli and Salmonella typhimurium and Gram‐positive Staphylococcus aureus, Bacillus cereus, and Enterococcus fecalis bacterial strains, whereas almost all the compounds were inactive against Listeria monocytogenes. All of the synthesized compounds showed moderate to very good activity against C. albicans.     

Biginelli‐like three component reaction: Synthesis of some new ethyl 6‐ethoxycarbonylmethyl‐4‐aryl‐2‐oxo‐1,2,3,4‐tetrahydropyrimidine‐5‐carboxylate derivatives

In the context of our high‐throughput organic synthesis program, we have studied the reactivity of special β‐keto esters toward the Biginelli reaction. We have found that a diethyl‐3‐oxoglutarate reacts with one molecule of urea and one molecule of aldehyde under solvent‐free conditions to give a new family of 3,4‐dihydropyrimidin‐2(1H)‐ones in good yields.     

Synthesis and biological activities of 2‐alkylthio‐5‐furylmethylidene‐4H‐imidazolin‐4‐ones

Novel 2‐alkylthio‐5‐furylmethylidene‐4H‐imidazolin‐4‐ones 4 have been synthesized via tandem aza‐ Wittig reaction. The structures were determined by ir, nmr, mass spectroscopy, and elemental analysis. They were screened for fungicidal activities against Fusarium oxysporium, Botryosphaeria berengeriana and Rhizoctonia solani, and growth inhibition of Barnyard grass and Cole root and stalk. A few of them possess significant biological activities.     

Syntheses of 4‐(5‐oxo‐1,2,4‐triazol‐3‐yl)‐sydnones and 4‐(4‐arylamino‐5‐oxo‐1,2,4‐triazol‐3‐yl)‐sydnones from Sydnone Derivatives and Their Fragments

4‐(5‐oxo‐1,2,4‐triazol‐3‐yl)‐sydnones 11 and 4‐(4‐arylamino‐5‐oxo‐1,2,4‐triazol‐3‐yl)‐sydnones 13 have been obtained from a‐chloroformylarylhydrazine hydrochloride 2 . Moreover, the intermediates, including 3, 4 , 9 and 10 , in this study are synthetically informative and valuable. It is also noteworthy that three reactants, 1, 2 and sydnonecarbaldehydes, were prepared from sydnone derivatives and their fragments. The oxidative cyclizations of sydnonecarbaldehyde semicarbazones 9 and carbazones 10 with two different oxidizing agents (Cu(ClO₄)₂ and Fe(ClO₄)₃) have been extensively examined. The reaction time and the yields of cyclizations were affected by the substituents of semicarbazones 9 and carbazones 10.     

Synthesis of 2‐amino‐4‐oxo‐5‐substitutedbenzylthiopyrrolo[2,3‐d]‐pyrimidines as potential inhibitors of thymidylate synthase

A series of ten novel 2‐amino‐4‐oxo‐5‐[(substitutedbenzyl)thio]pyrrolo[2,3‐d]pyrimidines 2‐11 were synthesized as potential inhibitors of thymidylate synthase and as antitumor agents. The analogues contain various electron withdrawing and electron donating substituents on the benzylsulfanyl ring of the side chains and were synthesized from the key intermediate 2‐amino‐4‐oxo‐6‐methylpyrrolo[2,3‐d]pyrimidine, 14 . Appropriately substituted benzyl mercaptans were appended to the 5‐position of 14 via an oxidative addition reaction using iodine, ethanol and water. The compounds were evaluated against human, Escherichia coli and Toxoplasma gondii thymidylate synthase and against human, Escherichia coli and Toxoplasma gondii dihydrofolate reductase. The most potent inhibitor, ( 6 ) which has a 4′‐methoxy substituent on the side chain, has an IC₅₀=25 μM against human thymidylate synthase. Contrary to analogues of general structure 1 , electron donating or electron withdrawing substituents on the side chain of 2‐11 had little or no influence on the human thymidylate synthase inhibitory activity.     

Synthesis and intramolecular cyclization of 2‐methylsulfany‐4‐oxo‐3(4H)‐quinazolinyl)acetohydrazide

Treatment of ambident sodium salt of 2‐methylsulfanyl‐4(3H)‐quinazolinone with methyl bromoacetate resulted in N₍₃₎‐alkyl ester formation. Reaction of the resulted ester with hydrazine hydrate gave 2‐methylsulfanyl‐4‐oxo‐3(4H)‐quinazolinyl)acetohydrazide, which underwent intramolecular cyclization under heating in dimethylformamide to give 1‐aminoimidazo[2,1‐b]quinazoline‐2,5(1H,3H)‐dione. The latter took place in acylation reaction and in condensation with aromatic aldehydes.     

Synthesis of novel 4‐pyrazolyl‐2‐oxo‐1,2,3,4‐tetrahydropyrimidines promoted by phosphotungstic acid

Phosphotungstic acid, a keggin's type heteropoly acid catatalysed Biginelli reaction was carried out using pyrazole aldehyde, ethyl acetoacetate and urea to synthesis novel 4‐pyrazolyl ‐2‐oxo‐1,2,3,4‐tetrahydropy‐ rimidines.     

Green Synthesis of Pyrazolo‐thiazolidine‐4‐ones Using Magnetic Nanocomposite of Multiwalled Carbon Nanotube

Magnetic multiwalled carbon nanotube nanocomposite as a recoverable catalyst for the synthesis of novel 1,3‐thiazolidine‐4‐ones at room temperature in a one‐pot procedure without additional organic solvents. IR, ¹HNMR, and ¹³CNMR spectroscopies and elemental analysis were used for the identification of these compounds. Moreover, the catalyst could be easily recovered by magnetic separation and recycled for five runs without significant loss of its catalytic activity. All of synthesized compounds were characterized by IR, NMR, and elemental analyses.     

2,2,2‐triaryl‐4‐oxo‐1,3,2‐benzoxazastibinines

The hitherto unreported 4‐oxo‐1,3,2‐benzoxazastibinines 2 have been synthesized by the cyclization of disodium salt of salicylanilide ( 1 ) with Ar₃SbBr₂ (Ar = Ph, p‐tolyl, or mesityl). These compounds have been characterized by elemental analyses, molecular weight determination, and by IR, far IR, ¹H, and ¹³C NMR spectral studies. © 2003 Wiley Periodicals, Inc. Heteroatom Chem 14:622–624, 2003; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/hc.10202     

Preparation of 2‐phenyl‐2‐hydroxymethyl‐4‐oxo‐1,2,3,4‐tetrahydroquinazoline and 2‐methyl‐4‐oxo‐3,4‐dihydroquinazoline derivatives formation

The cyclization of phenacyl anthranilate has been studied with the aim to develop the synthesis of 2‐(2′‐aminophenyl)‐4‐phenyloxazole. However, a different course of the reaction than expected was observed. 2‐Phenyl‐2‐hydroxymethyl‐4‐oxo‐1,2,3,4‐tetrahydroquinazoline ( 3a ) was formed by the reaction of phenacyl anthranilate ( 2 ) with ammonium acetate under various conditions. 3‐Hydroxy‐2‐phenyl‐4(1H)‐quinolinone ( 4 ) arose by heating compound 3a in acetic acid. The same compound was obtained by melting compound 3a , but the yield was lower. Different types of products resulted in the reaction of compound 3a with acetic anhydride. Under mild conditions acetylated products 2‐acetoxymethyl‐2‐phenyl‐4‐oxo‐1,2,3,4‐tetrahydroquinazoline ( 7a ) and 2‐acetoxymethyl‐3‐acetyl‐2‐phenyl‐4‐oxo‐1,2,3,4‐tetrahydroquinazoline ( 8 ) were prepared. If the reaction was carried out under reflux of the reaction mixture, molecular rearrangement took place to give cis and trans 2‐methyl‐4‐oxo‐3‐(1‐phenyl‐2‐acetoxy)vinyl‐3,4‐dihydroquinazolines ( 9a and 9b ). All prepared compounds have been characterised by their ¹H, ¹³C and ¹⁵N NMR spectra, IR spectra and MS.