Conventional and Microwave‐Assisted Synthesis of Benzimidazole Derivatives and Their In Vitro Inhibition of Human Cyclooxygenase

A large series of 1,2‐diaryl‐benzimidazole and 2‐aryl‐1H‐benzimidazole derivatives were synthesized with slight differences using both microwave irradiation and conventional heating methods. Usually higher yields and time reactions reduction were obtained with the former method. All compounds were assayed for their in vitro ability to inhibit human cyclooxygenases, and most of them showed an encouraging inhibitory activity and isoform selectivity in the micromolar range.     

Microwave‐Assisted One‐Pot Synthesis of 2‐(Substituted phenyl)‐1H‐benzimidazole Derivatives

A series of 2‐(substituted phenyl)‐1H‐benzimidazole derivatives with various 5‐and 6‐position substituents (‐H, ‐CH₃, ‐CF₃) were synthesized via microwave irradiation using a short synthetic route and Na₂S₂O₅ as oxidant. This simple, fast, and efficient preparation of benzimidazole derivatives has been developed using readily available and inexpensive reagents (aldehydes and 1,2‐phenylenediamines) under solvent‐free conditions.     

Microwave‐mediated synthesis and antibacterial activity of some novel 2‐(substituted biphenyl) benzimidazoles via Suzuki‐Miyaura cross coupling reaction and their N‐substituted derivatives

A series of some novel 2‐(substituted biphenyl) benzimidazoles and their N‐substituted derivatives were synthesized via microwave‐mediated Suzuki‐Miyaura coupling of 2‐(4‐iodophenyl)‐1H‐benzimidazole or 2‐(4‐iodophenyl)‐6‐amino‐1H‐benzimidazole and arylboronic acids. The method reported herein offers advantageous shorter reaction times, higher yields and is applicable to a large set of substrates. All the synthesized compounds were screened for their antibacterial activity against Staphylococcus aureus and Salmonella typhimurium bacterial species. J. Heterocyclic Chem., (2011).     

A Simple,Mild and Efficient One‐Pot Synthesis of 2‐Substituted Benzimidazoles in the Presence of H2O2/HCl under Microwave Irradiation

A simple, fast and efficient method for the preparation of several 2‐substituted benzimidazole derivatives is reported. Compounds were synthesized through a rapid one‐pot synthesis via microwave irradiation, starting from aldehydes and o‐phenylenediamine, in the presence of H₂O₂/HCl system in acetonitrile. The significant features of this method are short reaction times, high yields, easy and quick isolation of the products.     

First synthesis of novel pentaheterocyclic ring system of 1,2,4‐triazolo[2″,3″:6′,1′]pyrimido[4′,5′:2,3]pyrido[1,2‐a]benzimidazole

Reaction of 1‐amino‐3‐arylpyrido[1,2‐a]benzimidazole‐2,4‐dicarbonitrile (1) with dimethylformamide‐dimethylacetal (DMF‐DMA) gave 1 ‐[N,N‐(dimethylaminomethylene)amino]‐3‐arylpyrido[1,2‐a]benzimidazole‐2,4‐dicarbonitrile (2). Compounds (1) reacted with triethylorthoformate yielding 1‐[N‐(ethoxymethylene)amino]‐3‐arylpyrido[1,2‐a]benzimidazole‐2,4‐dicarbonitrile (3). 3‐Amino‐4‐imino‐5‐aryl‐6‐cyanopyrimido[5′,4′:5,6]pyrido[1,2‐α] benzimidazole (4) was synthesized via condensation of either (2) or (3) with hydrazine hydrate. Reactions of (4) with acetic anhydride, ethyl chloroformate or aryl isothiocyanate yielded the respective derivative of the new ring system namely 1,2,4‐triazolo[2″,3″:6′,1′]pyrimido[4′,5′:2,3]pyrido[1,2‐a]benzimidazole (5–7).     

Microwave‐promoted Synthesis of Novel Fused Osthole Analogues

Osthole is a natural coumarin derivative and has a broad scope of biological activities. Two series of novel fused osthole analogues were designed, and synthesized through a highly efficient microwave‐promoted synthetic protocol via the reaction of 4‐hydroxycoumarins and β‐ketoesters. The reaction conditions including solvent, catalyst, microwave power and irradiation time were also optimized. The pyrano[3,2‐c]chromene‐2,5‐diones and furo[3,2‐c]coumarins were obtained through two distinct intramolecular cyclization processes, and the proposed mechanism was also discussed.     

1,3-二甲基-2-二茂铁甲基苯并咪唑碘盐的合成、表征、晶体结构及量子化学计算

A novel benzimidazole derivative, 1,3-dimethyl-2-ferrocenylmethylbenzimidazolium iodide （1） was synthesized and characterized by elemental analysis, MS, IH NMR and IR spectra. Its crystal structure was determined by X-ray single crystal diffraction, and the title compound belongs to monoclinic system with space group P2（1）/c. According to the crystal structure, the quantum chemistry calculation was performed by Gaussian 03 program, and full geometry optimizations of the title compound were carried out with DFT method at B3LYP/6-31G level. Its structure, stability, frontier molecular orbital components and net charge distribution were discussed.     

Synthesis and Antitumor Activity of Heterocycles Related to Carbendazim

Three types of compounds were synthesized from carbendazim ( 1 ), a benzimidazole derivative (Scheme 1 ). They included a group of esters at N1 prepared by treating carbendazim with isocyanates bearing ester groups ( 2a , 2b , 2c ), carboxyalkyl‐1,2,3,4‐tetrahydro‐s‐triazino[1,2‐a]benzimidazole‐2,4‐dione esters ( 3a and 3b , 3d and 3c derived from 3a . The antitumor potencies of the N1 esters were in the range of 7 to 40 μM, which compares favorably with carbendazim, but their water solubilities were low. The s‐triazine derivatives showed activity against pancreatic tumor cells, and one of them ( 3b ) was active in mice, but they were not effective against other tumor types. Treatment of carbendazim with 3‐bromopropionyl chloride produced 1‐methoxycarbonyl‐4‐oxo‐1,2,3,4‐tetrahydropyrimido[1,2‐a]benzimidazole ( 4 ), which gave 1‐(3‐aminopropionyl)benzimidazole 2‐methylcarbamates, substituted on the amino nitrogen ( 5a , 5b , and 5d ), when treated with amines. These products showed some antitumor activity in cell cultures, and an ethoxy derivative ( 5c ), obtained by treating 1‐methoxycarbonyl‐4‐oxo‐1,2,3,4‐tetrahydropyrimido[1,2‐a]benzimidazole with sodium ethoxide, was active in the 67–150 μM range. Some of the new compounds had good water solubility. Carbendazim kills tumor cells by inhibiting tubulin; however, s‐triazine 3b , which differs from it in size and functional groups, does not act by this mechanism.     

Microwave‐Assisted Solid‐Phase Synthesis of a 1,2‐Disubstituted Benzimidazole Library by Using a Phosphonium Linker

An efficient and rapid microwave‐assisted solid‐phase method for the synthesis of 5‐methyl‐1,2‐disubstituted benzimidazoles derivatives has been developed. The phosphonium linker, obtained by reaction between polymer‐supported triphenylphosphine and 4‐fluoro‐3‐nitrobenzyl iodide, underwent aromatic substitution with primary amines, followed by one‐pot reaction with aldehydes in the presence of SnCl₂·2H₂O, yielded the benzimidazole system under microwave irradiation. The final products were released from the resin with NaOH under microwave irradiation and were obtained in high purity and good overall yield.     

Efficient MW‐Assisted Synthesis of Some New Isoquinolinone Derivatives With In Vitro Antitumor Activity

An efficient and convenient synthesis of novel [1,3]oxazino[3,2‐b]isoquinoline‐5,12‐dione derivative 4 was achieved by the reaction of anthranilic acid with homophthalic anhydride under microwave irradiation, followed by cyclization with acetic anhydride. Some new isoquinolinone and fused isoquinolinone derivatives were prepared via reaction of compound 4 with different nitrogen nucleophiles by using reflux and a focused microwave reactor. Microwave irradiation favored the formation of the desired products with improved yields and shortened reaction times. This is a simple and green method for the synthesis of isoquinolinone derivatives. The structures of the prepared compounds were elucidated by IR, ¹H‐NMR, and mass spectroscopy. Some of the newly prepared compounds were tested in vitro against a panel of three human tumor cell lines, namely, hepatocellular carcinoma (liver) HepG2, colon cancer HCT‐116, and mammary gland breast MCF‐7. Almost all of the tested compounds showed satisfactory activity.     

Conventional and Microwave‐Activated the Synthesis of a Novel Series of Imidazoles,Pyrimidines, and Thiazoles Candidates

A novel series of imidazoles, pyrimidines, and thiazoles were synthesized using microwave irradiation and conventional method from commercial available p‐aminobenzoic acid. Thus, one‐pot condensation of p‐aminobenzoic acid, urea, and chloroacetic acid have been provided two types of imidazole derivatives as separated mixture 2a and 2b . [3 + 2 + 1] Cyclocondensation of 2a , benzaldehyde, and urea/thiourea in acidic medium afforded imidazolo oxazine derivative 3 and Imidazolothiazine 4 . Coupling of 2a with benzene diazonium salt gave the phenyldiazenyl imidazolidine 5 . While the reaction of 2a , thiourea, and benzaldehyde in sodium ethoxide afforded imidazolothiazine 6 . Oxidative cyclization of thiourea derivative 7 resulted a mixture of benzithiazole derivative 7a and oxathiazole derivative 7b . Cyclocondensation of 7a with phenylenediamine and 4‐methyl phenylenediamine furnished imidazole 8 and 9 , respectively. Reaction of P‐aminobenzioc acid with potassium cyanate followed by Biginelli reaction with (acetyl acetone, ethyl acetoacetate, and diethyl malonate) and salicyladehyde in HCl tolerated pyrimidine derivatives 10a–c , respectively. In the same manner, the reactions and short reaction time make microwave technique one of the greenest methodology for synthesis of this class of heterocyclic system.     

Synthesis,characterization and microwave‐assisted catalytic activity of novel benzimidazole salts bearing piperidine and morpholine moieties in Heck cross‐coupling reactions

A mixture of novel benzimidazole salts (2a–f), Pd(OAc)₂ and K₂CO₃ in DMF? H₂O catalyzes, in high yield, the Heck cross‐coupling reaction assisted by microwave irradiation in a short time. All synthesized novel benzimidazole derivatives were characterized by elemental analysis and NMR spectroscopy. In addition, the molecular structure of 2a was determined by X‐ray crystallography. Copyright © 2011 John Wiley & Sons, Ltd.     

4‐Hydroxy‐1‐phenylquinolin‐2(1H)‐one in One‐pot Synthesis of Pyrimidoquinolines and Related Compounds under Microwave Irradiation and Conventional Conditions

Biginelli condensation reactions of 4‐hydroxy‐1‐phenylquinolin‐2(1H)‐one, aryl aldehydes and urea, or thiourea, 5‐amino‐1H‐1,2,4‐triazole, or 2‐amine‐1H‐benzimidazole ( 9 ) under microwave irradiation afforded the corresponding pyrimido[5,4‐c]quinolin‐5‐one derivatives in high yields. One‐pot synthesis of 2H‐pyrano[3,2‐c]quinolines is also reported.     

Novel Approach for Rapid and Efficient Synthesis of 2‐(3‐(4‐Aryl)‐1‐isonicotinoyl‐4,5‐dihydro‐1H‐pyrazol‐4‐yl)‐3‐phenylthiazolidin‐4‐one Derivatives and Screened Their Antimicrobial Activity

A series of compounds, viz. 2‐(3‐(4‐aryl)‐1‐isonicotinoyl‐4,5‐dihydro‐1H‐pyrazol‐4‐yl)‐3‐phenylthiazolidin‐4‐one 4 ( a – n ), have been synthesized by reaction of 3 ( a – n ) with thioglycolic acid in the presence of zinc chloride. Compounds 3 ( a – n ) have been synthesized by amination of formylated pyrazoles 2 ( A – B ), which were synthesized by formylation of 1 ( A – B ) by Vilsmeier–Haack reagent (POCl₃/DMF). Compounds 1 ( A – B ) were synthesized by condensation of hydrazide and substituted acetophenones under conventional method and microwave irradiation method. These compounds were identified on the basis of melting point range, Rf values, infrared, ¹H NMR, and mass spectral analysis. These compounds were evaluated for their in vitro antimicrobial activity, and their minimum inhibitory concentration was determined. Among them, compound 4b and compound 4l possess appreciable antimicrobial and antifungal activities. Antibacterial activity results showed that compounds containing electron‐withdrawing groups were more active than compounds containing electron‐releasing groups.     

Synthesis and microwave‐assisted catalytic activity of novel bis‐benzimidazole salts bearing furfuryl and thenyl moieties in Heck and Suzuki cross‐coupling reactions

A mixture of bis‐benzimidazole salts ( 1–7 ), Pd(OAc)₂ and K₂CO₃ in DMF ? H₂O catalyzes, in high yield, the Suzuki and Heck cross‐coupling reactions assisted by microwave irradiation in a short time. In particular, the yields of the Heck and Suzuki reactions with aryl bromides were found to be nearly quantative. The synthesized bis‐benzimidazole salts ( 1 – 7 ) were identified by ¹H? ¹³C NMR, IR spectroscopic methods and micro analysis. Copyright © 2010 John Wiley & Sons, Ltd.     

Microwave‐assisted Synthesis,Characterization, and Density Functional Theory Study of Biologically Active Ferrocenyl Bis‐pyrazoline and Bis‐pyrimidine as Organometallic Macromolecules

Organometallic macromolecules such as ferrocenyl bis‐pyrazoline ( 2 , 3 ) and bis‐pyrimidine ( 4 , 5 ) derivatives were synthesized by reacting ferrocenyl bis‐chalcone 1 with thiosemicarbazide/phenylhydrazine/guanidine hydrochloride/thiourea, respectively, under microwave irradiation. Ferrocenyl bis‐chalcone 1 was synthesized by reacting acetyl ferrocene with terephthalaldehyde. Synthesized compounds were characterized by using IR, ¹H NMR, ¹³C NMR, EI‐MS, and elemental analysis. In vitro antibacterial activity against two Gram‐negative and two Gram‐positive bacteria was determined by the disc diffusion assay. Moreover, minimum inhibition concentrations were also measured with reference to chloramphenicol. Thioamide functionally containing ferrocenyl bis‐pyrazoline derivative 2 shows the best antibacterial activity on Escherichia coli and Salmonella typhimurium, among all tested compounds including the reference drug chloramphenicol. The structure–activity relationship is also developed by using computational calculations with density functional theory (DFT)/B3LYP method.     

Protonation Equilibria of Hoechst 33258 in Aqueous Solution

The bis‐benzimidazole derivative Hoechst 33258 (2′‐(4‐hydroxyphenyl)‐5‐(4‐methylpiperazin‐1‐yl)‐2,5′‐bi‐1H‐benzimidazole) binds to the minor groove of DNA duplexes and is widely used as fluorescent cytological stain for DNA. The neutral compound, 1 , is amphiphilic with four basic and three acidic sites. We have determined all seven acidity constants by spectrophotometric titration to define the pH‐dependent distribution of species, from the fully protonated tetracation 1 ⁴⁺ to the fully deprotonated trianion 1 ^3?, in aqueous solution. The structures of the intermediate protonation states were assigned with the aid of density‐functional calculations. Electrostatic interaction free energies were calculated to adjust the acidity constants of the molecular subunits of 1 to their environment in the species 1 ⁴⁺ to 1 ^3?. The experimental and theoretical pK_a values agree well, but they differ substantially from previous estimates given in the literature.     

Synthesis,microwave‐promoted catalytic activity in Suzuki–Miyaura cross‐coupling reactions and antimicrobial properties of novel benzimidazole salts bearing trimethylsilyl group

A mixture of benzimidazole salts (2–7), Pd(OAc)₂ and K₂CO₃ in DMF–H₂O catalyzes the Suzuki–Miyaura cross‐coupling reactions promoted by microwave irradiation resulting in high yield within a short time. In particular, the yield of the Suzuki–Miyaura reactions with aryl bromides was found to be nearly quantitative. The synthesized benzimidazole salts (2–7) were identified by ¹H‐¹³C, NMR, IR spectroscopic methods and microanalysis. The molecular structure of 1 was determined by X‐ray crystallography. The antibacterial and antifungal activities of the novel benzimidazole derivatives (1–7) were also tested against standard strains. Copyright © 2011 John Wiley & Sons, Ltd.     

Conventional and Microwave‐Assisted Synthesis and Biological Activity Study of Novel Heterocycles Containing Pyran Moiety

Under both conventional and microwave methods, 2‐amino‐4H‐pyran‐3‐carbonitrile derivative 1 was synthesized and reacted with different reagents. Thus, 2‐amino‐4H‐pyran‐3‐carbonitrile derivative was treated with chloroacetyl chloride, phenyl isocyanate, cyanoacetic acid, benzoyl chloride, triethyl orthoformate, acetic anhydride/H₂SO₄, arylidene malononitrile, urea, and/or p‐aminosulphaguanidine producing chloroacetamide, 3‐phenylurea, cyanoacetamide, N‐benzoylpyran, ethylformimidate, pyranopyrimidin‐4‐one, pyranopyridine, pyranopyrimidin‐2‐one, and pyranopyrimidin‐2‐imine derivatives, respectively. Meanwhile, compound 1 was reacted with ethyl bromoacetate, phenacyl bromide, phthalic anhydride, different aromatic amines, and/or acetic acid/H₂SO₄ to produce 5‐aminopyrano[2,3‐b]pyrrole‐6‐carboxylate, dihydropyrano[2,3‐b]pyrrole‐6‐yl‐(phenyl)methanone, 1,3‐dioxoisoindolinyl pyran, 1,4‐dihydropyridine, and 2‐hydroxy‐1,4‐dihydropyridine derivatives, respectively. On the other hand, when compound 1 was allowed to react with maleic anhydride and/or hydrazine hydrate, pyran‐4‐oxobut‐2‐enoic acid and 3‐aminopyranopyrazole derivatives were obtained, respectively. Reaction of pyran‐4‐oxobut‐2‐enoic acid with malononitrile under different conditions gave 2‐(furan‐2‐yl)‐4H‐pyran and 2‐(4H‐pyran‐2‐yl)‐1H‐pyrrole derivatives, while condensation of 3‐aminopyranopyrazole with benzaldehyde gave 1,4‐dihydropyrano[2,3‐c]pyrazol‐3‐yl‐1‐phenylmethanimine derivative. The newly synthesized compounds were characterized by the spectroscopic tools IR, ¹H‐NMR, ¹³C‐NMR, MS, and elemental analysis. Some of these compounds have been screened in vitro for antimicrobial activity against different strains of bacteria and fungi and also were tested against two cancer cell lines: mammary gland breast cancer (MCF‐7) and colon cancer (HCT‐118).     

An Efficient One‐Pot Synthesis of New Coumarin Derivatives as Potent Anticancer Agents under Microwave Irradiation

An efficient and rapid synthesis of coumarin derivatives was accomplished via reactions of 3‐(3‐(4‐methoxyphenyl)acryloyl)‐2H ‐chromen‐2‐one ( 3 ) with different carbon nucleophiles such as ethyl acetoacetate, ethyl cyanoacetate, malononitrile, and ethyl benzoylacetate via conventional heating and microwave irradiation conditions and were used as source of pyran and pyridine derivatives bearing coumarin moiety 4 – 11 . Compound 9a was condensed with different carbon electrophiles triethylorthoformate, phenylisothiocyanate, carbon disulfide, benzoylchloride, and acetylchloride that afforded the corresponding chromen derivatives 12 – 16 . All the newly synthesized compounds were characterized by elemental and spectroscopic evidences. All of synthesized compounds were tested for in vitro cytotoxicity. The preliminary screening results showed that most of the compounds had moderate cytotoxic activity against HCT‐116 and MCF‐7 cell lines. Nevertheless, compound 10 exhibited potent activity against the two cell lines, which was comparable with the standard drug 5‐fluorouracil.