Utility of Enaminonitriles in Heterocyclic Synthesis: Synthesis of Some New Pyrazole,Pyridine, and Pyrimidine Derivatives

The starting (1,5‐dimethyl‐3‐oxo‐2‐phenyl‐2,3‐dihydro‐1H‐pyrazol‐4‐yl)carbonohydrazonoyl dicyanide ( 2 ) was used as key intermediate for the synthesis of 3‐amino‐2‐(1,5‐dimethyl‐3‐oxo‐2‐phenyl‐2,3‐dihydro‐1H‐pyrazol‐4‐ylazo)‐[3‐substituted]‐1‐yl‐acrylonitrile derivatives ( 3 – 10 ). In addition, nitrile derivative 2 reacted with hydrazine hydrate or malononitrile to afford the corresponding 3,5‐diaminopyrazole 11 and enaminonitrile derivative 13 , respectively. On the other hand, compound 3 was subjected to react with malononitrile, acetic anhydride, triethylorthoformate, N,N‐dimethylformamide (DMF)‐dimethylacetal, thiourea, and hydroxylamine hydrchloride to afford antipyrine derivatives 16 – 21 . Moreover, the reaction of enaminonitrile 3 with carbon disulfide in pyridine afforded the pyrimidine derivative 22 , whereas, in NaOH/DMF followed by the addition of dimethyl sulphate afforded methyl carbonodithioate 24 . The reaction of enaminonitrile derivatives 3 – 5 with phenylisothiocyanate afforded the thiopyrimidine derivatives 25a – c . Finally, the enaminonitrile 4 reacted with 3‐(4‐chloro‐phenyl)‐1‐phenyl‐propenone to afford the pyridine derivative 27 . The newly synthesized compounds were characterized by elemental analyses and spectral data (IR, ¹³C‐NMR, ¹H–NMR, and MS).     

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).     

Synthesis of a novel bifunctional oxyammonium-based ionic liquid: Application for the synthesis of pyrano[4,3-b]pyrans and tetrahydrobenzo[b]pyrans

In the present investigation, a novel bifunctional oxyammonium-based ionic liquid, namely, 2,2′-(ethane-1,2-diylbis[oxy])bis(ethan-1-aminium)-2,2,2-trifluoroacetate, was designed and synthesized. The structure of the titled ionic liquid was characterized using Fourier-transform infrared spectroscopy (FT-IR), proton nuclear magnetic resonance (¹HNMR), carbon nuclear magnetic resonance (¹³CNMR), fluorine nuclear magnetic resonance (¹⁹FNMR), homonuclear COSY nuclear magnetic resonance (NMR), thermogravimetry (TG), derivative thermogravimetry (DTG) analysis, X-ray diffraction patterns (XRD), scanning electron microscopy (SEM), and transmission electron microscopy (TEM). The described ionic liquid demonstrated robust catalytic performance in the synthesis of pyrano[4,3-b]pyrans and tetrahydrobenzo[b]pyran derivatives. The ionic liquid presents a high potential of recycling and reusing capability in both types of model reactions.     

Design,Synthesis of Novel Thiourea and Pyrimidine Derivatives as Potential Antitumor Agents

1,3‐Bis‐(arylidene)thiourea derivatives ( 11a‐c ) were prepared by reacting thiourea ( 9 ) with bezaldehyde, p‐chlorobenzaldehyde or p‐anisaldehyde ( 10a‐c ) respectively. Further reaction of ( 11b ) with acetyl acetone, ethyl acetoacetate, malononitrile and acetic anhydride gave tetrahydropyrimidine‐2‐thiones ( 12‐14 ) and 1,3‐diacetyl thiourea ( 15 ). Compound ( 11b ) reacted with chloroacetyl chloride to give the corresponding pyrimidin‐4‐one derivative ( 16 ). Reaction of ( 12‐14 ) with acetic acid in aqueous sodium nitrite yielded the corresponding oxime derivatives ( 17‐19 ). The triazole ( 20 ) was achieved via refluxing of ( 19 ) in dimethylformamide. Reaction of ( 16 ) with mercaptoacetyl chloride gave the sulfanyl‐acetic acid ( 21 ) which afforded the dihydrazinyl ( 22 ) up on treatment with hydrazine hydrate. Newly synthesized compounds ware characterized by elemental analyses and spectral data (IR, ¹H‐NMR, ¹³C‐NMR and mass spectra). The investigated compounds were screened for their cytotoxicity, i.e. compounds 19 , 20 and 22 exhibited highly potential antitumor activity.     

Synthesis and Reactions of Some Heterocyclic Candidates Based on 2‐Amino‐4,5,6,7‐tetrahydrobenzo[b]thiophene Moiety as Anti‐Arrhythmic Agents

In continuation of our previous work, a series of novel thiophene derivatives 4 , 5 , 6 , 8 , 9 , 9a , 9b , 9c , 9d , 9e , 10 , 10a , 10b , 10c , 10d , 10e , 11 , 12 , 13 , 14 , 15 , 16 were synthesized by the reaction of ethyl 2‐amino‐4,5,6,7‐tetrahydrobenzo[b]thiophene‐3‐carboxylate ( 1 ) or 2‐amino‐4,5,6,7‐tetrahydrobenzo[b]thiophene‐3‐carbonitrile ( 2 ) with different organic reagents. Fusion of 1 with ethylcyanoacetate or maleic anhydride afforded the corresponding thienooxazinone derivative 4 and N‐thienylmalimide derivative 5 , respectively. Acylation of 1 with chloroacetylchloride afforded the amide 6 , which was cyclized with ammonium thiocyanate to give the corresponding N‐theinylthiazole derivative 8 . On the other hand, reaction of 1 with substituted aroylisothiocyanate derivatives gave the corresponding thiourea derivatives 9a , 9b , 9c , 9d , 9e , which were cyclized by the action of sodium ethoxide to afford the corresponding N‐substituted thiopyrimidine derivatives 10a , 10b , 10c , 10d , 10e . Condensation of 2 with acid anhydrides in refluxing acetic acid afforded the corresponding imide carbonitrile derivatives 11 , 12 , 13 . Similarly, condensation of 1 with the previous acid anhydride yielded the corresponding imide ethyl ester derivatives 14 , 15 , 16 , respectively. The structures of newly synthesized compounds were confirmed by IR, ¹H NMR, ¹³C NMR, MS spectral data, and elemental analysis. The detailed synthesis, spectroscopic data, LD₅₀, and pharmacological activities of the synthesized compounds are reported.     

Synthesis of New Pyrrolo Heterocycles (I): Novel Synthesis of Pyrano[2,3‐c]pyrrole,Isoindoline, Pyrrolo[3,4‐b]pyridine,and Pyrrolo[3,4‐d]pyrimidine Derivatives

Michael addition of 1,5‐diaryl‐2,3‐dioxopyrrolidine derivatives with α‐cyanocinnamonitriles and ethyl α‐cyanocinnamates afforded 4H‐pyrano[2,3‐c]pyrrole derivatives in the presence of sodium ethoxide. Under the same reaction condition, the ylidenes of 1,5‐diaryl‐2,3‐dioxopyrrolidine were reacted with malononitrile or ethyl cyanoacetate to give isoindole derivatives; however, pyrrolo[3,4‐b]pyridine derivatives were formed when cyanoacetamide was used. Moreover, pyrrolo[3,4‐d]pyrimidine derivatives were synthesized by treating 4‐benzylidene‐1,5‐diphenyl‐2,3‐dioxopyrrolidine with urea and/or thiourea under basic conditions. The structures of all the new synthesized compounds were confirmed by elemental analysis, IR and NMR spectra.     

Synthesis of Thiazolinone,Aminopyrazole, Pyrazolopyrimidine,and Pyrazolotriazine Derivatives Starting from 1‐Naphthyl‐2‐Cyanoacetamide

Efficient and suitable methods for the synthesis of novel class of simple and fused heterocyclic compounds were prepared starting with 1‐naphthyl‐2‐cyanoacetamide and commercially available reagents. The cyclocondensation of 1‐naphthyl‐2‐cyanoacetamide with sulfanylacetic acid furnished phenylthiazolinone derivative. Stirring of the starting compound with PhNCS afforded thiocarbamoyl derivative which underwent heterocyclization with chloroacetyl chloride to give thiazolinone derivative. 5‐Aminopyrazole derivative was prepared by following mild procedures via refluxing the last thiocarbamoyl with hydrazine hydrate. Different synthetic approaches were discussed to obtain the novel fused pyrazolo[1,5‐a ]pyrimidine, 4H‐pyrazolo[3,4‐d ]pyrimidin‐4‐one moieties involving the reaction of the prepared 5‐aminopyrazole with a ) 1, 3‐dielectrophilic centers (acetylacetone, acetoacetanilide), b ) arylidines of malononitrile, and c ) isothiocyanate derivatives. The action of iced sodium nitrite solution in acidic medium on the last 5‐aminopyrazole gave pyrazolo[3,4‐d ][1,2,3]triazine. All novel structure were elucidated by different spectroscopic data (IR, MS, ¹H, and ¹³C NMR) and elemental analysis.     

One‐pot Synthesis of 1,2,3,4‐Tetrahydropyrimidin‐2(1H)‐thione Derivatives and their Biological Activity

2‐Thioxo/oxo‐1,2,3,4‐tetrahydropyrimidine‐5‐carboxylate derivatives 2a , 2b , 2c , 2d were prepared by the reaction of ethyl acetoacetate and thiourea or urea with aldehydes using NH₄Cl as a catalyst. Compounds 2a and 2c reacted with mono and bihalogenated compounds such as ethyl iodide, chloroacetonitrile, epichlorohydrin, acetyl chloride, ethyl bromoacetate, chloroacetic acid, chloroacetylchloride, and/or oxalyl chloride to afford compounds 3 , 4a , 4b , 5 , 6a , 6b , 7 , 8 , 9 and 10 , respectively. Compounds 2a , 2c , and 7 were allowed to react with p‐fluorobenzaldehyde to yield the corresponding products 11a , 11b , and 12 , respectively. Oxidation of 2a and 2c gave 2b , 13a , 13b , 14 , 15 , 16 dependent on the oxidizing agent used. Vilsmeiere‐Haack formylation of 2a and 2b with POCl₃/DMF afforded 17a and 17b . Chlorination of 2b and 2d gave the chlorinated derivative 18a and 18b , which reacted with thiourea to give thioureidopyrimidine 19a and 19b . Reactions of 2a with hydrazine monohydrate, semicarbazide hydrochloride, and sodium hydroxide gave compounds 20 , 21 , 22 , respectively. The cytotoxicity and in vitro anticancer evaluation of some prepared compounds have been assessed against two different human tumor cell lines including breast adenocarcinoma MCF‐7 and human hepatocellular carcinoma HepG2. Antimicrobial and antioxidant activities of some compounds were investigated. The newly synthesized compounds were characterized by IR, ¹H‐NMR, ¹³C‐NMR, and mass spectral data.     

Design,synthesis, and biological evaluation of novel substituted imidazo[2,1-a]isoindole derivatives as antibacterial agents

An efficient protocol has been developed for the synthesis of fused imidazo[2,1-a]isoindol-5-ones (2a–d) from 2-iodo benzoic acids and N,N-carbonyldiimidazole (CDI) using one-pot Pd-catalyzed C?C bond coupling. The reaction of imidazo[2,1-a]isoindol-5-one (2a–d) with substituted α-bromo ketones in toluene afforded corresponding imidazo[2,1-a]isoindolium derivatives (3a–i) in good yields. The structures of the title compounds were well established on the basis of infrared (IR), ¹H NMR, carbon-13 nuclear magnetic resonance (¹³C NMR), mass spectral data, and elemental analysis (C, H, and N). In vitro antibacterial results revealed that, the compounds 3b and 3i were found to possess an excellent broad spectrum of inhibiting potency against all the tested bacterial strains with minimum inhibitory concentration values ranging from 3.125 to 25?µg mL^?1.     

Halogen effect on structure and 13C NMR chemical shift of 3,6‐disubstituted‐N‐alkyl carbazoles

Structures of selected 3,6‐dihalogeno‐N‐alkyl carbazole derivatives were calculated at the B3LYP/6‐311++G(3df,2pd) level of theory, and their ¹³C nuclear magnetic resonance (NMR) isotropic shieldings were predicted using density functional theory (DFT). The model compounds contained 9H, N‐methyl and N‐ethyl derivatives. The relativistic effect of Br and I atoms on nuclear shieldings was modeled using the spin–orbit zeroth‐order regular approximation (ZORA) method. Significant heavy atom shielding effects for the carbon atom directly bonded with Br and I were observed (~?10 and ~?30 ppm while the other carbon shifts were practically unaffected). The decreasing electronegativity of the halogen substituent (F, Cl, Br, and I) was reflected in both nonrelativistic and relativistic NMR results as decreased values of chemical shifts of carbon atoms attached to halogen (C3 and C6) leading to a strong sensitivity to halogen atom type at 3 and 6 positions of the carbazole ring. The predicted NMR data correctly reproduce the available experimental data for unsubstituted N‐alkylcarbazoles. Copyright © 2013 John Wiley & Sons, Ltd.     

Synthesis,Characterization, and Screening for Anti‐inflammatory and Antimicrobial Activity of Novel Indolyl Chalcone Derivatives

Because of the great biological importance of substituted indole derivatives, in the present study, a series of pyrazolylindole, thiazolylindole, and pyrimidinylindole derivatives have been synthesized with good yield. The precursor indolyl chalcone 2a – d was prepared by reaction of 3‐chloro‐1H‐indole‐2‐carbaldehyde 1 with different ketones. Then, compounds 3b – d , 4 , and 5a – d have been synthesized by the reaction of chalcones 2a – d with hydrazine, phenylhydrazine, and thiosemicarbazide. When the chalcone derivative 2b subjected to react with hydroxylamine hydrochloride gave isoxazolylindole derivative 6b . N‐thiazolidine pyrazolyl indole 7 was obtained by reacting compound 5a with ethyl chloroacetate. On the other hand, when chalcone derivative 2b allowed to react with urea and thiourea gave the corresponding pyrimidinylindole derivatives 8 and 9 . Finally, when chalcone derivative 2b reacted with ethyl cyanoacetate or malononitrile gave pyridinylindole derivatives 10 and 11 . The structures of the all synthesized compounds were elucidated on the basis of spectral analysis infrared, NMR, and mass spectroscopy. Some of the synthesized compounds were screened for their antimicrobial and anti‐inflammatory activity. Compound 4b was the highest antibacterial activity against all strains of bacteria with values higher than those of the corresponding reference antibiotics (ciprofloxacin and levofoxacin, respectively) and almost the same as (gemifloxacin, moxifloxacin, clindamycin, gentamycin, and streptomycin). Compounds 4 , 5 , 6 , and 7 showed high anti‐inflammatory activity compared with the standard drug indomethacin.     

Synthesis and stereochemistry of some novel dihydropyrrolo[3,4-c]pyrazoles

Abstract  

Eleven novel dihydropyrrolo[3,4-c]pyrazole derivatives were obtained by the reaction of chiral (1R)-N-(1-phenylethyl)maleimide and C,N-aryl-substituted nitrilimines. The reaction afforded the cycloadducts as a regioisomeric mixture which can be separable in some cases. The structure and stereochemistry of cycloadducts were assigned on the basis of infrared (IR), ¹H and ¹³C nuclear magnetic resonance (NMR), mass and X-ray spectra, optical rotation measurements, and CHN analyses.     

Synthesis and Reactions of Some New Benzo[a]phenothiazine‐3,4‐dione Derivatives

The reaction of 2,3‐dihydro‐2,3‐epoxy‐1,4‐naphthoquinone ( 4 ) with substituted anilines furnished the corresponding benzo[fused]heterocyclic derivatives 5 , 6 , 6a , 6b , 7 , 8 . Furthermore, treatment of benzo[a]phenothiazine derivative 7 with halo compounds, namely, ethyl bromoacetate, phenacyl bromide, dibromoethane, or chloroacetone afforded ether derivatives 11 , 12 , 13 , 14 , respectively. Moreover, the reaction of 11 with o‐substituted aniline gave the corresponding benzo[a]phenothiazin‐5‐one derivatives 15 , 16 , 17 and benzo[d][1,3]oxazin‐4‐one 18 , respectively. Finally, the chromenone derivative 19 was synthesized via the reaction of ester derivative 11 with salicyaldhyde in refluxing pyridine. The newly synthesized compounds were characterized by spectroscopic measurements (IR, ¹H NMR, ¹³C NMR, and mass spectra).     

Synthetic Studies on the Synthesis of Some New Fused Heterocyclic Compounds Derived from 3,5‐Pyrazolidinedione

Condensation of 1‐phenylpyrazolidine‐3,5‐dione 1 with 3‐formylchromone afforded 4‐(chromenylmethylene)pyrazolidinedione 2 , which was reacted with hydrazine or hydroxylamine in different molar ratios and conditions to give the corresponding pyrazole and isoxazole derivatives 3 ‐ 8 , respectively. Compound 2 was subject to react with ammonia, N,S‐ or S,S‐acetals, mercaptoacetic acid, cyanoacetamide or cyanothioacetamide to give the corresponding pyridine, dithiine, thiazine and thiophene, 9 ‐ 14 , respectively. The reaction of compound 2 with thiourea, guanidine, cystamine, o‐aminothiophenol, ethylenediamine, o‐phenelenediamine or barbituric acid afforded the corresponding thiazine, pyrimidine, thiazepine, diazepine, and pyran derivatives 17 ‐ 23 , respectively. The study of the reaction of compound 2 with nucleophiles via chromene ring opening was investigated.     

Synthesis and Antimicrobial Evaluation of some Functionalized Heterocycles Derived from Novel Quinolinyl Chalcone

The reaction of 3‐acetyl‐4‐hydroxyl‐1‐methylquinolin‐2(1H )‐one (1) with 10‐oxo‐4,6,7,8,9,10‐hexahydropyrazolo[1,5‐a ][1]benzothieno[2,3‐d ]pyrimidine‐3‐carbaldehyde (2) afforded the novel enone system 3 . The latter compound was reacted with some 1,2‐binucleophilic reagents to give pyrazoline derivative 4 and isoxazoline derivative 5 . Treatment of chalcone 3 with 1,3‐binucleophilic reagents afforded pyrimidine and thiazine derivatives 6 – 8 . Moreover, reaction of compound 3 with active methylene reagents furnished pyridine, pyran, and cyclohexanone derivatives 9 – 12 . Cyclization of compound 12 by using hydrazine hydrate yielded indazol‐3‐one derivative 13. On the other hand, the cyclocondensation of the enone 3 with 1,4‐dinucleophilic reagents yielded diazepine derivative 14 and triazolothiadiazepine derivative 15 .The characterization of the newly synthesized heterocyles were confirmed on the basis of their elemental analysis and spectral data (IR, NMR, and MS). These compounds were also screened for their antibacterial activities.     

Synthesis and characterization of tungsten carbonyl complexes containing N-methyl substituted urea and thiourea ligands

Six new mixed-ligand tungsten carbonyl complexes containing N-methyl substituted urea and thiourea of the type W(CO)₄[RCH₂N-(C=X)NH₂] where X?=?O or S and R?=?morpholine, piperidine and diphenylamine are reported. These have been prepared by refluxing hexacarbonyl tungsten(0) with corresponding ligands in THF to produce cis-disubstituted products, [(L-L)W(CO)₄] where L-L?=?a chelating bidentate ligand, morpholinomethyl urea (MMU), morpholinomethyl thiourea (MMTU), piperidinomethyl urea (PMU), piperidinomethyl thiourea (PMTU), diphenylaminomethyl urea (DAMU) and diphenylaminomethyl thiourea (DAMTU). The compounds have been characterized by elemental analysis, IR, electronic and ¹³C NMR spectra, magnetic moments and conductivity measurements. The IR spectra suggests that in all the complexes, the ligands are bidentate chelating, coordinating the metal through carbonyl oxygen or thiocarbonyl sulphur and the ring nitrogen or tert-nitrogen of diphenylamine. The CO force constants and CO–CO interaction constants for these derivatives have also been calculated using Cotton–Kraihanzel secular equations, which indicate poor π-bonding ability of the ligands. ¹³C NMR and electronic spectra reveal loss of cis-carbonyl ligands to produce cis-disubstituted tetracarbonyl derivatives. Molecular modeling studies have been carried out using Hyperchem release 7.52 which suggest a distorted octahedral geometry for these complexes.     

Synthesis, Reactions, and Anti-arrhythmic activity of Substituted Heterocyclic Systems Using 5-Chloroanisic Acid as Starting Material

Summary. A series of substituted heterocyclic systems were prepared from N1-[4-(4-fluorocinnamoyl)phenyl]-5-chloro-2-methoxybenzamide, which was prepared from the corresponding 5-chloroanisic acid (2-methoxy-4-chlorobenzoic acid) as starting material. Treating of the cinnamoyl derivative with hydrazine hydrate in dioxane afforded a pyrazoline, which was reacted with morpholine and paraformaldehyde to give the N-substituted pyrazoline. Acylation of pyrazoline with acetyl chloride in dioxane afforded the N-acetyl analogue. Also, the cinamoyl derivative was reacted with methylhydrazine, phenylhydrazine, or ethyl cyanoacetate to yield the corresponding N-methyl-, N-phenylpyrazoline, pyrane, and pyridone derivatives. Condensation of the cinnamoyl derivative with cyanothioacetamide gave the pyridinethione derivative, which was treated with ethyl chloroacetate affording the ethyl carboxylate derivative. Also, it was reacted with malononitrile or ethyl acetoacetae to give the cyano amino analougues and ethyl carboxylate, which was reacted with methylhydrazine to give the (indazolyl)phenyl derivative. On the other hand, reaction of cinnamoyl derivative with acetyl acetone afforded the cyclohexenyl derivative, which was reacted with hydrazine hydrate to give the [methylindazolyl]phenyl derivative. Condensation of the cinnamoyl derivative with guanidine hydrochloride or thiourea afforded the aminopyrimidine derivative and thioxopyrimidine. The latter was condensed with chloroacetic acid to yield a thiazolopyrimidine, which was condensed with 2-thiophenealdehyde to yield the arylmethylene derivative, however, it was also prepared directly from thiopyrimidine by the action of chloroacetic acid, 2-thiophenealdehyde, and anhydrous sodium acetate. The pharmacological screening showed that many of these compounds have good anti-arrhythmic activity and low toxicity.     

Synthesis and Antioxidant Evaluation of Some Novel Thiophene,Pyrazole, Chromene,Pyrazolotriazine Derivatives Bearing Sulfonamide Moiety

As a part of ongoing studies in developing new potent antioxidant agents, N‐[4‐(aminosulfonyl)phenyl]‐2‐cyanoacetamide ( 3 ) was utilized as key intermediate for the synthesis of some new thiophene, chromene, and pyrazolotriazine pyridine derivatives. The structures of the newly synthesized compounds were confirmed by elemental analysis, IR, ¹H‐NMR, and mass spectral data. Representative compounds of the synthesized products were tested and evaluated as antioxidant. Compounds 7 and 30 are promising compounds.     

Synthesis and Biological Evaluation of Some Heterocyclic Compounds from Salicylic Acid Hydrazide

Different heterocyclic compounds were prepared starting from 2‐hydroxy benzohydrazide; for example, cyclization of hydrazide hydrazone 3 derived from 2‐hydroxybenzohydrazide 2 with acetic anhydride or concentrated sulfuric acid gave 1,3,4‐oxadiazole derivatives 4 – 5 . On the other hand, direct cyclization of 2‐hydroxy benzohydrazide 2 with one carbon cyclizing agent gave a new derivative of 1,3,4‐oxadiazole 7 , 8 , 9 , 10 , 11 . Heating of hydrazide hydrazone 3 with thioglycolic acid in pyridine gave thiazolidinone 12 . When 2‐hydroxy benzohydrazide 2 reacted with aliphatic carboxylic acids such as formic acid or acetic acid, it gave the corresponding N‐formyl or N‐acetyl derivatives 6 . Subsequent cyclization of 6 using phosphorous pentasulphide in pyridine gave 1,3,4‐thiadiazoles 13 . Cyclization of 2‐hydroxy benzohydrazide with ethyl acetoacetate gives pyrazolone derivative 14 . Finally, when an ethanolic solution of acid hydrazide 2 was treated with ammonium thiocyanate in 35% HCl, it gave the thiosemicarbazide 15 . Subsequent treatment of 15 with concentrated sulfuric acid or 10% sodium hydroxide gave 5‐amino‐1,3,4‐thiadiazole 16 and 1,2,4‐triazole 17 , respectively. The structures of all newly isolated compounds were confirmed using ¹H NMR, IR spectra, and elemental analyses. The antimicrobial activities for all isolated compounds were examined against different microorganisms.     

Synthesis of Some New [1,8]Naphthyridine,Pyrido[2,3‐d]‐Pyrimidine,and Other Annulated Pyridine Derivatives

2‐Aminopyridine‐3‐carbonitrile derivative 1 reacted with each of malononitrile, ethyl cyanacetate, benzylidenemalononitrile, diethyl malonate, and ethyl acetoacetate to give the corresponding [1,8]naphthyridine derivatives 3 , 5 , 8 , 11 , and 14 , respectively. Further annulations of 3 , 5 , and 8 gave the corresponding pyrido[2,3‐b][1,8]naphthyridine‐3‐carbonitrile derivative 17 , pyrido[2,3‐h][1,6]naphthyridine‐3‐carbonitrile derivatives 18 and 19 , respectively. The reaction of 1 with formic acid, formamide, acetic anhydride, urea or thiourea, and 4‐isothiocyanatobenzenesulfonamide gave the pyridopyrimidine derivatives 20a , b , 21 , 22a , b , and 26 , respectively. Treatment of compound 1 with sulfuric acid afforded the amide derivative 27 . Compound 27 reacted with 4‐chlorobenzaldehyde and 1H‐indene‐1,3(2H)‐dione to give the pyridopyrimidine derivative 28 and spiro derivative 30 , respectively. In addition, compound 1 reacted with halo compounds afforded the pyrrolopyridine derivatives 32 and 34 . Finally, treatment of 1 with hydrazine hydrate gave the pyrazolopyridine derivative 35 . The structures of the newly synthesized compounds were established by elemental and spectral data.