Synthetic Access to New Pyridone Derivatives through the Alkylation Reactions of Hydroxypyridines with Epoxides

General methods for the preparation of a variety of pyridone and oxypyridine derivatives are described. 2‐,3‐,4‐Hydroxy pyridine and 2‐pyridinemethanol were alkylated with ethylene‐, propylene‐, and stryrene‐oxide and epichlorohydrin in the presence of different Lewis acids as a catalyst. The best yield of 3a was achieved in the presence of CdI₂/BF₃ · OEt₂. The corresponding pyridone derivatives (3a–d, 7a–d) were obtained from the reaction of 2‐and 4‐hydroxypyridine with oxiranes in good yields, whereas oxypyridine derivatives (5a–d, 9a,b) were obtained from reactions of 3‐hydroxypyridine and 2‐pyridinemethanol with oxiranes. Chlorohydrines (3d, 5d, 7d) were easily converted to corresponding epoxy derivatives (10, 11, 12) in basic medium; then amino alcohols (13–17) were obtained from the reaction of these epoxy derivatives with amines.     

新型四硫富瓦烯硫杂冠醚衍生物的合成

在高度稀释条件下, 经4,5-二溴甲基-1,3-二硫杂环戊烯-2-硫酮(7)和多缩乙二醇的1,ω-二巯基衍生物的缩合反应, 方便地合成了4,5-位带二硫杂冠醚残基的2-硫代-1,3-二硫杂环戊烯的衍生物8a～8d, 中间体硫杂冠醚8c～8d的合成中有明显的“模板效应”. 在亚磷酸三乙酯存在下, 8a～8d经自偶联生成新型的对称双臂四硫富瓦烯(TTF)硫杂冠醚衍生物10a～10d, 而与4,5-二甲硫基-1,3-二硫杂环戊烯-2-酮(9)经交叉偶联生成新型的非对称单臂四硫富瓦烯硫杂冠醚衍生物11a～11d. 用循环伏安法研究了上述目标化合物的电化学性质和离子传感性质.     

2-(4-β-D-吡喃阿洛糖苷-苯基)-5-取代芳基-1,3,4-噁二唑的合成及镇静活性研究

以豆腐果苷为原料, 与取代苯甲酰肼反应生成中间体4-β-D-吡喃阿洛糖苷-苯甲醛取代苯甲酰腙(2a～2g), 在溴作催化剂的条件下发生关环反应, 合成了一系列豆腐果苷类似物3a～3g. 所有化合物结构经IR, ¹H NMR以及MS谱得以证实. 初步药理实验结果表明, 化合物3a, 3c, 3f与豆腐果苷相比有更好的镇静活性.     

Synthesis and biological evaluation of new 3,5-di(trifluoromethyl)-1,2,4-triazolesulfonylurea and thiourea derivatives as antidiabetic and antimicrobial agents

Fluorinated 1,2,4-triazoles 3 and benzenesulfonyl urea and thiourea derivatives as well as their cyclic sulfonylthioureas 4–10 were prepared as antimicrobial agents. The chemistry involves the condensation of sulfanilamide derivatives 1 with trifluoroacetic anhydride to give N-di(trifluoroacetyl)sulfonamides 2 which upon reaction with hydrazine hydrate afforded the corresponding triazole derivatives 3. Reaction of triazole derivative 3a with isocyanates and isothiocyanates gave the corresponding ureas 4 and thioureas 5. Cyclization of thiourea derivatives with ethyl bromoacetate, 1,2-diiodoethane, diethyl oxalate and α-bromoacetophenone derivatives yielded the corresponding 4-oxothiazolidines 7, thiazolidines 8, 4,5-dioxothiazolidines 9 and thiazolines 10. Preliminary biological screening of the prepared compounds revealed significant antimicrobial and mild antidiabetic activities.     

Synthesis and calming activity of helicid derivatives containing the 3,4-dihydropyrimidin-2(<Emphasis Type="Italic">H</Emphasis>)-one and 3,4-dihydropyrimidine-2(<Emphasis Type="Italic">H</Emphasis>)-thione moiety

A series of novel helicid derivatives containing 3,4-dihydropyrimidin-2(1H)-one and 3,4-dihydropyrimidine2(1H)-thione moiety (3a–3f and 4a–4f) were synthesized starting from helicid. The structure of the new compounds were characterized by ¹H NMR, IR and HR-MS spectra. The sedative-hypnotic activities of the target compounds were evaluated using the test of spontaneous locomotor activity in mice. All of the derivatives produced moderate to high activities; in particular, compound 4a presented the most potent sedative-hypnotic effect in comparison to the other derivatives, and derivatives 3a, 3c, 3d, 3e and 3f also showed potent activities.     

γ-Oxo Carboxylic Acids in Heterocyclic Synthesis IV. Synthesis of Some Pyridazines Containing Phthalyl and Tosyl Amino Acids Using Dcc as the Condensing Agent

The 3(2H)-oxo-, 3(2H)-thioxo- or 3-amino-pyridazine derivatives 4, 6 and 7 were coupled with N-phthalyl- or N-tosyl-amino acids in one-step using N,N′-dicyclohexyl-carbodiimide as the condensing agent to furnish the corresponding 3-(N-phthalyl- or N-tosyl-aminoacyl)pyridazine derivatives 8–10 respectively. Hydrazinolysis of the N-phthalyl derivatives in methanol yielded the corresponding unprotected derivatives 11–13. The antibacterial activities of the prepared compounds were tested.

     

Dapson in Heterocyclic Chemistry,Part II: Antimicrobial and Antitumor Activities of Some Novel Sulfone Biscompounds Containing Biologically Active Thioureido,Carbamothioate, Quinazoline,Imidazolidine, and Thiazole Moieties

The reaction of 4,4′-diisothiocyanato-1,1-diphenylsulfone 2 with aromatic amines and phenol derivatives afforded the corresponding thioureio derivatives 3–9 , respectively. Also, the reaction of 2 with catechol gave the corresponding carbamothioate derivative 11. Quinazoline derivatives 14 and 15 were obtained in good yield via reaction of 2 with anthranlic acid derivatives. Imidazolidine biscompounds 16 and 17 were readily synthesized from the reaction of 2 with N-(4-substituted-phenyl)cyanothioformanilides. The structure of the products was confirmed from elemental analysis as well as spectral data. Most of the synthesized compounds showed remarkable antimicrobial activity compared with chloramphenicol and Grisofluvine as positive controls. Compound 6 was almost as active an antitumor agent as the reference drug Doxorubicin.     

Two new 2-arylbenzofurnan derivatives from the leaves of Morus alba

Two new 2-arylbenzofuran derivatives, moracinfurol A and B (1–2), and ten known compounds (3–12) were isolated from the leaves of Morus alba. Their structures were determined on the basis of spectroscopic analysis including 1D, 2D NMR and HR-ESI-MS. All of the 2-arylbenzofuran derivatives were evaluated for cytotoxicity against A549 cells. Some cytotoxic 2-arylbenzofuran derivatives might induce autophagy characterized by the accumulation of LC-3 Ⅱ.     

Synthesis and Antimicrobial Properties of New Thiosemicarbazide, 1,2,4-Triazole,and 1,3,4-Thiadiazole Derivatives of Sulfanylacetic Acid

Abstract

1,2,4-triazole and 1,3,4-thiadiazole derivatives are still considered a viable lead structure for the synthesis of more efficient antimicrobial agents having a broad spectrum of activity. This study presents the synthesis and antimicrobial evaluation of a new series of substituted 1,2,4-triazole and 1,3,4-thiadiazole derivatives. Reaction of 4-phenyl-5-(pyridin-3-yl)-4H-1,2,4-triazole-3-thione with ethyl bromoacetate yields the corresponding ethyl acetate (1). In the subsequent reaction with 100% hydrazine hydrate, the hydrazide (2) was obtained, which was converted with isothiocyanates to new acyl derivatives of thiosemicarbazide (3a–l). The cyclization of these compounds in alkaline media resulted in the formation of new derivatives of 1,2,4-triazole (4a–i), whereas in acidic media new derivatives of 1,3,4-thiadiazole (5a,b,g) were obtained. All synthesized compounds were screened for their in vitro antimicrobial activities.     

Synthesis of Some Novel N-Substituted Phthalazinone and Pyridopyridazinone Derivatives

Phthalazinone and pyridopyridazinone derivatives 3, 5, and 9 were prepared via reaction ofappropriate lactams 2 and 8 with 2-bromoethylphthalimide, N-tosylaziridine, and N,O-ditosyl derivatives of N-methylethanolamine in a two-step process in the presence of MeONa/MeOH or NaH/dimethylformamide (DMF). Starting compounds 2 and 8 were obtained by reaction of hydrazine hydrate with isoindolinones 1 or azaisoindolinones 6. Selected N-(2-phthalimidoethyl)-phthalazinones were converted into corresponding 2-[2-(methylamino) ethyl]- derivatives in satisfactory yields by treatment with hydrazine.     

REACTIONS WITH THIAZOLINONES: A NEW ROUTE FOR THE SYNTHESIS OF THIAZOLONYLPYRIDAZONE AND THIAZOLYLPYRAZOLONE DERIVATIVES

Abstract

2-Amino-1.1.3-tricyanoprop-l-ene (1) reacted with thioglycollic acid to afford the key compound for this study namely: 2-amino-I,I-dicyano-3(2-thiazolin-4-on-2-yl)prop-1-ene 2. 2 reacted with hydrazines to afford the thiazolylmethylaminopyrazole derivatives 3 and 4. The reaction of 2 with diazotised primary aromatic amines afforded coupling products which were cyclised to the hydrazothiazolonylpyridazine derivatives 7. The reaction with aromatic aldehydes gave the his-ylidene derivatives 8. Structures are assigned based on elemental and spectroscopic analysis.     

Syntheses,spectroscopic and crystallographic characterizations of 4-nitrobenzyloxy derivatives and benzofurans from <Emphasis Type="Italic">ortho</Emphasis>-substituted benzaldehydes and 4-nitrobenzyl bromide

A series of benzyloxybenzaldehyde derivatives (1–3) were prepared by the reactions of 4-nitrobenzyl bromide with 4-hydroxy-3-methoxybenzaldehyde (vanillin), 2-hydroxy-3-methoxybenzaldehyde (o-vanillin) and 2-hydroxy-4-methoxybenzaldehyde. When the reaction time is quite long, benzofuran derivatives (4 and 5) were obtained by the reactions of ortho-hydroxyaldehydes with the 4-nitrobenzyl bromide. Condensation reactions among the three benzyloxybenzaldehyde derivatives (1–3) with 2-aminomethylfuran (furfurylamine) yielded the new imine compounds (6–8). The structures of these aldehydes (1–3), benzofuran derivatives (4 and 5) and imine compounds (6–8) were confirmed on the basis of elemental analyses, IR, ¹H NMR and ¹³C NMR and mass spectroscopy. The solid-state structures of compounds 4–6 were determined by single-crystal X-ray crystallography.     

Regiocontrolled Incorporation and Annulation of Glucose into Spirothiazole and Spirothiazoloxazole Derivatives

ABSTRACT

Cyclic ketones 1a-f reacted with mercaptoacetic acid in benzene and/or toluene in the presence of p-toluenesulfonic acid afforded the corresponding spiro-1,3-oxathialanone derivatives (2a-f). Compounds 2a-f reacted with glucosamine hydrochloride in a mixture of pyridine and ethanol to yield 3-(2′-glucosyl)-2-spiro[1′-cycloalkyl]thiazolidin-4-one derivatives 4a-f. Reaction of 4a-f with fused sodium acetate in a mixture of acetic anhydride and acetic acid gave annulated spirothiazoloxazologlucose derivatives 6a-f. All the synthesized spiro derivatives were identified by conventional methods (IR, ¹H NMR spectroscopy and elemental analyses).     

Design,synthesis of new pyrimidine derivatives as anticancer and antimicrobial agents

A new series of 6-aryl-5-cyano thiouracil derivatives were synthesized. Cyanouracil 1 was condensed with monochloroacetic acid and different aldehydes to give thiazolopyrimidine 2. On the other hand, treatment of cyanouracil 1 with 2-chloro-N-substituted-phenylac etamide afforded 4. Hydrazinolysis of 6 afforded the hydrazino derivatives 7 which upon reaction with different electrophilic reagents such as acetic anhydride, benzoyl chloride, and carbon disulfide yielded pyrimidine derivatives 8–15. Some of the new derivatives were explored for their antimicrobial activities. Compounds 7 and 9 have a promising activity, relatively equipotent to the reference drug. All of the new synthesized compounds were tested in vitro for their antiproliferative activities against HePG-2 and MCF-7 cell lines. Compounds 7, 9, and 2d displayed potent growth inhibitory effect toward the two cell lines more than the standard drug 5-FU. Furthermore, a docking study of the most active compounds was performed with thymidylate synthase enzyme.     

Synthesis of some heterocyclic compounds derived from indole as antimicrobial agents

Recently, indoles are considered interesting heterocyclic compounds due to their wide range of biological activities such as antimicrobial activity. Herein, some new indole derivatives containing heterocyclic moieties were synthesized using 3-chloro-1H-Indole-2-carbaldehyde (1) as a starting material, then allowed to react with compounds containing active methylene under Knoevenagel condensation and afforded the corresponding compounds (2, 3, 9). Also, the compound (1) when allowed to react with hydrazine derivatives gave the corresponding thiosemiccarbazone, semicarbazone, and hydrazone derivatives (4, 5, 6). Reaction of thiosemicarbazone derivatives with α-halognated carbonyl compounds gave the thiazolyl indole derivatives (10, 12a–b). Cyclic chalcones (11a–c) were obtained when compound (10) reacted with different aromatic aldehydes. The structures of all new synthesized compounds were confirmed on the basis of spectral analysis, IR, 1H NMR, 13C NMR, and MS spectroscopy. All synthesized compounds were evaluated for their antimicrobial activity. Compounds (2, 5, 7, 8, 11a, 12a) showed high antibacterial activity and compounds (3, 6, 9, 10, 11a, 12a) showed high antifungal activity.     

Novel Syntheses and Reactions of Polynuclear Heterocyclic Derivatives Derived From Thioxopyridopyrimidine,With a New Ring System

Pyridopyrimidine derivatives 2 reacted with hydrazonoylchloride derivatives and yielded triazolopyridopyrimidines 6a–f. Compound 4b reacted with aliphatic acids and afforded triazolo-pyridopyrimidines 7a,b, and the reaction with carbon disulfide afforded 10-mercapto-triazolopyridopyrimidine (10). Moreover, the reaction of 4b with β -ketoesters afforded 10-pyrazolyl-pyridopyrimidines derivatives 11, 13, 14, and 15. Compound 4b reacted with nitrous acid to give tetrazolopyridopyrimidine 16, which reduced to 10-amino-derivative 17. On the other hand, the reaction of 4b with aromatic aldehydes afforded arylidines derivatives 18a–c, which were later cyclized to triazolo-pyridopyrimidines deivatives 19a–c. Finally, 4b reacted with α-haloketones to give triazines derivativrs 20, with new ring systems.     

5-Anthracenylidene and 5-(4-Benzyloxy-3-methoxy)benzylidene-hydantoin and 2-Thiohydantoin Derivatives,Synthesis, and S-Alkylation

Abstract

5-Anthracenylidene- and 5-(4-benzyloxy-3-methoxy)benzylidene-hydantoin and 2-thiohydantoin derivatives 3a-g were prepared by condensation of anthracene-9-carboxaldehyde and 4-benzyloxy-3-methoxybenzylaldehyde with hydantoin and 2-thiohydantoin derivatives. Compounds 3a, b, f undergo Mannich reaction with formaldehyde and morpholine to give the corresponding Mannich products 4a–c. For the synthesis of alkylmercaptohydantoin 5a–o, the potassium salt of compounds 3a, b, e, f were reacted with an alkylhalide, either methyl iodide, phenacyl bromide, ethyl bromo acetate, allyl bromide, or methallyl bromide, under stirring at room temperature to afford the alkylmercaptohydantoins 5a–o. Acid hydrolysis of compounds 5a–c afforded the corresponding arylidene-hydantoin derivatives 3c, d, g. 2-Methylmercapto-hydantoin derivatives 5a, c were reacted with some secondary amines such as morpholine or piperidine to afford 5-(4-benzyloxy-3-methoxy)benzylidene-2-morpholino- or piperidino glycocyamidine derivatives 7a, 5-anthracenylidene-2-morpholin-, or piperidino glycocyamidine derivatives 7b, c.

Supplemental materials are available for this article. Go to the publisher's online edition of Phosphorus, Sulfur, and Silicon and the Related Elements to view the free supplemental file.

GRAPHICAL ABSTRACT     

Synthesis of Novel Bithiophene-Substituted Heterocycles Bearing Carbonitrile Groups

Symmetrical and unsymmetrical bithiophene-substituted heterocycles bearing carbonitriles including imidazo[1,2-a]pyridine, benzimidazole, and pyridine derivatives have been synthesized via different synthetic protocols. The bithiophene bis-imidazo[1,2-a]pyridine derivatives 3a,b were achieved in three steps starting from 2-acetyl-5-bromothiophene. Suzuki coupling reaction of 2a with 5-formylthiophen-2-ylboronic acid forms the formyl derivative 5, which by condensation with 3,4-diaminobenzonitrile in the presence of sodium bisulfite furnishes the unsymmetrical bithiophene derivative6. The bis-benzimidazole derivative 8 was obtained via hexabutylditin-mediated homocoupling of 5-bromothiophene-2-carboxaldehyde, while the benzimidazole derivatives 12a,b were prepared via the formyl derivatives 11a,b, a product of Velsmier formylation reaction of 10a,b. Two synthetic protocols for the aryl/hetaryl-2,2′-bithiophene derivative 14 have also been presented. In addition, the guanyl hydrazones of bithiophenes, 16 and 17, were prepared from bis(tri-n-butylstannyl)-2,2′-bithiophene through a Stille coupling reaction followed by a condensation step.     

1,3-dipolar cycloadditions of arylnitrile oxides and 2-diazopropane with 5-hydroxy-3-methyl-1,5-dihydropyrrol-2-one derivatives

The reactions of arylnitrile oxides 2 and 2-diazopropane 5 with 5-hydroxy-3-methyl-1,5-dihydropyrrol-2-one derivatives 1 have been studied. 1,3-dipolar cycloaddition of arylnitrile oxides and 2-diazopropane with 5-hydroxy-3-methyl-1,5-dihydropyrrol-2-one derivatives is taking place regiospecifically. The asymmetric induction expected by the chiral centre of the 5-hydroxy-3-methyl-1,5-dihydropyrrol-2-one derivatives was very effective, diastereoisomers 3 and 4 were formed in an approximate 90:10 ratio. The stereoselectivity of the 1,3-dipolar cycloaddition of the 2-diazopropane with the 5-hydroxy-3-methyl-1,5-dihydropyrrol-2-one derivatives are investigated. The attack of the 1,3-dipole occurred from the less hindered face of the dipolarophile, giving the isomer 6.     

Thiazolidinediones as a Novel Class of Algicides Against Red Tide Harmful Algal Species

This paper reports the synthesis of 28 thiazolidinedione derivatives along with their algicidal activity against microalgae causing harmful algal blooming. Among the 28 compounds tested, most showed effective algicidal activity against Heterosigma akashiwo, Chattonella marina, and Cochlodinium polykrikoides, while non-harmful algae were relatively tolerant to these thiazolidinedione derivatives. Compounds 6, 13, and 22 were the most potent against C. polykrikoides with IC₅₀ values <0.5 μM. Among the thiazolidinedione derivatives tested, compounds 7, 13, 27, and 28 were extremely competent and selective to C. polykrikoides with IC₅₀ values ranging from 0.1 to 2 μM, while C. marina and H. akashiwo showed an IC₅₀ value ranging from 30 to 130 μM. These results show that some thiazolidinedione derivatives can act as potent algicides against harmful algal blooms.