Dodecanoyl thiosemicarbazide derivatives as useful synthons in the synthesis of 1,2,4-triazole, 1,3,4-thiadiazole,and 1,3-benzothiazole derivatives

A convenient synthesis of the dodecanoyl thiosemicarbazide derivatives 3a, b has been achieved from the reaction of 2-benzamido-3-arylacryloylhydrazides 1a, b and lauroyl isothiocyanate (2). The thiosemicarbazide derivative 3a is used as precursor for synthesis of 1,2,4-triazole, 1,3,4-thiadiazole, and 1,3-benzothiazole derivatives. The antimicrobial activity of some of the synthesized compounds was tested.     

Synthesis, ring transformations, IR-, NMR and DFT study of heterocycles with two ferrocenyl units

Cyclization of 1,5-bis(ferrocenylmethylidene)thiocarbonohydrazide with DMAD afforded diastereomeric dimethyl-thiazole-4,5-dicarboxylates. The cis-isomer undergoes ring opening and recyclization to a thiazolone derivative. A further thiazolone was obtained from this precursor with ethyl chloroacetate employing a bifunctional organocatalyst. Due to its propensity to dehydrogenation evidenced by DFT calculations, the studied thiocarbonohydrazide underwent oxidative cyclizations under different conditions to yield a 1,3,4-thiadiazole and a 1,2,4-triazole derivative, respectively. Thermal isomerisation of 1,3,4-thiadiazole into 1,2,4-triazole was also observed. The DMAD-mediated cyclizations of the S-metylated thiocarbonohydrazide and the 1,5-bis(ferrocenylmethylideneamino)guanidine gave 1,2,4-triazole derivatives and a 4-pyrimidone, respectively. The structure of the new compounds was established by IR and NMR spectroscopy, including HMQC, HMBC and DEPT measurements. The solid state structure of a triazole was revealed by single crystal X-ray analysis.     

Synthesis of 1,2,4-Triazol-3-ylmethyl-, 1,3,4-Oxa-, and -Thiadiazol-2-ylmethyl-1H-[1,2,3]-triazolo[4,5-d]pyrimidinediones

1-Carbethoxymethyl-4,6-dimethyl-1H-[1,2,3]triazolo[4,5-d]pyrimidine-5,7(4H,6H)-dione was synthesized and treated with hydrazine hydrate to give the corresponding hydrazide. The latter hydrazide was treated either with phenylisothiocyanate or with carbon disulfide/alc. KOH to afford the corresponding thiosemicarbazide and oxadiazole derivatives. Alkylation of 2-mercapto-1,3,4-oxadiazole with dimethyl sulfate or ethyl chloroacetate gave the corresponding 2-methylthio-, and 2-ethylthioglycolate derivatives. Formation of 1,3,4-thiadiazole, 5-mercapto-1,2,4-triazole, and 1,3,4-oxadiazole were carried out by treating of the latter thiosemicarbazide with conc. H₂SO₄, NaOH/HCl, and HgO. Treating of 5-mercapto-1,2,4-triazole with ethyl chloroacetate afforded the thioglycolate ester. Hydrolysis of the latter with hydrazine hydrate afforded the hydrazide derivatives. Condensation of these hydrazides with monosaccharide aldoses gave the corresponding sugar hydrazones. The novel compounds were tested for antiviral activity against hepatitis B virus and showed moderate activities.     

Design,synthesis, and characterization of some new benzimidazole derivatives and biological evaluation

A new series of benzimidazole derivatives ( 1-15 ) containing 1,2,4-triazole, 1,3,4-thiadiazole, 1,3,4-oxadiazole, and thiazolidinon rings have been synthesized. All new synthesized benzimidazole compounds were confirmed by ¹H NMR, ¹³C NMR spectra, and LC-MS, and they were examined for their antioxidant and antimicrobial activities. Compounds 7 and 1 showed the highest and the lowest antioxidant activities, respectively. The lowest minimum inhibition concentration value found in compound 5 against Enterobacter aerogenes.     

New Approaches for the Synthesis of 1,3,4-Thiadiazole and 1,2,4-Triazole Derivatives with Antimicrobial Activity

The thiosemicarbazide derivatives 3a and 3b were cyclized in the presence of concentrated sulfuric acid to give the 5-cyanomethyl-1,3,4-thiadiazole derivatives 4a and 4b , respectively. The latter products were used for many heterocyclic transformations to form coumarin, 1,3,4-thiadiazolo[4,5-a]pyridine, and 5-thiophenylthiophene. In addition, compound 3b underwent cyclization in NaOH (2 N) solution to give the 1,2,4-triazole derivative 16 . The reactivity of the latter product towards some chemical reagents was studied. The antimicrobial activities of the newly synthesized products were measured and showed high activities.     

Synthesis of 1,2,4-Triazol-3-ylmethyl-, 1,3,4-Oxa-, and -Thiadiazol-2-ylmethyl-1<Emphasis Type="Italic">H</Emphasis>-[1,2,3]-triazolo[4,5-<Emphasis Type="Italic">d</Emphasis>]pyrimidinediones

Summary. 1-Carbethoxymethyl-4,6-dimethyl-1H-[1,2,3]triazolo[4,5-d]pyrimidine-5,7(4H,6H)-dione was synthesized and treated with hydrazine hydrate to give the corresponding hydrazide. The latter hydrazide was treated either with phenylisothiocyanate or with carbon disulfide/alc. KOH to afford the corresponding thiosemicarbazide and oxadiazole derivatives. Alkylation of 2-mercapto-1,3,4-oxadiazole with dimethyl sulfate or ethyl chloroacetate gave the corresponding 2-methylthio-, and 2-ethylthioglycolate derivatives. Formation of 1,3,4-thiadiazole, 5-mercapto-1,2,4-triazole, and 1,3,4-oxadiazole were carried out by treating of the latter thiosemicarbazide with conc. H₂SO₄, NaOH/HCl, and HgO. Treating of 5-mercapto-1,2,4-triazole with ethyl chloroacetate afforded the thioglycolate ester. Hydrolysis of the latter with hydrazine hydrate afforded the hydrazide derivatives. Condensation of these hydrazides with monosaccharide aldoses gave the corresponding sugar hydrazones. The novel compounds were tested for antiviral activity against hepatitis B virus and showed moderate activities.     

Synthesis of 3,6-bisubstituted phenyl-bi-1,2,4-triazolo[3,4-b]-1,3,4-thiadiazole derivatives

2,5-Bihydrazino-1,3,4-thiadiazole (2) was synthesized by condensation of 2,5-bimercapto-1,3,4-thiadiazole (1) with hydrazine hydrate, and compound 2 reacted with acyl chloride to give 2,5-biacylhydrazino-1,3,4-thiadiazole derivatives (3a–3e). Ring closure of compounds 3a–3e was achieved with POCl3 as the cyclization agent giving 3,6-bisubstituted phenyl-bi-1,2,4-triazolo[3,4-b]-1,3,4-thiadiazole derivatives (4a–4e), respectively. The novel compounds were identified by elemental analysis, and by infrared (IR), 1H-nuclear magnetic resonance (NMR), and mass (MS) spectrometry. The mechanism of the cyclization is also discussed. __________ Translated from Organic Chemistry, 2006, 26(12): 1720–1722 [译自: 有机化学]     

Synthesis and evaluation of antitrypanosomal activity of some thiosemicarbazide derivatives of 1-butyl-6-fluoro-7-morpholino-4-oxo-1,4-dihydroquinoline-3-carboxylic acid

The synthesis of thiosemicarbazide of 1-butyl-6-fluoro-7-morpholino-4-oxo-1,4-dihydroquinoline-3-carboxylic acid as well as its heterocyclic derivatives – 1,3,4-thiadiazole and 1,2,4-triazole are described; the modification of proper 1,2,4-triazole derivative by maleimides is also presented. Spectral properties of the prepared compounds and X-ray analysis for the selected compounds were studied. For the compounds antitrypanosomal potential and the toxicity were determined.     

Synthesis and pharmacological evaluation of 3-diphenylmethyl-6-substituted-1,2,4-triazolo[3,4-b]-1,3,4-thiadiazoles: A condensed bridgehead nitrogen heterocyclic system

A series of 3-diphenylmethyl-6-substituted-1,2,4-triazolo[3,4-b]-1,3,4-thiadiazole derivatives (4a–j and 5a–d) were synthesized by condensation of 4-amino-5-diphenylmethyl-4H-1,2,4-triazole-3-thiol with various substituted aromatic acids and aryl/alkyl-isothiocyanates. The structures of synthesized compounds were characterized by elemental analysis, IR, ¹H NMR, ¹³C NMR and mass spectroscopic studies. These compounds were tested in vivo for their anti-inflammatory activity. The compounds which showed activity comparable to the standard drug ibuprofen were screened for their analgesic, ulcerogenic, lipid peroxidation and hepatotoxic effects. Compounds 6-(4-chlorophenyl)-3-diphenylmethyl-1,2,4-triazolo[3,4-b]-1,3,4-thiadiazole (4a) and 6-(2,4-dichlorophenyl)-3-diphenylmethyl-1,2,4-triazolo[3,4-b]-1,3,4-thiadiazole(4c) emerged as the most active compounds of the series and were moderately more potent than the standard drug ibuprofen.     

Synthesis of some novel 3,4,5-trisubstituted triazole derivatives bearing quinoline ring and evaluation of their antimicrobial activity

Abstract

Some new 3,4,5-trisubstituted 1,2,4-triazole derivatives were synthesized and studied for their antimicrobial activity. The lead compounds were obtained starting from 8-hydroxyquinoline and ethyl 2-chloroacetate. The obtained ester compound (1) first reacted with hydrazine hydrate (2) then with phenyl isothiocyanate (3). Ring closure by KOH led to 3-mercapto-1,2,4-triazole derivative (4). Lastly, it reacted with 2-chloro-N-(substituted (benzo)/thiazole)acetamide derivatives to obtain the final compounds (5a–j). The structural elucidation of the compounds was performed by ¹H NMR and ¹³C NMR spectroscopy and high resolution mass spectrometry techniques and elemental analysis. The synthesized compounds were investigated for their antimicrobial activities against seven bacteria and four fungi. As a result of the activity studies, it was observed that compounds N-(6-nitrobenzothiazol-2-yl)-2-[[4-phenyl-5-((quinolin-8-yloxy)methyl)-4H-1,2,4-triazol-3-yl]thio]acetamide (5a) and N-(6-fluorobenzothiazol-2-yl)-2-[[4-phenyl-5-((quinolin-8-yloxy)methyl)-4H-1,2,4-triazol-3-yl]thio]acetamide (5d) were the most active molecules. Also, the antifungal activity of the compounds was found to be higher than their antibacterial activity although lower than the standard drug’s potential. Additionally, the physicochemical properties of the compounds were calculated which were evaluated to be at a suitable range for oral administration.     

6-硝基苯并咪唑杂环衍生物的合成

以６－硝基苯并咪唑－１－乙酰肼和５－（６－硝基苯并咪唑－１－亚甲基）－３－巯基－４－氨基－１,２,４－三唑为原料,在不同条件下合成了一系列新的均三唑〔３,４－ｂ〕－１,３,４－噻二唑,１,２,４－三唑和１,３,４－恶二唑衍生物。化合物的结构均经元素分析、＾１Ｈ ＮＭＲ、ＩＲ和ＭＳ确证,并对其波谱性质进行了讨论。     

A Convenient Route to 1,3,4-Thiadiazoles,Thiazolidinone, Thiazoles,Pyridones, Coumarins,Triazolo[5,1-c]triazines,and Pyrazolo[5,1-c]triazines Incorporating Pyrazolone Moiety and Their Use as Antimicrobial Agents

Condensation of 4-acetyl-5-methyl-2-phenyl-2,4-dihydropyrazol-3-one (1) with hydrazine derivatives (2a–d) afforded hydrazone derivatives (3a–d), which reacted with alkyl halides 4a–c to give bis(alkylthio)methylene derivatives (5a–e). Also, 3a,b reacted with hydrazonyl halides 6a–d to give 1,3,4-thiadiazole (7a–d). Cyclization of 3c with ethyl bromoacetate and haloketones gave thiazolidinone and thiazole derivatives (8, 10a,b) respectively. Treatment of hydrazone (3d) with benzylidine malononitrile 13a,b gave pyridine (14a,b). In addition, cyclocondensation of 3d with phenolic aldehydes furnished coumarin derivatives (16a–c). Coupling of 3d with heterocyclic diazonium salts gave triazol[5,1-c]triazine (20) and pyrazolo[5,1-c]triazine (22). Some of the prepared products showed potent antimicrobial activity.     

Efficient,One-Pot Synthesis of Triazolothiadiazinyl-pyrazolone and Pyrazolyl-triazolothiadiazine Derivatives via Multicomponent Reaction

A one-pot, multicomponent reaction of 3-(2-bromo acetyl)coumarins, 4-amino-5-hydrazino-4H-[1,2,4]triazole-3-thiol, and different derivatives of ethyl 2-(2-(aryl)hydrazono)-3-oxobutanoates provide an efficient and direct method for the synthesis of 4-(arylydrazono)-3-methyl-1-(6-(coumarin-3-yl)-7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazin-3-yl)-1H-pyrazol-5(4H)-ones (4a–h). A similar methodology was also developed for the synthesis of pyrazolyl-triazolothiadiazines (9a–f) using acetyl acetone, 4-amino-5-hydrazino-4H-[1,2,4]triazole-3-thiol, and different derivatives of phenacylbromide. The resulting products were characterized by analytical and spectral data.     

Synthesis,Antimicrobial, and Anthelmintic Activities of Some New 3-Chlorobenzothiophene-2-Carbonylchloride Derivatives

3-Chlorobenzothiophene-2-carbonylchloride 1 was prepared from cinnamic acid and then converted into the acid hydrazide 2. Reaction of 3-chloro-1-benzothiophene-2-carbohydrazide 2 with the appropriate isothiocyanate yielded the substituted thiosemicarbazides 3a–b, which are cyclized into thioxotetrahydropyrimidine 4a–b, 1,3,4-thiadiazoles 5a–b, thiazolidine 6a–b, 1,3,4-oxadiazole 7a–b, triazoles 8a–b, 1,2,4-triazole substitutedthioate 9a–f, and 1,3-thiazolylidenes 10a–b, respectively. The structures of the newly synthesized compounds were elucidated on the basis of elemental analyses, IR, ¹H NMR, and mass spectral data and have been screened for antimicrobial and anthelmintic activities.     

Synthesis of Some 1,3-Thiazole, 1,3,4-Thiadiazole, Pyrazolo[5,1-c]-1,2,4-triazine, and 1,2,4-Triazolo[5,1-c]-1,2,4-triazine Derivatives Based on the Thiazolo[3,2-a]benzimidazole Moiety

Summary. 3-(3-Methylthiazolo[3,2-a]benzimidazol-2-yl)-3-oxopropionitrile was synthesized by refluxing ethyl 3-methylthiazolo[3,2-a]benzimidazole-2-carboxylate, acetonitrile, and sodium hydride. Treatment of 3-(3-methylthiazolo[3,2-a]benzimidazol-2-yl)-3-oxopropionitrile with phenyl isothiocyanate, in the presence of KOH, furnished the corresponding potassium salt which was converted into thioacetanilide derivative upon neutralization. The thioacetanilide derivative reacts with α-chloroacetylacetone and ethyl α-chloroacetoacetate to give the 1,3-thiazole derivatives, while the reaction of the'thioacetanilide derivative with hydrazonyl chlorides gave 1,3,4-thiadiazole derivatives. On the other hand, 3-(3-methylthiazolo[3,2-a]benzimidazol-2-yl)-3-oxopropionitrile reacted with the diazonium salt of both 3-phenyl-5-amino-(1H)-pyrazole and 5-amino-l,2,4-(1H)-triazole to afford the corresponding hydrazones. The latter hydrazones underwent an intramolecular cyclization upon boiling in pyridine to give pyrazolo[5,1-c]-1,2,4-triazine and 1,2,4-triazolo[5,1-c]-1,2,4-triazine derivatives. Moreover, the behavior of thiazolo[3,2-a]benzimidazol-3(2H)-one towards phenyl isothiocyanate followed by the reaction with α-chloroketones or hydrazonyl chlorides was investigated. Some of the latter compounds exhibited moderate effects against some bacterial and fungal species.     

Synthesis of Some 1,3-Thiazole, 1,3,4-Thiadiazole, Pyrazolo[5,1-c]-1,2,4-triazine, and 1,2,4-Triazolo[5,1-c]-1,2,4-triazine Derivatives Based on the Thiazolo[3,2-a]benzimidazole Moiety

3-(3-Methylthiazolo[3,2-a]benzimidazol-2-yl)-3-oxopropionitrile was synthesized by refluxing ethyl 3-methylthiazolo[3,2-a]benzimidazole-2-carboxylate, acetonitrile, and sodium hydride. Treatment of 3-(3-methylthiazolo[3,2-a]benzimidazol-2-yl)-3-oxopropionitrile with phenyl isothiocyanate, in the presence of KOH, furnished the corresponding potassium salt which was converted into thioacetanilide derivative upon neutralization. The thioacetanilide derivative reacts with α-chloroacetylacetone and ethyl α-chloroacetoacetate to give the 1,3-thiazole derivatives, while the reaction of the'thioacetanilide derivative with hydrazonyl chlorides gave 1,3,4-thiadiazole derivatives. On the other hand, 3-(3-methylthiazolo[3,2-a]benzimidazol-2-yl)-3-oxopropionitrile reacted with the diazonium salt of both 3-phenyl-5-amino-(1H)-pyrazole and 5-amino-l,2,4-(1H)-triazole to afford the corresponding hydrazones. The latter hydrazones underwent an intramolecular cyclization upon boiling in pyridine to give pyrazolo[5,1-c]-1,2,4-triazine and 1,2,4-triazolo[5,1-c]-1,2,4-triazine derivatives. Moreover, the behavior of thiazolo[3,2-a]benzimidazol-3(2H)-one towards phenyl isothiocyanate followed by the reaction with α-chloroketones or hydrazonyl chlorides was investigated. Some of the latter compounds exhibited moderate effects against some bacterial and fungal species.     

Synthesis of 4-hetaryl-substituted 5-amino- and 5-sulfanyl-1,3-oxazole derivatives

Previously unknown 5-amino- and 5-sulfanyl-1,3-oxazole derivatives containing a 1,3,4-oxadiazole, 1,3,4-thiadiazole, or 1,2,4-triazole fragment at C⁴ were synthesized from accessible 1,3-oxazole-4-carboxylic acid hydrazides.     

Chromatographic and electrophoretic determination of thioamides based on thiazole, 1,3,4-thiadiazole, 1,2,4-triazole,and tetrazole

A procedure was developed for the determination of the following thioamides based on thiazole, 1,3,4-thiadiazole, 1,2,4-triazole, and tetrazole: 2-mercaptothiazole (I), 2-mercapto-1,3,4-thiadiazole (II), 2-mercapto-5-methyl-1,3,4-thiadiazole (III), 3-mercapto-1,2,4-triazole (IV), 3-mercapto-4-methyl-1,2,4-triazole (V), and 5-mercapto-1-methyltetrazole (VI). The determination was performed by reversed-phase HPLC on a column (150 × 4 mm) packed with Diaspher-110-C18 (5 μm) using elution with an acetonitrile-acetate buffer solution (pH 4.70) mixture (5: 95). Detection was performed at the light absorption maximums of compounds I (320 nm), II (305 nm), III (310 nm), IV (260 nm), V (254 nm), and VI (245 nm). The calibration graphs were linear over the following concentration ranges (μg/mL): 0.47–11.72 (I), 0.47–11.82 (II), 0.53–13.22 (III), 0.40–10.11 (IV), 0.46–11.52 (V), and 0.46–11.62 (VI). The limits of detection were 0.45, 0.43, 0.50, 0.37, 0.41, and 0.42 μg/mL for compounds I–VI, respectively. Conditions for the separation of a mixture of compounds I and III–V and for the quantitative determination of compounds I–VI by capillary zone electrophoresis (CZE) were optimized. CZE was performed on a quartz capillary of size 60 cm (effective length of 50 cm) × 75 μm at a voltage of 20 kV with a borate buffer solution (pH 9.18). The procedure allowed us to evaluate the concentrations of substances in the ranges of 1.17–93.75 (I), 1.18–94.54 (II), 1.32–105.76 (III), 1.01–101.13 (IV) 1.15–115.16 (V), and 1.16–116.15 (VI) μg/mL with the detection limits of 1.10, 1.11, 1.20, 0.96, 1.01, and 1.02 μg/mL for compounds I–VI, respectively.     

The Synthesis of Triazolothiadiazines and Thiadiazoles From 1,2-Bis-(4-amino-5-mercapto-1,2,4-triazol-3-yl)- Ethanol and Ethane

The reaction of DL-malic and succinic acids with thiocarbohydrazide afforded 1,2-bis[4-amino-5-mercapto-1,2,4-triazol-3-yl]-ethane derivatives 3a and 3b. The reaction of 3a,b with phenacyl bromide and benzoin afforded 1,2-bis-1,2,4-triazolo [3,4-b][1,3,4]thiadiazine derivatives 4 and 5. The carboethoxymethylation of 3a and 3b gave 6a and 6b, respectively, and their reactions with carbon disulfide and benzoylisothiocyanate gave the 1,2-bis-1,2,4-triazolo[3,4-b][1,3,4]thiadiazole 7 and 9, and with p-nitrobenzaldehyde gave a Schiff's base and dihydrothiadiazole 8. The structures were confirmed by using ¹ H and ¹³ C NMR spectra. Selected members of these compounds were screened for antimicrobial activity.     

微波辐射下合成5-(2-甲基/三氟甲基-苯并咪唑-1-亚甲基)-3-(苯基/p-取代苯基)-2H-1',2',4'-三唑[3,4-b]-1

分别采用微波辐射法和加热回流的常规方法, 将1-氨基-2-(2-甲基/三氟甲基-苯并咪唑-1-亚甲基)-5-巯基-1,3,4-三唑与α-溴代芳基乙酮3a～3e反应, 合成了一系列未见文献报道的1,2,4-三唑[3,4-b]-1',3',4'-噻二嗪类化合物4a～4e 和5a～5e. 微波辐射法具有反应时间短、产率高、副反应少等优点. 标题化合物经元素分析, IR, ¹H NMR, MS确证结构.