Novel syntheses of symmetrical 2,5-diaryl-1,3,4-oxadiazoles and 1,4-phenylenebis-1,3,4-oxadiazoles

The reactions of trichloromethylarenes with excess hydrazine hydrate in ethanol gives symmetrical 2,5-diaryl-1,3,4-oxadiazoles in 68–96% yields. The reaction of 1,4-bis(trichloromethyl)benzene with acylhydrazines in an ethanol-pyridine mixture gives the corresponding substituted or unsubstituted 1,4-phenylenebis-1,3,4-oxadiazoles in 35–51% yields. The mass spectra of 2,5-diaryl-1,3,4-oxadiazoles and 1,4-phenylenebis-1,3,4-oxadiazoles were studied. Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 11, pp. 2309–2316, November, 1998.     

Synthesis,Reactions, and Anticancer Activity of Some 1,3,4-Thiadiazole/Thiadiazine Derivatives of Carbazole

A novel method for the synthesis of 1,3,4-thiadiazole and 1,3,4-thiadiazine derivatives bearing a carbazole moiety is described. Carbazole was transformed into carbazole-9-thiocarbohydrazide in two steps. This compound was allowed to react with various electrophiles to yield 1,3,4-thiadiazole derivatives. The reaction with bifunctional electrophiles led to 1,3,4-thiadiazines. 2-(Carbazol-9-yl)-5,6-dihydro-4H-1,3,4-thiadiazin-5-one reacted with piperidine and formaldehyde to yield the 4-(piperidin-1-ylmethyl) derivative. The reaction with aromatic aldehydes led to the corresponding 6-arylidene derivatives, which were transformed into pyrimidino[4,5-e]-1,3,4-thiadiazines and pyrazolo[3,4-e]-1,3,4-thiadiazines by a reaction with guanidine, acetamidine, or phenylhydrazine, respectively. Structures of the products were confirmed by ¹H NMR, ¹³C NMR, IR, and mass spectrometric measurements. Selected examples of products were screened for anticancer activity.     

Synthesis of N-pyrimidin[1,3,4]oxadiazoles and N-pyrimidin[1,3,4]-thiadiazoles from 1,3,4-oxadiazol-2-amines and 1,3,4-thiadiazol-2-amines via Pd-catalyzed heteroarylamination

An efficient and practical procedure was developed to prepare various N-pyrimidin[1,3,4]oxadiazole and thiadiazole scaffolds using a Buchwald-type coupling. The products of this reaction are otherwise difficult to access and could be used as building blocks in drug design.     

Synthesis,identification and antimicrobial activity of substituted thiazolines and 1,3,4-thiadiazines from dehydroacetic acid

The reaction of thiosemicarbazones with various α-chloroketones in the presence of anhydrous NaOAc led to 4-thiazolines 5, 7 or 1,3,4-thiadiazines 11 in good yields. Structure elucidation was carried out by ¹H, ¹³C, and FT-IR spectroscopy. The purity of these new products was confirmed by HRMS. A possible mechanism for the formation of 5, 7, and 11 was discussed. All the synthesized novel 4-thiazoline and 1,3,4-thiadiazine derivatives were evaluated in vitro for their antibacterial and antifungal activities against six pathogenic bacteria and a strain of yeast: Escherichia coli ATCC 25992, Pseudomonas aeruginosa ATCC 27852, Staphylococcus aureus ATCC 25923 methicillin-resistant, Staphylococcus aureus ATCC 43300 methicillin-sensitive, Micrococcus luteus ATCC 4698 Enterococcus faecalis ATCC 29212 and Candida albicans IPA (200). Some compounds exhibited relatively significant antibacterial and antifungal activities.     

ZnCl2 catalyzed efficient synthesis of 1,3,4-oxadiazole and 1,3,4-thiadiazole

New methods for the synthesis of 1,3,4-oxadiazole and 1,3,4-thiadiazole have been described. No cyclizations took place in the absence of ZnCl₂. 1,3,4-Thiadiazoles are formed in the presence of ZnCl₂ alone, whereas oxadiazoles are produced when a base such as Et₃N or KOH was used along with ZnCl₂. % Yields are optimized.     

Design and synthesis of some new thiophene and 1,3,4-thiadiazole based heterocycles

Abstract

The reaction of 3-oxopropanenitriles with phenyl isothiocyanate in DMF containing KOH afforded the corresponding potassium salts. The latter salts were converted into ketene N,S-acetals upon acidification with hydrogen chloride. The reaction of the ketene N,S-acetals with 2-bromo-1-[5-methyl-1-(p-tolyl)-1H-1,2,3-triazol-4-yl]ethan-1-one or 3-(2-bromoacetyl)-2H-chromen-2-one gave novel thiophenes in good yields. Treatment of the ketene N,S-acetals with hydrazonyl halides afforded 1,3,4-thiadiazoles in good yields. The stereochemistry of the synthesized compounds was studied.     

Synthesis and Antibacterial Activity of Substituted Thiosemicarbazides and of 1,3,4-Thiadiazole or 1,2,4-Triazole Derivatives

The synthesized series of new thiosemicarbazide derivatives ( 1 , 6–10 ) in reactions with carbon disulphide produced, according to the reaction conditions, the dithioacids ( 4 , 30 ) or the 5-substituted 1,3,4-thiadiazolo-2-thiol derivatives ( 2 , 27 ). The dithioacids were cyclized, in the reaction with hydrazine, into the 4-ami-no-1,2,4-triazolo-2-thiol derivatives ( 5 , 31 ). One of these compounds ( 31 ) was transformed into the 1,2,4-triazolo-1,3,4-thiadiazine derivative ( 33 ). The compo-unds 6–9 were also exposed to the condensation with aldehydes. 4-phenylpipera-zinocarbothiohydrazide ( 6 ) was exposed to the action of isothiocyanates, which gave the compounds 16–20 , and these cyclized to the 1,3,4-thiadiazoloamino derivatives ( 21–23 ).

The susceptibility of aerobic and anaerobic bacteria to some of the new derivatives were tested. The anaerobes were the most susceptible at concentrations in ranges less than 6.2 to 100 μg/mL to derivative: 9 (64% were susceptible), 1 , 13 (for 60%), and 7 (for 56%).     

Synthesis of 1,3,4-thiaza- and 1,3,4-oxazaphosphol-2-lines based onN-phosphorylated (thio)ureas

The reactions ofO-phenyl chloromethylisothiocyanatothioxophosphonate andO-phenyl chloromethylisocyanatophosphonate with trimethylsilyldiethylamine lead to the formation of 1,3,4-thiazaphosphol-2-ine and 1,3,4-oxazaphosphol-2-ine, respectively. Phosphorylation ofN-methyl-N-phenyl-N,N-bis(trimethylsilyl)urea withO-phenyl chloromethylchlorophos phonate gives 1,3,4-diazaphospholidin-2-one.Translated fromIzvestiya Akademii Nauk, Seriya Khimicheskaya, No. 7, pp. 1857–1859, July, 1996.     

Synthesis of 1,3,4-oxazaphospholines based on phosphorylated carbamates

Addition of alcohols to bis(chloromethyl)phosphinoyl isocyanate, as well as the reaction of bis(chloromethyl)phosphinoyl chloride with urethanes or their silylated derivatives, gave the corresponding phosphorylated carbamates which undergo cyclization into 1,3,4-oxazaphospholines under the action of Et₃N. Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 4, pp. 810–811, April, 1999.     

Electrospray ionization mass spectrometric study of 1,3,4-oxadiazole–copper complexes

The complexes of 2,5-disubstituted-1,3,4-oxadiazoles, namely 2,5-diphenyl-1,3,4-oxadiazole (1), 2,5-bis(2-pyridyl)-1,3,4-oxadiazole (2) and 2,5-bis(4-pyridyl)-1,3,4-oxadiazole (3), with copper cation were studied by electrospray ionization mass spectrometry (ESI-MS). The ability of the compounds studied to form complexes with copper (under the ESI conditions) can be ordered as 2 > 1 > 3. The compounds studied tend to form both 1 : 1 and 2 : 1 chelate complexes with both copper(II) and copper(I). The complexes with copper(I) are formed in the ESI process. The influence of solvent polarity, solution flow-rate, counter ions (Cl⁻, NO₃⁻, CH₃COO⁻, SO₄²⁻, acetylacetonates) on the type of the ions observed was studied. Copyright © 2004 John Wiley & Sons, Ltd.     

A simple and efficient approach for the synthesis of a novel class aliphatic 1,3,4-thiadiazol-2(3H)-one derivatives via intramolecular nucleophilic substitution reaction

In this study, we synthesized a new series of substituted aliphatic 1,3,4-thiadiazol-2(3H)-one derivatives (6-24) in yields ranging from 42 to 70% with an interesting mechanism that involves internal nucleophilic substitution followed by an S_N2-type nucleophilic substitution. First, 1-(4-chlorophenyl)-2-((5-methyl-1,3,4-thiadiazol-2-yl)thio)ethanone (3) was synthesized from the reaction of 5-methyl-1,3,4-thiadiazole-2-thiol (1) with 2-bromo-1-(4-chlorophenyl)ethanone (2) in the presence of potassium hydroxide. Then, 1-(4-chlorophenyl)-2-((5-methyl-1,3,4-thiadiazol-2-yl)thio)ethanol (4) was synthesized by a reduction reaction of this compound using NaBH₄. Finally, 5-methyl-3-alkyl-1,3,4-thiadiazol-2(3H)-one derivatives (6-24), which are the target compounds, were synthesized from the reaction of this compound (4), which is a secondary alcohol with various alkyl halides (5a-n) in the presence of sodium hydride (NaH). This study presents an interesting reaction mechanism related to the synthesis of aliphatic 1,3,4-thiadiazol-2(3H)-one derivatives that is not recorded in the literature.     

One‐pot Synthesis of 2,5‐Disubstituted‐1,3,4‐oxadiazoles Based on the Reaction of N,N‐Dimethyl Amides with Acid Hydrazides

Convenient and efficient one pot method for the synthesis of 2,5‐disubstituted‐1,3,4‐oxadiazoles based on the reaction of N,N‐dimethyl amides with acid hydrazides has been developed. The methodology is applied to a wide range of difference aryl hydrazide and difference N,N‐dimethyl amides to 2,5‐disubstituted‐1,3,4‐oxadiazoles yield the in good to excellent yields. It will be possible wide useful application in synthesis.     

Ring-opening reaction of 1,3,4-oxadiazolone and 1,3,4-oxadiazolinethione: Reaction of 2-phenyl-1,3,4-oxadiazolin-5-one and 2-phenyl-1,3,4-oxadiazoline-5-thione with amines

The ring-opening abilities of amines toward 1,3,4-oxadiazolines, 2-phenyl-1,3,4-oxadiazolin-5-one ( 1a ) and 2-phenyl-1,3,4-oxadiazoline-5-thione ( 1b ), were investigated with relation to their basicities or pK_b values. Oxadiazolines 1a and 1b were easily reacted with amines such as benzylamine and aniline, but not with p-nitroaniline, to form the corresponding ring-opening adducts. The reactions of both 1a and 1b with o-phenylenediamine produced benzodiazoles with the liberation of benzoylhydrazide, whereas the reactions with o-aminobenzamide furnished quinazolines with the liberation of ammonia. o-Aminophenol and o-aminothiophenol were also reacted with 1a and 1b both of them giving 1,5-dibenzoylcarbohydrazide from 1a and 1,2-dibenzoylhydrazine from 1b. From the conditions affording the corresponding ring-opening adducts or reaction products, the ring-opening abilities of the amines toward 1a and 1b are in good correlation with the strength of their basicities or pK_b values. The ring-opening of oxadiazolines were proved to occur with anilines. Therefore, the other reactions are also supposed to proceed via the ring-opening steps.     

Synthesis and Biological Activities of Novel 1,4-Bridged Bis-1,2,4-Triazoles,Bis-1,3,4-Thiadiazoles and Bis-1,3,4-Oxadiazoles

Abstract

The terephthalic acid hydrazide(1) reacted with phenyl/benzyl isothiocyanate2a,bto yield the corresponding bis-thiosemicarbazides4a,b,viaacid hydrolysis of the intermediate 3whereas cyclization of4gave the bis-1,2,4-triazoles 5,6and bis-1,3,4-thiadiazoles7,8. Similarly, compound 1reacted with phenyl isocyanate9to give the bis-semicarbazide10, which was cyclized to the bis-oxadiazole 11and/or bis-1,2,4-triazole12in POCl_ti3and NaOH respectively.     

Reactions with Hydrazonoyl Halides 63: Synthesis and Anticancer Activity of Some New 1,3,4-Thiadiazoles, 1,3,4-Selenadiazoles,and 1,2,4-Triazolo[4,3-a]pyrimidines

2,3-Dihydro-1,3,4-thiadiazoles, 2,3-dihydro-1,3,4-selenadiazoles, and triazolino[4,3-a]pyrimidines containing benzoxazole or benzothiazole moieties were prepared from the reaction of each of ethyl 3-aza-3-(benzoxazol-2-ylamino)-2-chloroprop-2-enoate and ethyl 3-aza-3-(benzothiazolo-2-ylamino)-2-chloroprop-2-enoate with each of potassium thiocyanate, potassium selenocyanate, alkyl carbodithioate, and pyrmidine-2-thione derivatives. All the newly synthesized compounds were confirmed by elemental analysis, spectral data, and alternative route synthesis whenever possible. Some of the newly synthesized compounds were screened toward certain cancer tumors.

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.     

Synthesis of 2-amino-5-(5R-1,2,4-oxadiazolyl-3)-1,3,4-oxadiazoles

The interaction of 2-amino-1,3,4-oxadiazole-5-carboxamidoxime with nitriles in the presence of ZnCl₂ and HCl or with trichloroacetic anhydride affords 2-amino-5-(5R-1,2,4-oxadiazolyl-3)-1,3,4-oxadiazoles. Their reactions with N-nucleophiles have been studied.Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 12, pp. 2100–2103, December, 1993.     

Synthesis of 5-amino-1,3,4-thiadiazoles containing dithiocarbamate groups

Synthesis of alkyl ((5-[alkylamino]-1,3,4-thiadiazol-2-yl)methyl)carbamodithioates via the reaction of glycine-based dithiocarbamates with thiosemicarbazides in the presence of POCl₃ in ethanol is disclosed. The main advantages of this method including the use of ethanol as solvent, no need to column chromatography for purification and high to excellent yields of products are noteworthy.     

Utilization of Dipotassium Salt of Galactaric Acid Bis(Hydrazidocarbodithioic Acid) As a Synthone for Double-Headed 1,3,4-Thiadiazoline, 1,3,4-Oxadiazoline and 1,2,4-Triazoline Acyclo C-Nucleosides

Condensation of galactaric acid bis hydrazide (1) with carbon disulfide in the presence of ethanolic potassium hydroxide gave the dipotassium salt of galactaric acid bis (hydrazidocarbodithioic acid) (2). Heterocyclization of the key compound 2 produced three different types of double headed acyclo C-nucleosides: acid-catalyzed dehydrative cyclization afforded the 5-thioxo-1,3,4-thiadiazoline 3, base-catalyzed dehydrosulfurative cyclization gave the 5-thioxo-1,3,4-oxadiazoline 5, and condensative cyclization with concomitant dehydrosulfuration and dehydration with different nitrogen nucleophiles yielded the 5-thioxo-1,2,4-triazolines 7 and 9a, b. Acetylation of the prepared acyclo C-nucleosides 3, 5, 7 and 9a, b with acetic anhydride in the presence of pyridine at ambient temperature caused acetylation of the sugar hydroxyls as well as heterocyclo imino protons to give the tetra-O-acetates 4, 6, and 10a, b, respectively. Representative members of the prepared compounds were tested for antimicrobial activity.     

Synthesis and transformations of 2-(5-amino-(mercapto)-1,3,4-thiadiazolylthio)-7-methyl-5-oxo-5H-1,3,4-thiadiazolo[3,2-a]pyrimidines

The reactions of 2-amino-5-mercapto-(or 2,5-dimercapto)-1,3,4-thiadiazoles with 2-bromo-7-methyl-5-oxo-5H-1, 3,4-thiadiazolo[3, 2-a]pyrimidine to give the corresponding sulfides have been studied. The possibility of S-alkylation and addition of quinone at the free mercapto group in the 1,3,4-thiadiazole ring has been shown. The reactions at the amino group with benzoyl chloride and chloroformates have been investigated. The conditions of cyciodehydration at the amino group with ethyl acetoacetate and bromination of the pyrimidine fragment of 7-methyl-5-oxo-5H-1,3,4-thiadiazolo[3,2-a]pyrimidine have been found.Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 11, pp. 1954–1957, November, 1993     

1,3,4-Oxadiazole, 1,3,4-thiadiazole and 1,2,4-triazole derivatives as potential antibacterial agents

Since the introduction of the first antibiotic (penicillin, 1942) into medical practice, to date, there has been an ongoing “race” between scientists creating new drugs and pathogenic bacteria. Antibiotic-bacteria are becoming progressively common, and to make matters worse, more and more bacteria are becoming resistant to all known antibiotics. The traditional method for this problem is to introduce new antibiotics that kill the resistant mutants. This specific “arms race” resulted into thousands of potentially active chemicals are synthesized in laboratories around the world every day.1,3,4-Oxadiazole; 1,3,4-thiadiazole; 1,2,4-triazole and some of their derivatives are involved in modifications at the following axes: First, attaching a thio-group into heterocyclic rings. Second, introducing different substitutions at position 5 which often are the residuals of the synthetic starting materials such as simple aliphatic, substituted aliphatic chains, aromatic carbocyclic and heterocyclic residues.