The chemistry of 2-aminobenzoyl hydrazides. 1. Effects of orthoester substituents on the mode of cyclization

Treatment of substituted 2-aminobenzoyl hydrazides with orthoesters has been found to yield different products depending upon the type of orthoester employed. Equimolar quantities of orthoester and hydrazide yield 3-amino-4(3H)-quinazolinones, whereas utilization of a two-fold excess (or greater) of orthoester yields, in some cases, 3,4-dihydro-5H-1,3,4-benzotriazepin-5-ones as minor products in addition to N-[4(3H)-quinaz-olinon-3-yl]imidate esters as major products. Treatment of hydrazides with trimethyl orthobenzoate yields substituted 5-(2-aminophenyl)-1,3,4-oxadiazoles and 3,4-dihydro-5H-1,3,4-benzotriazepin-5-ones. The steric bulk of the phenyl group in trimethyl orthobenzoate effects the formation of adduct at the β-nitrogen of the hydrazide which cyclized to the oxadiazole and benzotriazepinone products. In the aliphatic orthoester series, the formation of adduct to the aromatic amino group appears to be favored which gives rise to quinazolinone and benzotriazepinone products.     

Synthesis of 2-(2′,3′-dihydroxypropyl)-5-amino-2H-1,2,4-thiadiazol-3-one and 3-(2′,3′-dihydroxypropyl)-5-amino-3H-1,3,4-thiadiazol-2-one

The synthesis of two new acyclic nucleoside analogs, 2-(2′,3′-dihydroxypropyl)-5-amino-2H-1,2,4-thiadiazol-3-one (1) and 3-(2′,3′-dihydroxypropyl)-5-amino-3H-1,3,4-thiadiazol-2-one (2), is reported. The first compound, 1, was obtained by reaction of 3-chloro-1,2-propanediol with the sodium salt of 5-amino-2H-1,2,4-thiadiazol-3-one (3) in anhydrous dimethylformamide. Similarly, 5-amino-3H-1,3,4-thiadiazol-2-one (4) reacted with 3-chloro-1,2-propanediol to give 2. The thiadiazole 4 was prepared by condensation-cyclization of hydrazothiodicarbonamide (9).     

FT-Raman spectroscopy of the reaction of polybutadiene with mercapto-thiadiazoles

Mercapto-thiadiazoles having potential anti-wear behaviour are reacted with polymers with existing viscosity index-improving properties in order to produce materials which may find a use as multifunctional lubricant additives. 2,5-Dimercapto-1,3,4-thiadiazole, 2-amino-5-mercapto-1,3,4-thiadiazole and 2-methyl-5-mercapto-1,3,4-thiadiadiazole were reacted with low MW polybutadiene containing vinyl-1,2, cis-1,4 and trans-1,4 (C=C) groups. The reactions were monitored using FT-Raman spectroscopy in order to determine quantitatively the consumption of the individual structural units when reacted with thiadiazoles. 2,5-Dimercapto-1,3,4-thiadiazole reacted readily with the polybutadiene, achieving 80% reaction within a few hours. The thiadiazole reacted selectively with the order of addition being cis>vinyl>trans. 2-Amino-5-mercapto-1,3,4-thiadiazole and 2-methyl-5-mercapto-1,3,4-thiadiazole were found to react more slowly and hence to a lesser extent (40 and 25%, respectively) over a similar time scale.     

2-Azido-1,3,4-thiadiazoles, 2-Azido-1,3-thiazoles,and Aryl Azides in the Synthesis of 1,2,3-Triazole-4-carboxylic Acids and Their Derivatives

Diazotization of 2-amino-1,3,4-thiadiazoles gave 1,3,4-thiadiazole-2-diazonium sulfates which were converted to 2-azido-1,3,4-thiadiazoles. The latter reacted with ethyl acetoacetate in the presence of sodium methoxide in methanol to produce 1-(5-R¹-1,3,4-thiadiazol-2-yl)-5-R²-1H-1,2,3-triazole-4-carboxylic acid derivatives. The reactions of 2-azido-5-methyl-1,3,4-thiadiazole and 2-azido-1,3-thiazole with ethyl 3-(1,3-benzodioxol-5-yl)-3-oxopropanoate led to the formation of 1,2,3-triazole ring under milder conditions (K₂CO₃, DMSO). Various 1,2,3-triazole-4-carboxylic acid derivatives were synthesized.     

Reactivity of 2-amino-1,3,4-thiadiazoles. Nucleophilic behaviour of some 2-amino-1,3,4-thiadiazoles: Model compounds

The ambident nucleophilic behaviour of some 2-amino-5-H-1,3,4-thiadiazoles in alkylation, acylation and nitrosation reaction has been verified. The structures assigned to the 2-amino-1,3,4-thiadiazoles ( 1a-i ) and to the Δ²-1,3,4-thiadiazolines ( 2a-e ) agree with the spectral data.     

Studies on condensed heterocyclic compounds II.Synthesis and antibacterial activity of 3-(4''''-pyridyl)-6-aroylamino/arylamino-S-triazolo[3,4-b]-1,3,4-thiadiazoles

3-(4′-Pyridyl)-4-amino-5-mercapto-1,2,4-triazole(1)reacted with aroyl isothiocyanates2a-1 to yield twelve novel 3-(4′-pyridyl)-6-aroylamino-S-triazolo[3,4-b]-1,3,4-thiadiazoles,4a-1.Triethylamine was necessary for the condensation of 1 with phenyl isothiocyanate(3)to give 3-(4′-pyridyl)-6-phenylamino-S-triazolo[3,4-b]-1,3,4-thiadiazole(6).The structures were confirmed bythe elemental and spectral analyses.Their antibacterial activity against B.Subtilis,E.Coli,E.aerogenes and S.aureus was observed preliminary.     

Chemistry of sulfonyl isocyanates and sulfonyl isothiocyanates. X. Possible routes to substituted imidazolidinethiones and hexahydropyrimidinethiones

4-Toluenesulfonyl isocyanate (I) reacted with 2-aminoethanol and 3-amino-l-propanol to give 2:1 isocyanate/amino alcohol addition products. 1-Amino-2-propanol and I gave 1:1 and 2:1 adducts while 2-amino-2-methyl-l-propanol afforded only a 1:1 adduct. 4-Toluenesulfonyl isothio-cyanate (III) gave 1:1 adducts with 2-aminoethanol, l-amino-2-propanol and 3-amino-l-propanol, the first two of which were cyclized by concentrated sulfuric acid to 1-(4-toluenesulfonyl)-imidazoline-2-thiones and the third to 1-(4-toluenesulfonyl)hexahydropyrimidine-2-thione. A 1:2 adduct was obtained from III and 2-amino-2-methyl-l-propanol. Amino acids reacted with I and with 4-chlorobenzenesulfonyl isocyanate (II) to give N-(arylsulfonyl)-N¹-(carboxylic acid)-ureas. N-(4-Toluenesulfonyl)-N¹-(acetic acid)-urea (XVI) was converted to the methyl ester (XIX) by concentrated sulfuric acid and methanol and to water-soluble unrecoverable products by sulfuric acid alone. Glycine and III gave N-(4-toluenesulfonyl)-N¹-(acetic acid)-thiourea (XX) which was converted to the methyl ester (XXII) by concentrated sulfuric acid/methanol and to the cyclic 1-(4-toluenesulfonyl)imidazolin-5-one-2-thione (XXI) by sulfuric acid alone.     

Studies on reactive intermediates. Part I. An approach to the synthesis of 2-phenyl-7-carbethoxy-5H-1,3,4-thiadiazolo[2,3-a]pyrimidin-5-one

2-Phenyltetrazolo[4,5-a]-1,3,4-thiadiazole ( 4 ), in its azido form, reacted with diethyl fumarate and diethyl maleate to give 2-phenyl-7-carbethoxy-5H-1,3,4-thiadiazolo[2,3-a]pyrimidin-5-one ( 5 ). To assign the structure of compound 5 , 2-phenyl-5-carbethoxy-7H-1,3,4-thiadiazolo[2,3-a]pyrimidin-7-one ( 6 ) was prepared from the reaction of 2-amino-5-phenyl-1,3,4-thiadiazole ( 7 ) with diethylacetylene dicarboxylate. Physical properties and spectral data of compound 6 were different from compound 5 . Theoretical and experimental aspects are discussed.     

On the preparation of substituted 4H- 1,3,4-thiadiazolo[2,3-c]-1,2,4-triazin-4-ones and 1,2,4-triazolo[3,4-b]-1,3,4-thiadiazoles

The reaction of benzoyl isothiocyanates and methoxycarbonyl isothiocyanate with 4-amino-4,5-dihydro-3-(methylthio)-1,2,4-triazin-5-ones in acetonitrile gave several substituted 4H-1,3,4-thiadiazolo[2,3-c]-1,2,4-triazin-4-ones VIa-h instead of the expected thioureas. In addition, benzoyl isothiocyanate reacted with 4-amino-3-(methylthio)-5-(trifluoromethyl)-4H-1,2,4-triazole to give the benzoyl thiourea IX and with 4-amino-3-mercapto-5-(trifluoromethyl)-4H-1,2,4-triazole to give the bicyclic compound N-[3-(trifluoromethyl)-1,2,4-triazolo[3,4-b]-1,3,4-thiadiazol-6-yl]benzamide IX .     

Formation of pyrimidine-5-carboxaldehydes, 1-aminoethylene-2,2-dicarboxaldehyde and 2-amino-4-anilino-1,3,5-triazine from triformylmethane and amidines

Triformylmethane ( 1 ) reacted with benzamidine, guanidine and S-methylisothiourea to give the corresponding 2-substituted pyrimidines-5-carboxaldehydes. However, reactions of 1 with acetamidine (or for-mamidine) and phenylbiguanide gave the unexpected 1-aminoethylene-2,2-dicarboxaldehyde ( 5 ) and 2-amino-4-anilino-1,3,5-triazine ( 9 ), respectively.     

Pyrimidine derivatives and related compounds. A novel synthesis of pyrimidines,pyrazolo[4,3-d]pyrimidines and isoxazolo[4,3-d] pyrimidine

Benzoylacetonitrile (II) reacted with trichloroacetonitrile (III) to yield the β-amino-β-trichloromethylacrylonitrile IV. Compound IV reacted with hydrazine hydrate to yield 5-amino-4-cyano-3-phenylpyrazole (V) and with 2-aminopyridine to yield the aminopyridine derivative VIII (cf., Chart I). Compound IV reacted with III to yield 2,4-bis(trichloromethyl)-5-cyano-6-phenylpyrimidine (I) which could be converted into a variety of pyrazolo[4,3-d]pyrimidine derivatives by treatment with hydrazine hydrate under a variety of different experimental conditions (cf., Chart II).     

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 5-fluoro-2-methyl-3-(2-trifluoromethyl-1,3,4-thiadiazol-5-yl)-4(3H)-quinazolinone and related compounds with potential antiviral and anticancer activity

The synthesis of ten new substituted 1,3,4-thiadiazolyl-4(3H)-quinazolinones 8–11, 13, 17 , and 20–23 is reported. Compounds 8–11 were prepared by condensation of 5-fluoro-2-methyl-3,1-benzoxazin-4-one (3) and 5-substituted 2-amino-1,3,4-thiadiazoles 4–7. Compound 13 was obtained by condensation of 5-fluoro-2-methyl-3,1-benzoxazin-4-one (3) with DL-α-amino-?-caprolactam (12) . Compound 17 was synthesized by condensation of 6-bromo-2-methyl-3,1-benzoxazin-4-one (16) and 2-amino-5-t-butyl-1,3,4-thiadiazole (5) . Compounds 20–23 were obtained by condensation of 5-chloro-6,8-dibromo-2-methyl-3,1-benzoxazin-4-one (19) and 5-substituted 2-amino-1,3,4-thiadiazoles 4–7, respectively. The substituted 3,1-benzoxazin-4-ones 3, 16, and 19 were obtained in good yield by refluxing the appropriate anthranilic acid, 1,15 , and 18 with acetic anhydride (2) .     

含三唑基的新型咪唑[2,1-b]-1,3,4-噻二唑的合成及表征

以2-(2-苯基-1,2,3-三唑-4-基)-5-氨基-1,3,4-噻二唑(1)为原料分别与ω-溴代芳基乙酮、ω-溴代-ω-(1H-1,2,4-三唑-1-基)芳基乙酮反应, 合成了一系列新型咪唑[2,1-b]-1,3,4-噻二唑类化合物2a～2e和3a～3e. 其结构经IR, ¹H NMR和MS及元素分析确证.     

Facile synthesis of fluorine-containing [4-aryl-4,5-dihydro-5-imino-1,3,4-thiadiazol-2-ylaryl]methanone, 2-amino-4-aryl-5-arylazothiazoles and 3-aroyl-4-acetyl/benzoyl-5-methyl-1-phenylpyrazoles through N-aryl-α-oxo-α-arylethanehydrazonoyl bromide

N-Aryl-α-oxo-α-arylethanehydrazonoyl bromides 2 react with potassium thiocyanate in ethanol leading to the formation of [4-aryl-4,5-dihydro-5-imino-1,3,4-thiadiazol-2-ylaryl]methanone 5 in quantitative yield. Treatment of 2 with thiourea and β-diketones affords 2-amino-4-aryl-5-arylazothiazoles 4 and 3-aroyl-4-acetyl/benzoyl-5-methyl-1-phenylpyrazoles 6 in 65–70 and 60–70% yields respectively. Compound 5 has also been subjected to acetylation and chloroacetylation. All the compounds are characterized by their analytical and spectral (ir, ¹H-nmr and ms) data. Mass fragmentation patterns of these compounds are discussed.     

4-(对取代苯基)-2-[2-(取代苯基)呋喃-4-甲酰胺]-1',3',4'-均三唑[1,2-d]-1,3,4-噻二唑类衍生物的合成和生物活性

以1-氨基-5-巯基-2-(对取代苯基)-1,3,4-均三唑和5-取代苯基-2-呋喃甲酰异硫氰酸酯为原料, 合成了10个未见文献报道的含苯环连呋喃的均三唑并噻二唑类衍生物, 通过元素分析, ¹H NMR, IR和MS确定化合物的结构, 初步生物活性测试表明标题化合物具有一定的除草活性.     

Reactions with Naphthoylhydroxlmoyl Chlorides: Synthesis of Derivatives of Isoxazole,Pyrrolidino[3,4-d]isoxazoiin-4,6-dione,lmidazo[1,2-a]pyridine,lmidazo[1,2-a]pyrimidine,Benzotriazine and Benzothiadiazine

Hydroximoyl chlorides 3 react with acrylonitrile, N-arylmaleimide and maleic anhydride to give isoxazolines 5 , pyrrolidino[3,4-d]isoxazolines 8 , and furolidino[3,4-d]isoxazolines 9 , respectively. 3 reacted with 2-aminopyridine, 2-aminopyrimidine, o-phenylenediamine and o-aminothiophenol to yield 3-ni-trosoimidazo[1,2-α]pyridines 20 , 3-nitrosopyrimidines 22 , 3-naphthoyl-1,4-dihydrobenzo-1,2,4-triazines 24 , and 3-naphthoyl-4H-1,3,4-benzothiadiazine 27 , respectively. Compound 3 reacted with benzoylacetonitrile, acetoacetanilide, thiophenol, benzencsulfinic acid in ethanolic sodium ethoxide solution to give the corresponding isoxazoles 12–13 and oximes 16–17 , respectively. The structures of these products were confirmed by elemental analyses, spectral data and, wherever possible, alternative synthesis.     

Synthesis of 5-aroylamino-3H-1,3,4-thiadiazole-2-thiones and their tautomerism

5-Aroylamino-3H-1,3,4-thiadiazole-2-thiones 2 have been synthesized by acylation of 5-amino-3H-1,3,4-thiadiazole-2-thione 1 . 5-Aroylamino-3H-1,3,4-thiadiazole-2-thiones can exist in two tautomeric forms — a thiol form and a thione form. On the basis of the ¹³C nmr spectra and additional experimental information, it has been established that the thione form is the stable form in which these compounds exist.     

Reactions with cyclic amidines II. The behaviour of cyclic amidines toward ethoxycarbonyl and aroyl isothiocyanates

The behaviour of the aminopyrazole derivatives 1a-c, 2-amino-4-phenylthiazole (2) and 2-amino-5-phenyl-1,3,4-thiadiazole (3) toward the action of ethoxycarbonyl and benzoyl iso-thiocyanate is reported. The data clearly demonstrates the dependence of the nature of the products obtained from the reaction of isothiocyanates with cyclic amidines on the nature of the substituents on the heterocyclic ring.     

Synthesis and Herbicidal Activity of 2‐Aroxy‐propanamides Containing Pyrimidine and 1,3,4‐Thiadiazole Rings

A series of novel N‐{5‐[2‐(4,6‐dimethoxy‐pyrimidin‐2‐yloxy)‐phenyl]‐[1,3,4]thiadiazol‐2‐yl}2‐aroxy‐propanamides were designed and synthesized by the multistep reactions. 2‐(4,6‐Dimethoxy‐pyrimidin‐2‐yloxy)‐benzaldehyde ( 1 ) reacted with aminothiourea to yield 2 , which undergoes ring closure to give 5‐[2‐(4,6‐dimethoxy‐pyrimidin‐2‐yloxy)‐phenyl]‐[1,3,4]thiadiazol‐2‐amine ( 3 ) in the presence of ferric chloride in refluxing ethanol. 3 reacted with 2‐aroxy‐propionyl chlorides to give the target compounds 4a , 4b , 4c , 4d , 4e , 4f , 4g , 4h , 4i in moderate to good yields. Their structures were confirmed by IR, ¹H‐NMR, EIMS, and elemental analyses. The preliminary bioassay indicated that some of them displayed moderate to good selective herbicidal activity against Brassica campestris L. at the concentration of 100 mg/L. However, these compounds did not possess inhibitory activity against Echinochloa crus‐galli at the tested concentrations.