Synthesis and electrophilic substitutions of novel pyrazolo[1,5-c]-1,2,4-triazolo[4,3-a]pyrimidines

5-Aryl-7-hydrazino-2-phenylpyrazolo[1,5-c]pyrimidines 1 were used as precursors for the preparation of a new series of 5-aryl-8-phenylpyrazolo[1,5-c]-1,2,4- triazolo[4,3-a]pyrimidines 2. The reactions of 2 with certain electrophilic reagents gave the respective 6-substituted derivatives 3-5 rather than the 7-isomeric products. Formylation of the key compounds 1 with ethyl formate yielded the formyl derivatives 6. Furthermore, boiling of compounds 1 with acetic acid afforded 7-acetylhydrazino-5-aryl-2-phenylpyrazolo[1,5-c]pyrimidines 7. Bromination of 7 yielded the dibromo- derivatives 8, while their iodination and nitration gave the monosubstituted derivatives 9 and 10, respectively. Also, treatment of 1 with boiling acetic anhydride yielded the triacetyl derivatives 11. The structure of synthesized products was confirmed by elemental analyses, IR, 1H NMR and MS spectra.     

The synthesis of 1-[2-(dimethylamino)ethyl]-7,12-dihydro-3H-[2]-benzoxepino[4,3-e]indole : A potential antidepressant agent

The structures of doxepin and serotonin were overlayed using molecular graphics and 1 - [2-(dimethylamino)ethyl] - 7, 12 - dihydro - 3H - [2] - benzoxepino[4,3-e]indole(1) was proposed as a potential antidepressant agent. This paper deals with the synthesis of the title compound. Key steps in the synthesis include a regioselective electrophilic substitution at C-4 of ethyl 5-hydroxy-1-indolecarboxylate (4) and subsequent modification to 7,12-dihydro-3H-[2]-benzoxepino[4,3-e]indole(12). Standard procedures were then used to construct the dimethylaminoethyl side chain to yeild the title compound (1).     

A novel pentacyclic pyridine dilactone. 7-methyl[1]benzopyrano[4,3-d][1]benzoxacino[4,3-b]pyridine-6,16-dione

When equimolar quantities of salicylaldehyde 2 and ethyl 3-amino-2-butenoate 3 or its constituents (ethyl 3-oxobutanoate and ammonia) were refluxed on a steam-bath for 6 hours with a trace of acetic acid, two products, a pentacyclic pyridine dilactone 4 and 3-acetyl coumarin 5 , resulted in 15% and 45% yields, respectively. The structure of 4 was elucidated as 7-methyl[1]benzopyrano[4,3-d][1]benzoxacino[4,3-b]-pyridine-6,16-dione on the basis of its spectral data. The mechanism of its formation has been discussed. The reaction has been extended to three more substituted salicylaldehydes.     

Synthese de s-triazolo[4,3-d] et [1,5-d] triazines-1,2,4

2-substituted s-triazolo[1,5-d] and 3-substituted s-triazolo [4,3-d]-1,2-4-triazine 8-ones were obtained starting from 5-(3)-alkyl-3(5)-carboxyhydrazino-1,2,4 triazoles and ethyl orthoformate. However, the same reaction was not found to be an efficient one in the case of 5(3)-β-D-ribofuranosyl-3(5)-carboxyhydrazino-1,2,4 triazole.     

Chemistry of 1,2,3-thiadiazole. IV. Synthesis of [1]benzoxepino-[3,4-d][1,2,3]thiadiazole, [1]benzothiepino-[3,4-d][1,2,3]thiadiazole, [1]benzoxepino[4,3-d][1,2,3]thiadiazole, [1]benzoxepino[4,3-d]oxazole and [1]benzoxepino[4,3-d]oxazole. Four novel heterocycles

Starting from the readily available 4-bromomethy-5-carbethoxy 1,2,3-thiadiazole (V), 5-bromomethy-4-carbethoxy-1,2,3-thiadiazole (IX) and ethyl 2-aryl-5-bromomethyloxazole-4-carboxylate (XIV), 4,10-dihydro-10-oxo[1]benzoxepino[3,4-d][1,2,3]thiadiazole (Ia), 4,10-dihydro-10-oxo[1]benzothiepino[3,4-d][1,2,3]thiadiazole (Ib), 4,10-dihydro-4-oxo[1]benzothiepino[4,3-d] [1,2,3]thiazole (II), 2-aryl-4,10-dihydro-4-oxo[1]benzoxepino[4,3-d]oxazoles (XIXa-XIXc) and 2-aryl-4,10-dihydro-4-oxo[1]benzothiepino[4,3-d]oxazoles (XIXd-XIXf) were prepared.     

Sur quelques analogues fluores des [1] benzothiopyrano[4,3-b]indoles et des 6H[1] benzothiopyrano[4,3-b] quinoleines

2-, 3-, and 4-Fluorinated analogs of the carcinogenic [1]-benzothiopyrano[4,3-b]indoles and of 6H[1]benzothiopyrano-[4,3-b]quinolines have been synthesized from the corresponding fluorothiochromanones. Nmr spectral data (at 60 Mc) of the six base molecules are reported. Biological tests for the possible carcinogenic activity of these new compounds, currently under way, have already shown one of them to be a powerful sarcomagen.     

Heterocyclization of Acetamidrazones. I. Synthesis of 1,2,4-triazolo[4,3-a]pyridines via ring closure of 6-(2-acylhydrazino)pyridine intermediates

The reaction of N¹-acyl-2-ethoxycarbonylacetamidrazones with ethyl ethoxymethylenecyanoacetate (EMCA) has been examined. The acetamidrazone 1a reacts with EMCA in boiling dimethyl sulphoxide to give the 1,2,4-triazolo[4,3-a]pyridin-3(2H)-one 2 in excellent yield. Similarly from the amidrazones 1b-h the 1,2,4-triazolo[4,3-a]pyridines 3b-h were obtained. When the reaction between the amidrazones and EMCA was performed in ethanolic solution, the 6-(2-acylhydrazino)-pyridines 4 were isolated. Ring closure of 4 afforded the 1,2,4-triazolo[4,3-a]pyridines.     

Synthesis and antiviral evaluation of some novel [1,2,4]triazolo[4,3-β][1,2,4]triazole nucleoside analogs

Ribosylation of 3-amino-5H-[1,2,4]triazolo[4,3-b][1,2,4]triazole ( 1 ) with l-O-acetyl-2,3,5-tri-O-benzoyl-D-ribofuranose and stannic chloride resulted in the following protected nucleoside analogs: 3-amino-1-(2,3,5-tri-O-benzoyl-β-D-ribofuranosyl)[1,2,4]triazolo[4,3-β][1,2,4]triazole ( 4 ), 3-amino-1-(2,3,5-tri-O-benzoyl-α-D-ribofuranosyl)[1,2,4]triazolo[4,3-β][1,2,4]triazole ( 5 ), 3-amino-1-(2,3,5-tri-O-benzoyl-β-D-ribofuranosyl)[1,2,4]triazolo[4,3-β][1,2,4]triazole ( 5 ), and 3-(2,3,5-tri-O-benzoyl-β-D-ribofuranosyl) amino-5H-[1,2,4]triazolo[4,3-b]-[1,2,4]triazole ( 7 ). Compounds 4–6 were deprotected to 3-amino-1-β-D-ribofuranosyl[1,2,4]triazolo[4,3-b][1,2,4]-triazole ( 3 ), 3-amino-1-α-D-ribofuranosyl[1,2,4]triazolo[4,5-b][1,2,4]triazole ( 8 ), and 3-imino-2H-2-β-D-ribo-furanosyl[1,2,4]triazolo[4,3-b][1,2,4]triazole ( 9 ), while 7 could not be deprotected without decomposition. Compounds 1, 4, 6, 7 , and 9 were screened and found to have no antiviral activity.     

Synthesis and anticonvulsant activities of 5-(2-Chlorophenyl)-7H-pyrido[4,3-f][1,2,4]triazolo[4,3-a][1,4]diazepines

A group of 5-(2-chlorophenyl)-10-(substituted)-7H-pyrido[4,3-f][1,2,4]triazolo[4,3-a][1,4]diazepines 7a-c were synthesized by the acid catalyzed reaction of 5-(2-chlorophenyl)-2-hydrazino-3H-pyrido[3,4-e]-[1,4]diazepine ( 6 ) with either trimethyl orthoformate, triethyl orthoacetate or triethyl orthobenzoate, respectively. 5-(2-Chlorophenyl)-7H-pyrido[4,3-f][1,2,4]triazolo[4,3-a][1,4]diazepine ( 7a ) and 5-(2-chlo-rophenyl)-10-methyl-7H-pyrido[4,3-f][1,2,4]triazolo[4,3-a][1,4]diazepine ( 7b ) exhibited good anticonvulsant activity in the subcutaneous metrazol anticonvulsant screen which serves as a model for absence (petit mal) epilepsy.     

Synthesis of 3-methyl-6-r-6h-thiazolo-[4,3-<Emphasis Type="Italic">b</Emphasis>]-1,2,4-triazolo[4,3-<Emphasis Type="Italic">d</Emphasis>]-1,3,4-thiadiazoles

A one-reactor method has been developed for the synthesis of 3-methyl-6-R-6H-thiazolo[4,3-b]-1,2,4-triazolo[4,3-d]-1,3,4-thiadiazoles by the condensation of aromatic aldehydes, thioglycolic acid, and 4-amino-5-methyl-1,2,4-triazole-3(2H)-thione in a sulfuric acid medium.     

Preparation of 5-substituted- and 3,5-disubstituted-s-triazolo[4,3-a]pyridines

Cyclization of N-acyl-N′-(6-chloropyrid-2-yl)hydrazines ( 2a-2e ) with phosphorus oxychloride has produced several 5-chloro-s-triazolo[4,3-a]pyridines ( 3a-3e ). Nucleophilic displacement of the chlorosubstituent of 5-chloro-s-triazolo[4,3-a]pyridine ( 3a ) availed the 5-ethoxy ( 4a ) and 5-thioethoxy ( 4b ) derivatives and di(s-triazolo[4,3-a]pyrid-5-yl)sulfide ( 8 ) while reaction of 5-ethylsulfonyl-s-triazolo[4,3-a]pyridine ( 4d ) with potassium hydroxide yielded the 5-hydroxy/5-one system ( 4c or 6 ). Further reaction of 3a with bromine to give 3-bromo-5-chloro-s-triazolo-[4,3-a]pyridine ( 3g ) has provided the corresponding 3-cyano- and 3-carboxamido-5-chloro-s-triazolo[4,3-a]pyridine derivatives ( 3h and 3i ). Treatment of 6-chloro-2-hydrazinopyridine ( 1 ) with cyanogen bromide has provided 3-amino-5-chloro-s-triazolo[4,3-a]pyridine ( 3f ) which, with bromoacetaldehyde dimethyl acetal, transformed into 7-chloroimidazo[1,2-b]-s-triazolo[4,3-a]-pyridine ( 7 ). Finally, attempts at cyclizing N-oxalyl-N′-(6-chloropyrid-2-yl)hydrazine derivatives ( 2g-2i ) with intentions of preparing various 3-acyl-5-chloro-s-triazolo[4,3-a]pyridines for entry into other 3,5-disubstituted systems were unsuccessful.     

Synthesis,X-ray crystal structure determination and antiinflammatory activity of the regioisomers: 5-phenyl-6-(4-pyridyl)-2,3-dihydroimidazo[2,1-b]thiazole and 6-phenyl-5-(4-pyridyl)-2,3-dihydroimidazo[2,1-b]thiazole. A structural reassignment

A regiospecific synthesis of 6-phenyl-5-(4-pyridyl)-2,3-dihydroimidazo[2,1-b]thiazole ( 2 ) was accomplished by treatment of 6-phenyl-2,3-dihydroimidazo[2,1-b]thiazole ( 10 ) with the reactive complex of pyridine and ethyl chloroformate followed by oxidation with chromium(VI) oxide. Reaction of 4-phenyl-5-(4-pyridyl)imidazole-2-thione ( 12 ) with 1,2-dibromoethane in the presence of base also gave 2 together with its regioisomer 3 . The structures of 2 and 3 were confirmed by X-ray crystallography. Evaluation, on oral administration, in a one hour arachidonic acid-induced mouse ear inflammation assay, showed the inhibition of edema by 2 (48%) and 3 (34%) to be less than that of the 6-(4-fluorophenyl) analog 1 (SK&/F 86002) (69%), a known antiinflammatory agent.     

Synthesis of 4(pyrazol-3-yl)[1,2,4]triazolo[4,3-a]quinoxalines and tetrazolo analog

The transformation of 2-chloro-3-[5-(acetoxymethyl)-1-phenylpyrazol-3-yl]quinoxaline 3 to 1-aryl-4-[5-(hydroxymethyl-1-phenylpyrazol-3-yl][1,2,4]triazolo[4,3-a]quinoxalines 4a-c has been achieved upon treatment with aroylhydrazines in boiling butanol. Compounds 4a-c were smoothly acetylated by acetic anhydride to give their acetyl derivatives 5a-c in good yield. 4-[5-(Acetoxymethyl)-1-phenylpyrazol-3-yl]-1-methyl[1,2,4]triazolo[4,3-a]quinoxaline was prepared by ring closure of 2-hydrazino-3-[5-(hydroxymethyl)-1-phenylpyrazol-3-yl]quinoxaline 6 by the action of acetic anhydride. The reaction of 6 with acetylacetone afforded 3-[5-(hydroxymethyl)-1-phenylpyrazol-3-yl]-2-(3,5-dimethylpyrazol-1-yl)quinoxaline 8 . In addition, the reaction of 3 with sodium azide in boiling N, N-dimethylformamide yielded the fused tetrazolo[1,5-a]quinoxaline 9 .     

Synthesis of mesoionic triazolo[4,3-a]quinoxalines

The reaction of 6-chloro-2-(1-methylhydrazino)quinoxaline 4-oxide 1 or 6-chloro-2-(1-methylhydrazino)-quinoxaline 5 with phenyl isothiocyanate under reflux in N,N-dimethylformamide gave 7-chloro-3-methyl-1,2,4-triazolo[4,3-a]quinoxalin-3-ium-1-thioate 4 , which was also obtained by refluxing of 6-chloro-2-[1-methyl-2-(N-phenylthiocarbamoyl)hydrazino]quinoxaline 4-oxide 2b or 6-chloro-2-[1-methyl-2-(N-phenylthiocarbamoyl)hydrazino]quinoxaline 6 in N,N-dimethylformamide.     

Synthesis and antimicrobial activity of some new pyrazole, fused pyrazolo[3,4-d]-pyrimidine and pyrazolo[4,3-e][1,2,4]-triazolo[1,5-c]pyrimidine derivatives

Hydrazonyl bromides 2a,b reacted with active methylene compounds (dibenzoylmethane, acetylacetone, ethyl acetoacetate, phenacyl cyanide, acetoacetanilide, ethyl cyanoacetate, cyanoacetamide and malononitrile) to afford the corresponding 1,3,4,5- tetrasubstituted pyrazole derivatives 5-12a,b. Reaction of 12a,b with formamide, formic acid and triethyl orthoformate give the pyrazolo[3,4-d]pyrimidine, pyrazolo[3,4- d]pyrimidin-4(3H)one and 5-ethoxymethylene-aminopyrazole-4-carbo-nitrile derivatives 13-15a,b, respectively. Compounds 15 a,b reacted with benzhydrazide and hydrazine hydrate to afford pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidine and [4-iminopyrazolo- [3,4-d]pyrimidin-5-yl]amine derivatives 16 a,b and 17 a,b. Reactions of compounds 17 a,b with triethyl orthoformate and carbon disulfide give the corresponding pyrazolo[4,3-e]- [1,2,4]triazolo[1,5-c]pyrimidine derivatives 18a,b and 19 a,b, respectively.     

1,2,4-Triazolo[4,3-c]pyrimidines from 4-acylhydrazinopyrimidines

The reaction of N¹-acetylacetamidrazones 1 with N-[bis(methylthio)methylene]cyanamide (2) at room temperature in the presence of potassium carbonate in dimethyl sulfoxide affords good yields of ethyl 4-acylhydrazino-2-amino-6-methylthio-5-pyrimidine carboxylate 3 . By briefly refluxing compounds 3 in dimethyl sulfoxide, 1,2,4-triazolo[4,3-c]pyrimidine derivatives 4 were obtained. When equimolecular amounts of N¹-acylacetamidrazones and compounds 2 were refluxed in dimethyl sulfoxide/toluene, compounds 4 were obtained directly.     

Synthesis of new pyrazolo[4,3-c]quinolin-3-one derivatives and some oxazolo[4,5-c]quinoline-2,4-diones

The new pyrazolo[4,3-c]quinolin-3-one derivatives 3a-c and 6a-c were prepared by the following three steps: first the preparation of ethyl 4-hydroxyquinoline-3-carboxylate derivatives 1 and 4 by reaction of isatoic anhydrides and ethyl malonate and ethyl acetoacetate respectively, then chloration of 1 and 4 with phosphorus oxychloride to give 2 and 5 and finally the condensation of 2 and 5 with hydrazine and its derivatives. In addition, the successful synthesis of oxazolo[4,5-c]quinoline-2,4-diones 9a-f are reported.     

REACTIONS OF HYDRAZONOYL HALIDES 371: SYNTHESIS OF TRIAZOLO[4,3-a]PYRIMIDINES, 1,3,4-THIADIAZOLES AND 1,3,4-SELENADIAZOLES

1,2,4-Triazolo[4,3-a]pyrimidines, thiadiazolines and selenadiazolines synthesized via reactions of hydrazonoyl halides with each of ethyl 4-(3,4-dimethoxyphenyl)-6-methyl-2-methylthio-3,4-dihydropyrimidine-5-carboxylate (or ethyl 6-(3,4-dimethylphenyl)-4-methyl-2-thio1,3,6-trihydropyrimidine-5-carboxylate), ethyl 4-(2,3-dimethoxyphenyl)- 6-methyl-2-methylthio-3,4-dihydropyrimidine-5-carboxylate, potassium thiocyanate, potassium selenocyanate, and carbodithioates respectively.     

Addition compounds of nucleophiles and 3-ethylthio-6-oxo-6H-1,2-dithiolo[4,3-c]1,2-dithiolium tetrafluoroborate. Synthesis of 3H,6H-1,2-dithiolo[4,3-c]1,2-dithiole-3-one-6-thione

Summary A smooth method of synthesizing 3H, 6H-1,2-dithiolo[4,3-c]1,2-dithiole-3,6-dithione (3), and also its partial desulfuration to yield 3H, 6H-1,2-dithiolo[4,3-c]1,2-dithiole-3-one-6-thione (4) is presented. The ethylation product5 of the monothione4 reacts with various nucleophilic reagents to form remarkably stable adducts. The adducts of5 with methanol,tert-butyl mercaptan, and with aniline could be isolated and characterized by their¹H-NMR spectra.

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Anlagerungsverbindungen von Nukleophilen an 3-Ethylthio-6-oxo-6H-1,2-dithiolo[4,3-c]1,2-dithioliumtetrafluoroborat. Synthese von 3H,6H-1,2-Dithiolo[4,3-c]1,2-dithiol-3-on-6-thion

Zusammenfassung Eine glatte Synthese für 3H,6H-1,2-Dithiolo[4,3-c]1,2-dithiol-3,6-dithion (3) und für dessen partielle Entschwefelung zu 3H,6H-1,2-Dithiolo[4,3-c]1,2-dithiol-3-on-6-thion (4) wird angegeben. Das Ethylierungsprodukt5 des Monothions4 reagiert mit unterschiedlichen Nukleophilen zu bemerkenswert stabilen Addukten. Die Addukte mit Methanol,tert.-Butylmercaptan und mit Anilin wurden isoliert und durch ihr¹H-NMR-Spektrum charakterisiert.

     

Synthesis of 7-(1-pyrrolidinyl)-1,2,4-triazolo[4,3-b]pyridazines

The reactions of secondary amines (pyrrolidine, piperidine and morpholine) with 3,4,5-trichloropyridazine ( 4 ) was investigated. With 4 and excess amine, disubstitution occurred in good yield and selectively at positions 3 and 5. Treatment of 4 with 2 equivalents of the amine in ethanol afforded high yields of products resulting from monosubstitution at position 5. 3,4-Dichloro-5-(1-pyrrolidinyl)pyridazine ( 6a ), resulting from 4 and 2 equivalents of pyrrolidine, was converted cleanly to 4-chloro-3-hydrazino-5-(1-pyrrolidinyl)pyridazine ( 8 ) with hydrazine hydrate. Pyridazine 8 was cyclized with formic acid to give a 1:1 complex ( 9 ) of formic acid and 8-chloro-7-(1-pyrrolidinyl)-1,2,4-triazolo[4,3-b]pyridazine ( 13 ). Triazolopyridazine 13 also formed a monohydrate ( 12 ) and a monohydrochloride salt ( 14 ). Catalytic hydrogenation of 9 gave 7-(1-pyrrolidinyl)-1,2,4-triazolo[4,3-b]pyridazine ( 3 ), which was a target compound of this investigation.