Utilization of cleavage of the [1]benzofuro[2,3‐e][1,2,4]triazine ring for the synthesis of oxygen,nitrogen and sulfur derivatives of [1,2,4]triazine

A series of 6‐azacytosines 4a‐4k and 5a‐5c were prepared by nucleophilic cleavage of furan ring of [1]benzofuro[2,3‐e][1,2,4]triazine derivative 1 . Some of them were used for the preparation of derivatives of [1,2,4]triazolo[4,3‐d][1,2,4]triazine ( 6a‐6d ) and tetrazolo[1,5‐d][1,2,4]triazine (7). The reaction of 1 with hydrogen sulfide afforded the corresponding 6‐(2‐hydroxyphenyl)‐2‐phenyl‐5‐thioxo‐4,5‐dihydro‐1,2,4‐tri‐azin‐3(2H)‐one ( 8 ), while with hydrogen selenide 6‐(2‐hydroxyphenyl)‐2‐phenyl‐4,5‐dihydro‐1,2,4‐triazin‐3(2H)‐one ( 9 ) was formed. The prepared compounds were tested for biological activity.     

Synthesis of novel pyrazolo[3,4‐d]pyrimidines peri‐fused with 1,4‐diazepine, 1,4‐thiazepine,and 1,2,4‐triazepine rings

A simple and efficient synthesis of novel ortho‐ and peri‐annulated heterocyclic systems—2,6,7,9‐tetrahydro‐8H‐pyrazolo[5,4,3‐de]pyrimido[4,5‐e][1,4]diazepine, 2,6,7,9‐tetrahydro‐8H‐pyrazolo[5,4,3‐de]pyrimido [5,4‐f][1,4]thiazepine, and 6,9‐dihydro‐2H‐pyrazolo[3,4,5‐ef]pyrimido[5,4‐f][1,2,4]triazepine is described. J. Heterocyclic Chem.,, (2012).     

Synthesis and antitumor activity of new 1,2,4‐triazine and [1,2,4]triazolo[4,3‐b][1,2,4]triazine derivatives and their thioglycoside and acyclic C‐nucleoside analogs

New 1,2,4‐triazine and their derived 1,2,4‐triazolo[3,4‐b][1,2,4]triazine derivatives were synthesized starting from 5,6‐diphenyl‐1,2,4‐triazine‐3‐thiol. Furthermore, the corresponding 1,2,4‐triazolo[3,4‐b][1,2,4]‐triazine thioglycosides and acyclic C‐nucleoside analogs were synthesized. The newly synthesized compounds were evaluated for their antitumor activity and some of them showed high inhibition activities. J. Heterocyclic Chem., 2011.     

Synthesis of some novel pyrazolo[1,5‐a]pyrimidine, 1,2,4‐triazolo[1,5‐a]pyrimidine,pyrido[2,3‐d]pyrimidine,pyrazolo[5,1‐c]‐1,2,4‐triazine and 1,2,4‐triazolo[5,1‐c]‐1,2,4‐triazine derivatives incorporating a thiazolo[3,2‐a]benzimidazole moiety

E‐3‐(N,N‐Dimethylamino)‐1‐(3‐methylthiazolo[3,2‐a]benzimidazol‐2‐yl)prop‐2‐en‐1‐one ( 2 ) was synthesized by the reaction of 1‐(3‐methylthiazolo[3,2‐a]benzimidazol‐2‐yl)ethanone ( 1 ) with dimethylformamide‐dimethylacetal. The reaction of 2 with 5‐amino‐3‐phenyl‐1H‐pyrazole ( 4a ) or 3‐amino‐1,2,4‐(1H)‐triazole ( 4b ) furnished pyrazolo[1,5‐a]pyrimidine and 1,2,4‐triazolo[1,5‐a]pyrimidine derivatives 6a and 6b , while the reaction of enaminone 2 with 6‐aminopyrimidine derivatives 7a,b afforded pyrido[2,3‐d]pyrimidine derivatives 9a,b , respectively. The diazonium salts 11a or 11b coupled with compound 2 to yield the pyrazolo[5,1‐c]‐1,2,4‐triazine and 1,2,4‐triazolo[5,1‐c]‐1,2,4‐triazine derivatives 13a and 13b . Some of the newly synthesized compounds exhibited a moderate effect against some bacterial and fungal species.     

Synthesis of [1,4]benzodioxino[2,3‐c and 2,3‐d]pyridazinones

Reaction of chloropyridazin‐3‐one 1, 5 and 10 with catechol in the presence of potassium carbonate gave the corresponding [1,4]benzodioxino[2,3‐e and/or 2,3‐d]pyridazinones 2, 7, 8 and 11 .     

Synthesis of Novel Polyfunctionally Substituted Thieno[2,3‐c]pyridazines

4‐Cyano‐5,6‐dimethylpyridazin‐3‐(2H)‐thione 3b was used as a key intermediate for the synthesis of novel polysubstituted thieno[2,3‐c]pyridazines.     

Synthesis and reactivity of cyanomethyl 2‐amino‐4‐methylthiazolyl ketone. A facile synthesis of novel pyrazolo[5,1‐c]1,2,4‐triazine, 1,2,4‐triazolo[5,1‐c]1,2,4‐triazine, 1,2,4‐triazino[4,3‐a]benzimidazole,pyridazine‐6‐imine and 6‐oxopyridazinone derivatives

The novel and versatile cyanomethyl 2‐amino‐4‐methylthiazolyl ketone (5) was prepared by treatment of bromomethyl 2‐amino‐4‐methyl thiazolyl ketone (4) with potassium cyanide. Reaction of 5 with heterocyclic diazonium salts 6a,b and 10 afforded the corresponding hydrazones 7a,b and 11, respectively. Refluxing of the hydrazones in pyridine afforded the corresponding pyrazolo[5,1‐c]‐1,2,4‐triazine, 1,2,4‐triazolo[5,1‐c]‐1,2,4‐triazine, and 1,2,4‐triazolo[4,3‐a]benzimidazole derivatives 8a,b and 12, respectively, via intramolecular cyclization. Compound 5 coupled also with benzenediazonium chloride to afford the corresponding hydrazone 14, which is an excellent precursor for the synthesis of pyridazine‐6‐imine 17a and pyridazinone 17b. The pyridazine derivatives 17a,b were also prepared by an independent route, that is, the condensation with malononitriles and coupling with benzenediazonium chloride, followed by intramolecular cyclization. © 1999 John Wiley & Sons, Inc. Heteroatom Chem 10: 385–390, 1999     

Synthesis of new thieno[2,3‐d]pyrimidines,thieno[3,2‐e]pyridines,and thieno[2,3‐d][1,3]oxazines

o‐Aminothiophene dicarbonitrile 1 on neat reaction with cyclic ketones in anhydrous ZnCl₂ yielded mixture of fused aminopyridine 3 and iminospirooxazine 4 derivatives. Similarly, pyrimidine derivatives 5 and 8 were obtained by the reaction of this intermediate 1 with formic acid and DMF‐DMA followed by hydrazine hydrate, respectively. The reaction of o‐amino‐thiophene dicarboxamide 2 at ambient temperature with cyclic ketones yielded spiropyrimidine 10 as a sole product in quantitative yield. The regioselective anellated pyrimidine 9 , 11 , and dihydropyrimidine 12 derivatives were also obtained by the reaction with aromatic aldehydes in presence of piperidine and iodine respectively. J. Heterocyclic Chem., (2012).     

Synthesis and antifolate activity of new pyrrolo[2,3‐d]pyrimidine and thieno[2,3‐d]pyrimidine inhibitors of dihydrofolate reductase

Three previously undescribed dihydrofolate reductase (DHFR) inhibitors, N^α‐[4‐[N‐[(2,4‐diaminopyrrolo[2,3‐d]pyrimidin‐5‐yl)methyl]amino]benzoyl]‐N^δ‐hemiphthaloyl‐L‐ornithine (7) , N^α‐ [4‐ [N‐[(2,4‐diaminothieno[2,3‐d]pyrimidin‐5‐yl)methyl]amino]benzoyl]‐ N^δ‐hemiphthaloyl‐L‐ornithine (8) , and N‐[4‐[N‐[(2,4‐diaminothieno[2,3‐d]pyrimidin‐5‐yl)methyl]amino]benzoyl]‐L‐glutamic acid (12) , were synthesized and their antifolate activity was assessed. The ability of 7 and 8 to bind to DHFR and inhibit the growth of CCRF‐CEM human lymphoblastic leukemia cells in culture were dramatically reduced in comparison with the corresponding pteridine analogue, N^α‐(4‐amino‐4‐deoxypteroyl)‐N^δ‐hemiphmaloyl‐L‐ornithine ( 1 , PT523). In a similar manner, the antifolate activity of 12 was markedly reduced in comparison with that of the corresponding glutamate analogue, aminopterin ( 5 , AMT). In contrast, 7, 8 , and 12 all displayed excellent affinity for the reduced folate carrier (RFC) of CCRF‐CEM cells as measured by a standard competitive influx assay. Lack of a consistent correlation between the results of the growth inhibition assays and those of the DHFR and RFC binding assays results suggest that additional factors also play a role in the antifolate activity of these compounds.     

Synthesis of chiral fused heterocyclic compounds containing 1,2,4‐triazole ring

A series of new chiral (S)‐3‐ary1‐6‐pyrrolidin‐2‐yl‐[1,2,4]triazolo[3,4‐b]thiadiazole (II_1‐5), (S)‐1‐(3‐aryl‐[1,2,4]triazolo[3,4‐b][1,3,4]thiadiazol‐6‐yl)‐ethylamine (II_6‐8) and (S)‐1,2‐bis(3‐aryl‐[1,2,4]triazolo‐[3,4‐b][1,3,4]thiadiazol‐6‐yl)‐ethylamine (II_9‐11) were prepared by the condensation of 3‐aryl‐4‐amino‐5‐mercapto‐1,2,4‐triazoles with different L‐amino acids in the presence of phosphorus oxychloride and evaluated for their antibacterial activity.     

Polycyclic N‐Heterocyclic Compounds,Part 69: Synthesis of 5‐amino‐1,2‐dihydro[1]benzofuro[3,2‐d]furo[2,3‐b]pyridines and their transformations to related compounds

Reaction of 3‐(3‐cyanopropoxy)[1]benzofuran‐2‐carbonitriles with potassium tert‐butoxide gave 5‐amino‐1,2‐dihydro[1]benzofuro[3,2‐d]furo[2,3‐b]pyridines and 5‐amino‐2,3‐dihydro[1]benzofuro[3,2‐b]oxepin‐4‐carbonitriles as new ring systems. Reactions of the 5‐chloro derivative, obtained from 5‐amino‐1,2‐dihydro[1]benzofuro[3,2‐d]furo[2,3‐b]pyridine, produced a dihydrofuran ring‐opened compound and 5‐substituted compounds. J. Heterocyclic Chem.,(2011).     

Regioselective synthesis of some novel pyrazoles,isoxazoles, pyrazolo[3,4‐d]pyridazines and isoxazolo[3,4‐d]pyridazines pendant to benzimidazole

2‐Acetyl‐1‐methyl‐1H‐benzimidazole reacts with dimethylformamide‐dimethyl‐acetal (DMF‐DMA) to afford the corresponding E‐1‐(1‐methyl‐1H‐benzimidazol‐2‐yl)‐3‐N,N‐dimethylaminoprop‐2‐enone. The latter compound reacts regioselectively with some nitrilimines and nitrile oxides to afford the corresponding pyrazole and isoxazole derivatives, respectively. These reaction products react with hydrazine hydrate to give the novel pyrazolo[3,4‐d]pyridazine and isoxazolo[3,4‐d]pyridazine derivatives, respectively.     

A New Method of Dimroth Rearrangement in Fused Triazolo[1,5‐d]‐1,2,4‐triazine

Ethyl 7‐(2‐ethoxy‐2‐oxoethyl)‐3‐phenyl‐[1–3]triazolo[5,1‐c][1,2,4]triazine‐6‐carboxylate (the parent compound) was synthesized by reaction of 4‐phenyl–1H‐1,2,3‐triazole‐5‐diazonium chloride with diethyl‐2‐oxopropane‐1,3‐dicarboxylate at cooling for 2 h. During the reaction of the parent compound with p‐toluenesulphonyl azide in triethylamine, the Dimroth rearrangement occurred to give the tricyclic compound.     

Synthesis,characterization and biological activity of some 1,2,4‐triazine derivatives

4‐Amino‐6‐methyl‐3‐(2H)‐thioxo‐5‐(4H)‐oxo‐1,2,4‐triazine ( 1 ) was condensed with 2‐methyl (or phenyl)‐4H‐3,1‐benzoxazin‐4‐one ( 5a,b ) in boiling acetic acid to give compounds 8‐11 . Reacting 1 with chloroacetyl chloride afforded the corresponding chloroacetamido and triazinothiadiazine derivatives 12 and 13 . Condensing 2 with succinic anhydride and/or phthalic anhydride yielded compounds 14 and 15 . Benzoylation of 4‐amino‐6‐methyl‐3‐(2H)‐thioxo‐5‐(4H)‐oxo‐2‐(2,3,4,5‐tetra‐O‐acetyl‐α‐D‐glucopyra‐nosyl)‐1,2,4‐triazine ( 19 ) afforded the corresponding 4‐N,N‐dibenzoyl derivative 20 . Deblocking of the N‐2 glycoside 21 and the S‐glycoside 22 by methanolic ammonia gave compounds 23 and 24 . Acetylation of 4‐amino glycoside 25a afforded the corresponding 4‐mono‐ and 4‐diacetyl derivatives 26 and 27 . Deamination of 25a,b yielded compounds 28a,b . Methylation of compound 28b afforded the corresponding N4‐ and S‐methyl derivatives 29 and 30 .     

A Convenient Approach to 4,7‐Dihydrotetrazolo [5,1‐c][1,2,4]triazine Synthesis

Azo coupling of 1,3‐dicarbonyl compounds with tetrazolyl‐5‐diazonium chloride is used to develop a convenient one‐step procedure for the synthesis of 4,7‐dihydrotetrazolo[5,1‐c][1,2,4]triazines. In contrast to nonfluorinated analogs, 7‐hydroxy‐7‐polyfluoroalkyl‐4,7‐dihydrotetrazolo[5,1‐c][1,2,4]triazines undergo a ring‐chain isomerism resulting from the cleavage at the C7―N7a bond. A distinctive feature of nonfluorinated 4,7‐dihydrotetrazolo[5,1‐c][1,2,4]triazines is the possibility to dehydration, which is accompanied by an azide rearrangement due to the tetrazole ring cleavage with the formation of tetrazolo[1,5‐b][1,2,4]triazines.     

Synthesis of New [1,2,4]Triazolo[1,5‐a]pyrimidine Derivatives: Reactivity of 3‐Amino[1,2,4]triazole towards Enaminonitriles and Enaminones

A diversity of new 7 ‐substituted[1,2,4]triazolo[1,5‐a]pyrimidine and 6‐substituted[1,2,4]triazolo[1,5‐a]pyrimidine‐7‐amine derivatives has been synthesized via reaction of 3‐amino‐[1,2,4]triazole with enaminonitriles and enaminones. The regio orientation and the structure of the products were confirmed by spectral and analytical data and synthesis via an alternative route. The procedure proved to be simple, efficient, and high yielding, and diversities of [1,2,4]triazolo[1,5‐a]pyrimidines were obtained.     

Synthesis of New Furo[2,3‐d]pyrimidines and Pyrimido[4′,5′:4,5]furo[2,3‐d]pyrimidines

Sodium salt of 4‐hydroxy‐6‐methyl‐2‐phenylpyrimidine‐5‐carbonitrile ( 3 ) was subjected to alkylation with different a‐halo compounds, where the corresponding O‐alkylated products 4_a‐g were obtained. Ring closure of the O‐alkylated product 4_a‐c performed using sodium ethoxide in refluxing ethanol afforded furo[2,3‐d]pyrimidines 5_a‐c The latter compounds on reaction with a variety of reagents gave other new furopyrimidines as well as a number of furodipyrimidines.     

Structural Elucidation and Antimicrobial Evaluation of Novel [1,2,4]Triazolo[4,3‐a]pyrimidines and Pyrido[2,3‐d][1,2,4]triazolo[4,3‐a]pyrimidinones

1,3‐Di(thiophen‐2‐yl)prop‐2‐en‐1‐one ( 1 ) was utilized in the synthesis of 4,6‐di(thiophen‐2‐yl)‐3,4‐dihydropyrimidine‐2(1H)‐thione ( 2 ) and 5,7‐di(thiophen‐2‐yl)‐2‐thioxo‐2,3‐dihydropyrido[2,3‐d]pyrimidin‐4(1H)‐one ( 4 ). The latter thiones were used in the synthesis of two new series of [1,2,4]triazolo[4,3‐a]pyrimidines 10a – i and pyrido[2,3‐d][1,2,4]triazolo[4,3‐a]pyrimidinones 5a – i via reaction with the appropriate hydrazonoyl halides using triethylamine as a basic catalyst in dioxane. The mechanism of formation of the synthesized compounds was discussed, and the assigned structure was established via microanalysis, spectral data (infrared, ¹H NMR, and Mass), and density functional calculations. Moreover, the newly synthesized products were evaluated for their antimicrobial activities, and the results show that some derivatives have been well with mild activities. Finally, quantum chemistry calculations confirmed the mechanism and structure of the products.     

6-羟基富烯及环戊二烯并[d]哒嗪的合成

本文以6, 6-二烷基富烯与烯丙基格氏试剂反应所得的取代环戊二烯基负离子与芳酰氯反应, 合成了5个新的6-羟基富烯化合物(1-5)。用此化合物与肼反应, 合成了5个新的环戊二烯并[d]哒嗪化合物(6-10)。通过^1H NMR、IR及元素分析确定了它们的结构。