Thermally Stable 3,6‐Dinitropyrazolo[4,3‐c]pyrazole‐based Energetic Materials

3,6‐Dinitropyrazolo[4,3‐c]pyrazole was prepared using an efficient modified process. With selected cations, ten nitrogen‐rich energetic salts and three metal salts were synthesized in high yield based on the 3,6‐dinitropyrazolo[4,3‐c]pyrazolate anion. These compounds were fully characterized by IR and multinuclear NMR spectroscopies, as well as elemental analyses. The structures of the neutral compounds 4 and its salt 16 were confirmed by single‐crystal X‐ray diffraction showing extensive hydrogen‐bonding interactions. The neutral pyrazole precursor and its salts are remarkably thermally stable. Based on the calculated heats of formation and measured densities, detonation pressures (22.5–35.4 GPa) and velocities (7948–9005 m s^?1) were determined, and they compare favorably with those of TNT and RDX. Their impact and friction sensitivities range from 12 to >40 J and 80 to 360 N, respectively. These properties make them competitive as insensitive and thermally stable high‐energy density materials.     

Synthesis and Characterization of Salts of the 3,6‐Dinitro‐[1,2,4]triazolo[4,3‐b][1,2,4]triazolate Anion: Insensitive Energetic Materials Available From Economical Precursors

In this work, the treatment of 3,6,7‐triamino‐[1,2,4]triazolo[4,3‐b][1,2,4]triazole (TATOT)^[1] with sulfuric acid and sodium nitrite results in elimination of the N‐amine and the formation of the new energetic anion 3,6‐dinitro‐[1,2,4]triazolo[4,3‐b][1,2,4]triazolate (DNTT) via nitro‐Sandmeyer chemistry. This new energetic anion is available in a convenient and inexpensive three‐step process from inexpensive commercial starting materials. Several nitrogen rich salts of this material have been prepared and their chemical (infrared, Raman, NMR, single‐crystal X‐ray) and energetic (impact, friction, thermal) properties determined. As a rule, this class of energetic salts are insensitive energetic materials.     

Synthesis of New Fused and Spiro Heterocyclic Systems from 3,5‐Pyrazolidinediones

4‐Bromo‐1‐phenyl‐3,5‐pyrazolidinedione 2 reacted with different nucleophilic reagents to give the corresponding 4‐substituted derivatives 3–8 . The cyclized compounds 9–11 were achieved on refluxing compounds 3 , 4 or 6_a in glacial acetic acid or diphenyl ether. 4,4‐Dibromo‐1‐phenyl‐3,5‐pyrazolidinedione 12 reacted with the proper bidentates to give the corresponding spiro 3,5‐pyrazolidinediones 13–15 , respectively. The 4‐aralkylidine derivatives 16_a‐c , were subjected to Mannich reaction to give Mannich bases 17_a‐c‐22_a‐c , respectively. 4‐(p‐Methylphenylaminomethylidine)‐1‐phenyl‐3,5‐pyrazolidinedione 23 or 4‐(p‐methylphenylazo)‐1‐phenyl‐3,5‐pyrazolidinedione 29 were prepared and reacted with active nitriles, cyclic ketones and N,S‐acetals to give pyrano[2,3‐c]pyrazole, pyrazolo[4′,3′:5,6]pyrano[2,3‐c]pyrazole, spiropyrazole‐4,3′‐pyrazole and spiropyrazole‐4,3′‐[1,2,4]triazolane derivatives 24–34 , respectively.     

Studies on the reactions of cyclic oxalyl compounds with hydrazines or hydrazones : Synthesis and reactions of 4‐benzoyl‐1‐(3‐nitrophenyl)‐5‐phenyl‐1H‐pyrazole‐3‐carboxylic acid

The 1H‐pyrazole‐3‐carboxylic acid 2 , obtained from the furan‐2,3‐dione 1 and N‐Benzylidene‐N'‐(3‐nitrophenyl) hydrazine, was converted via reactions of its acid chloride 3 with various alcohols or N‐nucleo‐philes into the corresponding ester or amide derivatives 4 or 5 , respectively. Nitrile 6 and anilino‐pyrazole acid 7 derivatives of 2 were also obtained by dehydration of 5a in a mixture of SOCl₂ with DMF and reduction of 2 with sodium polysulphide, respectively. While cyclocondensation reactions of 2 or 7 with phenyl hydrazine or hydrazine hydrate and 6 with only anhydrous hydrazine lead to derivatives of pyrazolo[3,4‐d]‐pyridazinone 8 and pyrazolo[3,4‐d]pyridazine amine 9 , respectivel. The reaction of 2 with 2‐hydrazinopyri‐dine provided hydrazono‐pyrazole acid derivative 10 , which was decarboxylated to give hydrazono‐pyra‐zole derivative 11 . Pyrazolo[4,3‐d]oxazinone 12 and 2‐quinolyl pyrazolo[3,4‐d]pyridazine 13 derivatives were also prepared by cyclocondensation reactions of 2 with hydroxylamine hydrochloride and 7 with acetaldehyde, respectively.     

A new entry to pyrazolo[4,3‐e][1,4]diazepines. Facile synthesis of pyrazolo [4,3‐e][1,4]diazepin‐5,8‐diones, 5,6,8‐triones and pyrazolo[4,3‐e]pyrrolo‐[1,2‐a][1,4]diazepin‐5,10‐diones

A facile approach to pyrazolo[4,3‐e][1,4]diazepin‐5,8‐diones and pyrazolo[4,3‐e]pyrrolo[1,2‐a][1,4]‐diazepin‐5,10‐diones is reported. Strategy involved the utility of α‐amino acid as a three‐atom segment in the construction of diazepine skeleton on the preformed pyrazole ring.     

1‐[4‐(Methyl­sulfonyl)­phenyl]‐5‐phenyl‐1H‐pyrazole derivatives

Three related compounds containing a pyrazole moiety with vicinal phenyl rings featuring a methyl­sulfonyl substituent are described, namely 3‐methyl‐1‐[4‐(methyl­sulfonyl)­phenyl]‐5‐phenyl‐1H‐pyrazole, C₁₇H₁₆N₂O₂S, ethyl 1‐[4‐(methyl­sul­fonyl)­phenyl]‐5‐phenyl‐1H‐pyrazole‐3‐carboxyl­ate, C₁₉H₁₈N₂O₄S, and 1‐[4‐(methyl­sulfonyl)­phenyl]‐3‐[3‐(morpholino)­phenoxy­methyl]‐5‐phenyl‐1H‐pyrazole, C₂₇H₂₇N₃O₄S. The design of these compounds was based on celecoxib, a selective cyclo­oxy­genase‐2 (COX‐2) inhibitor, in order to study the influence of various substituents on COX‐2 and 5‐lipoxy­genase (5‐LOX) inhibition.     

Synthesis of N1‐substituted coumarino[4,3‐c] pyrazoles

3‐Acyl‐4‐hydroxy‐2‐oxo‐2H‐chromen derivatives 1a‐d were condensed with (7‐hydroxy‐2‐oxo‐2H‐chromen‐4‐yl)‐acetic acid hydrazide 2 , (4‐methyl‐2‐oxo‐2H‐chromen‐7‐yloxy)‐acetic acid hydrazide 3 , and (7‐hydrazinocarbonylmethoxy‐2‐oxo‐2H‐chromen‐4‐yl)‐acetic acid hydrazide 4 , to give corresponding 3‐alkyl‐1‐[2‐(7‐hydroxy‐2‐oxo‐2H‐chromeno‐4‐yl)‐acetyl]‐1H‐chromeno[4,3‐c]pyrazole‐4‐one 5a‐d , 3‐alkyl‐1‐[2‐(4‐methyl‐2‐oxo‐2H‐chromeno‐7‐yloxy)‐acetyl]‐1H‐chromeno[4,3‐c]pyrazole‐4‐one 6a‐d , and 1‐{4‐[(3‐alkyl‐1H‐chromeno[4,3‐c]pyrazole‐4‐one‐1‐yl)‐carbonylmethyl]‐2‐oxo‐2H‐chromen‐7‐yloxy‐acetyl}‐3‐alkyl‐1H‐chromeno[4,3‐c]pyrazole‐4‐one 7a‐d.     

An Expedient Method for the Synthesis of 1,2,4‐Triazolo‐fused 1,5‐Benzodiazepine, 1,5‐Benzoxazepine,and 1,5‐Benzothiazepine Scaffolds: A Novel Seven‐membered Ring System of Biological Interest

New heterocyclic compounds 1‐(3‐methyl‐9H‐dibenzo[b,f][1,2,4]triazolo[4,3‐d][1,4]diazepin‐6‐yl)ethanone 8a , 1‐(3‐methyldibenzo[b,f][1,2,4]triazolo[4,3‐d][1,4]oxazepin‐6‐yl)ethanone 8b , and 1‐(3‐methyldibenzo[b,f][1,2,4]triazolo[4,3‐d][1,4]thiazepin‐6‐yl)ethanone 8c are synthesized from benzodiazepinone, benzoxazepinone, and benzothiazepinone derivatives. These heterocyclic scaffolds have wide medicinal importance. Best results were obtained in antibacterial screening against Escherichia coli, Enterobacter cloacae, and Staphylococcus aureus and antifungal screening against Candida albicans and Fusarium oxysporum. 1,1‐Diphenyl‐2‐picrylhydrazyl radical scavenging activities of compounds 6c , 7c , and 8c were tested in doses 10, 20, 30, 40, and 50 μg/mL and were expressed as IC₅₀ values and percent of inhibition with means ± standard deviation of three different concentrations of synthesized compounds. The assignment of the structures of synthesized compounds was made by thin‐layer chromatography, elemental analysis, IR, ¹H‐NMR, ¹³C‐NMR, and liquid chromatography–mass spectrometry.     

Synthesis and antiproliferative evaluation of new aryl substituted pyrido[3′,2′:5,6]thiopyrano[4,3‐c]pyrazoles

The preparation and the cytotoxic properties of new derivatives of the planar pyrido[3′,2′:5,6]thiopyrano‐[4,3‐c]pyrazole system, carrying an arylic side group in the 1 or 2 positions, are described. The novel substituted derivatives were obtained by reaction of suitable arylhydrazines with the appropriate key intermediate 3‐hydroxymethylene‐2,3‐dihydrothiopyrano[2,3‐b]pyridin‐4(4H)‐ones. Moreover the preparation was reported of the 2‐carboxamidophenyl derivatives, which was accomplished from the previously obtained pyrido[3′,2′:5,6]thiopyrano[4,3‐c]pyrazole nucleus, by reaction with phenylisocyanate. All the new compounds were evaluated for their antiproliferative ability, by an in vitro assay on human tumor cell lines (HL‐60 and HeLa).     

Synthesis and Electrochemical Behavior of Electron‐Rich s‐Tetrazine and Triazolo‐tetrazine Nitrate Esters

We have prepared energetic nitrate ester derivatives of 1,2,4,5‐tetrazine and 1,2,4‐triazolo[4,3‐b]‐[1,2,4,5]‐tetrazine ring systems as model compounds to study the electrochemical behavior of tetrazines in the presence of explosive groups. The model compounds showed lower thermal stabilities relative to PETN (pentaerythritol tetranitrate), but slightly improved mechanical sensitivities. The presence of electron‐rich amine donors leads to a cathodic shift of the tetrazine redox potentials relative to those of previously reported tetrazine explosives. At these potentials, electron‐rich tetrazines with either covalently bound or co‐dissolved nitrate ester groups are irreversibly reduced. Effectively, changes in the electronic structure of tetrazines affect their electrochemical response to the presence of nitrate ester groups. Thus, it may be possible to develop tetrazine‐based electrochemical sensors for the detection of specific explosives and electrocatalysts for their disposal.     

Synthesis,Characterization, and Antioxidant Evaluation of Some Novel Pyrazolo[3,4‐c][1,2]diazepine and Pyrazolo[3,4‐c]pyrazole Derivatives

5‐Hydrazineyl‐3‐methyl‐1H‐pyrazole ( 1 ) was used as a starting material for the synthesis of novel pyrazolo[3,4‐c][1,2]diazepine derivatives 3 , 4 , and 6a,b by its reaction with acetylacetone, ethyl acetoacetate, and isatylidene derivatives 5a,b , respectively. Also, pyrazolo[3,4‐c][1,2]diazepine derivative 11 was synthesized via multicomponent reaction of 1 , benzaldehyde, and malononitrile. Moreover, compound 1 was used for synthesis novel pyrazolo[3,4‐c]pyrazole derivative 7 by its reaction with isatin. In addition, pyrazolo[3,4‐c]pyrazole derivatives 18a–c were synthesized by treatment of 2‐cyano‐N′‐(3‐methyl‐1H‐pyrazol‐5‐yl)acetohydrazide ( 13 ) with aromatic aldehydes 16a–c . The newly synthesized compounds were valeted by means of analytical and spectral data. All newly synthesized compounds were screened for their antioxidant activities. Compounds 3 , 13 , 18b , and 18c showed higher radical‐scavenging activities.     

Synthesis,Characterization, and Energetic Properties of 6‐Amino‐tetrazolo[1,5‐b]‐1,2,4,5‐tetrazine‐7‐N‐oxide: A Nitrogen‐Rich Material with High Density

The synthesis and energetic properties of a novel N‐oxide high‐nitrogen compound, 6‐amino‐tetrazolo[1,5‐b]‐1,2,4,5‐tetrazine‐7‐N‐oxide, are described. Resulting from the N‐oxide and fused rings system, this molecule exhibits high density, excellent detonation properties, and acceptable impact and friction sensitivities, which suggests potential applications as an energetic material. Compared to known high‐nitrogen compounds, such as 3,6‐diazido‐1,2,4,5‐tetrazine (DiAT), 2,4,6‐tri(azido)‐1,3,5‐triazine (TAT), and 4,4′,6,6′‐tetra(azido)azo‐1,3,5‐triazine (TAAT), a marked performance and stability increase is seen. This supports the superior qualities of this new compound and the advantage of design strategy.     

Synthesis,Modification, and Anticonvulsant Activity of 3′‐R1‐Spiro[indoline‐3,6′‐[1,2,4]triazino[2,3‐c]quinazolin]‐2,2′(7′H)‐diones Derivatives

Previously unknown 3′‐R¹‐5‐R²‐spiro[indoline‐3,6′‐[1,2,4]triazino[2,3‐c]quinazoline]‐2,2′‐(7′H)‐diones and their N‐substituted analogues were obtained via reaction of 6‐R¹‐3‐(2‐aminophenyl)‐1,2,4‐triazin‐5‐ones with isatin and its substituted derivatives. It was shown that alkylation of 3′‐R¹‐5‐R²‐spiro[indoline‐3,6′‐[1,2,4]triazino[2,3‐c]quinazolin]‐2,2′‐(7′H)‐diones by N‐R³‐chloroacetamides or chloroacetonitrile in the presence of а base proceeds by N‐1 atom of isatin fragment. The spectral properties (¹H and ¹³C NMR spectra) of synthesized compounds were studied, and features of spectral patterns were discussed. The high‐effective anticonvulsant and radical scavenging agents among 3′‐R¹‐5‐R²‐spiro[indoline‐3,6′‐[1,2,4]triazino[2,3‐c]quinazolin]‐2,2′(7′H)‐diones and their N‐substituted derivatives were detected. It was shown that compounds 2.2 , 2.8 , and 3.1 exceed or compete the activity of the most widely used in modern neurology drug—lamotrigine on the pentylenetetrazole‐induced seizures model. The aforementioned fact may be considered as a reason for further profound study of synthesized compounds using other pathology models.     

Design and Synthesis of Some Novel 2,3,4,5‐Tetrahydro‐1H‐pyrido[4,3‐b]indoles as Potential c‐Met Inhibitors

Since deregulation of the tyrosine‐kinase receptor c‐Met is implicated in several human cancers and is an attractive target for small‐molecule‐drug discovery, we report herein the synthesis of 2,3,4,5‐tetrahydro‐8‐[1‐(quinolin‐6‐ylmethyl)‐1H‐1,2,3‐triazolo[4,5‐b]pyrazin‐6‐yl]‐1H‐pyrido[4,3‐b]indoles 4a – 4c and 2,3,4,5‐tetrahydro‐8‐[3‐(quinolin‐6‐ylmethyl)‐1,2,4‐triazolo[4,3‐b]pyridazin‐6‐yl]‐1H‐pyrido[4,3‐b]indoles 5a – 5c . These indole derivatives demonstrated inhibition of c‐Met kinase activity. Concurrently, five key intermediates were synthesized. These compounds could be prepared in good yields.     

Syntheses of New Unsymmetrical 2,5‐Disubstituted‐1,3,4‐oxadiazoles and 1,2,4‐Triazolo[3,4‐b]‐1,3,4‐thiadiazoles Bearing Thieno[2,3‐c]pyrazolo Moiety

New series of (thieno[2,3‐c]pyrazolo‐5‐yl)‐[1,2,4]triazolo[3,4‐b][1,3,4]thiadiazoles 10a , 10b , 10c and (thieno[2,3‐c]pyrazol‐5‐yl)‐1,3,4‐oxadiazol‐3(2H)‐yl)ethanones 6a , 6b , 6c has been synthesized from thieno[2,3‐c]pyrazole‐5‐carbohydrazide 3 by multistep reaction sequence. (5‐Aryl‐1,3,4‐oxadiazol‐2‐yl)‐1H‐thieno[2,3‐c]pyrazoles 4a , 4b , 4c were also synthesized from thieno[2,3‐c]pyrazole‐5‐carbohydrazide 3 by cyclization with various aromatic carboxylic acids. The hydrazide 3 was obtained by reaction of thieno[2,3‐c]pyrazole‐5‐carboxylate 2 with hydrazine hydrate in good yield, and compound 2 was obtained by the reaction of 5‐chloro‐3‐methyl‐1‐phenyl‐1H‐pyrazole‐4‐carbaldehyde 1 and 2‐ethyl thioglycolate in presence of sodium alcoholate in good yield.     

Utility of 2‐[4‐(3‐oxobenzo[f]‐2H‐chromen‐2‐yl)‐1,3‐thiazol‐2‐yl]ethanenitrile in heterocyclic synthesis

Pyrazolo[4,3‐d]pyrimidines, pyrazolo[4,3‐d]triazolino[4,3‐a]pyrimidines, 3‐(2‐thiazolyl)thiophenes, thiazolo[3,2‐a]pyridine and pyrazolo[1,5‐a]pyrimidines were synthesized from 2‐[4‐(3‐oxobenzo[f]‐2H‐chromen‐2‐yl)‐1,3‐thiazol‐2‐yl]ethanenitrile. The newly synthesized compounds were elucidated by elemental analysis, spectral data, chemical transformation and alternative synthesis route whenever possible.     

Synthesis and Heterocyclization of 1‐Aryl‐2‐methyl‐4‐oxo‐1,4,5,6‐tetrahydropyridine‐3‐carboxylates

A series of novel isoxazole, dihydropyrazolone, and tetrahydropyridine derivatives were synthesized by the reaction of corresponding ethyl 1‐substituted aryl‐2‐methyl‐4‐oxo‐1,4,5,6‐tetrahydropyridine‐3‐carboxylates with different hydrazines and hydroxylamine. Reaction of tetrahydropyridone with N ,N‐dimethylformamide dimethyl acetal provided 1‐(5‐chloro‐2‐methylphenyl)‐2‐[2‐(dimethylamino)ethenyl]‐4‐oxo‐1,4,5,6‐tetrahydropyridine‐3‐carboxylate, which was cyclized into a bicyclic compound on treatment with ammonium acetate. The structures of all synthesized compounds were confirmed by IR, ¹H NMR, and ¹³C NMR spectroscopy data. The structure of 5‐(5‐chloro‐2‐methylphenyl)‐4‐methyl‐2‐phenyl‐2,5,6,7‐tetrahydro‐3H‐pyrazolo[4,3‐c]pyridin‐3‐one was unambiguously assigned by means of X‐ray analysis data.     

3,6,7‐Triamino‐[1,2,4]triazolo[4,3‐b][1,2,4]triazole: A Non‐toxic,High‐Performance Energetic Building Block with Excellent Stability

A novel strategy for the design of energetic materials that uses fused amino‐substituted triazoles as energetic building blocks is presented. The 3,6,7‐triamino‐7H‐[1,2,4]triazolo[4,3‐b][1,2,4]triazolium (TATOT) motif can be incorporated into many ionic, nitrogen‐rich materials to form salts with advantages such as remarkably high stability towards physical or mechanical stimuli, excellent calculated detonation velocity, and toxicity low enough to qualify them as “green explosives”. Neutral TATOT can be synthesized in a convenient and inexpensive two‐step protocol in high yield. To demonstrate the superior properties of TATOT, 13 ionic derivatives were synthesized and their chemical‐ and physicochemical properties (e.g., sensitivities towards impact, friction and electrostatic discharge) were investigated extensively. Low toxicity was demonstrated for neutral TATOT and its nitrate salt. Both are insensitive towards impact and friction and the nitrate salt combines outstanding thermal stability (decomposition temperature=280 °C) with promising calculated energetic values.     

Azido and Tetrazolo 1,2,4,5‐Tetrazine N‐Oxides

This study presents the synthesis and characterization of the oxidation products of 3,6‐diazido‐1,2,4,5‐tetrazine ( 1 ) and 6‐amino‐[1,5‐b ]tetrazolo‐1,2,4,5‐tetrazine ( 2 ). 3,6‐Diazido‐1,2,4,5‐tetrazine‐1,4‐dioxide was produced from oxidation with peroxytrifluoroacetic acid, and more effectively using hypofluorous acid, and 2 can be oxidized to two different products, 6‐amino‐[1,5‐b]tetrazolo‐1,2,4,5‐tetrazine mono‐N‐oxide and di‐N‐oxide. These N‐oxide compounds display promising performance properties as energetic materials.     

2,5‐Disubstituted Pyrazolo[4,3‐c]cinnolin‐3‐ones

Complementary strategies to 2,5‐disubstituted pyrazolo[4,3‐c ]cinnolin‐3‐ones are reported herein, providing late stage substituent introduction at either the 2‐ or the 5‐position. Treating a readily prepared 4‐thiocinnoline ester with substituted hydrazines afforded late stage access to the 2‐position, while late stage substituent introduction at the 5‐position was achieved via two different strategies: alkylation of 4‐hydrazonopyrazol‐3‐ones, followed by a ring‐closing intramolecular S_NAr tactic and direct reaction of 5‐(2‐fluorophenyl)‐2,4‐dihydro‐3H‐pyrazol‐3‐ones with aryl diazonium salts, followed by cyclization. The strategies described herein provide practical and general methods to prepare 2,5‐disubstituted pyrazolo[4,3‐c ]cinnolin‐3‐ones.