Cycloaddition reactions of cyclic ketene-N,S-acetals with 1,2,4,5-tetrazines

Reaction of 3,6-diphenyl-, 3,6-bis(2-pyridyl)- and the unsubstituted 1,2,4,5-tetrazine with 4,5-dihydro-1-methyl-2-(methylthio)pyrrole ( 2 ) and 1-raethyl-2-(methylthio)-4.5,6,7-tetrahydroazepine ( 3 ) gives 4,7-di-R-2,3-dihydro-1-methylpyrrolo[2,3-d]pyridazine ( 4 , R = phenyl, 2-pyridyl, hydrogen) and 6,9-di-R-1-methyl-2,3,4,5-tetrahydropyridazino[4,5-6]azepine ( 5 ), R = phenyl, 2-pyridyl, hydrogen), respectively, in reasonable to good yields. The compounds 4 (R = phenyl, hydrogen) are converted into their corresponding 1-methylpyrrolo-[2,3-d]pyridazines 6 by reaction with potassium permanganate in butanone. Reaction of 3-phenyl-1,2,4,5-te-trazine with 2 and 3 leads to the exclusive formation of the 7-phenyl isomer 4d and 9-phenyl isomer 5d , respectively, indicating that the cycloaddition is regiospecific. The mechanism is discussed.     

Synthesis and antimalarial effects of N,N-dialkyl-6-(substituted phenyl)-1,2,4,5-tetrazin-3-amines

The synthesis of a series of N,N-dialkyl-6-(substituted phenyl)-1,2,4,5-tetrazin-3-amines (IV) by two routes is described. The first route (Scheme I) involved the oxidative cyclization of formazans (II) to 3-bromo-6-(substituted phenyl)-1,2,4,5-tetrazines (III), followed by treatment with amines. The second (Scheme II) utilized the treatment of 3-(methylthio)-6-(substituted phenyl)-1,2,4,5-tetrazines (VII) with amines to provide the desired products. The intermediate 3-(methylthio)-6-(substituted phenyl)-1,2,4,5-tetrazines (VII) were obtained by thiobenzoylation of hydrazinecarbohydrazonothioic acid methyl ester with [[(substituted phenyl)thioxomethyl]thio]-acetic acids (V) to afford the 1,2-dihydro-3-(methylthio)-6-(substituted phenyl)-1,2,4,5-tetrazines (VI). Oxidation with bromine in acetic acid provided the desired intermediates. The target 6-(substituted phenyl)-1,2,4,5-tetrazin-3-amines (IV) displayed modest antimalarial activity.     

Polycyclic N‐Heterocyclic Compounds. Part 81: Synthesis and Evaluation of Pentacyclic 1,2,4,5‐Tetrahydro[1]benzothieno[2′,3′:6,7]thiepino[4,5‐e]imidazo[1,2‐c]pyrimidine and Related Compounds as Potential Antiplatelet Aggregators

Dehydrative ring closure reactions were carried out on fused 4‐(2‐hydroxyethylamino) (or 2‐hydroxyethoxy or 2‐hydroxyethylthio)pyrimidines ( 2a , 2b , 2c ) to give fused 2,3‐dihydroimidazo[1,2‐c] (or 2,3‐dihydrooxazolo[3,2‐c] or 2,3‐dihydrothiazolo[3,2‐c])pyrimidines. This reaction produced the pentacyclic 1,2,4,5‐tetrahydro[1]benzothieno[2′,3′:6,7]thiepino[4,5‐e]imidazo[1,2‐c]pyrimidine ( 3a ) and 1,2,4,5‐tetrahydro[1]benzothieno[2′,3′:6,7]thiepino[4,5‐e]thiazolo[3,2‐c]pyrimidinium chloride ( 3c ) from the 2‐hydroxyethylamino‐derivative and 2‐hydroxyethylthio‐derivative, respectively. In contrast, 2‐hydroxyethoxy‐derivative ( 2b ) gave the rearrangement product, 3‐(2‐chloroethyl)‐5,6‐dihydro[1]benzothieno[3′,2′:2,3]thiepino[4,5‐d]pyrimidin‐4(3H)‐one ( 4 ). Effects of the synthesized compounds on collagen‐induced platelet aggregation were also evaluated.     

Bridgehead nitrogen heterocycles derived from the potassium salt of 2,3,5,6,7,8-hexahydro-3-amino-2-thioxo benzothieno[2,3-d ]pyrimidin-4-(1H)-one

Derivatives of tetraheterocyclic linear system 2, 4 and 5 were prepared by reacting the potassium salt 1 with the appropriate alpha-halocarbonyl compounds. Moreover, through reaction of methyl mercapto 6 with hydrazine the new heterocyclic system 1,4,7,8,9,10-hexahydro-6H-[1]benzothieno[2′,3′:4,5]pyrimido[1,2-b]-[1,2,4,5]tetrazin-6-one ( 8 ) was also obtained.     

2‐Arylimino(diferrocenyl)‐ and (di‐p‐anisyl)dihydropyrimidines: Novel Synthesis,Structures, and Electrochemistry

2,3‐Differocenyl‐ and 2,3‐dianisyl‐1‐methylsulfanylcyclopropenilium iodides react with 1,3‐diphenyl‐ and 1,3‐di‐o‐tolylguanidine to give 1‐aryl‐2‐arylimino‐5,6‐ ( 5a , 5b ) and ‐4,5‐diferrocenyl‐1,2‐dihydropyrimidines ( 6a , 6b ) (～ 2:1) and, respectively, 5,6‐ and 4,5‐dianisyl‐3‐phenyl‐2‐phenylimino‐1,2‐dihydropyrimidines (～ 2:1). Their structures were established based on the spectroscopic data and X‐ray diffraction analysis of 5,6‐diferrocenyl‐1‐(o‐tolyl)‐2‐(o‐tolyl)imino‐ and 4,5‐diferrocenyl‐1‐phenyl‐2‐phenylimino‐1,2‐dihydropyrimidines ( 5b and 6a , respectively). Electrochemical behavior of compounds 5b, 6b, and 5a+6a were investigated using experiments of cyclic voltammetry and chronoamperometry. For all the compounds, two electrochemical processes ( I , II ), attributed to the oxidations of the ferrocenes moieties were observed. The values of ΔE^0′ ( II‐I ) and comproportionation constant K_com are also reported. Additionally, an electrochemical oxidation with a fast coupled chemical reaction related to the pyrimide ring was also detected.     

Polycyclic N-Heterocyclic Compounds,Part 77: Synthesis of [1]Benzothieno[3′,2′:2,3]oxepino[4,5-d]pyrimidines and Evaluation of Their Antiplatelet Aggregation Activity

Reaction of 3-(3-cyanopropoxy)[1]benzothiophene-2-carbonitrile with sodium hydride gave 5-amino-1,2-dihydro[1]benzothieno[3,2-d]furo[2,3-b]pyridine and 5-amino-2,3-dihydro[1]benzothieno[3,2-b]oxepin-4-carbonitrile. The latter compound served as a convenient scaffold for the synthesis of the new heterocycles [1]benzothieno[3′,2′:2,3]oxepino[4,5-d]pyrimidines and the parent 1,2,4,5-tetrahydro[1]benzothieno[2′,3′:6,7]oxepino[4,5-e]imidazo[1,2-c]pyrimidine heterocyclic system. The new compounds described in this report were evaluated as inhibitors of platelet aggregation in vitro.

Supplemental materials are available for this article. Go to the publisher's online edition of Synthetic Communications® to view the free supplemental file.     

Synthesis and photovoltaic performances of benzo[1,2‐b:4,5‐b']dithiophene‐alt‐2,3‐diphenylquinoxaline copolymers pending functional groups in phenyl rings

Two donor/acceptor (D/A)‐based benzo[1,2‐b:4,5‐b′]dithiophene‐alt‐2,3‐biphenyl quinoxaline copolymers of P 1 and P 2 were synthesized pending different functional groups (thiophene or triphenylamine) in the 4‐positions of phenyl rings. Their thermal, photophysical, electrochemical, and photovoltaic properties, as well as morphology of their blending films were investigated. The poly(4,8‐bis((2‐ethyl‐hexyl)oxy)benzo[1,2‐b:4,5‐b'] dithiophene)‐alt‐(2,3‐bis(4′‐bis(N,N‐bis(4‐(octyloxy) phenylamino)‐ 1,1′‐biphen‐4‐yl)quinoxaline) ( P 2) exhibited better photovoltaic performance than poly(4,8‐bis((2‐ethylhexyl)oxy)benzo[1,2‐b:4,5‐b'] dithiophene)‐alt‐(2,3‐bis(4‐(5‐octylthiophen‐2‐yl)phenyl)quinoxaline) ( P 1) in the bulk‐heterojunction polymer solar cells with a configuration of ITO/PEDOT:PSS/polymers: [6,6]‐phenyl‐C₇₁‐butyric acid methyl ester (PC₇₁BM)/LiF/Al. A power conversion efficiency of 3.43%, an open‐circuit voltage of 0.80 V, and a short‐circuit current of 9.20 mA cm^?2 were achieved in the P 2‐based cell under the illumination of AM 1.5, 100 mW cm^?2. Importantly, this power conversion efficiency level is 2.29 times higher than that in the P 1‐based cell. Our work indicated that incorporating triphenylamine pendant in the D/A‐based polymers can greatly improved the photovoltaic properties for its resulting polymers.     

Polycyclic N-hetero compounds. XXXVII. A convenient synthesis and evaluation of anti-platelet aggregation activity of 1,2,4,5-tetrahydro[1]- benzothiepino[4,5-e]imidazo[1,2-c]pyrimidine and its related compounds

A simple and highly efficient methodology for the synthesis of 1,2,4,5-tetrahydro[1]benzothiepino[4,5-e]-imidazo[1,2-c]pyrimidine ( XI ) having a novel ring system via 4-substituted 5,6-dihydro[1]benzothiepino-[5,4-d]pyrimidines VII-X is described. The anti-platelet aggregation activity for it and its related compounds against collagen-induced aggregation of rabbit blood platelets in vitro was found.     

A convenient one‐pot synthesis and antimicrobial activity of pyrimido[1,2‐b][1,2,4,5]tetrazines

The synthesis of the hitherto unreported 3‐amino‐2,3‐dihydro‐6‐phenyl‐2‐thioxo‐4(1H)‐pyrimidine 2 and 3‐amino‐2‐methylthio‐6‐phenyl‐4(3H)‐pyrimidinone 3 is described. Reactions of hydrazonoyl halides 1 with either 2 or 3 afforded 6H‐pyrimido[1,2‐b][1,2,4,5]tetrazin‐6‐ones 6. The latter products were screened for their antifungal and antibacterial properties. The mechanism of the studied reactions is discussed.     

A Convenient One‐Pot Synthesis of Thieno[2′,3′:4,5]Pyrimido[1,2‐b]‐[1,2,4,5]Tetrazines

A novel series of thieno[2′,3′:4,5]pyrimido[1,2‐b][1,2,4,5]tetrazin‐6‐one derivatives 14 were prepared from the reaction of 3‐amino‐2‐thioxo‐1,2,3,5,6,7‐hexahydro‐4H‐cyclopenta[4,5]thieno[2,3‐d]pyrimidin‐4‐one 3 or its methylthio 4 with hydrazonoyl chlorides 9 . The mechanism of the studied reactions has been discussed and further evidence for the assigned structure of the products is based on alternative synthesis. A single crystal X‐ray analysis of compound 14e has been carried out.     

Palladium‐Catalyzed Annulation of 9‐Halophenanthrenes with Alkynes: Synthesis,Structural Analysis,and Properties of Acephenanthrylene‐Based Derivatives

The palladium‐catalyzed annulation of 9‐bromo‐ and 9‐chlorophenanthrenes with alkynes gave 4,5‐disubstituted acephenanthrylenes in yields of 58–95 % (9 examples). Asymmetric alkynes, such as 1‐phenyl‐1‐propyne, 1‐phenyl‐1‐hexyne, and 1‐cyclopropyl‐2‐phenylethyne, regioselectively form (cyclo)alkyl‐substituted products, following the regular rule that governs the carbopalladation of alkynes. This synthetic protocol can also be utilized in annulations with several π‐extended bromoarenes, such as 7‐bromo[5]helicene, 5‐bromo[4]helicene, 9‐bromoanthracene, 3‐bromoperylene, and 3‐bromofluoranthene, to give the corresponding annulated products in moderate to good yields (51–86 %; 6 examples). Similarly, bromocorannulene produced highly curved 1,2‐disubstituted cyclopentacorannulenes. Reactions of 6,12‐dibromochrysene and 4,7‐dibromo[4]helicene with di(4‐tolyl)ethyne provided the twofold annulated products in moderate yields. 4,5‐Diphenylacephenanthrylene and 6,7‐diphenylbenzo[a]acephenanthrylene thus generated were converted into phenanthro[9,10‐e]acephenanthrylene and benzo[a]phenanthro[9,10‐e]acephenanthrylene, respectively, by oxidative cyclodehydrogenation. The structures of 4,5‐diphenylacephenanthrylene, 4,5‐diphenyldibenzo[a,l]acephenanthrylene, 1,2‐diarylcyclopentacorannulenes, and benzo[a]phenanthro[9,10‐e]acephenanthrylene were verified by X‐ray crystallography. The photophysical and electrochemical properties of the selected annulated products were investigated.     

Polycyclic N‐Heterocyclic Compounds. Part 75: Synthesis of 2,4‐Disubstituted 5,6‐dihydro[1]benzoxepino[5,4‐d]pyrimidines and 12‐Substituted 1,2,4,5‐Tetrahydro[1]benzoxepino[4,5‐e]imidazo[1,2‐c]pyrimidines as Potential Antiplatelet Aggregators

Libraries of tricyclic 2‐substituted 4‐alkylamino‐5,6‐dihydro[1]benzoxepino[5,4‐d]pyrimidines and tetracyclic 12‐substituted 1,2,4,5‐tetrahydro[1]benzoxepino[4,5‐e]imidazo[1,2‐c]pyrimidines were synthesized as part of our research to develop new effective antiplatelet drugs. Several alkyl and aryl groups were used as substituents at the 2‐position. Evaluation of the effects of the newly synthesized compounds on collagen‐induced platelet aggregation revealed several promising antiplatelet candidates with potencies superior to aspirin.     

Green One‐Pot Solvent‐Free Synthesis of Pyrazolo[1,5‐a]pyrimidines,Azolo[3,4‐d]pyridiazines,and Thieno[2,3‐b]pyridines Containing Triazole Moiety

Synthesis of pyrazolo[1,5‐a]pyrimidines, [1,2,4]triazolo[1,5‐a]pyrimidine, 8,10‐dimethyl‐2‐(5‐methyl‐1‐phenyl‐4,5‐dihydro‐1H‐1,2,3‐triazol‐4‐yl)pyrido[2′,3′:3,4]‐pyrazolo[1,5‐a]pyrimidine, benzo[4,5]imidazo[1,2‐a]pyrimidine via heterocyclic amines, and sodium 3‐hydroxy‐1‐(5‐methyl‐1‐phenyl‐1H‐1,2,3‐triazole‐4‐yl)prop‐2‐en‐1‐one were carried out. Also, synthesis of isoxazoles, and pyrazoles from sodium 3‐hydroxy‐1‐(5‐methyl‐1‐phenyl‐1H‐1,2,3‐triazole‐4‐yl)prop‐2‐en‐1‐one and hydroxymoyl chlorides and hydrazonoyl halides, respectively, were made. Analogously, (1,2,3‐triazol‐4‐yl)thieno[2,3‐b]pyridine derivatives were obtained from sodium 3‐hydroxy‐1‐(5‐methyl‐1‐phenyl‐1H‐1,2,3‐ triazole‐4‐yl)prop‐2‐en‐1‐one and cyanothioacetamide followed by its reacting with active methylene compounds. In addition to full characterization of all synthesized compounds, they were tested to evaluate their antimicrobial activities, and some compounds showed competitive activities to those of tetracycline, the typical antibacterial drug, and clotrimazole, the typical antifungal drug.     

Cyclothiomethylation of aryl hydrazines with formaldehyde and hydrogen sulfide

Cyclothiomethylation of phenyl hydrazine with CH₂O and H₂S in a ratio of 1: 3: 2 in an acidic medium (HCl) afforded previously unknown 3-phenyl-1,3,4-thiadiazolidine (35% yield) and N-phenyl(perhydro-1,3,5-dithiazin-5-yl)amine (35% yield). The analogous reaction in an alkaline medium (BuONa) produced N-phenyl(perhydro-1,3-thiazetidin-3-yl)amine (22% yield). The reaction of 1,2-diphenyl hydrazine with CH₂O and H₂S in an alkaline medium gave 1,2,4,5-tetraphenylhexahydro-1,2,4,5-tetrazine and previously unknown 3,4-diphenyl-1,3,4-thiadiazolidine and 5,6-diphenyltetrahydro-1,3,5,6-dithiadiazepine in 39 and 22% yields, respectively. Cyclothiomethylation of benzyl hydrazine afforded previously unknown bis[(6-benzyl-4,2,6-thiadiazolidin-2-yl)methyl] sulfide (60% yield) and N-benzyl(perhydro-1,3,5-dithiazin-5-yl)amine (19% yield). The reaction of tosyl hydrazine produced 3-[(p-tolyl)sulfonyl]-1,3,4-thiadiazolidine, N-(perhydro-1,3,5-dithiazin-5-yl)-p-tolylsulfonamide, and 3,7-bis(p-tolylsulfonylamino)-1,5-dithia-3,7-diazacyclooctane in 21, 38, and 41% yields, respectively. Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 10, pp. 1758–1767, October, 2006.     

Five-membered 2,3-dioxoheterocycles: LXVII. Pyrroledione-pyrroledion recyclization of isopropyl 2-(1-aryl-4,5-dioxo-2-phenyl-4,5-dihydro-1H-pyrrol-3-yl)-2-oxoacetates under the action of arylamines. Crystal and molecular structure of (z)-isopropyl 2-hydroxy-4,5-dioxo-1-phenyl-3-[phenyl(phenylamino)-methylene]pyrrolidine-2-carboxylate

Reactions of isopropyl 2-(1-aryl-4,5-dioxo-2-phenyl-4,5-dihydro-1H-pyrrol-3-yl)-2-oxoacetates with aromatic amines involve a pyrroledione-pyrroledione recyclization to form isopropyl 1-aryl-2-hydroxy-4,5-dioxo-3-[phenyl(arylamino)methylene]pyrrolidine-2-carboxylates. The crystal and molecular structure of (Z)-isopropyl 2-hydroxy-4,5-dioxo-1-phenyl-3-[phenyl(phenylamino)methylene]pyrrolidine-2-carboxylate was proved by XRD analysis.     

Synthesis and optoelectronic properties of novel benzodifuran semiconducting polymers

Two new semiconducting polymers poly{4,8‐bis(4‐decylphenylethynyl)benzo[1,2‐b:4,5‐b′]difuran} ( P1 ) and poly {4,8‐bis(4‐decylphenylethynyl)benzo[1,2‐b:4,5‐b′]difuran‐alt‐4,8‐bis(4‐decylphenylethynyl)benzo[1,2‐b:4,5‐b′]dithiophene} ( P2 ) have been synthesized. These polymers were tested in bulk heterojunction solar cells yielding power conversion efficiencies of 1.19% for P1 and 0.79% for P2 . The surface morphology of the solar cell devices indicated that both the polymers display a granular morphology with smoother films displaying higher power conversion efficiencies. © 2012 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2012     

A re-investigation of the reactions of pyromellitic acid and its dianhydride with sulphur tetrafluoride

The fluorination of pyromellitic acid (1) with sulphur tetrafluoride or pyromelliticdianhydride (2) by means of an SF₄---HF mixture gave, besides the expected 1,2,4,5-tetrakis(trifluoromethyl)benzene (3), considerable amounts of 5,6-bis(trifluoromethyl)-1,1,3,3-tetrafluoro-1,3-dihydroisobenzofuran (4) and detectable quantities of1,1,3,3,5,5,7,7-octafluoro-1,3,5, 7-tetrahydrobenzo[1,2-c:4,5-c′]difuran (5). Acidic hydrolysisof 4 gave 4,5-bis(trifluoromethyl)phthalic acid (6) which on treatment with SF₄ andHF yielded compounds 3 and 4.     

Tetrazinodiheteroarene: ‘Charge-Transfer’-Komplexbildung mit Akzeptorverbindungen

Charge-Transfer Complexes of Tetrazinodiheteroarenes with Acceptor Compounds The formation of charge-transfer complexes and radical-ion pairs of donor compounds 1 – 6 with acceptor compounds 7 – 12 has been investigated by means of VIS/NIR-spectroscopic methods. The equilibrium constants K_CT up to 1100_M-1 for the donor/acceptor couple dipyrido[1,2-b:1,2′-e][1,2,4,5]tetrazine ( 2 )/ethylenetetracarbonitrile ( 11 ) and spectra of the CT complexes have been determined in 1,2-dichloroethane solution at 25°. Results are discussed in relation to known CT-complex properties and to voltammetric redox-potentials E_1/2.     

An improved synthesis of 3,6-diamino-1,2,4,5-tetrazine. I

Treatment of 1,3-diaminoguanidine monohydrochloride ( 1 ) with 2,4-pentanedione ( 2 ) in alcohols under carefully controlled conditions gave 3,6-diamino-1,2-dihydro-1,2,4,5-tetrazine monohydrochloride ( 3 ) in 45-50% yields along with 3,5-dimethyl-1H-pyrazole ( 4 ) and its hydrochloride 5 . Oxidation of 3 with sodium perborate produced 3,6-diamino-1,2,4,5-tetrazine ( 6 ) in quantitative yield.     

The photochemical synthesis of novel heterocyclic compounds from s-triazolo [4,3-b] pyridazine,III

s-Triazolo[4,3-b]pyridazine (I) reacted photochemieally with bieyélo[2.2.1] hepla-2,5-diene, 1,5-cyclooctadiene, 1,3-cyclooctadiene, methylene cyclohexane, diethyl cis-1,2,3,6-tetrahydro-phthalate and ethyl 2-cyclopentene-1-acetate to givt: the following products: the endo and exo isomers of 4a, 5, 8a, 9-tetrahydro-9-rnethylene-5,8-rnethano-8H-s-triuzolo[1, 5-a]indole (II) and the endo and exo-9-cyanometliyl products (III and IV) from bicyclo[2.2.1] hepta-2,5-diene; 4a,5,-9, 10, 10a, 11-huxahydro-11-methylene-6H-cycloocta[4,5]pyrrolo[1,2-b]-s-triazole (V) and the 11-cyanomethyl product VI from 1,5-cyclooctadiene: 4a,7,8,9,10,10a-hexahydro-11 -inethylene-11H-cycloocta[4,5]pyrrolo[1,2-b]-s-triazole(VII),4a, 5, 7, 8, 10a, 11-hexahydro-11-methylene-6H-cycloocta[4,5]pyrroIo[1,2-b]-s-triazole (VIII) and their respective 9-cyanomethyl products (X and 1X) from 1,3-cyclooctadiene; 6′, 7′ -dihydro-7′ -methylenespiro[cyclohexane-1, 5′-[5H] pyr-rolo[1,2-b]-s-triazole] (XI), 6′, 7′-dihydro-7′-meth) lene. spiro cyclohexane-1, 6′-[5H]pyrrolo[1,2-b]-s-triazole] (XII) and their respective 7 -eyanomethyl products (XIII and XIV) from melhylene cyclohexane; 6,7-dicarbethoxy-9-cyanomelhyl-4a, 5, 7, 8, 8a, 9-hexahydro-6H-s-triazolo[1,5-a]indole (XV) from diethyl cis-1, 2, 3, 6-tetrahydrophlhalate: and 5-earl)elhoxymethyl-8-eyanomethyl-4a, 5, 6, 7, 7a, 8-hexahydrocyclopenta[4,5]pyrrolo( 1, 2-b]-s-triazole (XVI) from ethyl 2, 2-cyclo-pentene-1-acetate. Many other alkenes, particularly the phenyl ethylenes, did not react with compound 1. In general, more than one product was isolated for each reaction except in the case of the two ester alkenes where a single eyanomethyl product was observed.