Polycyclic N‐Heterocyclic Compounds. Part 80: Synthesis and Evaluation of Effects on In Vitro Pentosidine Formation of 5,6‐Dihydro[1]benzothieno[3′,2′:2,3]thiepino[4,5‐d]pyrimidine and Related Compounds

Reaction of 3‐(3‐cyanopropylthio)[1]benzothiophene‐2‐carbonitrile with tert‐BuONa gave 5‐amino‐1,2‐dihydro[1]benzothieno[3,2‐d]thieno[2,3‐b]pyridine and 5‐amino‐2,3‐dihydro[1]benzothieno[3,2‐b]thiepin‐4‐carbonitrile. The latter compound served as a convenient scaffold for the synthesis of the new heterocycles, [1]benzothieno[3′,2′:2,3]thiepino[4,5‐d]pyrimidines. All of our new tetracyclic products were evaluated for in vitro inhibitory activity on the formation of pentosidine, which is one of representative advanced glycation end products.     

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.     

Ring Opening and Recyclization Reactions with Chromone‐3‐carbonitrile

Chemical transformations of chromone‐3‐carbonitrile ( 1 ) with some substituted hydrazines, namely, thiosemicarbazide, S‐methyl/benzyldithiocarbazate, 7‐chloro‐4‐hydrazinoquinoline, and 3‐hydrazino‐5,6‐diphenyl‐1,2,4‐triazine, led to substituted pyrazoles 2 , 5 – 8 . Ring opening of carbonitrile 1 followed by recyclization with 3‐amino‐1,2,4‐triazole and 2‐aminobenzimidazole gave triazolo[1,5‐a]pyrimidine 9 and pyrimido[1,2‐a]benzimidazole 10 , respectively. Treatment of carbonitrile 1 with some heterocyclic amines produced 2‐amino‐3‐substituted‐chromones 11 and 12 . The novel 3‐hydroxychromeno[4,3‐b]pyrazolo[4,3‐e]pyridin‐5(1H)‐one ( 13 ) was efficiently synthesized from the ring conversion of carbonitrile 1 with cyanoacetohydrazide. A mixture of chromeno[2,3‐b]naphthyridine 14 and chromeno[4,3‐b]pyridine 15 was obtained from base catalyzed transformation of carbonitrile 1 with malononitrile dimer. A diversity of novel annulated chromeno[2,3‐b]pyridines 16 – 22 was also synthesized. Chromeno[2,3‐b]pyrrole‐2‐carboxylate 23 was obtained from the reaction of carbonitrile 1 with ethyl chloroacetate. Structures of the new synthesized products were deduced on the basis of their analytical and spectral data.     

Syntheses of Three New Pyridyl Thienopyridine Ligands via the Hurtley Reaction

The tridentate pyridyl thienopyridines 5‐phenyl‐7‐(pyridin‐2‐yl)thieno[2,3‐c]pyridine ( L1 ), 7‐(pyridin‐2‐yl)‐5‐(thiophen‐2‐yl)‐thieno[2,3‐c]pyridine ( L2 ) and 5,7‐di(pyridin‐2‐yl)thieno[2,3‐c]pyridine ( L3 ) have been synthesized via the Hurtley reaction. L1 and L2 were synthesized by condensing 3‐bromothiophene‐2‐carboxylic acid with phenyl‐1,3‐butanedione and 1‐thienyl‐1,3‐butanedione respectively. L3 was synthesized by condensing 3‐bromothiophene‐2‐carboxylic acid with benzoylacetonitrile. Ring closure and a subsequent Negishi or Stille cross‐coupling afforded L1 , L2 , and L3 in an overall yield of 20, 3, and 6%, respectively.     

Utility of Pyridine‐2(1H)‐thiones in the Synthesis of Novel Bis‐Thieno[2,3‐b]pyridines and Their Fused Azines

The starting materials pyridine‐2(1H)‐thiones are prepared and reacted with halogen‐containing reagents in ethanolic sodium acetate solution to give the corresponding 2‐S‐alkylpyridines, which cyclized upon their boiling in methanolic sodium methoxide solution at reflux to give the corresponding thieno[2,3‐b]pyridines in excellent yields. Bis (thieno[2,3‐b]pyridine‐2‐carboxamides), incorporating 2,6‐dibromophenoxy moiety, are prepared by the bis‐O‐alkylation of thieno[2,3‐b]pyridine‐2‐carboxamide derivatives. Two synthetic routes are designed to prepare the target molecules pyrido[3′,2′:4,5]thieno[3,2‐d]pyrimidin‐4(3H)‐ones, pyrido[3′,2′:4,5]thieno[3,2‐d][1,2,3]triazin‐4(3H)‐ones, and their bis‐analogues using thieno[2,3‐b]pyridine‐2‐carboxamides and their bis‐analogues. The structure of the target molecules is elucidated using elemental analyses as well as spectral data.     

Synthesis and Antimicrobial Activity of Novel Furothienoquinoxalines,Pyranothienoquinoxalines and Pyrimidopyranothienoquinoxalines

The reaction of ethyl‐3‐mercaptoquinoxaline‐2‐carboxylate with phenacyl bromide, ethyl chloroacetate, chloroacetonitrile or chloroacetone furnished the corresponding 3‐hydroxy thieno[2,3‐b]quinoxaline. 2‐Cyano‐3‐hydroxythieno[2,3‐b]quinoxaline and 2‐acetyl‐3‐hydroxythieno[2,3‐b]quinoxa line were employed as precursors in the synthesis of some novel furo[2′,3′:4,5]thieno[2,3‐b]quinoxaline, pyrano[2′,3′:4,5]thieno[2,3‐b]quinoxaline and other heterocyclic systems fused with thieno[2,3‐b]quinoxalines. The antibacterial and antifungal activities of some the synthesised compounds were studied.     

Novel synthesis of thieno[2,3‐b]pyridine and substituted 2‐thienylthiourea derivatives as antibiotic agents

Derivatives of thieno[2,3‐b]pyridine, 2‐thienylthiourea, 2‐thienylurea, 2‐thienylacetamide incorporating the 2‐phthalimidomethyl moiety have been synthesized. The synthesized compounds were then investigated for antibacterial activity against Escherichia coli, Bacillus subtilis and Staphylococcus aureus. The compounds were also investigated for antifungal activity against Aspergillus niger and Fusarium oxysporium. The structures of the newly synthesized compounds have been established on the basis of their analytical and spectral data.     

Convenient and Efficient Synthesis of 11‐Amino‐2,8‐substituted‐2,3,8,9‐tetrahydrobenzo[4,5]thieno[2,3‐b]quinolinone Derivatives

The Gewald reactions of 5‐substituted‐1,3‐cyclohexanedione, malononitrile, and powdered sulfur were carried out to give the corresponding products 2‐amino‐5‐substituted‐7‐oxo‐4,5,6,7‐tetrahydrobenzo[b]thiophene‐3‐carbonitrile derivatives 1 . The intermediate enamines 2 were prepared by reaction of compounds 1 and 5‐substituted‐1,3‐cyclohexanedione with hydrochloric acid as catalyst. The title compounds 11‐amino‐2,8‐substituted‐2,3,8,9‐tetrahydrobenzo[4,5]thieno[2,3‐b]quinolinone 3 were synthesized by cyclization of compounds 2 in the presence of K₂CO₃ and Cu₂Cl₂. The structures of all compounds were characterized by elemental analysis, IR, MS, and ¹H‐NMR spectra.     

Synthesis and biological effects of new derivatives of azines incorporating coumarin

New synthetic routes for triazolopyridine, pyridopyrimidine, pyridotriazine, imidazopyridine and pyri‐dazine derivatives incorporating a coumarin moiety with interesting biological activities are reported. Reactions of the 2‐oxo‐4‐(2‐dimethylaminoethenyl)‐2H‐chromene‐3‐carbonitrile ( 4 ) and 2‐amino‐4‐(2‐dimethylaminoethenyl)quinoline‐3‐carbonitrile ( 5 ) with benzotriazol‐1‐yl‐acetic acid hydrazide ( 6 ) affords the substituted [1,2,4]triazolo[1,5‐a]pyrido[3,4‐c]coumarines 9 and quinoline 12 , respectively. Treatment of 4 with 2‐amino‐pyridine, glycine, urea, 3‐aminocrotononitrile or cyanothioacetamide affords 14–18 , respectively. Treatment of 3‐amino‐3,4‐dihydro‐4‐imino‐chromeno[3,4‐c]pyridin‐5‐one (10) with α‐chloro‐acetylacetone affords pyridotriazine derivative 21 . Compound 4 was also coupled with benzenediazonium chloride to afford 2‐oxo‐4‐[2‐oxo‐1‐(phenyl‐hydrazono)‐ethyl]‐2H‐chromene‐3‐carbonitrile 25 . Treatment of the latter product with malononitrile afforded the 1‐phenyl‐3‐(3′‐Cyano‐2′‐oxo‐coumarin‐4′‐yl)‐6‐oxo‐pyridazine‐5‐carbonitrile ( 27 ). The structures of the newly synthesized compounds have been established on the basis of analytical and spectral data.     

Synthesis and antitumor evaluation of some new derivatives and fused heterocyclic compounds derived from thieno[2,3‐b]pyridine

On the basis of the proven activity of thieno[2,3‐b]pyridines as anticancer, we have designed to synthesize a novel several heterocyclic compounds utilizing thieno[2,3‐b]pyridine as a skeleton through various chemical reactions. The synthesized compounds bear rings that are either directly attached to the thieno[2,3‐b]pyridine as in compounds 4 to 6 and 9 or connected through an amide bridge as compounds 2 , 3a ‐ b , 7 , and 8 . As well as, compounds 10 , 12 to 28 , 30 , 31 , and 33 to 36 bear fused rings to the thieno[2,3‐b]pyridine backbone. The newly synthesized compounds were screened for their antiproliferative activity in vitro against hepatocellular carcinoma (HepG‐2) and breast cancer (MCF‐7) compared with the standard drug (doxorubicin). Compounds 3b , 4 , 6 , 22 , and 28 exhibited promising growth inhibitory effect toward both HepG‐2 and MCF‐7 cell lines with IC₅₀ values ranging from 5.88 to 11.70 μg/mL and 9.64 to 15.10 μg/mL, respectively.     

Thieno[2,3‐d]pyrimidines in the Synthesis of New Fused Heterocyclic Compounds of Prospective Antitumor and Antioxidant Agents (Part II)

Diethyl azodicarboxylate and 3,4,5,6‐tetrachloro‐1,2‐benzoquinone react with cyclopentano‐ and cycloheptano‐fused thienopyrimidines to form the oxidative dimer of the starting material via S—S bond formation. Reaction of two equivalents of 2,2′‐(cyclohexa‐2′,5′‐diene‐1,4‐diylidene)dimalononitrile with thienopyrimidines afforded 3‐(4′,4′‐dicyanomethylene‐cycloalka[a]‐2,5‐dienyl)‐4‐oxo‐6,7,8,9‐tetrahydro‐5H‐cyclo‐hepta[4,5]‐[1,3]thiazolo[3,2‐a]‐thieno[2,3‐d]pyrimidin‐2‐ylidene‐2‐dicarbonitriles. The thioenopyrimidines react with 2‐[1,3‐dioxo‐1H‐inden‐2(3H)‐ylidene]malononitrile to produce 1,3,5′‐trioxo‐1,3,3′,5′‐tetrahydrospiro‐(indene‐2,2′‐thiazolo[2,3‐b]‐cycloalkyl[b]‐thieno[2,3‐d]pyrimidine)‐3′‐carbonitriles. However, the reaction of thienopyrimidines with 2,3‐dicyano‐1,4‐naphthoquinone proceeded to afford the fused cycloalkyl‐thieno form of naphtho[1,3]thiazolo[3,2‐a]thieno[2,3‐d]pyrimidine‐6.7,12‐triones. Reaction of 2‐hydrazino‐5,6,7,8‐tetrahydrobenzo[b]thieno[2,3‐d]pyrimidine‐4(1H)‐one with dimethyl acetylenedicarboxylate and ethyl propiolate, respectively, afforded cyclohexano‐fused (Z)‐dimethyl 2[(E)‐4‐oxo‐3,4‐dihydrothieno[2,3‐d]pyrimidine‐2(1H)‐ylidene)hydrazono]succinate and thieno‐pyrimidinotriazine. Both oxidative dimers of thienopyrimidines showed high inhibition of Hep‐G2 cell growth compared with the growth of untreated control cells. Moreover, the cycloheptano‐fused thiazinothienopyrimidine indicates a promising specific antitumor agent against Hep‐G2 cells because its IC₅₀ is < 20 μM.     

Reactions of hydrazonoyl halides 43 : Synthesis of some new 2,3‐dihydro‐1,3,4‐thiadiazoles,pyrazoles, pyrazolo[3,4‐d]‐pyridazines,thieno[2,3‐b]pyridines,pyrimidino[4′,5′:4,5]thieno[2,3‐b]‐pyridines and pyrrolo[3,4‐d]pyrazoles

2,3‐Dihydro‐1,3,4‐thiadiazoles, pyrazoles, pyrazolo[3,4‐d]pyridazines, thieno[2,3‐b]pyridines, pyrim‐idino[4′,5′:4,5]thieno[2,3‐b]pyridines and pyrrolo[3,4‐d]pyrazoles were obtained in a good yields by treatment of hydrazonoyl halides with each of alkyl carbodithioates, 3‐(dimethylamino)‐1‐naphtho[1,2‐d]furan‐2‐ylprop‐2‐en‐1‐one and N‐arylmalemides.     

Alternating narrow band gap copolymers derived from indeno[1,2‐b]fluorene and thiophene‐cored‐thieno[3,4‐b]pyrazine derivatives—Synthesis,characterization and comparative studies of photochemical stability

Alternating narrow band gap (NBG) conjugated polymers derived from 6,6′,12,12′‐tetraoctylindeno[1,2‐b]fluorene (IF) and 2,3‐dimethyl‐5,7‐dithien‐2‐yl‐thieno[3,4‐b]pyrazine (DTTP), 2,3‐diphenyl‐5,7‐dithien‐2‐yl‐thieno[3,4‐b]pyrazine (DPTP) or 2,3‐dioctyl‐5,7‐dithien‐2‐yl‐thieno[3,4‐b]pyrazine (DOTP), named as PIF‐DTTP, PIF‐DPTP, and PIF‐DOTP, respectively, were synthesized by Suzuki coupling reaction and characterized. The photochemical stabilities of the copolymers and copolymer derived from IF and 5,7‐dithien‐2‐yl‐thieno[3,4‐b]pyrazine (DTP) were investigated by the UV absorptions, PL spectra, FT‐IR spectra, and photovoltaic properties of the copolymers as a function of UV irradiation time. The studies revealed that the degradation of thieno[3,4‐b]pyrazine (TP) ring under UV irradiation can be retarded or eliminated by introducing phenyl group into the 2,3‐positions of TP ring, and indicated that 2,3‐diphenylthieno[3,4‐b]pyrazine could be used as durable electron deficient moiety to achieve donor–acceptor NBG‐conjugated polymers. © 2011 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2011     

A Convenient Synthesis and Pharmacological Activity of Novel Annelated Pyrimidine Derivatives

Simple and convenient synthesis for a series of 2,3‐diglycosylpyrimidine 4 , pyrazolo[3,4‐d]pyrimidine 8 , ditetrazolo[1,5‐a;1′,5′‐c]pyrimidine 9 , 2,9a,10‐triazaanthracene 12 , thieno[2,3‐d]pyrimidine 14 , 1,3,5,7‐tetraazafluorene‐8‐one 15 , 1,3,5‐triazafluorene‐8‐one 16 , 1,3‐diazafluorene 21a,b derivatives have been synthesized via a sequence of heterocyclization reactions of suitably functionalized 6‐[5‐(4‐bromophenyl)ox‐azol‐4‐yl]‐4‐oxo‐2‐thioxo‐1,2,3,4‐tetrahydropyrimidine‐5‐carbonitrile ( 2 ) with different electrophiles and nucleophiles. The new compounds were prepared with the objective to study their pharmacological properties.     

New synthetic approaches to bridgehead nitrogen heterocycles. Derived from 3‐amino‐2,3‐dihydro‐5,6‐dimethyl‐2‐thioxothieno[2,3‐d]pyrimidin‐4(1H)‐one and its salts

Bridgehead nitrogen heterocycles 3a , b and 6a , b containing the thieno‐pyrimidine system have been prepared from the versatile intermediates 3‐amino‐2,3‐dihydro‐5,6‐dimethyl‐2‐thioxo‐thieno[2,3‐d]pyrimidin‐4‐(1H)‐one 1 and its hydrazinium or potassium salts 4 ; their structural elucidation is also reported.     

Synthesis and reactions of 6‐methylsulfanyl‐2,4‐dithioxo‐1,2,3,4‐tetrahydropyrimidin‐5‐carbonitrile

The synthesis of 6‐methylsulfanyl‐2,4‐dithioxo‐1,2,3,4‐tetrahydropyrimidine‐5‐carbonitrile 4 is described. Compound 4 was reacted with various alkylants. The reaction with chloroacetic acid derivatives results in the formation of thieno[2,3‐d]pyrimidines 8 . When methyl iodide was used 2,4,6‐tris(methylsul‐fanyl)pyrimidine‐5‐carbonitrile 5 was obtained. The substitution of the methylsulfanyl groups in compound 5 by several N‐nuclophiles leads to amino substituted pyrimidines.     

Synthesis of thiabenzene oxides and azathiabenzene oxides

Fused thiabenzene oxide, 2-methyl-4-methylthiobenzo[b]thieno[3,2-c]thiapyran 2,5,5-trioxide (2) was synthesized by the reaction of 2,3-dihydro-2-bis(methylthio)methylene-3-oxobenzo[b]thiophene 1,1-dioxide (1) with trimethyl sulfoxonium iodide in the presence of sodium hydride in tetahydrofuran. Similarly, fused azathiabenzene oxide, 2-methyl-4-methylthiobenzo[b]thieno[2,3-c][1,2]thiazine 2,5,5-trioxide (3) was prepared from 1 and sulfoximine in good yield.     

Folate antagonists. 6. Synthesis and antimalarial effects of fused 2,4-diaminothieno[2,3-d]pyrimidines

2,4-Diamino-5,7-dihydro-6H-thiopyrano[4′,3′:4,5]thieno[2,3-d]pyrirnidine, 2,4-diamino-9H-mdeno[1′,2′:4,5]thieno[2,3-d]pyrimidine, 2,4-diamino-5H-indeno[2′,1′:4,5]thieno[2,3-d]pyrimidine, 9,11-diamino-5,6-dihydronaphtho[1′,2′:4,5]thieno[2,3-d]pyrimidine, 7,9-diamino-5,6-dihydronaphtho[2′,1′:4,5]thieno[2,3-d]pyrimidine, 2,4-diamino-7-benzy]-5,6,7,8-tetrahydropyrido[4′,3′:4,5]thieno[2,3-d]pyrimidine, and various 2,4-diamino-5,6,7,8-tetrahydro-[1]benzothieno[2,3-d]pyrimidines were synthesized by cyclization of the requisite fused 2-aminothio-phenene-3-carbonitriles utilizing chloroformamidine hydrochloride in diglyme. Several compounds exhibited strong inhibitory effects against Streptococcus faecalis (MGH-2), Staphylococcus aureus (UC-76), Streptococcus faecium (ATCC 8043), Lactobacillus casei (ATCC 7469), and Pediococcus cerevisiae (ATCC 8081) in vitro, and three compounds displayed antimalarial activity against Plasmodium berghei in mice and P. falciparum (Uganda I) in vitro.     

Synthesis and transformations of 3-(1H-pyrrol-1-yl)thieno[2,3-b]pyridines

Reactions of 2,5-dimethoxytetrahydrofuran with 3-aminothieno[2,3-b]pyridines afford a number of substituted 3-(1H-pyrrol-1-yl)thieno[2,3-b]pyridines. The possibility of the reaction and the yield of the product are determined by the character of a substituent in position 2 of thieno[2,3-b]pyridine. The Curtius rearrangement of 2-acylazido-3(1H-pyrrol-1-yl)thieno[2,3-b]pyridines yields 4,5-dihydropyrido[3",2":4,5]thieno[2,3-e]pyrrolo[1,2-a]pyrazin-4-ones. The molecular and crystal structures of ethyl 4-methoxymethyl-6-methyl-3-(1H-pyrrol-1-yl)thieno[2,3-b]pyridine-2-carboxylate were determined by X-ray diffraction analysis.     

Derivatives of 5,6-Dimethoxybenzo[b]thiophen-2-(3H)one. Synthesis of 5,6-Dimethoxybenzo[b]thieno[2,3-b]quinoline

Substituted-3-benzylidenebenzo[b]thiophen-2-ones have been synthesized. 5,6-Dimethoxybenzo[b]-thiophen-2-(3H)one with aniline and triethyl orthoformate gives the 3-anilinomethylene compound, which can be hydrolysed to give the corresponding 3-hydroxymethylene derivative. Dimethoxybenzo[b]thieno[2,3-b]-quinoline has been synthesized.