Synthesis of novel 5H‐Pyrimido[5,4‐b]mdole‐(1H,3H)2,4‐diones as potential ligands for the cloned α1‐adrenoceptor subtypes

A new series of 3‐[ω‐[4‐(4‐substituted phenyl)piperazin‐1‐yl]alkyl]‐5H‐pyrimido[5,4‐b]indole‐(1H,3H)‐2,4‐diones ( 3–10 and 12–13 ) were synthesized from the N‐(2‐chloroethyl)‐N'‐[3‐(2‐ethoxycarbonyl)indolyl] urea ( 1 ) or the N‐(3‐chloropropyl)‐N'‐[3‐(2‐ethoxycarbonyl)indolyl] urea ( 2 ) and a number of 1‐(4‐substi‐tuted‐phenyl)piperazines. 3‐[2‐[4‐(4‐Aminophenyl)piperazin‐1‐yl]ethyl]‐5H‐pyrimido[5,4‐b]indole‐(1H,3H)2,4‐dione ( 14 ) was obtained by reduction of the parent nitro compound 8 . The obtained 5H‐pyrimido[5,4‐b]indole‐(1H,3H)2,4‐dione derivatives were tested towards cloned α_1A, α_1B and α_1D adrenergic receptors subtypes in binding assays. Some compounds showed good affinity and selectivity for the α_1D‐adrenoceptor subtype.     

Synthesis of Novel Spiro Thiazolotriazole Derivatives via 1,3‐Dipolar Cycloaddition of Azomethine Ylide

The 1,3‐dipolar cycloaddition of azomethine ylide generated in situ from isatin and sarcosine to 5‐arylmethylidene thiazolo[3,2‐b][1,2,4]triazol‐6(5H)‐ones afforded novel 1′‐methyl‐4′‐aryldispiro[indole‐3,2′‐pyrrolidine‐3′,5″‐[1,3]thiazolo[3,2‐b][1,2,4]triazole]‐2,6″ (1H)‐diones in moderate yields. The structures of all the products were characterized thoroughly by NMR, infrared spectroscopy (IR), mass spectroscopy (MS) elemental analysis together with X‐ray crystallographic analysis.     

Novel Pyrano[2,3‐d]thiazole and Thiazolo[4,5‐b]pyridine Derivatives: One‐pot Three‐component Synthesis and Biological Evaluation as Anticancer Agents,c‐Met,and Pim‐1 Kinase Inhibitors

Preparation of pyrano[2,3‐d]thiazole and thiazolo[4,5‐b]pyridine derivatives through multicomponent reactions (MCRs) was achieved by the reaction of 2‐(2‐amino‐4,5,6,7‐tetrahydrobenzo[b]thiophen‐3‐yl)thiazol‐4(5H)‐one with various active methylene reagents such as ethyl cyanoacetate or malononitrile in basic conditions containing diverse aromatic aldehyde. Furthermore, this study aims to evaluate the in vitro cytotoxic activity of the synthetic compounds against six cancer cell lines, and all the prepared compounds revealed valuable activity compared with the CHS‐828, which is the 2‐[6‐(4‐chlorophenoxy)hexyl]‐1‐cyano‐3‐pyridin‐4‐ylguanidine as the standard drug. Some of the pyrano[2,3‐d]thiazole and thiazolo[4,5‐b]pyridine derivatives showed the highest antitumor activity towards the six cancer cell lines. Moreover, (c‐Met) enzymatic activity of the most potent compounds showed that compounds 3b 2‐(2‐amino‐4,5,6,7 tetrahydrobenzo[b]thiophen‐3‐yl)‐5‐hydroxy‐7‐(2‐hydroxy‐phenyl)‐7H‐pyrano[2,3‐d]thiazole‐6 carbonitrile and 5e 2‐(2‐amino‐4,5,6,7‐tetrahydrobenzo[b]thiophen‐3‐yl)‐5‐hydroxy‐7‐phenyl‐4,7‐dihydrothiazolo[4,5‐b]pyridine‐6‐carbonitrile were with higher activities than foretinib. Three compounds were selected to examine their Pim‐1 kinase where compounds 3b and 7b showed the highest inhibitions.     

Synthesis of 6‐Aryl‐4H‐imidazo[1,2‐b][1,2,4]triazoles and 6‐Aryl‐thiazolo[3,2‐b][1,2,4]triazoles

The cyclization of the derivatives of 3‐aminotriazole, 2‐(5‐substituted 4H‐1,2,4‐triazol‐3‐ylamino)‐1‐arylethanones and 2‐(4H‐1,2,4‐triazol‐3‐ylthio)‐1‐arylethanones to yield 6‐aryl‐4H‐imidazo[1,2‐b][1,2,4]triazoles and 6‐aryl‐thiazolo[3,2‐b][1,2,4]triazoles has been described.     

A convenient synthesis of 2‐Arylidene‐5H‐thiazolo[2,3‐b]quinazo‐line‐3,5[2H]‐diones and their benzoquinazoline derivatives

Various 5H‐thiazolo[2,3‐b]quinazoline‐3,5[2H]‐diones (7a,b), 2‐arylidene‐5H‐thiazolo[2,3–b]quin‐azoline‐3,5[2H]‐diones ( 9a‐o ) and 2‐arylidene‐5H‐thiazolo[2,3‐b]benzoquinazoline‐3,5[2H]‐diones ( 12a,b ) have been synthesized via simple and efficient methods.     

The Influence of Condensed Cycle on Regiochemistry of Electrophilic Heterocyclization of 3‐Alkenyl‐2‐Thioxopyrimidin‐4‐One by p‐Alkoxyphenyltellurium Trichloride

Electrophilic heterocyclization of 5‐alkenyl‐1‐methyl‐6‐thioxopyrazolo[3,4‐d]pyrimidin‐4‐ones and 3‐alkenyl‐2‐thioxoquinazoline‐4‐ones under the action of p‐alkoxyphenyltellurium trichloride leads to annulation of thiazoline cycle with formation of 7‐[(p‐alkoxyphenyl)telluromethyl]‐1‐methyl‐6,7‐dihydropyrazolo[3,4‐d][1,3]thiazolo[3,2‐a]pyrimidin‐4(1H)‐ones hydrochlorides and 2‐(p‐alkoxyphenyl)dichlorotelluromethyl‐2,3‐dihydro ‐ 5H‐[1,3]thiazolo[2,3‐b]quinazolin‐5‐ones hydrochlorides. Reduction of salts by the action of excess of sodium sulfite leads to formation of arylhetaryl telluride.     

An Efficient Synthesis of Benzo[g]thiazolo[2,3‐b]quinazolin‐4‐ium and Benzo[g]benzo[4,5]thiazolo[2,3‐b]quinazolin‐14‐ium Hydroxides by a One‐pot,Three‐component Reaction under Green Conditions

A new series of benzo[g]thiazolo[2,3‐b]quinazolin‐4‐ium and benzo[g]benzo[4,5]thiazolo[2,3‐b]quinazolin‐14‐ium hydroxide derivatives have been synthesized by the one‐pot, three‐component reaction of aryl glyoxal monohydrates, 2‐hydroxy‐1,4‐naphthoquinone, and 2‐aminothiazole or 2‐aminobenzothiazole in the presence of triethylamine and p‐toluenesulfonic acid as organocatalysts in H₂O/acetone (2:1) at room temperature. This method offers mild reaction conditions, excellent yields, easy workup, and readily accessible starting materials and catalysts.     

Regioselectivity of cyclization of 3-allyl(propargyl)sulfanyl-5<Emphasis Type="Italic">H</Emphasis>-[1,2,4]triazino[5,6-<Emphasis Type="Italic">b</Emphasis>]indoles

The interaction of 3-allylsulfanyl-5H-[1,2,4]triazino[5,6-b]indole with iodine led to 1-iodomethyl-1,2-dihydro[1,3]thiazolo[2',3':3,4][1,2,4]triazino[5,6-b]indol-11-ium pentaiodide with an angular structure, on the basis of which 1-iodomethyl-1,2-dihydro[1,3]thiazolo-, 1-methylidene-1,2-di-hydro[1,3]thiazolo, and 1-methyl[1,3]thiazolo derivatives were obtained. The intramolecular cyclization of 3-propargyl(allyl)sulfanyl-5H-[1,2,4]triazino[5,6-b]indoles under the influence of concentrated sulfuric acid led to linear annelated products:3-methyl[1,3]thiazolo[3',2':2,3][1,2,4]tri-azino[5,6-b]indole or its 2,3-dihydro derivative.     

Synthesis of New Derivatives of 4‐(4,7,7‐Trimethyl‐7,8‐dihydro‐6H‐benzo[b]pyrimido[5,4‐e][1,4]thiazin‐2‐yl)morpholine

Cyclocondensation of 5‐amino‐6‐methyl‐2‐morpholinopyrimidine‐4‐thiol ( 1 ) and 2‐bromo‐5,5‐dimethylcyclohexane‐1,3‐dione ( 2 ) under mild reaction condition afforded 4,7,7‐trimethyl‐2‐morpholino‐7,8‐dihydro‐5H‐benzo[b ]pyrimido[5,4‐e ][1,4]thiazin‐9(6H )‐one ( 3 ). The ¹H and ¹³C NMR data of compound ( 3 ) are demonstrated that this compound exists primarily in the enamino ketone form. Reaction of compound ( 3 ) with phosphorous oxychloride gave 4‐(9‐chloro‐4,7,7‐trimethyl‐7,8‐dihydro‐6H‐benzo[b ]pyrimido[5,4‐e ][1,4]thiazin‐2‐yl)morpholine ( 4 ). Nucleophilic substitution of chlorine atom of compound ( 4 ) with typical secondary amines in DMF and K₂CO₃ furnished the new substituted derivatives of 4‐(4,7,7‐trimethyl‐7,8‐dihydro‐6H‐benzo[b ]pyrimido[5,4‐e ][1,4]thiazin‐2‐yl)morpholine ( 5a , 5b , 5c , 5d , 5e , 5f , 5g , 5h ). All the synthesized products were characterized and confirmed by their spectroscopic and microanalytical data.     

Modified Riemschneider Reaction of 3‐Thiocyanatoquinolinediones

The Riemschneider reaction of 3‐thiocyanatoquinoline‐2,4(1H,3H)‐diones with conc. H₂SO₄ was investigated. Using different reaction conditions, 13 types of reaction products were isolated. Compounds bearing a Me, Et, or Bu group at C(3) afforded mainly [1,3]thiazolo[5,4‐c]quinoline‐2,4‐diones and 1,9b‐dihydro‐9b‐hydroxythiazolo[5,4‐c]quinoline‐2,4‐diones. In the case of the 3‐Bu derivatives of the starting compounds, C‐debutylation was also observed. If a Bn group is present at C(3), rapid C‐debenzylation of the starting thiocyanates occurred, yielding [1,3]oxathiolo[4,5‐c]quinoline‐2,4‐diones, and mixtures of mono‐, di‐, and trisulfides derived from 4‐hydroxy‐3‐sulfanylquinoline‐2‐ones. The reaction mechanism of all of the transformations is discussed. All new compounds were characterized by IR, ¹H‐ and ¹³C‐NMR, and EI and ESI mass spectra, and in some cases, ¹⁵N‐NMR spectra were also used to characterize new compounds.     

Synthesis of novel 5H, 11H‐pyrido[2′,3′:2,3]thiopyrano[4,3‐b]‐indoles by fischer‐indole cyclization

The synthesis of the title compounds 5H, 11H‐pyrido[2′,3′:2,3]thiopyrano[4,3‐b]indoles was accomplished by the Fischer indole cyclization of some 2,3‐dihydrothiopyrano[2,3‐b]pyridin‐4(4H)‐one phenylhydrazones and 7‐methyl‐2,3‐dihydrothiopyrano[2,3‐b]pyridin‐4(4H)‐one phenylhydrazones. The synthesis of the new 2,3‐dihydrothiopyrano[2,3‐b]pyridin‐4(4H)‐one, which was used as one of the starting compounds, is also described.     

Thermal isomerization pathway of 1‐(4‐nitrophenyl)‐2‐phenyl­imino‐2,5‐di­hydro‐1H‐pyrido­[3,2‐b]­indole‐3‐carbo­nitrile discovered by laboratory powder data

The evidence for thermal isomerization of the title compound, C₂₄H₁₅N₅O₂, into 2‐[(4‐nitro­phenyl)­phenyl­amino]‐5H‐pyrido[3,2‐b]­indole‐3‐carbo­nitrile has been obtained as a consequence of crystal structure determinations from laboratory powder data.     

A New Four‐Component Reaction for the Synthesis of Spiro[4H‐indeno[1,2‐b]pyridine‐4,3′‐[3H]indoles]

A new four‐component synthesis of spiro[4H‐indeno[1,2‐b]pyridine‐4,3′‐[3H]indoles] and spiro[acenaphthylene‐1(2H),4′‐[4H‐indeno[1,2‐b]pyridines] by the reaction of indane‐1,3‐dione, 1,3‐dicarbonyl compounds, isatins (=1H‐indole‐2,3‐diones) or acenaphthylene‐1,2‐dione, and AcONH₄ in refluxing toluene in the presence of a catalytic amount of pyridine is reported.     

Five closely related 4‐chloro‐6,11‐dihydro‐5H‐benzo[b]pyrimido[5,4‐f]azepines: similar molecular structures but different supramolecular assemblies

Dibenz[b,f]azepine (DBA) is a privileged 6‐7‐6 tricyclic ring system of importance in both organic and medicinal chemistry. Benzo[b]pyrimido[5,4‐f]azepines (BPAs), which also contain a privileged 6‐7‐6 ring system, are less well investigated, probably because of a lack of straightforward and versatile methods for their synthesis. A simple and versatile synthetic approach to BPAs based on intramolecular Friedel–Crafts alkylation has been developed. A group of closely‐related benzo[b]pyrimido[5,4‐f]azepine derivatives, namely (6RS)‐4‐chloro‐6,11‐dimethyl‐6,11‐dihydro‐5H‐benzo[b]pyrimido[5,4‐f]azepine, C₁₄H₁₄ClN₃, (I), (6RS)‐4‐chloro‐8‐hydroxy‐6,11‐dimethyl‐6,11‐dihydro‐5H‐benzo[b]pyrimido[5,4‐f]azepine, C₁₄H₁₄ClN₃O, (II), (6RS)‐4‐<!?tlsb=‐0.14pt>chloro‐8‐methoxy‐6,11‐dimethyl‐6,11‐dihydro‐5H‐benzo[b]pyrimido[5,4‐f]azepine, C₁₅H₁₆ClN₃O, (III), and (6RS)‐4‐chloro‐8‐methoxy‐6,11‐dimethyl‐2‐phenyl‐6,11‐dihydro‐5H‐benzo[b]pyrimido[5,4‐f]azepine, C₂₁H₂₀ClN₃O, (IV), has been prepared and their structures compared with the recently published structure [Acosta‐Quintero et al. (2015). Eur. J. Org. Chem. pp. 5360–5369] of (6RS)‐4‐chloro‐2,6,8,11‐tetramethyl‐6,11‐dihydro‐5H‐benzo[b]pyrimido[5,4‐f]azepine, (V). All five compounds crystallize as racemic mixtures and they have very similar molecular conformations, with the azepine ring adopting a boat‐type conformation in each case, although the orientation of the methoxy substituent in each of (III) and (IV) is different. The supramolecular assemblies in (II) and (IV) depend upon hydrogen bonds of the O—H...N and C—H...π(arene) types, respectively, those in (I) and (V) depend upon π–π stacking interactions involving pairs of pyrimidine rings, and that in (III) depends upon a π–π stacking interaction involving pairs of phenyl rings. Short C—Cl...π(pyrimidine) contacts are present in (I), (II) and (IV) but not in (III) or (V).     

Synthesis of novel pyrido[3′,2′:5,6]thiopyrano[3,2‐b]indol‐5(6H)‐ones and 6H‐pyrido[3′,2′:5,6]thiopyrano[4,3‐b]quinolines,two new heterocyclic ring systems

The synthesis of new pyrido[3′,2′:5,6]thiopyrano[3,2‐b]indol‐5(6H)‐ones was accomplished by the Fischer‐indole cyclization of some 2,3‐dihydro‐3‐phenylhydrazonothiopyrano[2,3‐b]pyridin‐4(4H)‐ones, obtained from the 2,3‐dihydro‐3‐hydroxymethylenethiopyrano[2,3‐b]pyridin‐4(4H)‐one, by the Japp‐Klingemann reaction. 6H‐Pyrido[3′,2′:5,6]thiopyrano[4,3‐b]quinolines were obtained by reaction of 2,3‐dihydrothiopyrano‐[2,3‐b]pyridin‐4(4H)‐ones with o‐aminobenzaldehyde or 5‐substituted isatins. The preparation of some derivatives, functionalized with an alkylamino‐substituted side chain, is also described.     

Diastereoselective Synthesis of (Z)‐6‐(2‐Oxo‐1,2‐dihydro‐3H‐indol‐3‐ylidene)‐3,3a,9,9a‐tetrahydroimidazo[4,5‐e]thiazolo[3,2‐b]‐1,2,4‐triazin‐2,7(1H,6H)‐diones

Two efficient and diastereoselective procedures for the synthesis of (Z)‐6‐(2‐oxo‐1,2‐dihydro‐3H‐indol‐3‐ylidene)‐3,3a,9,9a‐tetrahydroimidazo[4,5‐e]thiazolo[3,2‐b]‐1,2,4‐triazin‐2,7(1H,6H)‐diones by aldol‐crotonic condensation of 1,3‐dimethyl‐3a,9a‐diphenyl‐3,3a,9,9a‐tetrahydroimidazo[4,5‐e]thiazolo[3,2‐b]‐1,2,4‐triazin‐2,7(1H,6H)‐dione with isatins under acidic or basic catalysis are reported. Isomerization in (Z)‐7‐(1‐allyl‐2‐oxo‐1,2‐dihydro‐3H‐indol‐3‐ylidene)‐1,3‐dimethyl‐3a,9a‐diphenyl‐1,3a,4,9a‐tetrahydroimidazo[4,5‐e]thiazolo[2,3‐c]‐1,2,4‐triazin‐2,8(3H,7H)‐dione was observed under basic conditions.     

Synthesis of 4-hydrazino-5H-pyrimido[5,4-b]indole and related compounds

This paper describes the synthesis of two 4-amino-5H-pyrimido[5,4-b]indoles 5 , 4-hydrazino-5H-pyrimido[5,4-b]indole 6 , two 1,2,4-triazolo[4,3-c]pyrimido[5,4-b]indoles 8 , and tetrazolo[4,5-c]pyrimido[5,4-b]indole 10 . Starting with ethyl 3-aminoindole-2-carboxylate 1 , 5H-pyrimido[5,4-b]indol-4-one 2 was obtained (80%) by condensing with formamide. Reactions of 2 with phosphorus oxychloride and phosphorus pentasulfide gave respectively, 4-chloro-5H-pyrimido[5,4-b]indole 3 (70%) and 5H-pyrimido[5,4-b]indole-4-thione 4 (80%). Compound 3 reacted with amines (morpholine, piperidine) to give the respective 4-amino-5H-pyrimido[5,4-b]-indoles 5 , and compound 4 reacted with hydrazine to give 4-hydrazino-5H-pyrimido[5,4-b]indole 6 (80%). Two hydrazones of 6 (benzylidene, isopropylidene) 7 were also prepared (90%). Compound 6 reacted with formic and acetic acids to give (65–75%) the respective 1,2,4-triazolo[4,3-c]pyrimido[5,4-b]indoles 8 and with nitrous acid to give tetrazolo[4,5-c]pyrimido[5,4-b]indole 9 (85%). All the new compounds 2 to 9 were characterized by elemental analysis and spectral data (ir, nmr).     

Efficient organic photovoltaic cells based on thiazolothiazole and benzodithiophene copolymers with π‐conjugated bridges

New donor–π–acceptor (D–π–A) type conjugated copolymers, poly[(4,8‐bis((2‐hexyldecyl)oxy)benzo[1,2‐b:4,5‐b′]dithiophene)‐alt‐(2,5‐bis(4‐octylthiophen‐2‐yl)thiazolo[5,4‐d]thiazole)] (PBDT‐tTz), and poly[(4,8‐bis((2‐hexyldecyl)oxy)benzo[1,2‐b:4,5‐b′]dithiophene)‐alt‐(2,5‐bis(6‐octylthieno[3,2‐b]thiophen‐2‐yl)thiazolo[5,4‐d]thiazole)] (PBDT‐ttTz) were synthesized and characterized with the aim of investigating their potential applicability to organic photovoltaic active materials. While copolymer PBDT‐tTz showed a zigzagged non‐linear structure by thiophene π‐bridges, PBDT‐ttTz had a linear molecular structure with thieno[3,2‐b]thiophene π‐bridges. The optical, electrochemical, morphological, and photovoltaic properties of PBDT‐tTz and PBDT‐ttTz were systematically investigated. Furthermore, bulk heterojunction photovoltaic devices were fabricated by using the synthesized polymers as p‐type donors and [6,6]‐phenyl‐C₇₁‐butyric acid methyl ester as an n‐type acceptor. PBDT‐ttTz showed a high power conversion efficiency (PCE) of 5.21% as a result of the extended conjugation arising from the thienothiophene π‐bridges and enhanced molecular ordering in the film state, while PBDT‐tTz showed a relatively lower PCE of 2.92% under AM 1.5 G illumination (100 mW/cm²). © 2018 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2018 , 56, 1978–1988     

Regioselectively Synthesis of Thiazolo[4,5‐a]acridines and Oxazolo[5,4‐a]thiazolo[5,4‐j]acridines via Multicomponent Domino Reactions

A regioselective three‐component reaction of aromatic aldehydes, 2‐hydroxy‐1,4‐naphthoquinone and benzo[d]thiazol‐5‐amine in HOAc under microwave irradiation has been developed. A series of new thiazolo‐fused benzo[h]acridines were synthesized with high chemical yields in this one‐pot reaction. The resulting thiazolo‐fused acridines were employed to further react with aldehydes and ammonium acetate to give polycyclic‐fused oxazolo[5,4‐a]thiazolo[5,4‐j]acridines. The present synthesis shows several advantages, such as operational simplicity, fast reaction rates, which makes it a useful and attractive process of library generation for drug discovery.     

Synthesis and Evaluation of Bioactivity of Thiazolo[3,2‐b]‐[1,2,4]‐triazoles and Isomeric Thiazolo[2,3‐c]‐[1,2,4]‐triazoles

Synthesis of 2‐(o‐nitrophenyl)‐6‐arylthiazolo[3,2‐b]‐[1,2,4]‐triazoles 4 and its isomer 3‐(o‐nitrophenyl)‐5‐arylthiazolo[2,3‐c]‐[1,2,4]‐triazoles 6 has been achieved starting from the appropriate 1‐(o‐nitrobenzoyl)‐3‐thiosemicarbazide 1 . Compound 1 on condensation with α‐haloketones gives 2‐(o‐nitrobenzoyl)hydrazino‐4‐arylthiazole hydrobromide 5 , which, on cyclization with POCl₃, affords thiazolo[3,2‐b]‐[1,2,4]‐triazoles 6 and not the isomeric thiazolo[3,2‐b]‐[1,2,4]‐triazoles 4 . This has been established by an unequivocal synthesis of 4 through polyphosphoric acid cyclization of 5‐aroylmethylmercapto‐3‐o‐nitrophenyl‐[1,2,4]‐triazole 3 . Compound 3 was synthesized by condensation of α‐haloketones with 5‐mercapto‐3‐(o‐nitrophenyl)‐[1,2,4]‐triazole 2 , obtained cyclization of 2‐(o‐nitrobenzoyl)hydrazinecarbothioamide 1 with NaOH. The antibacterial and antifungal activities of some of the compounds have also been evaluated.