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.     

Reactions of 2‐amino‐3‐cyano‐4,5,6,7‐tetrahydrobenzo[b]thiophene and 2‐amino‐3‐cyano‐4,7‐diphenyl‐5‐methyl‐4H‐pyrano[2,3‐c] pyrazole with phenylisocyanate,carbon disulfide,and thiourea

2‐Amino‐3‐cyano‐4,5,6,7‐tetrahydrobenzo[b]thiophene 1a or 2‐amino‐3‐cyano‐4,7‐di‐ phenyl‐5‐methyl‐4H‐pyrano[2,3‐c]pyrazole 2a reacted with phenylisocyanate in dry pyridine to give 2‐(3‐phenylureido)‐3‐cyanobenzo[b]thiophene 1b or 2‐disubstituted amino‐3‐cyanopyranopyrazole 2b derivative. However, when 1a and 2a were refluxed with carbon disulfide in 10% ethanolic sodium hydroxide solution, they afforded the thieno[2,3‐d]pyrimidin‐2,4‐dithione derivative 5 in the former case, 2,4‐dicyano‐1,3‐bis(dithio carboxamino)cyclobuta‐1,3‐ diene 6 and pyrazolopyranopyrido[2,3‐d]pyrimidin‐ 2,4‐dithione derivative 7 in the latter one. Treatment of 2a with thiourea in refluxing ethanol in the presence of potassium carbonate gave 2,2′‐dithiobispyrimidine derivative 9 (major) in addition to pyranopyrazole derivative 10 and 2,2′‐dithiobis ethoxypyrimidine derivative 11 in minor amounts. The structures of all products were evidenced by microanalytical and spectral data. © 2005 Wiley Periodicals, Inc. Heteroatom Chem 16:6–11, 2005; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/hc.20070     

Studies on the reaction of N‐(3‐carbethoxy‐4,5,6,7‐tetrahydrobenzo[b]thien‐2‐yl)‐N′‐phenylthiourea with hydrazine hydrate (Part 1)

The reaction of N‐(3‐carbethoxy‐4,5,6,7‐tetrahydrobenzo[b]thien‐2‐yl)‐N′‐phenylthiourea ( 1 ) with hydrazine hydrate in 1‐butanol afforded a mixture of compounds 2, 3 and 4 . Treatment of 3 and 4 with nitrous acid gave 6 and 8 respectively, while reactions of 3 with acetylacetone gave 7 . Synthesis of tetracyclic compounds 9a‐f and 11 from the reactions of 3 with ethyl orthoformate or appropriate acids, acid chloride, carbon disulphide and/or ethyl chloroformate. Also its reaction with isothiocyanate derivatives gave the corresponding thiosemicarbzides 12a,b which on, refluxing in alcoholic KOH gave the unexpected tetracyclic products 14a,b . Similarly the tetracyclic compounds 16a‐e and 19 were obtained by cyclization of 4 and 18 respectively.     

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.     

Syntheses of [1,2,3]selenadiazolo[4,5‐e]benzofuran or benzothiophene, [1,2,3]thiadiazolo[4,5‐e]benzofuran or benzothiophene,and 2‐benzofuranyl‐1,3,4‐oxodiazole derivatives

Dehydrogenation of ethyl 3‐methyl‐4‐oxo‐4,5,6,7‐tetrahydrobenzofuran‐2‐carboxylate 1 with 2,2′‐azobi‐sisobutyronitrile and N‐bromosuccinimide gave ethyl 4‐hydroxy‐3‐methylbenzofuran‐2‐carboxylate 3 . Reaction of compounds 3–4 with hydrazine hydrate afforded the corresponding hydrazides 5a‐b . The reaction of 5a‐b with aldehydes yielded substituted hydrazones 6a‐l . Compounds 7a‐d were prepared from compounds 6a‐d and bromine in acetic acid. Lead tetraacetate oxidation of compounds 6e‐l afforded substituted oxadiazoles 8e‐l . Selenium dioxide oxidation of 4‐oxo‐4,5,6,7‐tetrahydrobenzofuran semicarbazones 9, 14a and 4‐oxo‐4,5,6,7‐tetrahydrobenzothiophene 14b gave the tricyclic 1,2,3‐selenadiazoles 10, 15a and 15b respectively. Reaction of semicarbazones 9, 14a and 14b with thionyl chloride afforded the corresponding 1,2,3‐thiadiazoles 12, 16a and 16b respectively.     

A Novel Synthesis of Some 1,4‐Phenylene‐bis‐heterocyclic Derivatives and of Some Pyran,Pyrano[2,3‐c]pyrazole,and Pyrano[2,3‐d]pyrimidine Derivatives [1]

p‐Diacetyl benzene 1 undergoes bromination to afford p‐bromoacetyl phenacyl bromide 2 . Compound 2 reacts with twofold excess of malononitrile to afford 2‐{2‐[4‐(3,3‐Dicyanopropionyl)‐phenyl]‐2‐oxo‐ethyl}‐malononitrile 3 . Compound 3 could be cyclized to afford the 1,4‐phenylene‐bis‐furan derivative 4 . Compound 3 reacts also with a twofold excess of hydrazine hydrate and phenyl hydrazine under dry conditions at RT to afford the bis‐pyrazole derivatives 5a , 5b , respectively. The reaction of 5a , 5b with the same reagents in refluxing dioxane afforded the bis‐pyrazolopyridazine derivatives 7a , 7b , respectively. The azo coupling of compound 3 with arene diazonium salts afforded the bis‐pyrazole derivatives 9a , 9b , 9c . The β‐keto esters 10a , 10b react with benzaldehyde and malononitrile in a one pot synthesis to afford the pyran derivatives 11a , 11b . These latter compounds react with hydrazine hydrate and urea derivatives to afford the pyrano[2,3‐c]pyrazoles 15a , 15b and the pyrano[2,3‐d]pyrimidine derivatives 17a , 17b , respectively.     

Synthesis of Some New [1,8]Naphthyridine,Pyrido[2,3‐d]‐Pyrimidine,and Other Annulated Pyridine Derivatives

2‐Aminopyridine‐3‐carbonitrile derivative 1 reacted with each of malononitrile, ethyl cyanacetate, benzylidenemalononitrile, diethyl malonate, and ethyl acetoacetate to give the corresponding [1,8]naphthyridine derivatives 3 , 5 , 8 , 11 , and 14 , respectively. Further annulations of 3 , 5 , and 8 gave the corresponding pyrido[2,3‐b][1,8]naphthyridine‐3‐carbonitrile derivative 17 , pyrido[2,3‐h][1,6]naphthyridine‐3‐carbonitrile derivatives 18 and 19 , respectively. The reaction of 1 with formic acid, formamide, acetic anhydride, urea or thiourea, and 4‐isothiocyanatobenzenesulfonamide gave the pyridopyrimidine derivatives 20a , b , 21 , 22a , b , and 26 , respectively. Treatment of compound 1 with sulfuric acid afforded the amide derivative 27 . Compound 27 reacted with 4‐chlorobenzaldehyde and 1H‐indene‐1,3(2H)‐dione to give the pyridopyrimidine derivative 28 and spiro derivative 30 , respectively. In addition, compound 1 reacted with halo compounds afforded the pyrrolopyridine derivatives 32 and 34 . Finally, treatment of 1 with hydrazine hydrate gave the pyrazolopyridine derivative 35 . The structures of the newly synthesized compounds were established by elemental and spectral data.     

Synthesis of fluorine containing N‐benzyl‐1,2,3‐triazoles and N‐methyl‐pyrazoles from conjugated alkynes

1, 3‐Dipolar‐cycloaddition reaction of fluoro substituted 3‐aryl‐propynenitriles 1 with benzyl azide 2 afforded the expected 3‐benzyl‐5‐aryl‐3H‐[1,2,3]triazole‐4‐carbonitrile 3 and 1‐benzyl‐5‐aryl‐1H‐[1,2,3]‐triazole‐4‐carbonitrile 4 in good yield. However, 1,3‐dipolar cycloaddition of diazomethane 5 with 3‐aryl‐propynenitriles 1 resulted in the exclusive formation of N‐methyl‐pyrazole derivatives 6 and 7 .     

On the chemistry of 5‐aryl‐2‐hydrazino‐benzo[6,7]cyclohepta[1,2‐b]pyrido[2,3‐e] pyrimidin‐4‐one

Several pyrido[2,3‐e]pyrimidine fused with other rings have been prepared by intramolecular cyclization of 5‐(4‐chlorophenyl)‐2‐hydrazino‐benzo [6,7]cyclohepta‐[1,2‐b]pyrido[2,3‐e]pyrimidine‐4‐one ( 1 ) with acids, carbon disulfide to form triazole derivatives ( 2,4 ), halo‐ketones to give triazine derivative ( 5 ), β‐ketoesters, β‐cyanoesters, and β‐diketones to yield 2‐(1‐pyrazolyl) derivatives ( 7,9,10 ), and aldehydes to form arylhydrazone derivatives ( 11a,b ) which cyclized to form triazoles ( 12a,b ). Also, acyclic N‐nucleosides are prepared by heating under reflux 2‐hydrazino‐benzo[6,7]cyclohepta[1,2‐b]pyrido[2,3‐e] pyrimidin‐4‐one ( 1 ) with xylose and glucose to give the corresponding acyclic N‐nucleosides ( 13a,b ) which are cyclized to afford the corresponding protected tetra and penta–O‐acetate C‐nucleosides ( 14a,b ). Deacetylating of the latter nucleosides afforded the free acyclic C‐nucleosides ( 15a,b ). © 2007 Wiley Periodicals, Inc. Heteroatom Chem 18:34–43, 2007; Published online in Wiley InterScience ( www.interscience.wiley.com ). DOI 10.1002/hc.20248     

An efficient route for synthesis of 5,6‐diphenylimidazo‐[2,1‐b]thiazoles as antibacterial agents

The reaction of 4,5‐diphenylimidazol‐2‐thione ( 1 ) with aromatic ketones 2a‐i using the acidified acetic acid method afforded the 4,5‐diphenyl(2‐imidazolylthio)acetophenones 3a‐h in good yields. While, the cyclized product 4i was obtained directly upon reaction of 1 with α‐acetyl naphthalene. Compounds 3a‐h were cyclized directly to the corresponding 3‐aryl‐5,6‐diphenylimidazo[2,1‐b]thiazoles (4a‐c) and ( 4e‐h ). In the same manner the reaction of 1 with aliphatic and/or alicyclic ketones gave the 3‐(4,5‐diphenyl‐2‐imidazolylthio)acetone derivatives 5a‐d , 2‐(4,5‐diphenylimidazolylthio)cycloalkanones 8a,d and the tricyclic compounds 9b‐c respectively. The cyclized compounds 6a‐d and 9a,d were obtained by cyclization of 5a‐d and 8a,b respectively. Oxidation of 1 gives the corresponding bis(4,5‐diphenyl‐2‐imidazolyl)‐disulfide ( 10 ) in 90% yield. Some of the synthesized compounds were tested for antifungal and antibacterial activity.     

Synthesis and reactions of 3‐amino‐2‐methyl‐3H‐[1,2,4]triazolo[5,1‐b]‐quinazolin‐9‐one and 2‐hydrazino‐3‐phenylamino‐3H‐quinazolin‐4‐one

The reaction of 3‐N‐(2‐mercapto‐4‐oxo‐4H‐quinazolin‐3‐yl)acetamide ( 1 ) with hydrazine hydrate yielded 3‐amino‐2‐methyl‐3H‐[1,2,4]triazolo[5,1‐b]quinazolin‐9‐one ( 2 ). The reaction of 2 with o‐chlorobenzaldehyde and 2‐hydroxy‐naphthaldehyde gave the corresponding 3‐arylidene amino derivatives 3 and 4 , respectively. Condensation of 2 with 1‐nitroso‐2‐naphthol afforded the corresponding 3‐(2‐hydroxy‐naphthalen‐1‐yl‐diazenyl)‐2‐methyl‐3H‐[1,2,4]triazolo[5,1‐b]quinazolin‐9‐one ( 5 ), which on subsequent reduction by SnCl₂ and HCl gave the hydrazino derivative 6. Reaction of 2 with phenyl isothiocyanate in refluxing ethanol yielded thiourea derivative 7. Ring closure of 7 subsequently cyclized on refluxing with phencyl bromide, oxalyl dichloride and chloroacetic acid afforded the corresponding thiazolidine derivatives 8, 9 and 10 , respectively. Reaction of 2‐mercapto‐3‐phenylamino‐3H‐quinazolin‐4‐one ( 11 ) with hydrazine hydrate afforded 2‐hydrazino‐3‐phenylamino‐3H‐quinazolin‐4‐one ( 12 ). The reactivity 12 towards carbon disulphide, acetyl acetone and ethyl acetoacetate gave 13, 14 and 15 , respectively. Condensation of 12 with isatin afforded 2‐[N‐(2‐oxo‐1,2‐dihydroindol‐3‐ylidene)hydrazino]‐3‐phenylamino‐3H‐quinazolin‐4‐one ( 16 ). 2‐(4‐Oxo‐3‐phenylamino‐3,4‐dihydroquinazolin‐2‐ylamino)isoindole‐1,3‐dione ( 17 ) was synthesized by the reaction of 12 with phthalic anhydride. All isolated products were confirmed by their ir, ¹H nmr, ¹³C nmr and mass spectra.     

Reaction of ethyl 2‐diazo‐4,5,6,7‐tetrahydrobenzo[b]thiophene‐3‐carboxylate with 3‐iminobutyronitrile: synthesis of pyridazines,thiophenes, and their fused derivatives

Reaction of ethyl 2‐diazo‐4,5,6,7‐tetrahydrobenzo[b]thiophene‐3‐carboxylate 1 with 3‐iminobutyronitrile 2 gave the hydrazone derivative 3 . The reactivity of the latter product toward a variety of chemical reagents as well as the biological activity of the newly synthesized products were studied. © 2000 John Wiley & Sons, Inc. Heteroatom Chem 11:403–412, 2000     

Behavior of 3‐benzylamino‐5‐aryl‐2(3H)‐furanones towards some nitrogen nucleophiles

Ring closure of 2‐N‐benzylamino‐3‐aroylpropionic acids ( 3 ) with acetic anhydride afforded 3‐N‐benzylamino‐5‐aryl‐2(3H)‐furanones ( 4 ). The reaction of the furanones ( 4 ) with benzylamine in benzene was found to be time dependent. Thus refluxing the reaction mixture for 1 h only afforded the open‐chain amides ( 5a‐c ). When the reaction was conducted for 3 h the 2(3H)‐pyrrolones ( 6 ) were obtained. Hydrazine hydrate affected ring opening of the furanones to give the hydrazides ( 5d‐f ). Also, semicarbazide converted ( 4 ) into the corresponding semicarbazide derivatives ( 5g‐i ). The hydrazides ( 5d‐f ) were reacted with benzoyl chloride to give the corresponding diaroylhydrazines ( 5j‐l ). The open‐chain derivatives ( 5 ) were converted into a variety of heterocycles: isothiazolones ( 7 ), dihydropyridazinones ( 8 ), 1,3,4‐oxadiazoles ( 9 ) and 1,2,4‐triazole derivatives ( 10 ) via cyclization reactions.     

Microwave‐Assisted Synthesis of Arylated Pyrrolo[2,1‐a]Isoquinoline Derivatives via Sequential [3 + 2] Cycloadditions and Suzuki‐Miyaura Cross‐Couplings in Aqueous Medium

Treatment of 5‐bromo‐2‐(bromoacetyl)thiophene ( 1 ) with isoquinoline gave the isoquinolinium bromide 2 . Reaction of 2 with acrylic acid derivatives, in the presence of MnO₂, afforded the 3‐[(5‐bromothiophen‐2‐ylcarbonyl]pyrrolo[2,1‐a]‐isoquinolines 3a , 3b . Suzuki–Miyaura cross‐coupling reactions of the bromides 3a , 3b in aqueous solvent with several activated and deactivated aryl(hetaryl)boronic acids 4a , 4b , 4c , 4d , 4e , 4f using a Pd(II)‐complex under thermal heating as well as microwave‐irradiating conditions afforded the corresponding new arylated pyrrolo[2,1‐a]isoquinoline derivatives 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 in high to excellent isolated yields.     

2‐Pyrazolin‐5‐One‐Based Heterocycles: Synthesis and Characterization

A novel series of pyrazoline and thiazole derivatives incorporating 2‐pyrazolin‐5‐one moiety were synthesized starting from α,β‐unsaturated ketones under the effect of hydrazine derivatives and thiosemicarbazide. The obtained pyrazolines 4a , 4b were treated with different reagents to afford N‐substituted pyrazolines 5a , 5b , 6a , 6b , 7a , 7b , 8a , 8b . N‐Thiocarbamoyl pyrazolines 12a , 12b were cyclized using phenacyl bromide, 2,3‐dichloroquinoxaline, and monochloroacetic acid afforded the novel pyrazolinyl thiazoles 13a , 13b , 14a , 14b , 15a , 15b , 16a , 16b , 16c , 16d , 16e , 16f . The newly synthesized compounds were characterized by analytical and spectral data.     

Reaction of 2‐amino‐3‐cyano‐4,5,6,7‐tetrahydrobenzo‐[b]thiophene with ethyl acetoacetate: Novel syntheses of pyridines,pyrazoles, and their fused derivatives

The reaction of 2‐amino‐3‐cyano‐4,5,6,7‐tetrahydrobenzo[b]thiophene 1 with ethyl acetoacetate 2 gave compound 3 . The reactivity of the latter product toward a variety of chemical reagents was studied to give fused thiophene derivatives of potential pharmaceutical interest. © 2001 John Wiley & Sons, Inc. Heteroatom Chem 12:518–527, 2001     

Synthesis and characterization of substituted (benzo[b]thiophen‐2‐yl)‐4‐methyl‐4,5‐dihydro‐1H‐imidazol‐5‐ones

Reactions of 3‐chlorobenzo[b]thiophene‐2‐carbonyl chloride with 2‐alkyl‐2‐aminopropanamides have been used to prepare a series of carboxamides 1a‐d (yields 61‐85%). The products were submitted to base‐catalysed ring closure reactions to give the corresponding 4,5‐dihydro‐1H‐imidazol‐5‐ones 2a‐d (yields 69‐97%). By N‐methylation and N‐benzylation were prepared the corresponding 1‐alkyl derivatives 3a (91%) and 3b (85%). These two alkyl derivatives were studied from the standpoint of potential replacement of 3‐chlorine substituent by piperidine via the Buchwald‐Hartwig reaction. It was found that the reaction gives besides except required products of C‐N coupling 5a (14%) and 5b (12%) also products of reductive dechlorination 4a (max. 57%) and 4b (max. 56%). The reductive dechlorination product 4a is formed exclusively (42%) if butyl‐di‐(1‐adamantyl)phosphine (BDAP) is used.     

Synthesis of Some Novel 2‐Anilinothiophene, 2,3′‐Bithienyl and Thienylthiopyridine Derivatives Resistance to Penicillium Digitatum Effect the Fruit

Reaction of benzotriazol‐1‐yl acetone 1 with phenyl isothiocyanate followed with α‐chloroacetone or ethyl‐α‐chloroacetate afforded 2‐anilinothiophenes 3 or 4 , respectively. Treatment of 3 with malononitrile at different reaction conditions afforded 6 or 7 . Reaction of 1 with CS₂ in DMF and phenacylbromide afforded S‐alkylated thiophene 10 . Reactions of the latter compound with different active methylene nitriles afforded thienylthiopyridine derivatives 14 and 15 . Condensation of 10 with hydrazine hydrate afforded hydrazon derivative 16 . Reaction of thiophene 17 with formamide in DMF afforded 19 which converted to N‐thienylpyrimidine 20 when treated with malononitrile. The structure of the newly synthesized compounds has been established on the basis of their analytical and spectral data. The compounds were also investigated for antibacterial and antifungal activities.     

Action of Hydrazines on 2‐(2‐Oxindolin‐3‐ylidene)malononitrile, (E,Z)‐Ethyl 2‐cyano‐2‐(2‐oxindolin‐3‐ylidene)acetate and Isatin‐β‐thiosemicarbazone as a Source of Spiro Indoline‐pyrazole Systems

2‐(2‐Oxindolin‐3‐ylidene)malononitrile ( 1a ) or (E,Z)‐ethyl 2‐cyano‐2‐(2‐oxindolin‐3‐ylidene)acetate ( 1b ) or isatin‐β‐thiosemicarbazone ( 1c ) undergoes reactions with prototype hydrazine hydrate itself and some of its simple congeners to give hydrazone derivatives bearing indoline‐2‐one moiety ( 2 ). The hydrazone derivatives ( 2 ) when heated with acetyl acetone or ethyl acetoacetate in dry pyridine afforded the spiro indoline derivatives ( 3a , 3b ). Also, cinnoline derivative ( 9 ) is obtained by action of hydrazine hydrate on the N‐acetyl derivative of ( 6a ). The structures of the newly synthesized compounds were evaluated by IR, ¹H‐NMR spectroscopy, mass spectra and elemental analyses.