Reactions of N , N -Disubstituted 5-Arylmethylidene-2-amino-thiazol-4(5 H )-ones with CH Acids

 N,N-Disubstituted 5-arylmethylidene-2-aminothiazol-4(5H)-ones reacted with diethyl malonate, ethyl benzoylacetate, acetylacetone, or cyclopentadiene in refluxing toluene and in presence of powdered sodium to give the respective 5-arylmethylidene-2′-amino-2,5′-bithiazolylidene-4,4′-dione derivatives in moderate yields. 5-Benzylidene-2-morpholin-4-yl-2-thiazol-4(5H)-one reacted with malononitrile in toluene and in presence of powdered sodium under mild conditions to afford the 1:1 adduct, benzylmalononitrile, and 2-morpholin-4-yl-2-thiazol-4(5H)-one. However, similar treatment of 5-(4-methoxyphenylmethylidene)-2-morpholin-4-yl-2-thiazol-4(5H)-one with malononitrile yielded the 2,5′-bithiazolylidene-4,4′-dione derivative together with 4-methoxyphenylmethylidene malononitrile. Treatment of 5-benzylidene- and 5-(4-methoxyphenylmethylidene)-2-morpholin-4-yl-2-thiazol-4(5H)-ones with 3-phenyl-4-oxo-2-thioxo-1,3-thiazolidine in refluxing toluene and in presence of powdered sodium produced 5-arylmethylidene-3-phenyl-4-oxo-2-thioxo-1,3-thiazolidines in good yields. The structures of all products were deduced from microanalytical and spectroscopic data, mechanistic details are discussed.     

Reactions of N,N-Disubstituted 5-Arylmethylidene-2-amino-thiazol-4(5H)-ones with CH Acids

Summary.  N,N-Disubstituted 5-arylmethylidene-2-aminothiazol-4(5H)-ones reacted with diethyl malonate, ethyl benzoylacetate, acetylacetone, or cyclopentadiene in refluxing toluene and in presence of powdered sodium to give the respective 5-arylmethylidene-2′-amino-2,5′-bithiazolylidene-4,4′-dione derivatives in moderate yields. 5-Benzylidene-2-morpholin-4-yl-2-thiazol-4(5H)-one reacted with malononitrile in toluene and in presence of powdered sodium under mild conditions to afford the 1:1 adduct, benzylmalononitrile, and 2-morpholin-4-yl-2-thiazol-4(5H)-one. However, similar treatment of 5-(4-methoxyphenylmethylidene)-2-morpholin-4-yl-2-thiazol-4(5H)-one with malononitrile yielded the 2,5′-bithiazolylidene-4,4′-dione derivative together with 4-methoxyphenylmethylidene malononitrile. Treatment of 5-benzylidene- and 5-(4-methoxyphenylmethylidene)-2-morpholin-4-yl-2-thiazol-4(5H)-ones with 3-phenyl-4-oxo-2-thioxo-1,3-thiazolidine in refluxing toluene and in presence of powdered sodium produced 5-arylmethylidene-3-phenyl-4-oxo-2-thioxo-1,3-thiazolidines in good yields. The structures of all products were deduced from microanalytical and spectroscopic data, mechanistic details are discussed. Corresponding author. E-mail: kamalkandeel@hotmail.com Received November 5, 2001. Accepted (revised) December 17, 2001     

Synthesis of spiro[2H-indole-2,1′-1H-isoindole]-3,3′-diones,spiro[1H-isobenzofuran-1,2′-2H-indole]-3,3′-diones and spiro[benzofuran-2,1′-isobenzofuran]-3,3′-diones via transannular reactions of eight membered ring intermediates

An auto oxidation-rearrangement product 4 was isolated from a high dilution reaction of ninhydrin with 3,4,5-trimethoxyaniline in water. A general synthesis of this compound and its derivatives 4–6 was devised by oxidation of tetrahydroindeno[1,2-b]indol-10-ones 1–3 with sodium periodate to give isoindolo[2,1-a]-indole-6,11-diones 4–6 in good yield. Compounds 4–6 can be easily transformed into spiro[1H-isobenzofuran-1,2′-2H-indole]-3,3′-diones 8–10 , spiro[2H-indole-2,1′-1H-isoindole]-3,3′-diones 11–13 and isoindole[1,2-a:2′,1′-b]pyrimidine-5,15-diones 15, 16 in high yields. Analogous reactions were performed on 3-amino-5a, 10a-dihydroxybenzo[b]indeno[2,1-d]furan-10-one ( 17 ) to give a dibenzoxocintrione 18 , spiro-[benzofuran-2,1′-isobenzofuran]-3,3′-dione 19 and an isoindol-1-one 20 .     

An Efficient Synthesis of New Substituted Spiro Pyrazolethieno,Pyrimidinethieno, and Benzodiazepinethieno Pyridazine Derivatives with Biological Activities

3-Ethyl 2-amino-4-methyl-5-phenyl thiophene carboxylate 1 was used as a starting material to synthesize 2a,b via coupling with malononitrile or acetyl acetone, respectively. When heated, under reflux in sodium ethoxide solution, 2a,b give 3a,b. On the other hand, when compounds 3a,b were heated under reflux in ethanol with hydrazine hydrate, thiourea, or 1,1-phenylenediamine hydrochloride and a catalytic amount of piperidine 4a,b, 5a,b and 6a,b, were produced, respectively. The new compounds were tested for their antimicrobial activity. Compounds 2a–6b showed antibacterial activities, and 2a,2b and 4b showed antifungal activities.

Supplemental materials are available for this article. Go to the publisher's online edition of Phosphorus, Sulfur, and Silicon and the Related Elements to view the free supplemental file.     

Convenient synthesis,antimicrobial evaluation and molecular modeling of some novel quinoline derivatives

α, β-Unsaturated carbonyl compounds 2a, 2b, 3, and 4 were synthesized by the Knoevenagel condensation between 2-substituted quionoline-3-carboxaldehyde 1a and/or 1b with active methylene compounds. In addition, the synthesis of azlactone is achieved starting from 1a and N-acetylglycine. Synthesis of pyridine, pyrene, and pyrimidine derivatives 6–8 were accomplished via one-pot multicomponent reaction of 1b with acetyl acetone, malononitrile, and ammonium acetate; acetophenone, malononitrile, and NaOH; or acetyl acetone and urea in acidic medium. The new synthesized compounds showed good antimicrobial activities. The DFT calculations have been used to predict the electronic properties of the studied compounds.     

Synthesis of 1,1‐Dimethyl‐4‐indanol Derivatives

The synthesis of 1,1‐dimethyl‐4‐indanols (3a,b) has been achieved by intramolecular Friedel–Crafts cyclization of 2‐(3‐methyl‐2‐butenyl)phenols (5a,b) or 1‐methoxy‐2‐(3‐methyl‐2‐butenyl)benzenes (6a,b) followed by demethylation, respectively.It was found that the solvent was critical for the formation of different products in the intramolecular Friedel–Crafts reactions of 6. The unexpected product 4‐methoxy‐1,1,6,6‐tetramethyl‐as‐hydrindacene (11) was obtained from the Friedel–Crafts reactions of 6a, and its structure was confirmed by X‐ray diffraction analysis. The key intermediates 5a,b were prepared by ortho‐alkenylation of phenols with 1‐bromo‐3‐methyl‐2‐butene, and the reaction temperature exerted an obvious impact on the yield of 2‐(3‐methyl‐2‐butenyl)phenol (5a).     

Über die Struktur eines neuartigen Indolalkaloids,des Talbotins. 141. Mitteilung über Alkaloide [1]

From the leaves of the African Apocynacea Pleiocarpa talbotii Wernham a novel indole alkaloid, talbotine, C₂₁H₂₄N₂O₄, has been isolated. Talbotine ( 1 ) contains a secondary N_(b)-atom and a cyclic hemiacetal group. Catalytic hydrogenation leads to 19, 20-dihydrotalbotine ( 6 ), hydrogenation in the presence of formaldehyde gives N_(b)-methyl-19, 20-dihydrotalbotine ( 8 ). In the presence of sodium methoxide and methanol, 1 is converted into the lactone 12 and the methyl ester 13 . In these reactions carbon 17 is lost as formic acid. These data, together with the analyses of the NMR. spectra of talbotine and its derivatives as well as the interpretation of the various types of the mass spectral fragmentation, lead to formula 1 for the alkaloid. Dehydrogenation of talbotine methyl ether ( 3 ) with palladium and maleic acid gives the ß-carboline derivative 26 . The N_(b)-methiodide of the latter is converted into N_(b)-methyl-talbotine methyl ether on reduction with sodium borohydride. From these data as well as from the analyses of NMR. and IR. spectra the complete relative stereochemistry of talbotine could be derived. Application of the Horeau method to the nitrogen atom b of the methyl ether 3 on the one hand and to the hydroxyl group on C17 in N_(b)-methyl-19, 20-dihydrotalbotine ( 8 ) on the other hand gives consistent results and establishes S configuration of centre 15.     

Synthesis and characterization of mono- and bicyclic heterocyclic derivatives containing 1,2,4-triazole, 1,3,4-thia-, and -oxadiazole rings

A series of new N- and S-substituted 1,3,4-oxadiazole derivatives were synthesized. 5-Pyridin-3-yl-3-[2-(5-thioxo-4,5-dihydro-l,3,4-thiadiazol-2-yl)ethyl]-1,3,4-oxadiazole-2(3H)-thione and 5-[(5-(pyridin-3-yl)-1,3,4-oxadiazol-2-ylthio)methyl]-N-phenyl-1,3,4-thiadiazol-2-amine were formed by cyclization of 3-(5-pyridin-3-yl-2-thioxo-1,3,4-oxadiazol-3(2H)-ylpropanimidohydrazide and 2-[(5-pyridin-3-yl-1,3,4-oxadiazol-2-yl)thio]thiosemicarbazide with CS₂ and H₂SO₄. On the other hand, a number of new bicyclic 1,2,4-triazolo[3,4-b][1,3,4]thiadiazole derivatives were synthesized. 6-Pyridin-3-ylbis[1,2,4]‐triazolo[3,4-b:4′,3′-d][1,3,4]thiadiazole-3(2H)-thione was synthesized by reaction of 6-(hydrazino)-3-pyridine-3-yl[1,2,4]triazolo[3,4-b][1,3,4]thiadiazole with CS₂/KOH/EtOH. The structures of the newly synthesized compounds were elucidated by the spectral and analytical data IR, Mass, and ¹H NMR spectra. Correspondence: Adel A.-H. Abdel-Rahman, Department of Chemistry, Faculty of Science, Menoufia University, Shebin El-Koam, Egypt; Wael A. El-Sayed, National Research Centre, Department of Photochemistry, Cairo, Egypt.     

N‐Azolylmethyl ketones as building blocks in heterocyclic synthesis: Synthesis of new polyfunctionally substituted azolylarylazophenols,azolylpyridones and azolylthiophenes

The title compounds 1a‐b and 2 reacted with 2‐arylhydrazonopropanals 3a‐c to yield polyfunctionally substituted azolylarylazophenols 5 and 8. The reaction of 1b and 2 with phenylisothiocyanate in the presence of α‐haloketones afforded the azolylthiophenes 12a,b and 13a,b. The reaction of 20 with α‐haloketone afforded 5‐benzotriazol‐1‐yl‐6‐methyl‐2‐(2‐oxopropylsulfanyl)nicotinonitrile 21 that was utilized as building blocks for the synthesis of condensed pyridines. Compound 21 was condensed with dimethylformamide dimethylacetal to yield thieno[2,3‐b]pyridin‐3‐yl‐N, N‐dimethylformamidine derivative 22. This was further cyclized with sodium hydride to 1H‐fhieno[2,3‐b; 4,5‐b']dipyridin‐4‐one derivative 23.     

Cyclisierung von Oligomeren des Malodinitrils mit Amidinen Synthesen mit Nitrilen, 55. Mitt

Condensation of formamidine-acetate with dimeric malononitrile (1 a) leads to 2,4-diamino-3,5-pyridine-dicarbonitrile (3 a), with acetamidine-HCl the methyl derivative3 b is obtained. Reaction of the codimer of malononitrile and methyl cyanoacetate (1 b) with formamidine yields the aminopyridine3 c, while acetamidine and benzamidine, resp. with1 b react to the 1,4-dihydro-4-pyrimidinylidene-methyl-cyanoacetates4 a-b.

     

Michael additions to acrylonitrile,methyl acrylate and methyl vinyl ketone to Nb-benzylidenetryptophan methyl ester

Michael addition to methyl acrylate and methyl vinyl ketone of N_b-benzylidene-L-tryptophan methyl ester 1 gave 2-(3-indolylmethyl)glutamic dimethyl ester 2a and α-(3-oxobutyl)tryptophan methyl ester 2b respectively. Addition to acrylonitrile of 1 yielded α,N_a-dicyanoethyltryptophan methyl ester 3 .     

Experimental and theoretical studies on some new pyrrol-2,3-diones formation

4-Benzoyl-5-phenyl-2,3-furandione ( 1 ) reacts with asymmetric disubstituted urea derivatives like 1,1-dimethylurea ( 2a ) and 1,1-diethylurea ( 2b ) by the elimination of a H₂O molecule to give the 4-benzoyl-1-(N,N-dialkylcarbamyl)-5-phenyl-2,3-pyrroldiones 3a and 3b . The structures of 3a,b were determined by the ¹³C NMR, ¹H NMR, IR spectroscopic data and elemental analyses. The electronic structures of the reactants, their transition states, intermediate states, and final products of the reactions were investigated on the basis of AM1 and ab initio (DFT) methods. © 2003 Wiley Periodicals, Inc. Heteroatom Chem 15:9–14, 2004; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/hc.10204     

Total Synthesis of (±)-3-Deoxy-7,8-dihydromorphine, (±)-4-Methoxy-N-methylmorphinan-6-one and 2,4-Dioxygenated (±)-Congeners

A total synthesis of racemic 3-deoxy-7,8-dihydromorphine ((±)- 2 ) and 4-me-thoxy-ALmethylmorphinan-6-one ((±)- 3 ) is described. The key intermediate was 2,4-dihydroxy-N-formylmorphinan-6-one (11) , obtained from 3,5-dibenzyloxy-phenylacetic acid (4) in 41.8% overall yield. Bromination of 11 , and treatment with aqueous N_aOH-solution afforded, after N-deblocking and reductive N-methylation with concomitant removal of the aromatic bounded Br-atom, the morphinanone 14. Elimination of the HO–C(2) group in 14 was accomplished by hydrogenolysis of its N-phenyltetrazolyl ether 15 , to give 3-deoxy-6,0-didehydro-7,8-dihydromorphine (16). Reduction of 16 with L-Selectride at low temperature provided (±)- 2 in high yield. The ether 15 directly afforded, under more vigorous reduction conditions, 4-hydroxy-N-methylmorphinan-6-one (17). and after O-methylation of 17 , the methyl ether (±)- 3 was obtained. A (1:l)-mixture of 4-hydroxy-2-methoxy-N-methylmor-phinan-6-one (28) and its 2-hydroxy-4-methoxy isomer 30 svere obtained by Grewe-cyclization of a mono-methoxylated aromatic precursor similar to that which afforded 11. The 2,4-dioxygenated N-methylmorphinan-6-ones 29 , 31 and 38 were also prepared and characterized.     

Studies on the chemical transformations of rotenoids. 5 . Synthesis and cytotoxicity of 1,3-diazepino[5,6-b]benzofuran and pyridazino[4,5-b]benzofurans fused with thiazole,imidazole and pyrimidine

Novel benzofuro[2,3-d]pyridazinium chlorides fused with thiazole 5a , imidazole 5b-c and pyrimidine 5d-f were prepared starting from 4-chloropyridazino[4,5-b]benzofuran 3a . Treatment of 5b, 5d and 5e with 10% potassium carbonate solution provided the corresponding free bases 6a-c . Ring closure of methyl rotenononate 1b with amidines proceeded in the presence of sodium methoxide to give 1,3-diazepino[5,6-b]benzofuran-5-ones 7a-c . Compound 5d showed cytotoxicity against P388 and L1210 leukemia cells.     

STUDIES ON THIAZOLOPYRIDINES. PART 5: SYNTHESIS OF HITHERTO UNKNOWN THIAZOLINONE AND THIAZOLO[3,2-a]PYRIDINE DERIVATIVES HAVING IN THEIR STRUCTURE THE MORPHOLIN-4-YL MOIETY

Condensation of thiazolinone 1 with benzaldehydes 2a, b in ethanolic piperidine afforded the methylidene derivatives 3a, b. Cyclocondensation of compound 3b with malononitrile furnished the novel thiazolo[3,2-a]-pyridine 5. Also, compound 3b was condensed with dimethylformamide-dimethylacetal (DMF-DMA) and triethylortho-formate to yield N,N-dimethylamino 6 and ethoxymethylene 7 derivatives respectively. The novel thiazolo[3,2-a]pyridines 10a, b were obtained by cyclocondensation of compounds 3a, b with benzylidene-malononitriles 8a, b. Similarly, cyclocondensation of compound 3b with benzylidenemalononitrile 11 afforded the thiazolopyridines 12a–c. Ternary condensation of compound (12), 4-morpholinobenzaldehyde 2b and malononitrile (1:1:1 molar ratio) produced the thiazolopyridines 14a–c. When compound 10b was subjected to react with malononitrile in dioxane/piperidine under reflux the novel condensed heterocyclic system 18 was obtained. Treatment of ortho-aminocarbonitrile 10b with formic acid, aromatic aldehyde and triethylorthoformate furnished the thiazolo[2′,3′:1,6] pyrido[2,3-d] pyrimidine 20, azomethine 21a, b and ethoxymethylene 22 derivatives respectively. The structure of the synthesized compounds was established by analytical and spectral data.     

Synthesis of N,N′-bis and N,N,N′,N′-tetra-[(3,5-di-substituted-1-pyrazolyl)methyl]para-phenylenediamines: new candidate ligands for metal complex wires

A series of tridentate ligands N,N-bis-[(di-substituted-1-pyrazolyl)methyl]arylamines 2-3a,b and benzylamine 4a,b, tetradentate N,N′-bis-[(di-substituted-1-pyrazolyl)methyl]para-phenylenediamines 7a,b and hexadentate N,N,N′,N′-tetra-[(di-substituted-1-pyrazolyl)methyl]para-phenylenediamines 8a,b has been prepared in good yield by condensation of arylamines, benzylamine or para-phenylenediamine with N-hydroxymethyl disubstituted pyrazoles 1a,b. The synthesis and characterisation of these various polydentate ligands are described.     

Knoevenagel condensation of 2-carbethoxycyclohexanone and malononitrile: Synthesis of 4-cyano-3-ethoxy-1-hydroxy-5,6,7,8-tetrahydroisoquinoline,an isomer of the abnormal product

The structure of the abnormal product 1a formed in the Knoevenagel condensation of 2-carbethoxycyclohexanone and malononitrile has been further confirmed. Oxidation of the tetrahydroisoquinoline 3b using Na₂Cr₂O-AcOH-H₂SO₄ gave the keto isoquinoline 3d and the isoquinoline-1-carboxylic acid 5a. The acid chloride of 5a was condensed with diethyl ethoxymagnesiomalonate to afford after decarbethoxylation the methyl ketone 5d which on Baeyer-Villiger oxidation gave a mixture of the acetate 1g and the title compound 1b. The unambiguous synthesis of 1b confirms the structure assigned earlier to the title compound also formed during the partial hydrolysis of the diethoxy compound 1c. Condensation of 2-acetylcyclohexane-1,3-dione with malononitrile gave the quinoline derivative 4c which on ethylation yielded the ketoquinoline 4d. The present studies have confirmed that the quinoline compound 4a is also formed in the condensation of 2-acetylcyclohexanone and cyanoacetamide.     

Synthesis and evaluation of antiviral activity of 2′-deoxyuridines with 5-methylene-2-thiohydantoin substituents in the 5-position

Summary 1-(2-Deoxy-3,5-bis-O-(4-methylbenzoyl)-D-erythro-pentofuranosyl)-5-formyluracil (4) was synthesized from 5-formyluracil and an appropriate methyl glycoside and condensed with 2-thiohydantoin (5a) and its corresponding 3-phenyl derivative5b to give 5-[1-(2-deoxy-3,5-bis-O-(4-methylbenzoyl)-D-erythro-pentofuranosyl)uracil-5-ylmethylene]-2-thiohydantoins7a and7b, respectively, in 65–70% yield. They were deprotected with sodium methoxide in methanol to give both anomers of the free nucleosides. In a different route 5-formyluracil (1) was condensed with5b and subsequently with an appropriate methyl glycoside to give7b.On leave from Chemistry Department, Faculties of Science and Education, Tanta University, Tanta, Egypt     

Studies on the Synthesis of New 3-(3,5-Diamino-1-substituted-pyrazol-4-yl)azo-thieno[2,3-b]pyridines and 3-(2-Amino-5,7-disubstituted-pyrazolo[1,5-a]pyrimidine-3-yl)azothieno[2,3-b]pyridines

Coupling the diazonium salt of 3-amino-2-cyano-4,6-dimethylthieno[2,3-b]pyridine 1 with malononitrile 2 gave 2-cyano-3-(hydrazonomalononitrile)-4,6-dimethylthieno[2,3-b]pyridine 3 which then reacted with hydrazine compounds 4a-4h to yield corresponding 2-cyano-3-(3,5-diamino-1-substituted-pyrazol-4-yl)azo-4,6-dimethylthieno[2,3-b]pyridines 5a-5h. The 2-cyano-3-(2-amino-5,7-disubstituted-pyrazolo-[1,5-a]pyrimidine-3-yl)azo-4,6-dimethylthieno[2,3-b]pyridines 7a-7f were obtained in good yield by the cyclocondensation reaction of 2-cyano-3-(3,5-diamino-pyrazol-4-yl)azo-4,6-dimethylthieno[2,3-b]pyridine 5a with the appropriate 1,3-diketones 6a-6f under acidic condition.     

Synthesis of Pyrano‐ and Pyrido‐Anellated Pyranosides as Precursors for Nucleoside Analogues

The push‐pull activated methyl (3Z)‐4,6‐O‐benzylidene‐3‐[(methylthio)methylene]‐3‐deoxy‐α‐D‐erythro‐hexopyranosid‐2‐ulose (1) reacted with dialkyl malonate in the presence of potassium carbonate to give the alkyl (2R,4aR,6S,10bS)‐4a,6,8,10b‐tetrahydro‐6‐methoxy‐8‐oxo‐2‐phenyl‐4H‐pyrano[3′,2′:4,5]pyrano[3,2‐d][1,3]dioxine‐9‐carboxylates 2 and 3. Treatment of 1 with 3‐oxo‐N‐phenyl‐butyramide, N‐(4‐methoxy‐phenyl)‐3‐oxo‐butyramide, and 3‐oxo‐N‐o‐tolyl‐butyramide, respectively, in the presence of potassium carbonate and 18‐crown‐6 yielded the (2R,4aR,6S,10bS)‐9‐acetyl‐7‐aryl‐4,4a,7,10b‐tetrahydro‐6‐methoxy‐2‐phenyl[1,3]dioxino‐[4′,5′:5,6]pyrano[3,4‐b]pyridin‐8(6H)‐ones 4–6. (2R,4aR,6S,10bS)‐4,4a,8,10b‐Tetrahydro‐6‐methoxy‐8‐oxo‐2‐phenyl‐4H‐pyrano[3′,2′:4,5]pyrano[3,2‐d][1,3]dioxine‐9‐carboxamide (7) was prepared by anellation reactions of 1 either with malononitrile or with cyanoacetamide.