Effect of solvent on the regioselective synthesis of spiropyrazoles

1,3-Dipolarcycloaddition reactions of 6-arylmethylene-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ones (1) with nitrilimines 3 were investigated in benzene and chloroform. The reaction products were 2′,4′,6,7,8,9-hexahydro-2′,4′,5′-triaryl spiro[benzocycloheptene-6(5H),3′(3H-pyrazol)-5-ones (4) or 2′,3′,6,7,8,9-hexahydro-2′,3′,5′-triaryl spiro[benzocycloheptene-6(5H),4′(4H-pyrazol)-5-ones (5). X-ray crystallographic analysis was carried out for compound 5b. It was found that the regioselectivity of the produced compounds was altered based on changing solvent type.     

Synthesis of 1-(3′-deoxy-β-D-glycero-pentofuran-2′-ulosyl)uracil by selective elimination reactions

For the synthesis of y 1-(3′-deoxy-β-D-glycero-pentofuran-2′-ulosyl)uracil (16), the precursor, 5′-O-benzoyl derivative (2),² was elaborated in a variety of ways. 1-(5′-O-Benzoyl-3′-O-tosyl-β-D- lyxofuranosyl)uracil (4)² was benzoylated to N³-benzoyl-1-(2′,5′-di-O-benzoyl-3′-O-tosyl-β-D- lyxofuranosyl)uracil (5), which directly yielded 2 on treatment with sodium benzoate. 1-(3′,5′-Di-O- benzoyl-2′-O-tosyl-β-D-lyxofuranosyl)uracil (8) and its 3′,5′-O-isopropylidene analog (10) resisted elimination reactions, thus proving absolute selectivity in the elimination of the derivatives of 1-β-D- lyxofuranosyl-uracil. Seeking a more economical path to 2, 1-(5′-O-benzoyl-β-D-lyxofuranosyl)uracil (11) was first benzoylated to give 2′,5′-di-O-benzoate (12), accompanied by 3′,5′-di- and 2′,3′,5′-tri-O- benzoate. Mesylation of the major product (12) gave 1-(2′,5′-di-O-benzoyl-3′-O-mesyl-β-D- lyxofuranosyl)uracil (15), which, on treatment with sodium benzoate, gave 2 in an highly improved yield. Basic hydrolysis on 2 gave compound 16.     

Design,synthesis and biological evaluation of novel isoniazid hybrids

We herein report the design and synthesis of novel isoniazid derivatives. Isoniazid derived Schiff bases (3 a-d) were subjected to cyclization with acetic anhydride and sulphuric acid to yield the 5′-substituted-3′-acetyl-5-(pyridin-4-yl)-3H-spiro[indole-3, 2-[1′, 3′, 4’]oxadiazol]-2′-yl acetates (4 a-d) and 8′-substituted-3’-(pyridin-4-yl)[1′,3′,4’]oxadiazino [6,5-b]indoles (5 a-d) respectively. The advantages of spectral methods were used for the confirmation of the structure of all the newly synthesized hybrid molecules. Further, these compounds were evaluated for their antibacterial activity against B. Subtilis, S. aureus, E. coli & S. typhi, antifungal activity against C. albicans, C. oxysporum, A. Flavus & A. niger, and antimycobacterial activity against M. tuberculosis. Amongst, the compounds 4b, 4c and 5c showed excellent inhibitory activity against tested microorganisms. Also, the DNA cleavage activity of selected compounds was carried out by the AGE method.     

trans-Aconitic acid-based hetero-Diels-Alder reaction in the synthesis of thiopyrano[2,3-d][1,3]thiazole derivatives

The hetero-Diels-Alder reaction of 5-arylideneisorhodanines with trans-aconitic acid proceeds as a regio- and diastereoselective process with spontaneous decarboxylation of the [4+2]-adduct to furnish thiopyrano[2,3-d][1,3]thiazole (2) and chromeno[4′,3′:4,5]thiopyrano[2,3-d]thiazole (3) derivatives analogously to the use of itaconic acid as a dienophile. Conversely, the one-pot, three-component reaction of 5-arylideneisorhodanines, trans-aconitic acid and anilines proceeded without decarboxylation, leading to novel rel-(5′R,6′R,7′R)-5′-carboxy-7′-aryl-1-aryl-3′,7′-dihydro-2H,2′H,5H-spiro[pyrrolidin-3,6′-thiopyrano[2,3-d]thiazol]-2,2′,5-triones 4. Interestingly, the use of trans-aconitic acid trimethyl ester led to the opposite regioselectivity, yielding rel-(5R,6S,7S)-5-methyloxycarbonylmethyl-2-oxo-7-aryl-3,5,6,7-tetrahydro-2H-thiopyrano[2,3-d]thiazol-5,6-dicarboxylates 5. Selected compounds were examined for trypanocide activity against the bloodstream forms of Trypanosoma brucei where compound 4e showed the highest activity (IC₅₀ = 6.74 μM).     

Cyclopropanation of 2-arylmethylidenemalononitriles,alkyl 3-aryl-2-cyanoprop-2-enoates,and N-substituted 3-aryl-2-cyanoprop-2-enamides with bromine-containing zinc enolates

Zinc enolates derived from 2,2-dibromoindan-1-one and 2,2-dibromo-1,2,3,4-tetrahydronaphthalen-1-one reacted with 2-arylmethylidenemalononitriles, alkyl 3-aryl-2-cyanoprop-2-enoates, and N-substituted 3-aryl-2-cyanoprop-2-enamides to give, respectively, 3-aryl-1′-oxo-1′,3′-dihydrospiro[cyclopropane-1,2′-indene]-2-2-dicarbonitriles, 3-aryl-1′-oxo-3′,4′-dihydro-1′H-spiro[cyclopropane-1,2′-naphthalene]-2,2-dicarbonitriles, alkyl 3-aryl-2-cyano-1′-oxo-1′,3′-dihydrospiro[cyclopropane-1,2′-indene]-2-carboxylates, alkyl 3-aryl-2-cyano-1′-oxo-3′,4′-dihydro-1′H-spiro[cyclopropane-1,2′-naphthalene]-2-carboxylates, and N-substituted 3-aryl-2-cyanol-1′-oxo-3′,4′-dihydro-1′H-spiro[cyclopropane-1,2′-naphthalene]-2-carboxamides as a single diastereoisomer. The stereoconfiguration of the products was determined by ¹H and ¹³C NMR spectroscopy.     

Five-membered 2,3-dioxoheterocycles: XCVI. Reactions of 3-aroylpyrrolo[1,2-a]quinoxaline-1,2,4(5h)-triones with substituted 1,3,3-trimethyl-2-azaspiro[4.5]dec-1-enes

3-Aroylpyrrolo[1,2-a]quinoxaline-1,2,4(5H)-triones react with 1,3,3,7,9-pentamethyl-2-azaspiro-[4.5] deca-1,6,9-trien-8-one and 2′,5′,5′-trimethyl-4′,5′-dihydro-4H-spiro[naphthalene-1,3′-pyrrol]-4-one providing 3-aroyl-2-hydroxy-3a-{(3,3,7,9-tetramethyl-8-oxo-2-azaspiro[4.5]deca-1,6,9-trien-1-yl)methyl}pyrrolo[1,2-a-quinoxaline-1,4(3a H,5H)-diones and 3-aroyl-2-hydroxy-3a-{(5′,5′-dimethyl-4-oxo-4′,5′-dihydro-4H-spiro[naphthalene-1,3′-pyrrol]-2′-yl)methyl}pyrrolo[1,2-a]-quinoxaline-1,4(3aH,5H)-diones.     

Synthesis,magnetic properties and theoretical calculations of novel nitronyl nitroxide and imino nitroxide diradicals grafted on terpyridine moiety

The synthetic route based on Stille coupling between tributyltinpyridyl derivatives and bromo substituted mono- and dipyridyl-carbaldehyde is used for the synthesis of 5,5″-diformyl-2,2′:6′,2″-terpyridine (8). A sequence of Ullman coupling with 2,3-bis(hydroxylamino)-2,3-dimethylbutane followed by oxidation under phase transfer conditions affords either 5,5″-Bis(1-oxyl-3-oxo-4,4,5,5-tetramethylimidazolidin-2-yl)2,2′:6′,2″-terpyridine (10) (diNN-Terpy) or the related 5,5″-Bis(1-oxyl-4,4,5,5-tetramethylimidazolidin-2-yl)2,2′:6′,2″-terpyridine (11) (diIN-Terpy), where both biradicals display clear intramolecular ferromagnetic interaction between the single spin units as evidenced by ESR spectroscopy. Quantum chemical calculations (ROHF/AM1) are performed showing the triplet ground-state for both 10 and 11 radicals.     

Metal complexes with pyridone-based radicals: Preparation and properties of a dinuclear paddle-wheel copper(II) complex and a mononuclear palladium(II) complex

We prepared and characterized dinuclear copper(II) and mononuclear palladium(II) complexes coordinated with a pyridine-based open-shell ligand, 5-(4′,4′,5′,5′-tetramethylimidazoline-3′-oxide-1′-oxyl)-2(1H)-pyridone (=HL). In the copper(II) dinuclear complex [Cu₂(L)₄(DMF)₂] (1), four deprotonated ligands are coordinated as bridging ligands to form a paddle-wheel type unit. In the palladium(II) complex trans-[PdCl₂(HL)₂] (2), two HL ligands in the neutral hydroxypyridine form are coordinated to the trans positions of the metal ion via the nitrogen atoms. The hydroxyl groups of the ligands are hydrogen-bonded to the chlorine atoms of neighboring molecules, thereby creating a hydrogen-bonded double-chain molecular arrangement. Magnetic susceptibilities of these complexes were measured and analyzed. The small intramolecular antiferromagnetic interaction in the latter complex may originate from superexchange through the diamagnetic metal center.     

Synthesis of regioisomeric,stereoregular AABB-type polyamides from chiral diamines and diacids derived from natural amino acids

Two regioisomeric and stereoregular AABB-type polyamides have been synthesized using l-glutamic acid 1 and l-alaninol 4 as sources of chirality. From 4, two derivatives of chiral diamines were prepared and regioselectively condensed with pentachlorophenyl 5-oxo-(S)-2-tetrahydrofurancarboxylate 3, derived from 1. Manipulation of functional groups and convenient deprotections led to the ammonium salts of N-[1′-amino-(S)-2′-propyl]- and N-[(S)-2′-amino-1′-propyl]-5-oxo-(S)-2-tetrahydrofurancarboxyamide 11 and 15, respectively, in which the building blocks derived from 1 and 4 are linked through an amido group. Compounds 11 and 15 are, in fact, α,ω-amino acids having amino and lactone groups, and hence activated for polycondensation. Thus, polymerization of 11 took place under regio- and stereo-control to afford stereoregular poly[N-(1′-amino-(S)-2′-propyl)-carboxyamido-(S)-2-hydroxypentan-5-oic acid] (16). Similar polycondensation of 15, under the optimized conditions employed for the synthesis of 16, gave the regioisomeric polyamide 17, which exhibited a molecular weight lower than that of 16. The thermal and spectroscopic properties of optically active AABB-polyamides 16 and 17 are described.     

Optically active α-hydroxy-α-(tetrahydroquinoxalin-3-on-2-yl)esters by ring transformation of (R,R)-diethyl oxirane-2,3-dicarboxylate

The reaction of (R,R)-diethyl oxirane-2,3-dicarboxylate 6 with o-phenylendiamines 7 and 1,8-diaminonaphthalene gave optically active (2R,2′S)-2-hydroxy-2-(3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl)-acetates 8 or (2R,2′S)-2-hydroxy-2-(3-oxo-1,2,3,4-tetrahydronaphtho[1.8-ef][1.4]diazepin-2-yl)-acetate 9, respectively, in a regio and stereoselective manner. o-Phenylendiamines 7 with an electron-donating substituent gave other regioisomers to the electron-poor 7. Together with previous investigations in this field the present results demonstrate a dependence of the mode of the reaction of glycidates with o-phenylendiamines on the substituents at the glycidate.     

Flash vacuum pyrolysis of azolylacroleins and azolylbutadienes

2-Aryl-5-acroleinyl-1,2,3,4-tetrazoles (1a–d) and 2-aryl-5-butadienyl-1,2,3,4-tetrazoles (1e–g) were subjected to flash vacuum pyrolysis. Acroleinyl derivatives resulted in nitrogen extrusion to give nitrilimines followed by ring closure to give the corresponding indazoles 3a–d in good yields. On the other hand, butadiene derivatives underwent ring fragmentation to give p-substituted anilines without formation of the expected indazoles. Differences between thermal behaviour of 2-(4-chlorophenyl)-5-acroleinyl-1,2,3,4-tetrazole (1c) and 1-(4-chlorophenyl)-4-acroleinyl-1,2,3-triazole (2) were studied in details. DFT calculations have been used to examine the nitrilimine and carbene nature of the intermediates involved in the thermal reactions of azolyl derivatives.     

Synthesis,characterization, and investigations of antimicrobial activity of 6,6-dimethyl-3-aryl-3′,4′,6,7-tetrahydro-1′H,3H-spiro[benzofuran-2,2′-naphthalene]-1′,4(5H)-dione

Chalcone-like compounds 3a–l, 2-(benzylidene)-3,4-dihydronaphthalen-1(2H)-one, were synthesized from the addition of different benzaldehyde derivatives (2a–l) to 1,2,3,4-tetrahydro-1-napthalone (1) in basic medium. Mn(OAc)₃-mediated addition of dimedone (4) to chalcone-like compounds gave the spirobenzofuran derivatives (5a-l), 6,6-dimethyl-3-aryl-3′,4′,6,7-tetrahydro-1′H,3H-spiro[benzofuran-2,2′-naphthalene]-1′,4 (5H)-dione, in good yields. The structures of synthesized compounds 5a–l were elucidated on basis of spectral data (NMR, IR) and elemental analysis. In addition, their antibacterial activities were screened against some human pathogenic microorganisms.     

Ultrasound-promoted synthesis of novel 2-chloroquinolin-4-pyrimidine carboxylate derivatives as potential antibacterial agents

Ultrasound-promoted reaction of substituted 2,4-dichloroquinolines (1) with ethyl 4-(3-hydroxyphenyl)-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (2) in the presence of K₂CO₃ as mild base at moderate temperatures leads to 2-chloroquinolin-4-pyrimidine carboxylate derivatives (3) with high regioselectivity. All the compounds synthesized were characterized by use of spectral data and screened for their antibacterial activity against two Gram-positive (Staphylococcus aureus, Bacillus cereus) and two Gram-negative (Escherichia coli and Pseudomonas aeruginosa) bacteria. Activity was moderate.     

A study of the claisen rearrangement of 7-cinnamyloxy benzo-γ-pyrones

The Claisen rearrangement of 7-O-cinnamyl noreugenin (2) yields 4′,5′ - dihydro - 5 - hydroxy - 2,4′ - dimethyl - 5′ - phenyl - furo (2′,3′: 7,8) chromone (6) as established by its NMR spectrum, whereas that of 7-cinnamyloxyflavone (10a) and 5 - hydroxy - 7 - cinnamyloxy - 2 - methylisoflavone (10b) afford the corresponding furo derivatives (12a and 12b respectively). All these rearrangements are symmetry-allowed but are accompanied by further reactions of thermal cyclisation via 3-membered cyclic intermediate (5) and/or dehydrogenation.     

Antimicrobial and antispasmodic tetrahydroanthracenes from Cassia singueana

Four tetrahydroanthracene derivatives with antimicrobial and antispasmodic activities have been isolated from Cassia singueana. The evidence described in the following indicates them to be torosachrysone (1), germichrysone (4), and two new dimeric tetrahydroanthracenes, singueanol-I (7) or 6,6′-dimethoxy-3, 3′,8,8′,9,9′-hexahydroxy-3,3′,7,7′-tetramethyl-3,3′,4,4′-tetrahydro(10,10′-bianthracen)-1,1′(2H,2′H)-dione, and singueanol-II (8) or 6,6′-dimethoxy-3,3′,8,8′,9,9′-hexahydroxy-3,3′,7,7′-tetramethyl-3,3′,4,4′-tetrahydro(5,10′-bianthracen)- 1′(2H,2′H)-dione.     

Five-Membered 2,3-dioxoheterocycles: XCV. Recyclization of 4-benzoyl-5-phenylfuran-2,3-dione at the action of substituted 1,3,3-trimethyl-2-azaspiro[4.5]dec-1-enes. Crystal and molecular structure of substituted 5-(2-azaspiro[4.5]dec-1-ylidene)cyclopent-3-ene-1,2-dione

4-Benzoyl-5-phenylfuran-2,3-dione reacts with 2′,5′,5′-trimethyl-4′,5′-dihydro-4H-spiro[naphthalene-1,3′-pyrrol]-4-one and 8-(2-methoxy-5-methylphenyl)-1,3,3,9-tetramethyl-2-azaspiro[4.5]deca-1,7-dien-6-one with the formation of (Z)-3-benzoyl-5-(5′,5′-dimethyl-4-oxo-4H-spiro[naphthalene-1,3′-pyrrolidin]-2′-ylidene)-4-phenylcyclopent-3-ene-1,2-dione, whose structure was proved by XRD analysis, and of (Z)-3-benzoyl-5-{8-(2-methoxy-5-methylphenyl)-3,3,9-trimethyl-6-oxo-2-azaspiro[4.5]dec-7-en-1-ylidene}-4-phenylcyclopent-3-ene-1,2-dione.     

Reactions of 2′-oxo-1′,2′-dihydrospiro[cyclopropane-1,3′-indole]-2,2,3,3-tetracarbonitriles with nucleophiles

2′-Oxo-1′,2′-dihydrospiro[cyclopropane-1,3′-indole]-2,2,3,3-tetracarbonitriles reacted with oxygencentered nucleophiles to form addition products at the cyano groups with conservation of the three-membered ring. Reactions of the title compounds with alcohols required the presence of base catalyst, and the products, 2-amino-4,4-dialkoxy-2′-oxo-1′,2′-dihydrospiro[3-azabicyclo[3.1.0]hex-2-ene-6,3′-indole]-1,5-dicarbonitriles, were converted into the corresponding 2-imino-2′,4-dioxospiro[3-azabicyclo[3.1.0]hexane-6,3′-indole]-1,5-dicarbonitriles and 2,2′,4-trioxospiro[3-azabicyclo[3.1.0]hexane-6,3′-indole]-1,5-dicarbonitriles by the action of acetic and sulfuric acids, respectively. The reactions with ketone oximes occurred in the absence of a catalyst, yielding 2-amino-4,4-bis(alkylideneaminooxy)-2′-oxo-1′,2′-dihydrospiro[3-azabicyclo[3.1.0]hex-2-ene-6,3′-indole]-1,5-dicarbonitriles. The reactions with thiols, aliphatic amines, and anilines were accompanied by opening of the three-membered ring. In the reactions with triphenylphosphine and thiols 2-(2-oxo-2,3-dihydro-1H-indol-3-ylidene)malononitrile was obtained, while morpholine and N,N-dimethylaniline gave rise, respectively, to 3,3-diaryl-and 3,3-dimorpholino-1H-indol-2(3H)-ones and tri- and dicyanoethylene derivatives.     

Phosphorylation of nucleoside derivatives with aryl phosphoramidochloridates

The preparation of three aryl phosphorocyclohexylamidochloridates (7a, 7b and 7c) and an aryl phosphoromorpholidochloridate (8) is described. These aryl phosphoramidochloridates react with 2′,3′-O-methoxymethylene-uridine, -4-N-anisoylcytidine and -6-N-anisoyladenosine (9a, 9b and 9c, respectively), in the presence of the 1-ethylimidazole derivative (11a) to give high yields of the corresponding fully-protected 5′-phosphoramidates (10). Treatment of the latter compounds with aqueous alkali gives the nucleoside 5′-phosphoramidate derivatives (14) which, on mild acidic hydrolysis, give the corresponding unprotected 5′-nucleotides (15) in virtually quantitative yields. Phosphorylation of 2′-O-methoxytetrahydropyranyluridine (12) with 7a and 8, under the same conditions, occurs regiospecifically to give the corresponding 5′-phosphoramidate derivatives (13). The partially-protected dinucleoside phosphate (16b) has been prepared and phosphorylated with 7a to give, after removal of the protecting groups, the dinucleotide (18, pUpU) in high yield.     

Tetra-tert-butyl-pentafulvalen als Ligand in zweikernigen Molybdänkomplexen: cis-Anordnung ohne Metall-Metall-bindung

Reaction of 1,1′,3,3′-tetra-tert-butyl-5-′-pentafulvalenedipotassium (1) with hexacarbonylmolybdenum leads to hexacarbonyl-dipotassium(1,1′,3,′-tetra-tert-butyl-5,5′-pemtafulvalene)dimolybdate (2), which on further treatment with stoichiometric amounts of iodomethane yields the hexacarbonyldimethyl(1,1′-3,3′-tetra-tert-butyl-5,5′-pentafulvalene)dimolybdenum, (η⁵ : η⁵-^tBu₄C₁₀H₄)Mo₂(CO)₆-(CH)₃)₂ (3). Compound 3 is obtained as yellow needles and brownish cube-like crystals, and it is characterized by ¹H-NMR, ¹³C-NMR, IR, and MS data. The cubes crystallize in the space group C2/c with four molecules in the unit cell. Each molecule consists of two tricarbonylmethyl(cyclopentadienyl) molybdenum units which are connected by a central CC-bond, twisted against each other by 64.8° and bent by 25.8°. Due to the steric requirements of the tertbutyl substituents in the fulvalene ligand, 3 should be formed only from cis-configurated 2.     

Carbon-13 nuclear magnetic resonance study of a new ring-chain tautomerism of some pyridazine derivatives

The ¹³C NMR spectra of a number of pyridazine derivatives have been recorded in DMSO-d₆ solution and analysed. Examination of the most diagnostic resonances, with particular emphasis on those arising from the pyridazine ring system, enabled the ready establishment of the presence of a ring-chain tautomerism in 5-(o-aminophenylcarbamoyl)pyridazine-4-carboxylic acid, methyl 5-(o-aminophenylcarbamoyl)pyridazine-4-carboxylate, 5-(o-aminophenylcarbamoyl)-3,6,-dimethylpyridazine-4-carboxylic acid and 5-(2-amino-1,2-dicyanovinylenecarbamoyl)pyridazine-4-carboxylic acid. This gave rise to 3′,4′-dihydro-3′-oxospiro[pyridazine-5(2H),2′(1H)-quinoxaline]-4-carboxylic acid, methyl 3′,4′-dihydro-3′oxospiro[pyridazine-5(2H),2′(1′H)-quinoxaline]-4-carboxylate, 3′,4′-dihydro-3′-oxo-3,6-dimethylspiro[pyridazine-5(2H), 2′(1′H)-quinoxaline]-4-carboxylic acid and 5-oxo-2,3-dicyano-1,4,8,9-tetraazaspiro[5.5]undeca-2,7,10-triene-11-carboxylic acid, respectively.