Novel Syntheses and Reactions of Polynuclear Heterocyclic Derivatives Derived From Thioxopyridopyrimidine,With a New Ring System

Pyridopyrimidine derivatives 2 reacted with hydrazonoylchloride derivatives and yielded triazolopyridopyrimidines 6a–f. Compound 4b reacted with aliphatic acids and afforded triazolo-pyridopyrimidines 7a,b, and the reaction with carbon disulfide afforded 10-mercapto-triazolopyridopyrimidine (10). Moreover, the reaction of 4b with β -ketoesters afforded 10-pyrazolyl-pyridopyrimidines derivatives 11, 13, 14, and 15. Compound 4b reacted with nitrous acid to give tetrazolopyridopyrimidine 16, which reduced to 10-amino-derivative 17. On the other hand, the reaction of 4b with aromatic aldehydes afforded arylidines derivatives 18a–c, which were later cyclized to triazolo-pyridopyrimidines deivatives 19a–c. Finally, 4b reacted with α-haloketones to give triazines derivativrs 20, with new ring systems.     

Acetoacetanilides in Heterocyclic Synthesis,Part 1: An Expeditious Synthesis of Thienopyridines and Other Fused Derivatives

3-Oxo-N-{4-[(pyrimidin-2-ylamino)sulfonyl]phenyl}butanamide 1 reacts with arylidinecyanothioacetamide in refluxing ethanolic TEA to give the pyridinethione 2 rather than thiopyrane 4. Compound 2 reacts with α-haloketones to give the s-alkylated derivatives 7a–e. Compound 7a–e undergoes cyclization into thieno[2,3-b]pyridine derivatives 8a–e. The saponification of 8a gives the amino acid 9, which affords 10 when refluxed in Ac₂O. The treatment of 10 with NH₄OAc/AcOH gives 11. Compound II is also obtained when 8e is refluxed in Ac₂O. The reaction of 8a with hydrazine hydrate gives 12 and with formamide gives 13. Compound 13 also is obtained from the reaction of 8e with triethylorthoformate. The acetylation of 8a with Ac₂O gives the amide derivative 14, which, on treatment with aromatic amines, affords 15a–c. Compounds 15a–c are cyclized with H₂SO₄ to 16a–c. Compound 16 is obtained also from the acetylation of compound 8c, d by Ac₂O. Reactions of compound 8e with CS₂ in refluxing dioxane afford 17. The diazotization and self-coupling of 8e give the pyridothienotriazine 18. Finally, the chloronation of compound 13 with POCl₃ affords the chloride derivative 19.     

A Convenient Route to 1,3,4-Thiadiazoles,Thiazolidinone, Thiazoles,Pyridones, Coumarins,Triazolo[5,1-c]triazines,and Pyrazolo[5,1-c]triazines Incorporating Pyrazolone Moiety and Their Use as Antimicrobial Agents

Condensation of 4-acetyl-5-methyl-2-phenyl-2,4-dihydropyrazol-3-one (1) with hydrazine derivatives (2a–d) afforded hydrazone derivatives (3a–d), which reacted with alkyl halides 4a–c to give bis(alkylthio)methylene derivatives (5a–e). Also, 3a,b reacted with hydrazonyl halides 6a–d to give 1,3,4-thiadiazole (7a–d). Cyclization of 3c with ethyl bromoacetate and haloketones gave thiazolidinone and thiazole derivatives (8, 10a,b) respectively. Treatment of hydrazone (3d) with benzylidine malononitrile 13a,b gave pyridine (14a,b). In addition, cyclocondensation of 3d with phenolic aldehydes furnished coumarin derivatives (16a–c). Coupling of 3d with heterocyclic diazonium salts gave triazol[5,1-c]triazine (20) and pyrazolo[5,1-c]triazine (22). Some of the prepared products showed potent antimicrobial activity.     

NOVEL N,S-SUBSTITUTED DIENES BY THE REACTION OF 2-NITROTHIOSUBSTITUTED HALODIENES AND PRIMARY AMINES

Mono(thio)substituted 1a–c gave compounds 3a–c and 5a with o-toluidin (2) and m-toluidin (4) in ether. Compounds 9a–c and 11a, b were obtained from the reaction of compounds 1a–c with p-fluorophenylamine (8) and p-fluorobenzylamine (10). Compounds 7a and 15c were obtained from the reaction of 1a and 1c with p-phenylendiamine (6) and o-phenylendiamine (14). Compound 13c was synthesized from the reaction of compound 1c with benzidine (2).     

Einige Neue N,S-Substituierte 2-Nitrodienverbindungen Aus Reaktionen Von Mono(p-fluorarylthio)substituierten Dienen Mit Aminen

2-Nitrodiene compound 1 was stirred with p-fluorothiophenol for a long time and compound 3 was obtained. Compound 1 gave bis(thio)substituted 2-nitrodiene compound 4 and tris(thio)substituted compound 5 with 2 moles of p-fluorothiophenol in the presence of NaOH in ethanol. The compounds 9a–g have been prepared from 8a–g and 3. Compound 7 was obtained from the reaction of mono(thio)substituted 2-nitrodiene with morpholine. Compound 3 gives 11a–d in the reaction with piperidines in CH₂Cl₂ (or ether). Compound 13a–b have been obtained from the reaction of compound 3 with primary amines 12a–b. Compound 3 gives 15 and 16 in the reaction with 2,5-dimethylpiperazine in CH₂Cl₂.

     

Group-theoretical Foundations for the Concept of Mandalas as Diagrammatical Expressions for Characterizing Symmetries of Stereoisomers

Group-theoretical foundations for the concept of mandalas have been formulated algebraically and diagrammatically in order to reinforce the spread of the unit-subduced-cycle-index (USCI) approach (S. Fujita, Symmetry and Combinatorial Enumeration in Chemistry, Springer-Verlag, Berlin-Heidelberg, 1991). Thus, after the introducton of right coset representations (RCR) (H\)G and left coset representations (LCR) G(/H) for the group G and its subgroup H, a regular body of G-symmetry is defined as a diagrammatical expression for a right regular representation (C ₁\)G, which is an extreme case of RCRs. The |G| substitution positions of the regular body as a reference are numbered in accord with the numbering of the elements of G and segmented into |G|/|H| of H-segments, which are governed by the RCR (H\)G. By regarding each H-segment as a substitution position, the H-segmented regular body is reduced into a reduced regular body, which can be regarded as a secondary skeleton for generating a molecule. The reference regular body (or H-segmented one) is operated by every symmetry operations of G to generate regular bodies (or H-segmented ones), which are placed on the vertices of a hypothetical regular body of G-symmetry. The resulting diagram (a nested regular body) is called a mandala (or a reduced mandala), which is a diagrammatical expression for specifying the G-symmetry of a molecule. The effect of a K-subduction on the regular bodies of a mandala (or a reduced mandala) results in the K-assemblage of the mandala (or the reduced mandala), where the resulting K-assemblies governed by the LCR G(/K) construct a |G|/|K|-membered orbit, which corresponds to a molecule of K-symmetry. The sphericity of the RCR (or the LCR) is used to characterize symmetrical properties of substitution positions and those of stereoisomers. The fixed-point vector for each mandala (or reduced mandala) in terms of row view and the number of fixed points of K-assembled mandalas (or K-assembled reduced mandalas) in terms of column view are compared to accomplish combinatorial enumeration of stereoisomers. The relationship between a mandala and a reordered multiplication table is discussed.     

Design,synthesis and cholinesterase inhibitory activity of α-mangostin derivatives

Abstract

α-mangostin, a polyphenol xanthone derivative, was mainly isolated from pericarps of the mangosteen fruit (Garcinia mangostana L.). In present investigation, a series of derivatives were designed, synthesised and evaluated in vitro for their inhibitory activity of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). Among the synthesised xanthones, compounds 1, 9, 13 and 16 showed AChE selective inhibitory activity, 15 was a BuChE selective inhibitor while 2, 3, 5, 6, 7, 12 and 14 were dual inhibitors. The most potent inhibitor of AChE was 16 while 5 was the most potent inhibitor of BuChE with IC₅₀ values of 5.26?μM and 7.55?μM respectively.     

Anti-Alzheimer and Anti-COX-2 Activities of the Newly Synthesized 2,3′-Bipyridine Derivatives (II)

3-Amino-4-aryl-6-pyridin-3-ylthieno[2,3-b]pyridine-2-carbohydrazides 3a,b were used as the starting materials in the present study. Our targets here were represented by the synthesis of several 3-amino-N′-4-arylmethylenes 5a,b, N-formamides 8a,b, ethyl imidoformate 10b, N,N-dimethyl-N′-imidoformamides 12a,b, N-acetyl-N-acetamides 14a,b, 1,3,4-oxadiazole-2-thiol 16a,b, pyrazolothienopyridines 20a,b, 2-[(3,5-dimethyl-1H-pyrazol-1-yl)carbonyl]-4-aryl-6-pyridin-3-ylthieno[2,3-b]pyridin-3-amines 22a,b, 2-carbonyl-5-methyl-2,4-dihydro-3H-pyrazol-3-ones 24a,b, and 2-carbonyl-pyrazolidine-3,5-diones 26a,b. The newly synthesized heterocyclic compounds were tested as anti-Alzheimer and anti-COX-2 agents, and their structures were elucidated by considering the data of IR, ¹H NMR, mass spectra, and elemental analyses.

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.     

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.     

Chemical composition and antioxidant activity of a polar extract of Thymelaea microphylla Coss. et Dur.

Thymelaea microphylla Coss. et Dur. (Thymelaeaceae) is a rare medicinal plant endemic to Algeria. In order to continue our studies on this species, herein we report the isolation and characterisation of 20 compounds from a hydroalcoholic extract (EtOH–H₂O 7:3) of the aerial parts. They include monoterpene glucosides (1–3), phenolic acid derivatives (4, 8 and 9), phenylpropanoid glucosides (5 and 6), flavonoids (7, 10 and 11), a benzyl alcohol glucoside (12), ionol glucosides (13–16), lignans (17–19) and a bis-coumarin (20). All the structures were elucidated by spectroscopic methods including 1D and 2D NMR experiments, as well as ESI-MS analysis. Moreover, the extract of T. microphylla showed a significant and concentration-dependent free radical-scavenging activity in vitro, correlated to the presence of phenolic and chlorogenic acid derivatives (8, 9 and 4).     

ORGANISCHE PHOSPHORVERBINDUNGEN 80 HERSTELLUNG VON TRIAZOLYLMETHYL-PHOSPHONATEN UND VON TRIAZOLYL-METHYLPHOSPHONIUMSALZEN UND DEREN VERWENDUNG IN DER WITTIG-HORNER REAKTION

Abstract

Attempts to prepare 1H-1,2,4-triazol-1-ylmethylphosphonates (4 and 5) by a Mannichtype reaction or by transesterification of 1-hydroxymethyl-1H-1,2,4-triazol 1 with tertiary phosphites failed. On the other hand 4 and 5 are obtained by a Michaelis-Becker reaction from 1-chloromethyl-1H-1,2,4-triazol 3 and sodium phosphites in high yield. The Michaelis-Arbuzov reaction is less suited for the preparation of 4 and 5. 3 is obtained in good yield as a water clear liquid, b.p. 52–54°C/0.2 torr, from the interaction of 1 with thionyl chloride followed by treatment with a base. On standing at 0° or 20°C it decomposes within hours and yields the unsymmetrical methylen-bis(triazol) 3a in addition to other products. However an acetonitrile solution of 3 is stable for months. Heating this solution with tertiary phosphines gives triazolylsubstituted phosphoniumsalts 6 to 8. The Wittig-Horner reaction with 4 to 6 gives the olefinically substituted triazols 9–12 as a Z/E mixture in high yield. Alkylation of 4 with methyl-and ethyl iodide gives the corresponding alkylated diethyl-1H-1,2,4-triazol-1-yl-ethyl-1-and-propyl-1-phosphonates 14 and 15 which on hydrolysis with HCI yield 1H-1,2,4-triazol-1-yl-ethyl-1-and propyl-1-phosphonic acids 17 and 18, respectively. Hydrolysis of 4 gives the unsubstituted 1H-1,2,4-triazol-1-ylmethyl-phosphonic acid, 16.     

Facile Synthesis of Some New Pyrazole-Based 2-Thioxo-4-thiazolidinone

5-Ethoxymethylene-2-thioxo-4-thiazolidinone (1) reacts with hydrazine hydrate at room temperature to afford 5-(hydrazinylmethylene)-2-thioxo-4-thiazolidinone (3). Compound 3 condensed with different aromatic aldehydes 6a–d in ethanol in the presence of a few drops of piperidine to give the corresponding Schiff’s bases 7a–d. On the other hand, compound 3 reacts with o-hydroxybenzaldehyde derivatives 8a and 8b in refluxing ethanol catalyzed by a few drops of piperidine to yield 1H-inadzolyl-2-thioxo-4-thiazolidinones 9a and 9b. Reaction of compound 3 with α-ketoesters 10a and 10b or α-diketones 10c–e in refluxing glacial acetic acid furnished the pyrazolyl-2-thioxo-4-thiazolidinone derivatives 11a–e. Also, compound 3 reacts with some different enaminones 12a–f in refluxing glacial acetic acid to afford the new pyrazolyl-2-thioxo-4-thiazolidinone derivatives 13a–f. Pyrazoles 15a–d was obtained via reaction of compound 3 with chalcones 14a–d in dimethylformamide (DMF). The structures of all the newly synthesized products were confirmed on the basis of their elemental and spectral data, and a plausible mechanism has been postulated to account for their formation.     

Synthese von 3,3a-Dihydro-2H,5H-azeto[2,1-b]benzo[d]1,3-oxazin-2,5-dionen, 2. Mitt.

Starting from the thioformimidates4 a, b, c and substituted acetylchlorides, the 3R*/4S* 4-methylthio-2-azetidinones5, 13 a, b, c are synthesized.5 is dehalogenated to6. Debenzylation of6 leads to7 and10, which undergo ring closure to9 and12 by the action of chlorine inDME. Hydrazinolysis of13 a, b, c and acylation of the intermediates14 a, b, c afford15 a, b, c. Removal of the protective groups leads to16 d, e, f. The diastereomeric mixtures17 d, e, f, which are obtained by the chlorolysis of16 d, e, f, undergo ring closure to the 3R*/4S* isomers of the title compounds18 d, e, f either spontaneously or by action of silvertetrafluoroborate/silveroxide. Chlorolysis of19 yields the diastereomeric mixture20. Treatment of20 with silvertetrafluoroborate/silveroxide gives21 and22.

Herrn Professor Dr.Hermann Bretschneider zum 80. Geburtstag gewidmet.     

SYNTHESIS OF SOME NEW HETEROCYCLIC COMPOUNDS FROM BENZOPYRANO[2,3-c]PYRAZOL-3-ONE DERIVATIVES

The reaction of benzopyrano[2,3-c]pyrazol-3-one (1) with some active halo compounds, afforded compounds 4, 8 and 12, respectively. The cyanoethyl derivative 19 was synthesized and treated with active methylenes and sulfur or benzoylisothiocyanate and phenacyl bromide, to give compounds 24_a,b and 27. Compounds 25_a,b and 28 were obtained through the reaction of compounds 24_a,b with acrylonitrile or compound 27 with maleic anhydride. Thiation of compound 1 afforded the corresponding thio derivative 29. The reaction of 4-benzylidene-2-methyloxazolin-5-one with compounds 1 or 29 gave products 30_a,b , respectively.     

Incorporation of lipid domains in Cerasome, a morphologically-stable organic-inorganic vesicular nanohybrid

To extend the concept of the Cerasome, an organic-inorganic vesicular nanohybrid, this paper investigates the preparation and characterization of a “mixed” Cerasome. The system consists of a Cerasome-forming lipid 1, a cationic synthetic lipid 2, and a zwitterionic phospholipid 3. Lipid mixtures of 1 and 2 or 1 and 3 were used to prepare the mixed Cerasomes. Their lipid distributions were examined using differential scanning calorimetry (DSC), which showed that 1 and 2 (or 1 and 3) were phase-separated in the mixed Cerasomes. These results seem to be mainly attributable to the polymerizable nature of 1. Results of scanning electron microscopy (SEM) and energy-dispersive X-ray analysis (EDX) showed that 1 and 3 were both incorporated into a single Cerasome, not macroscopically separated to form separate vesicles from each lipid component. Mixed Cerasomes of 1 and 2 showed high morphological stability against a membrane-solubilizing surfactant, incorporating up to 70% of 2. On the other hand, the mixed Cerasomes from 1 and 3 were less stable than the mixed Cerasomes from 1 and 2. This relative instability might be attributable to differences between the mixed Cerasomes from 1 and 2 and 1 and 3 in terms of their vesicular sizes, lipid domain sizes, and their relative effectiveness for siloxane network formation. These results strongly support the formation of mixed Cerasomes that have lipid domains in-plane. Systems described in this study are useful to prepare variously mixed Cerasomes that have different surface functionalities and in-plane lipid distribution, but which have high morphological stability.     

Synthesis and Antimicrobial Activity of Some New 1,3-Diphenylpyrazoles Bearing Pyrimidine,Pyrimidinethione, Thiazolopyrimidine,Triazolopyrimidine, Thio-and Alkylthiotriazolop-Yrimidinone Moieties at the 4-Position

1,3-diphenyl-1H-pyrazole-4-carboxaldehyde (1) reacted with ethyl cyanoacetate and thiourea to give the pyrimidinethione derivative 2. The reaction of 2 with some alkylating agents gave the corresponding thioethers 3a–e and 7. Thione 2 was cyclized to 5 and 6 upon a reaction with chloroacetic acid and with benzaldehyde, respectively. Thioether 3c was cyclized to 4 upon boiling with sodium acetate in ethanol, and 7 was cyclized to 8 upon boiling in an acetic anhydride-pyridine mixture. The hydrazino derivative 9 was prepared either by boiling 2 and/or 3a with hydrazine. The reaction of 9 with nitrous acid, acetylacetone, triethyl orthoformate, acetic anhydride, and carbon disulfide gave 10–14. The alkylation of 14 with ethyl iodide, phenacyl bromide, and ethyl chloroacetate afforded the alkythiotriazolo pyrimidinone derivatives 15a–c. The dialkyl derivative 16 was produced upon the treatment of 2 with two equivalents of ethyl iodide. Boiling 16 with hydrazine afforded the hydrazino 17. The reaction of 17 with nitrous acid, carbon disulfide, ethyl cyanoacetate, ethyl acetoacetae, and phenacyl bromide gave 18–22, respectively. Some of the newly obtained compounds were tested for their antibacterial and antifungal activities.     

Insect growth regulators. XVI Syntheses of juvenoids with the 3,3-dimethylcyclohexane system

New cyclic juvenoids containing the 3,3-dimethylcyclohexane (esters16,18,22,26, and ethers28 a, b) or the 5,5-dimethyl-2-cyclohexene system (esters15,17,21,25, and ethers27 a,b) have been obtained by a several-step synthesis starting from dimedone (1). The compounds obtained exhibited morphogenetic activity against larvae ofDysdercus cingulatus and they were inactive on pupae ofTenebrio molitor.

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Insekten-Wachstumsregulatoren. XVI. Synthesen von Juvenoiden mit dem 3,3-Dimethylcyclohexan-System

Zusammenfassung Ausgehend von Dimedon (1) wurden in mehrstufigen Synthesen neue, cyclische Juvenoide hergestellt, die das 3,3-Dimethylcyclohexan- (Ester16,18,22,26 und Ether28 a, b) oder 5,5-Dimethyl-2-cyclohexen-System (Ester15,17,21,25 und Ether27 a, b) enthalten. Die erhaltenen Verbindungen zeigen morphogenetische Aktivität gegenüber Larven vonDysdercus cingulatus und sind inaktiv gegenüber Puppen vonTenebrio molitor.

     

A Facile Access to Some New Pyrazole, 1,3,4-Thiadiazole,and Thiophene Derivatives via β-Ketosulfones

3-Bromoacetyl-1,5-diphenyl-1H-pyrazole-4-carbonitrile (1) reacts with sodium benzenesulfinate to give the corresponding ketosulfone 2. Treatment of 2 with hydrazonoyl chlorides 3a,b gives the 3,3′-bipyrazoles 5a,b. Ketosulfone 2 reacts also with arylidenemalononitriles to give the pyrazolylpyridones 10a,b. The reaction of compound 2 with phenylisothiocyanate and potassium hydroxide and treating intermediate with hydrazonoyl halides and with α-haloketones gives the 1,3,4-thiadiazoles 18a–c and thiophenes 21a–f, respectively.     

Some Cyclization Reactions with 2-Ethoxycarbonylmethylidene-4,5-Dihydro-4-Thiazolinone

2-Ethoxycarbonylmethylidine-4,5-dihydro-4-thiazolinone (1) was condensed with bis aromatic aldehydes such as terephthalaldehyde or 4,4′-bisformyl-diphenylether (2a,b) (2:1 molar ratio) and furnished bis-4-thiaozlidinones (3a,b). The reaction of (3a,b) with malononitrile and aromatic aldehydes (1:2:2 molar ratio) gave bis thiazolopyridines (4a–d). Bis-(thiazolopyridine) derivative (6) was obtained by reaction of 4-thiaozlinone (5c) with bis aldehyde (2b) in refluxing ethanol containing piperidine. Cyclization of 4-thiazolinones (5a,b) with different α-cyanocinnamonitriles gave thiazolo[3,2-a]pyridines (7a–d). Compound 9 was produced via the reaction of 8 with thioglycolic acid, which reacted with p-chlorobenzaldehyde to produce 10. Compound 10 was condensed with hydrazine hydrate and afforded 11. Compounds 12 and 16a,b were produced by the reaction of 9 with isatin and α-ethoxycarbonylcinnamonitriles, respectively.     

Three lanthanide complexes with mixed salicylate and 1,10-phenanthroline: syntheses,crystal structures,and luminescent/magnetic properties

Three new lanthanide complexes incorporating salicylate (HSA or SA) and 1,10-phenanthroline (phen), Ln₃(HSA)₅(SA)₂(phen)₃ [Ln = Ho (1) and Er (2)], and Sm₂(HSA)₂(SA)₂(phen)₃ (3), have been synthesized. X-ray structural analysis reveals that 1 and 2 are isostructural with a trinuclear pattern, and 3 exhibits a binuclear structure. Comparison of the structural differences between 1/2 and 3 suggests that the identity of metal plays an important role in construction of such complexes. The magnetic properties of 1 are discussed. Moreover, 2 and 3 are both photoluminescent materials, and their emission properties are closely related to their corresponding Ln^III centers.