Pyridine-2(1H)-thione in heterocyclic synthesis: synthesis and antimicrobial activity of some new thio-substituted ethyl nicotinate,thieno[2,3-b]pyridine and pyridothienopyrimidine derivatives

3-(4-Bromophenyl)-2-cyanoprop-2-enethioamide (1) reacted with ethyl 3-oxo-3-phenylpropanoate (2) to give ethyl 4-(4-bromophenyl)-5-cyano-2-phenyl-6-thioxo-1,6-dihydropyridine-3-carboxylate (3). Compound 3 was taken as a starting material for the synthesis of thio-substituted ethyl nicotinate derivatives 5a–d, which underwent cyclization to the corresponding thieno[2,3-b]pyridines 6a–d. Also 3 reacted with hydrazine hydrate to give the pyrazolo[3,4-b]pyridine derivative 7, which upon diazotization gave the diazonium derivative 8. Compound 6a condensed with dimethylformamide–dimethylacetal to afford thieno[2,3-b]pyridine derivative 9, which reacted with different amines 10a–e to afford the pyridothienopyrimidine derivatives 12a–e through the Dimroth rearrangement. Moreover, compound 6a reacted with different reagents to give pyridothienopyrimidine derivatives 14a and b, 17 and pyrazolothienopyridine derivative 18. In addition, acetylating compound 6c with chloroacetylchloride afforded the 3-[(2)-chloroacetylamino]thieno[2,3-b]pyridine derivative 20, which upon cyclization yielded the corresponding 2-chloromethylpyrido[3′,2′:4,5]thieno[3,2-d]pyrimidine derivative 21. Some of the newly synthesized compounds were screened in vitro for their antimicrobial activities.

     

Stereoselective synthesis of dominicalure 1 and 2: Components of aggregation pheromone from male lesser grain borerRhyzopertha dominica (F.)

Dominicalure 1 (9a) and dominicalure 2 (9b), were synthesized by esterification of ,-unsaturated acids4a and4b with (S)-(+)-2-pentanol (8). The key step was the asymmetric reduction of 3-penten-2-one (5) to give the chiral intermediate6, which, upon diimide reduction, DNB derivatization, recrystallization, and hydrolysis, yielded8 in 63% ee. Acids4a and4b were prepared in a simple and efficient three-step synthesis with an overall yield of 54% and 62%, respectively, in stereoisomerically pure form.     

Synthesis and derivatization of angular 3-chloro-3-chlorosulfenyl naphtho[1,2-b]pyran(4H)-4-ones with evaluation of antiviral activity

Angular 2,3-dihydronaphtho[1,2-b]pyran(4H)-4-ones 1a,b react with an excess of thionyl chloride to give the α-chlorosulfenyl chlorides 2a,b, which are reduced by iodide ion to give the corresponding 1,3,4-oxadithiino derivatives 3a,b. However, the aducts 4a,b and 5a,b were obtained by reduced 2a,b with iodide ion in the presence of 2,3-dimethyl-1,3-butadiene and 1,3-cyclohexadiene, respectively. Direct oxidation of 2a,b afford 3,3-dichloronaphthopyran-4-ones 6a,b, whilst conversion to the sulfenamides 7a,b prior to oxidation provides 3-chloronaphthopyranones 8a,b. While α-chloro β-oxo sulfenyl chlorides 2a,b undergo straight forward substitution with 1-methylpiperazine and with potassium cyanide to give 9a,b and 10a,b, respectively. Some of the prepared products were selected and tested for their antiviral activity against herpes simplex virus type-1 (HSV-1). Plaque reduction infectivity assay was used to determine virus count reduction as a result of treatment with test compounds. Compound 5a showed moderate effect against HSV-1.     

Synthesis and Digestibility Inhibition of Diarylheptanoids: Structure–Activity Relationship

(±)-5-Hydroxy-1,7-bis-(4-hydroxyphenyl)-3-heptanone (2a), (±)-5-hydroxyl-1-(4-hydroxyphenyl)-7-phenyl-3-heptanone (2b), (±)-5-hydroxy-7-(4-hydroxyphenyl)-1-phenyl-3-heptanone (2c), and (±)-5-hydroxy-1,7-bis-(phenyl)-3-heptanone (2d) have been synthesized to study the structure–activity relationship regarding digestibility inhibition in vitro in cow rumen fluid. The activities were compared with the activity of chiral (S)-2a and its glucoside platyphylloside (1), isolated from Betula pendula. Compound 2a was slightly less active, 2b and 2c were more active, and 2d was less active than (S)-2a and platyphylloside.     

Steric effect in the free radical polymerization of vinyl ethers containing electron-deficient olefin groups

Summary o-(2-Vinyloxyethoxy)benzylidenemalononitrile (3a), methyl o-(2-vinyloxyethoxy)benzylidenecyanoacetate (3b), 1,3-di-(2'-dicyanovinyl)-5-methyl-2-(2'-vinyloxyethoxy)benzene (4a), methyl 1,3-di-(2'-carbomethoxy-2'-cyanovinyl)-5-methyl-2-(2'-vinyloxyethoxy)benzene (4b), 2,3,4-tri-(2'-vinyloxyethoxy)benzylidenemalononitrile (5a), methyl 2,3,4-tri-(2'-vinyloxyethoxy)benzylidenecyanoacetate (5b), 2,4,6-tri-(2'-vinyloxyethoxy)benzylidenemalononitrile (6a), and methyl 2,4,6-tri-(2'-vinyloxyethoxy)benzylidenecyanoacetate (6b) were prepared by the condensation of o-(2-vinyloxyethoxy) benzaldehyde (1a), 2-(2'-vinyloxyethoxy)-5-methylisophthaldehyde (1b), 2,3,4-tri-(2'-vinyloxyethoxy)benzaldehyde (2a), 2,4,6-tri-(2'-vinyloxyethoxy)benzaldehyde (2b) with malononitrile or methyl cyanoacetate, respectively. Vinyl ether compounds 3a–b and 5a–b were polymerized readily by free radical initiators to give optically transparent swelling poly(vinyl ethers) 7a–b and 9a–b. Compounds 4a–b and 6a–b did not polymerize by radical initiators due to the steric hindrance. Polymers 7a–b and 9a–b were not soluble in common organic solvents such as acetone and DMSO due to crosslinking. Polymers 7a–b and 9a–b showed a thermal stability up to 300°C in TGA thermograms. Received: 1 December 1999/Revised version: 14 February 2000/Accepted: 16 February 2000     

Synthesis and Properties of Polyimides Based on an Ether Ketone Diamine, 4,4'-Bis(4-aminophenoxy)benzophenone

A diamime monomer with ether-ketone group, 4,4'-Bis(4-aminophenoxy)benzophenone (II) was prepared through the nucleophilic substitution reaction of 1-chloro-4-nitrobenzene with 4,4'-Dihydroxybenzophenone in the presence of potassium carbonate in N,N-dimethylformamide, followed by catalytic reduction with hydrazine and Pd/C. Polyimides (PI) V _a–f (H), V _a–f (C) and copolyimides (co-PI) V _{b–d/m(e–f)} were synthesized from II and six kinds of commercial aromatic dianhydrides (III _a–f )via thermal or chemical imidization method. Poly(amic acid) (IV _a–f )had inherent viscosities range from 0.81 to 0.98 dL/g. PI of thermal imidization method was showed poor solubility even sulfuric acid. But PI of chemical imidization method V _e,f (C) and (co-PI(C)) could be dissolved. The reason is that the ketone group of poly(amic acid) segments linked with the terminal amino group of polymer chains during thermal imidization. PI films V _a–f (H) had tensile strengths of 101–118 MPa, elongations to break of 11–32%, and initial moduli of 2.1–2.8 GPa. The glass transition temperatures of V series were in the range of 252–278°C, and the temperatures of 10% weight loss (T ₁₀) were above 529°C and their residues more than 50% at 800°C in nitrogen. V series also measured the color, dielectric constants and moisture absorptions. Their films had cutoff wavelengths between 378–421 nm, b ^* values ranging from 16.4 to 77.1, dielectric constants of 3.47–3.85 (1 MHz), and moisture absorptions in the range of 0.31–0.46 wt%.     

5-Pyrenylidene-hydantoin, 2-thiohydantoin derivatives: synthesis,S- and N-alkylation

5-Pyrenylidene-2-thiohydantoin derivatives 2a–d were prepared by condensation of pyrene-1-carboxaldehyde with 2-thiohydantoin derivatives. Compounds 2a,b undergo Mannich reaction with formaldehyde and morpholine to give the corresponding Mannich products 3a,b respectively. S- and N-monoalkyl-5-pyrenylidene-hydantoin derivatives 5a,b and 6a,b were prepared by reaction of 5-pyrenylidene-2-thiohydantoin sodium salts with 1,3-dioxolan-methylsulfate derivatives. Deprotection of the products afforded 5-pyrenylidene-hydantoin (7), S- and N-dihydroxy derivatives 8a,b and 9a,b respectively. Reaction of 2a with methyl iodide afforded the corresponding S-methyl derivative 10, which reacted with secondary amines such as morpholine and piperidine afforded the glycocymidine derivatives 11a,b. Reaction of 2a with (2,3,4,6-tetra-O-acetyl-α-? D-glucopyranosyl)bromide afforded a mixture of S- and N-glucoside derivatives 12 and 13 respectively. Deprotection of 12 afforded compound 7, while deprotection of 13 furnished 5-Pyrenylidene-3-? D-glucopyranosyl-2-thiohydantoin (14). Reaction of 7 with propargyl chloride in DMF afforded the monoalkynyl- and bis-alkynyl-hydantoin derivatives 15 and 16, respectively. Reaction of 15 with p-bromophenyl-ether derivative 17 yielded the bis-alkynyl derivative 18.     

Bis-(cyanoacetamide)alkanes in heterocyclic synthesis: synthesis of bis-heteryl(carboxymido)alkanes and bis-(heteryl)alkanes of thiophene,pyrrole, thiazole and pyrimidinone series

Bis-N-substituted cyanoacetamides 3a and b reacted with active methylene-containing compounds 2a–c and elemental sulfur to give bis-thiophene 4a and b and bis-pyrrole 6a and b derivatives. Compounds 4a and b reacted with ethyl cyanoacetate 2a to afford bis-thienopyrimidine derivatives 5a and b; on the other hand, 6a and b reacted with cyanothioacetamide 2c to give the corresponding bis-thioxopyrrolopyrimidine derivatives 7a and b. Compounds 7a and b reacted with methyl iodide to give the corresponding bis-2-S-methylpyrrolopyrimidine derivatives 8a and b, which could be, in turn, cyclized into the bis-pyrazolopyrrolopyrimidine derivatives 9a and b by refluxing with hydrazine hydrate. On the other hand, 7a and b reacted with ethyl chloroacetate to yield the corresponding bis-thienopyrrolopyrimidine derivatives 10a and b. Finally, compounds 3a and b reacted with phenylisothiocyanate and elemental sulfur to give the corresponding bis-2-thioxoaminothizole derivatives 11a and b.     

Investigation of the role of diterpenes produced by marine pulmonatesTrimusculus reticulatus andT. conica

The intertidal pulmonate limpetTrimusculus reticulatus, which is found in caves or crevices along the California coast, was previously reported to contain two novel diterpenoids, 6-isovaleroxylabda-8,13-dien-7,15-diol (1) and 2,7-diacetoxy-6-isovaleroxylabda-8,13-dien-15-ol (2). Dissection of the animals prior to extraction revealed that the diterpenoids were concentrated in the mantle, foot, and mucus, but not in the viscera. The presence ofT. reticulatus or its mucus was toxic to veliger larvae of the sabellariid reef-building tube wormPhragmatopoma californica. The major diterpenoid1 was responsible for the observed larvicidal activity. Protection against overgrowth by settling invertebrate larvae is important for the survival of this sessile filter-feeding pulmonate. A related pulmonate,T. conica, which was found in similar intertidal habitats in New Zealand, contained 6-acetoxy-7-isovaleroxylabda-8,13-dien-15-oic acid (3) and 1,7,12,18-tetraacetoxy-cholest-5-en-3-ol (4). The diterpene3 was also localized in the foot, mantle, and mucus ofT. conica but was not larvicidal toP. californica.     

Synthesis of some new fused thiopyrano[2,3-d]thiazoles and their derivatives

A series of some new fused thiopyrano[2,3-d]thiazole derivatives have been synthesized by a stereo-selective hetero-Diels-Alder reaction of 5-(2,4-dihydroxy-benzylidene)-4-thioxo-thiazolidine derivatives 3a,b with acrylonitrile, ethyl acrylate, N-phenylmale-imide, ω-nitrostyrene and N-phenyl-1, 3, 4-triazole-2,5-dione. 5-Amino-9-hydroxy-dihydro-benzopyrano[3′,4′:4,5]thiopyrano[2,3-d]thiazol-6-one derivatives 14a,b have been synthesized by Michael addition of 3a,b with malononitrile. Structures and conceivable mechanisms are discussed.     

Studies toward the synthesis of the shark repellent pavoninin-5

Sharks are the most dangerous predators of people in the sea, resulting in people being mauled and killed each year. A shark repellent could help to diminish this danger. The aglycone of the shark repellent pavoninin-5, (25R)-cholest-5-en-3β,15α,26-triol (5a), was synthesized from diosgenin (9). Removing mercury from the Clemmensen reduction of 9 gave a higher yield of (25R)-cholest-5-en-3β,16β,26-triol, 10a, and was also more environmentally friendly. Attempted methods for the transposition of the C-16β hydroxyl to the 15α position are described. A successful method for this transposition via the 15α-hydroxy-16-ketone, 8a, using the Barton deoxygenation reaction on the 16-alcohol 14b, is reported.     

A new route to steroid ring C aromatization from readily available precursors

3β-Acetoxy-8α,9α-epoxy-5α-cholest-14-ene (1); 3β-acetoxy-14α,15α-epoxy-5α-cholest-8-ene (2); 3β-acetoxy-5α-cholest-8(14)-ene-9α,15α-diol (3); and 3β-acetoxy-5α-cholesta-8(14),9(11)-dien-15α-ol (4) have been aromatized to a 9∶1 mixture of 3β-hydroxy-12-methyl-18-nor-5α,17β(H)-cholesta-8,11,13-triene (5a) and 3β-hydroxy-12-methyl-18-nor-5α,17α(H)-cholesta-8,11,13-triene (5b) in ethanol solution by using hydrochloric acid. The aromatization by action ofp-toluenesulfonic acid gave mainly the epimer with the natural C-17 configuration as the acetate 5c at the appropriatep-toluenesulfonic acid concentration. 3β-Acetoxy-5α-cholesta-7,9(11),14-triene (7a) and 3β-hydroxy-5α-cholesta-8,11,14-triene (8a), 2 intermediary compounds in the aromatization, were isolated and characterized.     

A new cucurbitacin profile forCucurbita andreana: A candidate for cucurbitacin tissue culture

In addition to previously reported cucurbitacins B,1, and D,2, cucurbitacin E,3, and I,4, aglycones and their glucosides 2-O--glucopyranosyl-cucurbitacin E,5, and 2-O--glucopyranosyl-cucurbitacin I,6, were isolated and identified as constituents ofCucurbita andreana on the basis of MS, FD-MS, 1 H NMR and¹³C NMR spectroscopy. Also, 2-O--glucopy-ranosyl-cucurbitacin B, 7, cucurbitacin B glucoside was isolated and identified.     

Synthesis of 9Z,11E-octadecadienoic and 10E,12Z-octadecadienoic acids, the major components of conjugated linoleic acid

Linoleic acid was efficiently converted into the two major components of conjugated linoleic acid, 9Z,11E-octadecadienoic (1a) and 10E,12Z-octadecadienoic acid (1b) using either the superbase (n-butyllithium/potassium tert-butoxide) or by simply refluxing with KOH in 1-butanol. In turn, 1a and 1b were separated from each other using the lipase from Aspergillus niger via stereoselective esterification in 1-butanol. This enzyme has a preference for the 9Z,11E isomer, 1a, and has excellent selectivity. This method has allowed the ready preparation of gram quantities of 1a and 1b in their highly purified forms, which are not readily accessible by current methods.     

Synthesis, Properties, and Functionalization of Poly(ferrocenylsilane)s with Chloroalkyl Side Chains

A series of poly(ferrocenylsilane)s containing chloroalkyl side chains of increasing length is reported. By reacting fcLi₂· tmeda with Cl₂SiMeR, the corresponding [1]ferrocenophanes were prepared (2a, R=CH₂Cl; 2b, R=CH₂CH₂Cl; and 2c, R=CH₂CH₂CH₂Cl). Transition metal-catalyzed or thermal ring-opening polymerization (ROP) of these monomers yielded the polyferrocenes 3a, 3b, and 3c. The chlorine substituents of polymers 3a and 3b were unreactive toward nucleophilic substitution. In contast, polymer 3c could be reacted with 4-dimethylaminopyridine in DMF to afford the water-soluble poly(ferrocenylsilane) 4. This represents a new method for the preparation of water-soluble polyferrocenes.     

Synthesis and electrochemical characterisation of benzylmercapto and dodecylmercapto tetra substituted cobalt, iron, and zinc phthalocyanines complexes

The work reports on cyclic voltammetry (CV), square wave voltammetry and spectroelectrochemistry of the following complexes: tetrakis (benzylmercapto) phthalocyanine complexes of Zn(II) (ZnTBMPc, 4a), Co(II) (CoTBMPc, 5a), and Fe(II) (FeTBMPc 6a); tetrakis (dodecylmercapto) phthalocyanine complexes of Zn(II) (ZnTDMPc, 4b), Co(II) (CoTDMPc, 5b), and Fe(II) (FeTDMPc, 6b). More reversible CV couples were observed for complexes 4a, 5a, and 6a containing thiol phenyl ring substituents. Complexes 4b, 5b, and 6b containing long chain thiol substituents showed less reversible couples. Complexes 6a and 6b showed a relatively large number of redox processes (5 for 6a and 6 for 6b) within the potential window employed in this work. The processes for FePc derivatives (6a) are assigned to Fe^IIIPc⁻¹/Fe^IIIPc⁻², Fe^IIIPc⁻²/Fe^IIPc⁻², Fe^IIPc⁻²/Fe^IPc⁻², Fe^IPc⁻²/Fe^IPc⁻³, and Fe^IPc⁻³/Fe^IPc⁻⁴ and for the CoPc derivative (5a) to Co^IIIPc⁻¹/Co^IIIPc⁻², Co^IIIPc⁻²/Co^IIPc⁻², Co^IIPc⁻²/Co^IPc⁻², and Co^IPc⁻²/Co^IPc⁻³.     

Enantiospecific Effect of Pulegone and Pulegone-Derived Lactones on Myzus persicae (Sulz.) Settling and Feeding

The effect of pulegone chiral center configuration on its antifeedant activity to Myzus persicae was examined. Biological consequences of structural modifications of (R)-(+)- and (S)-(−)-pulegone, the lactonization, iodolactonization, and incorporation of hydroxyl and carbonyl groups were studied, as well. The most active compounds were (R)-(+)-pulegone (1a) and δ-hydroxy-γ-spirolactones (5S,6R,8S)-(−)-6-hydroxy-4,4,8-trimethyl-1-oxaspiro[4.5]decan-2-one (5b) and (5R,6S,8S)-6-hydroxy-4,4,8-trimethyl-1-oxaspiro[4.5]decan-2-one (6b) derived from (S)-(−)-pulegone (1b). The compounds deterred aphid probing and feeding at preingestional, ingestional, and postingestional phases of feeding. The preingestional effect of (R)-(+)-pulegone (1a) was manifested as difficulty in finding and reaching the phloem (i.e., prolonged time preceding the first contact with phloem vessels), a high proportion of probes not reaching beyond the mesophyll layer before first phloem phase, and/or failure to find sieve elements by 20% of aphids during the 8-hr experiment. The ingestional activity of (R)-(+)-pulegone (1a) and hydroxylactones 5b and 6b resulted in a decrease in duration of phloem sap ingestion, a decrease in the proportion of aphids with sustained sap ingestion, and an increase in the proportion of aphid salivation in phloem. δ-Keto-γ-spirolactone (5R,8S)-(−)-4,4,8-trimethyl-1-oxaspiro[4.5]decan-2,6-dione (8b) produced a weak ingestional effect (shortened phloem phase). The postingestional deterrence of (R)-(+)-pulegone (1a) and δ-hydroxy-γ-spirolactones (5R,6S,8R)-(+)-6-hydroxy-4,4,8-trimethyl-1-oxaspiro[4.5]-decan-2-one (5a), 5b, (5S,6R,8R)-6-hydroxy-4,4,8-trimethyl-1-oxaspiro[4.5]decan-2-one (6a), 6b, and δ-keto-γ-spirolactone 8b prevented aphids from settling on treated leaves. The trans position of methyl group CH₃–8 and the bond C5–O1 in lactone 6b appeared to weaken the deterrent activity in relation to the cis diastereoisomer (5b).