Synthesis,Voltammetric and Analytical Applications of Some Fluorine Substituted Spirosteroidalthiazolidin‐4‐one Derivatives of Sulfa Drugs

A new 5‐arylidene‐4‐oxo‐(sulfonamoyl phenyl)‐spiro[thiazolidinone‐2,2′‐steroids] series (7–10) was prepared by condensation of sulfanilamide, sulfapyridine and sulfadiazine sulfa drugs with testosterone, epiandrosterone and progesterone steroids, respectively. The resultant imino derivatives 1–3 upon cycloaddition with thioacetic acid in dry 1,4‐dioxane afforded 3‐sulfo‐namoylphenylspiro[4‐oxo‐thiazolidin‐2,2′steroids] (4–6). The latter compounds (4–6) upon condensation with p‐fluorobenzaldehyde in ethanol‐piperidine yielded the corresponding 4‐fluoroarylidene derivatives 7, 8 & 9, respectively. All the newly synthesized compounds were confirmed by UV, IR, ¹H NMR, ¹³C NMR, mass spectral data, elemental analysis and molecular weight determination. In vitro antimicrobial screening of some of the synthesized compounds showed good antimicrobial activities towards some pathogenic Gram‐positive, Gram‐negative bacteria and fungi vs. piperacillin and mycostatine antibiotics as standard antibacterial and antifungal agents, respectively. The voltammetric behavior of two newly spirothiazolidinone steroids ( 2a & 5a ) was critically studied. Compound 5a physically immobilized polyurethane foam solid sorbent was successfully used for removal and/or separation of bismuth(III) from water.     

Synthesis of a 2-Methyl-4-sulfanilamido-s-triazine derivative

An attempt to obtain 2-methyl-4-sulfanilamido-s-triazine (XXI) by condensation of 2-amino-4-methyl-s-triazine (II) with p-acetamidobenzenesulfonyl chloride (III) in pyridine and in benzene containing trimethylamine gave instead the unexpected products, guanidine N-acetylsulfanilate (IV) (after hydrolysis) and N¹,N¹-dimethylsulfanilamide (V), respectively. On the other hand, 2-methyl-4-methylthio-6-sulfanilamido-s-triazine (XIX) was obtained from 4,6-dimethylthio-s-triazine (XVII), but the reduction of XIX with Raney nickel in aqueous sodium hydroxide solution also gave an unexpected compound, sulfaguanidine (XX).     

Spectrophotometric determination of sulfanilamides by a condensation reaction with <Emphasis Type="Italic">p</Emphasis>-dimethylaminocinnamaldehyde

p-Dimethylaminocinnamaldehyde has been proposed as a reagent for the spectrophotometric determination of sulfanilamides. This reagent was shown to undergo in acetonitrile a condensation reaction with sulfanilamide, Sulfamethoxypyridazine, Sulfachloropyridazine, Sulfamethoxazole, and Sulfamethazine to form colored products. Optimal reaction conditions were found. A procedure for the spectrophotometric determination of sulfanilamide compounds with detection limit n × 10^?2 μg/mL was developed. Determination of Sulfamethoxazole and Sulfamethazine in pharmaceuticals was carried out.     

Synthese von heterocyclen. V. 1, 3, 4-thiadiazol-2 (3 H)-one

A new and highly versatile method for the synthesis of 1, 3, 4-thiadiazol-2 (3 H)ones 1 is described. Methoxy-1,3,4-thiadiazoles- 5 , which are readily available by condensation of O-methyl thiocarbazate ( 2 ) with acid derivatives 3 , undergo an efficient cleavage to 1 and methyl chloride with hydrochloric acid in an anhydrous medium. Many new 5-substituted thiadiazolones, unavailable by earlier routes, were synthesized. Preparative as well as mechanistic aspects are discussed. With the aid of ¹³C-NMR. spectroscopy, the tautomerism of 1 was studied, and the tautomeric equilibria was shown to be dependent on the nature of the substituent in the 5-position. The thiadiazolones 1 exist predominantly in the oxo form. The percentage of the hydroxy form, however, increases with strongly electron withdrawing substituents in the 5-position. A good correlation with pK^a? and σ-values was observed.     

Synthesis of 1,3,4-thiadiazoles containing the trifluoromethyl group

The following compounds have been synthesized: 2-Amino-5-trifluoromethyl-1,3,4-thiadiazole; N-(5-trifluoromethyl - 1,3,4-thiadizol-2-yl)benzenesulfonamide; N¹-(5-trifluoromethyl-1,3,4-thiadiazol-2-yl)sulfanilamide, its N⁴-acetyl, N⁴-succinyl, and N⁴-pathalyl derivatives; o - m - and p-trifluoromethylbenzoylthiosemicarbazide, their corresponding 2-amino-1,3,4-thiadiazoles, their corresponding sulfanilamides, their N⁴-acetyl, N⁴-succinyl and N⁴-phthalyl derivatives; 3-o-trifluoromethylphenyl-4H-1,2,4-triazole-5-thiol. Preliminary in-vitro assays show that synthesized sulfanilamide derivatives have antibacterial activity against Staphylococcus aureus.     

Nucleotides,Part LXII,Pyridinium Salts – An Effective Class of Catalysts for Oligonucleotide Synthesis

Various pyridinium salts (see 1 – 9 ) have been tested as catalysts for the condensation step in the phosphoramidite approach of oligonucleotide synthesis. Pyridinium chloride ( 1 ) turned out to be the most effective activator, speeding up the condensation tremendously. Pyridinium bromide ( 2 ) and 4-methylbenzenesulfonate ( 4 ) can also be regarded as powerful substitutes for the commonly used 1H-tetrazole. The acidic pK_a of the pyridinium cation provides an optimal range for phosphoramidite activation, which is followed by a nucleophilic attack of the pyridine ring to give the P-pyridinio intermediate 11 as the most likely precursor of phosphite ester formation (Scheme). ³¹P-NMR Studies support this proposal indirectly.     

Pteridines. Part XLI. Synthesis and properties of 6,7,8-trimethyl-4-thiolumazine

The first representative of the 8-substituted 4-thiolumazine series has been synthesized. In a sequence of reactions, 4,6-dichloropyrimidin-2-(1H)-one ( 1 ) is first converted into 4-chloro-6-(methylamino)pyrimidin-2(1H)-one ( 6 ), then the Cl-atom displaced by the thioxo group (→7) followed by a coupling reaction with 4-chlorophenyldiazonium chloride to introduce the necessary N-function into the 5-position (→ 9 ; Scheme 1). Reduction of the p-chlorophenylazo group leads to the 6-(methlyamino)-4-thiouracil-5-amine ( 10 ) which on condensation with diacetyl gives 6,7,8-trimethyl-4-thiolumazine ( 8 ). The physical properties of 8 are compared with the 2-thio analog and 6,7,8-trimethyllumazine indicating that 8 possesses the highest acidity and the longest UV absorption.     

Reactions of Sulfenamides with Compounds of Trivalent Phosphorus

Chloro-dimethylamino-phenyl-p-tolylthio-phosphonium chloride 2 , dimethylamino-diphenyl-p-tolylthio-phosphonium chloride 3 , bis(diethylamino)-dimethylamino-p-tolylthiophosphonium chloride 4 and tert-butyl-dimethylamino-phenyl-p-tolylthio-phosphonium chloride 5 were prepared by the reaction of N,N-dimethylamino-p-tolylsulfenamide 1 with PhPCl₂, Ph₂PCl, (Et₂N)₂PCl and ^tBu(Ph)PCl, respectively. The reaction of N,N′-dimethyl-N,N′-bis(trimethylsilyl)urea 9 and N-methyl-N′-phenyl-N,N′-bis(trimethylsilyl)urea 10 with phenylsulfenyl chloride 6 or p-nitrophenylsulfenyl chloride 8 furnished the N-arylthio-N,N′-diorgano-N′-(trimethylsilyl)-ureas 11 – 14 . The reaction of 11 – 14 and of the previously known compounds 15 and 16 with MePCl₂, ClCH₂PCl₂, ^tBuPCl₂ and PhPCl₂ resulted in the formation of the 2-arylthio-2-chloro-1,2,3-triorgano-1,3,2λ⁵-diazaphosphetidin-4-ones 17 – 26 . 1,3-Dimethyl-2-(1,1,1,3,3,3-hexafluoro-2-propoxy)-2-phenyl-2-phenylthio-1,3,2λ⁵-diazaphosphetidin-4-one 29 and the 2-arylthio-1,3-dimethyl-2-(p-nitrophenoxy)-2-organyl-1,3,2λ⁵-diazaphosphetidin-4-ones 30 – 32 were obtained in the reactions of compounds 17, 24 and 27 with 1,1,1,3,3,3-hexafluoro-2-propanol or p-nitrophenol in the presence of triethylamine. The reaction of compound 21 with thiophenol in the presence of triethylamine resulted in a mixture of products, from which 1,3,4,5,7-pentamethyl-1,3,5,7-tetraaza-4λ⁵-phosphaspiro[3.3]heptan-2,6-dione 33 was isolated. The identity and structure of all the new compounds were established by ¹H-, ¹³C- and ³¹P-NMR spectroscopy and by elemental analysis. A possible mechanism of reaction of sulfenamides with compounds of trivalent phosphorus is discussed. For the compounds 5a, 32 and 33 X-ray structure analyses were conducted. The cation of compound 5a involves four-coordinate phosphorus (essentially tetrahedral geometry) and is a rare example of a P–S single bond in such a system (P–S 207.37(9) pm). In 32 the geometry at phosphorus is distorted trigonal bipyramidal, with axial positions occupied by oxygen and nitrogen atoms. In the spirophosphorane 33 the geometry at phosphorus is intermediate between trigonal bipyramidal and square pyramidal, with essentially planar four-membered rings.     

Study of photopolymer. XVII. Synthesis of novel photosensitive polymers with pendant photosensitive group and photosensitizer groups

Novel photosensitive polymers with pendant photosensitive group, such as cinnamic ester, and photosensitizer groups, such as N-carbamoyl-p-nitroaniline and N-carbamoly-4-nitro-1-naphthylamine, were synthesized from radical copolymerizations of (2-cinnamoyloxy)ethylmethacrylate with photosensitizer monomers, such as p-nitrophenylmethacrylamide and 4-nitro-1-na-phthylmethacrylamide, by using asobisisobutyronitrile (AIBN) in benzene and from the copolymerizations of (2-hydroxy)ethylmethacrylate or (2-hydroxy)ethylacrylate with photosensitizer monomers by using AIBN in DMF. This procedure was followed by condensation reactions of the copolymers with cinnamoyl chloride with pyridine as HCL acceptor in the same reaction flask. The photoreactivities of the polymers obtained were influenced by the concentration of photosensitive group and photosensitizer groups and their ratio in the polymer matrix. In addition, the photosensitivity of cinnamic ester groups attached to a soft polymer segment was higher than that of cinnamic ester group attached to a hard polymer segment when these polymers had the same pendant N-carbamoyl-p-nitroaniline group as photosensitizer. Furthermore, the spacer length between the polymer chain and photosensitizer group was important for increasing the photoreactivity of the photosensitive group in the polymers with pendant cinnamic ester and N-carbamoyl-p-nitroaniline groups.     

Kinetics of styrylquinolinc formation

A comprehensive kinetic investigation of reactions occurring in the formation of styryl-quinolines has been conducted. Specific rate data such as rate equations, rate constants, and thermodynamic activation values have been determined and utilized in a study of which factors are of greatest importance in the reactions forming 2-styrylquinolines. A mechanism has been proposed for the condensation reaction which agrees with rate relationships found. Gas-liquid partition chromatography was used to follow the kinetics of the condensation reactions. A rate constant of 5.41 × 10^?2M^?1min^?1 was found for the reaction of benzaldehyde with 2-methyl-quinoline using zinc chloride as a catalyst at 104.0°. Rate constants of 1.28 × 10^?2 MT^?1 min^?1 and 1.05 × 10^?2 M^?1 min^?1 were found for the reactions of p-methylbenzaldehyde and p-methoxybenzaldehyde with quinaldine to form 2-(p-methylstyryl)quinoline and 2-(p-methoxystyryl)-quinoline, respectively at 92.4°. A linear relationship was found using the Hammett equation. An Arrhenius plot was constructed from rate constants determined at five different temperatures for the reaction of benzaldehyde and quinaldine to form 2-styrylquinoline, using zinc chloride as a catalyst. The energy of activation, E_a, was found to be 22.2 kcal/mole for this reaction. The enthalpy of activation, ΔH?, free energy of activation, ΔF?, and entropy of activation, ΔS?, were found to be 21.4 kcal/mole, 27.7 kcal/mole and -16.7 eu/mole, respectively, at 104.0°. The mechanism proposed in the formation of 2-styrylquinoline involves the fast formation of a carbanion-zinc chloride complex, which then attacks, in the rate determining step, the aldehyde utilized in the reaction. The lack of reaction of certain methylquinolines is attributed to the inadequacy of the carbanion formed and not to the difficulty involved in the initial formation of the carbanion.     

Derivatives Of ditraizinylamine and tritriazinylamine

2-Arylamino-4,6-dichloro-s-triazine reacts with cyanuric chloride in the presence of alkali to yield N,N-bis(4,6-dichloro-s-triazin-2-yl)-arylamine. In like manner, 2-substituted o-chloro-, p-chloro-, o-nitro- and p-carbomethoxyphenylamino-4,6-dimethoxy-s-triazines react with cyanuric chloride to yield the corresponding 4,6-dichloro-s-triazin-2-yl-4′,6′-dimethoxy-s-triazin-2′-ylaryl-amine, while anilino-, p-toluidino, o- and p-methoxyphenylamino and o-carbomethoxyphenylamino derivatives did not. The reaction of cyanuric chloride with 2,4-dichloro-6-ethylamino-s-triazine in the presence of alkali yields the condensation product of the ditriazinylamine type and the reaction of cyanuric chloride with ammonia yields N,N-bis(4,6-dichloro-s-triazin-2-yl)- or tris(4,6-dichloro-s-triazin-2-yl)amine.     

Synthesis and Microbial Studies of New Pyridine Derivatives-Ill

2-Amino substituted benzothiazole 4a--4I and p-acetamidobenzenesulfonyl chloride 2 were used to prepare 2-（p-aminophenylsulfonamido） substituted benzothiazole 6a--6I using mixture of pyridine and acetic anhydride which formed an electrophilic complex （N-acetyl pyridinium） to facilitate condensation to give desired product by removal of HC1. 2-{p-[（3-Carboxypyrid-2-y1）amino]phenylsulfonamido}benzothiazoles 8a--81 were synthesized from 2-chloropyridine-3-carboxylic acid 7 and 6a--6I in 2-ethoxy ethanol using Cu-powder and K2CO3. Acid chlorides 9a--91 were condensed with 2-hydroxyethyl piperazine 10 and 2,3-dichloropiperazine 11 for amide deriva- tives 2-（p-（（3-（4-（2-hydroxyethy1）piperazin-1-ylcarbonyl）pyrid-2-y1）amino）phenylsulfonamido）benzothiazoes 12a -121 and 2-{p-[3-（2,3-dichloropiperazin-l-ylcarbonyl）pyrid-2-ylamino]phenylsulfonamido}benzothiazoles 13a- 131 respectively. The structures of the new compounds have been established on the basis of their chemical analysis and spectral data （IR, 1↑H NMR and mass）. All the compounds have been screened for their antibacterial and antifungal activities.     

A Mild and Highly Efficient Synthesis of Chiral N‐Dichloroacetyl‐4‐ethyl‐1,3‐oxazolidines

Chiral 2‐amino‐butanols ( 4 and 5 ) were obtained via the isolation of diastereomeric salt. Then, chiral compounds ( 6 – 9) were synthesized by a sequential procedure involving condensation of chiral 2‐amino‐butanol with ketone and dichloroacetyl chloride. All the compounds were characterized by IR, ¹H NMR, ¹³C NMR, and element analysis. The absolute configurations of ( S )‐ 8 was determined by X‐ray crystallography.     

Irreversible enzyme inhibitors. XC. candidate active-site-directed irreversible inhibitors of thymidylate synthetase. I. 2-amino-5-(benzenesulfonamidopropyl)-6-methyl-4-pyrimidinol with substituents on the benzene ring

2-Amino-5-[p- (bromoacetamidomethyl)benzenesulfonamidopropyl]-6-methyl-4-pyrimidinol (XV) was synthesized by acylation of 2-amino-5-aminopropyl-6-methyl-4-pyrimidinol (III) with p-cyanobenzenesulfonyl chloride followed by catalytic reduction and reaction of the resultant aminomethyl group with p-nitrophenyl bromoacetate. A second irreversible inhibitor of thymidylate synthetase, namely 2-amino-5-[p-(bromoacetyl)benzene-sulfonamidopropyl]-6-methyl-4-pyrimidinol (XVI), was synthesized by acylation of in with p-acetylbenzenesulfonyl chloride followed by bromination. Both XV and XVI were good reversible inhibitors of thymidylate synthetase and inactivated the enzyme when the candidate compound was incubated with the enzyme. Iodoacetamide, which does not form a complex with enzyme, could inactivate thymidylate synthetase almost as well as XV; therefore it appears that XV inactivated the enzyme by a random bimolecular mechanism rather than by the desired active-site-directed mechanism via an enzyme-inhibitor complex. Similar conclusions were reached with XVI since phenacyl bromide could inactivate the enzyme somewhat more rapidly than XVI.     

Synthesis and characterization of new ketooximes and their complexes

The starting point of the research was the reaction of chloroacetyl chloride with biphenyl in the presence of aluminum chloride. 4-Biphenylhydroximoyl chloride (HL) was obtained by reacting synthesized 4-(chloroacetyl)biphenyl with alkyl nitride. Four new substituted 4-(alkylaminoisonitrosoacetyl)biphenyles (ketooximes) were prepared by reacting 4-biphenylhydroximoyl chloride with corresponding amines in EtOH. The following amines were used for ligands: p-toluidine, p-chloroaniline, pyrrolidine, and 4-aminoacetophenone. Mononuclear complexes with a metal-ligand ratio of 1: 2 were prepared using cadmium(II), cobalt(II), copper(II), nickel(II), lead(II), and zinc(II) salts. These compounds have been characterized by elemental analyses, AAS, infrared spectra and magnetic susceptibility measurements. The ligands have been further characterized by ¹H NMR. The results suggest that the ketooximes act as bidentate ligands which bond metal ions through the oxime and carbonyl oxygen. The text was submitted by the authors in English.     

Crystal structure of cis-diaquabis(sulfapyridazinato) nickel(II)

We have previously found that ethazole and sulfadimethoxine (sulfanilamide representatives) do not coordinate to Mg(II), Mn(II), Co(II), Ni(II), Cu(II), and Zn(II) metals, and they are outer-sphere anions in the complex compounds of these metals. This work presents the results of the structural study of yet another sulfanilamide representative: the [Ni(A)₂(OH₂)₂] compound containing sulfapyridazine. Here A is the sulfapyridazine anion (C₁₁H₁₁N₄O₃S is 6-(p-aminobenzenesulfamido)-3-methoxypyridazine) coordinated by nitrogen atoms (N(1) and N(2)), thus functioning as a bidentate cyclic ligand. The symmetry and unit cell parameters are as follows: monoclinic, C2/c space group, a = 20.116(3) ?, b = 8.221(2) ?, c = 16.923(4) ?, β = 75.19(5)°, V = 2705.6(7) ?³, T = 293 K, and Z = 4. The final value of R = 0.048 was obtained for 1930 independent reflections with I > 2σ(I). The structure consists of complex molecules.     

Synthesis,Photophysical, and Electrochemical Properties of Ruthenium(II) Polypyridyl Complexes containing Open‐Chain Crown Ether

Four polypyridyl bridging ligands BL¹⁻⁴ containing open‐chain crown ether, where BL¹⁻³ formed by the condensation of 4,5‐diazafluoren‐9‐oxime with diethylene glycol di‐p‐tosylate, triethylene glycol di‐p‐tosylate, and tetraethylene glycol di‐p‐tosylate, respectively. BL⁴ formed by the reaction of 4‐(1,10‐phenanthrolin‐5‐ylimino)methylphenol with triethylene glycol di‐p‐tosylate, have been synthesized. Reaction of Ru(bpy)₂Cl₂·2H₂O with BL, respectively, afforded four bimetallic complexes [(bpy)₂RuBL¹⁻⁴Ru(bpy)₂]⁴⁺ as [PF₆]⁻ salts. Electrochemistry of these complexes is consistent with one Ru^II‐based oxidation and several ligand‐based reductions. These complexes show metal‐to‐ligand charge transfer absorption at 439‐452 nm and emission at 570‐597 nm.     

A novel synthesis of 2-aryl-4-piperidones by mannich cyclization of iminoketals

2-Aryl-4-piperidones have been synthesized by condensation between an aromatic aldehyde and a β-aminoketone ethylene ketal, and further cyclization of the resulting iminoketal with dry hydrogen chloride or anhydrous p-toluensulfonic acid. Alternatively, reaction of the above iminoketals with methyl fluorosulfonate followed by dry hydrogen chloride treatment and acid hydrolysis gives directly N-methyl-4-piperidones. The application of these reactions to the synthesis of some 2-aryl-3-acetylpyrrolidine systems is also described.     

Heterocyclic variants of the 1,5-benzodiazepine system. V. Derivatives of 2-(ortho-R1-anilino)-4-(p-R2-phenyl)-3H-1,5-benzodiazepines

Mono-N-methylation of 2-(ortho-R₁-anilino)-4-(p-R₂-phenyl)-3H-1,5-benzodiazepines IV is achieved in moderate yield with sodium hydride in methyl iodide. Reaction of the N-methyl derivatives I with methoxyacetyl chloride gave the compounds II and III . The structure of all products was confirmed by ir, ¹H-nmr and mass spectrometry.     

NOVEL COPOLYMERS OF TRISUBSTITUTED ETHYLENES WITH STYRENE. I. 2-HALOPHENYL-1,1-DICYANOETHYLENES

Electrophilic trisubstituted ethylene monomers, 2-halophenyl-1,1-dicyanoethylenes, RC₆H₄CH=C(CN)₂ (where R is o-Cl, m-Cl, p-Cl, p-Br, and p-F) were prepared and copolymerized with styrene. The monomers were synthesized by the piperidine catalyzed Knoevenagel condensation of ring-substituted benzaldehydes and malononitrile, and characterized by CHN elemental analysis, IR, ¹H and ¹³C-NMR. All the ethylenes were copolymerized with styrene (M₁) in solution with radical initiation (AIBN) at 70°C. The compositions of the copolymers were calculated from nitrogen analysis and the structures were analyzed by IR, ¹H and ¹³C-NMR. The order of relative reactivity (1/r ₁) for the monomers is p-Cl (14.8) >m-Cl (2.67)> o-Cl (1.82) > p-Br (1.52) > p-F (1.36). High T _g's of the copolymers (> 150°C) in comparison with that of polystyrene indicate a substantial decrease in the chain mobility of the copolymers due to the high dipolar character of the trisubstituted monomer unit. Gravimetric analysis indicated that the copolymers decompose in the range 300–400°C.