β-Fur-2-yl-α-halogenacrylonitrile. VII. Reaktionen von β-(5-Brom-fur-2-yl)-α-bromacrylonitril mit Mercaptan,Thioharnstoff und Thioharnstoffderivaten

β-Fur-2-yl-α-halogenacrylonitriles. VII. Reactions of β-(5-Bromo-fur-2-yl)-α-bromoacrylonitriles with Mercaptans, Thiourea and Thiourea Derivatives β-(5-Bromo-fur-2-yl)-α-bromoacrylonitrile 1 reacts with ethylmercaptan to yield β-(5-bromo-fur-2-yl) β-ethylthioacrylonitrile 3 . With thiourea β,β′-thio-bis[β-(5-bromo-fur-2-yl)]-acrylonitrile 2 is formed. The pyrimidines 4 and 5 have been prepared by the reaction of 1 with s-methylthiourea and 2-aminothiazole, respectively. The structure of the new compounds were determined by means of x-ray analysis, ¹H-n.m.r., ¹³C-n.m.r. and mass-spectroscopy.     

Radikalreaktionen von N-Heterocyclen. I. Synthese und Struktur eines N,N-verknüpften Bipyrazols

Radical Reactions of N-Heterocyclic Compounds. I. Synthesis and Structure of an N,N-Linked Bipyrazole 5(3)-Amino-3(5)-(phenylamino)-pyrazole-4-carboxylic acid ethyl ester ( 1 ), which is a very good antioxidant, reacts under mild reaction conditions with dibenzoyl peroxide or with tert.-butoxy radicals under formation of a bipyrazole 4 . Evidence of the structure of 4 is given by ¹H-n.m.r., ¹³C-n.m.r., i.r. and u.v. spectroscopic measurements, respectively and especially by ¹⁵N-n.m.r. measurements of ¹⁵N labelled compounds 1 and 4 . The bispyrazole 4 reacts with Pb(IV)-acetate, the product isolated was the 5-amino-e-anilino-1-(1-anilino-2-cyano-2-ethoxycarbonylethenyl-azo)-pyrazole-4-carboxylic acid ethyl ester (7). The formation of this substance is a chemical proof of the structure of 4 .     

Über die Reaktionen von Benzimidazol-2-carbonsäurehydrazid mit Elektrophilen

About the Reactions of Benzimidazole-2-carbohydrazide with Electrophilic Compounds Benzimidazole-2-carbohydrazide ( 1 ) reacts with aldehydes and ketones to form N-alkylidene-benzimidazole-2-carbohydrazides( 2a–j ). With carbon disulfide, diphenyl carbonate and cyanates, ring closure takes place to afford 1,2,4-triazines and 1,3,4-oxadiazoles. Attempts to synthezise 2-isocyanato-benzimidazole failed. ¹H-n.m.r. and ¹³C-n.m.r. spectroscopic data of the compounds are given.     

Eine neue Synthese des Cinnamoyliminodithiokohlensäure-S,S-dimethylesters und Umsetzungen mit Nucleophilen

New Synthesis of Dimethyl-cinnamoylimino-dithiocarboxylate and Reactions with Nucleophiles A new general synthesis of dimethyl-cinnamoylimino-dithiocarboxylate 1d is possible by reaction of 4-nitro-cinnamoylamide with carbon disulfide in the presence of sodium hydride and following alkylation. With the unsubstituted dimethyl-cinnamoylimino-dithiocarboxylate 10 is in-vestigated the reaction behavior with nucleophilic compounds. The treatment of 1c with primary amines, respectively, by mono- and disubstitution of the methylthio groups yields isothiourea 2 or guanidines 3 . Benzocondensed heterocycles are formed by reaction of 1c with o-bifunctional nucleo-philes. The compounds 5, 6 and 7 have been synthesized from 1c with cysteamine, p-phenylenediamine and ethylenediamine. The oxadiazole 8 and isothiosemicarbazide 9 are obtained by reaction of the dithioester 1c with hydrazides. On the other hand cyclisation to the 1,2,4-triazole 11 over the intermediate 10 and to the 1,3,5-triazine 12 are possible. The reaction of 1c with carbanions in a basic medium affords acrylic derivatives 13 . In the same way we isolated by reaction of dithioester 1c with a benzothiazolium salt the dark coloured compound 14 . The physical properties of synthesized compounds are discussed by mass-, ¹H-n.m.r.-, i.r.- and u.v.-spectra.     

Synthese und Strukturermittlung von Sulfamoyl-guanidinen

Synthesis and Structure Elucidation of Sulfamoyl Guanidines A series of sulfamoyl guanidines 2a--hyphen;p and 4 was synthesized by addition of sulfurylchloride to dialkylcyanoamides and subsequent aminolysis of the N,N-dialkyl-N′-chlorosulfonyl-chloroformamidines with primary or secondary amines. Advantageously, the aminolysis can be performed with trimethylsilylamines as amine component by continuous withdrawing of the formed trimethylchlorosilane. Phase transfer catalyzed methylation led to a specific alkylation of the sulfamoyl group to form the 2-(aryl-methyl-sulfamoyl)-guanidines ( 5a--hyphen;5g, 5h ). All compounds were characterized by m.s.-, i.r.-, ¹H-n.m.r.- and ¹³C-n.m.r.-spectra. I.r. and ¹H-n.m.r. data show the existence of an intramolecular hydrogen bonding between the guanidine NH group and the SO₂ group.     

Reaktionen von Aroyl(Hetaroyl)iminodithiokohlesäureestern mit Carbanionen CH-acider Verbindungen

Reactions of Dimethyl N-Aroyl(Hetaroyl)carbimidodithioates with Carbanions CH-acidic Compounds Reactions of dimethyl N-aroyl(hetaroyl)carbimidodithioates 1 with carbanions 2 present new possibilities to synthesize 3-acyl-amino-3-methylthio-2-subst.-acrylnitriles 3 by monosubstitution of methylthiogroup. The reaction of 1 with 2-alkyl-benzothiazolium salts 4 yield deeply coloured N-acyl-(2,3-dihydrobenzothiazole-2-yliden) thioacetimido acid-methylates 5 of the 2-subst.-benzothiazoliumperchlorates 6 . The structures of the final products are determined by i.r.-, ¹H.-n.m.r.- and u.v.-spectra.     

Synthesen mit 1,3-Dithietanen. IX [1]. Reaktionen des 2,4-Bis-(äthoxycarbonyl-cyan-methylen)-1,3-dithietans und des 2-Cyan-3,3-bis-(methylmercapto)-acrylsäureäthylesters mit Carbonsäurehydraziden

Syntheses with 1,3-Dithietanes. IX. Reactions of 2,4-Bis(ethoxycarbonyl-cyano-methylene)-1, 3-dithietane and of Ethyl 2-cyano-3, 3-bis(methylmercapto)acrylate with Carboxylic Acid Hydrazides 2, 4-Bis(ethoxycarbonyl-cyano-methylene)-1, 3-dithietane 1 reacts with carboxylic acid hydrazides to yield ethyl 1-aroyl-5-imino-3-mercapto-Δ³-pyrazoline-4-carboxylates 4. 4 and hydrazin hydrate yield ethyl 1-aroyl-5-imino-3-hydrazino-Δ³-pyrazoline-4-carboxylates 5 which are transformed by heat to the ethyl 3(5)-amino-5(3)-(2-aroyl-hydrazino)pyrazole-4-carboxylates 6 . The reaction of ethyl 2-cyano-3,3-bis(methylmercapto)acrylate 8 with carboxylic acid hydrazides yield ethyl 1-aroyl-3-amino-5-methylmercapto-pyrazole-4-carboxylates 10 . Compounds 10 are compared with S-methyl derivatives of 4 .     

Organoarsen-Verbindungen. XXVIII [1]. Reaktionen 2-aminofunktioneller Arsine mit Acetylenen

Organo-arsenic Compounds. XXVIII. Reactions of 2-Aminofunctional Arsines with Acetylenes Phenylacetylene and isopropenylacetylene add secondary 2-aminoethylarsines or o-aminophenylarsines to give mixtures of the cis- and trans-styrylarsines and of the trans-4,3-(90%) and 4,1-adducts (10%) to the enine, resp. ¹H-n.m.r.-and i.r.-data of the compounds are recorded.     

Synthesis of bispiroheterocyclic systems as antimicrobial agents via the reaction of 2-(cycloalkylidene)-1-thia-4-azaspiro[4.4]-nonan-3-one and/or [4.5] decan-3-one with hydrazines,hydroxylamine, urea and thiourea derivatives

1-Oxa-4-thiaspiro[4.4]nonan-2-one ( 1 ) and/or 1-oxa-4-thiaspiro[4.5]-decan-2-one ( 2 ) reacted with 1-naphthylamine to afford 1-thia-4-(1-naphthyl)-4-azaspiro[4.4]nonan-3-one ( 3 ) and/or 1-thia-4-(1-naphthyl)-4-azaspiro[4.5]decan-3-one (4). Reactions of 3 and/or 4 with cyclopentanone or cyclohexanone gave the corresponding 2-cycloalkylidene-4-(1-naphthyl)-1-thia-4-azaspiro[4.4]nonan-3-ones ( 5 and 6 ) and 2-cycloalkylidene-4-(1-napthyl)-1-thia-4-azaspiro[4.5]-decan-3-ones ( 7 and 8 ). Reaction of compounds 5 – 8 with hydrazine hydrate, phenylhydrazine, hydroxylamine hydrochloride, urea and thiourea afforded the corresponding bispirothiazolopyrazolines ( 9 – 16 ), bispirothiazoloisoxazolines ( 17 – 20 ), bispirothiazolopyrimidinones ( 21 – 24 ) and bispirothiazolothiopyrimidinones ( 25 – 28 ) respectively. All the synthesized bispiroheterocyclic derivatives were identified by conventional methods (IR, ¹H-NMR) and elemental analyses. All the prepared compounds were tested for their antimicrobial activities in comparison with tetracycline as a reference compound.     

Spaltung von 1,2,4-Thiadiazol-3-onen mit Triphenylphosphan: Triphenylphosphonio-thioimidazolate und ihre Folgereaktionen

Fission of 1,2,4-Thiadiazol-3-ones by Triphenylphosphane: gewidinet Triphenylphosphonio Thioimidazolates and Their Consecutive Reactions Treatment of benzimidazo[1,2-d][1,2,4]thiadiazol-3(2H)-ones ( 1 ) and imidazo[1,2-d]-[1,2,4]thiadiazol-3(2H)-ones ( 17 ) with triphenylphosphan leads to the liberation of isocyanate and the formation of triphenylphosphonio-thiobenzimidazolat ( 4 ) and triphenylphosphonio-thioimidazolat ( 18 ), respectively. 2,4-Diphenyl-5-phenylimino-1,2,4-thiadiazol-3-one ( 23 ) is desulfurized with Ph₃P and decomposed into phenyl isocyanate and diphenylcarbodiimide whereas the N-unsubstituted imino-thiadiazol-3-one ( 25 ) is attacked at the exocyclic imino group by Ph₃P to give the N-phosphoranylidene thiourea ( 26 ). The structure of 4 can be rationalized as a dynamic system between polar and apolar valence isomeres. Reactions of 1 and 17 with cyanates, isocyanates, carbon disulfide, acetic anhydride, amines, benzyl chloride, grignard compounds, and CH acidic compounds are described.     

The reaction between trityl hexachloroantimonate and 1,2-dimethoxy-4-(1-propenyl)-benzene

Summary Reactions between triphenylmethyl hexachloroantimonate and 1,2-dimethoxy-4-(1-propenyl) benzene in methylene dichloride were studied by liquid chromatography, n.m.r. and visible spectroscopy. The system is characterised by slow initiation, shown to proceed through an addition reaction, and propagation only to the dimer stage, enabling simple analysis of the initiation kinetics. Similarities between this system and the anethole-trityl salt system were observed including initiation rate constants on the order of 10^–3dm³ · mol^–1 · sec^–1 and the development of a chromophore at 545 nm which is probably due to a side reaction of the propagating cation.     

Synthesis,Molecular Docking,and Preliminary Evaluation of 2-(1,2,3-Triazoyl)benzaldehydes As Multifunctional Agents for the Treatment of Alzheimer's Disease

We described here our results on the use of thiourea as a ligand in the copper catalysed azide-alkyne cycloaddition (CuAAC) of 2-azidobenzaldehyde with alkynes. Reactions were performed reacting 2-azidobenzaldehyde with a range of terminal alkynes using 10 mol % of copper iodide as a catalyst, 20 mol % of thiourea as a ligand, triethylamine as base, DMSO as solvent at 100 °C under nitrogen atmosphere. The corresponding 2-(1H-1,2,3-triazoyl)-benzaldehydes (2-TBH) were obtained in moderated to excellent yields and according our experiments, the use of thiourea decreases the formation of side products. The obtained compounds were screened for their binding affinity with multiple therapeutic targets of AD by molecular docking: β-secretase (BACE), glycogen synthase kinase (GSK-3β) and acetylcholinesterase (AChE). The three compounds with highest affinity, 5 a (2-(4-phenyl-1H-1,2,3-triazol-1-yl)benzaldehyde), 5 b (2-(4-(p-tolyl)-1H-1,2,3-triazol-1-yl)benzaldehyde), and 5 d (2-(4-(4-(tert-butyl)phenyl)-1H-1,2,3-triazol-1-yl)benzaldehyde) were selected and evaluated on its antioxidant effect, in view of select the most promising one to perform the in vivo validation. Due the antioxidant potential ally to the affinity with BACE, GSK-3β and AChE, compound 5 b was evaluated in a mouse model of AD induced by intracerebroventricular injection of streptozotocin (STZ). Our results indicate that 5 b (1 mg/kg) treatment during 20 days is able to reverse the cognitive and memory impairment induced by STZ trough the modulation of AChE activity, amyloid cascade and GSK-3β expression.     

Aza-Enamine. VI. Umsetzungen von N,N-Dialkylhydrazonen aromatischer Aldehyde mit Sulfonylisocyanaten

Aza-enamines. VI. Reactions of N,N-Dialkylhydrazones of Aromatic Aldehydes with Sulfonyl Isocyanates The electrophilic attack of the sulfonyl isocyanates 2 on the arylaldehyde-N,N-dialkylhydrazones 1 takes place in dependence upon the substitutents R¹ and NR₂ at the nitrogen or carbon of the azomethine-group giving the 5-amino-hexahydro-1,3,5-triazine-2,4-diones 3 , the phenylglyoxylic-acid-sulfonamide-N,N-dialkylhydrazones 4 and/or the imidazolidine-2,4-diones 5 . The preparation and the u.v.-, i.r.- and n.m.r.-spectroscopic dates of the compounds 3 – 5 are reported.     

β-Fur-2-yl-α-halogenacrylonitrile. V [1] Darstellung von β-(5-Nitro-fur-2-yl)-α-azidoacrylonitril und β-(5-Nitro-fur-2-yl)-α-aminoacrylonitril

β-Fur-2-yl-α-halogenacrylonitriles. V. Preparation of β-(5-Nitro-fur-2-yl)-α-azidoacrylonitrile and β-(5-Nitro-fur-2-yl)-α-aminoacrylonitrile β-(5-Nitro-fur-2-yl)-α-chloroacrylonitrile ( 1 ) reacts with sodium azide to yield β-(5-nitro-fur-2-yl)-α-azidoacrylonitrile ( 2 ). By Staudinger-reaction β-(5-nitro-fur-2-yl)-α-aminoacrylonitrile ( 5 ) is formed. The ¹H- and ¹³C-n.m.r. spectra of E/Z isomers are discussed.     

Synthese neuer, 3-substituierter 2H-Thiopyran-Derivate via [4+2]-Cycloaddition mittels acceptorsubstituierter Enaminothione

Synthesis of New 3-Substituted 2H-Thiopyran Derivatives via [4+2] Cycloaddition Reactions using Acceptor Substituted Enaminothiones 3- and 4-Nitro acetophenones as well as 3- and 4-trifluoromethyl acetophenones react with POCl₃/DMF (Vilsmeier reagent) to give dimethyliminium perchlorates 1a–d after addition of perchloric acid to the reaction mixture. Substitution of the chloro atom in 1 by using sodium sulfide nonahydrate occurs under mild conditions (in case of nitro compounds at −5°C) leading to enaminothiones 2a–d . Reactions with acroleine and methylvinylketone in refluxing benzene give exclusively 2H-thiopyran derivatives 4a–h , which were isolated in good yields after spontaneous fast elimination of dimethylamine. In contrast, the introduction of 1-nitro-2-phenylethene as the dienophile allows stepwise reaction to give stable adducts 3k and 3l , respectively, and also 3m under mild conditions (reaction at room temperature). ¹H n.m.r. spectroscopic data as well as the elimination of dimethylamine to 4k–m permit the elucidation of the structure of adducts 3k–m .     

On the Structure of Carbamoylated 2-Phenylaminopyridines

Unambiguous preparations of 2-(N-alkoxycarbonyl-N-phenyl)aminopyridine 1-oxides are used to prove that the product from 2-phenylaminopyridine 3 and phenyl isocyanate is the expected urea 2a . Recently a 1,2-dihydropyridine derivative 1 [4] has been claimed to be the product from 3 and phenyl isocyanate. The exocyclic nitrogen of 3 invariably reacts as the nucleophile towards electrophiles such as carbonyl chloride, esters of chloromethanoic acid and aryl isocyanates. ¹H n.m.r. and ¹³C n.m.r. spectra support the assigned structures of the products from these ractions.     

Oxidation of Amino Acids,Peptides and Proteins by Ozone: A Review

The kinetics and products of the reaction of ozone with specific amino acids, peptides, and proteins are reviewed based on studies reported in the literature. Ozone reacts mainly with the unprotonated amino group of the acids and the second-order ozone rate constants for these reactions, except for cysteine, methionine, and tryptophan, vary by about two-orders from 2.6?×?10⁴ to 4.4?×?10⁶ M^?1s^?1. The site of attack on cysteine and methionine by O₃ is at the sulfhydryl rather than the amino group to give sequential O-atom addition products. The order of reactivity for the oxidation of amino acids by O₃ at pH 8 is cysteine > tryptophan ≈ methionine > phenylalanine ≈ histidine > others, with half-lives mostly in the range of milliseconds to tens of seconds (1 mg L^-1 O₃ dose). Reactions of O₃ with aliphatic amino acids form nitrate, ammonia, and one or two carbon atom-containing carbonyl and carboxylic byproducts. In the ozonolysis of peptides and proteins, oxidation by O₃ occurs at the tyrosine, tryptophan, histidine, cysteine, and methionine residues. Oxidation of proteins results in changes in their folding ability and tertiary structures.     

Cycloadditions-Eliminierungsreaktionen von Phenylisocyanat mit Oxo-und Thionoderivaten aliphatisch substituierter 5-Imino-1,2,4-dithiazolidine und 3-Thiono-1,2,4-thiadiazolidine (Senföloxide und Senfölsulfide)

Cycloaddition Elimination Reactions of Phenylisocyanate with Oxo and Thiono Derivatives of Aliphatic Substituted 5-Imino-1,2,4-dithiazolidines and 3-Thiono-1,2,4-thiadiazolidines (Mustard Oil Oxides and Sulfides) 5-Imino-1,2,4-dithiazolidin-3-ones 1 and-3-thiones 3 react with phenylisocyanate to afford 5-imino-1,2,4-thiadiazolidin-3-ones 6 . In comparison isomeric 3-thiono-1,2,4-thiadiazolidin-5-ones 2 , 5 , and -5-thiones 4 yield 3-imino-1,2,4-thiadiazolidin-5-ones 8 , 10 , and -5-thiones 7 . Thermolyses of thiadiazolidines 5 and 10 afford further 1,2,4-thiadiazolidines 9 , 11 . Compounds 8–11 are available also by reaction of substituted guanidines with chlorocarbonyl sulfenylchloride.     

Reaktionen geminaler Dithiolate mit (Z)-1,4-Dichlor-but-2-en

Reactions of Geminal Dithiolates with (Z)-1,4-Dichloro-but-2-ene Geminal dithiolates 2 and 7 react with (Z)-1,4-dichloro-but-2-ene either to give 4-vinyl-1,3-dithiolanes 3 or 4, 7-dihydro-1,3-dithiepines 4 and 8 , respectively. Another method for the synthesis of 4 and 8 is the reaction of ketene dichlorides 5 or isocyanide dichloride 9 with the disodium salt of (Z)-but-2-ene-1,4-dithiol. The formation of the corresponding 1,3-dithiolanes can be excluded in these cases. ¹H- and ¹³C-n.m.r. spectra are in accordance with the structures and are discussed.     

Synthese und Reaktionen von 1,3-Azaphosphorinan-2-thionen

Synthesis and Reactions of 1,3-Azaphosphorinane-2-thiones Aminopropylphosphines, R P(H) (CH₂)₃ NH₂, react with carbon disulfide to give 1,3-azaphosphorinane-2-thiones. In presence of strong bases the title compounds are converted by alkyl halides into 2-alkylthio-3, 4, 5, 6-tetrahydro-1, 3-azaphosphorines whereas in absence of bases quaternization at the phosphorus atom occurs to give 2-thiono -1,3-azaphosphorinanium salts. The structures of the compounds prepared are elucidated by IR. ¹H-n.m.r. and mass spectra.