Basisch substituierte 5,6-Dimethoxy- und 4,5,6-Trimethoxy-benzo[b]thiophene

Zusammenfassung N-substituierte -{5,6-Dimethoxy-benzo[b]thienyl-(3)}-äthylamine, -{4,5,6-Trimethoxy-benzo[b]thienyl-(3)}-äthylamine und -{5,6-Dimethoxy-benzo[b]thienyl-(3)}-propylamine wurden mittels LiAlH₄-Reduktion der entsprechenden von uns schon früher synthetisierten Säureamide hergestellt.

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N-substituted -{5,6-dimethoxy-benzo[b]thienyl-(3)}-ethylamines, -{4,5,6-trimethoxy-benzo[b]thienyl-(3)}-ethylamines and -{5,6-dimethoxy-benzo[b]thienyl-(3)}-propylamines were prepared by LiAlH₄ reduction of the corresponding amides previously synthesized by us.

     

Eine Ringschlußreaktion zu Derivaten der β-{Benzo[b]thienyl(3)}-propionsäure

Zusammenfassung Acylierung von p-Methylthioanisol mit Bernsteinsäureanhydrid ergab -(2-Methylthio-5-methyl-phenyl)--oxo-buttersäure, welche mit Chloressigsäure zu -{2-Carboxy-5-methylbenzo[b]thienyl-(3)}-propionsäure ringgeschlossen wurde.Partielle Decarboxylierung lieferte -{5-Methyl-benzo[b]-thienyl-(3)}-propionsäure.Acylation of p-methylthioanisole by succinic acid anhydride gave -(2-methylthio-5-methyl-phenyl)--oxo-butyric acid, which reacted with chloroacetic acid to give -{2-carboxy-5-methyl-benzo[b]thienyl-(3)}-propionic acid.Partial decarboxylation yielded -{5-methyl-benzo[b]thienyl-(3)}-propionic acid.Herrn Prof.L. Schmid mit besten Wünschen zum 70. Geburtstag gewidmet.     

Beiträge zur Chemie schwefelhaltiger Heterocyclen, 1. Mitt.: Synthesen von Benzo[b]thieno[2,3−d]pyrimidin-Derivaten

Zusammenfassung 4-Oxo-3,4,5,6,7,8-hexahydro-benzo[b]thieno[2,3–d]pyrimidin sowie die 2-Methyl- und 2-Phenyl-Derivate davon wurden durch Ringschlußreaktionen aus 2-Acylamino-4,5,6,7-tetrahydrobenzo[b]thienyl-(3)-carbonsäureamiden gewonnen; das 2-Phenyl-Produkt entstand auch durch thermische Cyclisierung von 2-Benzylidenamino-4,5,6,7-tetrahydro-benzo[b]-thienyl-(3)-carbonsäureamid.

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4-Oxo-3,4,5,6,7,8-hexahydro-benzo[b]thieno[2,3–d]pyrimidine as well as its 2-methyl and 2-phenyl derivatives were synthesized by cyclization of the corresponding 2-acylamino-4,5,6,7-tetrahydro-benzo[b]thienyl-(3)-carboxamides; the 2-phenyl compound was also prepared by thermal cyclization of 2-benzylideneamino-3-carbamoyl-4,5,6,7-tetrahydro-benzo[b]thienyl-(3)-carboxamide.

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Mit 1 Abbildung     

Beiträge zur Chemie schwefelhaltiger Heterocyclen, 3. Mitt.: Ringschlußreaktionen zu N-substituierten 2-Aminomethyl-Derivaten des 4-Oxo-3,4,5,6,7,8-hexahydro-benzo[b]thieno-[2,3-d]pyrimidins

Zusammenfassung Eine Gruppe von [2-Acylamino-4,5,6,7-tetrahydro-benzo[b]-thienyl-(3)]-carbonsäureamiden mit einem basischen Rest am Substituenten der 2-Stellung wurde nach zwei Methoden zu entsprechend substituierten 2-Alkyl-4-oxo-3,4,5,6,7,8-hexahydro-benzo[b]thieno[2,3-d]pyrimidinen cyclisiert. Die Herstellung der Ausgangsmaterialien erfolgte durch Umsetzung von [2-Chloracetylamino-4,5,6,7-tetrahydro-benzo[b]thienyl-(3)]-carbonsäureamid mit sekundären Aminen bzw. Benzylamin.

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A series of [2-acylamino-4,5,6,7-tetrahydro-benzo[b]thienyl-(3)]-carboxamides with a basic group in the substituent at position 2 was cyclized by two methods to the corresponding substituted 2-alkyl-4-oxo-3,4,5,6,7,8-hexahydro-benzo[b]thieno-[2,3-d]pyrimidines. The starting materials were prepared by reaction of [2-chloracetylamino-4,5,6,7-tetrahydro-benzo[b]-thienyl-(3)]-carboxamide with secondary amines or benzylamine.

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Mitt.:F. Sauter, Mh. Chem.99, 1591 (1968).     

Synthesis of dithienopyrrole derivatives

Reactions of N-substituted succinimides with the Vilsmeier reagent leading to isomeric diformyldichloropyrroles were studied. The latter compounds were used for the synthesis of N-substituted dithieno[2,3-b:2′,3′-d]pyrrole and dithieno[2,3-b:3′,2′-d]pyrrole and their bromo derivatives as well. Dimers of N-alkyldithieno[2,3-b:2′,3′-d]pyrrole, novel promising materials for organic semiconductors, were synthesized.     

A novel and easy two-step,microwave-assisted method for the synthesis of halophenyl pyrrolo[2,3-b]quinoxalines via their pyrrolo precursors. Evaluation of their bioactivity

A novel, two-step, facile route for the synthesis of pyrrolo[2,3-b]quinoxalines via 2,3-dioxopyrroles, enhanced by microwave irradiation, is presented. The newly synthesized 2,3-dioxo-5-halophenyl pyrrolo precursors 4a–c as well as the non-aromatized ethyl 2-(4-halophenyl)-1-methyl-2,4-dihydro-1H-pyrrolo[2,3-b]quinoxaline-3-carboxylates 6a–c and the aromatized ethyl 2-(4-halophenyl)-1-methyl-1H-pyrrolo[2,3-b]quinoxaline-3-carboxylates 7a–c were evaluated for their antioxidant, cytostatic, and antiviral properties. Most of them proved to be potent hydroxyl radical scavengers and inhibited in vitro lipid peroxidation. The compounds showed moderate antiproliferative activity, while 6a inhibited vaccinia virus at an EC₅₀ value of 2 μM, and 4c and 6c inhibited Sindbis virus at EC₅₀ values of 4 μM.     

Synthesis of tricyclic isoindoles and thiazolo[3,2-c][1,3]benzoxazines

The thermolysis of (3R,9bS)-5-oxo-2,3,5,9b-tetrahydrothiazolo[2,3-a]isoindole-3-carboxylic acids in Ac₂O led to novel 3-methylene-2,5-dioxo-3H,9bH-oxazolo[2,3-a]isoindoles and chiral (9bS)-5-oxo-2,3,5,9b-tetrahydrothiazolo[2,3-a]isoindoles were obtained on FVP. Starting from l-cysteine methyl ester (3R,10bR)-5-oxo-2,3-dihydro-10bH-[1.3]thiazolo[3,2-c][1,3]benzoxazines were obtained as single stereoisomers. The thermolysis of (3R,10bR)-5-oxo-2,3-dihydro-10bH-[1.3]thiazolo[3,2-c][1,3]benzoxazine-3-carboxylic acid in Ac₂O gave 5-acetyl-2-phenyl-2,3-dihydrothiazole. The structures of methyl (3R,9bS)-5-oxo-2,3,5,9b-tetrahydrothiazolo[2,3-a]isoindole-3-carboxylate 1a and methyl (2R,4R)-N-chlorocarbonyl-2-(2-hydroxyphenyl)thiazolidine-4-carboxylate 9 were determined by X-ray crystallography.     

Unambiguously confirmed structure of 2-phenacylidene-1,2-dihydro-4H-pyrido[2,3-b]pyrazin-3-one and 3-phenacylidene-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one

To determine the structures of two isomeric products, 2-phenacylidene-1,2-dihydro-4H-pyrido[2,3-b]pyrazin-3-one (2) and 3-phenacylidene-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one (3) obtained by condensation of 2,3-diaminopyridine (1) with ethyl benzoylpyruvate [1–3], these compounds were hydrolyzed to give 2-methyl-4H-pyrido[2,3-b]pyrazin-3-one (4) and 3-methyl-1H-pyrido[2,3-b]pyrazin-2-one (5) , respectively [4,5]. Both hydrolysates 4 and 5 were hydrogenated to afford 2-methyl-1,2-dihydro-4H-pyrido[2,3-b]pyrazin-3-one (6) and 3-methyl-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one (7) . The latter compound was identical with an unequivocally synthesized compound providing proof for the structures of all these compounds.     

Functional sulfur-containing compounds

The Thorpe-Ziegler intramolecular cyclization of 2-RCH₂S-, 2-RCH₂S(O)-, and 2-RCH₂SO₂-substituted nicotinic acid esters and nitriles (R is alkyl, aryl, and 2-thienyl) upon the action of potassium tert-butoxide has been studied. The reaction results in the formation of the corresponding 2-R-substituted 3-aminothieno[2,3-b]pyridines, 3-aminothieno[2,3-b]pyridine 1-oxides, and 3-aminothieno[2,3-b]pyridine 1,1-dioxides with the reaction taking place only in the case if R is aryl or 2-thienyl. Methyl esters of 2-RCH₂S-, 2-RCH₂S(O)-, and 2-RCH₂SO₂-substituted nicotinic acids also undergo the intramolecular cyclization of the Dieckmann type to form the corresponding 2-R-substituted 3-hydroxythieno[2,3-b]pyridines, thieno[2,3-b]pyridin-3(2H)-one 1-oxides, and thieno[2,3-b]pyridin-3(2H)-one 1,1-dioxides. Such a reaction takes place for all the R groups except when R = AlkCH₂S and AlkCH₂S(O).     

Chemistry of benzo[b]furan. V.. Synthesis of substituted thia-analogs and oxa-analogs of dihydrorutecarpine and evodiamine

Cycloaddition of 3,4-dihydrobenzo[b]thieno[2,3-c]pyridine ( 6 ) with the sulfinamide anhydride 9 (R = H) afforded the thia-analog of dihydrorutecarpine ( 2a ). Condensation of the imine 6 with the sulfinamide anhydride 9 (R = CH₃) gave the thia-analog of evodiamine ( 2b ). Starting from 1-methyl-3,4-dihydrobenzo[b]thieno[2,3-c]pyridine ( 12 ) and 1-methyl-3,4-dihydrobenzo[b]furo[2,3-c]pyridine ( 14 ), a series of 3-methyl derivatives of thia-analogs of dihydrorutecarpine and evodiamine ( 2c-2i ) and oxa-analogs of dihydrorutecarpine and evodiamine ( 1a-1g ) were similarly prepared.     

5,6-Dimethoxy- und [4,5,6-Trimethoxy-benzo[b]-thienyl-(3)]-acylamine

Zusammenfassung Umsetzung von 5,6-Dimethoxy- und [4,5,6-Trimethoxy-benzo[b]thienyl-(3)]-essigsäure mit PCl₅ lieferte die methoxysubstituierten [Benzo[b]thienyl-(3)]-essigsäurechloride, die mit sekundären Aminen zu den entsprechenden Amiden reagierten.Die homologen Verbindungen mit einer C₃-Brücke wurden durchArndt-Eistert-Reaktion des Diazomethylketons in Gegenwart der entsprechenden sekundären Amine erhalten.

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Reaction of 5.6-dimethoxy- and [4.5.6-trimethoxybenzo[b]-thienyl-(3)]-acetic acid with PCl₅ gave the methoxy-substituted [benzo[b]thienyl-(3)]-acetic acid chlorides, which reacted with secondary amines to the corresponding amides.The homologous compounds with a C₃-bridge were synthesized viaArndt-Eistert reaction of the diazomethyl ketone in presence of the corresponding secondary amines.

     

Chemistry of Spontaneous Alkylation of Methimazole with 1,2-Dichloroethane

Spontaneous S-alkylation of methimazole (1) with 1,2-dichloroethane (DCE) into 1,2-bis[(1-methyl-1H-imidazole-2-yl)thio]ethane (2), that we have described recently, opened the question about its formation pathway(s). Results of the synthetic, NMR spectroscopic, crystallographic and computational studies suggest that, under given conditions, 2 is obtained by direct attack of 1 on the chloroethyl derivative 2-[(chloroethyl)thio]-1-methyl-1H-imidazole (3), rather than through the isolated stable thiiranium ion isomer, i.e., 7-methyl-2H, 3H, 7H-imidazo[2,1-b]thiazol-4-ium chloride (4a, orthorhombic, space group Pnma), or in analogy with similar reactions, through postulated, but unproven intermediate thiiranium ion 5. Furthermore, in the reaction with 1, 4a prefers isomerization to the N-chloroethyl derivative, 1-chloroethyl-2,3-dihydro-3-methyl-1H-imidazole-2-thione (7), rather than alkylation to 2, while 7 further reacts with 1 to form 3-methyl-1-[(1-methyl-imidazole-2-yl)thioethyl]-1H-imidazole-2-thione (8, monoclinic, space group P 2₁/c). Additionally, during the isomerization of 3, the postulated intermediate thiiranium ion 5 was not detected by chromatographic and spectroscopic methods, nor by trapping with AgBF₄. However, trapping resulted in the formation of the silver complex of compound 3, i.e., bis-{2-[(chloroethyl)thio]-1-methyl-1H-imidazole}-silver(I)tetrafluoroborate (6_, monoclinic, space group P 2₁/c), which cyclized upon heating at 80 °C to 7-methyl-2H, 3H, 7H-imidazo[2,1-b]thiazol-4-ium tetrafluoroborate (4b, monoclinic, space group P 2₁/c). Finally, we observed thermal isomerization of both 2 and 2,3-dihydro-3-methyl-1-[(1-methyl-1H-imidazole-2-yl)thioethyl]-1H-imidazole-2-thione (8), into 1,2-bis(2,3-dihydro-3-methyl-1H-imidazole-2-thione-1-yl)ethane (9), which confirmed their structures.     

N-Substituierte Benzo [b]thiophen-3-acetamide und 3-(β-Aminoäthyl)-benzo [b]thiophene

Zusammenfassung Die Synthese der Titelverbindungen erfolgte über die Benzo[b]thiophen-3-essigsäure, deren Chlorid mit Diäthylamin und N-Methylpiperazin zu den entsprechenden N-substituierten Benzo[b]thiophen-3-acetamiden reagierte; diese wurden mit LiAlH₄ zu tertiären Aminen reduziert.Die Synthese der homologen 2-Methylverbindungen ging vom 2-Methyl-3-acetyl-benzo[b]thiophen aus: Haloformreaktion gab 2-Methyl-benzo[b]thiophen-3-carbonsäure;Wolff-Umlagerung des entsprechenden Diazomethylketons in Gegenwart von sekundären Aminen lieferte verschiedene N-substituierte 2-Methyl-benzo[b]thiophen-3-acetamide, von denen drei mit LiAlH₄ zu tertiären Aminen reduziert wurden.

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The title substances were synthesized using benzo[b]thiophene-3-acetic acid as an intermediate, the acid chloride of which reacted with diethylamine and N-methylpiperazine to give the corresponding N-substituted benzo[b]thiophene-3-acetamides; these were reduced by LiAlH₄ to tertiary amines.The synthesis of the homologous 2-methyl compounds started from 2-methyl-3-acetyl-benzo[b]thiophene: haloform reaction gave 2-methyl-benzo[b]thiophene-3-carboxylic acid;Wolff-rearrangement of the corresponding diazomethyl ketone in the presence of secondary amines yielded various N-substituted 2-methyl-benzo[b]thiophene-3-acetamides; three of them were reduced by LiAlH₄ to tertiary amines.

     

Reaction of N-substituted 2-oxochromen-3-carboxamides with bromoderivatives of zinc enolates prepared from alkyl 2,2-dialkyl-4,4-dibromo-3-oxoalkanoates and zinc

Zinc enolates obtained from ethyl 2,2-dialkyl-4,4-dibromo-3-oxobutanoates and zinc react with N-substituted 2-oxochromen-3-carboxamides forming ethyl 3-{1a-(R³-carbamoyl)-2-oxo-1a,7b-dihydrocyclopropa[c]chromen-1-yl}-2,2-dialkyl-3-oxopropanoate isomer with a Z-position of methine hydrogens. Zinc enolates prepared from alkyl 2,2-dialkyl-4,4-dibromo-3-oxopentanoates and-hexanoates and zinc react with N-substituted 2-oxochromen-3-carboxamides to give rise to esters of 3-{1-alkyl-1a-(R³-carbamoyl)-2-oxo-1a,7b-dihydrocyclopropa-[c]chromen-1-yl}-2,2-dialkyl-3-oxopropanoic acid as isomers with the E-position of the methine proton and the alkyl substituent. The reaction carried out in the presence of small quantities of THF and HMPA leads to the formation of 9c-alkyl-2-R³-9b,9c-dihydro-5-oxa-2-azacyclopenta[2,3]-cyclopropa[1,2-a]naphthalene-1,3,4-triones. Zinc enolates from alkyl 2,2-dialkyl-4,4-dibromo-3-oxopentanoates and-hexanoates and zinc with the secondary amides of 2-oxochromen-3-carboxylic acid form alkyl 3-{2-oxo-1a-(piperidinocarbonyl)-and 3-{6-R¹-1a-(morpholinocarbonyl)-2-oxo-1a,7b-dihydrocyclopropa[c]chromen-1-yl}-2,2-R²,R²-3-oxopropanoates as single geometrical isomers.     

N-Substituierte 6-Methoxy-benzo [b] thienyl-(3)-alkylamine

Zusammenfassung Umsetzung von 6-Methoxy-benzo[b]thienyl-(3)-essigsäurechlorid mit sekundären Aminen gab die entsprechenden Amide; ein entsprechendes Propionylpiperazid wurde durchArndt-Eistert-Reaktion hergestellt. Alle Amide wurden mittels LiAlH₄ zu den Titelverbindungen reduziert. Die als Ausgangsmaterial verwendete 6-Methoxy-benzo[b]thienyl-(3)-essigsäure wurde durch Cyclisierung von -(3-Methoxy-phenylthio)-acetessigester und anschlie\ende Hydrolyse dargestellt.

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Reaction of 6-methoxy-benzo[b]thienyl-(3)-acetic acid chloride with secondary amines gave the corresponding amides; a corresponding propionyl piperazide was prepared byArndt-Eistert reaction. All amides were reduced by LiAlH₄ to the title substances. The 6-methoxy-benzo[b]thienyl-(3)-acetic acid used as starting material was synthesized by cyclization of ethyl -(3-methoxy-phenylthio)-acetoacetate, followed by hydrolysis.

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A-1060 Wien, Getreidemarkt 9.     

Unprecedented InCl3-catalyzed formation of cis-fused perhydrofuro[2,3-b]oxepines

2-Methylindole and its N-substituted derivatives react smoothly with 2,3-dihydrofuran (DHF) in the presence of a catalytic amount of InCl₃ under mild conditions to afford the corresponding 2-methyl-3-perhydrofuro[2,3-b]oxepin-4-yl-1H-indole derivatives in fairly good yields with high diastereoselectivity, while 3,4-dihydro-2H-pyran (DHP) affords exclusively 5,5-di(1H-3-indolyl)-1-pentanol derivatives in high yields under similar reaction conditions.     

Synthesis and transformations of 3-(1H-pyrrol-1-yl)thieno[2,3-b]pyridines

Reactions of 2,5-dimethoxytetrahydrofuran with 3-aminothieno[2,3-b]pyridines afford a number of substituted 3-(1H-pyrrol-1-yl)thieno[2,3-b]pyridines. The possibility of the reaction and the yield of the product are determined by the character of a substituent in position 2 of thieno[2,3-b]pyridine. The Curtius rearrangement of 2-acylazido-3(1H-pyrrol-1-yl)thieno[2,3-b]pyridines yields 4,5-dihydropyrido[3",2":4,5]thieno[2,3-e]pyrrolo[1,2-a]pyrazin-4-ones. The molecular and crystal structures of ethyl 4-methoxymethyl-6-methyl-3-(1H-pyrrol-1-yl)thieno[2,3-b]pyridine-2-carboxylate were determined by X-ray diffraction analysis.     

A new synthetic route to compounds of the AFDX-type with affinity to muscarinic M2-receptor

[3-(1,3-Dioxo-1,3-dihydroisoindol-2-yl)-propyl]dimethyl-{6-[(1-{2-[(6-oxo-5,6-dihydro-benzo[e]pyrido[3,2-b][1,4]diazepine-11-carbonyl)amino]ethyl}piperidin-2-yl-methyl)-propylamino]hexyl}ammonium bromide a hybride containing a fragment of the antagonist of muscarinic receptor AFDX-384 and a W84 moiety known as allosteric modulator of antagonist binding, was synthesized in a divergent synthesis starting from pipecolic acid, phthalic anhydride and 3-amino-2-chloropyridine. This new microwave assisted route is very convenient and allows to modify the piperidine ring, the benzodiazepine system, the phthalimide moiety and the chains connecting the ring systems. Yields and reproducibility were satisfying.     

Synthesis,molecular structure,conformation and biological activity of Ad-substituted N-aryl-tetraoxaspiroalkanes

An efficient method has been developed for the synthesis of 7′-arylspiro{adamantane-[2,3′]-(1′,2′,4′,5′,7′-tetraoxazocanes)} by the ring transformation reaction of spiro{adamantane-[2,3’]-(1′,2′,4′,5′,7′-pentaoxacane)} with arylamines in the presence of Sm(NO₃)₃·6H₂O as the catalyst. NMR signals of the synthesized compounds were assigned considering the conformation dynamics of the tetraoxazocane ring with two rigid peroxide bonds. The structures of some of the compounds were studied by X-ray diffraction. The thermal stability of single crystal was determined by DSC method. Compounds 7′-(2-methylphenyl)spiro{adamantane-[2,3′]-(1′,2′,4′,5′,7′-tetraoxazocane)} and 7′-(4-fluorophenyl)spiro{adamantane-[2,3′]-(1′,2′,4′,5′,7′-tetraoxazocane)} exhibited cytotoxicity towards cancer cells.     

Synthesis and photochemical properties of phenoxy derivatives of anthra[2,3-b]furan-5,10-dione

Nucleophilic replacement of the hydroxy groups in ethyl 4,11-dihydroxy-2-methyl-5,10-dioxo-5,10-dihydroanthra[2,3-b]furan-3-carboxylate by chlorine upon treatment with phosphorus acid chlorides gave the corresponding 4(11)-chloro derivatives which were converted into photochromic ethyl 4(11)-phenoxy-2-methyl-5,10-dioxo-5,10-dihydroanthra[2,3-b]furan-3-carboxylates. Photoinduced decomposition of the latter leads to the formation of phenol and fluorescent hydroxyanthra[2,3-b]furandiones.