A palladium- and copper-free cross-coupling of ethyl 3-halo-2-propynoates with 4,5,6,7-tetrahydroindoles on alumina

Ethyl 3-halo-2-propynoates undergo facile (no heating, no base, no solvent) palladium- and copper-free cross-coupling with 4,5,6,7-tetrahydroindoles on alumina to afford the corresponding 4,5,6,7-tetrahydroindole-2-propynoates in 46% and 71% yields. The yield of the by-products [ethyl 3,3-di(4,5,6,7-tetrahydro-1H-indol-2-yl)acrylates] under appropriate conditions can reach 79%.     

Cross-coupling of 4,5,6,7-tetrahydroindole with functionalized haloacetylenes on active surfaces of metal oxides and salts

Screening was performed of metal oxides (MgO, CaO, ZnO, BaO, Al₂O₃, TiO₂, ZrO₂) and salts (CaCO₃, K₂CO₃, ZrSiO₄) as active surfaces for the reaction of ethynylation of 4,5,6,7-tetrahydroindole with ethyl bromopropynoate and bromobenzoylacetylene. It was established that Ca, Mg, Zn, and Ba oxides assist the ethynylation of 4,5,6,7-tetrahydroindole, and their activity in the reaction with ethyl bromopropynoate considerably exceeds that of aluminum oxide. The ethynylation is accompanied with the formation of intermediate E-2-(1-bromoethenyl)-4,5,6,7-tetrahydroindole and side 1,1-di(4,5,6,7-tetrahydroindol-2-yl)ethenes and 1,1-di(4,5,6,7-tetrahydroindol-2-yl)bromoethanes.     

Novel Selected Tandem Transformations of the Amino and Carbonyl/Nitrile Groups in the Gewald Thiophenes

Novel transformations of the amino and carbonyl/nitrile groups in the Gewald thiophenes were studied for thienopyrimidine synthesis. It was found that 2-amino-thiophene-3-carboxamides and ethyl 2-(acetylamino)-4,5,6,7-tetrahydro-1-benzothiophene-3-carbo- xylate did not yield tetrazole derivatives, neither in the reaction with triethyl orthoformate and sodium azide, nor in the reaction with phosphorus oxychloride and sodium azide, correspondingly. On the contrary, derivatives of thieno[2,3-d]pyrimidin-4(3H)-one and thieno[2,3-d][1,3]oxazin-4-one were isolated. New 2-azidothiophenes [2-azido-4,5,6,7-tetra hydro-1-benzothiophene-3-carbonitrile and 2-azido-4,5,6,7-tetrahydro-1-benzothiophen-3-yl(phenyl)methanone] were synthesized and used in anionic domino reactions with activated acetonitriles to yield thieno[3,2-e][1,2,3]triazolo[1,5-a]pyrimidines and/or 2-(5-amino-1H-1,2,3-triazol-1-yl)thiophenes. Finally, a new ring system of thieno[3,2-e]pyrazolo[1,5-a]pyrimidine was synthesized via a domino reaction of ethyl 2-[(2Z)-2-(1-chloro-2-ethoxy-2-oxoethylidene)hydrazino]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxylate with activated acetonitriles.     

From 4,5,6,7-tetrahydroindoles to 3- or 5-(4,5,6,7-tetrahydroindol-2-yl)isoxazoles in two steps: a regioselective switch between 3- and 5-isomers

(4,5,6,7-Tetrahydroindol-2-yl)alkynes, synthesized by cross-coupling of 4,5,6,7-tetrahydroindoles with aroyl(hetaroyl)bromoalkynes or ethyl bromopropynoate in the presence of K₂CO₃, regioselectively cyclize with hydroxylamine to either 3- or 5-(4,5,6,7-tetrahydroindol-2-yl)isoxazoles depending on the acidity of the reaction mixture: in the presence of acetic acid 3-isomers are formed (ca. 100% selectivity), while under neutral conditions the reaction is switched to 5-isomers (94–97% selectivity).     

From 4,5,6,7-tetrahydroindole to functionalized furan-2-one-4,5,6,7-tetrahydroindole-cyclobutene sequence in two steps

Ethyl 3-(4,5,6,7-tetrahydroindol-2-yl)propynoate, readily available from 4,5,6,7-tetrahydroindole and ethyl bromopropynoate, when treated with dichlorodicyanobenzoquinone (DDQ) in methanol affords furan-2-one-4,5,6,7-tetrahydroindole-cyclobutene sequence in a 52% yield. As kinetic and minor products, a furan-2-one isomer along with bicycloheptadienone have been either isolated or identified. The reaction has been shown to proceed via the isolable intermediate the [2+2]-cycloadduct of ethyl 3-(4,5,6,7-tetrahydroindol-2-yl)propynoate with DDQ. Other alcohols react with the [2+2]-cycloadduct in a similar way. The effect of the alcohol structure on the products ratio has been analyzed. All the intermediates and products are formed as single diastereomer, thus indicating a concerted character of the rearrangement.     

Transformations of 2-trifluoroacetyl-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridines by the action of ethyl propynoate. A novel synthesis of 2-trifluoroacetyl-4,7,8,9-tetrahydro-1H-pyrrolo[2,3-d]azocines

2-Trifluoroacetyl-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridines reacted with ethyl propynoate in acetonitrile and methanol to give ethyl 2-trifluoroaceyl-4,7,8,9-tetrahydro-1H-pyrrolo[2,3-d]azocine-5-carboxylates. The reactions of 2-trifluoroacetyl-1-vinyl-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridines with ethyl propynoate in alcohols were accompanied by cleavage of the tetrahydropyridine fragment with formation of alkyl 3-{benzyl[2-(3-alkoxy-5-trifluoroacetyl-1-vinyl-1H-pyrrol-2-yl)ethyl]amino}acrylates.     

Beiträge zur Chemie schwefelhaltiger Heterocyclen, 5. Mitt.: Weitere Reaktionen in der Reihe der 5,6,7,8-Tetrahydro-[1]benzothieno[2,3-d]pyrimidine

Zusammenfassung 2,4-Dioxo-1,2,3,4,5,6,7,8-octahydro-[1]benzothieno[2,3-d]pyrimidin (2) wurde1. durch Umsetzung von 2-Amino-4,5,6,7-tetrahydro-benzo[b]thiophen-3-carbonsäureamid mit Phosgen, 2. durch Ringschlußreaktionen von 2-(N-Carbäthoxy-amino)-4,5,6,7-tetrahydro-benzo[b]thiophen-3-carbonsäureamid sowie 3. durch thermische Cyclisierung von 2-(N-Phenylureido)-4,5,6,7-tetrahydro-benzo[b]thiophen-3-carbonsäureamid gewonnen. Das entsprechende 3-Phenylderivat wurde durch Ringschlußreaktionen des Äthylesters oder des Amides der 2-(N-Phenylureido)-4,5,6,7-tetrahydro-benzo[b]thiophen-3-carbonsäure erhalten.Umsetzung von 2-Amino-4,5,6,7-tetrahydro-benzo[b]thiophen-3-carbonsäureamid mit Chlorkohlensäureester gab je nach den Reaktionsbedingungen entweder 2-(N-Carbäthoxy-amino)-4,5,6,7-tetrahydro-benzo[b]thiophen-3-carbonsäureamid oder 2-Äthoxy-4-oxo-3,4,5,6,7,8-hexahydro-[1]benzothieno[2,3-d]pyrimidin.

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Contributions to the chemistry of sulfur containing heterocycles, V: Further reactions of 5,6,7,8-tetrahydro-[1]benzothieno-[2,3-d]pyrimidines

2,4-Dioxo-1,2,3,4,5,6,7,8-octahydro-[1]benzothieno[2,3-d]pyrimidine was prepared in 3 different ways: by reaction of 2-amino-4,5,6,7-tetrahydro-benzo[b]thiophene-3-carboxamide with phosgene, by cyclization of 2-(N-carbethoxy-amino)-4,5,6,7-tetrahydro-benzo[b]thiophene-3-carboxamide, or by thermal cyclization of ethyl 2-(N-phenylureido)-benzo[b]thiophene-3-carboxylate. The corresponding 3-phenyl derivative was prepared by ring closure reactions of ethyl 2-(N-phenylureido)-4,5,6,7-tetrahydro-benzo[b]thiophene-3-carboxylate or-3-carboxamide. Reaction of 2-amino-4,5,6,7-tetrahydro-benzo[b]thiophene-3-carboxamide with ethyl chloroformate yielded either 2-(N-carbethoxy-amino)-4,5,6,7-tetrahydro-benzo[b]thiophene-3-carboxamide or 2-ethoxy-4-oxo-3,4,5,6,7,8-hexahydro-[1]benzothieno-[2,3-d]pyrimidine depending on reaction conditions.

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Mit 1 Abbildung

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Meinem sehr verehrten Lehrer, Herrn o. Prof. Dr.O. Hromatka, in Dankbarkeit zum 65. Geburtstag gewidmet.

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Aus patentrechtlichen Gründen bis jetzt zurückgehalten.

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4. Mitt.:F. Sauter undA. Dzerovicz, Mh. Chem.100, 913 (1969).     

Convenient synthesis of novel N-(5-allyl-7,7-difluoro)-4,5,6,7-tetrahydro-2H-indazol-3-yl)-carboxymides

5-Allyl-7,7-difluoro-2-(2,4-difluorophenyl)-6-(4-methoxyphenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-3-amine represents a fluorinated heterocyclic scaffold, potentially attractive. It was synthesized via Michael addition, Mannich reaction of the difluorinated ethyl bromoacetate with a benzotriazole derivative, followed by a Dieckmann condensation. Starting from simple materials, this efficient route which gives access to novel functionalized N-(5-allyl-7,7-dihalo)-4,5,6,7-tetrahydro-2H-indazol-3-yl)-carboxymides, was explored and adapted for parallel synthesis, resulting in a compound library.     

Synthesis and Crystal Structure of Ethyl 2-(6-(1,3-Dioxo-4,5,6,7-tetrahydro-1H-isoindol-2(3H)-yl)-7-fluoro-3-oxo-2H-benzo[b][1,4]oxazin-4(3H)-yl) Butanoate

The title compound ethyl 2-(6-(1,3-dioxo-4,5,6,7-tetrahydro-1H-isoindol-2(3H)-yl)-7-fluoro-3-oxo-2H-benzo[b][1,4]oxazin-4(3H)-yl) butanoate 3 was synthesized by the reaction of ethyl 2-(6-amino-7-fluoro-3-oxo-2H-benzo[b][1,4]oxazin-4(3H)-yl) butanoate with 4,5,6,7-tetraydrophthalic anhydride,and its structure was determined by X-ray single-crystal diffraction.The crystal belongs to the monoclinic system,space group P21/n with a = 9.3469(2),b = 16.7715(5),c = 13.7153(4) ,β = 104.9680(10)°,μ = 0.107 mm-1,Mr = 430.42,V = 2077.08(10) 3,Z = 4,Dc = 1.376 g/cm3,F(000) = 904,T = 296(2) K,R = 0.0508 and wR = 0.1478.     

Acid dimerization of N-vinyl-4,5,6,7-tetrahydroindole

Reaction of N-vinyl-4,5,6,7-tetrahydroindole with acids, the chlorides of iron, tin or titanium, or with organochlorosilanes leads to formation of 1-vinyl-2-[1-(4,5,6,7-tetrahydroindol-1-yl)ethyl]-4,5,6,7-tetrahydroindole.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 4, pp. 479–480, April, 1987.     

Chemistry of iminofurans. Recyclization of ethyl 2-[2-oxo-5-phenylfuran-3(2H)-ylideneamino]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxylate in reaction with amines

Russian Journal of Organic Chemistry - The reaction of ethyl 2-[2-oxo-5-phenylfuran-3(2H)-ylideneamino]-4,5,6,7-tetrahydro-1-benzothiophene- 3-carboxylate with primary amines (RNH2) in toluene...     

Vinyl sulfones in solid-phase synthesis: preparation of 4,5,6,7-tetrahydroisoindole derivatives

The preparation of functionalized 4,5,6,7-tetrahydroisoindole via a traceless solid-phase sulfone linker strategy is described. Thermolytic extrusion of SO(2) from polymer-bound 3-(phenylsulfonyl)-3-sulfolene (7) generated polymer-bound 2-(phenylsulfonyl)-1,3-butadiene (9) in situ which underwent Diels--Alder cycloaddition with various dienophiles to furnish vinyl sulfone resins 10-14. To complete a traceless linker cleavage strategy, (p-tolysulfonyl)methyl isocyanide or ethyl isocyanoacetate was employed to react with the vinyl sulfone moiety to liberate functionalized 4,5,6,7-tetrahydroisoindole products from the resin. Using this chemistry, nine tetrahydroisoindole derivatives (6, 15-22) were prepared in 32-41% overall yields from polystyrene/divinylbenzene sulfinate 1.     

Synthesis and isomerization reaction of 2-(benzoxazol-2-yl)-1,3-tropolones

An acid-catalyzed reaction of 2-methylbenzoxazole with 3,4,5,6-tetrachloro-1,2-benzoquinone leads to 2-(benzoxazol-2-yl)-5,6,7-trichloro-1,3-tropolone and 2-(benzoxazol-2-yl)-4,5,6,7-tetrachloro-1,3-tropolone. 1,3-Tropolones upon reflux in ethyl alcohol undergo the rearrangement resulted in the seven-membered ring contraction to form ethyl 2-(benzoxazol-2-yl)-5,6-dichloro-3-hydroxybenzoate and ethyl 2-(benzoxazol-2-yl)-4,5,6-trichloro-3-hydroxybenzoate. The molecular structure of the latter was established by X-ray diffraction analysis.     

Dimerization of 1-vinyl-4,5,6,7-tetrahydroindole in the presence of acids

In the presence of Bronsted and Lewis acids, I-vinyl-4,5,6,7-tetrahydroindole is transformed into its dimes, 1-vinyl-2-[1-(4,5,6,7-tetrahydroindolyl)ethyl]-4,5,6,7-tetrahydroindole, and polymers containing units of the dimer and segments of oxidized tetrahydroindole cycles.Translated fromIzvestiva Akademii Nauk. Seriya Khindcheskaya, No. 2, pp. 423–425, February, 1996.     

A NOVEL SYNTHESIS OF 2-SUBSTITUTED-4H-THIENO [2,3-d][1,3] OXAZIN-4-ONE AND 2,3-DISUBSTITUTED THIENO [2,3-d]PYRIMIDIN-4(3H)-ONE DERIVATIVES

Abstract

The synthesis of acetic 2-{[1-methyl-2-(4-oxo-5,6,7,8-tetrahydro-4H-benzo [4,5]-thieno [2,3-d] [1,3-oxazin-2-yl)ethylidene]amino}-4,5,6,7-tetrahydrohenzo[b]thiophene ?3-carboxylic acid anhydride 5 and 2-(oxopropyl)-5,6,7,8-tetrahydro-4H-benzo-[4,5] thieno[2,3-d][1,3]oxazin-4-one 7, has been achieved in three steps from ethyl 2-amino-4,5,6,7-tetrahydrobenzo(b]thiophene-3-carboxlate 1 via the reaction with ethyl acetoacetate followed by hydrolysis and acetic anhydride-induced cyclization. The 2-substituent in compound 5 has two functional groups i.e. active methylene and acid anhydride which are suitably located for intramolecular transformation. Thermal and/or base catalyzed intramolecular cyclization of 5 afforded 2-(4-acetoxy-(hydroxyl)-2-methyl-5,6,7,8-tetrahydrobenzo[4,5] thieno[2,3-b]pyridin-3-yl)-5,6,7,8- tetrahydro-4H-benzo[4,5]thieno[2,3-d] [1,3]oxazin-4-one 10 and 9 respectively. Treatment of 5 with hydrazine hydrate, aromatic and/or heterocyclic amines induced the same intramolecular cyclization with a concomitant oxazine-pyrimidine interconversion to give 3-amino(aryl or heteryl)-2-(4-hydroxy-5,6,7,8-tetrdhydrobenzo-[4,5]thieno[2,3-b]pyridin-3-yl)-3,4,5,6,7,8-hexahydrobenzo[4,5] thieno[2,3-d] pyrimid in-4-one 11–14 respectively.     

Neue Derivate der 2-Acylamino-thiophen-(und-benzo[b]thiophen-)-3-carbonsäure sowie des ([1]Benzo-)Thieno[2,3-d]-pyrimidin-4(3H)-ons

The title substances1 and2 were prepared by acylation of the corresponding ethyl 2-amino-thiophene- (or:-4,5,6,7-tetrahydro-benzo[b]thiophene)-3-carboxylates, in some cases followed by reactions introducing a basic substituent.Additionally a group of 2-aroylamino-thiophene-(or:-4,5,6,7-tetrahydro-benzo[b]thiophene)-3-carboxamides was subjected to ring closure reactions, yielding the corresponding 2-aryl-thieno[2,3-d]pyrimidin-4(3H)-ones and 2-aryl-[1]benzothieno[2,3-d]pyrimidin-4(3H)-ones (both:3).

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Zum Teil unter Mitarbeit vonFerdinand Fuhrmann     

一种新型Hsp90抑制剂的合成及其抑制活性

对氨基苯甲酸经重氮化后再与2-氯乙酰乙酸乙酯反应制得(Z)-4-[2-(1-氯-2-乙氧基-2-羰亚甲基)肼基]苯甲酸(1);1与二甲基环己二酮成环后再与对羟基环己胺完成酰胺化反应合成了一种新型Hsp90抑制剂——N-(4-羟基环己基)-4-[1-(6,6-二甲基-4-氧-3-乙酰氧基-4,5,6,7-四氢吲唑)]苯甲酰胺(3),其结构经1HNMR表征。荧光偏振法研究结果表明3对Hsp90α具有明显的抑制活性。     

Oligomerization of <Emphasis Type="Italic">N</Emphasis>-vinylpyrroles under the action of iodine

The oligomerization of N-vinylpyrroles (N-vinyl-4,5,6,7-tetrahydroindole, N-vinyl-2-[1-(1-4,5,6,7-tetrahydroindole)ethyl]-4,5,6,7-tetrahydroindole, N-vinyl-2-phenylpyrrole, N-vinyl-3-heptyl-2-phenylpyrrole, N-vinyl-2,3-diphenylpyrrole, and N-vinyl-2-(2-naphthyl)pyrrole) under the action of iodine vapor leads to the formation of iodine-containing oligomers with an iodine content of 17–52% and a yield of up to 99%. The oligomers are paramagnetic and possess conductivity; they are readily soluble in organic solvents (benzene, dioxane, and chloroform) and are stable up to 110–260°C.     

2-Methylthio-4,5,6,7-tetrahydro-1,2,4-triazolo[1,5-<Emphasis Type="Italic">a</Emphasis>]pyrimidin-5- and -7-Ones

The cyclocondensation of methylcinnamates and arylidene derivatives of Meldrums acid with 3-amino-5-methylthio-1,2,4-triazole in DMF gives 2-methylthio-4,5,6,7-tetrahydro-1,2,4-triazolo[1,5-a]-pyrimidin-5-ones. The reaction involving arylidene derivatives of Meldrums acid or its synthetic equivalents in ethyl acetate with a catalytic amount of pyridine gives a mixture of 2-methylthio-4,5,6,7-tetrahydro-1,2,4-triazolo[1,5-a]pyrimidin-5- and -7-ones.__________Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 2, pp. 246–251, February, 2005.     

Fusions of pyrido[4′,3′:4,5]thieno[2,3-d]pyrimidines with N-heterocyclic moieties

Versatile 2-thioxopyrimidine-type building blocks ethyl 3-(2-ethoxy-2-oxoethyl)- 4 -oxo-2-thioxo-1,2,3,4,5,6,7,8-octahydropyrido[4′,3′:4,5]thieno[2,3-d]pyrimidine-7-carboxylate ( 4 ) and ethyl 4-oxo-2-thioxo-1,2,3,4,5,6,7,8-octahydropyrido[4′,3′:4,5]thieno[2,3-d]pyrimidine-7-carboxylate ( 8 ) were synthesized from diethyl 2-amino-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3,6-dicarboxylate ( 1 ). Derivatives of linear and angular heterocyclic systems having the imidazole and 1,2,4-triazole ring were obtained from the key intermediates 4 and 8 , respectively.