Facile Synthesis of 2-(4-Hydroxybiphenyl-3-yl)-1H-indoles from Anilines and 5′-Bromo-2′-hydroxyacetophenone

2-Arylindoles are attractive scaffolds because they are found in many pharmacologically active molecules. In this study, we describe the facile synthesis of diverse 2-(2-hydroxyphenyl)-1H-indoles from anilines and 5′-bromo-2′-hydroxyacetophenone in two steps using palladium-catalyzed indole cyclization as a key reaction. The indole cyclization was primarily controlled by the substituent properties of anilines. Suzuki-coupling reactions of 2-(5′-bromo-2′-hydroxyphenyl)-1H-indoles with arylboronic acids provided the corresponding 2-(4-hydroxybiphenyl-3-yl)-1H-indoles in moderate yield.     

Tetrazole compounds. 10. Novel tetrazolylindoles by fischer indolization of substituted tetrazolylacetaldehyde phenylhydrazones

The acid-catalyzed reaction of substituted phenylhydrazines 1 with 1-aryl-5-(2-dimethylaminovinyl)-1H-tetrazoles 2 afforded (1-aryl-1H-tetrazol-5-yl)acetaldehyde phenylhydrazones 3 which on heating in acetic acid/perchloric acid underwent a Fischer indolization to give substituted 3-(1-aryl-1H-tetrazol-5-yl)-indoles 4a-k. Indoles of this type are also formed on subjecting 1 and 2 directly to indolization conditions; thus, starting from phenylhydrazine the tetrazolylindoles 41-s were obtained by a one-pot procedure. Indolization of corresponding N_α-methylphenylhydrazones 5 resulted in 1-methyl-3-(1-aryl-1H-tetrazol-5-yl)indoles 6 .     

Diels-Alder-Reaktionen von 2′-substituierten 3-Vinyl-1H-indolen zu neuen anellierten Indol-und Carbazol-Derivaten

Diels-alder Reactions of 2′-Substituted 3-Vinyl-1H-indoles to New Annellated Indole and Carbazole Derivatives New regio- and stereoselcctive cycloadditions between 2′- substituted 3-vinyl-l H -indoles and the dienophiles N-Phenylmaleimide, dimethyl acetylendicarboxylate, and methyl acrylate are reported. Products include some new carbazole derivatives and Michael adducts. In the presence of AlCl₃ as dicnophile-activating catalyst, ‘endo’ preference for deriving cycloadducts is observed. In some cases, Michael addition competes with[4+2] cycloaddition.     

1-(Pyrimidin-4-yl)pyrazol-5(4<Emphasis Type="Italic">H</Emphasis>)-one derivatives: II. Electrophilic substitution in 5-hydroxy-3-methyl-1-(6-methyl-2-methylsulfanylpyrimidin-4-yl)-1<Emphasis Type="Italic">H</Emphasis>-pyrazole

Electrophilic substitution of hydrogen in bicyclic 5-hydroxy-3-methyl-1-(6-methyl-2-methylsulfanylpyrimidin-4-yl)-1H-pyrazole occurs exclusively at the C⁴ atom of the five-membered heteroring. Unstable electrophilic substitution products are stabilized via addition of the second substrate molecule with formation of bridged adducts.     

Improved Method for Preparation of 3-(1H-Indol-3-yl)benzofuran-2(3H)-ones

3-(1H-Indol-3-yl)benzofuran-2(3H)-ones were efficiently accessed via polyphosphoric acid-mediated condensation of 3-(2-nitrovinyl)-1H-indoles with phenols.     

Condensation reactions of indole with acetophenones affording mixtures of 3,3-(1-phenylethane-1,1-diyl)bis(1H-indoles) and 1,2,3,4-tetrahydro-3-(1H-indol-3-yl)-1-methyl-1,3-diphenylcyclopent[b]indoles

Condensation of indole 1a with eight acetophenones 8a–h in ethanolic HCl afforded the corresponding mixtures of condensation products: 3,3-(1-phenylethane-1,1-diyl)bis(1H-indoles) 11a–h (2:1 condensation of indole:acetophenone, –H₂O) and diastereomers of substituted 1,2,3,4-tetrahydro-3-(1H-indol-3-yl)-1-methyl-1,3-diphenylcyclopent[b]indoles 12a–h and 13a–h (2:2 condensation of indole:acetophenone, –2H₂O). Each mixture was analyzed by ¹H NMR. The use of substituted electron-withdrawing acetophenones favored formation of 2:1 condensation products, whereas the use of substituted electron-donating acetophenones favored formation of 2:2 condensation products. Increased reaction temperature gave higher 2:2 condensation yields, but temperatures above 40?°C were unfavorable, giving complex, tarry mixtures.     

Tetrazole compounds. 9. A new approach to tetrazolyl-substituted quinoline derivatives

The acid-catalyzed reaction of 1-aryl-5-(2-dimethylaminovinyl)-1H-tetrazoles 2 with arylamines suitably functionalized in the ortho-position resulted in Z-configurated transamination products which were cyclized to novel 3-tetrazolylquinolines by the action of sodium ethoxide. Thus, on reacting 2 with 2-aminoacetophenone or 2-aminobenzophenone, respectively, the 2-[2-(1-aryl-1H-tetrazol-5-yl)vinyl-amino]aryl ketones 3a-g were obtained, the cyclization of which gave 4-substituted 3-(1-aryl-1H-tetrazol-5-yl)quinolines 4 . In the case of the transamination products 3h-1 , prepared from 2 and methyl anthranilate, the ring closure afforded 3-(1-aryl-1H-tetrazol-5-yl)-1H-quinolin-4-ones 5 . Starting from 2 and anthranilonitrile 4-amino-3-(1-aryl-1H-tetrazol-5-yl)quinolines 10 were obtained via the corresponding intermediates 9 .     

The Reaction of 3-(Dimethylamino)-2H-azirines with 2,3-Pyridinedicarboximide

Reaction of 2,2-dialkyl-3-(dimethylamino)-2H-azirines 1a and 1b with 2,3-pyridinedicarboximide ( 4 ) in MeCN or DMF at room temperature yielded two regioisomeric tricyclic 1:1 adducts, the azacyclols 11/12 and 16/17 , respectively (Schemes 3 and 4). The structure of 12 was established by X-ray crystallography. Methanolysis of 11/12 and 16/17 led to mixtures of methyl [4, 4-dialkyl-5-(dimethylamino)-4H-imidazol-2-yl] pyridine carboxylates 13/14 and 18/19 , respectively. The structure of compound 14 is closely related to that of the powerful herbicide 9 (Scheme 9), i.e. the described reactions offer a new synthetic approach to this class of compounds. A mechanistic interpretation for the formation of regioisomeric 1:1 adducts as well as methyl (imidazol-2-yl) pyridine carboxylates is depicted in Scheme 5.     

Functionalization of oxadiazolylindole systems

A new synthetic approach was developed to the preparation of functional derivatives of 3-(1,3,4-oxadiazol-2-yl)-1H-indoles starting with a synthetically available 3-[5-(chloromethyl)-1,3,4-oxadiazol-2-yl]-1H-indole. The versatility of the developed strategy was demonstrated in the synthesis of this kind compounds with a wide range of substituents.     

N-(2-tetrahydrofuranyl)azole nucleoside analogs by reactions of azoles with dihalomethanes in tetrahydrofuran

The reactions of the mono-N-substituted bispyrazolylpyridine 2-(1-methyl-4,5,6,7-tetxahydroindazol-3-yl)-6-(2H-4,5,6,7-tetrahydroindazol-3-yl)pyridine, 3,5-dimethylpyrazole and benzimidazole with sodium hydride and diiodomethane or dibromomethane in tetrahydrofuran produced the unexpected N-tetrahydrofuran-2-yl adducts as well as the expected diazolylmethanes. These side-reactions are thought to involve the 2-halo tetrahydrofuran derivative resulting from a free-radical halogenation by the dihalomethane.     

Synthesis of imidazolyl dithiocarbamates and their reactions with phenacyl bromides

The reactions of ethyl (5-carbamoyl-3H-imidazol-4-yl)dithiocarbamate with phenacyl bromides afford the S-alkylation products as a mixture of E/Z-isomers, which undergo cyclization to 5-(2-oxo-4-arylthiazol-3-yl)-1H-imidazole-4-carboxamides under the action of a base.     

CsF-Catalyzed alkylation of gamma-carbolines with fluorine-containing 3-vinylpyridines

CsF-Catalyzed alkylation of gamma-carbolines with 3-vinyl-5-fluoropyridine and 3-vinyl-6-trifluoromethylpyridine led to the formation of 5-[2-(5-fluoropyrid-2-yl)ethyl]-2,3,4-tetrahydro-1H-pyrido[4,3-b]-indoles and 5-[2-(6-trifluoromethylpyrid-2-yl)ethyl]-2,3,4-tetrahydro-1H-pyrido[4,3-b]indoles.     

Intramolecular cyclization of 4-amino-3-alkylsulfanyl-1,2,4-triazoles as a method for annelation of thiadiazine and thiadiazole rings

4-Amino-5-(pyridin-4-yl)-4H-1,2,4-triazole-3-thiols reacted with N-substituted isatins to give 2-oxo-3-[5-(pyridin-4-yl)-3-sulfanyl-4H-1,2,4-triazole-4-ylimino]-2,3-dihydro-1H-indoles which were treated with phenacyl bromides to obtain the corresponding S-phenacyl derivatives. The latter underwent base-catalyzed intramolecular cyclization with formation of 6,7-dihydro-5H-1,2,4-triazolo[3,4-b][1,3,4]thiadiazines spiro-fused to 2-oxo-2,3-dihydro-1H-indole fragment at C³. Analogous cyclization of 2,6-di-tert-butyl-4-[5-hetaryl-3-(2-aryl-2-oxoethylsulfanyl)-4H-1,2,4-triazole-4-ylimino]cyclohexa-2,5-dienones involved the imino nitrogen atom to produce the corresponding 6-aroyl-5-(3,5-di-tert-butyl-4-hydroxyphenyl)-3-hetaryl-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazoles.     

Iron(iii) chloride-catalyzed mechanochemical cascade synthesis of highly-substituted pyrrolyl indoles

Iron(iii) chloride has been found to serve as an efficient catalyst for a mechanochemical (ball milling) one-pot four- component cascade reaction of phenyl glyoxal, anilines, indoles and activated alkyne affording highly-substituted 3-(1H-pyrrol-2-yl)-1H-indoles. The procedure is beneficial because of mild conditions, easily available starting materials, cheap catalyst and possibility for scaling.     

Synthesis and study of some new <Emphasis Type="Italic">N</Emphasis>-substituted imide derivatives as potential antibacterial agents

Dibenzobarrelene (I) was used as a starting compound for the synthesis of some new 3a,4,9,9a-tetrahydro-4,9-[1,2]benzeno-1H-benzo[f]isoindole-1,3(2H)-diones, N-substituted with: 4-toluenesulfonyloxy, III; butoxy, IV; 3-bromopropoxy, V; 3-(4-phenylpiperazin-1-yl)propoxy, VI; 3-chloro-3-oxopropyl, VIII; 3-(4-phenylpiperazin-1-yl)-3-oxopropyl, IXa; 3-(4-methylpiperazin-1-yl)-3-oxopropyl, IXb; 3-oxo-3-(piperidin-1-yl)propyl, X; 3-morpholino-3-oxopropyl, XI; 3-phenylamino-3-oxopropyl, XII; 2-acetylaminoethyl, XIV; 2-aminoethyl, XV, and 2-acetoxyethyl, XVI. Newly synthesized compounds were characterized by IR, ¹H and ¹³C NMR, and mass spectral data. Selected products were tested for antimicrobial activity.     

Imidazolyl derivatives of the chroman ring 3

The synthesis of 2-methyl-3-(1-methyl-1H-imidazol-2-yl)-4H-1-benzopyran-4-ones 4 is described starting from 2-acetoxybenzoyl chlorides and 1,2-dimethylimidazole. Chromones 4 undergo alkaline ring opening to the corresponding 1-(2-hydroxyphenyl)-2-(1-methyl-1H-imidazol-2-yl)ethenols 5 which give ring closure to 2-substituted 3-(1-methyl-1H-imidazol-2-yl)-4H-1-benzopyran-4-ones or 2,3-dihydro-3-(1-methyl-1H-imidazol-2-yl)-4H-1-benzopyran-4-ones. The corresponding chromanols and chromenes can be easily obtained from chromones 4 .     

Amine exchange reactions of 3-<Emphasis Type="Italic">tert</Emphasis>-butyl-6-(methylsulfanyl)-1,2,3,4-tetrahydro-1,3,5-triazine hydroiodide with amino acids

3-tert-Butyl-6-(methylsulfanyl)-1,2,3,4-tetrahydro-1,3,5-triazine hydroiodide enters into the amine exchange reaction with glycine and β-alanine in aqueous solution. The final exchange products are [4-(methylsulfanyl)-5,6-dihydro-1,3,5-triazin-3-ium-1(2H)-yl] acetate and 3-[4-(methylsulfanyl)-5, 6-dihydro-1,3,5-triazin-3-ium-1(2H)-yl] propanoate, respectively, crystallizing together with t-butylamine hydroiodide from aqueous or aqueous alcoholic solutions as ion associates, which also can be detected in solution in DMSO-d ₆. [4-(Methylsulfanyl)-5,6-dihydro-1,3,5-triazin-3-ium-1(2H)-yl] acetate can be extracted directly from the reaction mixture after carrying out the amine exchange in aqueous isopropanol or 95% ethanol, as well as by “recrystallization“ of its associate with tert-butylamine hydroiodide from aqueous isopropanol.     

Research on photochemical and thermochemical reactions between indole and quinones in the absence of solvent

The solid state photochemical reaction of indole with 1,4-naphthoquinone yielded 5H-dinaphtho[2,3-a:-2′,3′-c]carbazole-6,11,12,17-tetrone ( 1 ) in addition to 2-(3-indolyl)-1,4-naphthoquinone ( 2 ) which was also the only product in the solution photoreaction. Solventless thermochemical reactions of indole with phenanthrenequinone in the presence or absence of zinc chloride gave 10-(1H-indol-3-yl)-9-phenanfhrenol ( 3 ) and 9,10-dihydro-9-(1H-indol-3-yl)-10-(3H-indol-3-ylidene)-9-phenanthrenol ( 4 ) or 10,10-di-1H-indol-3-yl-9(10H)-phenanthrenone ( 5 ), respectively. All of these products were only obtained in trace amount in corresponding solution reactions, and are different from the adduct 10-hydroxy-10-(1H-indol-3-yl)-9(10H)-phenanthrenone ( 6 ) obtained in the solution photoreaction. A possible mechanism for formation of 4 and 5 is described in terms of electron pair donor/acceptor complexation.     

Synthesis of novel 1-phenyl-1H-indole-2-carboxylic acids. II. Preparation of 3-dialkylamino, 3-alkylthio, 3-alkylsulfinyl,and 3-alkylsulfonyl derivatives

The synthesis of novel indole-2-carboxylic acids with amino- and sulfur-containing substituents in the indole 3-position is described. An Ullmann reaction with bromobenzene converted 1H-indoles with 3-(acetylamino)- and 3-(diethylamino)-substituents into 1-phenyl-1H-indoles. Reaction of 3-unsubstituted indoles with thionyl chloride provided indole 3-sulfinyl chlorides, which reacted with alkyl and aryl Grignard reagents to form the corresponding sulfoxides. The indole sulfoxides thus obtained were reduced to sulfides or oxidized to sulfones.     

Imidazolyl derivatives of the chroman ring. 2

The synthesis of 3-(1H-imidazol-1-yl)-4H-1-benzopyran-4-ones 2 and of 2-(1H-imidazol-1-yl)-4H-1-benzopyr-an-4-ones 11 are described. The former proceeds through chroman ring closure from 2-(1H-imidazol-1-yl)-2′-hydroxyacetophenones, the latter occurs reacting 3-bromo-4H-1-benzopyran-4-ones with imidazole and represents an example of a new synthesis of 2-heteroarylchromones. Compounds 2 can be easily reduced to the corresponding chromanones and chromanols previously described in Part 1.