Regioselective synthesis of 1-alkyl-5-(indol-3-yl- and -2-yl)pyrrolidin-2-ones from available reagents

The reaction under mild conditions of 1-alkyl-5-hydroxypyrrolidin-2-ones with different indoles having a free 3 position leads exclusively to 1-alkyl-5-(indol-3-yl)pyrrolidin-2-ones but if position 3 is occupied to 1-alkyl-5-(indol-2-yl)pyrrolidin-2-ones.     

2-Chloro-3H-indol-3-one and its reactions with nucleophiles

The title compound reacts with N- and S-nucleophiles to form 3-substituted indol-2-ones, but with C-nucleo-philes to afford either these or the corresponding 2-substituted indol-3-ones. This dichotomy of behavior is documented and rationalized.     

Convenient synthetic method for 3-(3-substituted indol-2-yl)quinoxalin-2-ones as VEGF inhibitor

It has already been reported that 3-(indol-2-yl)quinoxalin-2-ones have a potent inhibitory effect on the growth of tumor cells based on anti-angiogenesis activity. We have also carried out a structure-activity relationship (SAR) study of 3-(indol-2-yl)quinoxalin-2-ones, which showed a potent inhibitory activity toward the vascular endothelial growth factor (VEGF)-induced proliferation of human mesangial cells and the VEGF-induced auto-phosphorylation of human umbilical vein endothelial cells. Moreover, one of these compounds has a potent medicinal effect based on anti-angiogenic action, by oral administration (Chart 1, 9). However, since the existing synthetic methods for the preparation of 3-(indol-2-yl)quinoxalin-2-ones consist of multiple steps some of which require strict anhydrous conditions, a convenient and simple synthetic method in place of the existing method is desirable. As a result of the investigations into the synthetic procedures, 3-(3-substituted indol-2-yl)quinoxalin-2-ones can be easily prepared by the condensation of 3-substituted indoles with quinoxalin-2-ones in the presence of trifluoroacetic acid (TFA). Herein, we report the examination of these reaction conditions and the application of this new synthetic method to the synthesis of the derivatives as VEGF inhibitors.     

Photochemical and thermal cyclizations of 4-(2-azidophenyl)-3,4-dihydropyrimidin-2-ones for the synthesis of 4-methylenepyrimidino[5,4-b]indol-2-ones

Photochemical and thermal cyclization of 4-(2-azidophenyl)-3,4-dihydropyrimidin-2-ones could afford fused indoles, such as 1,2,3a,9b-tetrahydro-4-methylenepyrimidino[5,4-b]indol-2-ones and 1,3,5,6,7a,12b-hexahydroquinazolino[9,4-b]indol-2,7-dione in high yields via nitrene electrophilic addition and rearrangement reactions.     

An efficient synthesis of 3-(indol-3-yl)quinoxalin-2-ones with TfOH-catalyzed Friedel-Crafts type coupling reaction in air

An efficient one-pot synthetic approach to access a variety of 3-(indol-3-yl)quinoxalin-2-ones from various quinoxalin-2-ones and very wide scope of indoles through TfOH-catalyzed Friedel-Crafts type coupling reaction in DMF has been developed. Only 10 mol % Brønsted acid as a catalyst, air as an oxidizer, and very wide range of substrates are the prominent advantages of this method.     

Synthesis of trans-2-(indol-3-yl)-3-nitrothiochroman-4-ones from 3-nitrothiochromone and indoles

1,4-Nucleophilic addition reactions of 3-nitrothiochromone with indoles gave a number of novel trans-2-(indol-3-yl)-3-nitrothiochroman-4-ones in 36–89% yields. During the reactions, the thiopyrone ring underwent no opening.     

Rhodium-catalyzed intramolecular alkyne-carbodiimide Pauson-Khand-type reaction

[structure: see text]. An efficient, Rh-catalyzed intramolecular Pauson-Khand-type carbonylation of alkyne-carbodiimides leading to 4,5-dihydro-1H-pyrrolo[2,3-b]pyrrolin-2-ones and 1H-pyrrolo[2,3-b]indol-2-ones is described.     

Synthesis of 5H-pyridazo[4,5-b]indoles by condensation of 2-acylindole-3-carboxylic acids with hydrazine

5H-Pyridazo[4,5-b]indol-1-ones were obtained by heating 2-acetylindole-3- or 2-aroylindole-3-carboxylic acids with hydrazine hydrate in ethylene glycol or alcohol. 1-Chloro-5H-pyridazo[4,5-b]indoles are formed by treatment of 5H-pyridazo[4,5-b]indol-1-ones with phosphorus oxychloride.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 8, pp. 1064–1066, August, 1982.     

Novel schemes for the synthesis of pyrrolocoumarins

Two novel schemes have been developed for the synthesis of pyrrolocoumarin derivatives. A series of previously unknown 4,9-dimethylpyrano[3,2-e]indol-7(3H)-ones have been prepared.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No 10, pp. 1524–1532, October, 2004.     

Condensation of 1-Substituted 1,2,3,9a-Tetrahydro-9H-imidazo[1,2-a]indol-2-one Derivatives with Aromatic Aldehydes

Condensation of 1-alkyl-, 1-allyl-, and 1-benzyl-1,2,3,9a-tetrahydro-9H-imidazo[1,2-a]indol-2-ones with benzaldehydes in acetic acid and subsequent treatment of the reaction mixture with potassium hydroxide afforded 1-substituted 9a-(2-phenylethenyl)-1,2,3,9a-tetrahydro-9H-imidazo[1,2-a]indol-2-one derivatives. 1-Methyl- and 1-ethyl-9a-[2-(4-dimethylaminophenyl)ethenyl]-1,2,3,9a-tetrahydro-9H-imidazo[1,2-a]indol-2-ones were synthesized by alkylation of 9a-[2-(4-dimethylaminophenyl)ethenyl]-1,2,3,9a-tetrahydro-9H-imidazo[1,2-a]indol-2-one with methyl- and ethyl iodides in DMF in the presence of a strong base.     

Synthesis of 5H-pyridazino[4,5-b]indoles and their benzofurane analogues utilizing an intramolecular Heck-type reaction

The title ring systems were prepared from pyridazin-3(2H)-one precursors in novel, efficient pathways. 2-Methylbenzo[b]furo[2,3-d]pyridazin-1(2H)-one was synthesized via a regioselective nucleophilic substitution reaction of a 2-methyl-4,5-dihalopyridazin-3(2H)-one with phenol followed by an intramolecular Heck-type reaction. The same molecule and its 6-phenyl analogue were also prepared via reaction of 2-methyl-5-iodopyridazin-3(2H)-one or 2-methyl-5-chloro-6-phenylpyridazin-3(2H)-one, respectively, with 2-bromophenol or 2-iodophenol followed by Pd-catalyzed cyclodehydrohalogenation. Moreover, a new approach for the synthesis of 2-methyl-2,5-dihydro-1H-pyridazino[4,5-b]indol-1-ones was also elaborated utilizing a Heck-type ring closure reaction on 5-[(2-bromophenyl)amino]-2-methylpyridazin-3(2H)-ones which were obtained via Buchwald-Hartwig amination of 2-methyl-5-halopyridazin-3(2H)-ones with 2-bromoaniline.     

Synthesis of novel 7-substituted 5,6-dihydroindol-2-ones via a Suzuki-Miyaura cross-coupling strategy

A versatile method for the synthesis of new 7-substituted 5,6-dihydroindol-2-ones is described. The synthetic strategy proceeds through the use of the established palladium-catalyzed Suzuki-Miyaura cross-coupling reaction of halogenated indol-2-ones and arylboronic acids/esters.     

A thermal cascade route to pyrroloisoindolone and pyrroloimidazolones

Flash vacuum pyrolysis (FVP) of indol-1-ylacrylate derivatives 11 and 15 or the isomeric indol-3-ylacrylates 21, 22, and 24 at 925 degrees C (0.05 Torr) provides pyrrolo[1,2-a]indol-3-ones 2, 18, 28, and 29 in 53-90% yield by a cascade mechanism that involves a sigmatropic migration, elimination, electrocyclization sequence. Pyrrolo[1,2-a]imidazol-5-ones 3 and pyrrolo[1,2-c]imidazol-5-ones 4 were similarly obtained by FVP of corresponding 2,5-unsubstituted imidazol-1-ylacrylates (e.g., 33), with the former isomer predominating in ca. 80:20 ratio. Migration to the 2-position is therefore favored in the initial sigmatropic shift. FVP of 2-substituted imidazol-1-ylacrylates 35, 37, and 51 (825-875 degrees C) instead give pyrrolo[1,2-c]imidazol-5-ones 56-58 only (88-91%), and that of 4,5-disubstituted imidazol-1-ylacrylates 39 and 41 (825-850 degrees C) provide pyrrolo[1,2-a]imidazol-5-ones 59 and 60 exclusively (93-95%), and thus the selectivity of the initial shift can be controlled by the presence of substituents on the imidazole 2- and 5-positions. FVP of the benzimidazole analogues 61 and 62 at 950 degrees C gave the pyrrolo[1,2-a]benzimidazol-1-ones 6 (71%) and 63 (36%), respectively.     

Reaction of 2,3,3-trimethyl-3H-indole hydrochloride with methacrylic and crotonic amides

Reaction of 2,3,3-trimethyl-and 2,3,3,5-tetramethyl-3H-indole hydrochlorides with methacrylic and crotonic amides gives 3- and 4-methyl-1,2,3,4,10,10a-hexahydropyrimido[1,2-a]indol-2-ones. With perchloric acid these are converted to 1-carbamoylpropyl-3H-indolium perchlorates. The syntheses of 10a-(4-dimethylaminostyryl)- and 10a-[(4-dimethylaminophenyl)butadienyl]-3,10,10-trimethylpyrimido[1,2-a]indol-2-ones have been studied.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 5, pp. 625–627, May, 1990.     

A New Synthesis of 3-Vinylindoles

A new synthesis of substituted 3-vinylindoles from 3-[(1-hydroxy-2-substituted)ethylidene]indol-2(3H)-ones is reported.     

Acetylation of pyridazino[4, 5-b]indoles and their dihydro and tetrahydro derivatives. III

Acetylation of pyridazino[4,5-b]indol-4-ones with acetic anhydride gives the O-acetyl derivatives, and acetylation of 1,2-dihydropyridazino[4,5-b]indol-4-ones leads to the 2-acetyl and 2,4-diacetyl derivatives. Tetrahydropyridazino[4,5-b]indoles, obtained by reduction of the dihydro derivatives, undergo substitution by an acetyl group at the 2 position.See [1] for communication II.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 9, pp. 1218–1222, September, 1976.     

Synthesis and structures of benzo[<Emphasis Type="Italic">cd</Emphasis>]furo[2,3-<Emphasis Type="Italic">f</Emphasis>]indol-4(5<Emphasis Type="Italic">H</Emphasis>)-one derivatives

A procedure was developed for the synthesis of derivatives of the new heterocyclic system, benzo[cd]furo[2,3-f]indole, based on the cyclodehydration of 6-acylmethyloxy-1-alkyl-benzo[cd]indol-2(1H)-ones. Either 7- or 8-aryl derivatives of benzo[cd]furo[2,3-f]indol-4(5H)-ones can be prepared depending on the reaction conditions. The molecular and crystal structures of 7- and 8-phenylbenzo[cd]furo[2,3-f]indol-4(5H)-ones were established by X-ray diffraction.     

Ring opening reaction of furan with high regio- and diastereo-selectivity via controlled addition of isatin-derived diazoamides

Reaction of cyclic diazoamides with furan systems using rhodium(II) acetate as a catalyst afforded a variety of (3Z)-3-[(2E)-4-oxopent-2-en-1-ylidene]indol-2-ones in a regio- and diastereo-selective manner. The diastereoselectivity was based on the flow rate of cyclic diazoamides. The representative products were characterized by single-crystal X-ray analyses.     

Studies in spiroheterocycles,Part XV. Investigation of the reaction of 3-(2-oxocycloalkylidene)-indol-2-ones with thiourea and urea derivatives

The reaction of 3-(2-oxocycloalkylidene)indol-2-one 1 with thiourea and urea derivatives has been investigated. Reaction of 1 with thiourea and urea in ethanolic potassium hydroxide media leads to the formation of spiro-2-indolinones 2a-f in 40–50% yield and a novel tetracyclic ring system 4,5-cycloalkyl-1,3-diazepino-[4,5-b]indole-2-thione/one 3a-f in 30–35% yield. 3-(2-Oxocyclopentylidene)indol-2-one afforded 5′,6′-cyclopenta-2′-thioxo/ oxospiro[3H-indole-3,4′(3′H)pyrimidin]-2(1H)-ones 2a,b and 3-(2-oxocyclohexylidene)indol-2-one gave 2′,4′a,5′,6′,7′,8′- hexahydro-2′-thioxo/oxospiro[3H-indole-3,4′ (3′H)-quinazolin]-2(1H)-ones 2c-f . Under exactly similar conditions, reaction of 1 with fluorinated phenylthiourea/cyclohexylthiourea/phenylurea gave exclusively spiro products 2g-1 in 60–75% yield. The products have been characterized by elemental analyses, ir pmr. ¹⁹F nmr and mass spectral studies.     

Cu(I)/Pd(II)-Catalyzed Intramolecular Hydroamidation and C-H Dehydrogenative Coupling of ortho-Alkynyl-N-arylbenzamides for Access to Isoindolo[2,1-a]Indol-6-Ones

An efficient, atom-economic and one-pot synthesis of isoindolo[2,1-a]indol-6-ones via CuI/Pd(OAc)₂-catalyzed intramolecular hydroamidation of alkynyl group, and C-H dehydrogenative coupling of ortho-alkynyl-N-arylbenzamides has been developed. This transformation occurs with the use of oxygen as the oxidant, and water is the only by-product. The reaction shows a high tolerance to a variety of functional groups, and affords isoindolo[2,1-a]indol-6-ones in good to high yields.