Preparation of hydrogenated azepino[3,2,1-hi]indoles

A general method for the preparation of 4,5-dihydro-, 1,2,4,5-tetrahydro-, 4,5,6,7-tetrahydro- and 1,2,4,5,6,7-hexahydroazepino[3,2,1-hi]indoles was established by using intramolecular Friedel-Crafts alkylation of chloromethylthioacetamide as a crucial step.     

Synthesis of 2-(α-hydroxyalkyl)-1,3-heterocyclic alcohols and aryl carbamates

Several N-(substituted phenyl)carbamoyloxylalkyl-1,3-heterocycles of the structure 3 were prepared from their respective α-hydroxyalkyl-1,3-heterocyclic alcohols 1 . Efficient syntheses of the prerequisite novel 1,3-heterocyclic alcohols, such as 2-(α-hydroxyalkyl)-2-oxazolines, ?5,6-dihydro-1H-1,3-oxazines, ?1,4,5,6-tetra-hydropyrimidines, -imidazolines, and 4,5,6,7-tetrahydro-1H-1,3-diazepines were developed. Stannous octoate was found to effectively catalyze the formation of the carbamate 3 from heterocyclic alcohol 1 and aryl-isocyanate 2 .     

Electrochemical oxidation of 4,5,6,7-tetrahydro-1H-pyrazolo[3,4-d] pyrimidine-4,6-dione (oxipurinol) at the pyrolytic graphite electrode

The electrochemical oxidation of 4,5,6,7-tetrahydro-1H-pyrazolo[3,4-d] pyrimidine-4,6-dione (oxipurinol) at the pyrolytic graphite electrode (PGE) has been studied. Oxipurinol exhibits up to three voltammetric oxidation peaks at the PGE between pH 1–12. The first pH-dependent peak (peak I_a) is proposed to be an initial, irreversible 2e-2H⁺ reaction to give 5,6-dihydro-4H-pyrazolo[3,4-d] pyrimidine-4,6-dione. This primary product further reacts by two routes. The major route, accounting for ca. 90% of the latter compound, involves a Michael addition of water followed by further electrochemical oxidation and hydrolysis to give 5,6-dihydro-5,6-dihydroxy-5-carboxy-6-diazenouracil. The minor route involves further electrochemical oxidation of 5,6-dihydro-4H-pyrazolo[3,4-d]-pyrimidine-4,6-dione in a 2e-2H⁺ reaction to give 4,5,6,7-tetrahydro-3H-pyrazolo[3,4-d]-pyrimidine-3,4,6-trione.Decomposition and, generally, additional electrochemical reactions of 5,6-dihydro-5,6-dihydroxy-5-carboxy-6-diazenouracil result in the formation of alloxan, parabanic acid, 6-diazo-isobarbituric acid and 5′-hydroxy-5-carboxy-6,6′-azouracil. The two latter compounds have never previously been reported. Decomposition of 4,5,6,7-tetrahydro-3H-pyrazolo[3,4-d]pyrimidine-3,4,6-trione results in formation of uracil-5-carboxylic acid.Detailed reaction schemes have been proposed to explain the observed electrochemistry and the formation of the observed products.     

Preparation and some properties of 2H-imidazole 1,3-dioxides,derivatives of alicyclic 1,2-dioximes

The corresponding 2H-imidazole 1,3-dioxides were obtained by the reaction of cyclohexanedione and cycloheptadione 1,2-dioximes with acetone, cyclopentanone, and methyl ethyl ketone. The reactions of these compounds with hydroxylamine hydrochloride, NaBH₄, a Grignard reagent, and acetic anhydride in the presence of H₂SO₄ were studied in the case of 2,2-dimethyl-4,5,6,7-tetrahydro-2H-benzimidazole 1,3-dioxide. Bromination of the latter and 2,2-dimethylcyclohepta-2H-imidazole 1,3-dioxide with N-bromosuccinimide gave the corresponding dibromo derivatives, the bromine atoms in which are replaced by acetoxy and hydroxy groups. 4,7-Dihydroxy-2, 2-dimethyl-4,5,6,7-tetrahydro-2H-benzimidazole 1,3-dioxide, which was obtained by oxidation with MnO₂ was converted to a quinone, viz., 2,2-dimethyl-4,7-dioxo-4,7-dihydro-2H-benzimidazole 1,3-dioxide. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 6, pp. 808–813, June, 1980.     

Synthesis of 2-alkylidenepyrrolidines, pyrroles, and indoles by condensation of silyl enol ethers and 1,3-bis-silyl enol ethers with 1-azido-2,2-dimethoxyethane and subsequent reductive cyclization

The condensation of 1,3-bis-silyl enol ethers with 1-azido-2,2-dimethoxyethane and subsequent reductive cyclization allowed an efficient regio- and diastereoselective synthesis of a variety of 2-alkylidene-4-methoxypyrrolidines. The thermal elimination of methanol resulted in the formation of functionalized pyrroles. Similarly, 2,3,3a,4,5,6-hexahydro-2,3-benzopyrroles were prepared and transformed into 4,5,6,7-tetrahydro-2,3-benzopyrroles. In contrast, treatment of 2-alkylidenepyrrolidines with trifluoroacetic acid resulted in formation of indoles by [4 + 2] cycloaddition and subsequent extrusion of a nitrogen atom.     

Reaction of 2,3-Dihydro-1,5-benzothiazepines and Phenylacetyl Chloride in the Presence of Triethylamine： A New Aspect on the Formation Mechanism of Dihydro-1,3-oxazin-4-one Derivatives

2a,4-Disubstituted 2,2a,3,4-tetrahydro-2-phenyl-1H-azeto[2,1-d][ 1,5]benzothiazepin-1-ones, as well as 2-substi-tuted 2,3-dihydro-3-phenylacetyl-2-styryl-benzothiazoles and 4a,6-disubstituted 3- .benzyl-4a,5-d/hydro-2-phenyl-1H,6H-[1,3]oxazino[2,3-d][1,5]benzothiazepin-1-ones, were obtained from the reaction of 2,4-disubstituted 2,3-dihydro-1,5-benzothiazepines with phenylacetyl chloride in the presence of triethylamine. The mechanism for the formation of 4a,5-dihydro-1H,6H-[1,3]oxazino[2,3-d][1,5]benzothiazepin-1-ones, 2,3-dihydro-1,3-oxazin-4-one derivatives, was suggested.     

The synthesis of novel heteroaryl-fused 7,8,9,10-tetrahydro-6H-azepino[1,2-a]indoles, 4-oxo-2,3-dihydro-1H-[1,4]diazepino[1,7-a]indoles and 1,2,4,5-tetrahydro-[1,4]oxazepino[4,5-a]indoles. Effective inhibitors of HCV NS5B polymerase

Three synthetic approaches have been developed that allow efficient access to novel heteroaryl fused indole ring systems, including: 7,8,9,10-tetrahydro-6H-azepino[1,2-a]indoles, 4-oxo-2,3-dihydro-1H-[1,4]diazepino[1,7-a]indoles and 1,2,4,5-tetrahydro-[1,4]oxazepino[4,5-a]indoles. Each strategy is fully exemplified and the relative merits and limitations of the approaches are discussed. The hepatitis C virus (HCV) non-structural 5B (NS5B) polymerase inhibitory activities of select examples from each molecular class are briefly presented.     

Selenium-Containing Heterocycles. Synthesis and Reactions of 2-Amino-4,5,6,7-tetrahydro-1-benzoselenophene-3-carbonitrile with Anticipated Biological Activity

Reaction of 2-amino-4,5,6,7-tetrahydro-1-benzoselenophene-3-carbonitrile with ethylenediamine in the presence of a catalytic amount of carbon disulfide afforded 2-amino-3-(4,5-dihydro-1H-imidazol-2-yl)-4,5,6,7-tetrahydro-1-benzoselenophene. Cyclocondensation of the latter with triethyl orthoformate, benzaldehyde, and carbon disulfide gave tetracyclic imidazobenzoselenophenopyrimidine derivatives. Treatment of 2,3,5,6,8,9,10,11-octahydroimidazo[2,1-c][1]benzoselenopheno[3,2-e]pyrimidine-5-thione with hydrazine hydrate led to the corresponding 5-hydrazino derivative whose reactions with triethyl orthoformate and sodium nitrite were accompanied by closure of 1,2,4-triazole and tetrazole rings, respectively. Fused benzoseleno-phenopyrimidine systems were also obtained by reaction of 2-amino-4,5,6,7-tetrahydrobenzo-1-selenophene-3-carbonitrile with formamide, carbon disulfide, and phenyl isothiocyanate. Some newly synthesized compounds were tested for antimicrobial and antifungal activity.__________From Zhurnal Organicheskoi Khimii, Vol. 41, No. 3, 2005, pp. 406–410.Original English Text Copyright © 2005 by Abdel-Hafez.The original article was submitted in English.This study was presented at the 7th IUPAC International Conference on Heteroatom Chemistry (ICHAC-7), Shanghai, August 20–25, 2004.     

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.     

Quinazolines and 1,4-benzodiazepines. XLVI. Photochemistry of nitrones and oxaziridines

The cyclic nitrones 7-chloro-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one 4-oxide ( 5a ) and 1,3-dihydro-7-methylthio-5-phenyl-2H-1,4-benzodiazepin-2-one 4-oxide ( 5b ) are photoisomerized to readily isolable oxaziridines, 7-chloro-4,5-epoxy-5-phenyl-1,3,4–5-tetrahydro-2H-1,4-benzodiazepin-2-one ( 6a ) and 4,5-epoxy-5-phenyl-1,3,4,5-tetrahydro-7-methylthio-2H-1,4-benzo-diazepin-2-one ( 6b ). Oxaziridine 6b upon further irradiation gave ring expansion and ring contraction products, 4,6-dihydro-2-phenyl-9-methylthio-5H-1,3,6-benzoxadiazocin-5-one ( 7b ) and 4-benzoyl-3,4-dihydro-6-methylthioquinoxalin-2(1H)-one ( 8b ) respectively. The ring contraction product, 4-benzoyl-6-chloro-3,4-dihydroquinoxalin-2(1H)-one ( 8a ), was obtained from irradiation of oxaziridine 6a .     

Cycloaddition of benzoheteroazepine II Reactions and conformations of cycloadducts on1,5-benzothiazepines and 1,5-benzodiazepines with nitrile imine and nitrile oxides

Benzodiazepine and benzothiazepine derivatives have been well known as therapeutically important compounds. Four new tricyclic heterocyclic compounds, 3a,4,5,11-tetrahydro-3H-1,2,4-triazolo[4,3-d] [1, 5]benzothiazepines (3), 3a,4,5,11-tetrahydro-3H,6H-1,2,4-triazolo[4,3-d][1,5]benzodiazepine (4), 3a, 4,5,11-tetrahydro-1,2,4-oxadiazolo[4,5-d] [1,5]benzothiazepines (5, 6) and 3a,4,5,11-tetrahydro-6H-1, 2,4-oxadiazolo[4, 5-d] [ 1, 5 ] benzodiazepines (7,8), have been synthesized by 1,3-dipolar cycloaddition reactions of 2, 3-dihydro-1, 5-benzothiazepines and 2, 3-dihydro-1H-1, 5-benzodiazepine with benzonitrile N-phenylimine and benzonitrile oxides, respectively. The conformations of some cycloadducts and cycloaddition mechanism are described.     

Synthesis of alkyl thioethers of pyrazolo[3,4-<Emphasis Type="Italic">d</Emphasis>]pyrimidine

Reaction of 4-imino-1-methyl-5-phenyl-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-d]pyrimidine-6-thione with unsaturated alkyl halides gives 4-imino-6-methallylthio(cinnamylthio, allylthio)-1-methyl-5-phenyl-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidines.     

Microwave-assisted three-component synthesis of 7-aryl-2-alkylthio-4,7-dihydro-1,2,4-triazolo[1,5-a]-pyrimidine-6-carboxamides and their selective reduction

Multicomponent reactions (MCRs) and microwave-assisted organic synthesis (MAOS) have been used as key methods for the synthesis of fused dihydropyrimidine derivatives. The three-component condensation of 3-amino-5-alkylthio-1,2,4-triazoles with aromatic aldehydes and acetoacetamides under microwave irradiation was developed as a rapid and efficient solution-phase method for the high-yielding preparation of 7-aryl-2-alkylthio-4,7-dihydro-1,2,4-triazolo[1,5-a]pyrimidine-6-carboxamide libraries. In addition, the selective reduction of the formed dihydrotriazolopyrimidines to trans-trans-2-alkylthio-7-aryl-4,5,6,7-tetrahydro-1,2,4-triazolo[1,5-a]pyrimidine-6-carboxamides was established. The described synthetic protocols provide rapid access to novel and diversely substituted dihydroazolopyrimidine libraries.     

Synthesis and Biological Activity of 4,5,6,7-Tetrahydro-2H-indazole Derivatives

Russian Journal of General Chemistry - Novel 4,5,6,7-tetrahydro-2H-indazole derivatives were obtained via the reaction of N1,N3,2-triaryl-6-hydroxy-6-methyl-4-oxocyclohexane-1,3-dicarboxamides with...     

Quinazolines and 1,4-benzodiazepines XXXVI . The formation of 1,3-dihydro and 1,5-dihydro-1,4-benzodiazepines from tosyl and Mesyl - substituted 1,3,4,5-tetrahydro-5-phenyl- 1,4-benzodiazepine derivatives

The treatment of 4-sulfonyl derivatives of 5-phenyl-1,3,4,5-tetrahydro-1,4-benzodiazepin-2-ones (I) with base was shown to result in the formation of 1,3-dihydro or 1,5-dihydro-1,4-benzodiazepin-2-ones (III and II respectively) depending upon the conditions used. The base treatment of 1-sulfonyl substituted 2,3-dihydro-1,4-benzodiazepines (V) was shown to give the vinylimines VI.     

Synthesis of 5-hydroxy-2,3,4,5-tetrahydro-[1H]-2-benzazepin-4-ones: selective antagonists of muscarinic (M3) receptors

Two approaches to tetrahydro-[1H]-2-benzazepin-4-ones of interest as potentially selective, muscarinic (M(3)) receptor antagonists have been developed. Base promoted addition of 2-(tert-butoxycarbonylamino)methyl-1,3-dithiane with 2-(tert-butyldimethylsiloxymethyl)benzyl chloride gave the corresponding 2,2-dialkylated 1,3-dithiane which was taken through to the dithiane derivative of the parent 2,3,4,5-tetrahydro-[1H]-2-benzazepin-4-one by desilylation, oxidation and cyclisation via a reductive amination. After conversion into the N-tert-butyloxycarbonyl, N-toluene p-sulfonyl and N-benzyl derivatives , hydrolysis of the dithiane gave the N-protected tetrahydro-[1H]-2-benzazepin-4-ones . However, preliminary attempts to convert these into 5-cycloalkyl-5-hydroxy derivatives were not successful. In the second approach, ring-closing metathesis was used to prepare 2,3-dihydro-[1H]-2-benzazepines which were hydroxylated and oxidized to give the required 5-hydroxy-2,3,4,5-tetrahydro-[1H]-2-benzazepin-4-ones. Following preliminary studies, ring-closing metathesis of the dienyl N-(2-nitrophenyl)sulfonamide gave the dihydrobenzazepine which was converted into the 2-butyl-5-cyclobutyl-5-hydroxytetrahydrobenzazepin-4-one by hydroxylation and N-deprotection followed by N-alkylation via reductive amination, and oxidation. This chemistry was then used to prepare the 2-[(N-arylmethyl)aminoalkyl analogues , , and . N-Acylation followed by amide reduction using the borane-tetrahydrofuran complex was also used to achieve N-alkylation of dihydrobenzazepines and this approach was used to prepare the 5-cyclopentyl-5-hydroxy-2,3,4,5-tetrahydro-[1H]-2-benzazepin-4-one and the 5-cyclobutyl-8-fluoro-5-hydroxy-2,3,4,5-tetrahydro-[1H]-2-benzazepin-4-one . The structures of 2-tert-butyloxycarbonyl-4,4-propylenedithio-2,3,4,5-tetrahydro-[1H]-2-benzazepine and (4RS,5SR)-2-butyl-5-cyclobutyl-4,5-dihydroxy-2,3,4,5-tetrahydro-[1H]-2-benzazepine were confirmed by X-ray diffraction. The racemic 5-cycloalkyl-5-hydroxy-2,3,4,5-tetrahydro-[1H]-2-benzazepin-4-ones were screened for muscarinic receptor antagonism. For M(3) receptors from guinea pig ileum, these compounds had log(10)K(B) values of up to 7.2 with selectivities over M(2) receptors from guinea pig left atria of approximately 40.     

Reaction of acetylenedicarboxylic acids esters with 4,5-dihydro-1<Emphasis Type="Italic">H</Emphasis>-pyrazole-1-carbothioamides and 3,4,5,6-tetrahydro-2<Emphasis Type="Italic">H</Emphasis>-1,2,4-triazepine-3-thiones

The reactions of dimethyl acetylenecarboxylate with 3,4,5,6-tetrahydro-2H-1,2,4-triazepine-3-thiones and 4,5-dihydro-1H-pyrazole-1-carbothioamides are convenient methods for the synthesis of 7,8-dihydrothiazolo[3,2-b][1,2,4]triazepin-3-ones derivatives and methyl esters of (2Z)-[2-(4,5-dihydro-1H-pyrazol-1-yl)-4-oxo-1,3-thiazol-5(4H)-ylidene]acetic acids, respectively. The reaction of methyl propynoates with 4,5-dihydro-1H-pyrazole-1-carbothioamides or with 5,5,7-trimethyl-2,4,5,6-tetrahydro-3H-1,2,4-triazepine-3-thione gives 2-(4,5-dihydro-1H-pyrazol-1-yl)-4H-1,3-thiazin-4-ones.     

Fluoroalkyl-substituted lithium 1,3-diketonates in reactions with hetarylhydrazines

Fluoroalkyl-substituted lithium 1,3-diketonates reacted with 4-hydrazinyl-6-methylpyrimidin-2-amine, 2,6-dimethylpyrimidin-4-ylhydrazine, 7-fluoroquinoxalin-6-ylhydrazine, and benzothiazol-2-ylhydrazine to give the corresponding hetaryl-substituted pyrazoles. The molecular and crystal structures of 4-methyl-6-(3-methyl-5-trifluoromethyl-1H-pyrazol-1-yl)pyrimidin-2-amine and 4-(5-difluoromethyl-4,5,6,7-tetrahydro-2H-indazol-2-yl)-6-methylpyrimidin-2-amine were determined by X-ray analysis.     

Chemistry of iminofurans: X. Synthesis and hydrolysis of 5-aryl(hetaryl)-2-[(4,5,6,7-tetrahydro-1-benzothiophen-2-yl)imino]furan-3(2<Emphasis Type="Italic">H</Emphasis>)-ones

5-Aryl(hetaryl)furan-2,3-diones reacted with N-(triphenyl-λ⁵-phosphanylidene)-4,5,6,7-tetrahydro-1-benzothiophen-2-amines to give 5-aryl(hetaryl)-2-[(4,5,6,7-tetrahydro-1-benzothiophen-2-yl)imino]furan-3(2H)-ones whose acid hydrolysis afforded 4-aryl(hetaryl)-2-hydroxy-4-oxo-N-(4,5,6,7-tetrahydro-1-benzothiophen- 2-yl)but-2-enamides.     

A Convenient One Step Synthesis of 1,3-Diaryl-6-methyl-4-oxo-1,2,3,4-tetrahydro-2-thioxofuro [2,3-d] Pyrimidines

1,3-Diaryl-6-methyl-4-oxo-1,2,3,4-tetrahydro-2-thioxofuro (2,3-d) pyrimidines have been synthesised in one step in good yield by the reaction of 1,3-diaryl-1,3-dihydro-2-thioxo-2H,5H-pyrimidine-4,6-diones with chloroacetone in presence of triethylamine.