Synthesis of 5-amino-2,3-dihydro-1H-1,4-benzodiazepines

A number of 5-amino-2,3-dihydro-lH-1,4-benzodiazepines (II) have been prepared from the reaction of 5-methylmercapto-2,3-dihydro-1H-1,4-benzodiazepine (I) with amines. Another alternate approach based on the cyclodehydration of the ureic compounds (IV) was unsuccessful. The synthesis of I was accomplished by methylation of the 1,2,3,4-tetrahydro-5H-5-thioxo-1,4-benzodiazepine (VI) with dimethyl sulfate in methanol-dioxane. Another attempted method for the synthesis of I is also presented. J. Heterocyclic Chem., 14, 985 (1977)     

Nuclear magnetic resonance spectra of psychotherapeutic agents. V*—conformational analysis of 1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-2-ones

The conformational analysis of biologically active lofendazam (7-chloro-5-phenyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-2-one) is carried out by means of lanthanide shift reagent assisted ¹H NMR spectroscopy: the lanthanide induced shift computer simulation suggests that in deuteriochloroform the heterocyclic ring of lofendazam assumes a cycloheptene-like chair conformation, where 1-N moves away from trigonal stereochemistry to a very flattened pyramidal structure. At room temperature the conformational equilibrium is markedly shifted (85%) towards the conformer showing pseudoaxial H-1 and 5-Ph. The remarkable influence of steric requirements in controlling conformation, and the importance of 3- and/or 4-methyl groups in hindering the ring inversion at room temperature, have been verified by conformational analysis of suitable analogous 1,3,4,5-tetraydro-2H-1,5-benzodiazepin-2-ones.     

Nuclear magnetic resonance of 1,4-benzodiazepines. II Stereochemistry of 1,3-dihydro-2H-1,4-benzodiazepin-2-ones by lanthanide shift reagents

The sterochemistry of some 1,3-dihydro-2H-1,4-benxodiazepin-2-ones, employed as psychotherapeutic agents, is deduced by proton magnetic resonance using the paramagnetic shift reagent Eu(fod)₃. the lanthanide induced shifts are computer simulated on the basis of the geometric parameters of the protons in different model structures, having intermediate conformations between a cycloheptadiene- and a cyclohepatatriene-like system. N-Desmethyldiazepam shows a conformational equilibrium between two pseudoboat forms, while the 1-alkyl substituted derivatives exist, at room temperature, in olny one boat cycloheptatriene-like conformation.     

Quinazolines and 1,4-benzodiazepines LVII. 1H-1,4-benzodiazepines

The preparation of the title compounds 3 and 4 using two different methods of synthesis is described. These compounds are readily reduced to 2,3-dihydro-1H-derivatives 5 . Oxidation of 2-alkylthio-1H-1,4-benzodiazepines leads to the corresponding sulfoxides and sulfones. The oxidative rearrangement of sulfones 9 to a 2H-1,4-benzodiazepin-2-one derivative 10 is also given. The “normal” addition of azodicarboxylate together with an unusual addition of two moles of acetylenedicarboxylate to the enamine double bond of 1H compounds is discussed.     

Chemical properties of 2,2,4-trisubstituted 2,3-dihydro-1H-1,5-benzodiazepines

Acetylation and nitrosation of 2,4-diaryl-2-methyl-2,3-dihydro-1H-1,5-benzodiazepines take place at the azomethyne nitrogen. Reduction is stereoselective.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 8, pp. 1122–1126, August, 1987     

Synthesis and properties of 2,2,4-trisubstituted 2,3-dihydro-1H-1,5-benzodiazepines

General conditions for the condensation of acetylarenes with o-phenylenediamine hydrochloride, leading to the formation of 2,4-diaryl-2-methyl-2,3-dihydro-1H-1,5-benzodiazepines, have been worked out. It has been shown that this reaction is an equilibrium one, that the equilibrium is extremely sensitive to the amount of water in the reaction medium, and that the process takes place with the formation of bisazomethines as intermediates. The UV, IR, and PMR spectra and the dipole moments of the heterocyclic compounds obtained are discussed.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 1, pp. 126–131, January, 1984.     

Mass spectra of 1H-2,3-dihydro-1,4-benzodiazepine-2-thiones

The mass-spectrometric fragmentation of 1H-2,3-dihydro-1,4-benzodiazepine-2-thiones differs substantially from the fragmentation of the corresponding oxo derivatives with respect to the presence of [M - HCN]⁺ and [M - SH]⁺ ions. This is due to the tautomeric transformation of the molecular ions of the thiones to enethiol and eniminothiol tautomeric forms. The approximate percentages of each of the tautomeric forms were estimated.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 10, pp. 1412–1417, October, 1976.     

Nuclear magnetic resonance spectra of psychotherapeutic agents. III.. Stereochemistry of 1-methyl-5-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-2,4-diones

The stereochemistry of some 1-methyl-5-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-2,4-diones was determined by proton magnetic resonance using the paramagnetic shift reagent tris(6,6,7,7,8,8,8-heptafluoro-2,2-dimethyl-3,5-octanedionato)europium [Eu(fod)₃] two of these compounds, clobazam and triflubazam, are clinically used as psychotherapeutic agents. Several model structures, with intermediate stereochemistry in the range of the possible limit situations of benzocycloheptene, -cycloheptadiene or -cycloheptatriene type, are considered; LIS (3) are computer simulated on the basis of proton geometric parameters. It was found that at room temperature, these derivatives exist in only one pseudo-boat cycloheptadiene-like conformation, showing the 5-phenyl group directed pseudo-axially. This conformational preference is interpreted in terms of a balance between the steric requirements of the bulky substituent and electronic repulsion in the ring π-system.     

Synthesis of 2,4-disubstituted 2,3-dihydro-1H-1,5-benzodiazepines of the 1,3-indanedione series

2,4-Disubstituted 2,3-dihydro-1H-1,5-benzodiazepines were synthesized by reacting o-phenylenediamine with ,-unsaturated ketones of the indanedione series.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 3, pp. 379–381, March, 1989.     

Synthesis of 4-acyl-2,3-dihydro-4H-1,4-oxazines

The synthesis of 4-acyl-2,3-dihydro-4H-1,4-oxazines ( 6a-h ) via acid dehydration of 4-acyl 2- and 3-morpholinols is described. During dehydration of 2-morpholinols 3d,e , N-alkylisoquinolones 7a-e were also isolated.     

Mass spectra of 3-arylidene-1H-2,3-dihydro-1,4-benzodiazepin-2-ones

The scheme of the fragmentation of arylidene derivatives of 5-phenyl-1,4-benzodiazepin-2-ones was established by means of high-resolution mass spectrometry. One of the principal fragmentation pathways of these compounds is cleavage of the 2C-3C and 4N-5C bonds to give two fragments. Depending on the substituents in the arylidene portion of the molecule, the charge is localized primarily on one or the other of these fragments. The mechanism of the formation of the [ArCH₂]⁺ ions observed in the mass spectra of all of the investigated compounds was established on the basis of the mass spectrum of the 1N-deuterium-labeled compound. The specific fragmentation pathways due to the ortho effect of the nitro group are discussed.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 12, pp. 1690–1696, December, 1976.     

Nuclear magnetic resonance studies of internal rotation: IV—rotational barriers and conformation of phthalic amides

The rotational barriers about the C? N bond of the N,N,N′,N′-tetramethyldiamides of phthalic, isophthalic and terephthalic acids have been determined by the iterative total line shape NMR method. Some evidence about the conformation of these compounds in solution has also been obtained by infrared and dipole moment studies.     

Synthesis of 2-amino-3-hydroxy- and of 2,3-diamino-3H-1,4-benzodiazepines

A new synthesis of 7-chloro-2,3-diamino-5-phenyl-3H-1,4-benzodiazepines is described, which allows for the preparation of compounds bearing the same or different substituents at the 2 and 3 positions, starting from 2-amino-7-chloro-3-hydroxy-5-phenyl-3H-1,4-benzodiazepines.     

Synthesis of 2-(2-imidazolinyl) substituted 2,3-dihydro-4H-1,4-benzothiazine and 3,4-dihydro-2H-1,4-benzoxazines

An investigation into the synthesis of benzoxazine, benzoxathiane and benzothiazine derivatives of 2-(2-imidazolinyl)-1,4-benzodioxane has been carried out.     

Lewis Acid-Mediated Ring Contraction of 2,4-Diaryl-2,3-dihydro-1H-1,5-benzodiazepines: Access to 2-Aryl-1-styrylbenzimidazoles

2,4-Diaryl-2,3-dihydro-1H-1,5-benzodiazepines readily undergo a ring contraction to generate 2-aryl-1-styrylbenzimidazoles in the presence of some Lewis acids. Copper acetate shows high efficiency compared with other Lewis acids. The ring contraction includes Lewis acid-catalyzed intramolecular addition, ammonium-induced ring-opening of the generated four-membered azetidine ring, deprotonation, and amine-promoted nucleophilic styryl 1,2-shift and elimination. Copper acetate serves as Lewis acid, base, and oxidant. The current reaction provides an efficient method for the convenient synthesis of 2-aryl-1-styrylbenzimidazole derivatives from readily available 2,4-diaryl-2,3-dihydro-1H-1,5-benzodiazepines.     

Electrooxidation of 2,3-dihydro-1H-1,3,2-diazaphospholes

Electrooxidation of 2-R-1,3-dibutyl-4,5-dimethyl-2,3-dihydro-1H-1,3,2-diazaphospholes with tri- and tetracoordinated phosphorus atoms were studied. Reversible one-electron oxidation gives radical cations at potentials of −0.37 to +0.36 V. Magnetic parameters of the radical cations were measured. Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 8, pp. 1522–1524, August, 1998.     

Spectral properties and ring conformation of some novel 2,3-dihydro-1H-1,4-diazepinium cations

A series of 2,3-dihydro-1H-1,4-diazepinium salts, which includes fused ring systems of known ring-junction configuration, has been prepared. A study of the spectral properties indicates that this ring system is largely planar and is sufficiently flexible to permit cis and trans fusion at the 2,3-bond to 5- or 6-membered rings without significant distortion.