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 .     

Nuclear magnetic resonance of psychotherapeutic agents. IV—conformational analysis of 2,3-dihydro-1H-1,4-benzodiazepines

The lanthanide shift reagent (LSR)/¹H NMR study of some 7-chloro-5-phenyl-2,3-dihydro-1 H-1, 4-benzodiazepines shows that these compounds exist in CDCI₃ solution as two pseudo-boat conformers, rapidly interconverting at room temperature. Computer simulated lanthanide induced shifts (LIS) are consistent with LSR complexation by the imine nitrogen atom. The lanthanide shifts the conformational equilibrium towards conformer (a), with a pseudoequatorial 1-substituent: this effect may be the result of the greater basicity of 4-N when the 1-N lone pair is pseudoaxially directed, thus permitting an extended electron delocalization from 1- to 4-N through the fused benzene ring. The detection of H-9/1-Me through space spin-spin coupling in medazepam (7-chloro-1-methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepine) supports the observed higher availability of conformer (a) to LSR. A LIS computer calculation to predict the population ratio results in reasonable agreement with the conformational changes based on the response of ³J(HH) to lanthanide addition. The electronic and steric effects which determine the greater stability of conformer (a) may be effective in the drug-receptor interaction.     

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.     

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.     

Variable temperature n.m.r. behaviour of 1,5-benzodiazepinones and 1,5-benzodiazepinthiones

The n.m.r. variable temperature behaviour of the 7-membered ring in 1,3-dihydro-2H-1,5-benzodiazepin-2-one derivatives and in the corresponding 2-thiones has been investigated. The results indicate that the ring inversion barrier is higher in the thiones and dependent on substituents bonded at N-1. The activation parameters are obtained and discussed.     

Conformation of 7-chloro-5-phenyl-d5 −3(S)-methyl-dihydro-1,4-benzodiazepin-2-one in solution

7-Chloro-5-phenyl-d₅-3(S)-methyldihydro-1,4-benzodiazepin-2-one ( 1a ) was synthesized and its conformation in solution determined using a computer assisted LIS-NMR method. It was found, with Fr(fod)-d₂₇ as a shift reagent, that a lanthanide coordinates to a carbonyl oxygen at a 2.02 Å distance (bond angle 158.07°, torsional angle 39.53°), while the substrate 1a adopts an expected quasi-boat conformation with a C(3)-methyl group exposed in a quasi-equatorial position.     

On the reaction of 3-nitro-1,2-phenylenediamine with ethyl acetoacetate. Condensed dihydrodiazepinones

Condensation of 3-nitro-1,2-phenylenediamine with ethyl acetoacetate in boiling xylene gave two isomeric 2,3-dihydro-4-methyl-9-nitro- and 2,5-dihydro-4-methyl-6-nitro-1H-1,5-benzodiazepin-2-ones, the 9-nitro derivative thermal rearrangement product N-isopropenyl-4-nitrobenzimidazolone and a non cyclic acetoacetamide derivative. At room temperature these reactants afforded 2,3-dihydro-2-ethoxycarbonyl-methyl-2-methyl-4-nitrobenzimidazole.     

Heterocyclic variants of the 1,5-benzodiazepine system. VI. Derivatives of 2-methylthio-4-(p-r-phenyl)-3H-1,5-benzodiazepines

Ethyl 3-[3H-1,5-benzodiazepin-2-yl]carbazates II were prepared in moderate yields from the title compounds and ethyl carbazate. The compounds II were easily transformed into 1H-s-triazolo[4,3-a][1,5]benzodiazepin-1-ones III via a one-step procedure. Reaction of triazolo-1,5-benzodiazepinones III with sodium hydride in methyl iodide gave a mixture of products from which were isolated two compounds IV and V . The structure of all products was confirmed by ir, ¹H nmr and mass spectrometry.     

An anomalous reaction of 7-chloro-2-hydrazono-5-phenyl-1,2-dihydro-3H-1,4-benzodiazepine with sodium acetate and 1,1′-carbonyldiimidazole

The addition of 7-chloro-2-hydrazono-5-phenyl-1,2-dihydro-3H-1,4-benzodiazepine 3 to a mixture of sodium acetate and 1,1′-carbonyldiimidazole 1 at room temperature gave, in moderate yields, carbonyl-1,1′-bis[7-chloro-5-phenyl-1,2-dihydro-3H-1,4-benzodiazepin-2-ylidene hydrazone] 7 instead of the expected 2-acetylhydrazono-7-chloro-5-phenyl-1,2-dihydro-3H-1,4-benzodiazepine 4 .     

Azines and azoles: CXXVI. First example of a novel heterocyclic system: Pyrimido[1,6-<Emphasis Type="Italic">a</Emphasis>][1,5]benzodiazepines

4-Hydroxy-5-(2-R-2,3-dihydro-1H-1,5-benzodiazepin-4-yl)-2H-1,3-thiazine-2,6-diones readily undergo acylation at the N¹ atom of the benzodiazepine system by the action of acetic anhydride. Heating of the acetylated products in boiling dimethylformamide leads to the formation of 75–93% of the corresponding 7-acetyl-6-R-6,7-dihydropyrimido[1,6-a][1,5]benzodiazepine-1,3-diones that are derivatives of hitherto unknown fused heterocyclic system, pyrimido[1,6-a][1,5]benzodiazepine. 4-Hydroxy-5-(2-R-2,3-dihydro-1H-1,5-benzodiazepin-4-yl)-2H-1,3-thiazine-2,6-diones are converted into 1-(2-aminophenyl)-6-(2-R-vinyl)uracils on heating in boiling DMF.     

Ring transformation of 4-amino and 4-N-(substituted)amino-1H-1,5-benzodiazepine-3-carbonitriles with hydroxylamine. A new synthesis of benzimidazolidine and isoxazole derivatives

The reaction of 4-amino-1H-1,5-benzodiazepine-3-carbonitrile 1 with hydroxylamine provided the ring-opened hydroxylamine adduct 2 which was converted to 2-benzimidazolidinylidene-3-hydroxyiminopropio-nitrile 4 in hydrochloric acid. The reaction of 4-ethoxycarbonylamino-1H-1,5-benzodiazepine-3-carbonitrile 6a or N-(3-cyano-1H,5-benzodiazepin-4-yl)-N′-ethylurea 6b with hydroxylamine afforded 5-(o-aminoanilino)-4-cyanoisoxazole 3 which underwent a facile rearrangement into 4 with a base.     

5,6,7,8-Tetrafluoro-4-hydroxycoumarin derivatives in reactions with o-phenylenediamine

The reactions of 5,6,7,8-tetrafluoro-4-hydroxycoumarin derivatives with o-phenylenediamine occur with pyrone heterocycle cleavage and formation of substituted benzodiazepin-2-ones. 5,6,7,8-Tetrafluoro-4-hydroxycoumarin affords 4-(3,4,5,6-tetrafluoro-2-hydroxyphenyl)-2,3-dihydro-1H-1,5-benzodiazepin-2-one, 3-acetimidoyl-5,6,7,8-tetrafluoro-4-hydroxycoumarin produces 3-(3,4,5,6-tetrafluoro-2-hydroxybenzoyl)-4-methyl-1,2-dihydro-1H-1,5-benzodiazepin-2-one, and 3-acetyl-5,6,7,8-tetrafluoro-4-hydroxycoumarin yields both these heterocycles.     

1H n.m.r. spectra of some bicyclic compounds: I—relative configurations of the diastereomeric endo-α-methyl-5-norbornene-2-methanols,the corresponding saturated analogues,and their cyclization ether products

The configurational and conformational relationship at C-2 and C-α in the two racemic diastereomeric endo-α-methyl-5-norbornene-2-methanols and the corresponding saturated endo-α-methyl-2-norbornanemethanols were determined by first-order analysis of the ¹H n.m.r. spectra of these compounds and of their cyclization ether products, i.e. 3-methyl-2-oxatricyclo[4.2.1.0^4,8]nonanes and 5-methyl-4-oxatricyclo[4.3.0.0^3,8]nonanes. In addition, the conformational preference of the hydroxyl group in the unsaturated and saturated alcohols was confirmed by the lanthanide induced shift technique, using Eu(fod)₃ as shift reagent, combined with a computer program involving various conformations of the –CHOHMe group.     

Conformational analysis of 2,2-dimethyl-5-alkyl-1,3-dioxa-2-silacyclohexanes

Study of conformational isomerization of 2,2-dimethyl-5-alkyl-1,3-dioxa-2-silacyclohexanes using quantum-chemical HF/6-31G(d) and PBE/3z approximations showed that its route involves an equilibrium between the chair conformers with different orientation of substituent at C⁵ ring atom and proceeds through a transition state corresponding to the 2,5-twist conformation. Molecular dynamics method showed that at room temperature this conformation transforms into the equatorial or axial chair conformers through 1,4-twist or sofa forms. Based on the experimental and theoretical values of vicinal ¹H NMR coupling constants we determined quantitative conformational composition of the molecules of these compounds and the values of ??G ⁰ of the conformational equilibrium.     

The Solution Conformation of Lactal and ITS Hexa-O-Acetyl Derivative

Abstract

The conformation of lactal (1) in D₂O and DMSO-d₆ has been investigated by employing NMR techniques and molecular mechanics calculations. The glucal ring shows a ⁴ H₅ conformation in deuterium oxide and DMSO-d₆. In contrast, the glucal ring of the hexa-O-acetyl derivative (2) in CDCl₃ can be described as an equilibrium between the ⁴ H₅ and ⁴ H₅ forms. The disaccharide 1 has a restricted flexibility with the Φ angle oscillating about -105 ± 30° and the Ψ angle varying about -145 ± 30°. Compound 2 shows a similar conformational behaviour.     

Chiral 1, 4-Benzodiazepin-2-one,template for enantioselective synthesis of α-amino acids and their α-deuterio congeners. Preliminary communication

Absolute conformation of 7-chloro-5-phenyl-1-[(S)-α-phenylethyl]-1, 3-dihydro-2H-1, 4-benzodiazepin-2-one ( 1c ) in crystal, and its inversion rate in solution were determined, enabling prognosis of direction of asymmetric induction during C(3)-alkylation.     

Synthesis and stereochemistry of 2-benzylidene-4-carbethoxy-5-methyl-3-(2H)-furanones

The title products were obtained by Knoevenagel condensation between 4-carbethoxy-5-methyl-3-(2H)furanone and substituted benzaldehydes (or 4-chloroacetophenone). The configuration of the resulting compounds was investigated by ¹H nmr using the lanthanide shift reagent.     

Quantum chemical estimation of reactivity of 2,3,4,5-tetrahydro-1,5-benzodiazepin-2(1H)-ones in electrophilic aromatic substitution

DFT B3LYP calculation study was employed to estimate the regioselectivity of an electrophilic aromatic substitution in functionalized 2,3,4,5-tetrahydro-1,5-benzodiazepin-2(1H)-ones. Charge density, frontier molecular orbital study, energetics of σ-complex intermediates of electrophilic substitution reactions in the 2,3,4,5-tetrahydro-1,5-benzodiazepin-2(1H)-ones yield information on different reactivity of aromatic sites. © 2004 Wiley Periodicals, Inc. Heteroatom Chem 15:263–270, 2004; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/hc.20015     

Functionalization of 2,3,4,5-Tetrahydro-1,5-benzodiazepin-2(1 H)-ones by Electrophilic Aromatic Substitution

Highly substituted, novel, 8- and 9-nitro-2,3,4,5-tetrahydro-1,5-benzodiazepin-2(1H)-ones were obtained by direct nitration of the 7-bromo-5-trifluoroacetyl (or formyl)-substituted tetrahydrobenzodiazepinones. Alkaline and acidic hydrolysis of the novel mononitro derivatives was examined. Semiempirical AM1 calculations of aromatic substituents orientation in the nitration products are presented.     

NMR of some benzodiazepine drugs: Structure elucidation with lanthanide-induced shifts of N-1 substituted benzodiazepinones

Two 1,4-benzodiazepinones of psychopharmacological interest, pinazepam (2) and prazepam (3), were studied in solution by ¹³C and ¹H NMR. ¹H variable-temperature experiments showed that the seven-membered ring exists in a simple pseudo-boat form at room temperature, but the energy barrier is higher in 3 (ΔG_405°c = 82.8 kJ mol^?1) than in diazepam (1). Moreover, upon addition of LSR, the boat conformation is retained in the lanthanide ion-substrate complex, as with 1 in the solid state. Using a concentration-dependent shift technique and a computer-assisted LIS method, the conformations of the N-branched side-chain were investigated. Two preferred orientations were found for the propargyl group of 2, while three unequally populated conformations of the cyclopropyl moiety of 3 are distributed preferentially in the sterically unhindered space around the complex.