Molecular-crystal structure of 5-methyl-1,2-dihydro-3H-1,4-benzodiazepin-2-one

5-Methyl-1,2-dihydro-3H-1,4-benzodiazepin-2-one, which is an antagonist of 5-aryl-1,2-dihydro-3H-1,4-benzodiazepin-2-ones, was subjected to a complete x-ray diffraction study. The crystals have monoclinic syngony witha = 11.456(5), b = 8.195(3), c = 9.257(4) Å, = 93.10(3) °, and space group P2₁/b. The nonplanar molecules (with a boat conformation) form cyclic dimers by means of NH...O hydrogen bonds (2.937 Å) in the vicinity of the center of symmetry (0, 0, 1/2). Replacement of the phenyl ring in the 5 position by a less bulky methyl group does not lead to appreciable changes in the geometry and conformation of the heteroring. It is assumed that the substituent in the 5 position plays a role in determining the character of the pharmacological action of 1,4-benzodiazepines.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 7, pp. 985–988, July, 1982.     

An expedient synthesis of 3-amino-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one

Racemic 3-amino-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one, 2, was prepared in four steps utilizing a novel mercuric ion assisted ammonia displacement of an N-acyl alkylthioglycine amide 5.     

A facile large scale synthesis of optically active 3-amino-5-(2-pyridyl)-1,4-benzodiazepin-2-one derivatives

A facile method for the synthesis of 3-amino-5-(2-pyridyl)-1,4-benzodiazepin-2-ones (8) mediated by benzotriazole is described. The synthesis and optical resolution of the product by fractional crystallisation proceeds in high yield, under mild conditions and without recourse to toxic reagents or chromatographic separations and hence is amenable to the large scale preparation of these important precursors to potent CCK receptor ligands.     

Efficient solid-phase synthesis of highly functionalized 1,4-benzodiazepin-5-one derivatives and related compounds by intramolecular aza-Wittig reactions

Due to their widespread biological activities and favorable pharmacokinetic properties, benzodiazepines were among the first classes of small molecules to be synthesized on solid supports. Since then, there have been numerous reports on the synthesis of similar skeletons. We have employed the T1 triazene linker to yield 1,4-benzodiazepin-5-one. Starting from various substituted triazene resins, cleavage in the presence of an azide donor, such as trimethylsilylazide, gave rise to aryl azides. Intramolecular aza-Wittig reactions produced the appropriately functionalized N-heterocycles. By using this route, the natural product deoxyvasicinone and related compounds were prepared.     

2,3,6,7,8,9-hexahydro-8,8-dimethyl-5-phenyl-1-H1,4-benzodiazepin-6-one

Several approaches for the synthesis of the title compound 1 were investigated. Treatment of the ethane-1,2-diamine derivative 2 with phosphoryl chloride afforded 3-chloro-5,5-dimethylcyclohex-2-enone (3) and 1-(5,5-dimethyl-3-oxocyclohex-1-enyl)-4,5-dihydro-2-phenylimidazole (4) , The reaction of 2-benzoyl-dimedone (5) with an equimolar amount of ethane-1,2-diamine led to the 2:1 adduct 6 , whereas with an excess of ethane-1,2-diamine, 4,5-dihydro-2-phenylimidazole (7) and dimedone were obtained. The synthesis of the title compound 1 was achieved by reacting 2-benzoyl-3-chloro-5,5-dimethylcyclohex-2-enone (8) with ethane-1,2-diamine.     

Regioselective aminoethylation of 1,4-benzodiazepin-2-one under conventional heating and microwave irradiation

The regioselective aminoethylation of 1,4-benzodiazepin-2-one 1 can be carried out using classical heating or microwave irradiation as the source of energy to furnish either N-1 or N-4 aminoethylated products 2a-d and 3a-d, respectively. The regioselectivity observed has been rationalized using computational studies and has been traced to the disparity of the rate-determining steps along the N-1 product (N-1 PR) and N-4 product (N-4 PR) formation pathways.     

Memory of chirality trapping of low inversion barrier 1,4-benzodiazepin-2-one enolates

We have previously demonstrated that chiral, enantiopure 3-substituted 1,4-benzodiazepin-2-ones undergo retentive deprotonation/trapping at −78 °C, if the N1-substituent is sufficiently large (e.g., i-Pr). Stereocontrol in this reaction is attributed to the formation of an enantiopure, conformationally chiral enolate; at −78 °C a large N1 substituent (e.g., i-Pr) is needed to impart a sufficient barrier to enolate racemization. Herein, we report strategies to achieve high enantiomeric excess in deprotonation/alkylation of low inversion barrier 1,4-benzodiazepin-2-ones featuring small N1 substituents.     

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.     

Bromo derivatives of 4-phenyl-2,3-dihydro-1h-1,5-benzodiazepin-2-one

Monobromo and dibromo derivatives were synthesized by bromination of 4-phenyl-2,3-dihydro-1H-1,5-benzodiazepin-2-one with bromine under various conditions and with N-bromosuccinimide in CCl₄. 7-Bromo- and 8-bromo-4-phenyl-2,3-dihydro-1H-1,5-benzodiazepin-2-ones were obtained by condensation of 4-bromo-o-phenylenediamine with benzoylacetic ester in refluxing xylene. The UV and PMR spectra of the products are discussed.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 3, pp. 411–415, March, 1978.     

Chloro derivatives of 4-phenyl-2,3-dihydro-1H-1,5-benzodiazepin-2-one

The chlorination of 4-phenyl-2,3-dihydro-1H-1,5-benzodiazepin-2-one with N-chlorosuccinimide takes place at the methylene group to give mono and diehloro derivatives. In the reaction of the diazepinone with sulfuryl chloride chlorine is incorporated in the 1 or 3 position or in both the 1 and 3 positions, as well as in the para position of the phenyl substituent; in the presence of anhydrous aluminum chloride substitution takes place in the methylene group of the heteroring and in the 8 position of the annelated benzene ring.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 3, pp. 405–409, March, 1982.     

Enantioselective synthesis of "quaternary" 1,4-benzodiazepin-2-one scaffolds via memory of chirality

Glycine-derived 1,4-benzodiazepine-2-ones such as diazepam are chiral by virtue of the boat-shaped conformation of the diazepine ring and exist as a racemic mixture of conformational enantiomers. However, the presence of a chiral center at C-3 of the benzodiazepine perturbs this equilibrium and preferentially stabilizes one ring conformer. We report that N-i-Pr 1,4-benzodiazepine-2-ones derived from (S)-Ala and (S)-Phe can be deprotonated and alkylated in 86-99% ee, despite the fact that the original chiral center is destroyed in the deprotonation step. We attribute this highly enantioselective alkylation to the chiral memory of the benzodiazepine ring. This protocol provides easy access to the previously unexplored "quaternary" 1,4-benzodiazepine-2-ones.     

New synthesis of 7-bromo-1, 3-dihydro-3-hydroxy-5-(2′-pyridyl)-2H-1,4-benzodiazepin-2-one

A new synthesis of 7-bromo-1,3-dihydro-3-hydroxy-5-(2′-pyridyl)-2H-1,4-benzodiazepin-2-one ( 5 ) is described. Starting from bromazepam ( 3 ), C(3) acylation with lead tetraacetate/potassium iodide in acetic acid affords 4 , while its mild hydrolysis according to our recently described method (5) gives 5 . Improved hexamine cyclization of 1 into 3 , via quaternary hexaminium salt 2 , is discussed, and identification of the intermediates 7 and 8 is performed. Compound 5 undergoes on melting, or on brief heating in glacial acetic acid, the thermal rearrangement into quinazolin-2-aldehyde ( 13 ), the structure of which is confirmed by oxidation into the ester 14 , which in turn was hydrolyzed to the acid 15 . The same compound ( 5 ) rearranges on heating with manganese(III) acetate in acetic acid into the 3-amino-2-quinolone derivative 6 . On heating in glacial acetic acid in the presence of lead tetraacetate/potassium iodide (or iodine), compound 4 , in addition to giving the aldehyde 13 , ester 14 and acid 15 rearrangement products, affords 1,2-dihydroquinazolin-2-carboxylic acid 16 .     

A facile synthesis of novel 1,4-benzoxazepin-2-one derivatives

An efficient and simple synthesis of 1,4-benzoxazepin-2-one derivatives has been achieved via the reaction of isoquinoline, activated acetylenes, and 1-(6-hydroxy-2-isopropenyl-1-benzofuran-yl)-1-ethanone in water without using any catalyst. This one-pot reaction occurs in high yields under mild conditions.