Enantioselective synthesis of diversely substituted quaternary 1,4-benzodiazepin-2-ones and 1,4-benzodiazepine-2,5-diones

Benzodiazepines are privileged scaffolds in medicinal chemistry, but enantiopure examples containing quaternary stereogenic centers are extremely rare. We demonstrate that installation of the di(p-anisyl)methyl (DAM) group at N1 of 1,4-benzodiazepin-2-ones and 1,4-benzodiazepine-2,5-diones derived from enantiopure proteinogenic amino acids allows retentive replacement of the C3-proton via a deprotonation/trapping protocol. A wide variety of carbon and nitrogen electrophiles function well in this reaction, providing the corresponding quaternary benzodiazepines with excellent enantioselectivity. Deprotonation/trapping experiments on a pair of diastereomeric 1,4-benzodiazepine-2,5-diones provide evidence for a key role of conformational chirality in these enantioselective reactions. Acidic removal of the DAM group is fast and high-yielding and can be performed selectively in the presence of a N-Boc indole. Thus the synthesis of quaternary benzodiazepines with diverse N1 functionality can now be accomplished.     

Synthesis of imidazolidin-4-ones and their conversion into 1,4-benzodiazepin-2-ones

α-Haloacetanilides Ia-e react with hexamine in ethanol giving the bisimidazolidin-4-one derivatives IIa-e, which hydrolize, in acidic media into the corresponding mono-imidazolidin-4-ones IIIa-e. The compounds IIa-d were converted into 1,4-benzodiazepin-2-ones, under different conditions and in the presence of a variety of agents. The yields were between 50 and 100%.     

Convenient preparation of N-substituted 2-amino-4H-3,l-benzoxazin-4-ones and 3-substituted 2,4(1H,3H)-quinazolinediones

Room temperature treatment of 2-(3-arylureido)benzoic acids ( 1 ) and methyl 2-(3-alkyl-, or 3-arylureido)- benzoates ( 2 ) with concentrated sulfuric acid leads to N-substituted 2-amino-4H-3,l-benzoxazin-4-ones ( 3 ) in generally very good yields. The isomeric 3-substituted 2,4(1H,3H)-quinazolinediones ( 4 ) are conveniently made in high yield by the action of aqueous-ethanolic sodium hydoxide on 2.     

1,2,3,5-Tetrahydro-4H-1,5-benzodiazepin-4-ones and 1,2,3,4-tetrahydro-5H-1,4-benzodiazepin-5-ones from the reaction of hydrazoic acid on 1,2,3,4-tetrahydroquinolin-4-ones

The Schmidt reaction on 1,2,3,4-telrahydroquinolin-4-ones (1) gave 1,2,3,5-telrahydro-l,5-benzodiazepin-4-ones (II) and 1,2,3,4-tetrahydro-1,4-benzodiazepin-5)-ones(III). The ratio of II and III is dependent upon substituents present on the nitrogen ring atom of the quinolinones.     

A simple route to tetrahydro-1,4-benzodiazepin-3-ones bearing diverse N1, N4, and C10 functionalization

We describe an efficient synthesis of enantiopure tetrahydro-1,4-benzodiazepine-3-ones derived from l-alanine. Diverse substitution at N1, N4, and C10 can be achieved by coupling various N-alkyl derivatives of l-alanine and N-allyl-(2-fluoro-5-nitro)benzylamine. Cyclization of this intermediate proceeds in high yield and without racemization, providing diversity at N1. The NO₂ group was easily transformed into other functional groups or removed, providing diversity at C10. Finally, oxidative deallylation allows diverse substitution to be installed at N4.     

Convenient synthesis of some optically active 1,4-benzodiazepin-2,5-diones

Isatoic anhydride was reacted with several L-amino acids to give the corresponding （2S）-N-（o-aminobenzoyl）-2-alkylaminoacetic acids. The latter compounds were treated with phosphoryl chloride under reflux temperature to afford the cyclized products, （3S）-3-alkyl-3,4-dihydro- 1 H- 1,4-benzodiazepin-2,5-diones. 2007 M. Bakavoli. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.     

Solid phase synthesis of tetrahydro-1,4-benzodiazepin-2-ones

A novel solid phase route to tetrahydro-1,4-benzodiazepin-2-ones is described which involves construction of a core template in solution followed by diverse derivatization on solid phase.     

A tandem one-pot, microwave-assisted synthesis of regiochemically differentiated 1,2,4,5-tetrahydro-1,4-benzodiazepin-3-ones

A one-pot, two-step synthesis of the title compounds employs a multicomponent Ugi condensation reaction, microwave irradiation, and Fe(0) as a reductant. Two pathways are accessible; both routes utilize bifunctional, o-nitro-substituted arenes leading to either C2, N4, C5 substitution (A) or C2, N4 substitution (B).     

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.     

3-Phenylazo-4-methyl-2,3-dihydro-1,5-benzodiazepin-2-ones

The corresponding azo derivatives, which exist primarily in the azo form, are formed in the reaction of 2,3-dihydro-1,5-benzodiazepin-2-ones with diazonium cations. The hydrazone form of these compounds is possible in solutions of acids.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 11, pp. 1558–1560, November, 1978.     

One-pot synthesis of 2,4-benzodiazepin-1-ones using benzotriazole methodology

2, 4-Benzodiazepin-1-ones were prepared in moderate to good yields by reaction of bis(benzotriazolylmethyl)amines with ortho-metalated N-substituted benzamides.     

Stereoselective in-vitro aromatic-ring oxygenations of chiral 1,4-benzodiazepin-2-ones

Biological N(1)-demethylation and C(3)-hydroxylation of two enantiomeric 1,4-benzodiazepin-2-ones 1 and 2 (cf. scheme 2) were found to be nonstereoselective. Aromatic-ring hydroxylation, however, took place in the (S)-series only, leading to 3′- and 4′-hydroxylated, N(1)-demethylated, metabolites ( 54 and 56 , cf. scheme 5: these structures were unambiguously confirmed by comparing their UV., CD., and mass spectra with those of authentic specimens). Several compounds, theoretically conceivable as products of hydroxylation in the aromatic A-ring of 1 and 2 by mechanisms including the NIH-shift (cf. scheme 3), were synthesized but none of these compounds was yet isolated from in vitro incubation mixtures.     

Synthesis of 3-nitro- and 3-aminoquinoline-2,4-diones. An unexpected route to 3-hydroxyquinoline-2,4-diones

Nitration of 3-substituted-4-hydroxy-2(1H)-quinolones 1 with nitric acid leads either to 3-nitro- 2 or 3-hydroxyquinolinediones 3 , depending on the reaction conditions. 3-Substituted-3-hydroxyquinolinediones 3 are also obtained by oxidative hydroxylation with peracetic acid. Amination of 3-substituted-3-chloroquinolinediones 4 with ammonium hydroxide predominantly leads again to 3-substituted-3-hydroxyquinolinediones 3 , only in one case the 3-aminoquinolinedione 5 could be isolated. With morpholine or pyridine as amines the expected 3-aminoquinolinediones 6 and 7 were obtained.     

Rearrangement of 5-phenylthiazolidine-2,4-diones to chiral α-ketoamides via α-elimination

An unexpected reaction took place when 5-phenylthiazolidine-2,4-diones were treated in basic media to produce phenyl-α-ketoamides in good yields. The 5-phenylthiazolidine-2,4-diones used as reactants were achieved through a rearrangement, which took place in the corresponding N-acyloxazolidinethiones.     

New synthesis of 1,3-dihydro-1,4-benzodiazepin-2(2H)-ones and 3-amino-1,3-dihydro-1,4-benzodiazepin-2(2H)-ones: Pd-catalyzed cross-coupling of imidoyl chlorides with organoboronic acids

A new approach to the synthesis of 1,4-benzodiazepines and 3-amino-1,4-benzodiazepines, which employs the Pd-catalyzed cross-coupling reaction of an imidoyl chloride with an organometallic reagent as the key step, is described. A five-step synthesis of a key intermediate is described and it is shown that in only four further steps (three couplings and a TFA-mediated BOC-deprotection) a wide variety of N1-, C3-amino-, C5-carbon-, or nitrogen-substituted 1,4-benzodiazepines can be synthesized.     

Reaction of 3-aminoquinoline-2,4-diones with nitrourea. Synthetic route to novel 3-ureidoquinoline-2,4-diones and imidazo[4,5-c]quinoline-2,4-diones

1-Unsubstituted 3-alkyl/aryl-3-amino-1H,3H-quinoline-2,4-diones react with 1-substituted and 1,1-disubstituted ureas in boiling acetic acid to give 2,6-dihydro-imidazo[1,5-c]quinazoline-3,5-diones. In contrast, the reaction of these amines with nitrourea in dioxane affords novel 3-alkyl/aryl-3-ureido-1H,3H-quinoline-2,4-diones or 9b-hydroxy-3a-alkyl/aryl-3,3a,5,9b-tetrahydro-1H-imidazo[4,5-c]quinoline-2,4-diones, which can smoothly be dehydrated to 3a-alkyl/aryl-3,3a-dihydro-5H-imidazo[4,5-c]quinoline-2,4-diones. All three types of products can be converted to 2,6-dihydro-imidazo[1,5-c]quinazoline-3,5-diones by refluxing in acetic acid.