Synthesis of tetrahydro-1,4-benzodiazepine-2-ones on hydrophilic polyamide SynPhase lanterns

Solid-phase synthesis is greatly dependent on the solid support. Here, we report the use of a new hydrophilic grafted surface on SynPhase lanterns in solid-phase organic chemistry. A convenient and facile solid-phase synthesis of disubstituted 1,4-benzodiazepine-2-ones on polyamide SynPhase lanterns is described. The key step of the synthesis involved a reduction-cyclization of a nitroaryl methyl ester with a mixture of tin(II) chloride dihydrate and ammonium acetate in water and ethanol at elevated temperature to give the desired target compounds. A library of 21 disubstituted 1,4-benzodiazepine-2-ones was prepared.     

Parallel synthesis of 1,3-dihydro-1,4-benzodiazepine-2-ones employing catch and release

An efficient solid-phase method has been developed for the parallel synthesis of 1,3-dihydro-1,4-benzodiazepine-2-one derivatives. A key step in this procedure involves catching crude 2-aminobenzoimine products 4 on an amino acid Wang resin 10. Mild acidic conditions then promote a ring closure and in the same step cleavage from the resin to give pure benzodiazepine products 12. The 2-aminobenzoimines 4 can be synthesized from either 2-aminobenzonitriles 1 and Grignard reagents 2 or from iodoanilines 5 and nitriles 7 allowing a range of diversification. Further diversification can be introduced to the benzodiazepine products by N-alkylation promoted by a resin bound base and alkylating agents 13.     

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 1,4-benzodiazepine-3,5-diones

Even though benzodiazepines have a strong position in medicinal chemistry, very few synthetic routes to 1H-1,4-benzodiazepine-3,5(2H,4H)-diones have ever been published and the claimed products have often been poorly characterized. Through the present work several 1H-1,4-benzodiazepine-3,5(2H,4H)-diones have become available from N-carbamoylmethylanthranilic acids. The required ring closures were achieved only when the amino groups of the starting materials were substituted with electron withdrawing groups such as acetyl, alkyloxycarbonyl, or nitroso. During the synthetic work a novel ring contraction rearrangement from a 1-nitroso-1H-1,4-benzodiazepine-3,5(2H,4H)-dione to a 3H-quinazoline-4-one was observed. The proposed mechanism involves elimination of HNO followed by a proton-mediated loss of CO. The 1-nitrosated 1,4-benzodiazepinediones could be separately denitrosated to the corresponding amino compounds.     

Experimental and computational studies of ring inversion of 1,4-benzodiazepin-2-ones: implications for memory of chirality transformations

We recently reported the enantioselective syntheses of quaternary 1,4-benzodiazepin-2-ones via memory of chirality. The success of this method depends on formation of conformationally chiral enolates that racemize very slowly under the reaction conditions. As a prelude to undertaking experimental and computational studies on the racemization of these enolates, we have studied the ring-inversion process of the parent 1,4-benzodiazepin-2-ones. In this paper, we use dynamic and 2D-EXSY NMR to characterize inversion barriers. Using DFT calculations, we reproduce the experimental results with high accuracy (within 1-2 kcal/mol). Structural parameters obtained from DFT calculations provide valuable insights into the important effect of the N1 substituent on the ring-inversion barrier and shed light on the mechanism of the memory of chirality method. These measurements and calculations provide a foundation for future studies of benzodiazepine enolates and will be valuable in the design of new memory of chirality reactions.     

Divergent regioselective synthesis of 2,5,6,7-tetrahydro-1H-1,4-diazepin-2-ones and 5H-1,4-benzodiazepines

A novel and simple one-pot synthesis of 3-substituted 2,5,6,7-tetrahydro-1H-1,4-diazepin-2-ones from 1,2-diaza-1,3-dienes (DDs) and N-unsubstituted aliphatic 1,3-diamines is described. Here we also report a procedure to selectively obtain alkyl 5H-1,4-benzodiazepine-3-carboxylates from the DDs and 2-aminobenzylamine. Both processes occur by means of sequential 1,4-conjugated addition followed by regioselective 7-exo cyclization. The behavior of N-methyl- and N,N'-dimethyl-1,3-diaminopropanes toward the DDs furnished pyrazol-3-ones and bis-α-aminohydrazones, respectively.     

Facile synthesis of 4-substituted 1,2,4,5-tetrahydro-1,4-benzodiazepin-3-ones by reductive cyclization of 2-chloro-N-(2-nitrobenzyl)acetamides

A facile and efficient method was developed for the synthesis of 1,2,4,5-tetrahydro-1,4-benzodiazepine-3-ones from 2-chloro-N-(2-nitrobenzyl)acetamides through a reductive cyclization using iron-ammonium chloride in ethanol–water in good yields. This method provides a simple approach to these benzodiazepine-3-ones which are of high value in the field of medicinal chemistry research.     

Quinazolines and 1,4-benzodiazepines LXVIII. 5-Heterocyclic-substituted benzodiazepinones

The synthesis of a number of new 1,4-benzodiazepin-2-ones containg the 2-thiazolyl, 5-isothiazolyl, 1-rnethyl-2-imidazolyl. 1-methyl-5-pyrazolyl, and 3,5-dimethyl-4-isoxazolyl groups in the 5-position of the benzodiazepine ring are described.     

An efficient synthesis of 1,4-dideoxy-1,4-imino-d- and l-arabinitol and 1,4-dideoxy-1,4-imino-d- and l-xylitol from chiral aziridines

A highly efficient method for the synthesis of 1,4-dideoxy-1,4-imino-d- and l-arabinitol (d-AB1, 1 and l-AB1, 3) and 1,4-dideoxy-1,4-imino-d- and l-xylitol (d-DIX, 2 and l-DIX, 4) starting from commercially available chiral aziridines was developed. The general strategy employs a sequence involving two-carbon homologation, dihydroxylation, and regioselective aziridine ring opening/intramolecular five-membered iminosugar ring formation. The facile use of recrystallization to generate pure diastereomers makes the routes more amenable to large-scale synthesis.     

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.     

Stereoselective one-pot synthesis of constrained N,O-orthogonally protected C-glycosyl norstatines [C(1')-aminoglycosyl-1,3-dioxolan-4-ones

A procedure for the synthesis of conformationally constrained C-glycosyl norstatines has been developed. The key step of the reaction is the addition of (S)-N-sulfinyl azomethines to chiral (2S)-enolates of dioxolanones which exploits Seebach's "SRS" principle. The trisubstituted C-glycosyl-alpha-hydroxy-beta-amino acids are formed as N,O-orthogonally protected 1'-glycosyl-sulfinylamino-dioxolan-4-ones, usually with high diastereomeric excesses. Both the sulfinyl group at the nitrogen atom and the acetal moiety of the dioxolanone ring were selectively removed, thus demonstrating the orthogonality of the two protecting groups. In fact, the MeO(-) induced methanolysis of the acetal group gave the corresponding methyl C-glycosyl-sulfinylamino-isoserinates, while the acid induced removal of the sulfinyl group gave the Nu-deprotected 1'-glycosylamino-dioxolan-4-ones, which were in several cases subjected to a one-pot base-induced cyclization yielding the corresponding glycosyl-beta-lactams. This allowed the stereochemical configuration assessment of the parent 1'-glycosyl-sulfinylamino-dioxolan-4-ones by chemical correlation methods or by NOE experiments performed on the beta-lactams.     

1,4-Benzodiazepines and their derivatives

A series of compounds of the merocyanine dye type was obtained by the reaction of 1-acetyl-1,3-dihydro-2H-1,4-benzodiazepin-2-ones and 1,3-dihydro-2H-1,4-benzodiazepine-2-thiones with 2-methylmercapto-3-ethylbenzothiazolium tosylate, 2-methylmercapto-3,4,5-trimethylthiazolium bromide, 2-methylmercapto-3-methyl-5-phenyloxazolium methosulfate, and 1,3,3-trimethyl-2-formylmethyleneindoline. The hydrogen atoms of the methylene group of the 1-unsubstituted and 1-alkyl-substituted 1,3-dihydro-2H-1,4-benzodiazepin-2-ones are of low mobility, and the indicated compounds do not undergo condensation reactions with electrophilic agents.See [6] for communication VI.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 7, pp. 992–994, July, 1971.     

Asymmetric Ir-catalyzed hydrogenation of 1,3-dihydro-2<Emphasis Type="Italic">H</Emphasis>-1,5-benzodiazepin-2-ones using phosphoramidites

A series of phosphoramidite ligands was tested in the asymmetric hydrogenation of 4-arylsubstituted 1,3-dihydro-2H-benzodiazepine-2-ones and up to 52% ee was achieved. The effects of various factors (solvents, hydrogen pressure, and addition of phosphine ligands) on the hydrogenation were studied.     

Reactions of 4-acetoxy-2H-1,4-benzoxazin-3-ones with some nucleophiles

O-Acetates of 4-hydroxy and 4-hydroxy-7-methoxy-2H-1,4-benzoxazin-3-ones reacted with nucleophiles such as phenols, indoles and ethanethiol. The major reaction center is the positively-charged nitrogen atom. In the reaction with 2-methylindole, 6-position of the benzoxazinone ring is another major reaction center.     

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.     

Synthesis and structure of 3-arylidene and 3-hetarylidene-1,2-dihydro-3H-1,4-benzodiazepin-2-ones and their affinity toward CNS benzodiazepine receptors

The condensation of 5-aryl-7-bromo-1,2-dihydro-3H-1,4-benzodiazepin-2-ones with aromatic aldehydes gives 5-aryl-3-arylidene-and 5-aryl-7-bromo-3-hetarylidene-1,2-dihydro-3H-1,4-benzodiazepin-2-ones. X-ray diffraction structural analysis yielded the molecular and crystal structures of 7-bromo-3-(4′-methoxybenzylidene)-5-phenyl-1,2-dihydro-3H-1,4-diazepin-2-one and showed that this compound has cis configuration. Radioligand analysis was used to study the affinity of these products toward central nervous system and peripheral benzodiazepine receptors. __________ Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 8, pp. 1213–1225, August, 2007.     

Practical synthesis of potential endothelin receptor antagonists of 1,4-benzodiazepine-2,5-dione derivatives bearing substituents at the C3-, N1- and N4-positions

The expedient synthesis of various 1,4-benzodiazepine-2,5-dione compounds, particularly those having substituents at the C3-, N1- and N4-positions is achieved. The important features in these synthetic strategies include: (i) using the coupling reaction of isatoic anhydride with alpha-amino ester for direct construction of the core structure of 1,4-benzodiazepine-2,5-dione; (ii) using potassium carbonate as the base of choice for selective alkylation at the N1-site, while using lithiated 2-ethylacetanilide as the required base to furnish the N4-alkylation; and (iii) using 2-nitrobenzoyl chloride as a synthetic equivalent of anthranilic acid to facilitate the polyethylene resin-bound liquid-phase combinatorial synthesis. The prepared 1,4-benzodiazepine-2,5-dione compounds are evaluated for endothelin receptor antagonism by a functional assay that measures the inhibitory activity against the change of intramolecular calcium ion concentration induced by endothelin-1. The preliminary results indicate that 1,4-benzodiazepine-2,5-diones bearing two flanked aryl substituents at the N1- and N4-sites show better inhibitory activity than the corresponding unalkylated and N-monoalkylated compounds. A promising candidate, 1-benzyl-7-chloro-3-isopropyl-4-(3-methoxybenzyl)-1,4-benzodiazepine-2,5-dione (17b), exhibits an IC50 value in low nM range.     

Highly Z-selective asymmetric 1,4-addition reaction of 5H-oxazol-4-ones with alkynyl carbonyl compounds catalyzed by chiral guanidines

An asymmetric 1,4-addition reaction of 5H-oxazol-4-ones with alkynyl carbonyl compounds was developed, and, for the first time, high enantiomeric and geometric control was achieved to afford the thermodynamically unstable Z-isomer predominantly using chiral guanidine catalysts bearing a hydroxy group at the appropriate position. The method provides synthetically useful γ-butenolide ester bearing a chiral quaternary stereogenic center.     

Synthesis of a new compound family, 1-aryl-3H-pyrrolo[2,1-d][1,2,5]triazepin-4(5H)-ones

Representatives of a new family, 1-aryl-3H-pyrrolo[2,1-d][1,2,5]triazepin-4(5H)-ones have been synthesized at our laboratory as bioisosters of biologically active 1-aryl-2,3-benzodiazepine-4-ones. The efficient synthetic route described applies the synthesis of 2-(2-aroylpyrrol-1-yl)acyl hydrazides followed by ring closure under acidic conditions. The N(3)-unsubstituted title compounds thus obtained can optionally be N-alkylated rendering the preparation of variously substituted derivatives possible. Scope and limitations of the new protocol and some interesting side reactions are also discussed in detail.     

Enantiomeric separation of close analogs to naturally occurring 1,4-benzoxazin-3-ones by liquid chromatography using β-cyclodextrin-modified stationary phase

Summary A liquid chromatographic procedure on a 5 m LiChroCART column using chemically bonded -cyclodextrin (ChiraDex) as chiral selector was developed for the enantiomeric separation of four 2H-1,4-benzoxazin-3(4H)-ones which are close analogs of the cyclic hydroxamic acids 2,4-dihydroxy-2H-1,4-benzoxazin-3(4H)-one (DIBOA) and 2,4-dihydroxy-7-methoxy-2H-1,4-benzoxazin-3 (4H)-one (DIMBOA) naturally occurring inGramineae species.