1.3- Benzodiazepin-5-ones, formation

Alkaline hydrolysis of 1/7-1,4-benzodiazepin-2(3//)-one 4-oxides results in ring opening, e.g. formation of l.223-224... 

Methyl-17/-l,5-benzodiazepin-2(37/)-one undergoes addition to nitrile imines at the 4,5-bond, e.g. formation of 33.-10 1... 

Diazepam From a chemical point of view, diazepam, 7-chloro-l,3-dihydro-l-methyl-5-phenyl-2H-l,4-benzodiazepin-2-one (5.1.2), is the most simple of all of the examined derivatives of l,4-benzodiazepin-2-ones. Various ways for the synthesis of diazepam from 2-amino-5-chlorobenzophenone have been proposed. The first two ways consist of the direct cyclocondensation of 2-amino-5-chlorobenzophenone or 2-methylamino-5-chlorobenzophenone with the ethyl ester of glycine hydrochloride. The amide nitrogen atom of the obtained 7-chloro-l,3-dihydro-5-phenyl-2H-l,4-benzodiazepin-2-one (5.1.1), is methylated by dimethylsulfate, which leads to the formation of diazepam (5.1.2). 

Formation of this bond as an amide linkage has been much used but most often as the first or last step in a type ac synthesis of l,4-benzodiazepin-2-ones, e.g. (151) or (154). Monocyclic 1,4-diazepines have been prepared by the cyclization of a,o>-aminoesters... 

Reaction of the spiroepoxy lactone 125 with phenylenediamine in EtOH at reflux provided the 1,5-benzodiazepin-2-one after amide formation, mediated by /-BuMgBr (Scheme 75) <2003S1209>. The scope of this approach may be limited since the single spiroepoxy lactone substituted on the epoxide ring that was studied was an ineffective partner. 

Synthesis of annelated diazepines based on unsaturated aromatic diazepines may involve the preliminary transformation of ketones into the corresponding l,3-diaryl-2,3-dibromopropane-3-ones (chalcone dibromides). The interaction between o-PDA or some of its substituted analogues with chalcone dibromides leads to the formation of aziridine derivatives [64] (see Chap. 1). However, in the case of 4-nitro-o-PDA, either azirenoquinoxalynes 53 or benzodiazepine derivatives 54 may be obtained depending on the reaction conditions [65] (Scheme 4.15). Diazepine derivatives 56 are obtained by the condensation of chalcone dibromides 51 with 5,6-diamino-1,3-dimethyluracil 55 [66], but aziridine derivatives are not isolated in this reaction. It should be noted that compounds 54 and 56 are formed owing to cyclization of the intermediate (3-enaminoketones [65, 66, 67] and are easily isolated from the reaction mixture. 

An intriguing enantioselective preparation of substituted quaternary 1,4-benzodiazepin-2-one scaffolds has been reported by Carlier et al. <03JA11482>. Enantioselective alkylation is used to prepare chiral products 64 (e.g. R = H R = Me, PhCH2 R = Me2CH) from non-racemic glycine-derived 1,4-benzodiazepinones. If the N1 substituent is sufficiently large (e.g. an isopropyl group) then the stereochemistry at the 3-position of the 3-substituted 1,4-benzodiazepinones is transmitted to the product despite the loss of chirality at C-3 on intermediate enolate anion formation. 

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