1.4- Diazepine ring, 2,3-dihydro

The imidazo[4,5-J][l, 2]diazepine diribonucleoside (585) upon treatment with methanolic ammonia at room temperature undergoes a base-catalyzed ring contraction of the diazepine ring to give 4-amino-1,3-dihydro-l,3-bis(/ -D-ribofuranosyl)imidazo[4,5-c]pyridin-2-one (586) (58%) (Scheme 74) <86Ti5ii>. 

Benzothiazepines. These are closely related compounds to benzodiazepines. The nitrogen atom in the diazepine ring is replaced by a sulfur atom (27). Among these compounds BTM-1086 was found to be an Ml receptor antagonist (106). It is cis(-)-2,3-dihydro-3-(4-methylpiperazinyl)-2-phe-nyl-l,5-benzothiazepin-4(57f)-one monohydrochloride. It inhibits acetylcholine release from parasympathetic nerves and also gastric secretion. 

Benzodiazepines (1) are the 2,3-benzo-fused derivatives of the dihydrodiazepines of the previous Chapter. The reader should note that the numbering systems required (IUPAC Chemical Abstracts) for the benzo series and the dihydro compounds proceed in opposite directions about the diazepine rings. 

The other way of synthesis of clozapine is from 8-chloro-10,ll-dihydro-5H-dibenzo[b,e]l, 4-diazepin-ll-thione, which is alkylated at the sulfur atom of the dibenzodiazepine ring by 4-nitrobenzylchloride in the presence of potassium fert-butoxide, giving iV-methyl derivative (6.5.8). Reaction of this with A-methylpiperazine gives the desired clozapine (6.5.7) [59]. 

An electron-withdrawing sulfoxide substituent at C4 of a /3-lactam was an even more effective activating element, since the /3-lactam 130 underwent a ring-expansion reaction by simply stirring at 25 °C in a pH 9 buffer (Scheme 83) <2001SC2713>. In this reaction, the /3-lactam is sufficiently activated to react with an amide as the nucleophilic species, affording the N-substituted 3,4-dihydro-17/-l,4-diazepin-2,7-dione 131 in 80% yield, as a white solid. The structure was confirmed by both NMR methods and single crystal X-ray analysis. 

In several synthetic studies, cyclopropane derivatives were used as synthones or building elements for ring enlargement steps, e.g. reaction of enamines with cyclopropenone [65], synthesis of 2,3-dihydro-l,4-diazepine by thermal isomerization of 1,2-diamino-cyclopropanes [32] [66], and preparation of 3-amino-fulvenes from methylencyclopropenes with alkynamines [67]. 

---