%0 Journal Article
%T A Simple and Advantageous Synthesis of the Privileged 1,4-Benzodiazepine Nucleus
%A Neetu Jain
%A Dharma Kishore
%J Advances in Chemistry
%D 2014
%R 10.1155/2014/628326
%X A novel domino approach has been described for an easy access of the privileged nucleus of 5-carbomethoxy substituted 1,4-benzodiazepin-2-ones 4(a–i) from an in situ methanolic hydrolysis of an incipient species formed from the interaction of 1-chloroacetylisatin 2(a–i), hexamethyldisilazane, and n-butyl lithium. The reaction is believed to take place through a consecutive series of intramolecular reactions in a cascade to first generate a highly reactive carbene intermediate 3(a–i) from 1-chloroacetylisatin and n-butyl lithium which is simultaneously trapped by hexamethyldisilazane before undergoing its in situ hydrolysis with methanol to initiate its concomitant cyclocondensation to produce 4(a–i) in high yield and purity. 1. Introduction Exploration of synthetic processes that lead to the development of small molecules of medicinal interest by telescoping the multicomponent operations into a single step or resorting to a process such as domino reactions is a rapidly emerging subject in medicinal chemistry. Ever since Koch et al. [1] carried out a quantitative analysis of physiologically active natural product scaffolds and showed that ones with two or three rings were most often found in bioactive natural products, the interest on various facets of the chemistry of small molecules has expanded exponentially thereafter. Benzodiazepines and their analogues have been recognized recently to belong to the class of privileged heterocyclic structures, [2–5] by virtue of their ability to form ligands to a number of functionally and structurally discrete biological receptors [6–13]. This property stimulated chemists to utilize their potential in the design and development of molecular probes for biological evaluations. Ubiquitous presence of this nucleus in the psychopharmacologically active agents and in molecules active against HIV infection, for example, TIBO (1) [14–17] and FDA approved dipyrido diazepine analogue nevirapine (2) [18–24] in Figure 1 provided an impetus for an enormous research effort to be directed towards the development of their structural analogues of medicinal importance [25, 26]. Figure 1 2. Results and Discussion This communication reports the application of a novel domino process for an easy access of the privileged nucleus of 5-carbomethoxy substituted 1,4-benzodiazepin-2-ones 4(a–i) from the ring expansion of 1-chloroacetylisatins 2(a–i), initiated by hexamethyldisilazane under the influence of n-butyl lithium. N-Butyl lithium formed an obvious choice since it has been used as a catalyst in amination of active alkyl halides with
%U http://www.hindawi.com/journals/ac/2014/628326/