Water Extract of Onion Catalyst: A Sustainable Approach for the Synthesis of 4-Substituted 1,5-Benzodiazepine Derivatives via an In Situ Generated Enaminones

Abstract

Aim: To develop a green protocol for the one-pot synthesis of biologically active 4- substituted-1,5-benzodiazepine derivatives. Background: Benzodiazepines acquired significant attention in medicinal chemistry owing to their wide spectrum of biological and pharmacological activities such as anti-HIV (reverse transcriptase inhibitor) drugs, HIV-1 protease inhibiting, hepatitis C virus (HCNV) NS5B, anti-malarial, antibacterial, anti-inflammatory, anti-depressant, anti-coagulant, analgesic agents, anti-cancer, cholecystokinin- B receptor antagonists. It was made through three-component condensation of 1,2-diamine, 1,3-cyclic diketone and an aldehyde under various conditions such as (COOH)2/H2O, AcOH/EtOH. Method: 1. To develop simple, convenient and environmentally benign green protocol for the onepot synthesis of 4-substituted-1,5-benzodiazepines through three-component reaction of 1,2-diamine, 1,3-cyclic diketone with an aldehyde catalyzed by water extract of onion. 2. To optimize the reaction conditions. 3. To study scope and mechanism of the reaction 4. To characterize the structure by single crystal X-ray analysis. Result: Finally, EtOH and 0.5 mL of onion extract are suitable for reaction conditions. 4. To examine the electronic effect on reaction time and yields, the aromatic aldehydes having electron releasing functional group such as 4-OH, 4-N,N-dimethyl, 4-OMe, 4-Me, phenyl, and 3,4-dimethoxy gave the desired product in good yields. (90-92%; 5a-5e and 5m). The aromatic aldehydes bearing electron withdrawing group such as 4-Br, 4-Cl, 4-F, 4-CF3, 4-CN, 4-NO2, 3,4-dichloro, 3-bromo- 4-fluoro gave excellent yields (93-97%; 5f-5k, 5n and 5o). 5. Further, to expand the diamine substrates, we have employed 4-hydroxybenzaldehyde 4a, benzaldehyde 4e and 4-nitrobenzaldehyde 4k as model substrates and examined different diamines (4-methylbenzene-1,2-diamine 1b and 4- chlorobenzene-1,2-diamine 1c) with dimedone 2a and gave good yields (89-92%; 5v-5z and 5aa. 6. substituted-1,5-benzodiazepines. Further, the methodology was applied to large-scale reactions. Conclusion: In conclusion, employing aqueous onion extract as a gentle, affordable catalyst, we have developed a simple, effective, and environmentally friendly method for the synthesis of 4- substituted-1,5-benzodiazepines derivatives from 1,2-diamine, diketone, and an aldehyde. Excellent yields, simple workup, inexpensive, non-toxic, and environment-friendly reaction conditions are the prominent features of this procedure.