Domino S_N2 And Cu-catalyzed Coupling Reaction-Synthesis Of Chiral 1,3,4,5-tetrahydro-1,4-benzodiazepin-2-ones

In organic chemistry or related field, about half of the research involves heterocyclic structures, especially in medicines, pesticides and veterinary drugs, a large part of these products involve heterocyclic structure.This shows the heterocyclic chemistry is an important part of organic chemistry.Benzodiazepines compounds are a class of nitrogen heterocyclic compounds which have extensive pharmacological activities and biological activities and widely used in the medical field. Since clozapine was found in the 1950s, benzodiazepines have become the important privileged structure in medical research fields. Benzodiazepines were seen as a privileged structure in drugsdue to the ability to combine with the specific sites of protein. The compounds have good biological activities and wide applications, such as opioid receptor antagonist, vasopressin receptor antagonist, anti-epileptic drugs, anxiolytics, antibiotics, anti-aids drugs, anti-inflammatory drugs, and sleeping pills.Compounds with a 1,3,4,5-tetrahydro-1,4-benzodiazepin-2-one scaffold have demonstrated promising diverse pharmacological activities in recent researches, such as endothelin receptor antagonists, anti-HIV agents, anti-ischemic agents, modulators of retinoic acid receptor ?RAR?-related and peptidomimeticsfor G-protein coupled receptors ?GPCRs?. Therefore it can facilitate the development of drug research to explore novel and simple synthetic methods for diverse 1,3,4,5-tetrahydro-1,4-benzodiazepin-2-ones.We noticed that the synthesis of chiarl 1,3,4,5-tetrahydro-1,4-benzodiazepine-2-ones needs multistep reactions. So we imagine if the synthetic method can be realized through one-pot reaction. Through inverse synthetic analysis, these compounds may synthesized by amino acid amide and ortho halide benzyl halide after the S_N2 nucleophilic substitution reaction and metal catalytic C-N coupling reaction. Our laboratory found the selectivity C-N coupling reaction synthesized by chiral amino acid amide and halogenated aromatics two years ago. On this basis, we successfully found these compounds can be synthesized by tandem S_N2 nucleophilic substitution and Cul-catalyzed C-N coupling reaction.Firstly, L-phenylalaninamide and 2-iodobenzyl bromide were selected as reaction substrates to optimize reaction conditions. The types and amount of catalyst, reaction time, temperature, bases, reaction time, and solvents has been researched. The optimizing condition is 10 mol% CuI as catalyst, K₂CO₃ as base, DMF?5ml? as solvent,110? as reaction temperature,24 hours as reaction time, feed molar ratio is aryl halides:amides:catalyst:base= 1:1.5:0.1:2?mole ratio?.Secondly, the reactions of L-phenylalaninamide and aryl halides, the reaction of various amino acid amides and 2-iodobenzyl bromide have been researched. Results showed that catalytic system used in this paper was fit for aryl bromide and aryl iodides, in order to verify whether racemization occured during the reaction, the enantiomericexcess of the products of L-phenylalaninamide and L-alaninamidewere analyzed by chiral HPLC on an OJ-H column. The chiral HPLC results demonstrated the ee value is as high as 97%.In conclusion, we found a direct and efficient way by S_N2 nucleophilic substitution and copper-catalyzed C-N cross-coupling reaction to synthesis the 1,3,4,5-tetrahydro-1,4- benzodiazepine-2-ones. The method is simple operation less steps, reactants available, low production cost, and conforms to the concept of green chemical synthesis method, with the application prospect in the industrial production.All compounds in this article were characterized by 1H NMR,13C NMR, IR spectroscopy, andmass spectrometer.