Studies On The Cyanation Of Isochromene Acetals And Their Potential Pharmacological Activity

Isochromenes or chromenes belong to the benzopyran heterocyclic compounds,this skeleton is widely present in natural and non-natural products,bioactive molecules and pharmaceuticals,this class of compounds has a strong biological activity.The sources of natural products containing nitrile are also very extensive,with thousands of metabolites from land and sea,of which amino acid nitrile compounds derived from plants,animals and bacteria are used in many natural products,organic materials and marketed drugs.Moreover,the combination of nitrile group and a variety of small molecule inhibitors has good biocompatibility,the structure is relatively stable.In most cases metabolism is easy,in the body metabolism,there is no change in the body transmission.It can be seen that isochromene/chromene compounds and nitrile compounds have good drug activity and have the prospect of research and development of drugs.At present,there are many studies on the activity of isochromene drugs and nitrile drugs at home and abroad,but there are almost no systematic studies on cyanidation modification of isochromene acetals.Therefore,this study hope to splice the two skeletons,hoping to get a more active drug.The research content of this article is divided into three parts:1.2-bromobenzaldehyde and phenylacetylene were used as raw materials to generate2-（phenylethynyl）benzaldehyde structures by Sonogashira coupling reaction,and the isochromene acetals structure was synthesized from this product and methanol,and then the optimal conditions for cyanidation reaction were screened out in different catalyst and solvent conditions with isochromene acetals and trimethylsilyl cyanide（TMSCN）as raw materials:the catalyst Fe（OTf）₃（1 mol%）,1-methoxy-3-phenyl-1H-isochromene（47.6 mg,0.2 mmol）,TMSCN（39.7 mg,0.4 mmol）and solvent DCM（2.0 m L）were added under nitrogen conditions.Then it is placed at room temperature and stirred overnight to generate1-carbonitrile-3-phenyl-1H-isochromene with a high yield,which is a simple,gentle and efficient synthesis method.2.The wide applicability of the catalytic system to the synthesis of 1-cyano-isochromenes was evaluated under optimal reaction conditions.Using phenylacetylene compounds and2-bromobenzaldehyde compounds as raw materials,the corresponding 2-alkynyl benzaldehyde compounds were generated by Sonogashira coupling reaction,and then the isochromene acetals corresponding to the synthesis of these products and methanol were used.Then isochromene acetals and TMSCN were used as raw materials to screen out the optimal conditions for cyanogenation reaction:the catalyst Fe（OTf）₃（1-20 mol%）,isochromene acetals（0.2 mmol）,TMSCN（39.7 mg,0.4 mmol）and solvent DCM（2.0 m L）were added under nitrogen conditions.Then it was reacted at room temperature to obtain a series of 1-cyano-isochromenes with excellent yields.3.A series of 1-cyano-isochromenes（3a-3r）were tested for pharmacological activity to screen out compounds with anti-liver cancer and antidepressant activities.The results showed that 13 compounds had potential inhibitory effects on hepatocellular carcinoma cell Hep G;and 5 of them had a good protective effect on nerve cells PC-12,especially compound 3k,which may had a good antidepressant activity.