The Benzyl C(sp~3)-H Functionalization Of 2-methylazaarenes Via Three Green Methods

Aromatic hydrocarbon compounds such as quinoline and pyridine are important structural units of various biologically active compounds.They are widely used in pharmaceutical chemistry,organic catalysis,and material synthesis.The quinoline and pyridine units can be modified via benzyl C(sp~3)-H bond functionalization of azaarenes,to obtain pharmaceutical moleculess substituted with azaarene,which possess different structure and function.Therefore,the reaction have been widely concerned about the organic synthesis workers.At present,the synthesis methods mainly use transition metals,Lewis or Br?nsted acids as catalysts.In addition,most of the reaction media are used organic solvents with high toxicity.In view of this,it is necessary to develop new green synthesis methods.This paper developed three green methods for the synthesis of azaarene derivativesviathe study of benzyl C(sp~3)-H functionalization of 2-methylazaarenes,The main contents are as follows:The enzyme-catalyzed addition reaction of benzylic C(sp~3)-H to electron-deficient olefin was developed.2-methylquinoline and N-phenylmaleimide as template reaction substrates,after a series of conditions were filtered,finally under the condition of 60?,and DMSO as solvent,the reactions were catalyzed by 20 mg pepsin from pig gastric mucosa,19 azaarene derivatives were obtained in 12%~87%yield.Compare with the conventional catalysts,the catalyst used in this method has not only ensure high catalytic activity in milder reaction conditions,but also exhibit good substrate applicability.Then,the benzyl C(sp~3)-H bond functionalization of 2-methylazaarenes can be carried out in ionic liquid aqueous solution without the addition of catalyst was established.After investigating the effect of a series of conditions on the reaction,it was determined that the 20%ionic liquid(1-Octyl-3-Methylimidazolium Tetrafluoroborate)aqueous solution as the solvent,the reaction was best at 70?,and a series of azaarene derivatives were obtained in 18%~82%yield.Compared with the system using organic solvent as the reaction medium,the system is more mild and has higher reaction efficiency without the need of adding additional catalyst,and most importantly,avoids the use of a certain toxic organic solvent.Finally,a novel approach for the addition reaction between 2-methylazaarene and electron-deficient olefins with deep eutectic solvent as the solvent under catalyst-free condition was been studied.After a series of conditions were selected,19azaarene derivatives were obtained in 22%~86%yield under 0.5 mL DES(choline chloride/citric acid=1:1)at 80?.Compared with previous studies,this method has shorter reaction time and higher yield,meanwhile,the DES can be recovered and reused,which is more in line with the trend of green chemistry today.