Iron-catalyzed Regioselective C5-H Benzylation Of 8-Aminoquinolines

Quinoline is an important substance that has a prominent role in many natural products,bioactive molecules,drugs and functional materials,and has attracted wide attention.Therefore,the synthetic methods of the chemical modification of quinoline derivatives had been the focus in recent 10 years.Several successful transformations are mainly focusing on the functionalization at the C2-H、C3-H and C4-H positions.However,much less effort had been taken to the functionalization at the C5-H position of quinolone derivatives with high regio-selectivity.Therefore,the C5-H activation reaction of aminoquinoline plays an important role in enriching the aminoquinoline molecular library and expanding its application in medicine and materials.This study focused on the benzylation reaction of 8-amidoquinoline amides with high regioselectivity by using N-（quinoline-8-yl）pivalamide as the reaction substrate and the cheap and readily available iron（III）chloride as catalyst.The main conclusions of the study are as follows:（1）The benzylation of aminoquinoline C5-H catalyzed by FeCl₃,which was cheap and readily available,were demonstrated.Under the argon atmosphere,（0.2mmol）N-（quinolin-8-yl）pivalamide as the reaction substration,（0.6 mmol）1-phenylethyl acetate as the benzyl source,（15 mol%）FeCl₃ as the catalyst,（0.5 mL）1,2-dichloroethane was used as the solvent,the reaction temperature was 140℃,the reaction time was 24 h,and the reaction yield was 91%.The results indicated that the reaction could synthesize 8-aminoquinolinebenzylated derivative with high regio-selectivity and high yield.（2）With the optimized reaction conditions in hand,we subsequently investigated the substrate scope of 8-aminoquinoline amides and benzylic acetates.The experimental results showed that both linear and cyclic alkyl,aromatic and heterocyclic protected 8-aminoquinolinamides,as well as various electron donating groups and electron withdrawing group substituted benzyl acetates,could smoothly take part in the reaction procedure.In addition,it was suitable for gram-scale synthesis and late-stage functionalization of pharmaceutically valuable molecules.（3）Using the“one-pot boiling”method,the anhydride and the benzyl alcohol could be directly used as the reaction raw material which could react with the aminoquinoline compound to form the benzylated aminoquinoline product.The reaction conditions were as follows:（15 mol%）FeCl₃ as a catalyst,（0.2 mmol）N-（quinoline-8-yl）pivalamide and（0.6 mmol）DL-1-phenylethanol as raw materials,and（2 eq）succinic anhydride as an additive.A C5-H benzylated aminoquinoline derivative with an isolated yield of 83%could be obtained.The reaction process conditions were simpler and the reaction was more efficient.（4）The structure of the product was characterized by ¹H-NMR,¹³C-NMR and¹⁹F-NMR.