Zinc(?)-Catalyzed Intramolecular Hydroarylation-Redox CDC Reaction To Construct 2-Substituted Tetrahydroquinolines

Tetrahydroquinolines were commonly found in natural products and drugs.They had a variety of biological activities,such as antitumor,antibacterial,antiviral,anti-Alzheimer's and antidiabetes.Most of the existing synthetic methods,including partial reduction of quinoline ring,Povarov reaction,and intramolecular bonding reaction,needed strong acids,strong reducing agents or halogen substituents.An Intramolecular Hydroarylation Redox Cross Dehydrogenation Coupling reaction catalyzed by Zn???has been developed by our group,and it has been applied to the green synthesis of 2-indole-1,2,3,4-tetrahydroquinolines.The alkyne bond in the propargyl aniline acted as a hydrogen atom acceptor to be firstly cyclized by the activation of Zn???,and then underwent 1,3-hydrogen transfer to obtain the imine positive ion and followed by the nucleophilic addition reaction of indole to afford the final product.There were no addition of external oxidants,and the atomic utilization rate was 100%.In this work,the IH-Redox CDC reaction of N-propargylanilines with nitromethane?sp³carbon pronucleophile?was performed in the presence of ZnBr₂?10 mol%?at 100 ^oC for 24 h under nitrogen atmosphere.Thirteen 2-methylnitro-1,2,3,4-tetrahydroquinoline compounds were constructed with yields ranging from 15%to 70%,and the substrates had good applicability.Three important pharmaceutical intermediates and MT₂ melatonin receptor agonists were prepared from the final product 3a.The IH-Redox CDC reaction of of N-propargylanilines with Phenylacetylene was performed in the presence of ZnBr₂?20 mol%?at 120 ^oC in 1,2-dichloroethane?DCE?for 24 h under nitrogen atmosphere.Eighteen 2-ethynylbenzene-1,2,3,4-tetrahydroquinoline compounds were successfully constructed with yields ranging from 51%to 80%,and the substrates had good applicability.Based on this reaction,two natural alkaloids?caspareine and galipinine?were prepared,and a fused ring compound was prepared from the final product 9ca.Based on the deuterium labeling experiment study of our group on the reaction mechanism of IH-Redox CDC,two deuterium labeling experiments of indole were supplemented,confirming that the deuterium hydrogen at the C4 position in the final product was from N-benzyl-N-?2-alkynyl-3-deuteropropyl?aniline retaining in situ position after being formed into a ring.And the N-benzyl-N-?2-alkynyl-3-deuteropropyl?aniline was formed from the exchange reaction of hydrogen atom with deuterium atom.Three deuterium labeling experiments?N-benzyl-N-?2-alkyn-3-deuteropropyl?aniline,N-benzyl-N-?1-deutero-2-propargyl?aniline,1-deuterated phenylacetylene?were carried out to confirm the existence of 1,3-hydrogen transfer between C2 and C4 in the IH-Redox CDC reaction,which further verified the accuracy of the IH-Redox CDC reaction mechanism.