Primary Amine Directed Pd Catalyzed C-2 Arylation Of Tryptamine

Indole is a privileged scaffold found in numerous natural products and biologically important drug molecules.Particularly,C-2 arylated tryptamine derivatives have drawn tremendous interest among synthetic and medicinal chemistry community because of their interesting biological profiles and unique structural features.Discouragingly,available methods for the synthesis of 2-aryltryptamines are only applicable to protected tryptamine substrates.Additionally,the drawbacks of these methods,including tedious steps,narrow substrate scope,low yields,the use of pre-prepared substrates,etc.,restrict the synthetic practicability.Hence,new protocols enabling efficient synthesis of 2-aryltryptamine derivatives are highly desirable.The directing group（DG）assisted C-H activation has become a promising synthetic strategy for its higher reactivity,selectivity,and step economy,among which the use of native substrates without covalently installing external DGs remains one of the major challenges in directed C-H activation.Although bulky amine-directed C-H functionalization reactions have been developed,the non-steric NH₂-directed C-H functionalization has been less realized and needs further investigation.In this context,we developed the non-steric NH₂-directed Pd（II）-catalyzed intramolecular C（sp²）-H arylation that enables efficient synthesis of biologically important 2-aryltryptamines（38 examples,up to 98%yield）in a regioselective manner via six-membered cyclopalladated complex using tryptamines as substrates.The gram scale reaction of compound 4e was carried out with slightly decreased yield,indicating the robust applicability and practicability of this method.In addition,late-stage elaborations of 2-aryltryptamine achieved the core skeletons of three types of important natural products,which further demonstrated the powerful application potential of this method.Then,based on the experimental results and related literature reports,we proposed a possible catalytic cycle of the reaction.Eventually,the inhibitory effects of these compounds at a concentration of 10μmol/L against the tumor targets LSD1 and SHP2 as well as the evaluation of their anti-tumor activity in vitro were determined.Compound 4d has the best inhibitory effect on LSD1（inhibition rate:35.7%）;Compound 3g has the best inhibitory effect on SHP2（inhibition rate:42.1%）;Compounds 4a-d have a general inhibitory effect on tumor cells,and the trend is EC109>MGC-803>A549.The structure-activity relationship is that the larger the indole NH substituent,the better the inhibitory effect.The research provides an efficient method for the synthesis of 2-aryltryptamine and a material basis for activity screening based on diverse compound library.Further biological activity evaluation results provide a structural basis for the design of anti-tumor inhibitors based on structural modification and optimization.