Palladium-Catalyzed C-2 Arylation Of Indoles Promoted By Novel Biphenyl Carboxylic Acid Ligands

Transition metal catalyzed C-H bond functionalization is a powerful organic synthesis strategy,with high atomic economy,wide application range of substrates,mild reaction conditions,etc.,and has a wide range of applications in biology,medicine and other fields.In recent years,the carboxylate-assisted transition metal catalyzed C-H bond functionalizations has been fully developed,broadening the scope of application of C-H bond functionalization.The development of novel carboxylic acid ligands for palladium-catalyzed C-H bond functionalization is important,for example,effectively increasing the reactivity,generating new chemical selectivity,etc.,is an important proposition in the field of C-H bond functionalization research.Our research approach is based on concerted metalation-deprotonation mechanism to develop and evaluate novel biphenyl carboxylic acids that act as ligand and proton shuttle for C-H bond functionalization.Compared to traditional pivalic acid ligand,the novel biphenyl carboxylic acids are effective in promoting C-H bond functionalization under milder conditions,achieving faster reaction rates,better substrate application range and regioselectivity.As analogs of Buchwald's ligands,we designed and evaluated the application of various substituted 2-arylbenzoic acids in palladium-catalyzed regioselective C-2 arylation of indoles and aryl bromides.Through a large number of ligand designs and synthesis,we have found that 3-ethoxy-2-phenylbenzoic acid as a ligand can give excellent yield and selectivity.In addition,we also studied the impact of the carboxylic acid loading on the reaction results and found that the best results were obtained with the addition of 30 mol%of 3-ethoxy-2-phenylbenzoic acid.The reaction has good functional group compatibility and is well compatible with various important functional groups such as nitro,alcoholic hydroxyl groups,aldehydes and esters.The kinetic isotope effect experiment preliminarily speculated that the reaction undergoes a concerted metallization-deprotonation pathway.In summary,through a large number of ligand design synthesis and condition optimization,we screened to obtain a novel 2-arylbenzoic acid ligand with a skeleton structure similar to Buchwald's ligand.We applied the above ligands to palladium-catalyzed C-2 arylation of indoles,which showed excellent reaction yield,regioselectivity and compatibility of sensitive functional groups.