Oxidative Coupling And Conjugate Addition Of Indole/Aromatic Carboxylic Acids

In recent years,oxidative coupling reactions and conjugate addition reactions of C-H bonds to polar double bonds have been developed as important methods in catalytic synthetic chemistry due to their high efficiency and high atomic utilization.These two reactions have made remarkable progress in the design of synthetic routes,related catalytic systems,and selectivity.Some processes have been used in the synthesis of natural products,physiologically active molecules,and important fine organic intermediates.Based on the review of the oxidative coupling reaction of indoles and aromatic acids,and the conjugated addition reaction of carboxyl-directed C-H bonds to polar C=C bonds in the past decade,this thesis carried out the following four works using cheap and commercially available indoles and aromatic acids as starting materials by the activation of C-H bonds.(1)The oxidative coupling reaction of indole and DMF has been achieved by using N,N-dimethylformamide(DMF)as the methylenating reagent,the copper-catalyzed C-H bond activation of indole was demonstrated as an efficient and facile protocol for synthesizing 3,3'diindolemethane(DIM)and its derivatives.The results indicate that the reaction affords an excellent regioselectivity and good yield when TBHP as an oxidant.The reactivity of N-methylindole and indole was greatly different due to the electron-donating effect of methyl groups.When monovalent CuCl is used as the catalyst,N-methylindole can react smoothly,but indole without substituent on the nitrogen atom requires divalent Cu(OAc)2 as catalyst to obtain the target product in good yield.(2)A palladium-catalyzed tandem process of simple aromatic acids has been achieved to afford meta-substituted biaryls in moderate to good yields.The reaction proceeds via carboxyl-directed intermolecular cross-dehydrogenative coupling,and subsequent decarboxylation.The new C-C bonds in this transformation are formed in the ortho position of carboxyl and the reaction tolerates electron-rich acids.Both symmetrical and unsymmetrical meta-substituted biaryls can be directly synthesized via this method.(3)A cross-dehydrogenation coupling reaction of carboxylic acid and acetonitrile using copper acetate,potassium bromide and water as additives was achieved in O2 to afford cyanomethyl benzoate compounds.This protocol features commercially available starting materials,broad substrate scope,high atomic utilization,insensitivity to air and water,and avoiding noble metal catalyst.This method provides a simple and efficient way for the synthesis of cyanomethyl benzoate compounds.(4)A ruthenium-catalyzed protocol to access conjugate addition or decarboxylative conjugate addition of aromatic acids with maleimides has been developed.The reaction shows interesting chemoselectivity with different substituted benzoic acids.The reaction pathway of C-H alkylation is controlled by the intrinsic property of aromatic acids but not reaction conditions.Under almost the same reaction conditions,carboxyl can act as either a classical directing group or a traceless directing group,thereby generating two kinds of products,i.e.,2-alkyl substituted benzoic acids and alkyl substituted benzenes.These two reactions proceeded under mild and redox-neutral conditions in neat water under the atmosphere of air,and could be easily scaled up to grams.The decarboxylative conjugate addition,where carboxyl acts as a traceless directing group,can be realized without the addition of any ligand,silver or copper salt.