Synergistic Catalysis Of Photoredox And Hydrogen Bonding To Construct Quinoxalin-2-one C3-α Chiral Center

Quinoxalin-2-one,a special kind of nitrogen heterocyclic skeleton,widely exists in a variety of natural products and drug molecules,especially the C3-substituted quinoxalin-2-one derivatives show unique biological activities.In recent years,great efforts have been devoted to the synthesis of C3-substituted quinoxalin-2-ones,and considerable research results have also been achieved,among which reports of visible light-driven or photoredox catalysis have grown exponentially.Although there have been a lot of reports on the construction of the heterocyclic derivatives,there are relatively few studies on asymmetry,and no one has reported the method of directly functionalizing the heterocyclic ring to construct a chiral center at the C3-α position.Based on the important value of the quinoxalinone structure,we envisage that the three-component substrate undergoes a radical series reaction by photoredox,and a chiral catalyst is added to control the chirality,thereby constructing a quinoxalin-2-one C3-α Stereocenter.This study used the photosensitizer DPZ(dicyanopyrazine photosensitive compound)independently developed by our research group and chiral Br(?)nsted acid for synergistic catalysis.N-Methylquinoxalin-2(1H)-one,bromoacetophenone,styrene template substrate realizes its multi-component tandem addition reaction,by screening different Br(?)nsted acids and reaction conditions,and finally synthesized with high enantioselectivity A series of quinoxalin-2(1H)-one derivatives withα-chiral center at C3 position.Among them,the substrates substituted with different electrical groups have good tolerance,and can get moderate to good yields,with ee up to 96%.The reaction mechanism was explored by linear correlation experiments between catalysts and products,quenching experiments,and cyclic voltammetry experiments,and a reasonable hypothesis was put forward: bromoacetophenone was reduced to an alkyl radical by a photosensitizer,and the radical added to styrene,a new benzyl radical is generated,which is then added to the carbon-nitrogen double bond of the protonated quinoxalin-2(1H)-one,and then undergoes the process of oxidative deprotonation to obtain the final product.This paper mainly accomplishes three challenges: 1)High chemical selectivity: multi-component reactions can easily lead to chaos in the reaction system,formation of free radicals and regioselectivity of addition,and the sequence of multi-component substrate reactions will affect the the final result of the reaction.2)High enantioselectivity: The chiral Br(?)nsted acid activates the quinoxalin-2(1H)-one,and there is a hydrogen bond between the protonic acid and the N atom,which provides a chiral environment for the subsequent free radical addition.3)Construction of α-chiral center at C3 position of quinoxalin-2(1H)-one:The reports on the chiral center of quinoxalin-2(1H)-one compounds mostly focus on the construction of C3 position of quinoxalin-2(1H)-one.In this work,the α-chiral center at the C3 position of quinoxalin-2(1H)-one was constructed under mild reaction conditions by using photoredox and hydrogen bonding synergistic catalysis.A more general and direct synthesis method is provided for the diversification of quinoxalin-2(1H)-one drug molecules.