Visible Light-Catalyzed Synthesis Of 3-Sulfonylated Thioflavones And 3-Acetalized 2（1H）-Quinolones

In recent years,in order to achieve the rapid derivatization of the dominant skeleton with biological activity,free radical cyclization and C-H activation reaction as a reliable and convenient strategy have attracted more and more attention.We have achieved the green synthesis of 3-sulfonylated thioflavonoids and the direct C3 acetalization of the 2（1H）-quinoxalinone nucleus through the mechanism of free radical reaction under the catalysis of visible light.The structural modification of the dominant framework commonly used in the development of these two drugs which are based on thioflavones and quinolones provides a new method with strong operability.We have synthesized a total of 61 brand-new derivatives with dominant backbones,and the later activity screening work is currently underway in the laboratory.As the isostere of flavonoids,thioflavonoids have gradually become one of the dominant frameworks commonly used in researches for new drugs.Drugs such as Meticrane and Dorzolamide take thioflavonoids as the core and have strong biological activity.Traditional methods for the construction and derivatization of thioflavonoids require heating,transition metals and a large amount of organic solutions,which easily cause environmental pollution and heavy metal residues.Therefore,the construction of thioflavonoids without metal catalysis and the development of derivatization methods by green mediums has become an urgent synthetic problem in the research of new drugs.We have developed a visible light catalytic system using EG as the green solvent and 9-resorcinol-10-methylpyrimidine perchlorate（Acr⁺–Mes·Cl O₄^-）as the photocatalyst.The construction of thioflavonoids and benzene sulfonylation are realized in one step.We use 1-（2-（methylmercapto）phenyl）-3-phenyl-2-propyn-1-one as the raw material,benzenesulfonyl hydrazide as the benzenesulfonyl radical donor,and K₂S₂O₈ or O₂ as the oxidant,Using（Acr⁺–Mes·Cl O₄^-）as the photocatalyst,EG as the green solvent,reacting at room temperature under the irradiation of blue LEDs,through the sulfonation/cyclization cascade reaction involving free radicals to realize the construction and derivatization of thioflavonoids as advantageous skeleton.Through this multifunctional catalytic system,we can also realize the sulfonation of indole and quinoline-2,4（1H,3H）-dione.This method has the characteristics of broad functional group tolerance,excellent regioselectivity,mild conditions and ease of operation.Quinolone is a nitrogen heterocyclic ring which widely found in drugs and biologically active compounds.The 2（1H）-quinoxalinone skeleton is one of the most important structural motifs.It has significant biological activity and excellent drug properties,such as anti-blood clogging,anti-diabetic,anti-inflammatory,anti-tumor,anti-microbial infection and Aldose reductase inhibitor activity.Therefore,in the past few years,the derivatization of 2（1H）-quinoxalinone core has become one of the important directions of designing for new drugs.The C-3 position of the 2（1H）-quinoxalinone nucleus has become the main site for derivatization of this type of compound because of its unique chemical properties.Through the direct functionalization of the C-3 position,many new 2（1H）-quinoxalinone derivatives have been synthesized,including C-3 amination,arylation,amidation,benzylation,alkylation,and acylation,hosphorylation and phosphonate reaction,etc.Although these studies are of great significance,so far,no method for acetalization of quinolone C3 has been reported.Based on the research foundation of the green derivatization of the dominant framework in the early stage,we developed a C-H direct acetalization reaction of 2（1H）-quinoxalinone without the participation of transition metals catalyzed by visible green light.This method uses low-toxic DMF as a solvent,green light（λmax=520 nm）as a light source,4-Cz IPN as catalyst,and cesium carbonate as an additive.This method not only realizes the acetalization of2（1H）-quinoxalinone with different substituents on the benzene ring,but also realizes the acetalization of2（1H）-quinoxalinone with various side chains attached to N-Acetalization.We also realized the later modification of various drugs and active compounds including dehydrocholic acid,indomethacin,levulinic acid by this method and provided a new type of drug structure modification strategy.