Azidative And Silylative Aromatization Of Quinone Methides Under Metal And Solvent Free Conditions

In recent years,para-quinone methides(p-QMs)have emerged as attractive and versatile synthons in organic synthesis owing to their high reactivity.Consequently,p-QM chemistry has attracted increasing attention and remarkable advances have been achieved.Among the numerous transformations involving p-QMs,catalytic reactions play a pivotal role,and a variety of catalytic systems mediated by Lewis acids,Br(?)nsted acids,bases,transition metals,N-heterocyclic carbenes,and other catalysts have been established for performing 1,6-conjugate addition reactions.Various molecular scaffolds have been constructed using p-QMs to obtain the core structures of numerous natural and synthetic substances of chemical and biomedical relevance.Among various biologically active drugs,organic azides play an important role for their special structures.Because azide can be converted into amines and triazoles,and these groups are common in bioactive drugs,therapeutic drugs and functional materials,organic azide compounds have been widely used in material synthesis,drug development and biochemistry.Because organic azide compounds are active intermediates with great research and application value,a large number of reports on the synthesis,preparation and performance research of organic azide compounds were publised every year.Heterotrophic organisms cannot synthesize organosilicon compounds by themselves,but they can ensure their own metabolism by absorbing organosilicon from plants.In the field of drug development,increasing the activity of drugs by replacing functionalized groups with silicon-containing groups in biologically active molecules has attracted much more attention.The last decades witnessed a tremendous development in the use of organosilicon compounds for organic synthesis.Based on the obviously activity of p-QMs,we designed an efficient and general azidation and silylation of p-quinone methides under tansiton-metal-free and solvent-free conditions.The method,especially the azidation of p-QMs,has achieved the goal of green chemistry which performed without transition-metal,solvent and can get high purity product without column chromatography.This paper including the following aspects:Chapter 1,the research backgroundThe research progress of p-quinone methides,azidation reaction and silylative addition reaction in medicinal chemistry and organic synthesis in last years are reviewed.Chapter 2,experiment preparationThis chapter introduced the reagents used and the anhydrous treatment methods of several solvents,and the synthesis of p-quinone methides and o-quinone methides substrates.Chapter 3,study on the azidation reaction of quinone methidesWe designed a method for the azidation reaction of quinone methides under transition-metal-free and solvent-free conditons.By screening the factors that affect the activity of the experiment,we obtained the optional reaction conditions and achieved the corresponding products in quantitative yields.In addition to the aromatic and aliphatic substituted p-quinone methides,the applicable substrates of this method are also applicable to o-quinone methides.The reaction operation is simple and the conditions are mild,and the recycled cesium carbonate maintains excellent catalytic activity.The diphenyl azide products obtained by the reaction can generate a triazole compound through a click reaction,or it can undergo a reduction reaction through Pd/C catalysis under the protection of Boc to generate the corresponding amine.Chapter 4,study on the silylative addition of p-quinone methidesWe designed a method for the silylative addition reaction of p-quinone methides under transition-metal-free and solvent-free conditions.The reaction is catalyzed by the inorganic base cesium carbonate,and water is used as an additive to obtain diphenylsilyl products with high yield.The diphenylsilyl products produced by the reaction can be catalyzed by cesium fluoride to react with CO2 to generate the corresponding acid.Chapter 5,study on the chiral carbene-catalyzed enantioselective silylative aromatization of p-qunine methidesAfter screening a series of aza-carbene ligands,as well as conditions such as solvents and base types,we finally selected carbene ligands with[2,2]paracycolphane,and successfully reacted with the silyl addition reaction of p-quinone methides in up to more than 90%ee.The innovation of this paper:1.Under the reports that azidation and silylation are transition-metal catalyzed mostly,we propose inorganic base catalyzed azidization and silylation to avoid the potential hazards of transition-metals in the chemical biology studies and pharmaceutical synthesis;2.In the reaction process,no additional organic solvent is added to efficiently obtain the reaction products;3.In the post-treatment of the azide reaction,high-purity reaction products can be obtained without column chromatography for purification,further achieving the goal of green chemistry.4.For the first time,the asymmetric silyl addition reaction of p-quinone methides has been studied,and the enantioselectivity of the reaction can reach up to 96%ee.