Copper-catalyzed Interrupt Click Reaction:Synthesis Of Multisubstituted Triazoles Containing Sulfur

In 2002,Sharpless and Meldal simultaneously reported the absolute region-selective preparation of 1,4-dis-triazoles by Huisgen cycloaddition reactions using copper as catalyst and starting with small organic molecules of terminal alkynes and azides,known as CuAAC reactions.Sharpless and Meldal were awarded the 2022 Nobel Prize in Chemistry for their outstanding work on the CuAAC reaction.Traditionally,1,2,3-triazoles are prepared by heating to promote the Huisgen 1,3-dipole cycloaddition reaction between acetylene and azide;however,this reaction usually requires higher temperatures and longer action times.When acetylene is used as a starting material,a mixture of two regional isomers is usually obtained,and these mixtures are difficult to separate.Compared with Huisgen’s 1,3-dipole cycloaddition,CuAAC reaction has many advantages,such as mild reaction conditions,high reaction efficiency,significant chemical and regional selectivity,and good compatibility with functional groups.Cuaac reaction has become a typical representative of "click chemistry".In addition,the 1,2,3-triazole obtained from the reaction is a special skeleton,which is used in many fields such as drug development,biochemistry and materials science.1,2,3-triazole is also used as a ligand,a high efficiency promoter for C-H activation,and as a precursor of carbene in the preparation process.In recent years,the application of organic preparation methods of triazoles has been widely concerned by scholars at home and abroad,and a large number of results on organic preparation of triazoles have been published.The traditional CuAAC method can only obtain 1,4-di-substituted triazoles.Due to the poor activity of non-alkynes and their adverse regional selective regulation,the efficient preparation of 1,4,5-tri-substituted triazoles is difficult.In our previous work,we found that the cycloaddition of alkynes and azides with a specific skeleton can be used for the efficient preparation of multi-substituted triazoles.However,the catalyst required for this method is precious metal,and the range of substrates is relatively narrow,which is not universal.Therefore,the preparation of polysubstituted triazoles is very challenging.In this context,we propose a multi-component "one-pot" copper catalyzed click interrupt reaction to achieve absolute regional selectivity in the construction of multi-substituted triazoles.The main work of this paper includes four parts:Chapter 1:Preparation of multisubstituted triazolsulfone compounds by Cupric(Ⅰ)catalyzed four-component interrupt click free reaction.The synthesis of multisubstituted triazolsulfone compounds by Cupric(Ⅰ)catalyzed terminal alkyne,organic azide organic small molecule,DABSO(1,4-diazo diannulus[2.2.2]octane bis(sulfur dioxide)and aryl diazo salt is achieved in series.In this method,cuprous iodide was used as the catalyst,terminal alkyne,organic azide organic small molecules,DABSO(1,4-diazo diannulus[2.2.2]octane diazo(sulfur dioxide)and aryl diazo salt were used as the starting materials,sodium bicarbonate as the reaction base,dried tetrahydrof uran as the solvent,nitrogen at 60oC.Multi-substituted triazolsulfone compounds were prepared efficiently.This method has many advantages,including no need to use smelly mercaptan or disulfide as the sulfur source,relatively green environmental protection;The reaction condition is mild,the compatibility is good,all kinds of functional groups are applicable.We developed the first copper(Ⅰ)catalyzed four-component click reaction to obtain triazolsulfone,a novel interrupt click reaction and free radical relay process.Chapter 2:Preparation of multi-substituted sulfur-containing triazoles using elemental sulfur as sulfur source copper(Ⅰ)catalyzed multi-component interrupt click reaction.First,we designed the preparation of azide halides by combining azide with halide.On this basis,in the presence of copper catalysis,with terminal alkyne,azide iodide and elemental sulfur as the initial raw materials,the preparation of various 5-thiotriazole and 5-selenotriazole rings,including various medium and large rings,has been achieved in three components in one step,with absolute regional selectivity.After the establishment of the three-component click reaction,the four-component click reaction was realized at a relatively high temperature,and the efficient preparation of various 5-thiotriazole and 5-selenotriazole was realized.The method started from the elemental sulfur,took cuprous thiocyanide as the catalyst,and took terminal alkyne,azide organic small molecules and aryl iodide as the initial raw materials.Polysubstituted triazoles were prepared with DMSO as solvent,sodium bicarbonate as base and nitrogen.The main characteristic of this method is to generate active electrophilic sulfide reagent by activating elemental sulfur,and to prepare the target product by intercepting the click intermediate cupritriazole with in situ thiophile electrophilic reagent.Chapter 3:Preparation of N-1 and N-2 substituted triazolsulfone compounds by copper catalyzed three-component series reaction.We have achieved a "one-pot"method for the controlled and selective preparation of N-1 and N-2 substituted triazolsulfone compounds by three-component copper catalyzed terminal alkynes,trimethylazide silanes and arylsulfonic acid.In this method,a series of N-1 and N-2 substituted triazolsulfone compounds were selectively prepared by controlling the type of copper catalyst,alkyne,azide trimethylsilane and arylsulfonic acid,using copper as catalyst.Chapter 4:Preparation of 2-substituted benzof urans by[3+2]cycloaddition reaction between benzoquinone and vinyl azide catalyzed by Lewis acid.Using transition metal(silver or scandium)as catalyst,benzoquinone and vinyl azide compounds as starting raw materials,adding molecular sieve additives,2-substituted benzof uran compounds were efficiently prepared at room temperature.A series of 2-substituted benzof urans were prepared in one step by using a simple and readily available starting material.The main characteristics of this reaction are mild reaction conditions,insensitive to air,good compatibility,all kinds of functional groups are applicable.