A Modular Synthesis Study Based On Diacetylenes

As an excellent synthesis method,click chemistry has been widely used in many areas such as chemistry,material,medicine,and so on,the representative of which is the copper(I)catalyzed alkyne-azide cycloaddition reaction(Cu AAC).It is challenging to get one of the subsentences,the organic azides,efficiently.In 2019,the discovery of fluoro sulfonyl azide(FSO2N3)in the efficient and specific conversion of primary amines to the corresponding azide compounds enabled the high-throughput synthesis of azide compounds.Established by FSO2N3 and a great number of primary amines,the modular click reaction between the terminal alkyne and the azide library achieves the modular synthesis of triazole compounds.In order to double the utilization efficiency of the azide compound library,and inspired by the alkyne introducing strategy of drug modification,we tried to modify a large number of existing terminal alkynes into corresponding multiyne compounds and then carry out a Cu AAC reaction to realize the wider application of azide compound library.The paper focuses on the construction of 1,3-diyne and its Cu AAC reaction.First,based on a comparison of reactivity,selectivity,and reaction conditions,we chose the Cadiot-Chodkiewicz reaction as the standard 1,3-diyne modifying reaction for its significant reactivity,high selectivity,and low cost.By screening the acetylene bromide substitutes made from acetylene blocks commonly used in the laboratory,we finally selected triisopropyl silicyl acetylene bromide as the standard acetylene modifying block and kinds of triisopropyl silicyl(TIPS)protected diynes were produced with it.The method is simple to operate,with mild reaction conditions and good compatibility for various functional groups.The product,silicon-protected diyne compounds,has good air stability and is easy to synthesize,purify,and amplify.After obtaining several silicon-protected diynes,we removed the protecting group.Then we found that the high instability of terminal diynes made it challenging to separate,purify,or storge,so the terminal diynes should be made and used timely.Therefore,we developed a one-pot strategy to directly perform Cu AAC reaction on silicon-protected 1,3-diyne,which skips the purification process of 1,3-diyne.In this method,only the catalytic amount of fluoride ion was added as the protecting group remover,and the commercially available Cu AAC ligand was needed to ensure the efficiency of Cu AAC reaction after deprotection.Subsequently,the substrate scope of this method also showed that this method has good deprotection activity and Cu AAC reactivity.In addition,the strategy has the advantages of simple operation,mild conditions,high efficiency,excellent yield,and broad functional group compatibility.The strategy can not only be widely used in Cu AAC reaction of existing siliconprotected 1,3-diynes,but also be used in any alkynyl compounds that will become unstable after deprotecting silicon protecting groups,which shows broad application prospects and practical value.