Synthesis Of Multisubstituted Triazoles With Interrupted Click Reaction

In 2002,Sharpless et al.and Meldal et al.reported a copper-catalyzed azide-alkyne cycloaddition(CuAAC reaction)leading to 1,4-disubstituted 1,2,3-triazoles with an ideal regioselectivity.The synthesis of 1,2,3-triazoles have conventionally been achieved using the thermal Huisgen cycloaddition between alkynes and azides to afford a mixture of the 1,4-and 1,5-substituted 1,2,3-triazoles,but with high reaction temperature and poor regioselectivity.The CuAAC reaction has received significant attention due to its numerous advantages,including dramatic rate acceleration,high reaction efficiency,mild reaction conditions,simple operation and separation and complete regioselectivity,and has found widespread applications in organic chemistry,polymer chemistry,materials science,and biological conjugation and thus has become a prime example of current click chemistry.In addition,the 1,2,3-triazoles obtained by this reaction are not only a link unit,but also an important nitrogen heterocyclic compounds and have found widespread applications in drug discovery and medicial chemistry because of their unique structural and special chemical and biological properties.The 1,2,3-triazoles are also widely used as ligands for metal catalysis and asymmetric catalysis,and also directing groups for transition-metal-catalyzed C-H activation.The classical CuAAC reaction affords only 1,4-disubstituted triazoles using terminal alkyne as an essential substrate;however,such reactions of internal alkyne affording 1,4,5-trisubstituted triazoles are much more difficult because of their low reactivity and difficulty in regiocontrol.This becomes a fundamental problem of current click reactions.The recent developed Ruthenium and Iridium-catalyzed azide-alkyne cycloaddition reactions have partially addressed this challenge,however the regioselectivities are highly substrate-dependent and noble metal catalysts are required.Based on the above issues,in this thesis,we have developed an intercept click reaction strategy using some approptiate electrophiles to intercept the in situ formed cuprate-triazole intermediate forming some multisubstituted triazoles in one-pot with complete regioselectivity.The thesis includes four parts:Chapter ?,a copper(?)-catalyzed tandem CuAAC/alkynylation reaction of various alkynes,organic azides,and bromoalkynes to provide rapid access to multisubstituted 5-alkynyl-triazoles has been developed.This reaction offers a new method to afford fully substituted triazoles in high yields with complete regioselectivity and good functional group compatibility under mild reaction conditions.The alkyne moiety can be further converted into other functional groups or heterocycles.Chapter ?,a copper(?)-catalyzed interrupted click reaction to construct multisubstituted 5-amino-triazoles is described.The reaction proceeded via a copper-catalyzed alkyne azide cycloaddition followed by interception of the in sute formed cuprate-triazole intermediate with electrophilic O-benzoyl-N,N-dibenzylhydroxylamine.The reaction proceeds under very mild conditions with complete regioselectivity.It also features a broad substrate scope with respect to alkynes,azides and also different electrophiles.Chapter ?,we have developed a copper(?)-catalyzed interrupted click reaction to access multisubstituted 5-thio-and 5-seleno-triazoles.The reaction proceeds under very mild conditions with complete regioselectivity and no required ligands.It also features a broad substrate scope and good functional group compatibility.The reaction can be used to construct bicyclic triazoles with 5-to 14-membered rings in moderate to good yields.A notable feature of this reaction is the late-stage functionalization of bioactive compounds.Chapter ?,a copper(I)-catalyzed interrupted click reaction to synthesize multisubstituted 5-disulfur-triazoles has been developed.The reaction proceeds under very mild conditions with a broad substrate scope and no required ligands or additives.This electrophilic disulfur reagent is also efficient with aryl boronic acids,terminal alkynes and thiols afforded corresponding unsymmetrical disulfides and trisulfides.More importantly,we have obtained an unstable and short-lived hydropersulfide under acidic conditions which plays a very important role in redox cell signaling.This reaction offers a new method to afford asymmetric disulfides and polysulfides.In summary,we have developed an intercept click reaction strategy using approptiate electrophiles to intercept the cuprate-triazole intermediate forming some multisubstituted triazoles.These reactions offered a new method to afford fully substituted triazoles and polysulfides and have found widespread applications in medicial chemistry and polymer chemistry.