Study Of C-H Functionalization Base On4-Aminobenzotriazole As A Novel Directing Group

Transition-metal-catalyzed C-H functionalization has been considered as one of the most important reactions in chemical synthesis,since it provides an efficient approach to access complex molecular skeletons through late-stage functionalization.To achieve good selectivity of specific C-H bond activation,directing group（DG）has often been applied.Among all the directing groups,amide N-heterocycle as a bidentate directing group could be installed by readily converting COOH-containing substrates and amino N-heterocycle into amide.These bidentate directing groups include 8-aminoquinoline（AQ）,2-（2-pyridyl）-2-propanamine（PIP）,2-pyridyl methylamine,and1,2,3-triazole derivatives（TAM）,which greatly enriched the field of selective C-H bond activation.In this dissertation,for the first time,we developed a novel aromatic amine bidentate directing group,4-Aminobenzotriazole（ABTA）,to expand the types of the bidentate directing group.Compared to other directing groups,we can explore more reaction modes by modifying the directing group.Therefore,to explore the properties of the directing group and functional groups transformations,we used 4-Aminobenzotriazole as the directing group to achieve ortho C-H bond activation with palladium.（1）Pd-Catalyzed 4-Aminobenzotriazole-Directed C（sp²）-H OlefinationThe synthesis of N1,N2,and N3 alkyl and aryl substituted 4-aminobenzotriazoles were explored for the first time with inexpensive benzotriazole.By mixing the synthesized amide substrate with Pd（OAc）₂（1:1）,two novel（5,5）and（6,5）metallocycles intermediates were obtained.Comparing the metal coordination ability of ABTA and other different directing groups（AQ,PIP and TAM）with Pd,the ratios of（6,5）ring metallocycles intermediates were determined as ABTA to AQ（8:1）,PIP（5:1）and TAM（2:1）,which reflected the ABTA’s stronger coordination ability.Then,when using 6,5-metallocycles intermediates to react with tert-butyl acrylate,ABTA,as a novel directing group,showed a better olefination results and thermal stability than other directing groups.Subsequently,the olefination condition was optimized with Pd（OAc）₂ as catalyst,Ag OAc as cocatalyst,O₂ as oxidant and KOAc as base in DCE and successfully obtained the products of alkenylations in 92%yield.Under the standard conditions,the scope of substrate was explored by expanding different amides and alkenes（>40）to obtained different olefination products in high yields（up to 95%）,which reflected its broad substrate applicability.The ABTA directing group could be removed under mild conditions and recycled in more than 90%yield.Comprehensive experimental results indicated that ABTA as a novel bidentate directing group had good chemical reactivity in Pd（0/II）cycling system,including stronger coordination ability and thermal stability,broad substrate scope,and mild reaction conditions.This new methodology provided an efficient and convenient way to synthezie olefination products.（2）Pd-Catalyzed 4-Aminobenzotriazole-Directed C（sp²）-H MacrocyclizationWe continued to explore the more complex and challenging macrocyclization reactions with ABTA directing group,which successfully obtained different macrocyclization products（>16）of 14-22 ring sizes in high yields（up to 77%）with Pd（OAc）₂ as catalyst and Ag OAc as the oxidant.Notably,the ring size as an important factor has a large impact on the E/Z selectivity determined by NOESY.Smaller rings（14-16）were favored for the Z-configuration,while rings（>16）were favored for the E-configuration.Under the optimal reaction conditions,compared with other different directing groups（AQ,PIP,TAM and Dipeptide）,ABTA still has a greater advantage in macrocyclization as a new directing group.Meanwhile,the directing group was successfully removed in mild condition,which also provides a new approach to synthesize bioactive small molecules efficiently.（3）Pd-Catalyzed 4-Aminobenzotriazole-Directed C-H Arylationwe continued to explore the reaction properties in Pd（II/IV）cycling system with ABTA directing group,and obtained 5,5-metallocycles intermediates by mixing the substrate with Pd（OAc）₂（1:1）.As a result,ABTA can not only achieve the C（sp²）-H bond activation,but also achieve the C（sp³）-H bond activation.ABTA still has stronger coordination ability through competing experiment with AQ,PIP and TAM.Subsequently,the arylation product was successfully obtained in 95%yield under optimal condition.Meanwhile,the arylation competition reaction was carried out under the standard condition with other directing groups,and the ratio of arylation products was ABTA to AQ（1:3）,PIP（1:2.1）and TAM（1:1.2）.The outcome suggested other directing groups didn’t reflect obvious advantages.Therefore,as a novel directing group,it still has potential application value.The scope of substrate was explored by expanding different amides and aryl iodides（>35）to obtained various arylation products in high yields（up to 97%）under the standard conditions,which reflected its broad substrate applicability.The ABTA directing group could be removed under mild conditions and recycled in>90%yield.Comprehensive experimental results indicated that ABTA as a novel bidentate directing group has good chemical properties in C-H arylation,including stronger coordination ability,high tolerance,broad substrate scope,and mild reaction conditions,providing an efficient and convenient method for arylation reaction.