Ir(?)-Catalyzed C-H Bond Amination Reaction And Its Application In The Synthesis Of Bioactive Molecules

Transition metal-catalyzed C-H amination has been emerged as a novel strategy in the traditional retrosynthetic analysis of total synthesis.Over the last few decades,it has been a central problem of the methodology in organic synthesis.This thesis mainly focuses on the reaction of different catalytic systems and amino sources in Ir?III?-Catalyzed C-H amination.The main contents include:The first chapter simply reviews the history and the current status of the development of transition-metal catalyzed C-H amination.The different reaction types of transition metal-catalyzed C-H amination were summarized from the view point of the reaction mechanism?C-H activation,C-H insertion,SET?.By comparing the examples of transition-metal catalyzed C-H amination with different amino sources,we finally concluded the unique characters and the frontier of transition metal-catalyzed C-H amination?The key to expanding the reaction type of transition metal-catalyzed C-H amination and its application in organic synthesis is to develop new catalytic systems and to make use of a variety of amino sources?.In chapter 2,we think the key point to apply Ir?III?-Catalyzed C-H amination in organic synthesis to diversify amino sources.In order to applying more effective aminating reagents,we choose a series of alkyl azides with functional group?for example,sugar,steroid and amino acid derivatives?and benzamides as the substrates.With the promotion of catalytic amount base?CsOAc?,the orthor C-H amination of benzamides was achieved.Various substrates were selectively aminated under standard conditions with high functional-group tolerance.The reaction offers a valuable approach to introducing different alkyl amines to aryl groups.Meanwhile,we successfully isolated and characterized the key iridacycle intermediate to gain insight into reaction mechanisms.This protocol provides a new method to postsynthetically modify complex alkyl azides with important physiological activity.In chapter 3,considering the good functional-group tolerance of the above mentioned amination reaction,we can design a kind of functional alkyl azides as amino sources to realize cascade reaction via using amide group of substrates,amino group of products and azides with functional group as reaction blocks.Under this guidance,we synthesized alkyl azides with aldehyde group as amino sources and achieved cascade cyclization of molecular C-H amination,intramolecular condensation,nucleophilic addition of benzamides and alkyl azides to construct a series of tetrahydroisoquinolino[2,1-a]quinazolinone derivatives containing chiral center.Meanwhile,we preliminary discussed the reaction enantioselectivity in Ir???/CPA catalytic system?62%yield,31%ee?.The new protocol provides an approach to synthesize benzohetercyclic-fused compounds containing chiral center.In chapter 4,direct introducing of amide group remains a challenge in C-H amination process,which suffers from low reaction activity and narrow scope of substrate.Based on our previous work?the C-H insertion amination reaction using acyl azide as nitrogen source?,for the first time,we want to make use of TrocN₃ as amino source in C-H activation amination.Due to the strong electron-withdrawing effect and easy-to-leave property of-OCH₂CCl₃ group in azide,the reaction activity could be promoted and the products could be further directly transformated.Under the direction of this idea,we successfully synthesized a series of substituted nitrogen containing heterocyclic compounds-quinazolinone derivatives in high yields and selectivity using cascade reaction of Ir???-catalyzed ortho-position C-H amination and intramolecularly SN₂ type nucleophilic substitution.This offers a direct and convenient route for the synthesis of functionalized quinazoline-2,4?1H,3H?-diones,which are important building blocks and key synthetic intermediates for applications in biology and medicine.In addition,based on high reactivity and easy conversion characteristics of TrocN₃,we realized Ir???-Catalyzed directed C-H amidation of unactivated C?sp³?-H bond by using TrocN₃ as amino source.With the promotion of catalytic amount acid?pentanoic acid?or base?NaOAc?,the reaction was very easy to take place under mild conditions.Various substrates containing inert C?sp³?-H bonds smoothly undergo this process with relative broad functional-group tolerance and complete monoselectivity.The amidated products not only can be directly deprotected to form primary alkyl amines,can also be transformated to carbamate and urea compounds by nucleophilic attack.Meanwhile,a cationic fivemembered iridacycle complex has been established for the first time as a possible intermediate,which help us gain insight into the reaction mechanism.Because of the high functional-group tolerance of the reaction,it provides the basis for its application in the synthesis of the active drug molecules.