Palladium-Catalyzed Synthesis Of Ortho-aminated Benzonitriles And ?-(Trifluoromethyl) Arylmethylamines

Transition metal-catalyzed C-C and C-heteroatom bond forming reactions are among the most widely used catalytic reactions in synthetic organic chemistry.Among them,special attention has been paid to palladium-catalyzed reactions due to their broad functional group tolerance and diverse reaction pathways.Herein,We developed methods for the synthesis of ortho-aminated benzonitriles and ?-?trifluoromethyl?arylmethylamines catalyzed by palladium.This thesis includes two parts as below.1.The Catellani reaction is a powerful method for the synthesis of highly substituted aromatic compounds and fused aromatic rings due to the capability of functionalizing both the ortho-and ispo-position of aryl iodides in a single transformation.Although the scope of terminating reagents for ispo-C-I functionalization has been broadened considerably since its discovery,ortho-C-H functionalization is largely limited to alkylation and arylation.Recently,the palladium-catalyzed norbornene-mediated ortho-C-H amination of aryl iodides was reported and then this a synthetic strategy has been extended to a wide variety of terminating reagents.However,it was not known if this type of ortho-amination reaction could tolerate cyanide as the nucleophile has not been realized.Herein,a palladium-catalyzed norbornene-mediated tandem amination/cyanation reaction via Catellani-type C-H functionalization was developed by using N-benzoyloxyamines as the amination reagent and Zn?CN?₂ as the terminating agent.This transformation,in which one C-N bond and one C-C bond are formed,provides an efficient approach for the synthesis of ortho-aminated benzonitriles.In the cases of aryl iodides lacking an ortho-substituent 2,6-diaminated benzonitriles can be obtained.The advantage of the reaction is ortho-aminated benzonitriles can be synthesized in moderate to excellent yields and with good functional group tolerance.This method is complementary to the reported protocols for the Catellani-type reaction and further demonstrates that cyanide can act as a terminating reagent in the ortho-C-H amination reactions of aryl iodides.Moreover,it should stimulate the design of new synthetic methodologies to access valuable arylamine and benzonitrile derivatives.2.Chiral amines are structures commonly found in natural and synthetic biologically active compounds where their ability to from hydrogen bonds is one of their most desirable features.In view of the prevalence of organofluorine compounds in medicinal chemistry,as well as the occurrence of ?-?trifluoromethyl?amines in several biologically actives.?-?trifluoromethyl?amines have attracted the interest of organic and medicinal chemists.Previous reports on the enantioselective synthesis of ?-?trifluoromethyl?amines are in the fields of catalytic hydrogenation,nucleophilic addition to fluorinated imines,trifluoromethylation of C=N bonds,and the cinchonaalkaloid-catalyzed isomerization of fluorinated imines.Among these methods,those involving nucleophilic addition to fluorinated imines have received the most attention,likely due to the variety of nucleophiles that can be used?Grignard,organolithium,organozinc,boronic acids?in racemic or asymmetric versions.In this area,complexes of rhodium?I?with chiral dienes or phosphorus-based ligands have most often been employed.In comparison,there are few reports featuring the use of the less expensive palladium?II?as the catalyst for this transformation.we reported the palladium?II?-catalyzed enantioselective addition of arylboroxines to N,O-acetals of trifluoroacetaldehyde for the preparation of ?-?trifluoromethyl?arylmethylamines.This operationally simple protocol was,however,only applicable to electron-neutral and electron-rich arylboroxines.In order to overcome this limitation,we recognized that modifications would have to be made to the catalytic system to improve its activity.Herein,we describe the development of such a system,which ultimately enabled a broad scope of arylboroxines,including electron-poor ones,to participate in this palladium?II?-catalyzed reaction.It was ultimately found that the reaction of electron-poor and ortho-substituted boroxines was enabled after modification of the catalytic system by using Pd?PyOx?Cl₂ catalyst with AgBF₄ system.Under these sets of conditions,we prepared 34 ?-?trifluoromethyl?arylmethylamines in 57-91% yield and in most cases with greater than 90% ee.At last,this protocol was applied to the synthesis of trifluoromethylated analogues of cinacalcet,a calcimimetic drug.In conclusion,we developed two different methods to synthesize ?-?trifluoromethyl?arylmethylamines and ortho-aminated benzonitriles catalyzed by palladium.In the first project,a palladium-catalyzed,norbornene-mediated tandem amination/cyanation reaction via Catellani-type C-H functionalization was developed to synthesize ortho-aminated benzonitriles,providing a new approach to access valuable arylamine and benzonitrile derivatives.In the second project,We developed a palladium?II?-catalyzed enantioselective synthesis of ?-?trifluoromethyl?arylmethylamines involving 1,2-addition of arylboroxines to ?-?trifluoromethyl?acetaldimines.This method is applied to the synthesis of trifluoromethylated analogues of cinacalcet,a calcimimetic drug.