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1、Rhodium(III)-Catalyzed Amidation of Unactivated C(sp3)-H BondsHe Wang,Guodong Tang,and Xingwei Li*,C-H Activation,Research background,2,The significance of C(sp3)-H activation leading to C-N bond formation has been extensively exemplified because C-N linkages are ubiquitous in pharmaceuticals,biolog
2、ically active compounds,and natural products.Consequently,the direct amination/amidation of unactivated C(sp3)-H bonds has received increasing attention.In the past decade,only limited examples of direct amination of C(sp3)-H Bonds has been reported by using palladium,rhodium(II),copper,iridium,and
3、other catalysts.Recently,rhodium(III)-catalyzed C-H activation has been increasingly explored,and provides unique synthetic methodologies with high activity,selectivity,broad substrate scope,and functional-group tolerance.Despite these attractive processes,the coupling reactions are mostly based on
4、C(sp2)-H activation.,3,Research background,Thus,there are only a few examples on the functionalization of unactivated C(sp3)-H bonds using rhodium(III)catalysis,as in the coupling with alkynes,activated forms of arenes,and azides.Recently,Chang and co-workers reported an elegant iridium(III)-catalyz
5、ed amidation for a broad scope of C(sp3)-H bonds using organic azides.Despite the progress,rhodium(III)-catalyzed C(sp3)-H activation reactions,especially amidation reactions,typically suffer from limited substrate scope and harsh reaction conditions,and only amidation of benzylic C-H bonds,such as
6、that in 8-methylquinolines,has been realized.,4,The challenges associated with C(sp3)-H bond activation can be ascribed to the steric hindrance of C(sp3)-H bonds and the low reactivity of the resulting Rh-C(alkyl)species.Therefore,the stability,coordinating capacity,and reactivity of the coupling pa
7、rtner are major criteria for our design.,Research background,5,We now report a mild rhodium(III)-catalyzed C(sp3)-H amidation for a broad scope of substrates,including 8-alkylquinoline and aliphatic cyclic and acyclic ketoximes.This amidation reaction utilizes 3-substituted 1,4,2-dioxazol-5-ones as
8、theamide sources,and they are particularly attractive nitrenetransfer reagents owing to their high activity,stability,and synthetic accessibility.,6,We initiated our studies with the screening of reaction conditions in the coupling of 8-methylquinoline(1a)with 3-phenyl-1,4,2-dioxazol-5-one(2a;Table
9、1).,a Reactions were carried out by using RhCp*Cl22(4.0 mol%)/AgSbF6(16 mol%),AgOAc(8 mol%),8-methylquinoline(0.2 mmol)and 3-phenyl-1,4,2-dioxazol-5-one(0.24 mmol)in a solvent(3 mL)under nitrogen at 25 for 12 h.b Yield of product isolated after column chromatography.c Reaction was performed with 5-p
10、henyl-1,3,2,4-dioxathiazole 2-oxide.d Reaction was performed with 5,5-dimethyl-3-phenyl-1,4,2-dioxazole.e No AgSbF6 was used.f No rhodium catalystwas used.g IrCp*Cl22 was used to replace RhCp*Cl22.Cp*=C5Me5,DCE=1,2-dichlorethane.,7,The scope with respect to the amidating reagent was examined next in
11、 the coupling of 1a(Scheme 2).,Scheme 2.C-H amidation of 8-methylquinoline(1a).Reaction conditions:1a(0.2 mmol),2(0.24 mmol),AgOAc(8 mol%),RhCp*Cl22(4 mol%),AgSbF6(16 mol%),CH2Cl2(3 mL),25,12 h,sealed tube under nitrogen.Yield is that of product isolated after column chromatography.a Reaction was pe
12、rformed with AgOPiv(8 mol%)at 60。b Reaction was performed at 80。,8,To further define the scope and limitations of this reaction,amidation of the oxime ether of L-(-)carvone has been examined(Scheme 3).,Scheme 3.CH amidation of aliphatic O-methyl ketoxime.Reaction conditions:oxime ether of L-(-)-carv
13、one(0.2 mmol),2(0.21 mmol),AgOAc(8 mol%),RhCp*Cl22(4 mol%),AgSbF6(16 mol%),CH2Cl2(3.0 mL),25,12 h,sealed tube under nitrogen.Yield is that ofproduct isolated after column chromatography.a Reaction was performed at 60,9,This amidation reaction can be further extended to aliphatic cyclic and acyclic k
14、etoximes which are embedded within other backbones(Scheme 4).,Scheme 4.CH amidation of other aliphatic O-methyl ketoximes.Reaction conditions:1(0.2 mmol),2m(0.21 mmol),AgOPiv(32 mol%),RhCp*Cl22(4 mol%),AgSbF6(16 mol%),DCE(3.0 mL),80 8C,12 h,sealed tube under nitrogen.Yield is that of product isolate
15、d after column chromatography.a Reaction was performed with AgOAc(8 mol%)in CH2Cl2 at 258C.b Reaction was performed with AgOAc(8 mol%)in CH2Cl2 at 808C.,10,To further demonstrate the applicability of this protocol to the late-stagefunctionalization of natural products,the oximeether of(-)-santonin(1
16、o)was synthesized and subjected to the optimal reaction conditions(6080;Scheme 5).,Scheme 5.Late-stage C(sp3)-H amidation.Reaction conditions:1o(0.2 mmol),2(0.21 mmol),AgOPiv(32 mol%),RhCp*Cl22(4 mol%),AgSbF6(16 mol%),DCE(3.0 mL),80,12 h,sealed tube under nitrogen.Yield is that of product isolated a
17、fter column chromatography.a Reaction was performed with 2(0.24 mmol),AgOPiv(8 mol%),CH2Cl2 at 608C.,11,The amidated product can undergo further transformations,such as the ready removal of the DG(Scheme 6).,12,Several experiments have been performed to explore the mechanism(Scheme 7).,13,Surporting
18、 Information,summary,14,we have developed an efficient rhodium(III)-catalyzed C(sp3)-H amidation of alkyl C-H bonds using 3-substituted 1,4,2-dioxazol-5-ones as an amidating reagent.This amidation reaction expands the scope of both coupling partners and proceeds with functional-group tolerance under
19、 relatively mild reaction conditions.Importantly,the alkyl C-H groups have been extended beyond benzylic and allylic C-H ones.The amidated products can be further transformed into useful products.In the context of C(sp3)-H activation reactions,our method is applicable to the late-stage functionalization of natural products or other complex molecules.Future applications of rhodium(III)-catalyzed activation of other types of unreactive C-H bonds are underway in our laboratories.,THANKS FOR WATCHING,
