金属有机化学ppt.pptx

Research background2The significance of C(sp3)-H activation leading to C-N bond formation has been extensively exemplified because C-N linkages are ubiquitous in pharmaceuticals, biologically 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 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 C(sp2)-H activation.3Research backgroundThus,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)-catalyzed 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 that in 8-methylquinolines, has been realized.4The 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 partner are major criteria for our design.Research background5We 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 theamide sources, and they are particularly attractive nitrenetransfer reagents owing to their high activity, stability, and synthetic accessibility.6We 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 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-phenyl-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.7The scope with respect to the amidating reagent was examined next in 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 performed with AgOPiv (8 mol%) at 60 。b Reaction was performed at 80。8To 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-(-)-carvone (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 609This amidation reaction can be further extended to aliphatic cyclic and acyclic ketoximes 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 isolated 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.10To further demonstrate the applicability of this protocol to the late-stagefunctionalization of natural products, the oximeether of (-)-santonin (1o) 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 after column chromatography.a Reaction was performed with 2 (0.24 mmol), AgOPiv(8 mol%), CH2Cl2 at 608C.11The amidated product can undergo further transformations,such as the ready removal of the DG (S