reaction mixture was diluted with E2O and washed with H2O. The aqueous layer was extracted with E2O three times. The combined organic layer was washed with H2O (three times) and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (0→70% EtOAc/hexanes) to afford the desired trifluoromethylated alkyne S5 as a white solid (0.26 g, 44% yield); 1 H NMR (500 MHz, CDCl3) δ
Ag-catalyzed nitrene transfer (NT) converts C–H bonds into valuable C–N bonds. These reactions offer a promising strategy for catalyst-controlled regiodivergent functionalization of different types of reactive C–H bonds, as the regioselectivity is tunable by varying the steric and electronic environments around the Ag nitrene, as well as the identity of the nitrene precursors and the tether length. Therefore, a unified understanding of how these individual factors affect the regioselectivity is key to the rational design of highly selective and regiodivergent C–H amination reactions. Herein, we report a computational study of various Ag-catalyzed NT reactions that indicates a concerted H-atom transfer (HAT)/C–N bond formation mechanism. A detailed analysis was carried out on the effects of the C–H bond dissociation enthalpy (BDE), charge transfer, ligand–substrate steric repulsions, and transition state ring strain on the stability of the C–H insertion transition states with different Ag nitrene complexes. The ancillary ligands on the Ag and the nitrene precursor identity both affect transition state geometries to furnish differing sensitivities to the BDE, tether length, and electronic effects of the reactive C–H bonds. Based on our understanding of the dominant factors that control selectivity, we established a rational catalyst and precursor selection approach for regiodivergent amination of diverse C–H bonds. The computationally predicted regiodivergent amination of β- and γ-C–H bonds of aliphatic alcohol derivatives was validated by experimental studies.
A new Au(I)-catalyzed method for the preparation of trisubstituted indolizines from easily accessible 2-propargyloxy-pyridines is reported. The reaction tolerates a wide range of functionality, allowing for diversity to be introduced in four distinct regions of the product (R, R 1 , R 2 , and Ar). The proposed mechanism proceeds via enol addition to an allenamide intermediate and explains the observed increase in yields when electron poor methyl ketones are utilized.
Nitrene transfer (NT) is a convenient strategy to directly transform C–H bonds into more valuable C–N bonds and exciting advances have been made to improve selectivity. Our work in silver-based NT has shown the unique ability of this metal to enable tunable chemo-, site-, and stereoselective reactions using simple N-dentate ligand scaffolds. Manipulation of the coordination environment and noncovalent interactions around the silver center furnish unprecedented catalyst control in selective NT and provide insights for further improvements in the field.1 Introduction1.1 Strategies for Nitrene Transfer1.2 Brief Summary of Chemocatalyzed Nitrene Transfer1.3 Focus of this Account2 Challenges in Chemocatalyzed Nitrene Transfer2.1 Reactivity Challenges2.2 Selectivity Challenges2.3 Chemoselective Nitrene Transfer2.4 Site-Selective Nitrene Transfer2.5 Enantioselective Nitrene Transfer3 Summary and Perspective3.1 Future Opportunities and Challenges3.2 Conclusion
Asymmetric C–H amination via nitrene transfer (NT) is a powerful tool for the preparation of enantioenriched amine building blocks from abundant C–H bonds. Herein, we report a highly regio- and enantioselective synthesis of -alkynyl -amino alcohol motifs via a silver-catalyzed propargylic C–H amination. The protocol was enabled by development of a new bis(oxazoline) (BOX) ligand through a rapid structure-activity relationship (SAR) analysis. The method utilizes readily accessible carbamate ester substrates bearing -propargylic C–H bonds and furnishes versatile products in good yields and with excellent enantioselectivity (90–99% ee). A putative Ag–nitrene intermediate is proposed to undergo an enantiodetermining hydrogen-atom transfer (HAT) during the C–H amination event. Density functional theory (DFT) calculations were performed to investigate the origin of enantioselectivity in the HAT step.
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