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Tunable catalyst-controlled syntheses of β- and γ-amino alcohols enabled by silver-catalysed nitrene transfer

Abstract

Carbon–hydrogen bond functionalization methods are important tools for efficiently upgrading simple precursors to more valuable compounds. The ubiquity of amines in pharmaceuticals and natural products has led to considerable interest in strategies for the selective amidation of C–H bonds in a tunable manner. An ongoing challenge involves achieving control in situations where targeted bonds have varying bond strengths or similar steric/electronic environments. Herein, we report two complementary silver catalysts that are capable of selecting between β- or γ-C–H bonds that reside in similar steric/electronic environments, overriding a reaction at a weaker C–H bond in favour of a stronger one and activating primary C–H bonds. The mild conditions, low cost of silver, good yields and easy purification make this approach ideal for late-stage functionalizations to furnish valuable 1,2- and 1,3-aminoalcohols from easily prepared carbamate esters.

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Fig. 1: Challenges in tunable site-selective C–H bond amidation.
Fig. 2: Principles guiding the design of new catalysts.
Fig. 3
Fig. 4: Steric control of site-selective C–H amidation.
Fig. 5

Data availability

The data supporting the findings of this study are available within the manuscript and its Supplementary Information, or available from the author on reasonable request. Experimental details and full spectroscopic characterization data for all new compounds and copies of proton and carbon NMR spectra are provided in the Supplementary Information. The X-ray crystallographic coordinates for [(Py5Me2)AgOTf]2 in this study have previously been reported and have been deposited at the Cambridge Crystallographic Data Centre under deposition no. 1491194. These data can be obtained free of charge from the Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif. Furthermore, the corresponding author can be contacted directly.

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Acknowledgements

J.M.S. is grateful to the NSF (award no. 1664374) for financial support. The following instrumentation in the Paul Bender Chemistry Instrumentation Center was supported by Thermo Q Exactive Plus by NIH 1S10 OD020022-1; Bruker Quazar APEX2 and Bruker Avance-500 by a generous gift from P. J. Bender and M. M. Bender; Bruker Avance-600 by NIH S10 OK012245; Bruker Avance-400 by NSF CHE-1048642 and the University of Wisconsin–Madison; Varian Mercury-300 by NSF CHE-0342998. C. G. Fry and H. Hofstetter at University of Wisconsin–Madison are thanked for valuable discussions about NMR equipment and techniques. M. M. Vestling of University of Wisconsin–Madison is thanked for help with mass spectrometry characterization. D. J. Weix and K. J. Garcia are thanked for access to chiral supercritical fluid chromatography instrumentation.

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J.M.S., M.J. and M.H. conceived the project. M.J., M.H., L.E.V. and M.D. performed the synthetic experiments. J.M.R. performed the DFT calculations. J.M.S., M.J., M.H., L.E.V. and J.M.R. wrote the manuscript.

Corresponding author

Correspondence to Jennifer M. Schomaker.

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Ju, M., Huang, M., Vine, L.E. et al. Tunable catalyst-controlled syntheses of β- and γ-amino alcohols enabled by silver-catalysed nitrene transfer. Nat Catal 2, 899–908 (2019). https://doi.org/10.1038/s41929-019-0339-y

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