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Rapid heteroatom transfer to arylmetals utilizing multifunctional reagent scaffolds

Nature Chemistry volume 9, pages 681–688 (2017)Cite this article

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Abstract

Arylmetals are highly valuable carbon nucleophiles that are readily and inexpensively prepared from aryl halides or arenes and widely used on both laboratory and industrial scales to react directly with a wide range of electrophiles. Although C−C bond formation has been a staple of organic synthesis, the direct transfer of primary amino (−NH2) and hydroxyl (−OH) groups to arylmetals in a scalable and environmentally friendly fashion remains a formidable synthetic challenge because of the absence of suitable heteroatom-transfer reagents. Here, we demonstrate the use of bench-stable N−H and N−alkyl oxaziridines derived from readily available terpenoid scaffolds as efficient multifunctional reagents for the direct primary amination and hydroxylation of structurally diverse aryl- and heteroarylmetals. This practical and scalable method provides one-step synthetic access to primary anilines and phenols at low temperature and avoids the use of transition-metal catalysts, ligands and additives, nitrogen-protecting groups, excess reagents and harsh workup conditions.

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Figure 1: Current approaches to primary arylamine and phenol synthesis from arylmetals in the absence of transition-metal catalysts, impact of steric hindrance on kinetic acidity and the discovery of multifunctional oxaziridine reagents for heteroatom-transfer reactions.
Figure 2: Three-dimensional representation of competitive amination and proton-transfer transition states, and the proposed mechanism of N transfer and deuterium-trapping experiments.

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Acknowledgements

L.K. gratefully acknowledges the generous financial support from Rice University, National Institutes of Health (R01 GM-114609-01), National Science Foundation (CAREER:SusChEM CHE-1455335), the Robert A. Welch Foundation (Grant C-1764), Amgen (2014 Young Investigators' Award) and Biotage (2015 Young Principal Investigator Award), which are greatly appreciated. D.H.E. thanks BYU and the Fulton Supercomputing Lab. We thank S. Sutton and P. Richardson at Pfizer LaJolla for the thorough DSC analysis of the oxaziridine reagents used in this manuscript—the full DSC analysis and interpretation data are included in the Supplementary Information. We also thank E. M. Carreira, A. J. Catino, E.J. Corey, F. A. Davis, A. Ganesan, M. M. Joullie, J. Lopchuk, I. Marek, A. G. Myers, K.C. Nicolaou, J. Njardarson, A. Padwa, R. Sarpong, A. Toro and E. Vedejs for helpful commentary. We dedicate this article to Professor K. C. Nicolaou on the occasion of his 70th birthday.

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Authors and Affiliations

  1. Department of Chemistry, Rice University, BioScience Research Collaborative, Houston, 77005, Texas, USA

    Hongyin Gao, Zhe Zhou, Nicole Erin Behnke & László Kürti

  2. Department of Chemistry and Biochemistry, Brigham Young University, Provo, 84602, Utah, USA

    Doo-Hyun Kwon, James Coombs, Steven Jones & Daniel H. Ess

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  1. Hongyin Gao
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Contributions

H.G. and L.K. conceived this work; H.G., Z.Z. and L.K. designed the organic chemistry experiments; H.G., Z.Z. and N.E.B. conducted the organic chemistry experiments and analysed the data; D.-H.K., D.H.E. and L.K. designed the computational studies; D.-H. K., J.C., S.J. and D.H.E. conducted the calculations and analysed the data; D.H.E. and L.K. wrote the manuscript.

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Correspondence to Daniel H. Ess or László Kürti.

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Gao, H., Zhou, Z., Kwon, DH. et al. Rapid heteroatom transfer to arylmetals utilizing multifunctional reagent scaffolds. Nature Chem 9, 681–688 (2017). https://doi.org/10.1038/nchem.2672

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