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Multicomponent alkene azidoarylation by anion-mediated dual catalysis

Nature volume 598, pages 597–603 (2021)Cite this article

Subjects

Abstract

Molecules that contain the β-arylethylamine motif have applications in the modulation of pain, treatment of neurological disorders and management of opioid addiction, among others, making it a privileged scaffold in drug discovery1,2. De novo methods for their assembly are reliant on transformations that convert a small class of feedstocks into the target compounds via time-consuming multistep syntheses3,4,5. Synthetic invention can drive the investigation of the chemical space around this scaffold to further expand its capabilities in biology6,7,8,9. Here we report the development of a dual catalysis platform that enables a multicomponent coupling of alkenes, aryl electrophiles and a simple nitrogen nucleophile, providing single-step access to synthetically versatile and functionally diverse β-arylethylamines. Driven by visible light, two discrete copper catalysts orchestrate aryl-radical formation and azido-group transfer, which underpin an alkene azidoarylation process. The process shows broad scope in alkene and aryl components and an azide anion performs a multifaceted role both as a nitrogen source and in mediating the redox-neutral dual catalysis via inner-sphere electron transfer10,11. The synthetic capabilities of this anion-mediated alkene functionalization process are likely to be of use in a variety of pharmaceutically relevant and wider synthetic applications.

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Fig. 1: Background and concept.
Fig. 2: Development of alkene azidoarylation reaction.
Fig. 3: Scope of alkene azidoarylation reaction.
Fig. 4: Alkene azidoarylation as a powerful method to explore the chemical space around the Akt inhibitor CCT128930.
Fig. 5: Mechanistic investigation of the alkene azidoarylation reaction.

Data availability

Materials and methods, optimization studies, experimental procedures, mechanistic studies, 1H NMR, 13C NMR and 19F NMR spectra, and high-resolution mass spectrometry, infrared, ultraviolet–visible and cyclic voltammetry data are available in the Supplementary Information. Crystallographic data are available free of charge from the Cambridge Crystallographic Data Centre under the reference numbers CCDC 2027142, CCDC 2027143 and CCDC 2032989. Raw data are available from the corresponding author on reasonable request.

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Acknowledgements

We thank the Herchel Smith Fund at the University of Cambridge for a postdoctoral fellowship to A.B., the AstraZeneca–University of Cambridge PhD programme for studentship (Y.A.) and the Royal Society for Wolfson Merit Award to M.J.G.

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Authors and Affiliations

  1. Yusuf Hamied Department of Chemistry, University of Cambridge, Cambridge, UK

    Ala Bunescu, Yusra Abdelhamid & Matthew J. Gaunt

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  1. Ala Bunescu
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Contributions

A.B. and M.J.G. conceived the project. A.B. and Y.A. conducted the experiments. A.B., Y.A. and M.J.G. analysed and interpreted the results. A.B., Y.A. and M.J.G. wrote the manuscript.

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Correspondence to Matthew J. Gaunt.

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Supplementary Information

This file contains Supplementary Text, Materials and Methods, Figs. 1–40, Tables 1–10 and Refs. 1–155.

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Bunescu, A., Abdelhamid, Y. & Gaunt, M.J. Multicomponent alkene azidoarylation by anion-mediated dual catalysis. Nature 598, 597–603 (2021). https://doi.org/10.1038/s41586-021-03980-8

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