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Metallaphotoredox-enabled deoxygenative arylation of alcohols

Nature volume 598, pages 451–456 (2021)Cite this article

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Abstract

Metal-catalysed cross-couplings are a mainstay of organic synthesis and are widely used for the formation of C–C bonds, particularly in the production of unsaturated scaffolds1. However, alkyl cross-couplings using native sp3-hybridized functional groups such as alcohols remain relatively underdeveloped2. In particular, a robust and general method for the direct deoxygenative coupling of alcohols would have major implications for the field of organic synthesis. A general method for the direct deoxygenative cross-coupling of free alcohols must overcome several challenges, most notably the in situ cleavage of strong C–O bonds3, but would allow access to the vast collection of commercially available, structurally diverse alcohols as coupling partners4. We report herein a metallaphotoredox-based cross-coupling platform in which free alcohols are activated in situ by N-heterocyclic carbene salts for carbon–carbon bond formation with aryl halide coupling partners. This method is mild, robust, selective and most importantly, capable of accommodating a wide range of primary, secondary and tertiary alcohols as well as pharmaceutically relevant aryl and heteroaryl bromides and chlorides. The power of the transformation has been demonstrated in a number of complex settings, including the late-stage functionalization of Taxol and a modular synthesis of Januvia, an antidiabetic medication. This technology represents a general strategy for the merger of in situ alcohol activation with transition metal catalysis.

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Fig. 1: Direct deoxygenative arylation of alcohols.
Fig. 2: Proposed mechanism and nitrogen-heterocyclic carbene evaluation for deoxygenative arylation.
Fig. 3: Alcohol scope for deoxygenative arylation.
Fig. 4: Chirality transfer from chiral diol and late-stage drug molecule functionalization.

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Data availability

The data supporting the findings of this study are available within the paper and its Supplementary Information.

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Acknowledgements

Research reported in this publication was supported by the NIH National Institute of General Medical Sciences (R35 GM134897-02) and gifts from Merck, Bristol-Myers Squibb, Eli Lilly, and Janssen Research and Development LLC. The authors thank C. Liu and R. Lambert for assistance in preparing this manuscript.

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Authors and Affiliations

  1. Merck Center for Catalysis at Princeton University, Princeton, NJ, USA

    Zhe Dong & David W. C. MacMillan

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  1. Zhe Dong
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  2. David W. C. MacMillan
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Contributions

Z.D. performed and analysed the experiments. Z.D. and D.W.C.M. designed the experiments. Z.D. and D.W.C.M. prepared this manuscript.

Corresponding author

Correspondence to David W. C. MacMillan.

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The authors declare no competing interests.

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Extended data figures and tables

Extended Data Fig. 1 Aryl halide scope for deoxygenative arylation.

Both (hetero)aryl bromides and chlorides can be utilized under same reaction conditions. All yields are isolated. Experiments typically run with 1.0 equivalent of aryl halide, 1.7 equivalent of alcohol and 1.6 equivalent of NHC on 0.5 mmol scale. *See Supplementary Information for experimental details.

Supplementary information

Supplementary Information

Supplementary Figs. 1–15, Tables 1–8and supplementary text.

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Dong, Z., MacMillan, D.W.C. Metallaphotoredox-enabled deoxygenative arylation of alcohols. Nature 598, 451–456 (2021). https://doi.org/10.1038/s41586-021-03920-6

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