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Metallaphotoredox-enabled deoxygenative arylation of alcohols

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.

Data availability

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

References

  1. 1.

    Corbet, J.-P. & Mignani, G. Selected patented cross-coupling reaction technologies. Chem. Rev. 106, 2651–2710 (2006).

    CAS  Article  Google Scholar 

  2. 2.

    Choi, J. & Fu, G. C. Transition metal–catalyzed alkyl-alkyl bond formation: another dimension in cross-coupling chemistry. Science 356, eaaf7230 (2017).

    Article  Google Scholar 

  3. 3.

    Herrmann, J. M. & König, B. Reductive deoxygenation of alcohols: catalytic methods beyond Barton–McCombie deoxygenation. Eur. J. Org. Chem. 2013, 7017–7027 (2013).

    CAS  Article  Google Scholar 

  4. 4.

    Blakemore, D. C. et al. Organic synthesis provides opportunities to transform drug discovery. Nat. Chem. 10, 383–394 (2018).

    CAS  Article  Google Scholar 

  5. 5.

    Ruiz-Castillo, P. & Buchwald, S. L. Applications of palladium-catalyzed C–N cross-coupling reactions. Chem. Rev. 116, 12564–12649 (2016).

    CAS  Article  Google Scholar 

  6. 6.

    Walters, W. P., Green, J., Weiss, J. R. & Murcko, M. A. What do medicinal chemists actually make? a 50-year retrospective. J. Med. Chem. 54, 6405–6416 (2011).

    CAS  Article  Google Scholar 

  7. 7.

    Zuo, Z. et al. Merging photoredox with nickel catalysis: coupling of α-carboxyl sp3-carbons with aryl halides. Science 345, 437–440 (2014).

    CAS  Article  ADS  Google Scholar 

  8. 8.

    Everson, D. A., Jones, B. A. & Weix, D. J. Replacing conventional carbon nucleophiles with electrophiles: nickel-catalyzed reductive alkylation of aryl bromides and chlorides. J. Am. Chem. Soc. 134, 6146–6159 (2012).

    CAS  Article  Google Scholar 

  9. 9.

    Sakai, H. A., Liu, W., Le, C. & MacMillan, D. W. C. Cross-electrophile coupling of unactivated alkyl chlorides. J. Am. Chem. Soc. 142, 11691–11697 (2020).

    CAS  Article  Google Scholar 

  10. 10.

    Suga, T. & Ukaji, Y. Nickel-catalyzed cross-electrophile coupling between benzyl alcohols and aryl halides assisted by titanium co-reductant. Org. Lett. 20, 7846–7850 (2018).

    CAS  Article  Google Scholar 

  11. 11.

    Ertl, P. & Schuhmann, T. A systematic cheminformatics analysis of functional groups occurring in natural products. J. Nat. Prod. 82, 1258–1263 (2019).

    CAS  Article  Google Scholar 

  12. 12.

    Jia, X.-G., Guo, P., Duan, J. & Shu, X.-Z. Dual nickel and Lewis acid catalysis for cross-electrophile coupling: the allylation of aryl halides with allylic alcohols. Chem. Sci. 9, 640–645 (2018).

    CAS  Article  Google Scholar 

  13. 13.

    Guo, P. et al. Dynamic kinetic cross-electrophile arylation of benzyl alcohols by nickel catalysis. J. Am. Chem. Soc. 143, 513–523 (2021).

    CAS  Article  Google Scholar 

  14. 14.

    Li, Z. et al. Electrochemically enabled, nickel-catalyzed dehydroxylative cross-coupling of alcohols with aryl halides. J. Am. Chem. Soc. 143, 3536–3543 (2021).

    CAS  Article  Google Scholar 

  15. 15.

    Barton, D. H. R. & McCombie, S. W. A new method for the deoxygenationof secondary alcohols. J. Chem. Soc. Perkin Trans. 1 16, 1574–1585. (1975).

    Article  Google Scholar 

  16. 16.

    Zhang, L. & Koreeda, M. Radical deoxygenation of hydroxyl groups via phosphites. J. Am. Chem. Soc. 126, 13190–13191 (2004).

    CAS  Article  Google Scholar 

  17. 17.

    Vara, B. A., Patel, N. R. & Molander, G. A. O-benzyl xanthate esters under Ni/photoredox dual catalysis: selective radical generation and Csp3 –Csp2 cross-coupling. ACS Catal. 7, 3955–3959 (2017).

    CAS  Article  Google Scholar 

  18. 18.

    Yang, C.-T. et al. Copper-catalyzed cross-coupling of nonactivated secondary alkyl halides and tosylates with secondary alkyl grignard reagents. J. Am. Chem. Soc. 134, 11124–11127 (2012).

    CAS  Article  Google Scholar 

  19. 19.

    Zhang, X. & MacMillan, D. W. C. Alcohols as latent coupling fragments for metallaphotoredox catalysis: sp3 –sp2 cross-coupling of oxalates with aryl halides. J. Am. Chem. Soc. 138, 13862–13865 (2016).

    CAS  Article  Google Scholar 

  20. 20.

    Ye, Y., Chen, H., Sessler, J. L. & Gong, H. Zn-mediated fragmentation of tertiary alkyl oxalates enabling formation of alkylated and arylated quaternary carbon centers. J. Am. Chem. Soc. 141, 820–824 (2019).

    CAS  Article  Google Scholar 

  21. 21.

    Coulembier, O. et al. Alcohol adducts of N-heterocyclic carbenes: latent catalysts for the thermally-controlled living polymerization of cyclic esters. Macromolecules 39, 5617–5628 (2006).

    CAS  Article  ADS  Google Scholar 

  22. 22.

    McNally, A., Prier, C. K. & MacMillan, D. W. C. Discovery of an α-amino C–H arylation reaction using the strategy of accelerated serendipity. Science 334, 1114–1117 (2011).

    CAS  Article  ADS  Google Scholar 

  23. 23.

    Joe, C. L. & Doyle, A. G. Direct acylation of C(sp3)−H bonds enabled by nickel and photoredox catalysis. Angew. Chem. Int. Ed. 55, 4040–4043 (2016).

    CAS  Article  Google Scholar 

  24. 24.

    Slinker, J. D. et al. Efficient yellow electroluminescence from a single layer of a cyclometalated iridium complex. J. Am. Chem. Soc. 126, 2763–2767 (2004).

    CAS  Article  Google Scholar 

  25. 25.

    Dinnocenzo, J. P. & Banach, T. E. Deprotonation of tertiary amine cation radicals. A direct experimental approach. J. Am. Chem. Soc. 111, 8646–8653 (1989).

    CAS  Article  Google Scholar 

  26. 26.

    Kochi, J. K. Chemistry of alkoxy radicals: cleavage reactions. J. Am. Chem. Soc. 84, 1193−1197 (1962).

    CAS  Article  Google Scholar 

  27. 27.

    Zhao, L., Zhang, C., Zhuo, L., Zhang, Y. & Ying, J. Y. Imidazolium salts: a mild reducing and antioxidative reagent. J. Am. Chem. Soc. 130, 12586–12587 (2008).

    CAS  Article  Google Scholar 

  28. 28.

    Trnka, T. M. et al. Synthesis and activity of ruthenium alkylidene complexes coordinated with phosphine and N-heterocyclic carbene ligands. J. Am. Chem. Soc. 125, 2546–2558 (2003).

    CAS  Article  Google Scholar 

  29. 29.

    Bellemin-Laponnaz, S. Synthesis of N,O-heterocyclic carbene and coordination to rhodium(I) and copper(I). Polyhedron 29, 30−33 (2010).

    CAS  Article  Google Scholar 

  30. 30.

    Sladojevich, F., Arlow, S. I., Tang, P. & Ritter, T. Late-stage deoxyfluorination of alcohols with PhenoFluor. J. Am. Chem. Soc. 135, 2470–2473 (2013).

    CAS  Article  Google Scholar 

  31. 31.

    Kato, T., Matsuoka, S. & Suzuki, M. N-heterocyclic carbene-mediated redox condensation of alcohols. Chem. Commun. 52, 8569–8572 (2016).

    CAS  Article  Google Scholar 

  32. 32.

    Gusev, D. G. Electronic and steric parameters of 76 N-heterocyclic carbenes in Ni(CO)3(NHC). Organometallics 28, 6458–6461 (2009).

    CAS  Article  Google Scholar 

  33. 33.

    Yuan, M., Song, Z., Badir, S. O., Molander, G. A. & Gutierrez, O. On the nature of C(sp3)–C(sp2) bond formation in nickel-catalyzed tertiary radical cross-couplings: a case study of Ni/photoredox catalytic cross-coupling of alkyl radicals and aryl halides. J. Am. Chem. Soc. 142, 7225–7234 (2020).

    CAS  Article  Google Scholar 

  34. 34.

    Gonnard, L., Guérinot, A. & Cossy, J. Cobalt-catalyzed cross-coupling of 3- and 4-iodopiperidines with grignard reagents. Chem. Eur. J. 21, 12797–12803 (2015).

    CAS  Article  Google Scholar 

  35. 35.

    Kutchukian, P. S. et al. Chemistry informer libraries: a chemoinformatics enabled approach to evaluate and advance synthetic methods. Chem. Sci. 7, 2604–2613 (2016).

    CAS  Article  Google Scholar 

  36. 36.

    Zhang, R. et al. Profiling and application of photoredox C(sp3)–C(sp2) cross-coupling in medicinal chemistry. ACS Med. Chem. Lett. 9, 773–777 (2018).

    CAS  Article  Google Scholar 

Download references

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

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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Peer review information Nature thanks the anonymous reviewer(s) for their contribution to the peer review of this work.

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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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