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Decarboxylative cross-nucleophile coupling via ligand-to-metal charge transfer photoexcitation of Cu(ii) carboxylates

Nature Chemistry volume 14, pages 94–99 (2022)Cite this article

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Abstract

Reactions that enable carbon–nitrogen, carbon–oxygen and carbon–carbon bond formation lie at the heart of synthetic chemistry. However, substrate prefunctionalization is often needed to effect such transformations without forcing reaction conditions. The development of direct coupling methods for abundant feedstock chemicals is therefore highly desirable for the rapid construction of complex molecular scaffolds. Here we report a copper-mediated, net-oxidative decarboxylative coupling of carboxylic acids with diverse nucleophiles under visible-light irradiation. Preliminary mechanistic studies suggest that the relevant chromophore in this reaction is a Cu(ii) carboxylate species assembled in situ. We propose that visible-light excitation to a ligand-to-metal charge transfer (LMCT) state results in a radical decarboxylation process that initiates the oxidative cross-coupling. The reaction is applicable to a wide variety of coupling partners, including complex drug molecules, suggesting that this strategy for cross-nucleophile coupling would facilitate rapid compound library synthesis for the discovery of new pharmaceutical agents.

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Fig. 1: Common strategies for decarboxylative coupling usually involve prefunctionalizations of either or both reacting partners, whereas the current strategy enables direct decarboxylative coupling.
Fig. 2: Mechanistic studies.

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

References

  1. Xuan, J., Zhang, Z.-G. & Xiao, W.-J. Visible-light-induced decarboxylative functionalization of carboxylic acids and their derivatives. Angew. Chem. Int. Ed. 54, 15632–15641 (2015).

    Article  CAS  Google Scholar 

  2. Rodríguez, N. & Goossen, L. J. Decarboxylative coupling reactions: a modern strategy for C–C-bond formation. Chem. Soc. Rev. 40, 5030–5048 (2011).

    Article  PubMed  Google Scholar 

  3. Arshadi, S., Ebrahimiasl, S., Hosseinian, A., Monfared, A. & Vessally, E. Recent developments in decarboxylative cross-coupling reactions between carboxylic acids and N–H compounds. RSC Adv. 9, 8964–8976 (2019).

    Article  CAS  Google Scholar 

  4. Zeng, Z., Feceu, A., Sivendran, N. & Gooßen, L. J. Decarboxylation‐initiated intermolecular carbon–heteroatom bond formation. Adv. Synth. Catal. 363, 2678–2722 (2021).

    Article  CAS  Google Scholar 

  5. Scott, E., Peter, F. & Sanders, J. Biomass in the manufacture of industrial products—the use of proteins and amino acids. Appl. Microbiol. Biotechnol. 75, 751–762 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Gallezot, P. Conversion of biomass to selected chemical products. Chem. Soc. Rev. 41, 1538–1558 (2012).

    Article  CAS  PubMed  Google Scholar 

  7. Patra, T. & Maiti, D. Decarboxylation as the key step in C–C bond-forming reactions. Chem. Eur. J. 23, 7382–7401 (2017).

    Article  CAS  PubMed  Google Scholar 

  8. Gooßen, L. J., Deng, G. & Levy, L. M. Synthesis of biaryls via catalytic decarboxylative coupling. Science 313, 662–664 (2006).

    Article  PubMed  Google Scholar 

  9. Moon, P. J. & Lundgren, R. J. Metal-catalyzed ionic decarboxylative cross-coupling reactions of C(sp3) acids: reaction development, mechanisms and application. ACS Catal. 10, 1742–1753 (2010).

    Article  Google Scholar 

  10. Zuo, Z. & MacMillan, D. W. C. Decarboxylative arylation of α‑amino acids via photoredox catalysis: a one-step conversion of biomass to drug pharmacophore. J. Am. Chem. Soc. 136, 5257–5260 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Zuo, Z. et al. Enantioselective decarboxylative arylation of α‑amino acids via the merger of photoredox and nickel catalysis. J. Am. Chem. Soc. 138, 1832–1835 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Shibutani, S. et al. Organophotoredox-catalyzed decarboxylative C(sp3)−O bond formation. J. Am. Chem. Soc. 142, 1211–1216 (2020).

    Article  CAS  PubMed  Google Scholar 

  13. Mao, R., Frey, A., Balon, J. & Hu, X. Decarboxylative C(sp3)–N cross-coupling via synergetic photoredox and copper catalysis. Nat. Catal. 1, 120–126 (2018).

    Article  CAS  Google Scholar 

  14. Kolbe, H. Beobachtungen über die oxydirende Wirkung des Sauerstoffs, wenn derselbe mit Hülfe einer elektrischen Säule entwickelt wird. J. Prakt. Chem. 41, 137–139 (1847).

    Article  Google Scholar 

  15. Hofer, H. & Moest, M. Ueber die Bildung von Alkoholen bei der Elektrolyse fettsaurer Salze. Justus Liebigs Ann. Chem. 323, 284–323 (1902).

    Article  CAS  Google Scholar 

  16. Xiang, J. et al. Hindered dialkyl ether synthesis with electrogenerated carbocations. Nature 573, 398–402 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Eberson, L. & Nyberg, K. Studies on the Kolbe electrolytic synthesis. V. An electrochemical analogue of the Ritter reaction. Acta Chem. Scand. 18, 1567–1568 (1964).

    Article  CAS  Google Scholar 

  18. Kochi, J. K. A new method for halodecarboxylation of acids using lead(IV) acetate. J. Am. Chem. Soc. 87, 2500–2502 (1965).

    Article  CAS  Google Scholar 

  19. Bacha, J. & Kochi, J. K. Alkenes from acids by oxidative decarboxylation. Tetrahedron 24, 2215–2226 (1968).

    Article  CAS  Google Scholar 

  20. Wang, Z. in Comprehensive Organic Name Reactions and Reagents (ed. Wang, Z.) 1646–1649 (Wiley, 2010).

  21. Agterberg, F. P. W., Driessen, W. L., Reedijk, J., Oeveringb, H. & Buijs, W. Copper-catalyzed oxidative decarboxylation of aliphatic carboxylic acids. Stud. Surf. Sci. Catal. 82, 639–646 (1994).

    Article  CAS  Google Scholar 

  22. Serguchev, Y. A. & Beletskaya, I. P. Oxidative decarboxylation of carboxylic acids. Usp. Khim. 49, 2257–2285 (1980).

    Article  CAS  Google Scholar 

  23. Kong, D., Moon, P. J., Bsharat, O. & Lundgren, R. L. Direct catalytic decarboxylative amination of aryl acetic acids. Angew. Chem. Int. Ed. 59, 1313–1319 (2020).

    Article  CAS  Google Scholar 

  24. Liang, Y., Zhang, X. & MacMillan, D. W. C. Decarboxylative sp3 C–N coupling via dual copper and photoredox catalysis. Nature 559, 83–88 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Sakakibara, Y., Ito, E., Fukushima, T., Murakami, K. & Itami, K. Late‐stage functionalization of arylacetic acids by photoredox‐catalyzed decarboxylative carbon–heteroatom bond formation. Chem. Eur. J. 24, 9254–9258 (2018).

    Article  CAS  PubMed  Google Scholar 

  26. Drapeau, M. P., Bahri, J., Lichte, D. & Gooßen, L. J. Decarboxylative ipso amination of activated benzoic acids. Angew. Chem. Int. Ed. 58, 892–896 (2019).

    Article  Google Scholar 

  27. Nguyen, V. T. et al. Visible light‐enabled direct decarboxylative N‐alkylation. Angew. Chem. Int. Ed. 59, 7921–7927 (2020).

    Article  CAS  Google Scholar 

  28. Reed, N. L. & Yoon, T. P. Oxidase reactions in photoredox catalysis. Chem. Soc. Rev. 50, 2954–2967 (2021).

    Article  CAS  PubMed  Google Scholar 

  29. Reed, N. L., Herman, M. I., Miltchev, V. P. & Yoon, T. P. Photocatalytic oxyamination of alkenes: copper(II) salts as terminal oxidants in photoredox catalysis. Org. Lett. 20, 7345–7350 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Reed, N. L., Herman, M. I., Miltchev, V. P. & Yoon, T. P. Tandem copper and photoredox catalysis in photocatalytic alkene difunctionalization reactions. Beilstein J. Org. Chem. 15, 351–356 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Lee, B. J., DeGlopper, K. S. & Yoon, T. P. Site-selective alkoxylation of benzylic C–H bonds via photoredox catalysis. Angew. Chem. Int. Ed. 59, 197–202 (2020).

    Article  CAS  Google Scholar 

  32. Reed, N. L., Lutovsky, G. A. & Yoon, T. P. Copper-mediated radical-polar crossover enables photocatalytic oxidative functionalization of sterically bulky alkenes. J. Am. Chem. Soc. 143, 6065–6070 (2021).

    Article  CAS  PubMed  Google Scholar 

  33. Guideline for Elemental Impurities Q3D, Current Step 4 version (European Medicines Agency, 2014).

  34. Morimoto, J. Y. & DeGraff, B. A. Photochemistry of copper complexes. The copper(ll) malonate system. J. Phys. Chem. 79, 326–331 (1975).

    Article  CAS  Google Scholar 

  35. Sun, L., Wu, C.-H. & Faust, B. C. Photochemical redox reactions of inner-sphere copper(II)-dicarboxylate complexes: effects of the dicarboxylate ligand structure on copper(I) quantum yields. J. Phys. Chem. A 102, 8664–8672 (1998).

    Article  CAS  Google Scholar 

  36. Sun, L., Wu, C.-H. & Faust, B. C. Photochemical formation of copper(I) from copper(II)-dicarboxylate complexes: effects of outer-sphere versus inner-sphere coordination and of quenching by malonate. J. Phys. Chem. A 104, 4989–4996 (2000).

    Article  Google Scholar 

  37. Xu, P., López–Rojas, P. & Ritter, T. Radical decarboxylation carbometalation of benzoic acids: a solution to aromatic decarboxylative fluorination. J. Am. Chem. Soc. 143, 5349–5354 (2021).

    Article  CAS  PubMed  Google Scholar 

  38. Zhao, C., Rakesh, K. P., Ravidar, L., Fang, W.-Y. & Qin, H.-L. Pharmaceutical and medicinal significance of sulfur (SVI)-containing motifs for drug discovery: a critical review. Eur. J. Med. Chem. 162, 679–734 (2019).

    Article  CAS  PubMed  Google Scholar 

  39. Tsybizova, A. et al. Speciation behavior of copper(II) acetate in simple organic solvents-revealing the effect of trace water. Eur. J. Inorg. Chem. 2014, 1407–1412 (2014).

    Article  CAS  Google Scholar 

  40. Kochi, J. K., Bemis, A. & Jenkins, C. L. Mechanism of electron transfer oxidation of alkyl radicals by copper(II) complexes. J. Am. Chem. Soc. 90, 4616–4625 (1968).

    Article  CAS  Google Scholar 

  41. Dendrinou-Samara, C. et al. Copper(II) complexes with anti-inflammatory drugs as ligands. Solution behaviour and electrochemistry of mono- and bi-nuclear complexes. J. Chem. Soc. Dalton Trans. 1992, 3259–3264 (1992).

    Article  Google Scholar 

  42. Graddon, D. P. The absorption spectra of complex salts—IV cupric alkanoates. J. Inorg. Nucl. Chem. 17, 222–231 (1961).

    Article  CAS  Google Scholar 

  43. Kyuzou, M., Mori, W. & Tanaka, J. Electronic structure and spectra of cupric acetate mono-hydrate revisited. Inorg. Chim. Acta 363, 930–934 (2010).

    Article  CAS  Google Scholar 

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Acknowledgements

We thank W. B. Swords for helpful discussions. Funding for this work was provided by the NIH (R01GM095666, T.P.Y.), an ACS GCI Pharmaceutical Roundtable Research Grant (T.P.Y.) and Pfizer (T.P.Y.). S.N.G. thanks the NIH for a fellowship grant (F32GM139373) and G.A.L. is the recipient of a 3M Science & Technology Fellowship. Analytical facilities at UW–Madison are funded by the NIH (S10OD012245), NSF (CHE-9304546) and a generous gift from the Paul J. and Margaret M. Bender Fund.

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Author notes

  1. These authors contributed equally: Qi Yukki Li, Samuel N. Gockel.

Authors and Affiliations

  1. Department of Chemistry, University of Wisconsin–Madison, Madison, WI, USA

    Qi Yukki Li, Samuel N. Gockel, Grace A. Lutovsky, Kimberly S. DeGlopper & Tehshik P. Yoon

  2. Medicine Design, Pfizer Inc, Groton, CT, USA

    Neil J. Baldwin, Mark W. Bundesmann, Joseph W. Tucker & Scott W. Bagley

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Contributions

Q.Y.L., S.N.G., G.A.L., K.S.D. and T.P.Y. conceived the project. Experimental work was conducted by Q.Y.L., S.N.G., N.J.B., M.W.B. and J.W.T. S.W.B. and T.P.Y. supervised the research. All authors contributed to the writing and editing of the manuscript.

Corresponding author

Correspondence to Tehshik P. Yoon.

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Competing interests

N.J.B., M.W.B., J.W.T. and S.W.B. are employees and shareholders of Pfizer, Inc. The remaining authors declare no competing interests.

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Peer review information Nature Chemistry thanks the anonymous reviewers for their contribution to the peer review of this work.

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Supplementary information

Supplementary Information

General information, select optimization results, substrate preparation, isolation and characterization, additional mechanistic studies, references, spectral data, Tables 1–25 and Figs. 1–10.

Supplementary Data 1

An excel spreadsheet containing the raw data obtained from the UV–vis spectrometer for the carboxylate titration study. A brief walkthrough of the data processing to obtain the final, published plot is included.

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Li, Q.Y., Gockel, S.N., Lutovsky, G.A. et al. Decarboxylative cross-nucleophile coupling via ligand-to-metal charge transfer photoexcitation of Cu(ii) carboxylates. Nat. Chem. 14, 94–99 (2022). https://doi.org/10.1038/s41557-021-00834-8

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