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Hindered dialkyl ether synthesis with electrogenerated carbocations


Hindered ethers are of high value for various applications; however, they remain an underexplored area of chemical space because they are difficult to synthesize via conventional reactions1,2. Such motifs are highly coveted in medicinal chemistry, because extensive substitution about the ether bond prevents unwanted metabolic processes that can lead to rapid degradation in vivo. Here we report a simple route towards the synthesis of hindered ethers, in which electrochemical oxidation is used to liberate high-energy carbocations from simple carboxylic acids. These reactive carbocation intermediates, which are generated with low electrochemical potentials, capture an alcohol donor under non-acidic conditions; this enables the formation of a range of ethers (more than 80 have been prepared here) that would otherwise be difficult to access. The carbocations can also be intercepted by simple nucleophiles, leading to the formation of hindered alcohols and even alkyl fluorides. This method was evaluated for its ability to circumvent the synthetic bottlenecks encountered in the preparation of 12 chemical scaffolds, leading to higher yields of the required products, in addition to substantial reductions in the number of steps and the amount of labour required to prepare them. The use of molecular probes and the results of kinetic studies support the proposed mechanism and the role of additives under the conditions examined. The reaction manifold that we report here demonstrates the power of electrochemistry to access highly reactive intermediates under mild conditions and, in turn, the substantial improvements in efficiency that can be achieved with these otherwise-inaccessible intermediates.

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Fig. 1: Background and reaction development.
Fig. 2: Applications, and partial scope of hindered ether synthesis via electrochemical decarboxylation.
Fig. 3: Applications and partial scope of trapping electrogenerated carbocations with other nucleophiles along with scalability demonstration.

Data availability

The data that support the findings of this study are available within the paper and its Supplementary Information. Metrical parameters for the structures of (2R)-77 and (11R)-138 are available free of charge from the Cambridge Crystallographic Data Centre ( under reference numbers 1918528 and 1903823, respectively.


  1. Roughley, S. D. & Jordan, A. M. The medicinal chemist’s toolbox: an analysis of reactions used in the pursuit of drug candidates. J. Med. Chem. 54, 3451–3479 (2011).

    CAS  Article  Google Scholar 

  2. Fischer, J. & Ganellin, C. R. (eds) Analogue-based Drug Discovery 206–217 (Wiley, 2006).

  3. Williamson, W. Ueber die theorie der aetherbildung. Justus Liebigs Ann. Chem. 77, 37–49 (1851).

    CAS  Article  Google Scholar 

  4. Kürti, L. & Czakó, B. Strategic Applications of Named Reactions in Organic Synthesis 484–485 (Elsevier, 2005).

  5. Swamy, K. C. K., Kumar, N. N. B., Balaraman, E. & Kumar, K. V. P. P. Mitsunobu and related reactions: advances and applications. Chem. Rev. 109, 2551–2651 (2009).

    CAS  Article  Google Scholar 

  6. Beyerman, H. C. & Heiszwolf, G. J. Reaction of steroidal alcohols with isobutene. Usefulness of t-butyl as a hydroxyl-protecting group in a synthesis of testosterone. Recl. Trav. Chim. Pays-Bas 84, 203–212 (1965).

    CAS  Article  Google Scholar 

  7. Smith, M. B. & March, J. March’s Advanced Organic Chemistry 1037–1041 (Wiley, 2007).

  8. Abraham S. et al. Aurora kinase compounds and methods of their use. International patent no. WO2011088045A1 (2011).

  9. 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 

  10. Hofer, H. & Moest, M. Mittheilung aus dem elektrochemischen Laboratorium der Königl, Technischen Hochschule zu München. Justus Liebigs Ann. Chem. 323, 284–323 (1902).

    CAS  Article  Google Scholar 

  11. Corey, E. J., Bauld, N. L., La Londe, R. T., Casanova, J., Jr & Kaiser, E. T. Generation of cationic carbon by anodic oxidation of carboxylic acids. J. Am. Chem. Soc. 82, 2645–2646 (1960).

    CAS  Article  Google Scholar 

  12. Luo, X., Ma, X., Lebreux, F., Markó, I. E. & Lam, K. Electrochemical methoxymethylation of alcohols – a new, green and safe approach for the preparation of MOM ethers and other acetals. Chem. Commun. 54, 9969–9972 (2018).

    CAS  Article  Google Scholar 

  13. Bunyan, P. J. & Hey, D. H. The electrolysis of some aryl-substituted, aliphatic acids. J. Chem. Soc. 1360–1365 (1962).

  14. Iwasaki, T., Hrorikawa, H., Matsumoto, K. & Miyoshi, M. Electrochemical synthesis and reactivity of α-alkoxy α-amino acid derivatives. Bull. Chem. Soc. Jpn. 52, 826–830 (1979).

    CAS  Article  Google Scholar 

  15. Tajima, T., Kurihara, H. & Fuchigami, T. Development of an electrolytic system for non-Kolbe electrolysis based on the acid−base reaction between carboxylic acids as a substrate and solid-supported bases. J. Am. Chem. Soc. 129, 6680–6681 (2007).

    CAS  Article  Google Scholar 

  16. Shtelman, A. V. & Becker, J. Y. Electrochemical synthesis of 1,2-disilylethanes from α-silylacetic acids. J. Org. Chem. 76, 4710–4714 (2011).

    CAS  Article  Google Scholar 

  17. Torii, S., Inokuchi, T., Mizuguchi, K. & Yamazaki, M. Electrolytic decarboxylation reactions. 4. Electrosyntheses of 3-alkyl-2-cycloalken-1-ol acetates from 1-alkyl-2-cycloalkene-1-carboxylic acids. Preparation of dl-muscone from cyclopentadecanone. J. Org. Chem. 44, 2303–2307 (1979).

    CAS  Article  Google Scholar 

  18. Coleman, J. P., Lines, R., Utley, J. H. P. & Weedon, B. C. L. Electro-organic reactions. Part II. Mechanism of the kolbe electrolysis of substituted phenylacetate ions. J. Chem. Soc., Perkin Trans. 2 1064–1069 (1974).

    Article  Google Scholar 

  19. Mao, R., Balon, J. & Hu, X. Decarboxylative C(sp3)–O cross-coupling. Angew. Chem. Int. Ed. 57, 13624–13628 (2018).

    CAS  Article  Google Scholar 

  20. Yan, M., Kawamata, Y. & Baran, P. S. Synthetic organic electrochemical methods since 2000: on the verge of a renaissance. Chem. Rev. 117, 13230–13319 (2017).

    CAS  Article  Google Scholar 

  21. Ross, S. D. & Finkelstein, M. Anodic oxidations. V. The Kolbe oxidation of phenylacetic acid and 1-methylcyclohexaneacetic acid at platinum and at carbon. J. Org. Chem. 34, 2923–2927 (1969).

    CAS  Article  Google Scholar 

  22. Schäfer, H. J. Recent contributions of Kolbe electrolysis to organic synthesis. Top. Curr. Chem. 152, 91–151 (1990).

    Article  Google Scholar 

  23. Koehl, W. J. Anodic oxidation of aliphatic acids at carbon anodes. J. Am. Chem. Soc. 86, 4686–4690 (1964).

    CAS  Article  Google Scholar 

  24. Iwasaki, T., Horikawa, H., Matsumoto, K. & Miyoshi, M. An electrochemical synthesis of 2-acetoxy-2-amino acid and 3-acetoxy-3-amino acid derivatives. J. Org. Chem. 42, 2419–2423 (1977).

    CAS  Article  Google Scholar 

  25. Huang, X., Liu, W., Hooker, J. M. & Groves, J. T. Targeted fluorination with the fluoride ion by manganese-catalyzed decarboxylation. Angew. Chem. Int. Ed. 54, 5241–5245 (2015).

    CAS  Article  Google Scholar 

  26. 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).

    CAS  Article  Google Scholar 

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Financial support for this work was provided by Pfizer, Inc., the National Science Foundation (CCI Phase 1 grant 1740656), and the National Institutes of Health (grant number GM-118176). China Scholarship Council and Jilin University supported a fellowship to J.X., Zhejiang Yuanhong Medicine Technology Co. Ltd supported a fellowship to M.S., The Hewitt Foundation supported a fellowship to Y.K., The Swedish Research Council supported a fellowship to H.L., Fulbright Fellowship supported a fellowship to P.M., and S.H.R. acknowledges an NSF Graduate Research Fellowship Program (no. 2017237151) and a Donald and Delia Baxter Fellowship. We thank D.-H. Huang and L. Pasternack for assistance with NMR spectroscopy; J. Chen for measuring the high-resolution mass spectroscopy data, and A. Rheingold, C. E. Moore and M. A. Galella for X-ray crystallographic analysis.

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Authors and Affiliations



J.X., M.S. and P.S.B. conceived the project. J.X., M.S., Y.K., H.L., D.G.B. and P.S.B. designed the experiments and analysed the data. J.X. and M.S. developed the electrochemical decarboxylative methods and performed their applications. H.L. and Y.K. carried out the mechanistic study. J.X., M.S., S.H.R., M.C., P.M., G.B., M.R.C., A.D., M.D.B., G.M.G., J.E.S., J.S. and S.Y. conducted experiments to demonstrate the substrate scope. P.S.B. wrote the manuscript. J.X., M.S., Y.K., S.H.R., P.M., H.L. and D.G.B. assisted in writing and editing the manuscript.

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Correspondence to Phil S. Baran.

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The authors declare no competing interests.

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Supplementary information

Supplementary Information

Supplementary Data 1

Cif file of (2R)-77

Supplementary Data 2

Cif file of (11R)-138

Supplementary Data 3

Checkcif of (2R)-77

Supplementary Data 4

Checkcif of (11R)-138

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

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