Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Direct C–H metallation of tetrahydrofuran and application in flow


The direct C–H metallation of tetrahydrofuran (THF) to generate α-anionic THF is one of the most straightforward methods for the functionalization of THF. However, the stability of THF makes it difficult to activate the α-proton and the instability of α-anionic THF leads to an uncontrollably rapid cleavage. These factors are well-known challenges for both the generation and utilization of α-anionic THF. Here we develop a reaction for the direct metallation of THF using a strong base as well as precise control of the temperature and reaction time in a microfluidic system. Various electrophiles, which include those with complex structures, were introduced to give products in high yields. Also, transmetallations to α-cuprated THF and α-borylated THF were successfully achieved and α-borylated THF was further functionalized via cross-coupling reactions, which demonstrates the value of this microfluidic approach.

This is a preview of subscription content, access via your institution

Access options

Buy this article

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Methods for α-functionalization of THF through an anionic reaction pathway.
Fig. 2: Generation and utilization of α-anionic THF in flow.
Fig. 3: Cupration and borylation of α-anionic THF in the integrated flow microreactor.
Fig. 4: Synthetic applications of α-borylated THF and plausible mechanisms.

Similar content being viewed by others

Data availability

Crystallographic data for the structures reported in this article have been deposited at the Cambridge Crystallographic Data Centre, under deposition numbers CCDC 2098707 (9e). Copies of the data can be obtained free of charge via All other data that support the findings of this study, which include experimental procedures and compound characterization, are available within the paper and its Supplementary Information.


  1. Wilson, E. R. & Frankel, M. B. Synthesis of novel energetic compounds. 7. Azido derivatives of pentaerythritol. J. Org. Chem. 50, 3211–3212 (1985).

    Article  CAS  Google Scholar 

  2. Hrkach, J. S. & Matyjaszewski, K. Cationic polymerization of tetrahydrofuran initiated by trimethylsilyl trifluoromethanesulfonate. Macromolecules 23, 4042–4046 (1990).

    Article  CAS  Google Scholar 

  3. Clayden, J. & Yasin, S. A. Pathways for decomposition of THF by organolithiums: the role of HMPA. New J. Chem. 26, 191–192 (2002).

    Article  CAS  Google Scholar 

  4. Mulvey, R. E. et al. Cleave and capture chemistry illustrated through bimetallic-induced fragmentation of tetrahydrofuran. Nat. Chem. 2, 588–591 (2010).

    Article  CAS  PubMed  Google Scholar 

  5. Miles, S. M., Marsden, S. P., Leatherbarrow, R. J. & Coates, W. J. Reagent-controlled stereoselective synthesis of lignan-related tetrahydrofurans. J. Org. Chem. 69, 6874–6882 (2004).

    Article  CAS  PubMed  Google Scholar 

  6. Rye, C. E. & Barker, D. An acyl-Claisen approach to tetrasubstituted tetrahydrofuran lignans: synthesis of fragransin A2, talaumidin, and lignan analogue. SynLett 2009, 3315–3319 (2009).

    Article  CAS  Google Scholar 

  7. Rudroff, F. et al. Synthesis of tetrahydrofuran-based natural products and their carba analogs via stereoselective enzyme mediated Baeyer–Villiger oxidation. Tetrahedron 72, 7212–7221 (2016).

    Article  CAS  Google Scholar 

  8. Albright, J. D., Howell, C. F. & Sum, F. W. The synthesis of heterocyclic C-terminal units which mimic the transition-state in the cleavage of the Leu–Val bond of angiotensinogen by renin. Heterocycles 35, 737–754 (1993).

    Article  CAS  Google Scholar 

  9. Pauli, L., Tannert, R., Scheil, R. & Pfaltz, A. Asymmetric hydrogenation of furans and benzofurans with iridium–pyridine–phosphinite catalysts. Chem. Eur. J. 21, 1482–1487 (2015).

    Article  CAS  PubMed  Google Scholar 

  10. Trost, B. M. The atom economy—a search for synthetic efficiency. Science 254, 1471–1477 (1991).

    Article  CAS  PubMed  Google Scholar 

  11. Wender, P. A., Verma, V. A., Paxton, T. J. & Pillow, T. H. Function-oriented synthesis, step economy, and drug design. Acc. Chem. Res. 41, 40–49 (2008).

    Article  CAS  PubMed  Google Scholar 

  12. Kennedy, A. R., Klett, J., Mulvey, R. E. & Wright, D. S. Synergic sedation of sensitive anions: alkali-mediated zincation of cyclic ethers and ethene. Science 326, 706–708 (2009).

    Article  CAS  PubMed  Google Scholar 

  13. Elvira, K. S., Solvas, X. C. I., Wootton, R. C. R. & deMello, A. J. The past, present and potential for microfluidic reactor technology in chemical synthesis. Nat. Chem. 5, 905–915 (2013).

    Article  CAS  PubMed  Google Scholar 

  14. Ley, S. V., Fitzpatrick, D. E., Myers, R. M., Battilocchio, C. & Ingham, R. J. Machine-assisted organic synthesis. Angew. Chem. Int. Ed. 54, 10122–10136 (2015).

    Article  CAS  Google Scholar 

  15. Cambie, D., Bottecchia, C., Straathof, N. J. W., Hessel, V. & Noel, T. Applications of continuous-flow photochemistry in organic synthesis, material science, and water treatment. Chem. Rev. 116, 10276–10341 (2016).

    Article  CAS  PubMed  Google Scholar 

  16. Plutschack, M. B., Pieber, B., Gilmore, K. & Seeberger, P. H. The hitchhiker’s guide to flow chemistry. Chem. Rev. 117, 11796–11893 (2017).

    Article  CAS  PubMed  Google Scholar 

  17. Masuda, K., Ichitsuka, T., Koumura, N., Sato, K. & Kobayashi, S. Flow fine synthesis with heterogeneous catalysts. Tetrahedron 74, 1705–1730 (2018).

    Article  CAS  Google Scholar 

  18. Wiles, C. & Watts, P. Continuous flow reactors: a perspective. Green Chem. 14, 38–54 (2012).

    Article  CAS  Google Scholar 

  19. Fukuyama, T., Totoki, T. & Ryu, I. Carbonylation in microflow: close encounters of CO and reactive species. Green Chem. 16, 2042–2050 (2014).

    Article  CAS  Google Scholar 

  20. Gutmann, B., Cantillo, D. & Kappe, C. O. Continuous-flow technology—a tool for the safe manufacturing of active pharmaceutical ingredients. Angew. Chem. Int. Ed. 54, 6688–6728 (2015).

    Article  CAS  Google Scholar 

  21. Tsubogo, T., Oyamada, H. & Kobayashi, S. Multistep continuous-flow synthesis of (R)- and (S)-rolipram using heterogeneous catalysts. Nature 520, 329–332 (2015).

    Article  CAS  PubMed  Google Scholar 

  22. Movsisyan, M. et al. Taming hazardous chemistry by continuous flow technology. Chem. Soc. Rev. 45, 4892–4928 (2016).

    Article  CAS  PubMed  Google Scholar 

  23. Granda, J. M., Donina, L., Dragone, V., Long, D. L. & Cronin, L. Controlling an organic synthesis robot with machine learning to search for new reactivity. Nature 559, 377–381 (2019).

    Article  CAS  Google Scholar 

  24. Bedard, A. C. et al. Reconfigurable system for automated optimization of diverse chemical reactions. Science 361, 1220–1225 (2018).

    Article  CAS  PubMed  Google Scholar 

  25. Coley, C. W. et al. A robotic platform for flow synthesis of organic compounds informed by AI planning. Science 365, 557 (2019).

    Article  CAS  Google Scholar 

  26. Yoshida, J. Flash chemistry: flow microreactor synthesis based on high-resolution reaction time control. Chem. Rec. 10, 332–341 (2010).

    Article  CAS  PubMed  Google Scholar 

  27. Yoshida, J., Takahashi, Y. & Nagaki, A. Flash chemistry: flow chemistry that cannot be done in batch. Chem. Commun. 49, 9896–9904 (2013).

    Article  CAS  Google Scholar 

  28. Kim, H., Lee, H.-J. & Kim, D.-P. Integrated one-flow synthesis of heterocyclic thioquinazolinones through serial microreactions with two organolithium intermediates. Angew. Chem. Int. Ed. 54, 1877–1880 (2015).

    Article  CAS  Google Scholar 

  29. Kim, H., Lee, H.-J. & Kim, D.-P. Flow-assisted synthesis of [10]cycloparaphenylene through serial microreactions under mild conditions. Angew. Chem. Int. Ed. 55, 1422–1426 (2016).

    Article  CAS  Google Scholar 

  30. Kim, H. et al. Submillisecond organic synthesis: outpacing Fries rearrangement through microfluidic rapid mixing. Science 352, 691–694 (2016).

    Article  CAS  PubMed  Google Scholar 

  31. Kim, H., Yonekura, Y. & Yoshida, J. A catalyst-free amination of functional organolithium reagents by flow chemistry. Angew. Chem. Int. Ed. 57, 4063–4066 (2018).

    Article  CAS  Google Scholar 

  32. Lee, H.-J. et al. Enhanced controllability of Fries rearrangements using high-resolution 3D-printed metal microreactor with circular channel. Small 2015, 1905005 (2019).

    Article  CAS  Google Scholar 

  33. Lee, H.-J., Kwak, C., Kim, D.-P. & Kim, H. Continuous-flow Si–H functionalizations of hydrosilanes via sequential organolithium reactions catalyzed by potassium tert-butoxide. Green Chem. 23, 1193–1199 (2021).

    Article  CAS  Google Scholar 

  34. Lochmann, L., Pospisil, J. & Lim, D. On the interaction of organolithium compounds with sodium and potassium alkoxides. A new method for the synthesis of organosodium and organopotassium compounds. Tetrahedron Lett. 7, 257–262 (1966).

    Article  Google Scholar 

  35. Schlosser, M. Zur aktivierung lithiumorganischer reagenzien. J. Organomet. Chem. 8, 9–16 (1967).

    Article  CAS  Google Scholar 

  36. Yuan, X. X., Ma, X. L. & Cao, X. J. Preparation of ursodeoxycholic acid by direct electro-reduction of 7-ketolithocholic acid. Korean J. Chem. Eng. 31, 1276–1280 (2014).

    Article  CAS  Google Scholar 

  37. Knochel, P., Yeh, M. C. P., Berk, S. C. & Talber, J. Synthesis and reactivity toward acyl chlorides and enones of the new highly functionalized copper reagents RCu(CN)ZnI. J. Org. Chem. 53, 2390–2392 (1988).

    Article  CAS  Google Scholar 

  38. Knochel, P. & Singer, R. D. Preparation and reactions of polyfunctional organozinc reagents in organic synthesis. Chem. Rev. 93, 2117–2188 (1993).

    Article  CAS  Google Scholar 

  39. Moon, S. Y., Jung, S. H., Kim, U. B. & Kim, W. S. Synthesis of ketones via organolithium addition to acid chlorides using continuous flow chemistry. RSC Adv. 5, 79385–79390 (2015).

    Article  CAS  Google Scholar 

  40. Nagaki, A., Imai, K., Ishiuchi, S. & Yoshida, J. Reactions of difunctional electrophiles with functionalized aryllithium compounds: remarkable chemoselectivity by flash chemistry. Angew. Chem. Int. Ed. 54, 1914–1918 (2015).

    Article  CAS  Google Scholar 

  41. Sandford, C. & Aggarwal, V. K. Stereospecific functionalizations and transformations of secondary and tertiary boronic esters. Chem. Commun. 53, 5481–5494 (2017).

    Article  CAS  Google Scholar 

  42. Stymiest, J. L., Bagutski, V., French, R. M. & Aggarwal, V. K. Enantiodivergent conversion of chiral secondary alcohols into tertiary alcohols. Nature 456, 778–761 (2008).

    Article  CAS  PubMed  Google Scholar 

  43. Brown, H. C. & Zweifel, G. Hydroboration. IX. The hydroboration of cyclic and bicyclic olefins—stereochemistry of the hydroboration reaction. J. Am. Chem. Soc. 83, 2544–2551 (1961).

    Article  CAS  Google Scholar 

  44. Odachowski, M. et al. Development of enantiospecific coupling of secondary and tertiary boronic esters with aromatic compounds. J. Am. Chem. Soc. 138, 9521–95323 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Reilly, M. K. & Rychnovsky, S. D. DABO boronates: stable heterocyclic boronic acid complexes for use in Suzuki–Miyaura cross-coupling reactions. Synlett 2011, 2392–2396 (2011).

    Article  CAS  Google Scholar 

Download references


We acknowledge the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIP) (no. 2020R1C1C1014408 for H.K. and 2020R1I1A1A01067730 for H.-J.L.). We are grateful to the Chiral Technology Korea (CTK) corporation for help with HPLC analysis and H.-J. Lee (Seoul Women’s University) for X-ray crystallography.

Author information

Authors and Affiliations



H.K., J.Y. and H.-J.L. designed and directed the project. H.K., H.-J.L. and D.K. conceived and designed the experiments. D.K. and Y.S. assisted in conducting and analysing the chemical experiments. H.-J.L. and H.K. wrote the manuscript with contributions from D.K. All the authors contributed to discussions.

Corresponding author

Correspondence to Heejin Kim.

Ethics declarations

Competing interests

The authors declare no competing interests.

Peer review

Peer review information

Nature Synthesis thanks Varinder Aggarwal and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Primary Handling Editor: Peter Seavill, in collaboration with the Nature Synthesis team.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Supplementary Information

Experimental details, Supplementary Figs. 1–4 and Tables 1–7.

Supplementary Data 1

Crystallographic data for Compound 9e, CCDC 2098707

Source data

Source Data Fig. 1

Source data for graphs in Fig. 2b.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kim, D., Lee, HJ., Shimizu, Y. et al. Direct C–H metallation of tetrahydrofuran and application in flow. Nat. Synth 1, 558–564 (2022).

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI:

This article is cited by


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing