Site-selective alkene borylation enabled by synergistic hydrometallation and borometallation


The selective installation of boryl units at less-activated sites, which will facilitate easy access to a range of core structures embedded within bioactive molecules, is a longstanding challenge. Here, we show that catalytic amounts of an earth-abundant Fe(ii)-based complex promote efficient borylations at typically less-reactive positions vicinal (β) to common functional units. Utility is highlighted through the synthesis of drug-like scaffolds and regioconvergent transformation of olefin feedstock to value-added products bearing Cβ–B stereogenic centres. These reactions proceed through tandem alkene isomerization followed by protoboration, and require that the in-situ-generated iron-hydride and iron-boryl catalysts function in synergy. By tuning the two processes of olefin transposition and protoboration, the present Fe-catalysed protocol can provide selective access to 1-boryl-, 2-boryl- or 3-borylalkane isomers. The insights gained from our studies are expected to advance general efforts towards unlocking selective functionalizations at other unactivated sites along the hydrocarbon chain.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Fig. 1: The significance and challenges involved in developing remote β-selective borylation reactions.
Fig. 2: Striking a balance between hydrometallation and borometallation processes for β-selective borylation.
Fig. 3: Efficient and site-selective synthesis of β-borylated compounds.
Fig. 4: Application to chemical synthesis and regioselective convergent and divergent reactions.

Data availability

All data are available from the corresponding author upon reasonable request. An X-ray crystal structure data file (CCDC reference number 1996790) has been deposited with the Cambridge Crystallographic Data Centre and is available free of charge from


  1. 1.

    Hall, D. G. (ed.) Boronic Acids: Preparation and Applications in Organic Synthesis, Medicine and Materials Vol. 2 (Wiley-VCH, 2011).

  2. 2.

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

    CAS  Google Scholar 

  3. 3.

    Mlynarski, S. N., Schuster, C. H. & Morken, J. P. Asymmetric synthesis from terminal alkenes by cascades of diboration and cross-coupling. Nature 505, 386–390 (2014).

    CAS  PubMed  Google Scholar 

  4. 4.

    Diaz, D. B. & Yudin, A. K. The versatility of boron in biological target engagement. Nat. Chem. 9, 731–742 (2017).

    CAS  PubMed  Google Scholar 

  5. 5.

    Baker, S. J. et al. Therapeutic potential of boron-containing compounds. Future Med. Chem. 1, 1275–1288 (2009).

    CAS  PubMed  Google Scholar 

  6. 6.

    Qiu, F. et al. Recent advances in boron-containing conjugated porous polymers. Polymers 8, 191 (2016).

    PubMed Central  Google Scholar 

  7. 7.

    Yamamoto, E., Maeda, S., Taketsugu, T. & Ito, H. Transition-metal-free boryl substitution using silylboranes and alkoxy bases. Synlett 28, 1258–1267 (2017).

    CAS  Google Scholar 

  8. 8.

    Shintani, R. Recent progress in copper-catalyzed asymmetric allylic substitution reactions using organoboron nucleophiles. Synthesis 48, 1087–1100 (2016).

    CAS  Google Scholar 

  9. 9.

    Hemming, D. et al. Copper-boryl mediated organic synthesis. Chem. Soc. Rev. 47, 7477–7494 (2018).

    CAS  PubMed  Google Scholar 

  10. 10.

    Semba, K., Fujihara, T., Terao, J. & Tsuji, Y. Copper-catalyzed borylative transformations of non-polar carbon–carbon unsaturated compounds employing borylcopper as an active catalyst species. Tetrahedron 71, 2183–2197 (2015).

    CAS  Google Scholar 

  11. 11.

    Mkhalid, I. A. I., Barnard, J. H., Marder, T. B., Murphy, J. M. & Hartwig, J. F. C–H activation for the construction of C–B bonds. Chem. Rev. 110, 890–931 (2010).

    CAS  PubMed  Google Scholar 

  12. 12.

    Ros, A., Fernández, R. & Lassaletta, J. M. Functional group directed C–H borylation. Chem. Soc. Rev. 43, 3229–3243 (2014).

    CAS  PubMed  Google Scholar 

  13. 13.

    He, J., Wasa, M., Chan, K. S. L., Shao, Q. & Yu, J.-Q. Palladium-catalyzed transformations of alkyl C–H bonds. Chem. Rev. 117, 8754–8786 (2017).

    CAS  PubMed  Google Scholar 

  14. 14.

    Obligacion, J. V. & Chirik, P. J. Earth-abundant transition metal catalysts for alkene hydrosilylation and hydroboration. Nat. Rev. Chem. 2, 15–34 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. 15.

    Wei, D. & Darcel, C. Iron catalysis in reduction and hydrometalation reactions. Chem. Rev. 119, 2550–2610 (2019).

    CAS  PubMed  Google Scholar 

  16. 16.

    Chen, J., Guo, J. & Lu, Z. Recent advances in hydrometallation of alkenes and alkynes via the first row transition metal catalysis. Chin. J. Chem. 36, 1075–1109 (2018).

    CAS  Google Scholar 

  17. 17.

    Liu, Y., Zhou, Y., Wang, H. & Qu, J. FeCl2-catalyzed hydroboration of aryl alkenes with bis(pinacolato)diboron. RSC Adv. 5, 73705–73713 (2015).

    CAS  Google Scholar 

  18. 18.

    Cai, Y. et al. Copper-catalyzed enantioselective markovnikov protoboration of α-olefins enabled by a buttressed N-heterocyclic carbene ligand. Angew. Chem. Int. Ed. 57, 1376–1380 (2018).

    CAS  Google Scholar 

  19. 19.

    Sommer, H., Juliá-Hernández, F., Martin, R. & Marek, I. Walking metals for remote functionalization. ACS Cent. Sci. 4, 153–165 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. 20.

    Scheuermann, M. L., Johnson, E. J. & Chirik, P. J. Alkene isomerization−hydroboration promoted by phosphine- ligated cobalt catalysts. Org. Lett. 17, 2716–2719 (2015).

    CAS  PubMed  Google Scholar 

  21. 21.

    Chen, X., Cheng, Z. & Lu, Z. Asymmetric remote C–H borylation of internal alkenes via alkene isomerization. Nat. Commun. 9, 3939 (2018).

    PubMed  PubMed Central  Google Scholar 

  22. 22.

    Obligacion, J. V. & Chirik, P. J. Bis(imino)pyridine cobalt-catalyzed alkene isomerization−hydroboration: a strategy for remote hydrofunctionalization with terminal selectivity. J. Am. Chem. Soc. 135, 19107–19110 (2013).

    CAS  PubMed  Google Scholar 

  23. 23.

    Zheng, J., Sortais, J.-B. & Darcel, C. [(NHC)Fe(CO)4] efficient pre-catalyst for selective hydroboration of alkenes. ChemCatChem 6, 763–766 (2014).

    CAS  Google Scholar 

  24. 24.

    Ogawa, T., Ruddy, A. J., Sydora, O. L., Stradiotto, M. & Turculet, L. Cobalt- and iron-catalyzed isomerization−hydroboration of branched alkenes: terminal hydroboration with pinacolborane and 1,3,2-diazaborolanes. Organometallics 36, 417–423 (2017).

    CAS  Google Scholar 

  25. 25.

    Kawamorita, S., Murakami, R., Iwai, T. & Sawamura, M. Synthesis of primary and secondary alkylboronates through site-selective C(sp3)−H activation with silica-supported monophosphine−Ir catalysts. J. Am. Chem. Soc. 135, 2947–2950 (2013).

    CAS  PubMed  Google Scholar 

  26. 26.

    Larsen, M. A., Cho, S. H. & Hartwig, J. Iridium-catalyzed, hydrosilyl-directed borylation of unactivated alkyl C−H bonds. J. Am. Chem. Soc. 138, 762–765 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. 27.

    Zhang, S. et al. Delayed catalyst function enables direct enantioselective conversion of nitriles to NH2-amines. Science 364, 45–51 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. 28.

    Cummings, S. P., Le, T.-N., Fernandez, G. L., Quiambo, L. G. & Stokes, B. J. Tetrahydroxydiboron-mediated palladium-catalyzed transfer hydrogenation and deuteriation of alkenes and alkynes using water as the stoichiometric H or D atom donor. J. Am. Chem. Soc. 138, 6107–6110 (2016).

    CAS  PubMed  Google Scholar 

  29. 29.

    Neeve, E. C., Geier, S. J., Mkhalid, I. A. I., Westcott, S. A. & Marder, T. B. Diboron(4) compounds: from structural curiosity to synthetic workhorse. Chem. Rev. 116, 9091–9161 (2016).

    CAS  PubMed  Google Scholar 

  30. 30.

    Nakazawa, H. & Itazaki, M. Fe–H complexes in catalysis. Top. Organomet. Chem. 33, 27–81 (2011).

    CAS  Google Scholar 

  31. 31.

    Mayer, M., Welther, A. & von Wangelin, A. J. Iron-catalyzed isomerizations of olefins. ChemCatChem 3, 1567–1571 (2011).

    CAS  Google Scholar 

  32. 32.

    Crossley, S. W. M., Barabé, F. & Shenvi, R. A. Simple, chemoselective, catalytic olefin isomerization. J. Am. Chem. Soc. 136, 16788–16791 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. 33.

    Takaya, H. et al. Investigation of organoiron catalysis in kumada–tamao–corriu-type cross-coupling reaction assisted by solution-phase X-ray absorption spectroscopy. Bull. Chem. Soc. Jpn. 88, 410–418 (2015).

    CAS  Google Scholar 

  34. 34.

    Dang, L., Zhao, H., Lin, Z. & Marder, T. B. DFT studies of alkene insertions into Cu−B bonds in copper(I) boryl complexes. Organometallics 26, 2824–2832 (2007).

    CAS  Google Scholar 

  35. 35.

    Zhang, L., Peng, D., Leng, X. & Huang, Z. Iron-catalyzed, atom-economical, chemo- and regioselective alkene hydroboration with pinacolborane. Angew. Chem. Int. Ed. 52, 3676–3680 (2013).

    CAS  Google Scholar 

  36. 36.

    Clémancey, M. et al. Structural insights into the nature of Fe0 and FeI low-valent species obtained upon the reduction of iron salts by aryl grignard reagents. Inorg. Chem. 56, 3834–3848 (2017).

    PubMed  Google Scholar 

  37. 37.

    Bedford, R. B. et al. TMEDA in iron-catalyzed kumada coupling: amine adduct versus homoleptic ‘ate’ complex formation. Angew. Chem. Int. Ed. 53, 1804–1808 (2014).

    CAS  Google Scholar 

  38. 38.

    Neidig, M. L. et al. Development and evolution of mechanistic understanding in iron-catalyzed cross-coupling. Acc. Chem. Res. 52, 140–150 (2019).

    CAS  PubMed  Google Scholar 

  39. 39.

    Sears, J. D., Neate, P. G. N. & Neidig, M. L. Intermediates and mechanism in iron-catalyzed cross-coupling. J. Am. Chem. Soc. 140, 11872–11883 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. 40.

    Docherty, J. H., Peng, J., Dominey, A. P. & Thomas, S. P. Activation and discovery of earth-abundant metal catalysts using sodium tert-butoxide. Nat. Chem. 9, 595–600 (2017).

    CAS  PubMed  Google Scholar 

  41. 41.

    Larouche-Gauthier, R., Elford, T. G. & Aggarwal, V. K. Ate complexes of secondary boronic esters as chiral organometallic-type nucleophiles for asymmetric synthesis. J. Am. Chem. Soc. 133, 16794–16797 (2011).

    CAS  PubMed  Google Scholar 

  42. 42.

    Fang, W. K., Corpuz, E. G. & Chow, K. Disubstituted aryl azetidine derivatives as sphingosine-1-phosphate receptors modulators. US patent WO2015/021109 A1 (2015).

  43. 43.

    Lu, X. et al. Practical carbon–carbon bond formation from olefins through nickel-catalyzed reductive olefin hydrocarbonation. Nat. Commun. 7, 11129 (2016).

    PubMed  PubMed Central  Google Scholar 

  44. 44.

    Li, Z., Wang, Z., Zhu, L., Tan, X. & Li, C. Silver-catalyzed radical fluorination of alkylboronates in aqueous solution. J. Am. Chem. Soc. 136, 16439–16443 (2014).

    CAS  PubMed  Google Scholar 

  45. 45.

    Purohit, A. et al. Quinazoline derivatives as MC-I inhibitors: evaluation of myocardial uptake using positron emission tomography in rat and non-human primate. Bioorg. Med. Chem. Lett. 17, 4882–4885 (2007).

    CAS  PubMed  Google Scholar 

Download references


This research was supported by the National University of Singapore President’s Assistant Professorship start-up grant no. R-143-000-A50-133 (M.J.K.) and the National Research Foundation, Singapore (NRF) Investigator Award no. NRF-NRF12015-01 (K.P.L.). We thank G. K. Tan for X-ray crystallographic analysis. We also thank N. Yoshikai (Nanyang Technological University), W. Tang (Xi’an Jiaotong University), J. Wang (Dalian Institute of Chemical Physics, Chinese Academy of Sciences) and O. Gutierrez (University of Maryland) for helpful discussions.

Author information




X.Y., H.Z. and L.Q.H.L. developed the method and carried out the mechanistic studies. S.X. performed the EXAFS measurements and analysed the results. Z.C., X.W., L.W. and K.P.L. prepared the materials for EXAFS measurements. M.J.K. directed the investigations and wrote the manuscript with revisions provided by the other authors.

Corresponding author

Correspondence to Ming Joo Koh.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

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

Extended data

Extended Data Fig. 1 An alternative pathway for alkene chain-walking.

a, Radical clock experiment showing the possibility of radical species formation during the course of hydrometallation. Besides the expected remote protoboration product 7, detectable quantities of 8, likely generated from a hydrometallation/ring rupture/protonolysis/remote protoboration sequence were observed. b, Catalytic cycle for Fe-catalysed C=C bond migration involving hydrogen atom transfer. Conv. and product ratio are determined by GC analysis of unpurfied mixtures. pin, pinacolato; G, substituent; L, ligand.

Extended Data Fig. 2 Operando XANES and EXAFS measurements of Fe-1 and crude reaction mixture.

a, FT-k2χ(R) Fe K-edge EXAFS of the catalyst Fe-1 and reaction mixture at different temperatures. Inset shows an enlarged view of peak II. b, The corresponding Fe K-edge EXAFS spectra. c, The corresponding normalized Fe K-edge XANES spectra. Insets show the enlarged pre-edge peaks and main peaks. RT, room temperature (22 oC).

Extended Data Fig. 3 Temperature- and time-dependent EPR studies.

a, EPR spectra of the reaction mixture with Fe-1 (0.01 mmol), LiOt-Bu (0.30 mmol), B2(pin)2 (0.30 mmol) and 4a (0.20 mmol) in a mixture of DMA (0.16 mL) and toluene (0.34 mL) at various temperatures. b, EPR spectra of the same reaction mixture heated to 100 oC at various times. Test conditions: microwave power (1 mW), central field (317 mT), magnetic width (200 mT), modulation width (1.0 mT), time constant (0.03 s), measurement time (16 min), 120 K.

Supplementary information

Supplementary Information

Supplementary Tables 1–6, Figs. 1–6, methods, Note 1 and references

Crystallographic data 1

Crystallographic data for compound 13

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Yu, X., Zhao, H., Xi, S. et al. Site-selective alkene borylation enabled by synergistic hydrometallation and borometallation. Nat Catal 3, 585–592 (2020).

Download citation

Further reading


Sign up for the Nature Briefing newsletter for a daily update on COVID-19 science.
Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing