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Site-selective alkene borylation enabled by synergistic hydrometallation and borometallation

Nature Catalysis volume 3, pages 585–592 (2020)Cite this article

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Abstract

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.

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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.

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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 www.ccdc.cam.ac.uk/data_request/cif.

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Acknowledgements

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.

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Author notes

  1. These authors contributed equally: Xiaolong Yu, Haonan Zhao.

Authors and Affiliations

  1. Department of Chemistry, National University of Singapore, Singapore, Singapore

    Xiaolong Yu, Haonan Zhao, Zhongxin Chen, Xiaowei Wang, Lin Wang, Leroy Qi Hao Lin, Kian Ping Loh & Ming Joo Koh

  2. Institute of Chemical and Engineering Sciences, Agency for Science, Technology and Research (A*STAR), Jurong Island, Singapore

    Shibo Xi

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Contributions

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.

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Correspondence to Ming Joo Koh.

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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

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Yu, X., Zhao, H., Xi, S. et al. Site-selective alkene borylation enabled by synergistic hydrometallation and borometallation. Nat Catal 3, 585–592 (2020). https://doi.org/10.1038/s41929-020-0470-9

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