Article | Published:

Highly tunable multi-borylation of gem-difluoroalkenes via copper catalysis

Nature Catalysisvolume 1pages860869 (2018) | Download Citation

Abstract

Multi-borylated compounds are useful starting materials for the construction of complex molecules. Although certain classes of multi-borylated compounds, such as geminal and 1,2-bis(boronates), can now be accessed selectively by several well-established methods, the synthesis of one class—those containing more than two boronate substituents—remains a great challenge. Here, copper catalytic systems were developed for the borylation of gem-difluoroalkenes with B2pin2 via dual C–F bond activation to afford multi-borylate libraries—1,2-alkyldiboronates, 1,1,2-alkyltriboronates and 1,1,1,2-alkyltetraboronates—by slightly tuning the reaction conditions. The advantages of this strategy include not only avoiding the use of different methods and substrates for each type of multi-substituted alkyl boronate, but also the excellent functional group compatibility, readily accessible gem-difluorovinyl group and highly chemoselective process.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Data availability

Crystallographic data for the structures 5f and 6f reported in this paper have been deposited at the Cambridge Crystallographic Data Centre under deposition numbers 1855882 and 1855883. Copies of the data can be obtained free of charge via www.ccdc.cam.ac.uk/getstructures. All other data supporting the findings of this study, including experimental procedures and compound characterization, are available within the paper and its Supplementary Information, or from the corresponding author upon reasonable request.

Additional information

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

References

  1. 1.

    Hall, D. G. Boronic Acids: Preparation and Applications in Organic Synthesis, Medicine and Materials Vol. 1–2 (Wiley, Weinheim, 2011).

  2. 2.

    Brooks, W. L. A. & Sumerlin, B. S. Synthesis and applications of boronic acid-containing polymers: from materials to medicine. Chem. Rev. 116, 1375–1397 (2016).

  3. 3.

    Trippier, P. C. & McGuigan, C. Boronic acids in medicinal chemistry: anticancer, antibacterial and antiviral applications. Med. Chem. Comm. 1, 183–198 (2010).

  4. 4.

    Draganov, A., Wang, D. & Wang, B. in Atypical Elements in Drug Design (ed. Schwarz, J.) 1–27 (Springer, Basel, 2014).

  5. 5.

    Smoum, R., Rubinstein, A., Dembitsky, V. M. & Srebnik, M. Boron containing compounds as protease inhibitors. Chem. Rev. 112, 4156–4220 (2012).

  6. 6.

    Miyaura, N. & Yamamoto, Y. in Comprehensive Organometallic Chemistry III Vol. 9 (eds Crabtree, R. H. & Mingos, D. M. P.) Ch. 5 (Elsevier, New York, 2007).

  7. 7.

    Suzuki, A. Cross-coupling reactions of organoboranes: an easy way to construct C–C bonds (Nobel Lecture). Angew. Chem. Int. Ed. 50, 6722–6737 (2011).

  8. 8.

    Brown, H. C. Hydroboration (Benjamin/Cummings, San Francisco, 1980).

  9. 9.

    Crudden, C. M. & Edwards, D. Catalytic asymmetric hydroboration: recent advances and applications in carbon–carbon bond-forming reactions. Eur. J. Org. Chem. 2003 4695–4712 (2003).

  10. 10.

    Xu, L., Zhang, S. & Li, P. Boron-selective reactions as powerful tools for modular synthesis of diverse complex molecules. Chem. Soc. Rev. 44, 8848–8858 (2015).

  11. 11.

    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).

  12. 12.

    Issaian, A., Tu, K. N. & Blum, S. A. Boron–heteroatom addition reactions via borylative heterocyclization: oxyboration, aminoboration, and thioboration. Acc. Chem. Res. 50, 2598–2609 (2017).

  13. 13.

    Endo, K., Ohkubo, T., Hirokami, M. & Shibata, T. Chemoselective and regiospecific Suzuki coupling on a multisubstituted sp3-carbon in 1,1-diborylalkanes at room temperature. J. Am. Chem. Soc. 132, 11033–11035 (2010).

  14. 14.

    Zhang, Z.-Q. et al. Copper-catalyzed/promoted cross-coupling of gem-diborylalkanes with nonactivated primary alkyl halides: an alternative route to alkylboronic esters. Org. Lett. 16, 6342–6345 (2014).

  15. 15.

    Sun, C., Potter, B. & Morken, J. P. A catalytic enantiotopic-group-selective Suzuki reaction for the construction of chiral organoboronates. J. Am. Chem. Soc. 136, 6534–6537 (2014).

  16. 16.

    Bose, S. K. et al. Highly efficient synthesis of alkylboronate esters via Cu(ii)-catalysed borylation of unactivated alkyl bromides and chlorides in air. ACS Catal. 6, 8332–8335 (2016).

  17. 17.

    Jo, W., Kim, J., Choi, S. & Cho, S. H. Transition-metal-free regioselective alkylation of pyridine N-oxides using 1,1-diborylalkanes as alkylating reagents. Angew. Chem. Int. Ed. 55, 9690–9694 (2016).

  18. 18.

    Miralles, N., Gómez, J. E., Kleij, A. W. & Fernández, E. Copper-mediated SN2′ allyl–alkyl and allyl–boryl couplings of vinyl cyclic carbonates. Org. Lett. 19, 6096–6099 (2017).

  19. 19.

    Toribatake, K. & Nishiyama, H. Asymmetric diboration of terminal alkenes with a rhodium catalyst and subsequent oxidation: enantioselective synthesis of optically active 1,2-diols. Angew. Chem. Int. Ed. 52, 11011–11015 (2013).

  20. 20.

    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).

  21. 21.

    Blaisdell, T. P., Caya, T. C., Zhang, L., Sanz-Marco, A. & Morken, J. P. Hydroxyl-directed stereoselective diboration of alkenes. J. Am. Chem. Soc. 136, 9264–9267 (2014).

  22. 22.

    Crudden, C. M. et al. Iterative protecting group-free cross-coupling leading to chiral multiply arylated structures. Nat. Commun. 7, 11065–11071 (2016).

  23. 23.

    Fang, L., Yan, L., Haeffner, F. & Morken, J. P. Carbohydrate-catalysed enantioselective alkene diboration: enhanced reactivity of 1,2-bonded diboron complexes. J. Am. Chem. Soc. 138, 2508–2511 (2016).

  24. 24.

    Fawcett, A. et al. Regio- and stereoselective homologation of 1,2-bis(boronic esters): stereocontrolled synthesis of 1,3-diols and Sch 725674. Angew. Chem. Int. Ed. 55, 14883–14887 (2016).

  25. 25.

    Marder, T. B. & Norman, N. C. Transition metal catalysed diboration. Top. Catal. 5, 63–73 (1998).

  26. 26.

    Ramirez, J., Lillo, V., Segarra, A. M. & Fernández, E. Catalytic asymmetric boron–boron addition to unsaturated molecules. C. R. Chim. 10, 138–151 (2007).

  27. 27.

    Burks, H. E. & Morken, J. P. Catalytic enantioselective diboration, disilation and silaboration: new opportunities for asymmetric synthesis. Chem. Commun. 2007, 4717–4725 (2007).

  28. 28.

    Takaya, J. & Iwasawa, N. Catalytic, direct synthesis of bis(boronate) compounds. ACS Catal. 2, 1993–2006 (2012).

  29. 29.

    Cuenca, A. B., Shishido, R., Ito, H. & Fernández, E. Transition-metal-free B–B and B–interelement reactions with organic molecules. Chem. Soc. Rev. 46, 415–430 (2017).

  30. 30.

    Nallagonda, R., Padalaa, K. & Masarwa, A. gem-Diborylalkanes: recent advances in their preparation, transformation and application. Org. Biomol. Chem. 16, 1050–1064 (2018).

  31. 31.

    Miralles, N., Maza, R. J. & Fernándeza, E. Synthesis and reactivity of 1,1-diborylalkanes towards C–C bond formation and related mechanisms. Adv. Synth. Catal. 360, 1306–1327 (2018).

  32. 32.

    Gu, Y., Pritzkow, H. & Siebert, W. Synthesis and reactivity of monoborylacetylene derivatives. Eur. J. Inorg. Chem. 2001, 373–379 (2001).

  33. 33.

    Baker, R. T., Nguyen, P., Marder, T. B. & Westcott, S. A. Transition metal catalysed diboration of vinylarenes. Angew. Chem. Int. Ed. 34, 1336–1338 (1995).

  34. 34.

    Nguyen, P. et al. Rhodium(i) catalysed diboration of (E)-styrylboronate esters: molecular structures of (E)-p-MeO–C6H4–CH:CH–B(1,2-O2C6H4) and p-MeO–C6H4–CH2C{B(1,2-O2C6H4)}3. J. Organomet. Chem. 652, 77–85 (2002).

  35. 35.

    Huang, Z. & Zhang, L. Synthesis of 1,1,1-tris(boronates) from vinylarenes by co-catalyzed dehydrogenative borylations–hydroboration. J. Am. Chem. Soc. 137, 15600–15603 (2015).

  36. 36.

    Shimada, S., Batsanov, A. S., Howard, J. A. K. & Marder, T. B. Formation of aryl- and benzylboronate esters by rhodium-catalyzed C–H bond functionalization with pinacolborane. Angew. Chem. Int. Ed. 40, 2168–2171 (2001).

  37. 37.

    Cho, J. Y. et al. Remarkably selective iridium catalysts for the elaboration of aromatic C–H bonds. Science 295, 305–308 (2002).

  38. 38.

    Hartwig, J. F. Regioselectivity of the borylation of alkanes and arenes. Chem. Soc. Rev. 40, 1992–2002 (2011).

  39. 39.

    Hartwig, J. F. Borylation and silylation of C–H bonds: a platform for diverse C–H bond functionalizations. Acc. Chem. Res. 45, 864–873 (2012).

  40. 40.

    Bose, S. K. & Marder, T. B. A leap forward in C–H functionalization. Science 349, 473–474 (2015).

  41. 41.

    Mita, T., Ikeda, Y., Michigami, K. & Sato, Y. Iridium-catalysed triple C(sp3)–H borylations: construction of triborylated sp3-carbon centers. Chem. Commun. 49, 5601–5603 (2013).

  42. 42.

    Palmer, W. N., Obligacion, J. V., Pappas, I. & Chirik, P. J. Cobalt-catalysed benzylic borylation: enabling polyborylation and functionalization of remote, unactivated C(sp3)–H bonds. J. Am. Chem. Soc. 138, 766–769 (2016).

  43. 43.

    Krautwald, S., Bezdek, M. J. & Chirik, P. J. Cobalt-catalyzed 1,1-diboration of terminal alkynes: scope, mechanism and synthetic applications. J. Am. Chem. Soc. 139, 3868–3875 (2017).

  44. 44.

    Coombs, J. R., Zhang, L. & Morken, J. P. Enantiomerically enriched tris(boronates): readily accessible conjunctive reagents for asymmetric synthesis. J. Am. Chem. Soc. 136, 16140–16143 (2014).

  45. 45.

    Gao, G., Yan, J., Yang, K., Chen, F. & Song, Q. Base-controlled highly selective synthesis of alkyl 1,2-bis(boronates) or 1,1,2-tris(boronates) from terminal alkynes. Green Chem. 19, 3997–4001 (2017).

  46. 46.

    Castle, R. B. & Matteson, D. S. Methanetetraboroni and methanetriboronic esters. J. Organometal. Chem. 20, 19–28 (1969).

  47. 47.

    Matteson, D. S. Methanetetraboronic and methanetriboronic esters as synthetic intermediates. Synthesis 1975, 147–158 (1975).

  48. 48.

    Batsanov, A. S. et al. Fully borylated methane and ethane by ruthenium-mediated cleavage and coupling of CO. Angew. Chem. Int. Ed. 55, 4707–4710 (2016).

  49. 49.

    Liu, X.-W., Echavarren, J., Zarate, C. & Martin, R. Ni-catalyzed borylation of aryl fluorides via C–F cleavage. J. Am. Chem. Soc. 137, 12470–12473 (2015).

  50. 50.

    Niwa, T., Ochiai, H., Watanabe, Y. & Hosoya, T. Ni/Cu-catalyzed defluoroborylation of fluoroarenes for diverse C–F bond functionalizations. J. Am. Chem. Soc. 137, 14313–14318 (2015).

  51. 51.

    Zhou, J. et al. Preparing (multi)fluoroarenes as building blocks for synthesis: nickel-catalyzed borylation of polyfluoroarenes via C–F bond cleavage. J. Am. Chem. Soc. 138, 5250–5253 (2016).

  52. 52.

    Zhang, J., Dai, W., Liu, Q. & Cao, S. Cu-catalyzed stereoselective borylation of gem-difluoroalkenes with B2pin2. Org. Lett. 19, 3283–3286 (2017).

  53. 53.

    Sakaguchi, H. et al. Copper-catalyzed regioselective monodefluoroborylation of polyfluoroalkenes en route to diverse fluoroalkenes. J. Am. Chem. Soc. 139, 12855–12862 (2017).

  54. 54.

    Tan, D.-H. et al. Copper-catalyzed stereoselective defluorinative borylation and silylation of gem-difluoroalkenes. Adv. Synth. Catal. 360, 1032–1037 (2010).

  55. 55.

    Takachi, M., Kita, Y., Tobisu, M., Fukumoto, Y. & Chatani, N. Nickel-catalyzed cyclization of difluoro-substituted 1,6-enynes with organozinc reagents through the stereoselective activation of C–F bonds: synthesis of bicyclo[3.2.0]heptene derivatives. Angew. Chem. Int. Ed. 49, 8717–8720 (2010).

  56. 56.

    Gao, B., Zhao, Y. & Hu, J. AgF-mediated fluorinative cross-coupling of two olefins: facile access to α-CF3 alkenes and β-CF3 ketones. Angew. Chem. Int. Ed. 54, 638–642 (2015).

  57. 57.

    Tian, P., Feng, C. & Loh, T.-P. Rhodium-catalysed C(sp 2)–C(sp 2) bond formation via C–H/C–F activation. Nat. Commun. 6, 7472–7478 (2015).

  58. 58.

    Xie, J., Yu, J., Rudolph, M., Rominger, F. & Hashmi, A. S. K. Mono-fluoroalkenylation of dimethylamino compounds through radical–radical cross-coupling. Angew. Chem. Int. Ed. 55, 9416–9421 (2016).

  59. 59.

    Tian, P. et al. F nucleophilic-addition-induced allylic alkylation. J. Am. Chem. Soc. 138, 15869–15872 (2016).

  60. 60.

    Thornbury, R. T. & Toste, F. D. Palladium-catalyzed defluorinative coupling of 1-aryl-2,2-difluoroalkenes and boronic acids: stereoselective synthesis of monofluorostilbenes. Angew. Chem. Int. Ed. 55, 11629–11632 (2016).

  61. 61.

    Tang, H.-J., Lin, L.-Z., Feng, C. & Loh, T.-P. Palladium-catalyzed fluoroarylation of gem-difluoroalkenes. Angew. Chem. Int. Ed. 56, 9872–9876 (2017).

  62. 62.

    Wu, J.-Q. et al. Experimental and theoretical studies on rhodium-catalyzed coupling of benzamides with 2,2-difluorovinyl tosylate: diverse synthesis of fluorinated heterocycles. J. Am. Chem. Soc. 139, 3537–3545 (2017).

  63. 63.

    Lu, X. et al. Nickel-catalyzed defluorinative reductive cross-coupling of gem-difluoroalkenes with unactivated secondary and tertiary alkyl halides. J. Am. Chem. Soc. 139, 12632–12637 (2017).

  64. 64.

    Liu, Y., Zhou, Y., Zhao, Y. & Qu, J. Synthesis of gem-difluoroallylboronates via FeCl2‑catalyzed boration/β-fluorine elimination of trifluoromethyl alkenes. Org. Lett. 19, 946–949 (2017).

  65. 65.

    Hu, J., Han, X., Yuan, Y. & Shi, Z. Stereoselective synthesis of Z fluoroalkenes through copper-catalyzed hydrodefluorination of gem-difluoroalkenes with water. Angew. Chem. Int. Ed. 56, 13342–13346 (2017).

  66. 66.

    Kojima, R., Kubota, K. & Ito, H. Stereodivergent hydrodefluorination of gem-difluoroalkenes: selective synthesis of (Z)- and (E)-monofluoroalkenes. Chem. Commun. 53, 10688–10691 (2017).

  67. 67.

    Hong, K., Liu, X. & Morken, J. P. Simple access to elusive α-boryl carbanions and their alkylation: an umpolung construction for organic synthesis. J. Am. Chem. Soc. 136, 10581–10584 (2014).

Download references

Acknowledgements

We thank A. Lei at Wuhan University for assistance with the operando infrared experiments. This work was supported by the Funding Programs for the ‘1000 Youth Talents Plan’, National Natural Science Foundation of China (grant 2167020084), ‘Jiangsu Specially-Appointed Professor Plan’ and ‘Innovation and Entrepreneurship Talents Plan’ of Jiangsu Province.

Author information

Affiliations

  1. State Key Laboratory of Coordination Chemistry, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing, China

    • Jiefeng Hu
    • , Yue Zhao
    •  & Zhuangzhi Shi

Authors

  1. Search for Jiefeng Hu in:

  2. Search for Yue Zhao in:

  3. Search for Zhuangzhi Shi in:

Contributions

Z.S. conceived the study, supervised the project and wrote the paper. J.H performed the experiments and mechanism study, and analysed the data. Y.Z. performed the crystallographic studies.

Competing interests

The authors declare no competing interests.

Corresponding author

Correspondence to Zhuangzhi Shi.

Supplementary Information

  1. Supplementary Information

    Supplementary Methods, Supplementary References, Supplementary Figures 1–108

  2. Compound 5f

    Crystallographic data for compound 5f

  3. Compound 6f

    Crystallographic data for compound 6f

About this article

Publication history

Received

Accepted

Published

DOI

https://doi.org/10.1038/s41929-018-0147-9