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Photoinduced manganese-catalysed hydrofluorocarbofunctionalization of alkenes

Nature Synthesis volume 1, pages 475–486 (2022)Cite this article

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Abstract

The selective hydrofluorocarbofunctionalization of alkenes is an important synthetic strategy for efficiently constructing fluorine-containing compounds. However, existing methods often require expensive fluoroalkylating reagents and the generality of alkene substrates is usually limited to terminal alkenes. Here, we report a ligand-accelerated, manganese-catalysed hydrofluoroalkylation and hydropolyfluoroarylation of alkenes using visible light irradiation. A wide range of mono-, di- and polyfluoroalkyl, di- and trifluoromethyl, and polyfluoroaryl groups can be transferred from the corresponding fluoroalkyl bromides and polyfluoroaryl iodides to a series of structurally diverse alkenes. The utility of the process has been verified through reaction scale-up and onward synthetic transformations of the functionalized fluoroalkane products. Experimental and computational mechanistic studies revealed that a bidentate phosphine ligand significantly promotes the hydrofluoroalkylation process and plays an essential role in improving the stability and reactivity of the photoinduced manganese-centred radical.

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Fig. 1: Mn2(CO)10-catalysed radical transformations.
Fig. 2: Synthetic application of the strategy.
Fig. 3: Mechanistic studies of the hydrodifluoroalkylation reaction.
Fig. 4: Computational mechanistic study.

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Data availability

The data supporting the findings of this study are available within the paper and its Supplementary Information. The crystallographic data for the structures reported in this Article have been deposited at the Cambridge Crystallographic Data Centre, under deposition numbers CCDC 2100627 (L1Mn(CO)3Br), CCDC 2100626 (L1Mn(CO)3H) and CCDC 2127350 ((L1)2Mn(CO)2Cl). Copies of the data can be obtained free of charge via https://www.ccdc.cam.ac.uk/structures/.

References

  1. Prier, C. K., Rankic, D. A. & MacMillan, D. W. C. Visible light photoredox catalysis with transition metal complexes: applications in organic synthesis. Chem. Rev. 113, 5322–5363 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Jamatia, R., Mondal, A. & Srimani, D. Visible-light-induced manganese-catalyzed reactions: present approach and future. Adv. Synth. Catal. 363, 2969–2995 (2021).

    Article  CAS  Google Scholar 

  3. Herr, P., Kerzig, C., Larsen, C. B., Häussinger, D. & Wenger, O. S. Manganese(I) complexes with metal-to-ligand charge transfer luminescence and photoreactivity. Nat. Chem. 13, 956–962 (2021).

    Article  CAS  PubMed  Google Scholar 

  4. Carney, J. R., Dillon, B. R. & Thomas, S. P. Recent advances of manganese catalysis for organic synthesis. Eur. J. Org. Chem. 3912–3929 (2016).

  5. Luo, Y.-R. Comprehensive Handbook of Chemical Bond Energies (CRC Press, 2007).

  6. Yang, X. & Wang, C. Dichotomy of manganese catalysis via organometallic or radical mechanism: stereodivergent hydrosilylation of alkynes. Angew. Chem. Int. Ed. 57, 923–928 (2018).

    Article  CAS  Google Scholar 

  7. Yang, X. & Wang, C. Diverse fates of β-silyl radical under manganese catalysis: hydrosilylation and dehydrogenative silylation of alkenes. Chin. J. Chem. 36, 1047–1051 (2018).

    Article  CAS  Google Scholar 

  8. Wu, S. et al. Manganese catalyzed dehydrogenative silylation of alkenes: direct access to allylsilanes. Tetrahedron Lett. 61, 152053 (2020).

    Article  CAS  Google Scholar 

  9. Gilbert, B. C. et al. Radical cyclisations promoted by dimanganese decacarbonyl: a new and flexible approach to 5-membered N-heterocycles. Tetrahedron Lett. 40, 6095–6098 (1999).

    Article  CAS  Google Scholar 

  10. Friestad, G. K. & Qin, J. Intermolecular alkyl radical addition to chiral N-acylhydrazones mediated by manganese carbonyl. J. Am. Chem. Soc. 123, 9922–9923 (2001).

    Article  CAS  PubMed  Google Scholar 

  11. Friestad, G. K. & Ji, A. Mn-mediated coupling of alkyl iodides and ketimines: a radical addition route to α,α-disubstituted α-aminoesters. Org. Lett. 10, 2311–2313 (2008).

    Article  CAS  PubMed  Google Scholar 

  12. Li, Y. et al. Practical and general manganese-catalyzed carbonylative coupling of alkyl iodides with amides. ChemCatChem 9, 915–919 (2017).

    Article  CAS  Google Scholar 

  13. Nuhant, P. et al. Visible-light-initiated manganese catalysis for C–H alkylation of heteroarenes: applications and mechanistic studies. Angew. Chem. Int. Ed. 56, 15309–15313 (2017).

    Article  CAS  Google Scholar 

  14. Wang, L., Lear, J. M., Rafferty, S. M., Fosu, S. C. & Nagib, D. A. Ketyl radical reactivity via atom transfer catalysis. Science 362, 225–229 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Liang, H., Ji, Y.-X., Wang, R.-H., Zhang, Z.-H. & Zhang, B. Visible-light-initiated manganese-catalyzed E-selective hydrosilylation and hydrogermylation of alkynes. Org. Lett. 21, 2750–2754 (2019).

    Article  CAS  PubMed  Google Scholar 

  16. Dong, J. et al. Visible-light-initiated manganese-catalyzed Giese addition of unactivated alkyl iodides to electron-poor olefins. Chem. Commun. 55, 11707–11710 (2019).

    Article  CAS  Google Scholar 

  17. Liu, R.-Z. et al. Generation and reactivity of amidyl radicals: manganese-mediated atom-transfer reaction. Angew. Chem. Int. Ed. 59, 4428–4433 (2020).

    Article  CAS  Google Scholar 

  18. Ji, Y.-X., Li, J., Li, C.-M., Qu, S. & Zhang, B. Manganese-catalyzed N–F bond activation for hydroamination and carboamination of alkenes. Org. Lett. 23, 207–212 (2021).

    Article  CAS  PubMed  Google Scholar 

  19. Gilbert, B. C. et al. Initiation of radical cyclisation reactions using dimanganese decacarbonyl. a flexible approach to preparing 5-membered rings. J. Chem. Soc. Perkin Trans. 1. 1, 1187–1194 (2000).

    Article  Google Scholar 

  20. Xiong, X. et al. A versatile, fast, and efficient method of visible-light-induced surface grafting polymerization. Langmuir 30, 5474–5480 (2014).

    Article  CAS  PubMed  Google Scholar 

  21. Ciftci, M., Yoshikawa, Y. & Yagci, Y. Living cationic polymerization of vinyl ethers through a photoinduced radical oxidation/addition/deactivation sequence. Angew. Chem. Int. Ed. 56, 519–523 (2017).

    Article  CAS  Google Scholar 

  22. Dong, J. et al. Manganese-catalysed divergent silylation of alkenes. Nat. Chem. 13, 182–190 (2021).

    Article  CAS  PubMed  Google Scholar 

  23. Purser, S., Moore, P. R., Swallow, S. & Gouverneur, V. Fluorine in medicinal chemistry. Chem. Soc. Rev. 37, 320–330 (2008).

    Article  CAS  PubMed  Google Scholar 

  24. Ni, C., Hu, M. & Hu, J. Good partnership between sulfur and fluorine: sulfur-based fluorination and fluoroalkylation reagents for organic synthesis. Chem. Rev. 115, 765–825 (2015).

    Article  CAS  PubMed  Google Scholar 

  25. Feng, Z., Xiao, Y.-L. & Zhang, X. Transition-metal (Cu, Pd, Ni)-catalyzed difluoroalkylation via cross-coupling with difluoroalkyl halides. Acc. Chem. Res. 51, 2264–2278 (2018).

    Article  CAS  PubMed  Google Scholar 

  26. Ren, Y.-Y., Zeng, X. & Zhang, X. Bromotrifluoromethane: a useful reagent for hydrotrifluoromethylation of alkenes and alkynes. Synlett 29, 1028–1032 (2018).

    Article  CAS  Google Scholar 

  27. Barata-Vallejo, S., Cooke, M. V. & Postigo, A. Radical fluoroalkylation reactions. ACS Catal. 8, 7287–7307 (2018).

    Article  CAS  Google Scholar 

  28. Li, M., Xue, X.-S. & Cheng, J.-P. Establishing cation and radical donor ability scales of electrophilic F, CF3, and SCF3 transfer reagents. Acc. Chem. Res. 53, 182–197 (2020).

    Article  CAS  PubMed  Google Scholar 

  29. Hell, S. M. et al. Hydrofluoromethylation of alkenes with fluoroiodomethane and beyond. Chem. Sci. 12, 12149–12155 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Deneny, P. J., Kumar, R. & Gaunt, M. J. Visible light-mediated radical fluoromethylation via halogen atom transfer activation of fluoroiodomethane. Chem. Sci. 12, 12812–12818 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  31. Yu, C., Iqbal, N., Park, S. & Cho, E. Selective difluoroalkylation of alkenes by using visible light photoredox catalysis. Chem. Commun. 50, 12884–12887 (2014).

    Article  CAS  Google Scholar 

  32. Lin, Q.-Y., Xu, X.-H., Zhang, K. & Qing, F.-L. Visible-light-induced hydrodifluoromethylation of alkenes with a bromodifluoromethylphosphonium bromide. Angew. Chem. Int. Ed. 55, 1479–1483 (2016).

    Article  CAS  Google Scholar 

  33. Supranovich, V. I., Levin, V. V., Struchkova, M. I., Hu, J. & Dilman, A. D. Visible light-mediated difluoroalkylation of electron-deficient alkenes. Beilstein J. Org. Chem. 14, 1637–1641 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Meyer, C. F., Hell, S. M., Misale, A. A., Trabanco, A. & Gouverneur, V. Hydrodifluoromethylation of alkenes with difluoroacetic acid. Angew. Chem. Int. Ed. 58, 8829–8833 (2019).

    Article  CAS  Google Scholar 

  35. Hu, X.-S. et al. Regioselective Markovnikov hydrodifluoroalkylation of alkenes using difluoroenoxysilanes. Nat. Commun. 11, 5500 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Yang, J., Zhu, S., Wang, F., Qing, F.-L. & Chu, L. Silver-enabled general radical difluoromethylation reaction with TMSCF2H. Angew. Chem. Int. Ed. 60, 4300–4306 (2021).

    Article  CAS  Google Scholar 

  37. Zhou, X., Ni, C., Deng, L. & Hu, J. Electrochemical reduction of fluoroalkyl sulfones for radical fluoroalkylation of alkenes. Chem. Commun. 57, 8750–8753 (2021).

    Article  CAS  Google Scholar 

  38. Mizuta, S. et al. Catalytic hydrotrifluoromethylation of unactivated alkenes. J. Am. Chem. Soc. 135, 2505–2508 (2013).

    Article  CAS  PubMed  Google Scholar 

  39. Wilger, D. J., Gesmundoa, N. J. & Nicewicz, D. A. Catalytic hydrotrifluoromethylation of styrenes and unactivated aliphatic alkenes via an organic photoredox system. Chem. Sci. 4, 3160–3165 (2013).

    Article  CAS  Google Scholar 

  40. Choi, S. et al. Hydrotrifluoromethylation and iodotrifluoromethylation of alkenes and alkynes using an inorganic electride as a radical generator. Nat. Commun. 5, 4881 (2014).

    Article  CAS  PubMed  Google Scholar 

  41. Straathof, N. J. W., Cramer, S. E., Hessel, V. & Noël, T. Practical photocatalytic trifluoromethylation and hydrotrifluoromethylation of styrenes in batch and flow. Angew. Chem. Int. Ed. 55, 15549–15553 (2016).

    Article  CAS  Google Scholar 

  42. Cheng, Y. & Yu, S. Hydrotrifluoromethylation of unactivated alkenes and alkynes enabled by an electron-donor–acceptor complex of Togni’s reagent with a tertiary amine. Org. Lett. 18, 2962–2965 (2016).

    Article  CAS  PubMed  Google Scholar 

  43. Xiang, J.-X., Ouyang, Y., Xu, X.-H. & Qing, F.-L. Argentination of fluoroform: preparation of a stable AgCF3 solution with diverse reactivities. Angew. Chem. Int. Ed. 58, 10320–10324 (2019).

    Article  CAS  Google Scholar 

  44. He, B., Pan, Q., Guo, Y., Chen, Q.-Y. & Liu, C. Cobalt-catalyzed radical hydrotrifluoroethylation of styrenes with trifluoroethyl iodide. Org. Lett. 22, 6552–6556 (2020).

    Article  CAS  PubMed  Google Scholar 

  45. Huang, X.-T. & Chen, Q.-Y. Nickel(0)-catalyzed fluoroalkylation of alkenes, alkynes, and aromatics with perfluoroalkyl chlorides. J. Org. Chem. 66, 4651–4656 (2001).

    Article  CAS  PubMed  Google Scholar 

  46. Chatterjee, T., Iqbal, N., You, Y. & Cho, E. J. Controlled fluoroalkylation reactions by visible-light photoredox catalysis. Acc. Chem. Res. 49, 2284–2294 (2016).

    Article  CAS  PubMed  Google Scholar 

  47. Singh, A., Kubik, J. J. & Weaver, J. D. Photocatalytic C–F alkylation; facile access to multifluorinated arenes. Chem. Sci. 6, 7206–7212 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Le, C., Chen, T. Q., Liang, T., Zhang, P. & MacMillan, D. W. C. A radical approach to the copper oxidative addition problem: trifluoromethylation of bromoarenes. Science 360, 1010–1014 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Hu, J. Nucleophilic, radical, and electrophilic (phenylsulfonyl)difluoromethylations. J. Fluor. Chem. 130, 1130–1139 (2009).

    Article  CAS  Google Scholar 

  50. Jia, R., Wang, X. & Hu, J. Recent advance in synthetic applications of difluoromethyl phenyl sulfone and its derivatives. Tetrahedron Lett. 75, 153182 (2021).

    Article  CAS  Google Scholar 

  51. Hu, J., Zhang, W. & Wang, F. Selective difluoromethylation and monofluoromethylation reactions. Chem. Commun. 48, 7465–7478 (2009).

    Article  Google Scholar 

  52. Surapanich, N., Kuhakarn, C., Pohmakotr, M. & Reutrakul, V. Palladium-mediated Heck-type reactions of [(bromodifluoromethyl)sulfonyl]benzene: synthesis of α-alkenyl- and α-heteroaryl-substituted α,α-difluoromethyl phenyl sulfones. Eur. J. Org. Chem. 2012, 5943–5952 (2012).

    Article  CAS  Google Scholar 

  53. Landelle, G., Panossian, A., Pazenok, S., Vors, J.-P. & Leroux, F. R. Recent advances in transition metal-catalyzed Csp2-monofluoro-, difluoro-, perfluoromethylation and trifluoromethylthiolation. Beilstein. J. Org. Chem. 9, 2476–2536 (2013).

    Google Scholar 

  54. Su, Y.-M. et al. Visible light-mediated C–H difluoromethylation of electron-rich heteroarenes. Org. Lett. 16, 2958–2961 (2014).

    Article  CAS  PubMed  Google Scholar 

  55. Ni, C., Liu, J., Zhang, L. & Hu, J. A remarkably efficient fluoroalkylation of cyclic sulfates and sulfamidates with PhSO2CF2H: facile entry into β-difluoromethylated or β-difluoromethylenated alcohols and amines. Angew. Chem. Int. Ed. 46, 786–789 (2007).

    Article  CAS  Google Scholar 

  56. Ji, Y.-X., Wang, L.-J., Guo, W.-S., Bi, Q. & Zhang, B. Intermolecular iodofluoroalkylation of unactivated alkynes and alkenes mediated by manganese catalysts. Adv. Synth. Catal. 362, 1131–1137 (2020).

    Article  CAS  Google Scholar 

  57. Feng, Z., Min, Q.-Q., Zhao, H.-Y., Gu, J.-W. & Zhang, X. A general synthesis of fluoroalkylated alkenes by palladium-catalyzed Heck-type reaction of fluoroalkyl bromides. Angew. Chem. Int. Ed. 54, 1270–1274 (2015).

    Article  CAS  Google Scholar 

  58. Xie, J. et al. Gold-catalyzed highly selective photoredox C(sp2)–H difluoroalkylation and perfluoroalkylation of hydrazones. Angew. Chem. Int. Ed. 55, 2934–2938 (2016).

    Article  CAS  Google Scholar 

  59. Green, S. A., Huffman, T. R., McCourt, R. O., Van der Puyl, V. & Shenvi, R. A. Hydroalkylation of olefins to form quaternary carbons. J. Am. Chem. Soc. 141, 7709–7714 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. McCulIen, S. B. & Brown, T. L. Preparation, properties, and kinetics of the reaction with tributyltin hydride of manganese(0) radicals Mn(CO)3(R3P)2. J. Am. Chem. Soc. 104, 7496–7500 (1982).

    Article  Google Scholar 

  61. Kidd, D. R., Cheng, C. P. & Brown, T. L. Formation and properties of substituted manganese carbonyl radicals. J. Am. Chem. Soc. 100, 4103–4107 (1978).

    Article  CAS  Google Scholar 

  62. Lu, T. & Chen, F. Multiwfn: a multifunctional wavefunction analyzer. J. Comput. Chem. 33, 580–592 (2012).

    Article  PubMed  Google Scholar 

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Acknowledgements

We thank the National Natural Science Foundation of China (22122103 and 21971108 to J.X., 22101130 to Jie Han, 22001116 to Jian Han and 21971111 and 21732003 to C.Z.), the National Key Research and Development Program of China (2021YFC2101901 to J.X.), the Natural Science Foundation of Jiangsu Province (grant no. BK20190006 to J.X.), the Fundamental Research Funds for the Central Universities (020514380252 to J.X.), the Guangdong Basic and Applied Basic Research Foundation (2020A1515110816 to J.H.) and the financial support of Advanced Catalytic Engineering Research Center of the Ministry of Education. Professor Congyang Wang and Professor Bo Zhang are kindly acknowledged for their generous support and helpful discussion. Professor Genwen Tan is also kindly acknowledged for his helpful discussion on the mechanistic experiments. Y. Li, Y. He and N. Li are warmly acknowledged for their reproduction of the experimental procedures for products 22′, 68′ and 90. All theoretical calculations were performed at the High-Performance Computing Center (HPCC) of Nanjing University.

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Author notes

  1. These authors contributed equally: Jian Han, Jie Han.

Authors and Affiliations

  1. State Key Laboratory of Coordination Chemistry, Jiangsu Key Laboratory of Advanced Organic Materials, Chemistry and Biomedicine Innovation Center, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing, China

    Jian Han, Jie Han, Shuai Chen, Tao Zhong, Yijie He, Xianli Yang, Chengjian Zhu & Jin Xie

  2. Key Laboratory of Mesoscopic Chemistry of the Ministry of Education, Institute of Theoretical and Computational Chemistry, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing, China

    Guoqiang Wang

  3. Green Catalysis Center, College of Chemistry and Molecular Engineering, Zhengzhou University, Zhengzhou, China

    Chengjian Zhu

  4. State Key Laboratory of Chemistry and Utilization of Carbon Based Energy Resources, College of Chemistry, Xinjiang University, Urumqi, China

    Jin Xie

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Contributions

Jian Han and J.X. conceived the work and designed the experiments. Jian Han, S.C., T.Z. and Y.H. performed the experiments and analysed the experimental data. X.Y. performed the EPR measurements. Jie Han. performed the DFT calculations and discussed the results with S.C., Q.W. Jian Han, C.Z. and J.X. co-wrote the manuscript with input from all the other authors.

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Correspondence to Jin Xie.

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Nature Synthesis thanks Takashi Koike and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Primary Handling Editor: Thomas West, in collaboration with the Nature Synthesis team.

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Extended data

Extended Data Fig. 1 Polarity and intermolecular interaction analyses.

a, Isosurfaces of dual descriptor Δf(r) = f(r)+ - f(r)- for substrates and catalysts, where blue and green represent electrophilicity and nucleophilicity, respectively. b, Molecular interaction analyses (IGMH) and the corresponding isosurfaces for TS2a and TS2a’, where blue, green and red represent strong interaction, weak interaction, and steric effect.

Supplementary information

Supplementary Information

Supplementary Sections 1–12.

Supplementary Data 1

Crystal structure of L1Mn(CO)3Br CCDC 2100627.

Supplementary Data 2

Crystal structure of L1Mn(CO)3H CCDC 2100626.

Supplementary Data 3

Crystal structure of (L1)2Mn(CO)2Cl CCDC 2127350.

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Han, J., Han, J., Chen, S. et al. Photoinduced manganese-catalysed hydrofluorocarbofunctionalization of alkenes. Nat. Synth 1, 475–486 (2022). https://doi.org/10.1038/s44160-022-00074-9

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