Skip to main content

Thank you for visiting nature.com. 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.

  • Review Article
  • Published:

Iron-catalysed radical difunctionalization of alkenes

Nature Synthesis volume 4, pages 1036–1055 (2025)Cite this article

Subjects

Abstract

Transition metal-catalysed difunctionalization of alkenes enables the rapid construction of complex molecules by converting a flat C(sp2)–C(sp2) π-fragment to form a three-dimensional structure with neighbouring sp3-hybridized carbons and two new C(sp3)–G bonds (G = carbon, heteroatom, halogen and so on) in a single step. Iron catalysis is attractive because of its lower cost, higher Earth abundance, lower mining carbon footprint and lower toxicity in comparison to traditional transition metal catalysts, but lags behind nickel and palladium in terms of synthetic applications and mechanistic understanding. Here we present an overview of recent reaction development progress and unmet challenges in iron-catalysed difunctionalization reactions, with a focus on three-component radical cross-coupling processes that use commercially available iron salts in combination with readily available ligands. For each case, we highlight the mechanistic insights gained from (in)organic synthesis, computational modelling and spectroscopic techniques that advance our understanding and guide the development of new transformations.

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

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to the full article PDF.

USD 39.95

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

Fig. 1: The unique role of iron in radical cross-coupling chemistry.
Fig. 2: Alkene alkyl–arylation via radical processes.
Fig. 3: Alkene dialkylation via radical or radical-polar crossover processes.
Fig. 4: Alkene carboheteroatom functionalization via radical or radical-polar crossover processes.
Fig. 5: Alkene hydrosilylation and hydroboration strategies via ligand design and reductant choice.
Fig. 6: Alkene diheteroatom functionalization via iron nitrenoids or radical processes.
Fig. 7: Photocatalytic alkene difunctionalization strategies.
Fig. 8: Further examples of photocatalytic alkene difunctionalization reactions.

Similar content being viewed by others

References

  1. Lovering, F., Bikker, J. & Humblet, C. Escape from Flatland: increasing saturation as an approach to improving clinical success. J. Med. Chem. 52, 6752–6756 (2009).

    Article  CAS  PubMed  Google Scholar 

  2. Lovering, F. Escape from Flatland 2: complexity and promiscuity. Med. Chem. Commun. 4, 515–519 (2013).

    Article  CAS  Google Scholar 

  3. Cox, B. et al. Escaping from Flatland: substituted bridged pyrrolidine fragments with inherent three-dimensional character. ACS Med. Chem. Lett. 11, 1185–1190 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Dhungana, R. K., KC, S., Basnet, P. & Giri, R. Transition metal-catalyzed dicarbofunctionalization of unactivated olefins. Chem. Rec. 18, 1314–1340 (2018).

    Article  CAS  PubMed  Google Scholar 

  5. Yin, G., Mu, X. & Liu, G. Palladium(II)-catalyzed oxidative difunctionalization of alkenes: bond forming at a high-valent palladium center. Acc. Chem. Res. 49, 2413–2423 (2016).

    Article  CAS  PubMed  Google Scholar 

  6. Zhang, J.-S., Liu, L., Chen, T. & Han, L.-B. Transition-metal-catalyzed three-component difunctionalizations of alkenes. Chem. Asian J. 13, 2277–2291 (2018).

    Article  CAS  PubMed  Google Scholar 

  7. Gao, P., Niu, Y.-J., Yang, F., Guo, L.-N. & Duan, X.-H. Three-component 1,2-dicarbofunctionalization of alkenes involving alkyl radicals. Chem. Commun. 58, 730–746 (2022).

    Article  CAS  Google Scholar 

  8. Ciesielski, J., Dequirez, G., Retailleau, P., Gandon, V. & Dauban, P. Rhodium-catalyzed alkene difunctionalization with nitrenes. Chem. Eur. J. 22, 9338–9347 (2016).

    Article  CAS  PubMed  Google Scholar 

  9. Zhang, Z., Su, B., Gong, J., Tao, H. & Mai, S. Rhodium-catalyzed difunctionalization of alkenes using cyclic 1,3-dicarbonyl-derived iodonium ylides. Org. Lett. 26, 1886–1890 (2024).

    Article  CAS  PubMed  Google Scholar 

  10. Wagner-Carlberg, N., Dorsheimer, J. R. & Rovis, T. Rh(III)-catalyzed alkene anti nucleoamidation to access diverse heterocycles. ACS Catal. 14, 17033–17038 (2024).

    Article  CAS  PubMed  Google Scholar 

  11. Wickham, L. M. & Giri, R. Transition metal (Ni, Cu, Pd)-catalyzed alkene dicarbofunctionalization reactions. Acc. Chem. Res. 54, 3415–3437 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Qi, X. & Diao, T. Nickel-catalyzed dicarbofunctionalization of alkenes. ACS Catal. 10, 8542–8556 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Egorova, K. S. & Ananikov, V. P. Which metals are green for catalysis? Comparison of the toxicities of Ni, Cu, Fe, Pd, Pt, Rh and Au salts. Angew. Chem. Int. Ed. 55, 12150–12162 (2016).

    Article  CAS  Google Scholar 

  14. Rana, S., Biswas, J. P., Paul, S., Paik, A. & Maiti, D. Organic synthesis with the most abundant transition metal-iron: from rust to multitasking catalysts. Chem. Soc. Rev. 50, 243–472 (2021).

    Article  CAS  PubMed  Google Scholar 

  15. Nuss, P. & Eckelman, M. J. Life cycle assessment of metals: a scientific synthesis. PLoS ONE 9, e101298 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  16. Bauer, I. & Knölker, H.-J. Iron catalysis in organic synthesis. Chem. Rev. 115, 3170–3387 (2015).

    Article  CAS  PubMed  Google Scholar 

  17. Fürstner, A. Iron catalysis in organic synthesis: a critical assessment of what it takes to make this base metal a multitasking champion. ACS Cent. Sci. 2, 778–789 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  18. Casnati, A., Lanzi, M. & Cera, G. Recent advances in asymmetric iron catalysis. Molecules 25, 3889 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Mondal, S., Das, K. K. & Panda, S. Iron catalysis: a new horizon towards organoboron-mediated C–C cross-coupling. Chem. Asian J. 17, e202200847 (2022).

    Article  Google Scholar 

  20. Plietker, B. & Beller, M. Iron Catalysis: Fundamentals and Applications. Topics in Organometallic Chemistry Vol. 33 (Springer, 2011).

  21. Kharasch, M. S. & Fields, E. K. Factors determining the course and mechanisms of Grignard reactions. IV. The effect of metallic halides on the reaction of aryl Grignard reagents and organic halides. J. Am. Chem. Soc. 63, 2316–2320 (1941).

    Article  CAS  Google Scholar 

  22. Tamura, M. & Kochi, J. K. Vinylation of Grignard reagents. Catalysis by iron. J. Am. Chem. Soc. 93, 1487–1489 (1971).

    Article  CAS  Google Scholar 

  23. Fabre, J.-L., Julia, M. & Verpeaux, J.-N. Couplage mixte entre sulfones vinyliques et réactifs de Grignard en présence de sels de métal de transition: synthèse stéréosélective d’oléfines trisubstituées. Tetrahedron Lett. 23, 2469–2472 (1982).

    Article  CAS  Google Scholar 

  24. Molander, G. A., Rahn, B. J., Shubert, D. C. & Bonde, S. E. Iron catalyzed cross-coupling reactions. Synthesis of arylethenes. Tetrahedron Lett. 24, 5449–5452 (1983).

    Article  CAS  Google Scholar 

  25. Cahiez, G. & Marquais, S. Highly chemo- and stereoselective Fe-catalyzed alkenylation of organomanganese reagents. Tetrahedron Lett. 37, 1773–1776 (1996).

    Article  CAS  Google Scholar 

  26. Cahiez, G. & Avedissian, H. Highly stereo- and chemoselective iron-catalyzed alkenylation of organomagnesium compounds. Synthesis 1998, 1199–1205 (1998).

    Article  Google Scholar 

  27. Fürstner, A. & Leitner, A. Iron-catalyzed cross-coupling reactions of alkyl-Grignard reagents with aryl chlorides, tosylates and triflates. Angew. Chem. Int. Ed. 41, 609–612 (2002).

    Article  Google Scholar 

  28. Fürstner, A., Leitner, A., Méndez, M. & Krause, H. Iron-catalyzed cross-coupling reactions. J. Am. Chem. Soc. 124, 13856–13863 (2002).

    Article  PubMed  Google Scholar 

  29. Martin, R. & Fürstner, A. Cross-coupling of alkyl halides with aryl Grignard reagents catalyzed by a low-valent iron complex. Angew. Chem. Int. Ed. 43, 3955–3957 (2004).

    Article  CAS  Google Scholar 

  30. Nagano, T. & Hayashi, T. Iron-catalyzed Grignard cross-coupling with alkyl halides possessing β-hydrogens. Org. Lett. 6, 1297–1299 (2004).

    Article  CAS  PubMed  Google Scholar 

  31. Nakamura, M., Matsuo, K., Ito, S. & Nakamura, E. Iron-catalyzed cross-coupling of primary and secondary alkyl halides with aryl Grignard reagents. J. Am. Chem. Soc. 126, 3686–3687 (2004).

    Article  CAS  PubMed  Google Scholar 

  32. Scheiper, B., Bonnekessel, M., Krause, H. & Fürstner, A. Selective iron-catalyzed cross-coupling reactions of Grignard reagents with enol triflates, acid chlorides and dichloroarenes. J. Org. Chem. 69, 3943–3949 (2004).

    Article  CAS  PubMed  Google Scholar 

  33. Nakamura, M., Ito, S., Matsuo, K. & Nakamura, E. Iron-catalyzed chemoselective cross-coupling of primary and secondary alkyl halides with arylzinc reagents. Synlett 2005, 1794–1798 (2005).

    Article  Google Scholar 

  34. Hatakeyama, T. et al. Iron-catalyzed Suzuki–Miyaura coupling of alkyl halides. J. Am. Chem. Soc. 132, 10674–10676 (2010).

    Article  CAS  PubMed  Google Scholar 

  35. Jin, M., Adak, L. & Nakamura, M. Iron-catalyzed enantioselective cross-coupling reactions of α-chloroesters with aryl Grignard reagents. J. Am. Chem. Soc. 137, 7128–7134 (2015).

    Article  CAS  PubMed  Google Scholar 

  36. Muñoz, S. B. III, Daifuku, S. L., Brennessel, W. W. & Neidig, M. L. Isolation, characterization and reactivity of Fe8Me12−: Kochi’s S = 1/2 species in iron-catalyzed cross-couplings with MeMgBr and ferric salts. J. Am. Chem. Soc. 138, 7492–7495 (2016).

    Article  PubMed Central  Google Scholar 

  37. Liu, L. et al. Intra- and intermolecular Fe-catalyzed dicarbofunctionalization of vinyl cyclopropanes. Chem. Sci. 11, 3146–3151 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Youshaw, C. R. et al. Iron-catalyzed enantioselective multicomponent cross-couplings of α-boryl radicals. Org. Lett. 25, 8320–8325 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Wu, X. et al. Enantioselective 1,2-difunctionalization of dienes enabled by chiral palladium complex-catalyzed cascade arylation/allylic alkylation reaction. J. Am. Chem. Soc. 137, 13476–13479 (2015).

    Article  CAS  PubMed  Google Scholar 

  40. Shu, W. et al. Ni-catalyzed reductive dicarbofunctionalization of nonactivated alkenes: scope and mechanistic insights. J. Am. Chem. Soc. 141, 13812–13821 (2019).

    Article  CAS  PubMed  Google Scholar 

  41. Ouyang, X.-H., Song, R.-J., Hu, M., Yang, Y. & Li, J.-H. Silver-mediated intermolecular 1,2-alkylarylation of styrenes with α-carbonyl alkyl bromides and indoles. Angew. Chem. Int. Ed. 55, 3187–3191 (2016).

    Article  CAS  Google Scholar 

  42. Wang, F., Wang, D., Mu, X., Chen, P. & Liu, G. Copper-catalyzed intermolecular trifluoromethylarylation of alkenes: mutual activation of arylboronic acid and CF3+ reagent. J. Am. Chem. Soc. 136, 10202–10205 (2014).

    Article  CAS  PubMed  Google Scholar 

  43. Wu, L. et al. Asymmetric Cu-catalyzed intermolecular trifluoromethylarylation of styrenes: enantioselective arylation of benzylic radicals. J. Am. Chem. Soc. 139, 2904–2907 (2017).

    Article  CAS  PubMed  Google Scholar 

  44. Dongol, K. G., Koh, H., Sau, M. & Chai, C. L. L. Iron-catalysed sp3–sp3 cross-coupling reactions of unactivated alkyl halides with alkyl Grignard reagents. Adv. Synth. Catal. 349, 1015–1018 (2007).

    Article  CAS  Google Scholar 

  45. Muñoz, S. B. et al. The N-methylpyrrolidone (NMP) effect in iron-catalyzed cross-coupling with simple ferric salts and MeMgBr. Angew. Chem. Int. Ed. 57, 6496–6500 (2018).

    Article  Google Scholar 

  46. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  48. Bakas, N. J. & Neidig, M. L. Additive and counterion effects in iron-catalyzed reactions relevant to C–C bond formation. ACS Catal. 11, 8493–8503 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Aguilera, M. C. et al. Insight into radical initiation, solvent effects, and biphenyl production in iron-bisphosphine cross-couplings. ACS Catal. 13, 8987–8996 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Liu, L. et al. Fe-catalyzed three-component dicarbofunctionalization of unactivated alkenes with alkyl halides and Grignard reagents. Chem. Sci. 11, 8301–8305 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Chierchia, M., Xu, P., Lovinger, G. J. & Morken, J. P. Enantioselective radical addition/cross-coupling of organozinc reagents, alkyl iodides, and alkenyl boron reagents. Angew. Chem. Int. Ed. 58, 14245–14249 (2019).

    Article  CAS  Google Scholar 

  52. Sun, S.-Z., Duan, Y., Mega, R. S., Somerville, R. J. & Martin, R. Site-selective 1,2-dicarbofunctionalization of vinyl boronates through dual catalysis. Angew. Chem. Int. Ed. 59, 4370–4374 (2020).

    Article  CAS  Google Scholar 

  53. Wang, X.-X., Lu, X., He, S.-J. & Fu, Y. Nickel-catalyzed three-component olefin reductive dicarbofunctionalization to access alkylborates. Chem. Sci. 11, 7950–7956 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Campbell, M. W., Compton, J. S., Kelly, C. B. & Molander, G. A. Three-component olefin dicarbofunctionalization enabled by nickel/photoredox dual catalysis. J. Am. Chem. Soc. 141, 20069–20078 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. García-Domínguez, A., Mondal, R. & Nevado, C. Dual photoredox/nickel-catalyzed three-component carbofunctionalization of alkenes. Angew. Chem. Int. Ed. 58, 12286–12290 (2019).

    Article  Google Scholar 

  56. Mega, R. S., Duong, V. K., Noble, A. & Aggarwal, V. K. Decarboxylative conjunctive cross-coupling of vinyl boronic esters using metallaphotoredox catalysis. Angew. Chem. Int. Ed. 59, 4375–4379 (2020).

    Article  CAS  Google Scholar 

  57. Liu, L. et al. General method for iron-catalyzed multicomponent radical cascades–cross-couplings. Science 374, 432–439 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Giese, B. Formation of C-C bonds by addition of free radicals to alkenes. Angew. Chem. Int. Ed. Engl. 22, 753–764 (1983).

    Article  Google Scholar 

  59. Fleming, I. in Molecular Orbitals and Organic Chemical Reactions 275–297 (Wiley, 2009).

  60. Parsaee, F. et al. Radical philicity and its role in selective organic transformations. Nat. Rev. Chem. 5, 486–499 (2021).

    Article  CAS  PubMed  Google Scholar 

  61. Rotella, M. E., Sar, D., Liu, L. & Gutierrez, O. Fe-catalyzed dicarbofunctionalization of electron-rich alkenes with Grignard reagents and (fluoro)alkyl halides. Chem. Commun. 57, 12508–12511 (2021).

    Article  CAS  Google Scholar 

  62. Sar, D. et al. Expanding the chemical space of enol silyl ethers: catalytic dicarbofunctionalization enabled by iron catalysis. Chem. Sci. 14, 13007–13013 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Rentería-Gómez, Á., Guerrero, M., Ramirez-Lopez, M. & Gutierrez, O. Regioselective fluoroalkylarylation of enamides enabled by an iron-catalyzed multicomponent radical cross-coupling strategy. Org. Lett. 25, 7440–7445 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  64. Guerrero, M., Rentería-Gómez, Á., Das, D. & Gutierrez, O. Fe-catalyzed fluoroalkyl(hetero)arylation of vinyl azaarenes: rapid and modular synthesis of unsymmetrical 1,1-bis(hetero)arylalkanes. Org. Lett. 26, 7015–7020 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Maity, T., Rentería-Gómez, Á. & Gutierrez, O. Stereoselective Fe-catalyzed decoupled cross-couplings: chiral vinyl oxazolidinones as effective radical lynchpins for diastereoselective C(sp2)-C(sp3) bond formation. ACS Catal. 14, 13049–13054 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Newcomb, M. in Encyclopedia of Radicals in Chemistry, Biology and Materials (eds Chatgilialoglu, C. & Studer, A.) Ch. 5, 107–124 (Wiley, 2012).

  67. Gutierrez, O., Tellis, J. C., Primer, D. N., Molander, G. A. & Kozlowski, M. C. Nickel-catalyzed cross-coupling of photoredox-generated radicals: uncovering a general manifold for stereoconvergence in nickel-catalyzed cross-couplings. J. Am. Chem. Soc. 137, 4896–4899 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Evans, D. J., Henderson, R. A., Hills, A., Hughes, D. L. & Oglieve, K. E. Involvement of iron alkyl complexes and alkyl radicals in the Kharasch reactions: probing the catalysis using iron phosphine complexes. J. Chem. Soc. Dalton Trans. 1992, 1259–1265 (1992).

    Article  Google Scholar 

  69. Geist, E., Kirschning, A. & Schmidt, T. sp3–sp3 coupling reactions in the synthesis of natural products and biologically active molecules. Nat. Prod. Rep. 31, 441–448 (2014).

    Article  CAS  PubMed  Google Scholar 

  70. Choi, J. & Fu, G. C. Transition metal-catalyzed alkyl-alkyl bond formation: another dimension in cross-coupling chemistry. Science 356, eaaf7230 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  71. Tan, T.-D. et al. Congested C(sp3)-rich architectures enabled by iron-catalysed conjunctive alkylation. Nat. Catal. 7, 321–329 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Tan, T.-D. et al. Kinetically controlled Z-alkene synthesis using iron-catalysed allene dialkylation. Nat. Synth. 4, 116–123 (2025).

    Article  CAS  Google Scholar 

  73. Xu, W. et al. Fe-catalyzed dicarbofunctionalization of vinylarenes with alkylsilyl peroxides and β-keto carbonyl substrates. Org. Lett. 24, 2641–2645 (2022).

    Article  CAS  PubMed  Google Scholar 

  74. Lux, D. M., Lee, D. J., Sapkota, R. R. & Giri, R. Iron-mediated dialkylation of alkenylarenes with benzyl bromides. J. Org. Chem. 89, 16292–16299 (2024).

    Article  CAS  PubMed  Google Scholar 

  75. Jian, W., Ge, L., Jiao, Y., Qian, B. & Bao, H. Iron-catalyzed decarboxylative alkyl etherification of vinylarenes with aliphatic acids as the alkyl source. Angew. Chem. Int. Ed. 56, 3650–3654 (2017).

    Article  CAS  Google Scholar 

  76. Qian, B., Chen, S., Wang, T., Zhang, X. & Bao, H. Iron-catalyzed carboamination of olefins: synthesis of amines and disubstituted β-amino acids. J. Am. Chem. Soc. 139, 13076–13082 (2017).

    Article  CAS  PubMed  Google Scholar 

  77. Xu, R. & Cai, C. Iron-catalyzed three-component intermolecular trifluoromethyl-acyloxylation of styrenes with NaSO2CF3 and benzoic acids. Org. Chem. Front. 7, 318–323 (2020).

    Article  CAS  Google Scholar 

  78. Li, W.-Y., Wang, Q.-Q. & Yang, L. Fe-catalyzed radical-type difunctionalization of styrenes with aliphatic aldehydes and trimethylsilyl azide via a decarbonylative alkylation-azidation cascade. Org. Biomol. Chem. 15, 9987–9991 (2017).

    Article  CAS  PubMed  Google Scholar 

  79. Wu, C.-S., Li, R., Wang, Q.-Q. & Yang, L. Fe-catalyzed decarbonylative alkylation-peroxidation of alkenes with aliphatic aldehydes and hydroperoxide under mild conditions. Green Chem. 21, 269–274 (2019).

    Article  CAS  Google Scholar 

  80. Zhu, C.-L. et al. Iron(II)-catalyzed azidotrifluoromethylation of olefins and N-heterocycles for expedient vicinal trifluoromethyl amine synthesis. ACS Catal. 8, 5032–5037 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Ge, L., Li, Y. & Bao, H. Iron-catalyzed radical acyl-azidation of alkenes with aldehydes: synthesis of unsymmetrical β-azido ketones. Org. Lett. 21, 256–260 (2019).

    Article  CAS  PubMed  Google Scholar 

  82. Xiong, H. et al. Iron-catalyzed carboazidation of alkenes and alkynes. Nat. Commun. 10, 122 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  83. Wei, R. et al. Iron-catalyzed alkylazidation of 1,1-disubstituted alkenes with diacylperoxides and TMSN3. Org. Lett. 22, 3195–3199 (2020).

    Article  CAS  PubMed  Google Scholar 

  84. Ge, L. et al. Iron-catalysed asymmetric carboazidation of styrenes. Nat. Catal. 4, 28–35 (2021).

    Article  CAS  Google Scholar 

  85. Liu, S. et al. Fe-catalyzed alkylazidation of α-trifluoromethylalkenes: an access to quaternary stereocenters containing CF3 and N3 groups. Org. Lett. 25, 1336–1341 (2023).

    Article  CAS  PubMed  Google Scholar 

  86. Zhu, F., Xue, J. & Wu, X.-F. Iron-catalyzed intermolecular 1,2-difunctionalization of alkenes with nucleophiles and using di-tert-butyl peroxide as the methylation reagent. Tetrahedron 149, 133735 (2023).

    Article  CAS  Google Scholar 

  87. Pozhydaiev, V., Vayer, M., Fave, C., Moran, J. & Lebœuf, D. Synthesis of unprotected β-arylethylamines by iron(II)-catalyzed 1,2-aminoarylation of alkenes in hexafluoroisopropanol. Angew. Chem. Int. Ed. 62, e202305108 (2023).

    Article  Google Scholar 

  88. Kambe, N., Iwasaki, T. & Terao, J. Pd-catalyzed cross-coupling reactions of alkyl halides. Chem. Soc. Rev. 40, 4937–4947 (2011).

    Article  CAS  PubMed  Google Scholar 

  89. Du, W. et al. Iron-catalyzed radical oxidative coupling reaction of aryl olefins with 1,3-dithiane. Org. Lett. 16, 2470–2473 (2014).

    Article  CAS  PubMed  Google Scholar 

  90. Liu, T. et al. Alcohol-mediated direct dithioacetalization of alkynes with 2-chloro-1,3-dithiane for the synthesis of Markovnikov dithianes. Org. Biomol. Chem. 15, 4068–4071 (2017).

    Article  CAS  PubMed  Google Scholar 

  91. Xu, T., Cheung, C. W. & Hu, X. Iron-catalyzed 1,2-addition of perfluoroalkyl iodides to alkynes and alkenes. Angew. Chem. Int. Ed. 53, 4910–4914 (2014).

    Article  CAS  Google Scholar 

  92. Deng, W., Li, Y., Li, Y.-G. & Bao, H. Iron-catalyzed carboiodination of alkynes. Synth 50, 2974–2980 (2018).

    Article  CAS  Google Scholar 

  93. Xu, C., He, Z., Yang, H., Chen, H. & Zeng, Q. FeCl3-catalyzed three-component aryl-selenylation of alkenes. Tetrahedron 91, 132239 (2021).

    Article  CAS  Google Scholar 

  94. Yu, X., Zheng, H., Zhao, H., Lee, B. C. & Koh, M. J. Iron-catalyzed regioselective alkenylboration of olefins. Angew. Chem. Int. Ed. 60, 2104–2109 (2021).

    Article  CAS  Google Scholar 

  95. Brunner, H. A new hydrosilylation mechanism—new preparative opportunities. Angew. Chem. Int. Ed. 43, 2749–2750 (2004).

    Article  CAS  Google Scholar 

  96. Bart, S. C., Lobkovsky, E. & Chirik, P. J. Preparation and molecular and electronic structures of iron(0) dinitrogen and silane complexes and their application to catalytic hydrogenation and hydrosilation. J. Am. Chem. Soc. 126, 13794–13807 (2004).

    Article  CAS  PubMed  Google Scholar 

  97. Tondreau, A. M. et al. Iron catalysts for selective anti-Markovnikov alkene hydrosilylation using tertiary silanes. Science 335, 567–570 (2012).

    Article  CAS  PubMed  Google Scholar 

  98. Greenhalgh, M. D., Frank, D. J. & Thomas, S. P. Iron-catalysed chemo-, regio- and stereoselective hydrosilylation of alkenes and alkynes using a bench-stable iron(II) pre-catalyst. Adv. Synth. Catal. 356, 584–590 (2014).

    Article  CAS  Google Scholar 

  99. Peng, D. et al. Phosphinite-iminopyridine iron catalysts for chemoselective alkene hydrosilylation. J. Am. Chem. Soc. 135, 19154–19166 (2013).

    Article  CAS  PubMed  Google Scholar 

  100. Chen, J., Cheng, B., Cao, M. & Lu, Z. Iron-catalyzed asymmetric hydrosilylation of 1,1-disubstituted alkenes. Angew. Chem. Int. Ed. 54, 4661–4664 (2015).

    Article  CAS  Google Scholar 

  101. Cheng, B., Liu, W. & Lu, Z. Iron-catalyzed highly enantioselective hydrosilylation of unactivated terminal alkenes. J. Am. Chem. Soc. 140, 5014–5017 (2018).

    Article  CAS  PubMed  Google Scholar 

  102. Hu, M.-Y. et al. Ligands with 1,10-phenanthroline scaffold for highly regioselective iron-catalyzed alkene hydrosilylation. Nat. Commun. 9, 221 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  103. Sun, W. et al. Phenanthroline-imine ligands for iron-catalyzed alkene hydrosilylation. Chem. Sci. 13, 2721–2728 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. 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).

    Article  CAS  PubMed  Google Scholar 

  105. 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).

    Article  CAS  Google Scholar 

  106. Chen, J., Xi, T. & Lu, Z. Iminopyridine oxazoline iron catalyst for asymmetric hydroboration of 1,1-disubstituted aryl alkenes. Org. Lett. 16, 6452–6455 (2014).

    Article  CAS  PubMed  Google Scholar 

  107. Zhang, H. & Lu, Z. Dual-stereocontrol asymmetric cobalt-catalyzed hydroboration of sterically hindered styrenes. ACS Catal. 6, 6596–6600 (2016).

    Article  CAS  Google Scholar 

  108. Su, W. et al. Ligand-free iron-catalyzed regioselectivity-controlled hydroboration of aliphatic terminal alkenes. ACS Catal. 10, 11963–11970 (2020).

    Article  CAS  Google Scholar 

  109. Lu, D.-F., Zhu, C.-L., Jia, Z.-X. & Xu, H. Iron(II)-catalyzed intermolecular amino-oxygenation of olefins through the N-O bond cleavage of functionalized hydroxylamines. J. Am. Chem. Soc. 136, 13186–13189 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Lu, D.-F., Zhu, C.-L., Sears, J. D. & Xu, H. Iron(II)-catalyzed intermolecular aminofluorination of unfunctionalized olefins using fluoride ion. J. Am. Chem. Soc. 138, 11360–11367 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Radović, A. et al. Mechanistic studies of iron-PyBOX-catalyzed olefin amino-oxygenation with functionalized hydroxylamines. Organometallics 42, 1810–1817 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  112. Legnani, L. & Morandi, B. Direct catalytic synthesis of unprotected 2-amino-1-phenylethanols from alkenes using iron(II) phthalocyanine. Angew. Chem. Int. Ed. 55, 2248–2251 (2016).

    Article  CAS  Google Scholar 

  113. Legnani, L., Prina-Cerai, G., Delcaillau, T., Willems, S. & Morandi, B. Efficient access to unprotected primary amines by iron-catalyzed aminochlorination of alkenes. Science 362, 434–439 (2018).

    Article  CAS  PubMed  Google Scholar 

  114. Falk, E., Makai, S., Delcaillau, T., Gürtler, L. & Morandi, B. Design and scalable synthesis of N-alkylhydroxylamine reagents for the direct iron-catalyzed installation of medicinally relevant amines. Angew. Chem. Int. Ed. 59, 21064–21071 (2020).

    Article  CAS  Google Scholar 

  115. Makai, S., Falk, E. & Morandi, B. Direct synthesis of unprotected 2-azidoamines from alkenes via an iron-catalyzed difunctionalization reaction. J. Am. Chem. Soc. 142, 21548–21555 (2020).

    Article  CAS  PubMed  Google Scholar 

  116. Wei, W. et al. Iron-catalyzed direct difunctionalization of alkenes with dioxygen and sulfinic acids: a highly efficient and green approach to β-ketosulfones. Org. Biomol. Chem. 12, 7678–7681 (2014).

    Article  CAS  PubMed  Google Scholar 

  117. Zhang, J. et al. An iron-catalyzed multicomponent reaction of cycloketone oxime esters, alkenes, DABCO·(SO2)2 and trimethylsilyl azide. Org. Chem. Front. 9, 917–922 (2022).

    Article  CAS  Google Scholar 

  118. Huang, B., Li, Y., Yang, C. & Xia, W. Three-component aminoselenation of alkenes via visible-light enabled Fe-catalysis. Green Chem. 22, 2804–2809 (2020).

    Article  CAS  Google Scholar 

  119. Yang, Y. et al. Iron-catalyzed intermolecular 1,2-difunctionalization of styrenes and conjugated alkenes with silanes and nucleophiles. Angew. Chem. Int. Ed. 56, 7916–7919 (2017).

    Article  CAS  Google Scholar 

  120. Lei, B., Wang, X., Ma, L., Li, Y. & Li, Z. NFSI-participated intermolecular aminoazidation of alkene through iron catalysis. Org. Biomol. Chem. 16, 3109–3113 (2018).

    Article  CAS  PubMed  Google Scholar 

  121. Wang, Y. et al. Iron(III)-catalyzed radical α,β-aminophosphinoylation of styrenes with diphenylphosphine oxides and anilines. Org. Biomol. Chem. 16, 7782–7786 (2018).

    Article  CAS  PubMed  Google Scholar 

  122. Ma, X. et al. Iron phthalocyanine-catalyzed radical phosphinoylazidation of alkenes: a facile synthesis of β-azido-phosphine oxide with a fast azido transfer step. Chin. J. Catal. 42, 1634–1640 (2021).

    Article  CAS  Google Scholar 

  123. Xuan, J. & Xiao, W.-J. Visible-light photoredox catalysis. Angew. Chem. Int. Ed. 51, 6828–6838 (2012).

    Article  CAS  Google Scholar 

  124. 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 

  125. Schultz, D. M. & Yoon, T. P. Solar synthesis: prospects in visible light photocatalysis. Science 343, 1239176 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  126. Ouyang, X.-H. et al. Intermolecular dialkylation of alkenes with two distinct C(sp3)-H bonds enabled by synergistic photoredox catalysis and iron catalysis. Sci. Adv. 5, eaav1291 (2019).

    Article  Google Scholar 

  127. Ye, J.-H. et al. Visible-light-driven iron-promoted thiocarboxylation of styrenes and acrylates with CO2. Angew. Chem. Int. Ed. 56, 15416–15420 (2017).

    Article  CAS  Google Scholar 

  128. Xu, R. & Cai, C. Three-component difluoroalkylation-thiolation of alkenes by iron-facilitated visible-light photoredox catalysis. Chem. Commun. 55, 4383–4386 (2019).

    Article  CAS  Google Scholar 

  129. Yuan, L. et al. Visible-light-driven iron-catalyzed 1,2-difluoroalkylthiolation of alkenes. Org. Lett. 26, 7066–7071 (2024).

    Article  CAS  PubMed  Google Scholar 

  130. Ilic, A. et al. Photoredox catalysis via consecutive 2LMCT- and 3MLCT-excitation of an Fe(III/II)-N-heterocyclic carbene complex. Chem. Sci. 13, 9165–9175 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Zhang, W. et al. Modular and practical 1,2-aryl(alkenyl) heteroatom functionalization of alkenes through iron/photoredox dual catalysis. Angew. Chem. Int. Ed. 62, e202310978 (2023).

    Article  CAS  Google Scholar 

  132. Jiang, X. et al. Iron photocatalysis via Brønsted acid-unlocked ligand-to-metal charge transfer. Nat. Commun. 15, 6115 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Feng, G., Wang, X. & Jin, J. Decarboxylative C–C and C–N bond formation by ligand-accelerated iron photocatalysis. Eur. J. Org. Chem. 2019, 6728–6732 (2019).

    Article  CAS  Google Scholar 

  134. Chinchole, A., Henriquez, M. A., Cortes-Arriagada, D., Cabrera, A. R. & Reiser, O. Iron(III)-light-induced homolysis: a dual photocatalytic approach for the hydroacylation of alkenes using acyl radicals via direct HAT from aldehydes. ACS Catal. 12, 13549–13554 (2022).

    Article  CAS  Google Scholar 

  135. Yuan, X.-Y., Wang, C.-C. & Yu, B. Recent advances in FeCl3-photocatalyzed organic reactions via hydrogen-atom transfer. Chin. Chem. Lett. 35, 109517 (2024).

    Article  CAS  Google Scholar 

  136. Kang, Y. C., Treacy, S. M. & Rovis, T. Iron-catalyzed photoinduced LMCT: a 1 °C-H abstraction enables skeletal rearrangements and C(sp3)–H alkylation. ACS Catal. 11, 7442–7449 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Wu, Q., Liu, W., Wang, M., Huang, Y. & Hu, P. Iron-catalyzed deconstructive alkylation through chlorine radical induced C-C single bond cleavage under visible light. Chem. Commun. 58, 9886–9889 (2022).

    Article  CAS  Google Scholar 

  138. Jin, Y. et al. Convenient C(sp3)–H bond functionalisation of light alkanes and other compounds by iron photocatalysis. Green Chem. 23, 6984–6989 (2021).

    Article  CAS  Google Scholar 

  139. Dai, Z.-Y., Zhang, S.-Q., Hong, X., Wang, P.-S. & Gong, L.-Z. A practical FeCl3/HCl photocatalyst for versatile aliphatic C-H functionalization. Chem. Catal. 2, 1211–1222 (2022).

    CAS  Google Scholar 

  140. Ding, L., Niu, K., Liu, Y. & Wang, Q. Visible light-induced hydrosilylation of electron-deficient alkenes by iron catalysis. ChemSusChem 15, e202200367 (2022).

    Article  CAS  PubMed  Google Scholar 

  141. Zhang, Q. et al. Iron-catalyzed photoredox functionalization of methane and heavier gaseous alkanes: scope, kinetics and computational studies. Org. Lett. 24, 1901–1906 (2022).

    Article  CAS  PubMed  Google Scholar 

  142. Klöpfer, V., Chinchole, A. & Reiser, O. Dual iron- and organophotocatalyzed hydroformylation, hydroacylation and hydrocarboxylation of Michael-acceptors utilizing 1,3,5-trioxanes as C1-synthone. Tetrahedron Chem 10, 100073 (2024).

    Article  Google Scholar 

  143. Bian, K.-J. et al. Photocatalytic hydrofluoroalkylation of alkenes with carboxylic acids. Nat. Chem. 15, 1683–1692 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. He, Y. et al. Remote functionalization of inert C(sp3)–H bonds via dual catalysis driven by alkene hydrofluoroalkylation using industrial feedstocks. Org. Lett. 26, 8278–8283 (2024).

    Article  CAS  PubMed  Google Scholar 

  145. Bian, K.-J., Kao, S.-C., Nemoto, D., Chen, X.-W. & West, J. G. Photochemical diazidation of alkenes enabled by ligand-to-metal charge transfer and radical ligand transfer. Nat. Commun. 13, 7881 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Bian, K.-J. et al. Photocatalytic, modular difunctionalization of alkenes enabled by ligand-to-metal charge transfer and radical ligand transfer. Chem. Sci. 15, 124–133 (2024).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

O.G. acknowledges NIH NIGMS (R35GM137797) and NSF (2528517) for funding. M.J.K. acknowledges support from the SUSTech-NUS Joint Research Center Project Fund (A-8002271- 00-00, A-8002271-01-00 and A-8002271-02-00). We also thank all the Gutierrez group members for proofreading and providing valuable feedback to the authors.

Author information

Authors and Affiliations

  1. Department of Chemistry and Biochemistry, University of California, Los Angeles, CA, USA

    Achyut R. Gogoi, Ángel Rentería-Gómez & Osvaldo Gutierrez

  2. Department of Chemistry, Texas A&M University, College Station, TX, USA

    Achyut R. Gogoi, Ángel Rentería-Gómez & Osvaldo Gutierrez

  3. Department of Chemistry, National University of Singapore, Singapore, Republic of Singapore

    Tong-De Tan, Jun Wei Ng & Ming Joo Koh

Authors
  1. Achyut R. Gogoi
    View author publications

    Search author on:PubMed Google Scholar

  2. Ángel Rentería-Gómez
    View author publications

    Search author on:PubMed Google Scholar

  3. Tong-De Tan
    View author publications

    Search author on:PubMed Google Scholar

  4. Jun Wei Ng
    View author publications

    Search author on:PubMed Google Scholar

  5. Ming Joo Koh
    View author publications

    Search author on:PubMed Google Scholar

  6. Osvaldo Gutierrez
    View author publications

    Search author on:PubMed Google Scholar

Contributions

A.R.G., A.R.-G., T.-D.T., J.W.N., M.J.K. and O.G. contributed equally to all aspects of the Article and wrote the manuscript. All authors contributed substantially to discussion of the content. All authors reviewed and edited the manuscript before submission.

Corresponding authors

Correspondence to Ming Joo Koh or Osvaldo Gutierrez.

Ethics declarations

Competing interests

The authors declare no competing interests.

Peer review

Peer review information

Nature Synthesis thanks the anonymous reviewers for their contribution to the peer review of this work. Primary Handling Editor: Thomas West, 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.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Gogoi, A.R., Rentería-Gómez, Á., Tan, TD. et al. Iron-catalysed radical difunctionalization of alkenes. Nat. Synth 4, 1036–1055 (2025). https://doi.org/10.1038/s44160-025-00860-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Version of record:

  • Issue date:

  • DOI: https://doi.org/10.1038/s44160-025-00860-1

Search

Advanced search

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