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Unlocking carbene reactivity by metallaphotoredox α-elimination

Abstract

The ability to tame high-energy intermediates is important for synthetic chemistry, enabling the construction of complex molecules and propelling advances in the field of synthesis. Along these lines, carbenes and carbenoid intermediates are particularly attractive, but often unknown, high-energy intermediates1,2. Classical methods to access metal carbene intermediates exploit two-electron chemistry to form the carbon–metal bond. However, these methods are usually prohibitive because of reagent safety concerns, limiting their broad implementation in synthesis3,4,5,6. Mechanistically, an alternative approach to carbene intermediates that could circumvent these pitfalls would involve two single-electron steps: radical addition to metal to forge the initial carbon–metal bond followed by redox-promoted α-elimination to yield the desired metal carbene intermediate. Here we realize this strategy through a metallaphotoredox platform that exploits iron carbene reactivity using readily available chemical feedstocks as radical sources and α-elimination from six classes of previously underexploited leaving groups. These discoveries permit cyclopropanation and σ-bond insertion into N–H, S–H and P–H bonds from abundant and bench-stable carboxylic acids, amino acids and alcohols, thereby providing a general solution to the challenge of carbene-mediated chemical diversification.

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Fig. 1: Enabling carbene reactivity by radical intermediates.
Fig. 2: Scope of photoredox-enabled iron carbene cyclopropanation using carboxylic acids as precursors.
Fig. 3: Scope of tri- and difluoromethyl cyclopropanation through carbene metallaphotoredox.
Fig. 4: Insertions of σ-bond through metallaphotoredox carbene formation.

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Data availability

All data supporting the findings of this study are available in the main text or in the Supplementary Information.

References

  1. Gessner, V. H. Stability and reactivity control of carbenoids: recent advances and perspectives. Chem. Commun. 52, 12011–12023 (2016).

    Article  CAS  Google Scholar 

  2. de Frémont, P., Marion, N. & Nolan, S. P. Carbenes: synthesis, properties, and organometallic chemistry. Coord. Chem. Rev. 253, 862–892 (2009).

    Article  Google Scholar 

  3. Green, S. P. et al. Thermal stability and explosive hazard assessment of diazo compounds and diazo transfer reagents. Org. Process Res. Dev. 24, 67–84 (2020).

    Article  CAS  PubMed  Google Scholar 

  4. Vaitla, J., Bayer, A. & Hopmann, K. H. Synthesis of indoles and pyrroles utilizing iridium carbenes generated from sulfoxonium ylides. Angew. Chem. Int. Ed. 56, 4277–4281 (2017).

    Article  CAS  Google Scholar 

  5. Müller, P., Fernandez, D., Nury, P. & Rossier, J.-C. ChemInform Abstract: metal-catalyzed carbenoid reactions with iodonium and sulfonium ylides. J. Phys. Org. Chem. 11, 321–333 (1998).

    Article  Google Scholar 

  6. Gandelman, M., Rybtchinski, B., Ashkenazi, N., Gauvin, R. M. & Milstein, D. A new general method for the preparation of metal carbene complexes. J. Am. Chem. Soc. 123, 5372–5373 (2001).

    Article  CAS  PubMed  Google Scholar 

  7. Slavík, P., Trowse, B. R., O’Brien, P. & Smith, D. K. Organogel delivery vehicles for the stabilization of organolithium reagents. Nat. Chem. 15, 319–325 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  8. Chan, A. Y. et al. Metallaphotoredox: the merger of photoredox and transition metal catalysis. Chem. Rev. 122, 1485–1542 (2022).

    Article  CAS  PubMed  Google Scholar 

  9. Webb, E. W. et al. Nucleophilic (Radio)Fluorination of redox-active esters via radical-polar crossover enabled by photoredox catalysis. J. Am. Chem. Soc. 142, 9493–9500 (2020).

    Article  CAS  PubMed  Google Scholar 

  10. Porter, N. J., Danelius, E., Gonen, T. & Arnold, F. H. Biocatalytic carbene transfer using diazirines. J. Am. Chem. Soc. 144, 8892–8896 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Cannalire, R. et al. Visible light photocatalysis in the late-stage functionalization of pharmaceutically relevant compounds. Chem. Soc. Rev. 50, 766–897 (2021).

    Article  CAS  PubMed  Google Scholar 

  12. Romero, N. A. & Nicewicz, D. A. Organic photoredox catalysis. Chem. Rev. 116, 10075–10166 (2016).

    Article  CAS  PubMed  Google Scholar 

  13. Shaw, M. H., Twilton, J. & MacMillan, D. W. C. Photoredox catalysis in organic chemistry. J. Org. Chem. 81, 6898–6926 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Horn, E. J., Rosen, B. R. & Baran, P. S. Synthetic organic electrochemistry: An enabling and innately sustainable method. ACS Cent. Sci. 2, 302–308 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Empel, C. & Koenigs, R. M. Sustainable carbene transfer reactions with iron and light. Synlett 30, 1929–1934 (2019).

    Article  CAS  Google Scholar 

  16. Charette, A. B. & Beauchem, A. in Organic Reactions (eds Overman, L. E. et al.) Vol. 58, 1–415 (Wiley, 2001).

  17. Afonso, C. A. M., Motherwell, W. B., O’Shea, D. M. & Roberts, L. R. An improved method for the generation of organozinc carbenoids and its application in dicarbonyl coupling reactions. Tetrahedron Lett. 33, 3899–3902 (1992).

    Article  CAS  Google Scholar 

  18. Ishikawa, S., Sheppard, T. D., D’Oyley, J. M., Kamimura, A. & Motherwell, W. B. A rapid route to aminocyclopropanes via carbamatoorganozinc carbenoids. Angew. Chem. Int. Ed. 52, 10060–10063 (2013).

    Article  CAS  Google Scholar 

  19. Zhang, L., DeMuynck, B. M., Paneque, A. N., Rutherford, J. E. & Nagib, D. A. Carbene reactivity from alkyl and aryl aldehydes. Science 377, 649–654 (2022).

    Article  CAS  PubMed  PubMed Central  ADS  Google Scholar 

  20. Zhang, L. & Nagib, D. A. Carbonyl cross-metathesis via deoxygenative gem-di-metal catalysis. Nat. Chem. 16, 107–113 (2024).

    Article  CAS  PubMed  Google Scholar 

  21. DeMuynck, B. M., Zhang, L., Ralph, E. K. & Nagib, D. A. Cyclopropanation of unactivated alkenes with non-stabilized iron carbenes. Chem 10, 1015–1027 (2024).

    Article  CAS  Google Scholar 

  22. Jia, M. & Ma, S. New approaches to the synthesis of metal carbenes. Angew. Chem. Int. Ed. 55, 9134–9166 (2016).

    Article  CAS  Google Scholar 

  23. Wei, Y., Tinoco, A., Steck, V., Fasan, R. & Zhang, Y. Cyclopropanations via Heme carbenes: basic mechanism and effects of carbene substituent, protein axial ligand, and porphyrin substitution. J. Am. Chem. Soc. 140, 1649–1662 (2018).

    Article  CAS  PubMed  Google Scholar 

  24. Halpern, J. Determination of transition metal-alkyl bond dissociation energies from kinetic measurements. Polyhedron 7, 1483–1490 (1988).

    Article  CAS  Google Scholar 

  25. Johnson, M. W., Hannoun, K. I., Tan, Y., Fu, G. C. & Peters, J. C. A mechanistic investigation of the photoinduced, copper-mediated cross-coupling of an aryl thiol with an aryl halide. Chem. Sci. 7, 4091–4100 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Goswami, M., de Bruin, B. & Dzik, W. I. Difluorocarbene transfer from a cobalt complex to an electron-deficient alkene. Chem. Commun. 53, 4382–4385 (2017).

    Article  CAS  Google Scholar 

  27. Neta, P. Radiation chemical studies of porphyrins and metalloporphyrins. Stud. Phys. Theor. Chem. 87, 453–479 (2001).

    Article  CAS  Google Scholar 

  28. Guldi, D. M., Kumar, M., Neta, P. & Hambright, P. Reactions of alkyl and fluoroalkyl radicals with nickel, iron, and manganese porphyrins. J. Phys. Chem. 96, 9576–9581 (1992).

    Article  CAS  Google Scholar 

  29. Brault, D. & Neta, P. Reactions of iron porphyrins with trifluoromethyl, trifluoromethylperoxy, and tribromomethylperoxy radicals. J. Phys. Chem. 91, 4156–4160 (1987).

    Article  CAS  Google Scholar 

  30. Karmakar, S., Silamkoti, A., Meanwell, N. A., Mathur, A. & Gupta, A. K. Utilization of C(sp3)-carboxylic acids and their redox-active esters in decarboxylative carbon−carbon bond formation. Adv. Synth. Catal. 363, 3693–3736 (2021).

    Article  CAS  Google Scholar 

  31. Liu, W., Lavagnino, M. N., Gould, C. A., Alcázar, J. & MacMillan, D. W. C. A biomimetic SH2 cross-coupling mechanism for quaternary sp3-carbon formation. Science 374, 1258–1263 (2021).

    Article  CAS  PubMed  PubMed Central  ADS  Google Scholar 

  32. Maldotti, A. et al. Photochemistry of iron-porphyrin complexes. Biomimetics and catalysis. Coord. Chem. Rev. 125, 143–154 (1993).

    Article  CAS  Google Scholar 

  33. Batista, V. F., Pinto, D. C. G. A. & Silva, A. M. S. Iron: a worthy contender in metal carbene chemistry. ACS Catal. 10, 10096–10116 (2020).

    Article  CAS  Google Scholar 

  34. Carreras, V., Tanbouza, N. & Ollevier, T. The power of iron catalysis in diazo chemistry. Synthesis 53, 79–94 (2021).

    Article  CAS  Google Scholar 

  35. Damiano, C., Sonzini, P. & Gallo, E. Iron catalysts with N-ligands for carbene transfer of diazo reagents. Chem. Soc. Rev. 49, 4867–4905 (2020).

    Article  CAS  PubMed  Google Scholar 

  36. Lee, W.-C. C., Wang, D.-S., Zhu, Y. & Zhang, X. P. Iron(III)-based metalloradical catalysis for asymmetric cyclopropanation via a stepwise radical mechanism. Nat. Chem. 15, 1569–1580 (2023).

    Article  CAS  PubMed  Google Scholar 

  37. Tanbouza, N., Keipour, H. & Ollevier, T. FeII-catalysed insertion reaction of α-diazocarbonyls into X–H bonds (X = Si, S, N, and O) in dimethyl carbonate as a suitable solvent alternative. RSC Adv. 9, 31241–31246 (2019).

    Article  CAS  PubMed  PubMed Central  ADS  Google Scholar 

  38. Ma, C. et al. Synthesis and characterization of donor–acceptor iron porphyrin carbenes and their reactivities in N–H insertion and related three-component reaction. J. Am. Chem. Soc. 145, 4934–4939 (2023).

    Article  CAS  PubMed  Google Scholar 

  39. Morandi, B. & Carreira, E. M. Iron-catalyzed cyclopropanation in 6 M KOH with in situ generation of diazomethane. Science 335, 1471–1474 (2012).

    Article  CAS  PubMed  ADS  Google Scholar 

  40. Reissig, H.-U. & Zimmer, R. Donor−acceptor-substituted cyclopropane derivatives and their application in organic synthesis. Chem. Rev. 103, 1151–1196 (2003).

    Article  CAS  PubMed  Google Scholar 

  41. Wu, W., Lin, Z. & Jiang, H. Recent advances in the synthesis of cyclopropanes. Org. Biomol. Chem. 16, 7315–7329 (2018).

    Article  CAS  PubMed  Google Scholar 

  42. Chen, D. Y.-K., Pouwer, R. H. & Richard, J.-A. Recent advances in the total synthesis of cyclopropane-containing natural products. Chem. Soc. Rev. 41, 4631–4642 (2012).

    Article  CAS  PubMed  Google Scholar 

  43. Gagnon, A., Duplessis, M. & Fader, L. Arylcyclopropanes: properties, synthesis and use in medicinal chemistry. Org. Prep. Proced. Int. 42, 1–69 (2010).

    Article  CAS  Google Scholar 

  44. Yedase, G. S., Venugopal, S., Arya, P., & Yatham, V. R. Catalyst-free Hantzsch Ester-mediated organic transformations driven by visible light. Asian J. Org. Chem. 11, e202200478 (2022).

    Article  Google Scholar 

  45. Broeckaert, L., Moens, J., Roos, G., Proft, F. D. & Geerlings, P. Intrinsic nucleofugality scale within the framework of density functional reactivity theory. J. Phys. Chem. A 112, 12164–12171 (2008).

    Article  CAS  PubMed  Google Scholar 

  46. Spahlinger, G. & Jackson, J. E. Nucleofugality in oxygen and nitrogen derived pseudohalides in Menshutkin reactions: the importance of the intrinsic barrier. Phys. Chem. Chem. Phys. 16, 24559–24569 (2014).

    Article  CAS  PubMed  Google Scholar 

  47. Stirling, C. J. M. Leaving groups and nucleofugality in elimination and other organic reactions. Acc. Chem. Res. 12, 198–203 (1979).

    Article  CAS  Google Scholar 

  48. Berger, K. J. & Levin, M. D. Reframing primary alkyl amines as aliphatic building blocks. Org. Biomol. Chem. 19, 11–36 (2021).

    Article  CAS  PubMed  Google Scholar 

  49. Katritzky, A. R. & Musumarra, G. New insights into aliphatic nucleophilic substitution reactions from the use of pyridines as leaving groups. Chem. Soc. Rev. 13, 47–68 (1984).

    Article  CAS  Google Scholar 

  50. Correia, J. T. M. et al. Photoinduced deaminative strategies: Katritzky salts as alkyl radical precursors. Chem. Commun. 56, 503–514 (2020).

    Article  Google Scholar 

  51. McNally, A., Prier, C. K. & MacMillan, D. W. C. Discovery of an α-amino C–H arylation reaction using the strategy of accelerated serendipity. Science 334, 1114–1117 (2011).

    Article  CAS  PubMed  PubMed Central  ADS  Google Scholar 

  52. Hu, J., Wang, J., Nguyen, T. H. & Zheng, N. The chemistry of amine radical cations produced by visible light photoredox catalysis. Beilstein J. Org. Chem. 9, 1977–2001 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  53. Rotella, D. P. in Advances in Heterocyclic Chemistry 1st edn, Vol. 134 (eds Scriven, E. F. V. & Ramsden, C. A.) 149–183 (Elsevier, 2021).

  54. 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  ADS  Google Scholar 

  55. Huang, H.-M., Bellotti, P., Erchinger, J. E., Paulisch, T. O. & Glorius, F. Radical carbonyl umpolung arylation via dual nickel catalysis. J. Am. Chem. Soc. 144, 1899–1909 (2022).

    Article  CAS  PubMed  Google Scholar 

  56. Grygorenko, O. O., Artamonov, O. S., Komarov, I. V. & Mykhailiuk, P. K. Trifluoromethyl-substituted cyclopropanes. Tetrahedron 67, 803–823 (2011).

    Article  CAS  Google Scholar 

  57. Wu, W.-F., Lin, J.-H., Xiao, J.-C., Cao, Y.-C. & Ma, Y. Recent advances in the synthesis of CF3- or HCF2-substituted cyclopropanes. Asian J. Org. Chem. 10, 485–495 (2021).

    Article  CAS  Google Scholar 

  58. Deadman, B. J., Collins, S. G. & Maguire, A. R. Taming hazardous chemistry in flow: the continuous processing of diazo and diazonium compounds. Chem. Eur. J. 21, 2298–2308 (2015).

    Article  CAS  PubMed  Google Scholar 

  59. Mykhailiuk, P. K. 2,2,2-Trifluorodiazoethane (CF3CHN2): a long journey since 1943. Chem. Rev. 120, 12718–12755 (2020).

    Article  CAS  PubMed  Google Scholar 

  60. Zhang, J. et al. Visible-light-induced alkoxyl radicals enable α-C(sp3)-H bond allylation. iScience 23, 100755 (2020).

    Article  CAS  PubMed  ADS  Google Scholar 

  61. Lombardi, L. et al. Direct synthesis of α-aryl-α-trifluoromethyl alcohols via nickel catalyzed cross-electrophile coupling. Angew. Chem. Int. Ed. 61, e202211732 (2022).

    Article  CAS  ADS  Google Scholar 

  62. Dötz, K. H. & Stendel, J. Jr Fischer carbene complexes in organic synthesis: metal-assisted and metal-templated reactions. Chem. Rev. 109, 3227–3274 (2009).

    Article  PubMed  Google Scholar 

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Acknowledgements

We acknowledge A. Y. Chan, C. P. Seath, J. A. Rossi-Ashton, R. T. Smith, C. A. Gould and A. Long for their discussions. We also thank R. M. Lambert for assisting with the preparation of this paper. Research reported in this work was supported by the National Institute of General Medical Sciences (NIGMS) of the National Institutes of Health (R35GM134897), the Princeton Catalysis Initiative, Janssen R&D, and gifts from Merck, Pfizer, Bristol-Myers Squibb, Genentech and Genmab. The content is solely the responsibility of the authors and does not necessarily represent the official views of NIGMS.

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Contributions

D.W.C.M., N.W.D. and B.T.B. conceptualized the radical approach to carbenes. B.T.B., N.W.D., C.B.K. and M.C.B. designed the experiments. B.T.B. and N.W.D. performed and analysed the experiments. B.T.B., C.B.K., M.C.B., N.W.D. and D.W.C.M. prepared the Article. D.W.C.M. directed the project.

Corresponding author

Correspondence to David W. C. MacMillan.

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D.W.C.M. declares an ownership interest in Penn PhD photoreactor, which is used to irradiate reactions in this work. The other authors declare no competing interests.

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Extended data figures and tables

Extended Data Fig. 1 Proposed mechanism for iron porphyrin carbene formation through metallaphotoredox catalysis.

Metallaphotoredox-mediated formation of iron porphyrin carbene intermediates exploiting a single-electron reduction mediated α-elimination. Me, methyl; Et, ethyl, Ac, acetyl; Phth, phthalimide; HEH•+, oxidized Hantzsch ester; Ir, Ir(dFCF3ppy)2dttbpy; Fe, iron porphyrin. For further commentary and discussion see Supplementary Fig. 1.

Supplementary information

Supplementary Information

This file contains the following sections: General Information, Optimization Studies, Control Experiments, Mechanistic Studies, General Procedures, Characterization Data, References and Spectra.

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Boyle, B.T., Dow, N.W., Kelly, C.B. et al. Unlocking carbene reactivity by metallaphotoredox α-elimination. Nature (2024). https://doi.org/10.1038/s41586-024-07628-1

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