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.

Catalytic multicomponent reaction involving a ketyl-type radical

Subjects

Abstract

The development of new strategies and concepts towards the synthetic utilization of carbonyl compounds is of pivotal relevance. Nevertheless, the generation of ketyl radicals requires relatively harsh conditions and a large excess of reductants, which represents a long-standing, unsolved problem that hampers the broad application of ketyl coupling processes. Several catalytic approaches have been developed to generate ketyl radicals and successfully applied in reductive cyclizations and two-component cross-coupling reactions. However, catalytic multicomponent reactions that involve a ketyl radical remain rare, but are in high demand owing to their ability to rapidly generate complexity in molecules. Here we report a multicomponent, redox-neutral photocatalytic manifold that combines readily available aldehydes, feedstock 1,3-butadiene and various nucleophiles to build architecturally complex and functionally diverse homoallylic alcohols in one pot. This operationally straightforward method exhibits a wide functional group tolerance, enables the synthesis of drug-like architectures that are not readily accessible by other methods and is applied towards key intermediates of several natural products, which makes the strategy of broad interest in areas such as synthetic and medicinal chemistry.

Your institute does not have access to this article

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Fig. 1: Development of a strategy for a catalytic MCR that involves ketyl radicals.
Fig. 2: Optimization of a MCR that involves ketyl-type radicals.
Fig. 3: Mechanistic studies.
Fig. 4: Computational calculations.
Fig. 5: Synthetic application of the methodology towards total synthesis and the generation of complex heterocyclic motifs.

Data availability

Materials and methods, detailed optimization studies, experimental procedures, mechanistic studies, DFT calculation details and NMR spectra are available in the Supplementary Information and from the corresponding authors upon reasonable request. NMR spectroscopy data in JCAMP-DX format, Cartesian coordinates of the DFT-optimized structures, step-by-step set-up pictures and ultraviolet–visible and fluorescence spectroscopy data are available at Zenodo under the Creative Commons Attribution 4.0 International license: https://doi.org/10.5281/zenodo.6425457.

References

  1. Wender, P. A. & Miller, B. L. Synthesis at the molecular frontier. Nature 460, 197–201 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  2. Young, I. S. & Baran, P. S. Protecting-group-free synthesis as an opportunity for invention. Nat. Chem. 1, 193–205 (2009).

    CAS  PubMed  Google Scholar 

  3. Rotstein, B. H., Zaretsky, S., Rai, V. & Yudin, A. K. Small heterocycles in multicomponent reactions. Chem. Rev. 114, 8323–8359 (2014).

    CAS  PubMed  Google Scholar 

  4. Touré, B. B. & Hall, D. G. Natural product synthesis using multicomponent reaction strategies. Chem. Rev. 109, 4439–4486 (2009).

    PubMed  Google Scholar 

  5. Ganem, B. Strategies for Innovation in multicomponent reaction design. Acc. Chem. Res. 42, 463–472 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Fazakerley, N. J., Helm, M. D. & Procter, D. J. Total synthesis of (+)-pleuromutilin. Chem. Eur. J. 19, 6718–6723 (2013).

    CAS  PubMed  Google Scholar 

  7. Farney, E. P., Feng, S. S., Schäfers, F. & Reisman, S. E. Total synthesis of (+)-pleuromutilin. J. Am. Chem. Soc. 140, 1267–1270 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Cha, J. Y., Yeoman, J. T. S. & Reisman, S. E. A concise total synthesis of (−)-maoecrystal Z. J. Am. Chem. Soc. 133, 14964–14967 (2011).

    CAS  PubMed  Google Scholar 

  9. Pan, S. et al. Enantioselective total synthesis of (+)-steenkrotin A and determination of its absolute configuration. Chem. Eur. J. 22, 959–970 (2016).

    CAS  PubMed  Google Scholar 

  10. Classen, M. J., Böcker, M. N. A., Roth, R., Amberg, W. M. & Carreira, E. M. Enantioselective total synthesis of (+)-euphorikanin A. J. Am. Chem. Soc. 143, 8261–8265 (2021).

    CAS  PubMed  Google Scholar 

  11. Roth, H. G., Romero, N. A. & Nicewicz, D. A. Experimental and calculated electrochemical potentials of common organic molecules for applications to single-electron redox chemistry. Synlett 27, 714–723 (2015).

    Google Scholar 

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

    CAS  Google Scholar 

  13. Streuff, J. The electron-way: metal-catalyzed reductive umpolung reactions of saturated and α,β-unsaturated carbonyl derivatives. Synthesis 45, 281–307 (2013).

    CAS  Google Scholar 

  14. Molander, G. A. & Harris, C. R. Sequencing reactions with samarium(II) iodide. Chem. Rev. 96, 307–338 (1996).

    CAS  PubMed  Google Scholar 

  15. Szostak, M., Fazakerley, N. J., Parmar, D. & Procter, D. J. Cross-coupling reactions using samarium(II) iodide. Chem. Rev. 114, 5959–6039 (2014).

    CAS  PubMed  Google Scholar 

  16. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Yan, M., Kawamata, Y. & Baran, P. S. Synthetic organic electrochemical methods since 2000: on the verge of a renaissance. Chem. Rev. 117, 13230–13319 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Tarantino, K. T., Liu, P. & Knowles, R. R. Catalytic ketyl–olefin cyclizations enabled by proton-coupled electron transfer. J. Am. Chem. Soc. 135, 10022–10025 (2013).

    CAS  PubMed  Google Scholar 

  19. Rono, L. J., Yayla, H. G., Wang, D. Y., Armstrong, M. F. & Knowles, R. R. Enantioselective photoredox catalysis enabled by proton-coupled electron transfer: development of an asymmetric aza-pinacol cyclization. J. Am. Chem. Soc. 135, 17735–17738 (2013).

    CAS  PubMed  Google Scholar 

  20. Lu, Z., Shen, M. & Yoon, T. P. [3+2] cycloadditions of aryl cyclopropyl ketones by visible light photocatalysis. J. Am. Chem. Soc. 133, 1162–1164 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Lee, K. N., Lei, Z. & Ngai, M.-Y. β-selective reductive coupling of alkenylpyridines with aldehydes and imines via synergistic Lewis acid/photoredox catalysis. J. Am. Chem. Soc. 139, 5003–5006 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Ye, C.-X. et al. Dual catalysis for enantioselective convergent synthesis of enantiopure vicinal amino alcohols. Nat. Commun. 9, 410 (2018).

    PubMed  PubMed Central  Google Scholar 

  23. Cao, G.-M. et al. Visible-light photoredox-catalyzed umpolung carboxylation of carbonyl compounds with CO2. Nat. Commun. 12, 3306 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Qi, L. & Chen, Y. Polarity-reversed allylations of aldehydes, ketones, and imines enabled by Hantzsch ester in photoredox catalysis. Angew. Chem. Int. Ed. 55, 13312–13315 (2016).

    CAS  Google Scholar 

  25. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Rafferty, S. M., Rutherford, J. E., Zhang, L., Wang, L. & Nagib, D. A. Cross-selective aza-pinacol coupling via atom transfer catalysis. J. Am. Chem. Soc. 143, 5622–5628 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Hu, P. et al. Electroreductive olefin–ketone coupling. J. Am. Chem. Soc. 142, 20979–20986 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Zhang, X. et al. Reductive arylation of aliphatic and aromatic aldehydes with cyanoarenes by electrolysis for the synthesis of alcohols. Org. Lett. 23, 3472–3476 (2021).

    CAS  PubMed  Google Scholar 

  29. Zhang, S. et al. Electrochemical arylation of aldehydes, ketones, and alcohols: from cathodic reduction to convergent paired electrolysis. Angew. Chem. Int. Ed. 60, 7275–7282 (2021).

    CAS  Google Scholar 

  30. Péter, Á., Agasti, S., Knowles, O., Pye, E. & Procter, D. J. Recent advances in the chemistry of ketyl radicals. Chem. Soc. Rev. 50, 5349–5365 (2021).

    PubMed  PubMed Central  Google Scholar 

  31. Xia, Q., Dong, J., Song, H. & Wang, Q. Visible-light photocatalysis of the ketyl radical coupling reaction. Chem. Eur. J. 25, 2949–2961 (2019).

    CAS  PubMed  Google Scholar 

  32. Ulich, L. H. & Adams, R. The reaction between acid halides and aldehydes. III. J. Am. Chem. Soc. 43, 660–667 (1921).

    CAS  Google Scholar 

  33. Yang, Z.-P. & Fu, G. C. Convergent catalytic asymmetric synthesis of esters of chiral dialkyl carbinols. J. Am. Chem. Soc. 142, 5870–5875 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. 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).

    CAS  PubMed  Google Scholar 

  35. Huang, H.-M., Bellotti, P., Ma, J., Dalton, T. & Glorius, F. Bifunctional reagents in organic synthesis. Nat. Rev. Chem. 5, 301–321 (2021).

    CAS  Google Scholar 

  36. Chuentragool, P., Kurandina, D. & Gevorgyan, V. Catalysis with palladium complexes photoexcited by visible light. Angew. Chem. Int. Ed. 58, 11586–11598 (2019).

    CAS  Google Scholar 

  37. Juliá, F., Constantin, T. & Leonori, D. Applications of halogen-atom transfer (XAT) for the generation of carbon radicals in synthetic photochemistry and photocatalysis. Chem. Rev. 122, 2292–2352 (2022).

    PubMed  Google Scholar 

  38. Dahlmann, M., Grub, J. & Löser, E. Butadiene in Ullmann’s Encyclopedia of Industrial Chemistry (Wiley-VCH, 2011).

  39. Huang, H.-M. et al. Catalytic radical generation of π-allylpalladium complexes. Nat. Catal. 3, 393–400 (2020).

    CAS  Google Scholar 

  40. Shing Cheung, K. P., Kurandina, D., Yata, T. & Gevorgyan, V. Photoinduced palladium-catalyzed carbofunctionalization of conjugated dienes proceeding via radical-polar crossover scenario: 1,2-aminoalkylation and beyond. J. Am. Chem. Soc. 142, 9932–9937 (2020).

    CAS  PubMed  Google Scholar 

  41. Trost, B. M. & Crawley, M. L. Asymmetric transition-metal-catalyzed allylic alkylations: applications in total synthesis. Chem. Rev. 103, 2921–2944 (2003).

    CAS  PubMed  Google Scholar 

  42. Maekawa, H., Yamamoto, Y., Shimada, H., Yonemura, K. & Nishiguchi, I. Mg-promoted mixed pinacol coupling. Tetrahedron Lett. 45, 3869–3872 (2004).

    CAS  Google Scholar 

  43. Kunkely, H. & Vogler, A. Photo-oxidation of bis[1,2-bis(diphenylphosphino)ferrocene]-palladium(0) in CCl4 induced by ferrocene to solvent charge transfer excitation. J. Organomet. Chem. 559, 215–217 (1998).

    CAS  Google Scholar 

  44. Koy, M., Bellotti, P., Katzenburg, F., Daniliuc, C. G. & Glorius, F. Synthesis of all-carbon quaternary centers by palladium-catalyzed olefin dicarbofunctionalization. Angew. Chem. Int. Ed. 59, 2375–2379 (2020).

    CAS  Google Scholar 

  45. Bellotti, P., Koy, M., Gutheil, C., Heuvel, S. & Glorius, F. Three-component three-bond forming cascade via palladium photoredox catalysis. Chem. Sci. 12, 1810–1817 (2021).

    CAS  Google Scholar 

  46. Ladouceur, S., Fortin, D. & Zysman-Colman, E. Enhanced luminescent iridium(III) complexes bearing aryltriazole cyclometallated ligands. Inorg. Chem. 50, 11514–11526 (2011).

    CAS  PubMed  Google Scholar 

  47. Hanss, D., Freys, J. C., Bernardinelli, G. & Wenger, O. S. Cyclometalated iridium(III) complexes as photosensitizers for long-range electron transfer: occurrence of a coulomb barrier. Eur. J. Inorg. Chem. 2009, 4850–4859 (2009).

    Google Scholar 

  48. Uoyama, H., Goushi, K., Shizu, K., Nomura, H. & Adachi, C. Highly efficient organic light-emitting diodes from delayed fluorescence. Nature 492, 234–238 (2012).

    CAS  PubMed  Google Scholar 

  49. Tamayo, A. B. et al. Synthesis and characterization of facial and meridional tris-cyclometalated Iridium(III) complexes. J. Am. Chem. Soc. 125, 7377–7387 (2003).

    CAS  PubMed  Google Scholar 

  50. McIntosh, J. M. 3-Sulfolene in Encyclopedia of Reagents for Organic Synthesis (John Wiley & Sons, Ltd, 2001).

  51. Pitzer, L., Schäfers, F. & Glorius, F. Rapid assessment of the reaction-condition-based sensitivity of chemical transformations. Angew. Chem. Int. Ed. 58, 8572–8576 (2019).

    CAS  Google Scholar 

  52. Tsubomura, T. et al. Strongly luminescent palladium(0) and platinum(0) diphosphine complexes. Inorg. Chem. 47, 481–486 (2008).

    CAS  PubMed  Google Scholar 

  53. Kakizoe, D. et al. Photophysical properties of simple palladium(0) complexes bearing triphenylphosphine derivatives. Inorg. Chem. 60, 9516–9528 (2021).

    CAS  PubMed  Google Scholar 

  54. Tsubomura, T. & Sakai, K. Photochemical reactions of palladium(0) and platinum(0) phosphine complexes. Coord. Chem. Rev. 171, 107–113 (1998).

    CAS  Google Scholar 

  55. Kancherla, R. et al. Oxidative addition to palladium(0) made easy through photoexcited-state metal catalysis: experiment and computation. Angew. Chem. Int. Ed. 58, 3412–3416 (2019).

    CAS  Google Scholar 

  56. Li, F. et al. Photocatalytic generation of π-allyltitanium complexes via radical intermediates. Angew. Chem. Int. Ed. 60, 1561–1566 (2021).

    CAS  Google Scholar 

  57. Chen, J. et al. Photoinduced copper-catalyzed asymmetric C–O cross-coupling. J. Am. Chem. Soc. 143, 13382–13392 (2021).

    CAS  PubMed  Google Scholar 

  58. Huang, H.-M. et al. Three-component, interrupted radical Heck/allylic substitution cascade involving unactivated alkyl bromides. J. Am. Chem. Soc. 142, 10173–10183 (2020).

    CAS  PubMed  Google Scholar 

  59. Consiglio, G. & Waymouth, R. M. Enantioselective homogeneous catalysis involving transition-metal-allyl intermediates. Chem. Rev. 89, 257–276 (1989).

  60. Kurandina, D., Parasram, M. & Gevorgyan, V. Visible light-induced room-temperature Heck reaction of functionalized alkyl halides with vinyl arenes/heteroarenes. Angew. Chem. Int. Ed. 56, 14212–14216 (2017).

    CAS  Google Scholar 

  61. Wang, G.-Z., Shang, R., Cheng, W.-M. & Fu, Y. Irradiation-induced Heck reaction of unactivated alkyl halides at room temperature. J. Am. Chem. Soc. 139, 18307–18312 (2017).

  62. Zhou, W.-J. et al. Visible-light-driven palladium-catalyzed radical alkylation of C−H bonds with unactivated alkyl bromides. Angew. Chem. Int. Ed. 56, 15683–15687 (2017).

  63. Zhao, G., Yao, W., Mauro, J. N. & Ngai, M.-Y. Excited-state palladium-catalyzed 1,2-spin-center shift enables selective C-2 reduction, deuteration, and iodination of carbohydrates. J. Am. Chem. Soc. 143, 1728–1734 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Kim, D., Lee, G. S., Kim, D. & Hong, S. H. Direct C(sp2)–H alkylation of unactivated arenes enabled by photoinduced Pd catalysis. Nat. Commun. 11, 5266 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Luo, Y.-C., Tong, F.-F., Zhang, Y., He, C.-Y. & Zhang, X. Visible-light-induced palladium-catalyzed selective defluoroarylation of trifluoromethylarenes with arylboronic acids. J. Am. Chem. Soc. 143, 13971–13979 (2021).

    CAS  PubMed  Google Scholar 

  66. Huang, H.-M., Bellotti, P. & Glorius, F. Transition metal-catalysed allylic functionalization reactions involving radicals. Chem. Soc. Rev. 49, 6186–6197 (2020).

    PubMed  Google Scholar 

  67. Huang, H.-M., Bellotti, P., Chen, P.-P., Houk, K. N. & Glorius, F. Allylic C(sp3)–H arylation of olefins via ternary catalysis. Nat. Synth. 1, 59–68 (2022).

    Google Scholar 

  68. Flynn, A. B. & Ogilvie, W. W. Stereocontrolled synthesis of tetrasubstituted olefins. Chem. Rev. 107, 4698–4745 (2007).

    CAS  PubMed  Google Scholar 

  69. Kazmaier, U. Transition Metal Catalyzed Enantioselective Allylic Substitution in Organic Synthesis vol. 38 (Springer, 2012).

  70. Norcott, P. & McErlean, C. S. P. Synthesis of highly enantio-enriched heliespirones A and C by a diastereoselective aromatic Claisen rearrangement. Aust. J. Chem. 71, 366–372 (2018).

    CAS  Google Scholar 

  71. Nakajima, N., Uoto, K., Yonemitsu, O. & Hata, T. Facile total synthesis of carbonolides by Witting–Hoener macro-cyclization and stereoselective epoxidation. Chem. Pharm. Bull. 39, 64–74 (1991).

    CAS  Google Scholar 

  72. Craig, D. C., Edwards, G. L. & Muldoon, C. A. A stereoselective approach to 2,6-disubstituted tetrahydropyrans by conjugate addition reactions of vinyl sulfones. Synlett 1997, 1318–1320 (1997).

Download references

Acknowledgements

We thank the Alexander von Humboldt Foundation and the start-up funding from ShanghaiTech University (H.-M.H.), the Deutsche Forschungsgemeinschaft (Leibniz Award, F.G.; SBF 858, P.B.) and the Institute for Basic Science (IBS-R010-D1, S.K.) of the Republic of Korea for generous financial support. We thank Prof. S. Chang (KAIST) for the kind support of this work, and M.J. Milner, J. E. Erchinger and S. Heuvel (WWU Münster) are acknowledged for experimental assistance.

Author information

Authors and Affiliations

Authors

Contributions

H.-M.H. and F.G. conceived the project and supervised the research. H.-M.H. and P.B. performed all of the experiments and analysed all of the data. X.Z. performed the cyclic voltammetry data acquisition and analysis. S.K. performed the DFT calculations. H.-M.H., P.B., S.K. and F.G. co-wrote the manuscript.

Corresponding authors

Correspondence to Huan-Ming Huang or Frank Glorius.

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: Peter Seavill, 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.

Supplementary information

Supplementary Information

Supplementary Sections 1–14, experimental details, Figs. 1–30, Tables 1–11 and NMR spectra.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Huang, HM., Bellotti, P., Kim, S. et al. Catalytic multicomponent reaction involving a ketyl-type radical. Nat. Synth 1, 464–474 (2022). https://doi.org/10.1038/s44160-022-00085-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s44160-022-00085-6

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