The 2016 discovery that a Rh(I)/N-heterocyclic-carbene/aminopyridine system catalytically activates the C–C bond of 3-arylcyclopentanones (coupling C–C cleavage to aryl C–H activation to give α-tetralones) opened redox-neutral skeletal editing of unstrained ketones, but left three linked gaps: (i) the method is substrate-dependent — six-membered-ring ketones (especially 3-phenylcyclohexanone-type substrates lacking a quaternary center) give only trace-to-moderate yields, and 'cut-and-sew' skeletal editing of unstrained cyclic ketones remains limited to 1-indanones; (ii) chirality transfer from β-H-bearing stereocenters is incomplete (94.5%), attributed only tentatively to reversible β-hydride elimination of the C–C activation intermediate; and (iii) the detailed mechanism and catalyst fate are not established experimentally — the proposed intermediates (rhodacycles and a rhodium-bridged bicyclic species) rest on DFT (density functional theory) together with isotope-labelling and kinetic-isotope data. A March 2025 account by the original group lists substrate generality, transient-directing-group economy and noble-metal dependence as the surviving challenges, and states that addressing them 'cannot go without deep understanding of the detailed mechanism and catalyst fate in these reactions'; no work resolving these gaps has been identified through mid-2026, later literature having resolved only adjacent sub-problems (complete stereo-retention for quaternary-center substrates; deacylative and alkyne-bridging alternatives that however sacrifice or reconfigure the carbonyl). The open problem is the completion of the original program: general, efficient, catalytic, redox-neutral C–C activation of unstrained ketones — including quaternary-free cyclohexanones and 'cut-and-sew' transformations of unstrained cyclic ketones beyond 1-indanones — with carbonyl retention, together with experimental understanding of the detailed mechanism and catalyst fate of these reactions, including the origin of the incomplete chirality transfer at β-H-bearing stereocenters.

Background

Carbon–carbon single bonds form the skeletons of organic molecules, yet they are kinetically inert and difficult to functionalize selectively. Transition-metal-mediated C–C bond activation addresses this: a metal inserts into an inert C–C bond to form more reactive metal–carbon bonds that can undergo downstream coupling. The classical tactic uses three- or four-membered carbocycles, where release of ring strain provides the thermodynamic driving force for the otherwise unfavorable cleavage. For unstrained substrates — five- and six-membered rings and acyclic compounds — the cleavage is close to thermoneutral or uphill, so oxidative addition (formal insertion of a low-valent metal into the C–C bond) is reversible and typically reverts by reductive elimination; this reversibility is the central obstacle. A powerful workaround is directing-group (DG) strategy: a coordinating group binds the metal near the target bond. Temporary DGs, such as the ketimines formed in situ between a ketone and 2-amino-3-picoline (Jun's strategy), are installed and removed catalytically, but for small rings the resulting metallacycles are too unstable for productive turnover.

In this context, Xia, Lu, Liu and Dong (Nature 539, 546–550; 2016) reported the first catalytic C–C activation of normal cyclopentanones: an imine formed transiently from a 3-arylcyclopentanone and 2-aminopyridine chelates a Rh(I) center bearing an N-heterocyclic carbene (NHC, a strongly donating ligand that promotes oxidative addition); C–C cleavage gives a rhodacycle that is trapped irreversibly by intramolecular aryl C–H activation and reductive elimination ('cut-and-sew'), furnishing α-tetralones and making the overall aliphatic-ketone-to-aryl-ketone conversion thermodynamically favored. The same study showed the strategy's limits: 3,3-disubstituted cyclohexanones (which carry a quaternary center) rearrange to α-indanones in only 34–46% yield under more forcing conditions, and 3-phenylcyclohexanone, which lacks the quaternary center, gives only a trace of product. Enantioenriched cyclopentanones transferred their chirality to the tetralone at only 94.5%, which the authors attributed tentatively to a reversible β-hydride (β-H) elimination — a common side process in which a metal alkyl abstracts a β-hydrogen to give an alkene — occurring at the C–C activation intermediate. Mechanistically, DFT (density functional theory) calculations (supported by isotope-labeling and kinetic isotope effects) favored a chloride-mediated metallation–deprotonation pathway for the C–H step, disfavored a 1,4-rhodium migration, and identified a rhodium-bridged bicyclic intermediate — but no intermediate was detected or isolated experimentally, and these species remain computed proposals.

The decade since has seen rapid but partial progress. Within the Rh/aminopyridine manifold, the Dong group extended the chemistry to ring-fused cyclopentanones, to 'cut-and-sew' ring expansions of 1-indanones with ethylene or alkynes, to Suzuki-type cross-couplings of simple ketones — a manifold in which acetophenones, acetone and even an unsymmetrical acyclic aliphatic ketone already give carbonyl-retaining 'aryl-exchanged' coupling products, albeit at moderate conversions — and to amide homologation; β-quaternary stereocenter substrates were later shown to rearrange with complete stereo-retention (consistent with the β-H-elimination picture, since quaternary centers carry no β-H). Complementary manifolds now cleave unstrained ketone C–C bonds by other means — Ir-catalyzed aromatization-driven deacylation, Ni/photoredox radical deacylation, and Pd-catalyzed alkyne-bridging esterification/lactamization (which even accepts cyclohexanone-derived enones) — but each sacrifices or fundamentally reconfigures the carbonyl group rather than retaining it in a redox-neutral oxidative-addition manifold, and none restores generality for six-membered rings. The field's most recent authoritative statement (Zhang and Dong, Acc. Chem. Res. 58, 991–1002; 2025, published March 2025) explicitly lists the surviving challenges: unstrained-cyclic-ketone cut-and-sew scope 'is limited to 1-indanones', directing-group efficiency, noble-metal dependence, and the need for 'deep understanding of the detailed mechanism and catalyst fate'.

Problem Statement

Complete the program begun by the catalytic C–C activation of cyclopentanones (Nature 539, 546–550; 2016) by addressing, under redox-neutral transition-metal catalysis that retains the carbonyl group in the product, the following linked questions. (1) Generality: extend efficient catalytic C–C activation/'cut-and-sew'-type skeletal rearrangement from 3-arylcyclopentanones to six-membered-ring ketones lacking quaternary centers (exemplified by, but not limited to, the 3-phenylcyclohexanone class that gave only trace product in 2016), and more generally to unstrained cyclic ketones beyond the 1-indanones that are currently the limit of 'cut-and-sew' scope, with useful yields under catalytic metal loadings — not merely via carbonyl-sacrificing deacylation or carbonyl-reconfiguring insertion. 'Efficient'/'useful yields' mean a reproducible isolated yield of at least 50% for the named quaternary-free six-membered-ring (3-phenylcyclohexanone) class of the target rearrangement — up from the trace level reported for that class in 2016 — obtained under substoichiometric, catalytic metal loadings. (2) Mechanism and catalyst fate: establish experimentally, rather than only computationally, the detailed mechanism and catalyst fate of the Rh/aminopyridine unstrained-ketone C–C activation system, including an experimentally determined origin of the incomplete (94.5%) chirality transfer observed at β-H-bearing stereocenters, for which reversible β-hydride elimination at the C–C activation intermediate remains a tentative hypothesis ('probably caused by') to be tested or refuted rather than assumed. The field's most recent account frames these as one program, in that addressing the generality, directing-group and metal-dependence challenges 'cannot go without deep understanding of the detailed mechanism and catalyst fate in these reactions'. The transient-directing-group economy and noble-metal dependence named in this framing are program-level context that bears on question (1)'s efficiency and 'catalytic metal loadings' requirement.

References

  1. Xia, Y.; Lu, G.; Liu, P.; Dong, G. Catalytic activation of carbon–carbon bonds in cyclopentanones. Nature 539, 546–550 (2016). DOI: 10.1038/nature19849; https://doi.org/10.1038/nature19849 (author manuscript at PMC5502808)
  2. Xia, Y.; Wang, J.; Dong, G. Distal-bond-selective C−C activation of ring-fused cyclopentanones: an efficient access to spiroindanones. Angewandte Chemie International Edition 56, 2376–2380 (2017). DOI: 10.1002/anie.201611642; https://doi.org/10.1002/anie.201611642
  3. Xia, Y.; Wang, J.; Dong, G. Suzuki–Miyaura coupling of simple ketones via activation of unstrained carbon–carbon bonds. Journal of the American Chemical Society 140, 5347–5351 (2018). DOI: 10.1021/jacs.8b02462; https://doi.org/10.1021/jacs.8b02462 (author manuscript at PMC5963696)
  4. Xia, Y.; Ochi, S.; Dong, G. Two-carbon ring expansion of 1-indanones via insertion of ethylene into carbon–carbon bonds. Journal of the American Chemical Society 141, 13038–13042 (2019). DOI: 10.1021/jacs.9b07445; https://doi.org/10.1021/jacs.9b07445
  5. Zhang, R.; Xia, Y.; Dong, G. Intermolecular [5+2] annulation between 1-indanones and internal alkynes by rhodium-catalyzed C−C activation. Angewandte Chemie International Edition 60, 20476–20482 (2021). DOI: 10.1002/anie.202106007; https://doi.org/10.1002/anie.202106007
  6. Zhang, R.; Yu, T.; Dong, G. Rhodium catalyzed tunable amide homologation through a hook-and-slide strategy. Science 382, 951–957 (2023). DOI: 10.1126/science.adk1001; https://doi.org/10.1126/science.adk1001
  7. Kan, L.; Zhang, R.; Lu, S.-L.; Hari, Y.; Dong, G. “Cut-and-sew” reactions of β-lactams via C–C bond activation. Journal of the American Chemical Society 147, 33379–33385 (2025). DOI: 10.1021/jacs.5c12770; https://doi.org/10.1021/jacs.5c12770
  8. Zhang, R.; Dong, G. Skeletal modification via activation of relatively unstrained C–C bonds. Accounts of Chemical Research 58, 991–1002 (2025). DOI: 10.1021/acs.accounts.5c00014; https://doi.org/10.1021/acs.accounts.5c00014 (NIHMS author manuscript at PMC12103097)
  9. Ochi, S.; Xia, Y.; Dong, G. Asymmetric synthesis of 1-tetralones bearing a remote quaternary stereocenter through Rh-catalyzed C–C activation of cyclopentanones. Bulletin of the Chemical Society of Japan 93, 1213–1217 (2020). DOI: 10.1246/bcsj.20200147; https://doi.org/10.1246/bcsj.20200147 (author manuscript at PMC8528243)
  10. Hou, S.-H.; Prichina, A. Y.; Zhang, M.; Dong, G. Asymmetric total syntheses of di- and sesquiterpenoids by catalytic C−C activation of cyclopentanones. Angewandte Chemie International Edition 59, 7848–7856 (2020). DOI: 10.1002/anie.201915821; https://doi.org/10.1002/anie.201915821
  11. Xu, Y.; Qi, X.; Zheng, P.; Berti, C. C.; Liu, P.; Dong, G. Deacylative transformations of ketones via aromatization-promoted C–C bond activation. Nature 567, 373–378 (2019). DOI: 10.1038/s41586-019-0926-8; https://doi.org/10.1038/s41586-019-0926-8
  12. Zhang, B.; Bai, H.; Zhan, B.; Wei, K.; Nie, S.; Zhang, X. Deacylative arylation and alkynylation of unstrained ketones. Science Advances 10, eado0225 (2024). DOI: 10.1126/sciadv.ado0225; https://doi.org/10.1126/sciadv.ado0225 (full text at PMC11051662)
  13. Huang, J.; Yan, X.; Xia, Y. Directing group-free formal Suzuki–Miyaura coupling of simple ketones enabled by activation of unstrained C−C bonds. Angewandte Chemie International Edition 61, e202211080 (2022). DOI: 10.1002/anie.202211080; https://doi.org/10.1002/anie.202211080
  14. Jiang, C.; Zheng, Z.-J.; Yu, T.-Y.; Wei, H. Suzuki–Miyaura coupling of unstrained ketones via chelation-assisted C–C bond cleavage. Organic & Biomolecular Chemistry 16, 7174–7177 (2018). DOI: 10.1039/c8ob02075b; https://doi.org/10.1039/c8ob02075b
  15. Jiang, C.; Wu, W.-Q.; Lu, H.; Yu, T.-Y.; Xu, W.-H.; Wei, H. Rhodium-catalyzed Hiyama coupling reaction of unstrained ketones via C−C bond cleavage. Asian Journal of Organic Chemistry 8, 1358–1362 (2019). DOI: 10.1002/ajoc.201900295; https://doi.org/10.1002/ajoc.201900295
  16. Ding, M.; Niu, M.; Hu, L.; Guan, Q.; Yuan, S.; Yu, Y.; Xiao, M.; Huang, S.; Lu, G.; Huang, X. Modular esterification of unstrained carbonyls through palladium-catalyzed alkyne bridging C-C bond activation. Nature Communications 16, 9260 (2025). DOI: 10.1038/s41467-025-64279-0; https://doi.org/10.1038/s41467-025-64279-0
  17. Yuan, S.; Guan, Q.; Peng, S.; Yu, Y.; Huang, S.; Huang, X. Modular access to medium-to-large sized lactams through alkyne-bridging C–C bond activation of unstrained carbonyls. Journal of the American Chemical Society 147, 32321–32328 (2025). DOI: 10.1021/jacs.5c08553; https://doi.org/10.1021/jacs.5c08553
  18. Xia, Y.; Dong, G. Temporary or removable directing groups enable activation of unstrained C–C bonds. Nature Reviews Chemistry 4, 600–614 (2020). DOI: 10.1038/s41570-020-0218-8; https://doi.org/10.1038/s41570-020-0218-8
  19. Deng, L.; Dong, G. Carbon–carbon bond activation of ketones. Trends in Chemistry 2, 183–198 (2020). DOI: 10.1016/j.trechm.2019.12.002; https://doi.org/10.1016/j.trechm.2019.12.002
  20. Song, F.; Gou, T.; Wang, B.-Q.; Shi, Z.-J. Catalytic activations of unstrained C–C bond involving organometallic intermediates. Chemical Society Reviews 47, 7078–7115 (2018). DOI: 10.1039/c8cs00253c; https://doi.org/10.1039/c8cs00253c
  21. Rong, Z.-Q.; Lim, H. N.; Dong, G. Intramolecular acetyl transfer to olefins by catalytic C−C activation of unstrained ketones. Angewandte Chemie International Edition 57, 475–479 (2018). DOI: 10.1002/anie.201711394; https://doi.org/10.1002/anie.201711394
  22. Wu, S.; Luo, S.; Guo, W.; Wang, T.; Xie, Q.; Wang, J.; Liu, G. Direct conversion of ethyl ketone to alkyl ketone via chelation-assisted rhodium(I)-catalyzed carbon–carbon bond cleavage: ligands play an important role in the inhibition of β-hydrogen elimination. Organometallics 37, 2335–2341 (2018). DOI: 10.1021/acs.organomet.8b00309; https://doi.org/10.1021/acs.organomet.8b00309
  23. Wang, Y.; Qiu, B.; Hu, L.; Lu, G.; Xu, T. Rh-catalyzed cascade C–C/C(olefin)–H activations and mechanistic insight. ACS Catalysis 11, 9136–9142 (2021). DOI: 10.1021/acscatal.1c02480; https://doi.org/10.1021/acscatal.1c02480
  24. Chen, Y.-W.; Qiu, Y.; Liu, Y.; Lin, G.-Q.; Hartwig, J. F.; He, Z.-T. Intermolecular asymmetric functionalization of unstrained C(sp3)–C(sp3) bonds in allylic substitution reactions. Nature Synthesis 3, 1011–1020 (2024). DOI: 10.1038/s44160-024-00555-z; https://doi.org/10.1038/s44160-024-00555-z
  25. Wang, H.; Choi, I.; Rogge, T.; Kaplaneris, N.; Ackermann, L. Versatile and robust C–C activation by chelation-assisted manganese catalysis. Nature Catalysis 1, 993–1001 (2018). DOI: 10.1038/s41929-018-0187-1; https://doi.org/10.1038/s41929-018-0187-1