Carbon–carbon (C–C) bonds make up the skeletons of most organic molecules. The selective manipulation of C–C bonds offers a direct approach to editing molecular scaffolds but remains challenging. The kinetic inertness of C–C bonds can be overcome with transition-metal catalysis, which, nevertheless, relies on a substrate being highly strained or bearing a permanent directing group (DG). The driving force for C–C activation in these cases is strain relief and the formation of a stable metallocycle, respectively. Over the past two decades, a strategy has emerged that uses temporary or removable DGs to effect C–C activation of more common and less strained compounds. A variety of C–C bonds in less strained organic molecules are converted into more reactive transition-metal–carbon (M–C) bonds, enabling downstream transformations as part of diverse synthetic methods. This Review highlights catalytic approaches using temporary or removable DGs to help activate unstrained C–C bonds. The content is organized according to the temporary or removable nature of the DGs and includes applications in the synthesis of natural products or bioactive molecules.
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Dong, G. (ed.) C–C Bond Activation (Springer, 2014).
Chen, F., Wang, T. & Jiao, N. Recent advances in transition-metal-catalyzed functionalization of unstrained carbon–carbon bonds. Chem. Rev. 114, 8613–8661 (2014).
Souillart, L. & Cramer, N. Catalytic C–C bond activations via oxidative addition to transition metals. Chem. Rev. 115, 9410–9464 (2015).
Murakami, M. (ed.) Cleavage of Carbon–Carbon Single Bonds by Transition Metals (Wiley-VCH, 2015).
Chen, P.-h, Billett, B., Tsukamoto, T. & Dong, G. “Cut and sew” transformations via transition-metal-catalyzed carbon–carbon bond activation. ACS Catal. 7, 1340–1360 (2017).
Nairoukh, Z., Cormier, M. & Marek, I. Merging C–H and C–C bond cleavage in organic synthesis. Nat. Rev. Chem. 1, 0035 (2017).
Kim, D.-S., Park, W.-J. & Jun, C.-H. Metal–organic cooperative catalysis in C–H and C–C bond activation. Chem. Rev. 117, 8977–9015 (2017).
Song, F., Gou, T., Wang, B.-Q. & Shi, Z.-J. Catalytic activations of unstrained C–C bond involving organometallic intermediates. Chem. Soc. Rev. 47, 7078–97115 (2018).
Deng, L. & Dong, G. Carbon–carbon bond activation of ketones. Trends Chem. 2, 183–198 (2020).
Rusina, A. & Vlček, A. A. Formation of Rh(i)-carbonyl complex by the reaction with some non-alcoholic, oxygen-containing solvents. Nature 206, 295–296 (1965).
Rubin, M., Rubina, M. & Gevorgyan, V. Transition metal chemistry of cyclopropenes and cyclopropanes. Chem. Rev. 107, 3117–3179 (2007).
Jiao, L. & Yu, Z.-X. Vinylcyclopropane derivatives in transition-metal-catalyzed cycloadditions for the synthesis of carbocyclic compounds. J. Org. Chem. 78, 6842–6848 (2013).
Seiser, T., Saget, T., Tran, D. N. & Cramer, N. Cyclobutanes in catalysis. Angew. Chem. Int. Ed. 50, 7740–7752 (2011).
Chen, P.-h. & Dong, G. Cyclobutenones and benzocyclobutenones: versatile synthons in organic synthesis. Chem. Eur. J. 22, 18290–18315 (2016).
Mack, D. J. & Njardarson, J. T. Recent advances in the metal-catalyzed ring expansions of three- and four-membered rings. ACS Catal. 3, 272–286 (2013).
Fumagalli, G., Stanton, S. & Bower, J. F. Recent methodologies that exploit C–C single-bond cleavage of strained ring systems by transition metal complexes. Chem. Rev. 117, 9404–9432 (2017).
Suggs, J. W. & Cox, S. D. Directed cleavage of sp 2–sp carbon–carbon bonds. J. Organomet. Chem. 221, 199–201 (1981). This paper demonstrates the first use of DGs in C–C bond activation.
Suggs, J. W. & Jun, C. H. Directed cleavage of carbon–carbon bonds by transition metals: the α-bonds of ketones. J. Am. Chem. Soc. 106, 3054–3056 (1984).
Miura, M. & Satoh, T. Catalytic processes involving β-carbon elimination. Top. Organomet. Chem. 14, 1–20 (2005).
Rousseau, G. & Breit, B. Removable directing groups in organic synthesis and catalysis. Angew. Chem. Int. Ed. 50, 2450–2494 (2011).
Bhattacharya, T., Pimparkar, S. & Maiti, D. Combining transition metals and transient directing groups for C–H functionalizations. RSC Adv. 8, 19456–19464 (2018).
Gandeepan, P. & Ackermann, L. Transient directing groups for transformative C–H activation by synergistic metal catalysis. Chem 4, 199–222 (2018).
Rej, S. & Chatani, N. Rhodium-catalyzed C(sp2)- or C(sp3)–H bond functionalization assisted by removable directing groups. Angew. Chem. Int. Ed. 58, 8304–8329 (2019).
Jun, C.-H. & Lee, H. Catalytic carbon–carbon bond activation of unstrained ketone by soluble transition-metal complex. J. Am. Chem. Soc. 121, 880–881 (1999). This paper describes the first use of temporary DGs in the activation of unstrained C–C bonds.
Willis, M. C. Transition metal catalyzed alkene and alkyne hydroacylation. Chem. Rev. 110, 725–748 (2010).
Suggs, J. W. Activation of aldehyde carbon–hydrogen bonds to oxidative addition via formation of 3-methyl-2-aminopyridyl aldimines and related compounds: rhodium based catalytic hydroacylation. J. Am. Chem. Soc. 101, 489 (1979).
Jun, C.-H., Lee, D.-Y., Lee, H. & Hong, J.-B. A highly active catalyst system for intermolecular hydroacylation. Angew. Chem. Int. Ed. 39, 3070–3072 (2000).
Ahn, J.-A. et al. Solvent-free chelation-assisted catalytic C–C bond cleavage of unstrained ketone by rhodium(i) complexes under microwave irradiation. Adv. Synth. Catal. 348, 55–58 (2006).
Jun, C.-H., Lee, D.-Y., Kim, Y.-H. & Lee, H. Catalytic carbon–carbon bond activation of sec-alcohols by a rhodium(i) complex. Organometallics 20, 2928–2931 (2001).
Wang, D. & Astruc, D. The golden age of transfer hydrogenation. Chem. Rev. 115, 6621–6686 (2015).
Jun, C.-H., Chung, K.-Y. & Hong, J.-B. C–H and C–C bond activation of primary amines through dehydrogenation and transimination. Org. Lett. 3, 785–787 (2001).
Murakami, M., Amii, H. & Ito, Y. Selective activation of carbon–carbon bonds next to a carbonyl group. Nature 370, 540–541 (1994).
Xia, Y., Lu, G., Liu, P. & Dong, G. Catalytic activation of carbon–carbon bonds in cyclopentanones. Nature 539, 546–550 (2016). This paper demonstrates the first use of temporary DGs in the activation of C–C bonds in cyclopentanones and cyclohexanones.
Chavan, S. P. & Khatod, H. S. Enantioselective synthesis of the essential oil and pheromonal component ar-himachalene by a chiral pool and chirality induction approach. Tetrahedron Asymmetry 23, 1410–1415 (2012).
Davies, H. M. L. & Walji, A. M. Direct synthesis of (+)-erogorgiaene through a kinetic enantiodifferentiating step. Angew. Chem. Int. Ed. 44, 1733–1735 (2005).
Elford, T. G., Nave, S., Sonawane, R. P. & Aggarwal, V. K. Total synthesis of (+)-erogorgiaene using lithiation–borylation methodology, and stereoselective synthesis of each of its diastereoisomers. J. Am. Chem. Soc. 133, 16798–16801 (2011).
Mukherjee, P. & Sarkar, T. K. Heteroatom-directed Wacker oxidations. A protection-free synthesis of (−)-heliophenanthrone. Org. Biomol. Chem. 10, 3060–3065 (2012).
Hayashi, T. & Yamasaki, K. Rhodium-catalyzed asymmetric 1,4-addition and its related asymmetric reactions. Chem. Rev. 103, 2829–2844 (2003).
Hou, S.-H., Prichina, A. Y., Zhang, M. & Dong, G. Asymmetric total syntheses of di- and sesquiterpenoids by catalytic C–C activation of cyclopentanones. Angew. Chem. Int. Ed. 59, 7848–7856 (2020).
Ochi, S., Xia, Y. & Dong, G. Asymmetric synthesis of 1-tetralones bearing a remote quaternary stereocenter through Rh-catalyzed C–C activation of cyclopentanones. Bull. Chem. Soc. Jpn. https://doi.org/10.1246/bcsj.20200147 (2020).
Xia, Y., Wang, J. & Dong, G. Distal-bond-selective C–C activation of ring-fused cyclopentanones: an efficient access to spiroindanones. Angew. Chem. Int. Ed. 56, 2376–2380 (2017).
de Meijere, A., Bräse, S. & Oestreich, M. (eds) Metal-Catalyzed Cross-Coupling Reactions and More (Wiley-VCH, 2014).
Matsuda, T., Makino, M. & Murakami, M. Rhodium-catalyzed addition/ring-opening reaction of arylboronic acids with cyclobutanones. Org. Lett. 6, 1257–1259 (2004).
Wang, J. et al. Direct exchange of a ketone methyl or aryl group to another aryl group through C–C bond activation assisted by rhodium chelation. Angew. Chem. Int. Ed. 51, 12334–12338 (2012).
Dennis, J. M., Compagner, C. T., Dorn, S. K. & Johnson, J. B. Rhodium-catalyzed interconversion of quinolinyl ketones with boronic acids via C–C bond activation. Org. Lett. 18, 3334–3337 (2016).
Xia, Y., Wang, J. & Dong, G. Suzuki–Miyaura coupling of simple ketones via activation of unstrained carbon–carbon bonds. J. Am. Chem. Soc. 140, 5347–5351 (2018). This work shows that aryl–carbonyl bonds in aromatic ketones can be activated via the temporary DG strategy.
Bergin, E. Cross-coupling ketones. Nat. Catal. 1, 309 (2018).
Just-Baringo, X. & Larrosa, I. Ketone C–C bond activation meets the Suzuki–Miyaura cross-coupling. Chem 4, 1203–1204 (2018).
Pérez-Rodríguez, M. et al. C–C reductive elimination in palladium complexes, and the role of coupling additives. A DFT study supported by experiment. J. Am. Chem. Soc. 131, 3650–3657 (2009).
Kakiuchi, F., Kan, S., Igi, K., Chatani, N. & Murai, S. A ruthenium-catalyzed reaction of aromatic ketones with arylboronates: a new method for the arylation of aromatic compounds via C–H bond cleavage. J. Am. Chem. Soc. 125, 1698–1699 (2003).
Dreis, A. M. & Douglas, C. J. Catalytic carbon–carbon σ bond activation: an intramolecular carbo-acylation reaction with acylquinolines. J. Am. Chem. Soc. 131, 412–413 (2009).
Wentzel, M. T., Reddy, V. J., Hyster, T. K. & Douglas, C. J. Chemoselectivity in catalytic C–C and C–H bond activation: controlling intermolecular carboacylation and hydroarylation of alkenes. Angew. Chem. Int. Ed. 48, 6121–6123 (2009).
Rong, Z.-Q., Lim, H. N. & Dong, G. Intramolecular acetyl transfer to olefins via catalytic C–C bond activation of unstrained ketones. Angew. Chem. Int. Ed. 57, 475–479 (2018).
Xia, Y., Ochi, S. & Dong, G. Two-carbon ring expansion of 1-indanones via insertion of ethylene into carbon–carbon bonds. J. Am. Chem. Soc. 141, 13038–13042 (2019).
Boussard, M.-F. et al. Preparation and pharmacological profile of 2-trifluoromethyl-benzo(8,9)-1,3-diaza-spiro(4,6)-undeca-2,8-diene and its enantiomers as new anti-obesity agents. Arzneimittelforsch. 50, 1084–1092 (2000).
Gingrich, D. E. et al. Discovery of an orally efficacious inhibitor of anaplastic lymphoma kinase. J. Med. Chem. 55, 4580–4593 (2012).
Gawaskar, S. et al. Design, synthesis, pharmacological evaluation and docking studies of GluN2B-selective NMDA receptor antagonists with a benzoannulen-7-amine scaffold. ChemMedChem 12, 1212–1222 (2017).
Jun, C.-H., Lee, H. & Lim, S.-G. The C–C bond activation and skeletal rearrangement of cycloalkanone imine by Rh(i) catalysts. J. Am. Chem. Soc. 123, 751–752 (2001).
Jun, C.-H., Lee, H., Park, J.-B. & Lee, D.-Y. Catalytic activation of C–H and C–C bonds of allylamines via olefin isomerization by transition metal complexes. Org. Lett. 1, 2161–2164 (1999).
Lee, D.-Y., Kim, I.-J. & Jun, C.-H. Synthesis of cycloalkanones from dienes and allylamines through C–H and C–C bond activation catalyzed by a rhodium(i) complex. Angew. Chem. Int. Ed. 41, 3011–3033 (2002).
Lewis, L. N. Reexamination of the deuteration of phenol catalyzed by an orthometalated ruthenium complex. Inorg. Chem. 24, 4433–4435 (1985). This is a seminal work on phenol ortho-C–H activation using a temporary DG.
Lewis, L. N. & Smith, J. F. Catalytic carbon–carbon bond formation via ortho-metalated complexes. J. Am. Chem. Soc. 108, 2728–2735 (1986).
Bedford, R. B., Coles, S. J., Hursthouse, M. B. & Limmert, M. E. The catalytic intermolecular orthoarylation of phenols. Angew. Chem. Int. Ed. 42, 112–114 (2003).
Gozin, M., Weisman, A., Ben-David, Y. & Milstein, D. Activation of a carbon–carbon bond in solution by transition-metal insertion. Nature 364, 699–701 (1993). A description of the first activation of non-polar, unstrained C–C bonds with homogeneous catalysis.
Zhu, J., Wang, J. & Dong, G. Catalytic activation of unstrained C(aryl)–C(aryl) bonds in 2,2′-biphenols. Nat. Chem. 11, 45–51 (2019).
Ruhland, K., Obenhuber, A. & Hoffmann, S. D. Cleavage of unstrained C(sp2)–C(sp2) single bonds with Ni0 complexes using chelating assistance. Organometallics 27, 3482–3495 (2008).
Obenhuber, A. & Ruhland, K. Activation of an unstrained C(sp2)–C(sp2) single bond using chelate-bisphosphinite rhodium(i) complexes. Organometallics 30, 4039–4051 (2011).
Grein, F. Twist angles and rotational energy barriers of biphenyl and substituted biphenyls. J. Phys. Chem. A 106, 3823–3827 (2002).
Zhu, J., Chen, P.-h., Lu, G., Liu, P. & Dong, G. Ruthenium-catalyzed reductive cleavage of unstrained aryl–aryl bonds: reaction development and mechanistic study. J. Am. Chem. Soc. 141, 18630–18640 (2019).
Li, H. et al. Pyridinyl directed alkenylation with olefins via Rh(iii)-catalyzed C–C bond cleavage of secondary arylmethanols. J. Am. Chem. Soc. 133, 15244–15247 (2011).
Lei, Z.-Q. et al. Extrusion of CO from aryl ketones: Rhodium(i)-catalyzed C–C bond cleavage directed by a pyridine group. Angew. Chem. Int. Ed. 51, 2690–2694 (2012).
Chen, K. et al. Reductive cleavage of the Csp2–Csp3 bond of secondary benzyl alcohols: rhodium catalysis directed by N-containing groups. Angew. Chem. Int. Ed. 51, 9851–9855 (2012).
Lei, Z.-Q. et al. Group exchange between ketones and carboxylic acids through directing group assisted Rh-catalyzed reorganization of carbon skeletons. J. Am. Chem. Soc. 137, 5012–5020 (2015).
Ozkal, E., Cacherat, B. & Morandi, B. Cobalt(iii)-catalyzed functionalization of unstrained carbon–carbon bonds through β-carbon cleavage of alcohols. ACS Catal. 5, 6458–6462 (2015).
Dermenci, A., Coe, J. W. & Dong, G. Direct activation of relatively unstrained carbon–carbon bonds in homogeneous systems. Org. Chem. Front. 1, 567–581 (2014).
Morioka, T., Nishizawa, A., Furukawa, T., Tobisu, M. & Chatani, N. Nickel-mediated decarbonylation of simple unstrained ketones through the cleavage of carbon–carbon bonds. J. Am. Chem. Soc. 139, 1416–1419 (2017).
Zhao, T.-T., Xu, W.-H., Zheng, Z.-J., Xu, P.-F. & Wei, H. Directed decarbonylation of unstrained aryl ketones via nickel-catalyzed C–C bond cleavage. J. Am. Chem. Soc. 140, 586–589 (2018).
Ackermann, L. & Lygin, A. V. Ruthenium-catalyzed direct C–H bond arylations of heteroarenes. Org. Lett. 13, 3332–3335 (2011).
Jiang, C., Zheng, Z.-J., Yu, T.-Y. & Wei, H. Suzuki–Miyaura coupling of unstrained ketones via chelation-assisted C–C bond cleavage. Org. Biomol. Chem. 16, 7174–7177 (2018).
Jiang, C. et al. Rhodium-catalyzed Hiyama coupling reaction of unstrained ketones via C–C bond cleavage. Asian J. Org. Chem. 8, 1358–1362 (2019).
Zhong, J. et al. Rhodium-catalyzed pyridine N-oxide assisted Suzuki–Miyaura coupling reaction via C(O)–C bond activation. Org. Lett. 21, 9790–9794 (2019).
Long, Y. et al. Rhodium-catalyzed transarylation of benzamides: C–C bond vs C–N bond activation. ACS Catal. 10, 3398–3403 (2020).
Li, G., Ji, C.-L., Hong, X. & Szostak, M. Highly chemoselective, transition-metal-free transamidation of unactivated amides and direct amidation of alkyl esters by N–C/O–C cleavage. J. Am. Chem. Soc. 141, 11161–11172 (2019).
Onodera, S., Ishikawa, S., Kochi, T. & Kakiuchi, F. Direct alkenylation of allylbenzenes via chelation-assisted C–C bond cleavage. J. Am. Chem. Soc. 140, 9788–9792 (2018). The authors demonstrate here that unstrained, non-polar C–C bonds can be activated via β-carbon elimination via a removable DG.
Onodera, S., Togashi, R., Ishikawa, S., Kochi, T. & Kakiuchi, F. Catalytic, directed C–C bond functionalization of styrenes. J. Am. Chem. Soc. 142, 7345–7349 (2020).
Wang, H., Choi, I., Rogge, T., Kaplaneris, N. & Ackermann, L. Versatile and robust C–C activation by chelation-assisted manganese catalysis. Nat. Catal. 1, 993–1001 (2018).
King, R. B. & Efraty, A. Pentamethylcyclopentadienyl derivatives of transition metals. II. Synthesis of pentamethylcyclopentadienyl metal carbonyls from 5-acetyl-1,2,3,4,5-pentamethylcyclopentadiene. J. Am. Chem. Soc. 94, 3773–3779 (1972).
Crabtree, R. H., Dion, R. P., Gibboni, D. J., Mcgrath, D. V. & Holt, E. M. Carbon–carbon bond cleavage in hydrocarbons by iridium complexes. J. Am. Chem. Soc. 108, 7222–7227 (1986).
Halcrow, M. A., Urbanos, F. & Chaudret, B. Aromatization of the B-ring of 5,7-dienyl steroids by the electrophilic ruthenium fragment “[Cp*Ru]+”. Organometallics 12, 955–957 (1993).
Youn, S. W., Kim, B. S. & Jagdale, A. R. Pd-catalyzed sequential C–C bond formation and cleavage: evidence for an unexpected generation of arylpalladium(ii) species. J. Am. Chem. Soc. 134, 11308–11311 (2012).
Smits, G., Audic, B., Wodrich, M. D., Corminboeuf, C. & Cramer, N. A β-carbon elimination strategy for convenient in situ access to cyclopentadienyl metal complexes. Chem. Sci. 8, 7174–7179 (2017).
Xu, Y. et al. Deacylative transformations of ketones via aromatization-promoted C–C bond activation. Nature 567, 373–378 (2019). This paper demonstrates how aromatization can be used as a driving force to achieve catalytic activation of C–C bonds in diverse, unstrained ketones.
Padwa, A. & Pearson, W. H. (eds) Synthetic Applications of 1,3-Dipolar Cycloaddition Chemistry Toward Heterocycles and Natural Products (Wiley, 2002).
Tian, M., Shi, X., Zhang, X. & Fan, X. Synthesis of 4-acylpyrazoles from saturated ketones and hydrazones featured with multiple C(sp3)–H bond functionalization and C–C bond cleavage and reorganization. J. Org. Chem. 82, 7363–7372 (2017).
Candeias, N. R., Paterna, R. & Gois, P. M. P. Homologation reaction of ketones with diazo compounds. Chem. Rev. 116, 2937–2981 (2016).
Karrouchi, K. et al. Synthesis and pharmacological activities of pyrazole derivatives: a review. Molecules 23, 134 (2018).
Pérez-Gómez, M. et al. Tandem remote Csp3–H activation/Csp3–Csp3 cleavage in unstrained aliphatic chains assisted by palladium(ii). Organometallics 38, 973–980 (2019).
Xia, Y., Qiu, D. & Wang, J. Transition-metal-catalyzed cross-couplings through carbene migratory insertion. Chem. Rev. 117, 13810–13889 (2017).
Tran, V. T., Gurak, J. A. Jr, Yang, K. S. & Engle, K. M. Activation of diverse carbon–heteroatom and carbon–carbon bonds via palladium(ii)-catalysed β-X elimination. Nat. Chem. 10, 1126–1133 (2018).
The authors thank NIGMS (2R01GM109054) for the generous support of their C–C activation projects. Y.X. acknowledges start-up funding from Sichuan University.
The authors declare no competing interests.
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Xia, Y., Dong, G. Temporary or removable directing groups enable activation of unstrained C–C bonds. Nat Rev Chem (2020). https://doi.org/10.1038/s41570-020-0218-8