Cyclopropanes are important substructures in natural products and pharmaceuticals. Although traditional methods for their incorporation rely on cyclopropanation of an existing scaffold, the advent of transition-metal catalysis has enabled installation of functionalized cyclopropanes using cross-coupling reactions. The unique bonding and structural properties of cyclopropane render it more easily functionalized in transition-metal-catalysed cross-couplings than other C(sp3) substrates. The cyclopropane coupling partner can participate in polar cross-coupling reactions either as a nucleophile (organometallic reagents) or as an electrophile (cyclopropyl halides). More recently, single-electron transformations featuring cyclopropyl radicals have emerged. This Review will provide an overview of transition-metal-catalysed C–C bond formation reactions at cyclopropane, covering both traditional and current strategies, and the benefits and limitations of each.
This is a preview of subscription content, access via your institution
Access Nature and 54 other Nature Portfolio journals
Get Nature+, our best-value online-access subscription
$29.99 / 30 days
cancel any time
Subscribe to this journal
Receive 12 digital issues and online access to articles
$119.00 per year
only $9.92 per issue
Rent or buy this article
Prices vary by article type
Prices may be subject to local taxes which are calculated during checkout
Dill, J. D., Greenberg, A. & Liebman, J. F. Substituent effects on strain energies. J. Am. Chem. Soc. 101, 6814–6826 (1979).
De Meijere, A. Bonding properties of cyclopropane and their chemical consequences. Angew. Chem. Int. Ed. 18, 809–886 (1979). This useful report details many properties and reactivity trends of cyclopropanes.
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).
Fan, Y.-Y., Gao, X.-H. & Yue, J.-M. Attractive natural products with strained cyclopropane and/or cyclobutane ring systems. Sci. China Chem. 59, 1126–1141 (2016).
Ma, S., Mandalapu, D., Wang, S. & Zhang, Q. Biosynthesis of cyclopropane in natural products. Nat. Prod. Rep. 39, 926–945 (2022).
Talele, T. T. The ‘cyclopropyl fragment’ is a versatile player that frequently appears in preclinical/clinical drug molecules. J. Med. Chem. 59, 8712–8756 (2016). This Perspective outlines contemporary pharmaceuticals and pharmaceutical candidates that contain a cyclopropane, as well as the contributions of a cyclopropyl ring to the properties of these drugs.
Časar, Z. Synthetic approaches to contemporary drugs that contain the cyclopropyl moiety. Synthesis 52, 1315–1345 (2020).
Ebner, C. & Carreira, E. M. Cyclopropanation strategies in recent total syntheses. Chem. Rev. 117, 11651–11679 (2017).
Sansinenea, E. & Ortiz, A. The chemistry of cyclopropanes and new insights into organocatalyzed asymmetric cyclopropanation. Eur. J. Org. Chem. 2022, e202200210 (2022).
Bartoli, G., Bencivenni, G. & Dalpozzo, R. Asymmetric cyclopropanation reactions. Synthesis 46, 979–1029 (2014).
Wenbing, J., Hua, Y. & Gongli, T. Strategies for construction of cyclopropanes in natural products. China J. Org. Chem. 38, 2324–2334 (2018).
Wu, W., Lin, Z. & Jiang, H. Recent advances in the synthesis of cyclopropanes. Org. Biomol. Chem. 16, 7315–7329 (2018).
Jana, R., Pathak, T. P. & Sigman, M. S. Advances in transition metal (Pd, Ni, Fe)-catalyzed cross-coupling reactions using alkyl-organometallics as reaction partners. Chem. Rev. 111, 1417–1492 (2011).
De Meijere, A. & Diederich, F. Metal-Catalyzed Cross-Coupling Reactions 2nd edn, Vol. 1 (Wiley-VCH, 2004).
De Meijere, A. & Diederich, F. Metal-Catalyzed Cross-Coupling Reactions 2nd edn, Vol. 2 (Wiley-VCH, 2004).
Rubin, M., Rubina, M. & Gevorgyan, V. Transition metal chemistry of cyclopropenes and cyclopropanes. Chem. Rev. 107, 3117–3179 (2007). This comprehensive review contains a thorough overview of early cross-coupling reactions at cyclopropane up to 2007 (that is, Suzuki, Kumada, Negishi, Stille and C–H activation).
Dian, L. & Marek, I. Asymmetric preparation of polysubstituted cyclopropanes based on direct functionalization of achiral three-membered carbocycles. Chem. Rev. 118, 8415–8434 (2018).
Blanksby, S. J. & Ellison, G. B. Bond dissociation energies of organic molecules. Acc. Chem. Res. 36, 255–263 (2003).
Pirenne, V., Muriel, B. & Waser, J. Catalytic enantioselective ring-opening reactions of cyclopropanes. Chem. Rev. 121, 227–263 (2021).
Wang, L. J. & Tang, Y. Asymmetric ring-opening reactions of donor–acceptor cyclopropanes and cyclobutanes. Isr. J. Chem. 56, 463–475 (2016).
Quan, L. G., Lee, H. G. & Cha, J. K. Acid- and Pd(0)-catalyzed ring opening of 1-(1-cycloalkenyl)cyclopropyl sulfonates. Org. Lett. 9, 4439–4442 (2007).
Sarel, B. S., Yovell, J. & Sarel-Imber, M. Recent developments in the stereochemistry of cyclopropane ring opening. Angew. Chem. Int. Ed. 7, 577–588 (1968).
DePuy, C. H. The chemistry of cyclopropanols. Acc. Chem. Res. 1, 33–41 (1968).
Schleyer, P. V. R., Su, T. M., Saunder, M. & Rosenfield, J. C. The stereochemistry of allyl cations from the isomeric 2,3-dimethylcyclopropyl chlorides. The stereomutation of allyl cations. J. Am. Chem. Soc. 91, 5174–5176 (1969).
Marek, I., Masarwa, A., Delaye, P.-O. & Leibeling, M. Selective carbon–carbon cleavage for the stereoselective synthesis of acyclic systems. Angew. Chem. Int. Ed. 54, 414–429 (2015).
Miyaura, N. in Metal-Catalyzed Cross-Coupling Reactions (eds de Meijere, A. & Diederich, F.) 41–124 (Wiley-VCH, 2004).
Wang, X.-Z. & Deng, M.-Z. Cross-coupling reaction of cyclopropylboronic acid with bromoarenes. J. Chem. Soc. Perkin Trans. 1, 2663–2664 (1996).
Ma, H.-R., Wang, X.-H. & Deng, M.-Z. Palladium-catalyzed cross-coupling reaction of stereodefined cyclopropylboronic acids with N-heterocycle bromides. Synth. Commun. 29, 2477–2485 (1999).
Yao, M.-L. & Deng, M.-Z. A practical approach to stereodefined cyclopropyl-substituted heteroarenes using a Suzuki-type reaction. N. J. Chem. 24, 425–428 (2000).
Yao, M.-L. & Deng, M.-Z. Palladium-catalyzed cross-coupling reaction of cyclopropylboronic acids with aryl triflates. Synthesis 8, 1095–1100 (2000).
Zhou, A.-M., Deng, M.-Z., Xia, L.-J. & Tang, M.-H. Efficient Suzuki-type cross-coupling of enantiomerically pure cyclopropylboronic acids. Angew. Chem. Int. Ed. 37, 2845–2847 (1998).
Rubina, M., Rubin, M. & Gevorgyan, V. Catalytic enantioselective hydroboration of cyclopropenes. J. Am. Chem. Soc. 125, 7198–7199 (2003).
Wallace, D. J. & Chen, C.-Y. Cyclopropylboronic acid: synthesis and Suzuki cross-coupling reactions. Tetrahedron Lett. 43, 6987–6990 (2002).
Lemhadri, M., Doucet, H. & Santelli, M. Suzuki coupling of cyclopropylboronic acid with aryl halides catalyzed by a palladium–tetraphosphine complex. Synth. Commun. 36, 121–128 (2006).
Zhang, W. et al. Facile synthesis of aryl(het)cyclopropane catalyzed by palladacycle. Tetrahedron 68, 900–905 (2012).
Zhou, S.-M., Yan, Y.-L. & Deng, M.-Z. A novel stereocontrolled synthesis of cyclopropyl-substituted α, β-unsaturated esters: palladium catalyzed cross-coupling of cyclopropylboronic acids with bromoacrylates. Synlett 2, 198–200 (1998).
Yao, M.-L. & Deng, M.-Z. Facile approach to 4-substituted 2(5H)-furanones. J. Org. Chem. 65, 5034–5036 (2000).
Yao, M.-L. & Deng, M.-Z. Palladium-catalyzed cross-coupling of cyclopropylboronic acids with alkenyl triflates. Tetrahedron Lett. 41, 9083–9087 (2000).
Chen, H. & Deng, M.-Z. A novel stereocontrolled synthesis of 1,2-trans cyclopropyl ketones via Suzuki-type coupling of acid chlorides with cyclopropylboronic acids. Org. Lett. 2, 1649–1651 (2000).
Chen, H. & Deng, M.-Z. Silver oxide mediated palladium-catalyzed cross-coupling reaction of cyclopropylboronic acids with allylic bromides. J. Org. Chem. 65, 4444–4446 (2000).
Lennox, A. J. J. & Lloyd-Jones, G. C. Selection of boron reagents for Suzuki–Miyaura coupling. Chem. Soc. Rev. 43, 412–443 (2014).
Hildebrand, J. P. & Marsden, S. P. A novel, stereocontrolled synthesis of 1,2-trans-cyclopropanes: cyclopropyl boronate esters as partners in Suzuki couplings with aryl halides. Synlett 9, 893–894 (1996). This is the first report of Suzuki coupling at a cyclopropane.
Chen, H. & Deng, M.-Z. A novel Suzuki-type cross-coupling reaction of cyclopropylboronic esters with benzyl bromides. J. Chem. Soc. Perkin Trans. 1, 1609–1613 (2000).
Charette, A. B. & De Freitas-Gil, R. Synthesis of contiguous cyclopropanes by palladium-catalyzed Suzuki-type cross-coupling reactions. Tetrahedron Lett. 38, 2809–2812 (1997).
Peitruszka, J., Witt, A. & Frey, W. Synthesis of ‘Garner’ aldehyde-derived cyclopropylboronic esters. Eur. J. Org. Chem. 2003, 3219–3229 (2003).
Löhr, S. & de Meijere, A. 2-(Bicyclopropylidenyl)- and 2-(trans−2’-cyclopropylcyclopropyl)−4,4,5,5-tetramethyl-1,3-dioxa-2-borolane and their palladium-catalyzed cross-coupling reactions. Synlett 4, 489–492 (2001).
Zimmer, L. E. & Charette, A. B. Enantioselective synthesis of 1,2,3-trisubstituted cyclopropanes using gem-dizinc reagents. J. Am. Chem. Soc. 131, 15624–15626 (2009).
Duncton, M. A. J. & Singh, R. Synthesis of trans−2-(trifluoromethyl)cyclopropanes via Suzuki reactions with an N-methyliminodiacetic acid boronate. Org. Lett. 15, 4284–4287 (2013).
Spencer, J. A., Jamieson, C. & Talbot, E. P. A. One-pot, three-step synthesis of cyclopropylboronic acid pinacol esters from synthetically tractable propargylic silyl ethers. Org. Lett. 19, 3891–3894 (2017).
Miyamura, S., Araki, M., Suzuki, T., Yamaguchi, J. & Itami, K. Stereodivergent synthesis of arylcyclopropylamines by sequential C–H borylation and Suzuki–Miyaura coupling. Angew. Chem. Int. Ed. 127, 860–865 (2015). This report details a unique stereodivergent Suzuki coupling to access 2-arylcyclopropylamines, in which the stereochemical outcome is determined by the presence of either an O2 or N2 atmosphere.
Speckmeier, E. & Maier, T. C. ART — an amino radical transfer strategy for C(sp2)–C(sp3) coupling reactions, enabled by dual photo/nickel catalysis. J. Am. Chem. Soc. 144, 9997–10005 (2022).
Soderquist, J. A., Huertas, R. & Leon-Colon, G. Aryl and vinyl cyclopropanes through the in situ generation of B-cyclopropyl-9-BBN and its Suzuki–Miyaura coupling. Tetrahedron Lett. 41, 4251–4255 (2000).
Fürstner, A. & Leitner, A. General and user-friendly method for Suzuki reactions with aryl chlorides. Synlett 2, 290–292 (2001).
Fang, G.-H., Yan, Z.-J. & Deng, M.-Z. Palladium-catalyzed cross-coupling of stereospecific potassium cyclopropyl trifluoroborates with aryl bromides. Org. Lett. 6, 357–360 (2004).
Hohn, E., Pietruszka, J. & Solduga, G. Synthesis of enantiomerically pure cyclopropyl trifluoroborates. Synlett 10, 1531–1534 (2006).
Charette, A. B., Mattieu, S. & Fournier, J.-F. Diastereoselective synthesis of 1,2,3-substituted potassium cyclopropyl trifluoroborates via an unusual zinc–boron exchange. Synlett 11, 1779–1782 (2005).
Molander, G. A. & Gorminsky, P. E. Cross-coupling of cyclopropyl- and cyclobutyltrifluoroborates with aryl and heteroaryl chlorides. J. Org. Chem. 73, 7481–7485 (2008).
Colombel, V., Rombouts, F., Oehlrich, D. & Molander, G. A. Suzuki coupling of potassium cyclopropyl- and alkoxymethyltrifluoroborates with benzyl chlorides. J. Org. Chem. 77, 2966–2970 (2012).
Primer, D. N. & Molander, G. A. Enabling the cross-coupling of tertiary organoboron nucleophiles through radical-mediated alkyl transfer. J. Am. Chem. Soc. 139, 9847–9850 (2017).
Charette, A. B. & Giroux, A. Palladium-catalyzed Suzuki-type cross-couplings of iodocyclopropanes with boronic acids: synthesis of transe-1,2-dicyclopropyl alkenes. J. Org. Chem. 61, 8718–8719 (1996).
Martin, S. F. & Dwyer, M. P. Iodocyclopropanes as versatile intermediates for the synthesis of substituted cyclopropanes. Tetrahedron Lett. 39, 1521–1524 (1998).
Maity, P. et al. Development of a scaleable synthesis of BMS-978587 featuring a stereospecific Suzuki coupling of a cyclopropane carboxylic acid. Org. Process. Res. Dev. 22, 888–897 (2018). This report details the Suzuki coupling of an iodocyclopropane as a key step for the large-scale synthesis of BMS-978587, an IDO inhibitor.
Li, Z., Jiang, Y.-Y. & Fu, Y. Theoretical study on the mechanism of Ni-catalyzed alkyl-alkyl suzuki cross-coupling. Chem. Eur. J. 18, 4345–4357 (2012).
Yotsuji, K. et al. Nickel-catalyzed Suzuki–Miyaura coupling of a tertiary iodocyclopropane with wide boronic acid substrate scope: coupling reaction outcome depends on radical species stability. Adv. Synth. Catal. 357, 1022–1028 (2015).
Yu, C. C., Ng, D. K. P., Chen, B.-L. & Luh, T.-Y. Nickel-catalyzed cross coupling of cyclopropyl grignard reagents with benzylic dithioacetals. Organometallics 13, 1487–1497 (1993).
Eberhart, A. J., Imbriglio, J. E. & Procter, D. J. Nucleophilic ortho allylation of aryl and heteroaryl sulfoxides. Org. Lett. 13, 5882–5885 (2011).
Zhang, Y., Chen, Y., Zhang, Z., Liu, S. & Shen, X. Synthesis of stereodefined trisubstituted alkenyl silanes enabled by borane catalysis and nickel catalysis. Org. Lett. 22, 970–975 (2020).
Ackermann, L., Kapdi, A. R. & Schulzke, C. Air-stable secondary phosphine oxide or chloride (pre)ligands for cross-couplings of unactivated alkyl chlorides. Org. Lett. 12, 2298–2301 (2010).
Malhotra, S., Seng, P. S., Koenig, S. G., Deese, A. J. & Ford, K. A. Chemoselective sp2-sp3 cross-couplings: iron-catalyzed alkyl transfer to dihaloaromatics. Org. Lett. 15, 3698–3701 (2013).
Greiner, R., Blanc, R., Petermayer, C., Karaghiosoff, K. & Knochel, P. Preparation of functionalized 2,7-naphthyridines by directed lithiation with (2,2,6,6-tetramethylpiperidyl)lithium and their regioselective iron-catalyzed cross couplings. Synlett 27, 231–236 (2015).
Bellan, A. B., Kuzmina, O. M., Vetsova, V. A. & Knochel, P. Chromium-catalyzed cross-coupling reactions of alkylmagnesium reagents with halo-quinolines and activated aryl chlorides. Synthesis 49, 188–194 (2017).
Andersen, C. et al. Introduction of cyclopropyl and cyclobutyl ring on alkyl iodides through cobalt-catalyzed cross-coupling. Org. Lett. 21, 2285–2289 (2019). This paper shows a robust method for C(sp3)–C(sp3) cross-coupling of cyclopropyl magnesium bromides.
Petruncio, G., Elahi-Mohassel, S., Girgis, M. & Paige, M. Copper-catalyzed sp3–sp3 cross-coupling of turbo grignards with benzyl halides. Tetrahedron Lett. 86, 153516 (2021).
Piers, E., Jean, M. & Marrs, P. S. Synthesis of vinylcyclopropanes via palladium-catalyzed coupling of cyclopropylzinc halides with vinyl iodides. Total syntheses of (±)-prezizanol and (±)-prezizaene. Tetrahedron Lett. 28, 5075–5078 (1987).
de Lang, R.-J. & Brandsma, L. The nickel and palladium catalysed stereoselective cross coupling of cyclopropyl nucleophiles with aryl halides. Synth. Commun. 28, 225–232 (2006).
Campbell, J. B., Firor, J. W. & Davenport, T. V. Facile palladium-catalyzed cross-coupling of monoorganozinc halides with 3-iodoanthranilonitriles. Synth. Commun. 19, 2265–2272 (1989).
Han, C. & Buchwald, S. L. Negishi coupling of secondary alkylzinc halides with aryl bromides and chlorides. J. Am. Chem. Soc. 131, 7532–7533 (2009).
Coleridge, B. M., Bello, C. S. & Leitner, A. General and user-friendly protocol for the synthesis of functionalized aryl- and heteroaryl-cyclopropanes by Negishi cross-coupling reactions. Tetrahedron Lett. 50, 4475–4477 (2009).
Shu, C. et al. Palladium-catalyzed cross-coupling of cyclopropylmagnesium bromide with aryl bromides mediated by zinc halide additives. J. Org. Chem. 75, 6677–6680 (2010).
Yang, Y., Niedermann, K., Han, C. & Buchwald, S. L. Highly selective palladium-catalyzed cross-coupling of secondary alkylzinc reagents with heteroaryl halides. Org. Lett. 16, 4638–4641 (2014).
Chawner, S. J., Cases-Thomas, M. J. & Bull, J. A. Divergent synthesis of cyclopropane-containing lead-like compounds, fragments and building blocks through a cobalt catalyzed cyclopropanation of phenyl vinyl sulfide. Eur. J. Org. Chem. 34, 5015–5024 (2017).
Greszler, S. N., Halvorsen, G. T. & Voight, E. A. Synthesis of substituted cyclopropanecarboxylates via room temperature palladium-catalyzed α-arylation of Reformatsky reagents. Org. Lett. 19, 2490–2493 (2017).
Keaveney, S. T., Kundu, G. & Schoenebeck, F. Modular functionalization of arenes in a triply selective sequence: rapid C(sp2) and C(sp3) coupling of C−Br, C−OTf, and C−Cl bonds enabled by a single palladium(I) dimer. Angew. Chem. Int. Ed. 57, 12573–12577 (2018).
Lutter, F. H. et al. Cobalt‐catalyzed cross‐coupling of functionalized alkylzinc reagents with (hetero)aryl halides. Angew. Chem. Int. Ed. 59, 5546–5550 (2020).
Yasui, M., Ota, R., Tsukano, C. & Takemoto, Y. Synthesis of all-cis-substituted cyclopropanes through stereocontrolled metalation and Pd-catalyzed Negishi coupling. Org. Lett. 20, 7656–7660 (2018).
Mendel, M., Gnägi, L., Dabranskaya, U. & Schoenebeck, F. Rapid and modular access to vinyl cyclopropanes enabled by air-stable palladium(I) dimer catalysis. Angew. Chem. Int. Ed. 62, e202211167 (2022).
An, L., Tong, F.-F., Zhang, S. & Zhang, X. Stereoselective functionalization of racemic cyclopropylzinc reagents via enantiodivergent relay coupling. J. Am. Chem. Soc. 142, 11884–11892 (2020). This report features sequential enantioselective and stereospecific cross-couplings at cyclopropane.
Peters, D., Hornfeldt, A.-B. & Gronowitz, S. Synthesis of 5-cyclopropyluracil and 5-cyclopropylcytosine by the Pd(0)-cat coupling reaction. J. Heterocycl. Chem. 26, 1629–1631 (1991).
Schmitz, W. D. & Romo, D. A new route to 2-substituted thiazolines stille cross couplings of 2-bromothiazolines. Tetrahedron Lett. 37, 4857–4860 (1996).
Heureux, N. et al. Preparation and applications of a novel bis(tributylstannyl)cyclopropane: a synthetic equivalent of a cyclopropane-1,2-dianion. Tetrahedron Lett. 46, 79–83 (2005).
Caló, F. P. & Fürstner, A. A heteroleptic dirhodium catalyst for asymmetric cyclopropanation with α-stannyl α-diazoacetate. ‘Stereoretentive’ Stille coupling with formation of chiral quarternary carbon centers. Angew. Chem. Int. Ed. 59, 13900–13907 (2020).
Gagnon, A., Duplessis, M., Alsabeh, P. & Barabé, F. Palladium-catalyzed cross-coupling reaction of tricyclopropylbismuth with aryl halides and triflates. J. Org. Chem. 73, 3604–3607 (2008).
Pérez, I., Sestelo, J. P. & Sarandeses, L. A. Palladium-catalyzed cross-coupling reactions of triorganoindium compounds with vinyl and aryl triflates or iodides. Org. Lett. 1, 1267–1269 (1999).
Pérez, I., Sestelo, J. P. & Sarandeses, L. A. Atom-efficient metal-catalyzed cross-coupling reaction of indium organometallics with organic electrophiles. J. Am. Chem. Soc. 123, 4155–4160 (2001).
Yang, S., Jiang, W.-T. & Xiao, B. Tertiary cyclopropyl carbagermatranes: synthesis and cross-coupling. Chem. Commun. 57, 8143–8146 (2021).
Beaulieu, L.-P. B., Delvos, L. B. & Charette, A. B. Dual role of silanol groups in cyclopropanation and Hiyama–Denmark cross-coupling reactions. Org. Lett. 12, 1348–1351 (2010). This is the only example of cross-coupling of a cyclopropyl silane.
Shintani, R., Fujie, R., Takeda, M. & Nozaki, K. Silylative cyclopropanation of allyl phosphates with silylboronates. Angew. Chem. Int. Ed. 53, 6546–6549 (2014).
Lee, T. & Hartwig, J. F. Rhodium‐catalyzed enantioselective silylation of cyclopropyl C−H bonds. Angew. Chem. Int. Ed. 55, 8723–8727 (2016).
Su, Y., Li, Q.-F., Zhao, Y.-M. & Gu, P. Preparation of optically active cis-cyclopropane carboxylates: cyclopropanation of α-silyl stryenes with aryldiazoacetates and desilylation of the resulting silyl cyclopropanes. Org. Lett. 18, 4356–4359 (2016).
Zhang, L. & Oestreich, M. Copper‐catalyzed enantio‐ and diastereoselective addition of silicon nucleophiles to 3,3‐disubstituted cyclopropenes. Chem. Eur. J. 25, 14304–14307 (2019).
Dian, L. & Marek, I. Cobalt-catalyzed diastereoselective and enantioselective hydrosilylation of achiral cyclopropenes. Org. Lett. 22, 4914–4918 (2020).
Dalziel, M. E., Chen, P., Carrera, D. E., Zhang, H. & Gosselin, F. Highly diastereoselective α-arylation of cyclic nitriles. Org. Lett. 19, 3446–3449 (2017).
McCabe Dunn, J. M., Kuethe, J. T., Orr, R. K., Tudge, M. & Campeau, L. C. Development of a palladium-catalyzed α-arylation of cyclopropyl nitriles. Org. Lett. 16, 6314–6317 (2014).
Wright, B. A. & Ardolino, M. J. Surprising reactivity in NiXantphos/palladium-catalyzed α-arylation of substituted cyclopropyl nitriles. J. Org. Chem. 84, 4670–4679 (2019).
He, Z. T. & Hartwig, J. F. Palladium-catalyzed α-arylation for the addition of small rings to aromatic compounds. Nat. Commun. 10, 4083 (2019).
Roman, D. S. & Charette, A. B. C–H functionalization of cyclopropanes: a practical approach employing a picolinamide auxiliary. Org. Lett. 15, 4394–4397 (2013).
Hoshiya, N., Kobayashi, T., Arisawa, M. & Shuto, S. Palladium-catalyzed arylation of cyclopropanes via directing group-mediated C(sp3)–H bond activation to construct quaternary carbon centers: synthesis of cis- and trans-1,1,2-trisubstituted chiral cyclopropanes. Org. Lett. 15, 6202–6205 (2013).
Hoshiya, N. et al. Entry to chiral 1,1,2,3-tetrasubstituted arylcyclopropanes by Pd(II)-catalyzed arylation via directing group-mediated C(sp3)-H activation. J. Org. Chem. 82, 2535–2544 (2017).
Hoshiya, N., Takenaka, K., Shuto, S. & Uenishi, J. Pd(II)-catalyzed alkylation of tertiary carbon via directing-group-mediated C(sp3)-H activation: synthesis of chiral 1,1,2-trialkyl substituted cyclopropanes. Org. Lett. 18, 48–51 (2016).
Wasa, M., Engle, K. M., Lin, D. W., Yoo, E. J. & Yu, J. Pd(II)-catalyzed enantioselective C–H activation of cyclopropanes. J. Am. Chem. Soc. 133, 19598–19601 (2011). This is the first example of enantioselective catalytic cyclopropyl C–H activation.
Jerhaoui, S., Poutrel, P., Djukic, J. P., Wencel-Delord, J. & Colobert, F. Stereospecific C-H activation as a key step for the asymmetric synthesis of various biologically active cyclopropanes. Org. Chem. Front. 5, 409–414 (2018).
Jerhaoui, S., Djukic, J. P., Wencel-Delord, J. & Colobert, F. Asymmetric, nearly barrierless C(sp3)-H activation promoted by easily-accessible N-protected aminosulfoxides as new chiral ligands. ACS Catal. 9, 2532–2542 (2019).
Shen, P. X., Hu, L., Shao, Q., Hong, K. & Yu, J. Q. Pd(II)-catalyzed enantioselective C(sp3)-H arylation of free carboxylic acids. J. Am. Chem. Soc. 140, 6545–6549 (2018).
Zhuang, Z. & Yu, J. Q. Pd(II)-catalyzed enantioselective γ-C(sp3)-H functionalizations of free cyclopropylmethylamines. J. Am. Chem. Soc. 142, 12015–12019 (2020).
Chan, K. S. L., Fu, H. Y. & Yu, J. Q. Palladium(II)-catalyzed highly enantioselective C-H arylation of cyclopropylmethylamines. J. Am. Chem. Soc. 137, 2042–2046 (2015).
Rodrigalvarez, J., Reeve, L. A., Miró, J. & Gaunt, M. J. Pd(II)-catalyzed enantioselective C(sp3)-H arylation of cyclopropanes and cyclobutanes guided by tertiary alkylamines. J. Am. Chem. Soc. 144, 3939–3948 (2022).
Rousseaux, S., Liégault, B. & Fagnou, K. Palladium(0)-catalyzed cyclopropane C–H bond functionalization: synthesis of quinoline and tetrahydroquinoline derivatives. Chem. Sci. 3, 244–248 (2012).
Ladd, C. L., Sustac Roman, D. & Charette, A. B. Palladium-catalyzed ring-opening of cyclopropyl benzamides: synthesis of benzo[c]azepine-1-ones via C(sp3)-H functionalization. Tetrahedron 69, 4479–4487 (2013).
Ladd, C. L., Sustac Roman, D. & Charette, A. B. Silver-promoted, palladium-catalyzed direct arylation of cyclopropanes: facile access to spiro 3,3′-cyclopropyl oxindoles. Org. Lett. 15, 1350–1353 (2013).
Saget, T., Perez, D. & Cramer, N. Synthesis of functionalized spiroindolines via palladium-catalyzed methine C-H arylation. Org. Lett. 15, 1354–1357 (2013).
Tsukano, C., Masataka, O. & Takemoto, Y. Synthesis of spirooxindoles from carbamoyl chlorides via cyclopropyl methine C(sp3)–H activation using palladium catalyst. Chem. Lett. 42, 735–755 (2013).
Ladd, C. L. & Charette, A. B. Access to cyclopropyl-fused azacycles via a palladium-catalyzed direct alkenylation strategy. Org. Lett. 18, 6046–6049 (2016).
Mayer, C., Ladd, C. L. & Charette, A. B. Utilization of BozPhos as an effective ligand in enantioselective C–H functionalization of cyclopropanes: synthesis of dihydroisoquinolones and dihydroquinolones. Org. Lett. 21, 2639–2644 (2019).
Pedroni, J., Saget, T., Donets, P. A. & Cramer, N. Enantioselective palladium(0)-catalyzed intramolecular cyclopropane functionalization: access to dihydroquinolones, dihydroisoquinolones and the BMS-791325 ring system. Chem. Sci. 6, 5164–5171 (2015).
Saget, T. & Cramer, N. Palladium(0)-catalyzed enantioselective C–H arylation of cyclopropanes: efficient access to functionalized tetrahydroquinolines. Angew. Chem. Int. Ed. 51, 12842–12845 (2012).
Wu, X., Lei, C., Yue, G. & Zhou, J. Palladium-catalyzed direct cyclopropylation of heterocycles. Angew. Chem. Int. Ed. 54, 9601–9605 (2015).
Wiest, J. M., Pöthig, A. & Bach, T. Pyrrole as a directing group: regioselective Pd(II)-catalyzed alkylation and benzylation at the benzene core of 2-phenylpyrroles. Org. Lett. 18, 852–855 (2016).
Liskey, C. W. & Hartwig, J. F. Iridium-catalyzed C-H borylation of cyclopropanes. J. Am. Chem. Soc. 135, 3375–3378 (2013).
Shi, Y., Gao, Q. & Xu, S. Chiral bidentate boryl ligand enabled iridium-catalyzed enantioselective C(sp3)-H borylation of cyclopropanes. J. Am. Chem. Soc. 141, 10599–10604 (2019).
Giri, R., Chen, X. & Yu, J. Palladium‐catalyzed asymmetric iodination of unactivated C–H bonds under mild conditions. Angew. Chem. Int. Ed. 44, 2112–2115 (2005).
Yi, L., Ji, T., Chen, K.-Q., Chen, X.-Y. & Rueping, M. Nickel-catalyzed reductive cross-couplings: new opportunities for carbon–carbon bond formations through photochemistry and electrochemistry. CCS Chem. 4, 9–30 (2022).
Walborsky, H. M. The cyclopropyl radical. Tetrahedron 37, 1625–1651 (1981).
Mills, L. R., Monteith, J. J., Gomes, G., Aspuru-Guzik, A. & Rousseaux, S. A. L. The cyclopropane ring as a reporter of radical leaving-group reactivity for Ni-catalyzed C(sp3)–O arylation. J. Am. Chem. Soc. 142, 13246–13254 (2020). The cyclopropane ring can act as a useful indicator of the reactivity of different redox-active leaving groups, as seen in this Ni-catalysed arylation of cyclopropanols.
Chan, A. Y. et al. Metallaphotoredox: the merger of photoredox and transition metal catalysis. Chem. Rev. 122, 1485–1542 (2022).
Zhang, P., Le, C. & MacMillan, D. W. C. Silyl radical activation of alkyl halides in metallaphotoredox catalysis: a unique pathway for cross-electrophile coupling. J. Am. Chem. Soc. 138, 8084–8087 (2016).
Smith, R. T. et al. Metallaphotoredox-catalyzed cross-electrophile Csp3–Csp3 coupling of aliphatic bromides. J. Am. Chem. Soc. 140, 17433–17438 (2018). This paper contains an example of C(sp3)–C(sp3) coupling at cyclopropane via metallaphotoredox catalysis.
Behnke, N. E., Sales, Z. S., Li, M. & Herrmann, A. T. Dual photoredox/nickel-promoted alkylation of heteroaryl halides with redox-active esters. J. Org. Chem. 86, 12945–12955 (2021).
Dong, Z. & MacMillan, D. W. C. Metallaphotoredox-enabled deoxygenative arylation of alcohols. Nature 598, 451–456 (2021).
Intermaddio, N. E., Millet, A., Davis, D. L. & MacMillan, D. W. C. Deoxytrifluoromethylation of alcohols. J. Am. Chem. Soc. 144, 11961–11968 (2022).
Cornella, J. et al. Practical Ni-catalyzed aryl–alkyl cross-coupling of secondary redox-active esters. J. Am. Chem. Soc. 138, 2174–2177 (2016).
Chen, T.-G. et al. Quaternary centers by nickel-catalyzed cross-coupling of tertiary carboxylic acids and (hetero)aryl zinc reagents. Angew. Chem. Int. Ed. 58, 2454–2458 (2019).
Qin, T. et al. Nickel-catalyzed Barton decarboxylation and Giese reactions: a practical take on classic transformations. Angew. Chem. Int. Ed. 56, 260–265 (2017).
Qin, T. et al. A general alkyl–alkyl cross-coupling enabled by redox-active esters and alkyl zinc reagents. Science 352, 801–805 (2016).
Everson, D. A. & Weix, D. J. Cross-electrophile coupling: principles of reactivity and selectivity. J. Org. Chem. 79, 4793–4798 (2014).
Liu, J.-H. et al. Copper-catalyzed reductive cross-coupling of nonactivated alkyl tosylates and mesylated with alkyl and aryl bromides. Chem. Eur. J. 20, 15334–15338 (2014).
Moragas, T. & Martin, R. Nickel-catalyzed reductive carboxylation of cyclopropyl motifs with carbon dioxide. Synthesis 48, 2816–2822 (2016).
Liao, J. et al. Deaminative reductive cross-electrophile couplings of alkylpyridinium salts and aryl bromides. Org. Lett. 21, 2941–2946 (2019).
Murarka, S. N-(acyloxy)phthalimides as redox-active esters in cross-coupling reactions. Adv. Synth. Catal. 360, 1735–1753 (2018).
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.
Kang, K. & Weix, D. J. Nickel-catalyzed C(sp3)–C(sp3) cross-electrophile coupling of in situ generated NHP esters with unactivated alkyl bromides. Org. Lett. 24, 2853–2857 (2022).
Salgeuiro, D. C., Chi, B. K., Guzei, I. A., García-Reynaga, P. & Weix, D. J. Control of redox-active ester reactivity enables a general cross-electrophile approach to access arylated strained rings. Angew. Chem. Int. Ed. 61, e202205673 (2022). An example of reductive coupling applied to synthesize a library of useful 1,1-diaryl cyclopropanes from cyclopropane NHP esters.
West, M. S., Gabbey, A. L., Huestis, M. P. & Rousseaux, S. A. L. Ni-catalyzed reductive cross-coupling of cyclopropylamines and other strained ring NHP esters with (hetero)aryl halides. Org. Lett. 24, 8441–8446 (2022). This report details a reductive coupling developed specifically for the synthesis of 1-arylcyclopropylamines from cyclopropylamine NHP esters.
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).
Li, H. et al. Ni-catalyzed electrochemical decarboxylative C–C couplings in batch and continuous flow. Org. Lett. 20, 1338–1341 (2018).
Truesdell, B. L., Hamby, T. B. & Sevov, C. S. General C(sp2)–C(sp3) cross-electrophile coupling enables by overcharge protection of homogenous electrocatalysts. J. Am. Chem. Soc. 142, 5884–5893 (2020).
Hamby, T. B., LaLama, M. J. & Sevov, C. S. Controlling Ni redox states by dynamic ligand exchange for electroreductive Csp2–Csp3 coupling. Science 376, 410–416 (2022). A recent electrochemical method that includes examples of cross-coupling at a cyclopropyl bromide.
Cyclopropyl cations. in Cyclopropane Derived Reactive Intermediates (1990) 117–173 (John Wiley & Sons, Ltd, 1990).
The authors declare no competing interests.
Peer review information
Nature Reviews Chemistry thanks the anonymous reviewers for their contribution to the peer review of this work.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
Cite this article
Gabbey, A.L., Scotchburn, K. & Rousseaux, S.A.L. Metal-catalysed C–C bond formation at cyclopropanes. Nat Rev Chem 7, 548–560 (2023). https://doi.org/10.1038/s41570-023-00499-6