Catalytic reactions occur readily at the sites of starting materials that are both innately reactive and sterically accessible, or that are predisposed by a functional group amenable to direct a catalyst. However, selective reactions at unbiased sites of substrates remain challenging and typically require additional preactivation steps or the use of highly reactive reagents. Here we report dual-catalytic transition metal systems that merge a reversible activation cycle with a functionalization cycle, which together enable the functionalization of substrates at their inherently unreactive sites. By engaging the Ru- or Fe-catalysed equilibrium between an alcohol and an aldehyde, methods for Pd-catalysed β-arylation of aliphatic alcohols and Rh-catalysed γ-hydroarylation of allylic alcohols were developed. The mild conditions, functional group tolerance and broad scope (81 examples) demonstrate the synthetic applicability of the dual-catalytic systems. This work highlights the potential of the multicatalytic approach to address challenging transformations to circumvent multistep procedures and the use of highly reactive reagents in organic synthesis.
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The crystallographic data for compound 7a have been deposited at the Cambridge Crystallographic Data Centre (CCDC) as CCDC 1821986 and can be obtained free of charge from the CCDC via www.ccdc.cam.ac.uk/getstructures. All the other data are available from the authors upon reasonable request.
Hartwig, J. F. Organotransition Metal Chemistry: from Bonding to Catalysis (University Science Books, Sausalito, 2010).
Hartwig, J. F. & Larsen, M. A. Undirected, homogeneous C–H bond functionalization: challenges and opportunities. ACS Cent. Sci. 2, 281–292 (2016).
Sambiagio, C. et al. A comprehensive overview of directing groups applied in metal-catalysed C–H functionalisation chemistry. Chem. Soc. Rev. 47, 6603–6743 (2018).
Cernak, T., Dykstra, K. D., Tyagarajan, S., Vachal, P. & Krska, S. W. The medicinal chemist’s toolbox for late stage functionalization of drug-like molecules. Chem. Soc. Rev. 45, 546–576 (2016).
Blakemore, D. C. et al. Organic synthesis provides opportunities to transform drug discovery. Nat. Chem. 10, 383–394 (2018).
Gandeepan, P. & Ackermann, L. Transient directing groups for transformative C–H activation by synergistic metal catalysis. Chem 4, 199–222 (2018).
Zhang, F.-L., Hong, K., Li, T.-J., Park, H. & Yu, J.-Q. Functionalization of C(sp 3)–H bonds using a transient directing group. Science 351, 252–256 (2016).
Park, H., Verma, P., Hong, K. & Yu, J.-Q. Controlling Pd(iv) reductive elimination pathways enables Pd(ii)-catalysed enantioselective C(sp 3)−H fluorination. Nat. Chem. 10, 755–762 (2018).
Corma, A., Navas, J. & Sabater, M. J. Advances in one-pot synthesis through borrowing hydrogen catalysis. Chem. Rev. 118, 1410–1459 (2018).
Watson, A. J. A. & Williams, J. M. J. The give and take of alcohol activation. Science 329, 635–636 (2010).
Wang, D. & Astruc, D. The golden age of transfer hydrogenation. Chem. Rev. 115, 6621–6686 (2015).
Hill, C. K. & Hartwig, J. F. Site-selective oxidation, amination and epimerization reactions of complex polyols enabled by transfer hydrogenation. Nat. Chem. 9, 1213–1221 (2017).
Guillena, G., Ramón, D. J. & Yus, M. Hydrogen autotransfer in the N-alkylation of amines and related compounds using alcohols and amines as electrophiles. Chem. Rev. 110, 1611–1641 (2010).
Bähn, S. et al. The catalytic amination of alcohols. ChemCatChem 3, 1853–1864 (2011).
Yang, Q., Wang, Q. & Yu, Z. Substitution of alcohols by N-nucleophiles via transition metal-catalyzed dehydrogenation. Chem. Soc. Rev. 44, 2305–2329 (2015).
Obora, Y. Recent advances in α-alkylation reactions using alcohols with hydrogen borrowing methodologies. ACS Catal. 4, 3972–3981 (2014).
Gunanathan, C. & Milstein, D. Applications of acceptorless dehydrogenation and related transformations in chemical synthesis. Science 341, 1229712 (2013).
Bender, M., Turnbull, B. W. H., Ambler, B. R. & Krische, M. J. Ruthenium-catalyzed insertion of adjacent diol carbon atoms into C–C bonds: entry to type II polyketides. Science 357, 779–781 (2017).
Nguyen, K. D. et al. Metal-catalyzed reductive coupling of olefin-derived nucleophiles: reinventing carbonyl addition. Science 354, aah5133 (2016).
Black, P. J., Harris, W. & Williams, J. M. J. Catalytic electronic activation: indirect addition of nucleophiles to an allylic alcohol. Angew. Chem. Int. Ed. 40, 4475 (2001).
Quintard, A., Constantieux, T. & Rodriguez, J. An iron/amine-catalyzed cascade process for the enantioselective functionalization of allylic alcohols. Angew. Chem. Int. Ed. 52, 12883–12887 (2013).
Roudier, M., Constantieux, T., Quintard, A. & Rodriguez, J. Triple iron/copper/iminium activation for the efficient redox neutral catalytic enantioselective functionalization of allylic alcohols. ACS Catal. 6, 5236–5244 (2016).
Goldman, A. S., Roy, A. H., Huang, Z., Schinski, W. & Brookhart, M. Catalytic alkane metathesis by tandem alkane dehydrogenation–olefin metathesis. Science 312, 257–261 (2006).
Haibach, M. C., Kundu, S., Brookhart, M. & Goldman, A. S. Alkane metathesis by tandem alkane-dehydrogenation–olefin-metathesis catalysis and related chemistry. Acc. Chem. Res. 45, 947–958 (2012).
Mo, F., Tabor, J. R. & Dong, G. Alcohols or masked alcohols as directing groups for C–H bond functionalization. Chem. Lett. 43, 264–271 (2014).
Bellina, F. & Rossi, R. Transition metal-catalyzed direct arylation of substrates with activated sp 3-hybridized C−H bonds and some of their synthetic equivalents with aryl halides and pseudohalides. Chem. Rev. 110, 1082–1146 (2010).
Smith, A. M. R. & Hii, K. K. Transition metal catalyzed enantioselective α-heterofunctionalization of carbonyl compounds. Chem. Rev. 111, 1637–1656 (2011).
Pirnot, M. T., Rankic, D. A., Martin, D. B. C. & MacMillan, D. W. C. Photoredox activation for the direct β-arylation of ketones and aldehydes. Science 339, 1593–1596 (2013).
Terrett, J. A., Clift, M. D. & MacMillan, D. W. C. Direct β-alkylation of aldehydes via photoredox organocatalysis. J. Am. Chem. Soc. 136, 6858–6861 (2014).
Zhang, X. & MacMillan, D. W. C. Direct aldehyde C–H arylation and alkylation via the combination of nickel, hydrogen atom transfer, and photoredox catalysis. J. Am. Chem. Soc. 139, 11353–11356 (2017).
Hazari, N., Melvin, P. R. & Beromi, M. M. Well-defined nickel and palladium precatalysts for cross-coupling. Nat. Rev. Chem. 1, 0025 (2017).
Simmons, E. M. & Hartwig, J. F. On the interpretation of deuterium kinetic isotope effects in C–H bond functionalizations by transition-metal complexes. Angew. Chem. Int. Ed. 51, 3066–3072 (2012).
Samec, J. S. M., Bäckvall, J.-E., Andersson, P. G. & Brandt, P. Mechanistic aspects of transition metal-catalyzed hydrogen transfer reactions. Chem. Soc. Rev. 35, 237 (2006).
Alcazar-Roman, L. M. & Hartwig, J. F. Mechanistic studies on oxidative addition of aryl halides and triflates to Pd(BINAP)2 and structural characterization of the product from aryl triflate addition in the presence of amine. Organometallics. 21, 491–502 (2002).
Hartwig, J. F. Electronic effects on reductive elimination to form carbon–carbon and carbon–heteroatom bonds from palladium(ii) complexes. Inorg. Chem. 46, 1936–1947 (2007).
Werner, E. W., Mei, T.-S., Burckle, A. J. & Sigman, M. S. Enantioselective Heck arylations of acyclic alkenyl alcohols using a redox-relay strategy. Science 338, 1455–1458 (2012).
Mei, T.-S., Patel, H. H. & Sigman, M. S. Enantioselective construction of remote quaternary stereocentres. Nature 508, 340–344 (2014).
Tian, P., Dong, H.-Q. & Lin, G.-Q. Rhodium-catalyzed asymmetric arylation. ACS Catal. 2, 95–119 (2012).
Hayashi, T. & Yamasaki, K. Rhodium-catalyzed asymmetric 1,4-addition and its related asymmetric reactions. Chem. Rev. 103, 2829–2844 (2003).
Bauer, I. & Knölker, H.-J. Iron catalysis in organic synthesis. Chem. Rev. 115, 3170–3387 (2015).
Bullock, R. M. An iron catalyst for ketone hydrogenations under mild conditions. Angew. Chem. Int. Ed. 46, 7360–7363 (2007).
Knölker, H.-J., Baum, E., Goesmann, H. & Klauss, R. Demetalation of tricarbonyl(cyclopentadienone)iron complexes initiated by a ligand exchange reaction with NaOH—X-ray analysis of a complex with nearly square-planar coordinated sodium. Angew. Chem. Int. Ed. 38, 2064–2066 (1999).
This work was financially supported by the University of Strasbourg, the French National Research Agency (‘Investments for the future’ programme of the IdEx Unistra framework), FRC & LabEx Chemistry of Complex Systems, the Polish National Science Centre (Etiuda fellowship no. 2016/20/T/ST5/00494 to D.L.), the European Union (Marie Curie Actions, PCOFUND-GA-2013-609102) through the Campus France (Prestige fellowship no. PRESTIGE-2017-4-0022 to D.L.), the Polish Ministry of Science and Higher Education (Mobilnosc Plus fellowship no. 1672/l/MOB/V/l 7/2018/0 to K.H.) and the Foundation for Polish Science (Start fellowship no. START-036.2018 to K.H.). We thank L. Karmazin for the crystallographic measurements, E. Richmond for help with the initial high-performance liquid chromatography analysis and W. Dzik for helpful discussions.
The authors declare no competing interests.
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Lichosyt, D., Zhang, Y., Hurej, K. et al. Dual-catalytic transition metal systems for functionalization of unreactive sites of molecules. Nat Catal 2, 114–122 (2019). https://doi.org/10.1038/s41929-018-0207-1