An air- and moisture-stable ruthenium precatalyst for diverse reactivity

nature chemistry Article https://doi.org/10.1038/s41557-024-01481-5 An air- and moisture-stable ruthenium precatalyst for diverse reactivity Received: 2 June 2023 Accepted: 20 February 2024 Gillian McArthur 1, Jamie H. Docherty 1,2, Mishra Deepak Hareram Marco Simonetti1,3, Iñigo J. Vitorica-Yrezabal1, James J. Douglas 1,4 & Igor Larrosa 1 , 1 Published online: xx xx xxxx Check for updates Versatile, efficient and robust (pre)catalysts are pivotal in accelerating the discovery and optimization of chemical reactions, shaping diverse synthetic fields such as cross-coupling, C–H functionalization and polymer chemistry. Yet, their scarcity in certain domains has hindered the advancement and adoption of new applications. Here we present a highly reactive air- and moisture-stable ruthenium precatalyst [(tBuCN)5Ru(H2O)] (BF4)2, featuring a key exchangeable water ligand. This versatile precatalyst drives an array of transformations, including late-stage C(sp2)–H arylation, primary/secondary alkylation, methylation, hydrogen/deuterium exchange, C(sp3)–H oxidation, alkene isomerization and oxidative cleavage, consistently outperforming conventionally used ruthenium (pre)catalysts. The generality and applicability of this precatalyst is exemplified through the potential for rapid screening and optimization of photocatalytic reactions with a suite of in situ generated ruthenium photocatalysts containing hitherto unknown complexes, and through the rapid discovery of reactivities previously unreported for ruthenium. The diverse applicability observed is suggestive of a generic platform for reaction simplification and accelerated synthetic discovery that will enable broader applicability and accessibility to state-of-the-art ruthenium catalysis. Synthetic chemistry has experienced substantial progress through the development of innovative catalysts, capable of modifying both simple and complex molecules with high efficiency and selectivity1,2. One crucial aspect of these advances has been the advent of robust catalysts that can be easily used and that operate under mild conditions, broadening their utility and applicability3,4. For example, the versatility of complexes such as palladium acetate or bis(cyclooctadiene) nickel(0), and their ability to form in situ new complexes, have been pivotal in shaping the development of palladium5,6 and nickel catalysis, respectively7,8. Ruthenium catalysts have exhibited powerful versatility for a broad selection of applications9. For example, a variety of synthetically powerful C–H functionalization reactions has been demonstrated using ruthenium catalysis10,11. However, despite their widespread utility, many of the developed protocols have necessitated either high reaction temperatures (80–140 °C) or light irradiation, which has limited overall ease of use and their suitability for the diversification of delicate high-complexity substrates and biomolecules12. This is a common occurrence when widely applied η6-arene coordinated ruthenium species such as [(p-cymene)RuCl2]2 1 (ref. 13) and benzene analogue 2 are used, as they typically require additional energy to access active catalyst species (Fig. 1a). In 2018, we reported the development of a monocyclometallated ruthenium catalyst, [(C6H4CH2NMe2)Ru(MeCN)4]PF6 4, that showed high activity at moderate temperatures (35–50 °C) for the C(sp2)–H arylation of arenes12. This precatalyst allowed for the direct late-stage C(sp2)–H arylation and alkylation of a wide array of pharmaceuticals Department of Chemistry, University of Manchester, Manchester, UK. 2Department of Chemistry, Lancaster University, Lancaster, UK. 3bp, Low Carbon Innovation Centre, Saltend Chemicals Park, Hull, UK. 4Early Chemical Development, Pharmaceutical Sciences, R&D, AstraZeneca, Macclesfield, UK. e-mail: 1 Nature Chemistry Article https://doi.org/10.1038/s41557-024-01481-5 a This work: RuAqua Cl Cl Ru Cl Ru Cl Cl Ru Cl Cl 1 Ru tBuCN Cl t BuCN NCtBu NCtBu Ru NCtBu OH2 2 [(p-cymene)RuCl2]2 (BF4)2 Me 3 NCMe N Ru NCMe PF6 NCMe NCMe 4 [(tBuCN)5Ru(H2O)](BF4)2 [(C6H6)RuCl2]2 b 5 ‘Pre-activated’ mono-cyclometallated complexes c Time: 0h 4h 24 h 72 h RuAqua 3 1. Zn, tBuCN, 115 °C, 2 h RuCl3 ·xH2O PF6 Me NCMe N NCMe Ru NCMe NCMe Ligand exchange rate constants k 298(CH3CN) = 8.9 × 10–11 s–1 k 298(H2O) = 1.8 × 10–2 s–1 Cyclometallated complexes 2. AgBF4 (2.5 equiv.) H2O, r.t., 1 h (77 mmol scale) RuAqua 3 26.3 g, 49% 4 5 d F t BuCN tBuCN NCtBu NCtBu Ru NCtBu OH2 (BF4)2 [(tBuCN)5Ru(H2O)](BF4)2 3 F + F Before N After F K2CO3 (5.0 equiv.) C6D6, NMP (19:1), 40 °C, 4 h 6 (10.0 equiv.) F N Ru F N NCtBu NCtBu 7 (80%) Fig. 1 | Design and synthesis of an air- and moisture-stable ruthenium(II) precatalyst. a, Selection of ruthenium(II) precatalysts typically used for application, discovery and synthetic method development within C–H functionalization chemistry. Broadly available air-stable precatalysts such as 1 and 2 exhibit poor levels of reactivity under mild reaction conditions and have high barriers that must be overcome to form active catalysts. Preactivated complexes such as 4 and 5 are highly reactive and operate under mild conditions but are extremely air sensitive. The air-stable complex [(tBuCN)5Ru(H2O)] (BF4)2 (3) provides an alternative that has broad reactivity without the need for harsh reaction conditions. b, Left: synthesis of complex 3 by zinc reduction of ruthenium(III) trichloride and chloride-to-tetrafluoroborate metathesis. Right: X-ray crystal structure of 3 with 50% probability thermal ellipsoids; BF4 counterions are omitted for clarity. Color coding: lilac, Ru; red, O; blue, N; grey, C. Ligand exchange rate constants for [Ru(H2O)6]2+ and [Ru(NCMe)6]2+ are given in ref. 15. c, Air-stability test of solid complex 3, 4 and 5 over 72 h. d, NMR study of stoichiometric arene C(sp2)–H bond activation under mild reaction conditions using 3 to give biscyclometallated species 7—a key species required for reactivity with halide nucleophiles. Yield was determined by 19F NMR using 1,4-difluorobenzene as an internal standard. r.t., room temperature. and other biologically relevant molecules. Despite its powerful reactivity, the considerable air sensitivity of 4 has limited its synthetic applicability, requiring specialized storage and handling techniques that have prevented general adoption in most synthetic laboratories and within industrial settings. Key to any broadly applicable synthetic innovation is the use of operationally simple reagents and precatalysts that enable use by both the specialist and non-expert scientist. Considering these limitations, the development of air-stable precatalysts with similar transformative power as air-sensitive complexes such as 4 is critical for increasing the accessibility and use of ruthenium catalysis. Therefore, we questioned the feasibility of designing a synthetically accessible precatalyst that would (...truncated)