Time for a round-up of this week’s #Reactionoftheday. On offer this time we have a novel nickel catalyst with advantages over traditional metal complexes in cross-coupling reactions, a method for the synthesis of 3-fluoropyridines from ring-opened Zincke intermediates, a method for synthesis of 1,3-disubstituted anilines and a synthesis of pyrrolidines by ring-contraction of pyridines.
A bench-stable fluorophosphine nickel(0) complex and its catalytic applications
Hanf et al, Angew. Chem. Int. Ed. 2025, e202506271
https://doi.org/10.1002/anie.202506271
Nickel offers several advantages as a catalyst, including its accessible oxidation states (0 to +III), its ability to facilitate single-electron processes, and its greater tendency toward oxidative addition compared to palladium. These properties have enabled the activation of challenging substrates, such as alkyl chlorides. However, a major drawback is the air sensitivity of Ni(0) species, which are commonly used as pre-catalysts in nickel-catalysed transformations.
The Hanf group has reported the first synthesis of a fluorophosphine-stabilized Ni(0) complex that is both air- and moisture-stable. This complex serves as a competent precatalyst and, when combined with ancillary ligands such as dppf, is active in a variety of coupling reactions. Unlike the COD ligand in traditional nickel systems—which can readily dissociate and poison the catalyst—the fluorophosphine ligand can be selectively decomposed in situ using UV light, thereby preventing site blockage on the metal centre. Ongoing efforts are focused on further tailoring the ligand framework to optimise performance.
- Trends in the usage of bidentate phosphines as ligands in nickel catalysis: J. Louie et al, Chem. Rev. 2020, 120, 6124-6196
- Latest developments in palladium and nickel-catalysed cross-couplings for aryl chlorides: Suzuki-Miyaura and Buchwald-Hartwig reactions: Y. Yamada et al, Synthesis 2024, 56, 3555-3574
- Nickel and palladium catalysis: stronger demand than ever: V. Ananikov et al, ACS Catal. 2022, 12, 1180-1200
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3-Selective pyridine fluorination via Zincke imine intermediates
A. McNally et al, J. Am. Chem. Soc. 2025
https://doi.org/10.1021/jacs.5c03091
Selective fluorination at the C-3 position of pyridine rings remains a synthetic challenge, with existing methods typically requiring pre-functionalized substrates. While direct C–H fluorination is an appealing approach, it is rarely reported. A recent study by the McNally group at Colorado State University introduces a novel method involving the fluorination of Zincke imines, followed by ring closure to access 3-fluoropyridines.
Regioselective fluorination of the imine intermediates is achieved using Selectfluor, and a one-pot procedure enhances the practicality of the transformation. The reaction proceeds under mild conditions, exhibits good functional group tolerance, and allows for the isolation of Zincke amine intermediates. However, the subsequent cyclization to form 3-fluoropyridines generally gives only modest yields.
Ongoing work aims to explore regioisomeric control, specifically targeting selective C–F bond formation at the pyridine C-5 position.
- Beyond the Zincke reaction: modern advancements in the synthesis and applications of N-aryl pyridinium salts: S. Wengryniuk et al, Tetrahedron 2024, 162, 134119
- Halogenation of the 3-position of pyridines through Zincke imine intermediates: McNally et al, Science 2022, 378, 773-779
- A formal meta- C-H -fluorination of pyridines and isoquinolines through dearomatized oxazinopyridine intermediates: A. Studer et al, J. Am. Chem. Soc. 2024, 146, 30758−30763
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Synthesis of 3,5-disubstituted anilines via sequential Mo-catalysed deoxygenative benzene formation and pd-catalysed amination reactions
X. Zhou et al, Synthesis 2025, 57, 1922-1927
https://doi.org/10.1055/a-2504-3357
An interesting paper by Zhou et al., describes the synthesis of meta, meta-disubstituted anilines. This work builds on their earlier 2023 work describing the molybdenum-catalysed synthesis of unsymmetric and unfunctionalized 1,3-di- and 1,3,5-trisubstituted halobenzenes. By combining this approach with Pd-catalysed C–N cross-coupling, they efficiently generate a range of 3,5-disubstituted aryl amines from ynones, allylic amines, and amines.
- Modular access to meta-substituted benzenes via Mo-catalyzed intermolecular deoxygenative benzene formation: X. Zhou et al, J. Am. Chem. Soc. 2023, 145, 8781–8787
- Anilines formation via molybdenum-catalysed intermolecular reaction of ynones with allylic amines: X. Zhou et a,l Angew. Chem. Int. Ed. 2024, e202412299
- Recent advances in molybdenum catalysed asymmetric organic transformations: X. Zhou et al, Trends Chem. 2024, 6, 487
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Pyrrolidine synthesis via ring contraction of pyridines
J. Takaya et al, Nat. Commun.2025, 16, 2426
https://doi.org/10.1038/s41467-025-57527-w
Ring contraction has emerged as a valuable synthetic strategy for accessing useful intermediates from simple, readily available precursors.
In this paper by Takaya et al they report the synthesis of pyrrolidines via a photo-induced ring contraction of pyridines-an inexpensive and abundant class of compounds—using silylboranes. The reaction yields azabicyclo[3.1.0]hex-3-ene derivatives, which serve as synthons for the construction of functionalised pyrrolidines. This approach provides a useful route to structurally diverse nitrogen-containing scaffolds, facilitating exploration of nitrogen chemical space.
- Pyrrolidine in drug discovery: a versatile scaffold for novel biologically active compounds: G. Petri et al, Top. Curr. Chem. 2021, 379, 34
- Carbon-to-nitrogen single-atom transmutation of azaarenes: M. Levin et al, Nature 2023, 623, 77–82
- Recent advances in the (3+2) cycloaddition of azo-methine ylide. New J. Chem. 2023, 47, 8997–9034
