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DOI: 10.1055/a-2201-9285
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Chemical Synthesis and Catalysis in Germany

Internal Atom Exchange in Oxazole Rings: A Blueprint for Azole Scaffold Evaluation

Davide Spinnato
,
Markus Leutzsch 
,
Feng Wang
,
Josep Cornella  ∗
Financial support for this work was provided by the Max-Planck-Gesellschaft, Max-Planck-Institut für Kohlenforschung. This project has received funding from the European Union’s Horizon 2020 research and innovation program under Agreement No. 850496 (ERC Starting Grant, J.C.). D.S. thanks the EU for a Marie Skłodowska-Curie postdoctoral fellowship (MSCA-IF Grant No. 101105383).
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Abstract

In this article, we provide a route to transform isoxazoles and oxadiazoles into the corresponding pyrazoles and 1,2,4-triazoles in one step using catalytic amounts of an air-stable Ni(0) complex. The reaction is a formal atom-exchange process at the internal heteroatoms of the aromatic cycle. This work provides a blueprint for reactivity that permits the rapid evaluation of different five-membered azole scaffolds, thus avoiding de novo synthesis of the molecule of interest.

Key words

nickel catalysis - heterocycle chemistry - hydrazine - isoxazoles - oxadiazoles - pyrazoles - triazoles

Supporting Information

    Supporting information for this article is available online at https://doi.org/10.1055/a-2201-9285.
  • Supporting Information


Publication History

Received: 25 September 2023

Accepted after revision: 31 October 2023

Accepted Manuscript online:
31 October 2023

Article published online:
04 December 2023

© 2023. Thieme. All rights reserved

Georg Thieme Verlag KG
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  • 14 Conversion of Oxadiazoles into 1,2,4-Triazoles (B); General Procedure An oven-dried culture tube was charged with Ni(4-CF3stb)3 (0.10 equiv, 0.010 mmol) and PPh3 (0.40 equiv, 0.040 mmol). The tube was then brought inside an argon-filled glovebox where anhydrous DMA (1.0 mL) was added followed by the desired starting material (1.0 equiv, 0.10 mmol). The tube was then transferred outside the glovebox and the tube was placed on a heating plate and stirred for 5 minutes at 70 °C. Finally, NH2NH2 in THF (1 M) (4.0 equiv, 0.40 mmol) was added and the reaction mixture was stirred for 24 h. The reaction mixture was then treated with the IS solution (0.10 mmol of 1,3,5-trimethoxybenzene in 0.50 mL of EtOAc), followed by the addition of trifluoroacetic acid (20 μL) in order to degrade the Ni-catalyst and to quench unreacted NH2NH2. The mixture was then diluted with EtOAc and treated with NaHCO3. The aqueous phase was extracted with EtOAc, and the combined organic layers were washed with brine, dried over Na2SO4, and the volatiles were evaporated. The crude mixture was then deposited on a preparative TLC plate to obtain the pure product. Note: In order to avoid contamination of the product with silica derived from the preparative TLC, the silica fraction containing the product was filtered through a layer of sand deposited on a glass-fritted filter (porosity IV) and rinsed several times with EtOAc. Note: The reactions can be performed outside the glovebox using standard Schlenk techniques. Compound 4c: By following General Procedure B, the reaction was performed with 3-phenyl-5-(1-phenylcyclopropyl)-1,2,4-oxadiazole (3c; 26.2 mg, 0.100 mmol). The crude mixture was purified by preparative TLC (hexane/EtOAc = 7:3) to afford product 4b (63%, 16.5 mg) as a white solid. 1H NMR (600 MHz, DMSO-d 6, 353 K): δ = 7.98–7.94 (m, 2 H), 7.47–7.42 (m, 2 H), 7.42–7.38 (m, 1 H), 7.38–7.35 (m, 2 H), 7.35–7.30 (m, 2 H), 7.27–7.21 (m, 1 H), 1.55–1.52 (m, 2 H), 1.34–1.31 (m, 2 H). *NH was not detected at this temperature. 13C NMR (151 MHz, DMSO-d 6, 353 K): δ = 162.2 (bs, C), 157.8 (bs, C), 141.4 (C), 129.7 (bs, C), 128.6 (CH), 128.2 (CH), 128.1 (CH), 127.8 (CH), 126.1 (CH), 125.5 (CH), 22.8 (C), 15.1 (CH2). Additional NMR analyses are attached in the spectra section of the Supporting Information. HRMS (ESI): m/z [M + H]+ calcd for C17H15N3: 262.133820; found: 262.133871.
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