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Synlett 2024; 35(09): 1015-1018
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.


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Key words

nickel catalysis - heterocycle chemistry - hydrazine - isoxazoles - oxadiazoles - pyrazoles - triazoles
Zoom Image
Scheme 1 (A) Our group’s external N-to-O exchange in heterocycles. (B) Heterocycle interconversion through deletion, insertion, and atom-exchange reactions. (C) Nickel-catalyzed internal O-to-N exchange in isoxazoles and oxadiazoles en route to pyrazoles and triazoles.

Aromatic heterocycles occupy a privileged position in drug design, as judged by the large portion of these scaffolds present in drugs[1] and agrochemical compounds.[2] Among these, five-membered rings bearing O, S, and N atoms (azoles) constitute a large portion.[3] Medicinal chemistry programs devote enormous efforts to scrutinizing large libraries of these heterocyclic scaffolds in order to identify an optimal structure. However, this process is effort- and resource-intensive, and time-consuming, as most of the approaches require a de novo synthesis, and, likely, a complete re-evaluation of the synthetic route. To this end, our group has been interested in providing practical solutions for practitioners in the field of organic synthesis that permit the rapid evaluation of compounds in late-stage contexts.[4] In particular, we have been interested in the replacement of N atoms in complex molecules through deaminative strategies, thus considering NH2 groups as linchpin sites for modification.[4a] [c] [d] Inspired by natural deaminases and imine-ketone condensations, we have recently disclosed a methodology that permits the replacement of NH2 with OH groups in heterocyclic amines (Scheme [1]A).[5] Despite the potential of this technique, the N-to-O exchange occurs at the peripheral atoms, thus leaving the heterocycle intact. Recently, rearrangement chemistry through deletion[6] or insertion[7] strategies have arisen as powerful tools to modify the internal atoms in heterocycles directly (Scheme [1]B). Whereas these processes permit five- to six-membered ring interconversion and vice-versa,[6] , [7`] [b] [c] [d] [e] [f] [g] [h] the exchange of a heterocycle with another through a formal internal atom exchange is still underdeveloped (Scheme [1]B). An example of internal atom exchange in six-membered rings is the use of 1,2,3-triazines as electrophiles to forge pyrimidines (Scheme [1]B, bottom).[8] [9] Based on our interest in O↔N exchange,[5] we wondered whether such reactivity would be feasible by formally replacing internal atoms in relevant five-membered heterocycles. In this report, we present the development of a catalytic strategy that permits the conversion of both isoxazoles and oxadiazoles into pyrazoles and 1,2,4-triazoles, respectively, through formal O-to-N exchange. The protocol is characterized by the use of catalytic amounts of the air-stable Ni(4-CF3stb)3 in combination with hydrazine (Scheme [1]C).[4b] Although examples of specifically substituted isoxazole-to-pyrazole interconversion exist, they require the use of stoichiometric[10] or sub-stoichiometric[11] amounts of metal mediators, thus leading to limited functional group tolerance. To our knowledge, examples of oxadiazole-to-triazole conversion are minimal, thus highlighting the potential of our approach.[12]

Investigations on our approach started with the transformation of 5-phenyl-isoxazole (1a) into the corresponding pyrazole 2a. When isoxazole 1a and a catalytic amount of our air-stable Ni(4-CF3stb)3 complex were mixed with 4 equiv of hydrazine in dimethylacetamide (DMA) at 70 °C, pyrazole 2a was detected in ca. 20% upon acidic treatment (Table [1], entry 1).[11] When 0.4 equiv. of an exogenous ligand such as triphenylphosphine was employed, the desired product could be isolated in excellent yield (entry 2). The use of alternative air-stable Ni(0) sources, Ni(II) complexes, or Pd(PPh3)4 was detrimental to the reaction outcome (entries 3–6). When the reaction was performed at lower temperatures, product 2 was obtained but in lower yields (entry 7).

Table 1 Isoxazole to Pyrazole Interconversion: Optimization Studies

Entry

Deviation from above

Yield of 2a (%)a

1

none

22

2

PPh3 (0.4 equiv.)

90b

3

Ni(tBustb)3/PPh3 (0.4 equiv.)

12

4

Ni(COD)(DQ) (0.1 equiv.)/PPh3 (0.4 equiv.)

 0

5

Ni(bipy)Cl2/PPh3 (0.4 equiv.)

 0

6

Pd(PPh3)4

10

7

40 °C/PPh3 (0.4 equiv.)

32

a Reactions performed on a 0.05 mmol scale of 1a; yields were determined by 1H NMR analysis of the crude mixture using trimethoxybenzene as the internal standard after aqueous workup.b Isolated yield when the reaction was carried out on a 0.1 mmol scale. Acidic workup was performed at 70 °C by adding HCl 1 M (0.5mL); TFA can also be used in place of HCl(aq.).

At this point, we explored the generality of the protocol. When isoxazole 1b — possessing a substitution pattern unexplored by the previously reported protocols — was subjected to the optimized conditions, 2b was obtained in 76% yield (Scheme [2]). Gratifyingly, our catalytic platform holds an appreciable functional group tolerance, as exemplified by isoxazoles bearing alcohol moieties (2d–e) or an amide (2c). Furthermore, isoxazole 1e, possessing a coordinating pyridine component, did not hamper the catalytic activity, affording the desired pyrazole 2e in good yield. It is interesting to note that neither of the benzylic alcohols 2d nor 2e, led to styrenyl derivatives under the reaction conditions.[13]

Zoom Image
Scheme 2 Evaluation of the scope of the reaction

Having demonstrated the ability of our catalytic system to promote the interconversion of isoxazoles to pyrazoles, we wondered whether related oxadiazoles could be transformed into the corresponding 1,2,4-triazoles. This transformation would represent a powerful approach to generating and evaluating Five-member-nitrogenated scaffolds. When 3a was tested under the optimized conditions (Table [1]), the desired triazole product 4a was obtained in 40% yield after 16 hours (see the Supporting Information for details). Dilution of the reaction in combination with a non-acidic treatment afforded 3a in 68% yield. When sterically hindered substrates were employed, the desired products 4b–c were obtained in good yields. Importantly, a chemical handle such as a C(sp2)–Cl bond could be accommodated without a substantial reduction in yield (4d). Furthermore, the methyl ester derivative of ataluren could be transformed into the corresponding oxadiazole 4e in acceptable yields. Finally, the pesticide Nemastrike™ could be easily converted into the corresponding oxadiazole 4f in 65% yield.[14] Importantly, the reaction can be scaled up to 1 mmol scale without compromising the chemical efficiency of the process (4b, Scheme [2])

A putative catalytic cycle based on a Ni(0)/Ni(II) redox couple is depicted in Scheme [3]. Initially, a Ni(0) complex supported by PPh3 undergoes oxidative addition into the N–O bond, affording Ni(II) intermediate II (detected by HR-MS).[15] In the presence of an excess of hydrazine, ligand exchange occurs, affording a Ni(II)–hydrazine ligated complex III, liberating intermediate IV. The latter is the result of a condensation reaction between a carbonyl compound and hydrazine, which evolves to afford the desired cyclized product, following a Knorr cyclo-condensation (with acid in the case of isoxazoles).[16] Heterogeneous Ni(II) systems have long been known to be reduced to Ni(0) complexes in the presence of NH2NH2;[17] [18] hence, we postulate that the catalytically active Ni(0) is regenerated through the dehydrogenation of hydrazine.

Zoom Image
Scheme 3 Plausible catalytic cycle based on a Ni(0)/Ni(II) manifold

In conclusion, we have demonstrated the ability of our Ni(4-CF3stb)3 to promote the catalytic interconversion of isoxazole and oxadiazole into the corresponding pyrazole and 1,2,4-triazole using NH2NH2 as both N source and reducing agent. The protocol has been demonstrated with various heterocycles and shows a decent functional group tolerance. We hope that this reactivity blueprint will serve practitioners to expedite five-membered scaffold evaluation in synthetic campaigns.


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Conflict of Interest

The authors declare no conflict of interest.

Acknowledgment

We are thankful to all analytical services at the MPI Kohlenforschung for help. We are thankful to Prof. Dr. A. Fürstner for the generous support.

Supporting Information

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

  • References and Notes

  • 1 Vitaku E, Smith DT, Njardarson JT. J. Med. Chem. 2014; 57: 10257
    CrossrefPubMedSearch in Google Scholar
  • 2 Lamberth C. Pest Manage. Sci. 2013; 69: 1106
    CrossrefPubMedSearch in Google Scholar
  • 3 Baumann M, Baxendale IR, Ley SV, Nikbin N. Beilstein J. Org. Chem. 2011; 7: 442
    CrossrefPubMedSearch in Google Scholar
  • 5 Ghiazza C, Wagner L, Fernández S, Leutzsch M, Cornella J. Angew. Chem. Int. Ed. 2023; 62: e202212219
    CrossrefPubMedSearch in Google Scholar
  • 10 Sviridov SI, Vasil’ev AA, Shorshnev SV. Tetrahedron 2007; 63: 12195
    CrossrefPubMedSearch in Google Scholar
  • 11 Rey M, Beaumont S. Synthesis 2019; 51: 3796
    Thieme ConnectSearch in Google Scholar
  • 12 When the C-5 in oxadiazoles is substituted with a Perfluorinated moiety (e.g. CF3) oxadiazole-to-triazole interconversion is allowed via ANRORC-type mechanism, see: Buscemi S, Pace A, Piccionello AP, Pibiri I, Vivona N, Giorgi G, Mazzanti A, Spinelli D. J. Org. Chem. 2006; 71: 8106
    CrossrefPubMedSearch in Google Scholar
  • 13 Conversion of Isoxazoles into Pyrazoles (A); 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 (0.50 mL) was added followed by the desired starting material (1.0 equiv, 0.10 mmol). The tube was then transferred outside of the glovebox, NH2NH2 in THF (1 M) (4.0 equiv, 0.40 mmol) was added, and the reaction mixture was stirred at 70 °C. After 24 h, the reaction mixture was treated with IS solution (0.10 mmol of 1,3,5-trimethoxybenzene in 0.50 mL of EtOAc), followed by the addition of 1 M HCl (aq.) (0.50 mL) and the mixture was stirred for an additional 5 h at 70 °C. Note: the acidic workup can be alternatively carried out at the same temperature by adding trifluoroacetic acid (4 equiv). After 5 hours the reaction mixture was 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 volatiles were evaporated. The crude mixture was then deposited on a preparative thin-layer chromatography plate to obtain the pure product. Note: 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 2d: By following General Procedure A, the reaction was performed with 1-(3,5-dimethoxyphenyl)-2-(3-methylisoxazol-5-yl)ethan-1-ol (1d; 26.4 mg, 0.100 mmol). The crude mixture was purified by preparative TLC (hexane/EtOAc = 7:3) to afford product 2d (76%, 20.0 mg) as a white solid. 1H NMR (600 MHz, CDCl3): δ = 6.54 (d, J = 2.3 Hz, 2 H), 6.53 (bs, 2 H,), 6.36 (t, J = 2.3 Hz, 1 H), 5.87 (s), 4.91 (dd, J = 8.4, 4.1 Hz, 1 H), 3.77 (s, 6 H), 3.06–2.91 (m, 2 H), 2.28 (s, 3 H). 13C NMR (151 MHz, CDCl3): δ = 161.0 (C), 147.1 (C), 146.4 (C), 143.4 (C), 104.7 (CH), 103.8 (CH), 99.7 (CH), 73.4 (CH), 55.5 (CH3), 37.0 (CH2), 11.9 (CH3). HRMS (ESI): m/z [M + Na]+ calcd for C14H18N2O3: 285.121080; found: 285.120961.
  • 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.
  • 15 Bogdos MK, Müller P, Morandi B. Organometallics 2023; 42: 211
    CrossrefPubMedSearch in Google Scholar
  • 16 Knorr L. Ber. Dtsch. Chem. Ges. 1884; 17: 1635
    CrossrefPubMedSearch in Google Scholar
  • 18 Malatesia L, Angoletta M. J. Chem. Soc. 1957; 1186
    Crossref

Corresponding Author

Josep Cornella
Department of Organometallic Chemistry, Max-Planck-Institut für Kohlenforschung
Kaiser-Wilhelm-Platz, 1, 45470, Mülheim an der Ruhr
Germany   

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
Rüdigerstraße 14, 70469 Stuttgart, Germany

  • References and Notes

  • 1 Vitaku E, Smith DT, Njardarson JT. J. Med. Chem. 2014; 57: 10257
    CrossrefPubMedSearch in Google Scholar
  • 2 Lamberth C. Pest Manage. Sci. 2013; 69: 1106
    CrossrefPubMedSearch in Google Scholar
  • 3 Baumann M, Baxendale IR, Ley SV, Nikbin N. Beilstein J. Org. Chem. 2011; 7: 442
    CrossrefPubMedSearch in Google Scholar
  • 5 Ghiazza C, Wagner L, Fernández S, Leutzsch M, Cornella J. Angew. Chem. Int. Ed. 2023; 62: e202212219
    CrossrefPubMedSearch in Google Scholar
  • 10 Sviridov SI, Vasil’ev AA, Shorshnev SV. Tetrahedron 2007; 63: 12195
    CrossrefPubMedSearch in Google Scholar
  • 11 Rey M, Beaumont S. Synthesis 2019; 51: 3796
    Thieme ConnectSearch in Google Scholar
  • 12 When the C-5 in oxadiazoles is substituted with a Perfluorinated moiety (e.g. CF3) oxadiazole-to-triazole interconversion is allowed via ANRORC-type mechanism, see: Buscemi S, Pace A, Piccionello AP, Pibiri I, Vivona N, Giorgi G, Mazzanti A, Spinelli D. J. Org. Chem. 2006; 71: 8106
    CrossrefPubMedSearch in Google Scholar
  • 13 Conversion of Isoxazoles into Pyrazoles (A); 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 (0.50 mL) was added followed by the desired starting material (1.0 equiv, 0.10 mmol). The tube was then transferred outside of the glovebox, NH2NH2 in THF (1 M) (4.0 equiv, 0.40 mmol) was added, and the reaction mixture was stirred at 70 °C. After 24 h, the reaction mixture was treated with IS solution (0.10 mmol of 1,3,5-trimethoxybenzene in 0.50 mL of EtOAc), followed by the addition of 1 M HCl (aq.) (0.50 mL) and the mixture was stirred for an additional 5 h at 70 °C. Note: the acidic workup can be alternatively carried out at the same temperature by adding trifluoroacetic acid (4 equiv). After 5 hours the reaction mixture was 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 volatiles were evaporated. The crude mixture was then deposited on a preparative thin-layer chromatography plate to obtain the pure product. Note: 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 2d: By following General Procedure A, the reaction was performed with 1-(3,5-dimethoxyphenyl)-2-(3-methylisoxazol-5-yl)ethan-1-ol (1d; 26.4 mg, 0.100 mmol). The crude mixture was purified by preparative TLC (hexane/EtOAc = 7:3) to afford product 2d (76%, 20.0 mg) as a white solid. 1H NMR (600 MHz, CDCl3): δ = 6.54 (d, J = 2.3 Hz, 2 H), 6.53 (bs, 2 H,), 6.36 (t, J = 2.3 Hz, 1 H), 5.87 (s), 4.91 (dd, J = 8.4, 4.1 Hz, 1 H), 3.77 (s, 6 H), 3.06–2.91 (m, 2 H), 2.28 (s, 3 H). 13C NMR (151 MHz, CDCl3): δ = 161.0 (C), 147.1 (C), 146.4 (C), 143.4 (C), 104.7 (CH), 103.8 (CH), 99.7 (CH), 73.4 (CH), 55.5 (CH3), 37.0 (CH2), 11.9 (CH3). HRMS (ESI): m/z [M + Na]+ calcd for C14H18N2O3: 285.121080; found: 285.120961.
  • 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.
  • 15 Bogdos MK, Müller P, Morandi B. Organometallics 2023; 42: 211
    CrossrefPubMedSearch in Google Scholar
  • 16 Knorr L. Ber. Dtsch. Chem. Ges. 1884; 17: 1635
    CrossrefPubMedSearch in Google Scholar
  • 18 Malatesia L, Angoletta M. J. Chem. Soc. 1957; 1186
    Crossref

   Permissions and Reprints All articles of this category
Zoom Image
Scheme 1 (A) Our group’s external N-to-O exchange in heterocycles. (B) Heterocycle interconversion through deletion, insertion, and atom-exchange reactions. (C) Nickel-catalyzed internal O-to-N exchange in isoxazoles and oxadiazoles en route to pyrazoles and triazoles.
Zoom Image
Scheme 2 Evaluation of the scope of the reaction
Zoom Image
Scheme 3 Plausible catalytic cycle based on a Ni(0)/Ni(II) manifold