Abstract
Methanol is a key building block in the chemical industry. In recent years, it has been used as a C1 source in various organic transformations in the presence of a transition-metal catalyst. This protocol describes the ruthenium- and cobalt-catalyzed utilization of methanol in different types of methylation reactions and heterocycle synthesis. Initially, we describe the synthesis of tridentate ligands (L1–L3) and their corresponding Ru(II) complexes (Ru-1, -2 and -3) and then detail how to apply these Ru(II) complexes and Co/PP3 (PP3 = P(CH2CH2PPh2)3) in various methanol dehydrogenative coupling reactions. We discuss six types of transformations by using methanol or a methanol/water mixture. The experimental setup for all the catalytic reactions is similar and involves adding all the respective reagents and solvents to an argon-filled pressure tube, which is sealed (by screw cap) and refluxed at the indicated temperature before the desired products are isolated and characterized. The catalytic systems described in this protocol work well for both small-scale and preparative-scale synthesis of various N-methylated amines/amides, C-methylated products and quinazolinones. These catalytic reactions are greener and more sustainable than conventional synthesis methods, with only H2 and/or H2O as by-products, and we evaluate the ‘green chemistry metrics’ for a typical substrate. The total time required for the catalytic experiments described in this protocol is 16–28 h, and the operation time is 4 h. An average level of expertise in organic synthesis is required to carry out these protocols.
Key points
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This protocol describes methods for using methanol as a C1 source for the generation of various products, including N-methylated amines/amides, C-methylated products and quinazolinones.
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The technique uses ruthenium and cobalt catalysts, which allow for a more sustainable approach than other methods for these processes, with only H2 and H2O produced as by-products.
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Data availability
Additional data related to this protocol are available in Key references using this protocol. Analytical data for the four different compounds described here are presented in the primary papers (see Related links).
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Acknowledgements
This work is financially supported by the Science and Engineering Research Board (SERB), India and the Council of Scientific & Industrial Research (CSIR), India. B.P. and S.K. thank the Department of Chemistry, IIT Kanpur, India for support. Prof. Edward Anderson, Department of Chemistry, University of Oxford, United Kingdom and Marie Skłodowska-Curie actions for an Individual Fellowship are also sincerely acknowledged by B.P.
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B.P. and S.K. contributed intellectually and practically to the development of the transformations.
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Related links
Key references using this protocol
Paul, B. et al. ChemSusChem 10, 2370–2374 (2017): https://doi.org/10.1002/cssc.201700503
Chakrabarti, K. et al. Org. Lett. 19, 4750–4753 (2017):https://doi.org/10.1021/acs.orglett.7b02105
Paul, B. et al. ACS Catal. 8, 2890−2896 (2018):https://doi.org/10.1021/acscatal.8b00021
Paul, B. et al. Org. Lett. 21, 5843–5847 (2019): https://doi.org/10.1021/acs.orglett.9b01925
Paul, B. et al. ACS Catal. 9, 10469−10476 (2019):https://doi.org/10.1021/acscatal.9b03916
Extended data
Extended Data Fig. 1 Methanol distillation.
a, Full setup for methanol distillation from magnesium cake. b, Correct storage of distilled solvent in a round-bottom flask with a Suba seal under N2 atmosphere. c, Argon inlet to solvent flask during use. After each use of distilled methanol, purge it with argon and handle the distilled solvent very carefully to prevent contamination with moisture. For the long-term use of distilled methanol, store it over 4-Å activated molecular sieves.
Extended Data Fig. 2 Ace pressure tubes.
a–c, Different types of pressure tube (2.5, 4 and 9 mL) used in the protocol. d, Cap and front seal. e, Front seal on the cap. f, PTFE tape. g, Front seal and thread on the cap cover by PTFE. Here, PTFE tape is used to avoid any leakage of solvent during the reaction at high temperature and to increase the lifespan of the front seal (O-ring) by avoiding direct contact of the O-ring with hot solvent during the experiment.
Extended Data Fig. 3 Experimental setup for the synthesis of ligand and images of dried reagent and ligand.
a, Detailed setup for the syntheses of NNN-OMe (L1) and NNN-Me (L3) ligands. b, Image of 2-bromo-1,10-phenanthroline. c, Image of ligand NNN-Me (L3).
Extended Data Fig. 4 Ruthenium(II) precursors.
a, Tris(triphenylphosphine)ruthenium (II) dichloride (RuCl2(PPh3)3). b, Dichloro (p-cymene) ruthenium (II) dimer ([RuCl2(p-cymene)]2).
Extended Data Fig. 5 Experimental setup for the synthesis of ruthenium (II) complexes and images of selected Ru (II) complexes.
a, Detailed setup for the syntheses of Ru-1 and Ru-2. b, Image of [RuCl(phenpy-OMe)(CH3CN)2]Cl (Ru-1). c, Image of trans-RuCl(phenpyMe)(PPh3)2PF6 (Ru-3).
Extended Data Fig. 6 Selected substrates and products.
a–d, Substrates: nitrobenzene (a), benzonitrile (b), acetophenone (c) and benzamide (d). e–h, Products: N-methyl aniline (e), N,N-dimethyl benzylamine (f), 2-methyl-1-phenylpropan-1-one (g) and N-methyl benzamide (h).
Extended Data Fig. 7 Experimental setup for the synthesis of trans-RuCl(phenpyMe)(PPh3)2PF6 (Ru-3).
a, Reaction flask with magnetic stir bar. b, Full setup, during reflux. c, Reaction mixture at the end.
Extended Data Fig. 8 Experimental setup for the synthesis of NNN-OH (L2) ligand.
Synthesis of L2 ligand from ligand L1 and aqueous HBr.
Extended Data Fig. 9 Ligand and cobalt precursors.
a, Tris[2-(diphenylphosphino)ethyl]phosphine (PP3). b, Cobalt(II) bromide (CoBr2). c, Cobalt(II) nitrate hexahydrate (Co(NO3)2 · 6 H2O).
Extended Data Fig. 10 Catalytic experimental setup with different types of pressure tubes.
a,c and e, Pressure tube with all reagents before adding solvent. b,d and f, Full experimental setup with 2.5-, 4- and 9-mL pressure tube, respectively.
Supplementary information
Supplementary Information
Supplementary Methods, Box 1, References and Figs. 1–6
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Paul, B., Kundu, S. The use of methanol as a C1 building block. Nat Protoc (2024). https://doi.org/10.1038/s41596-024-00978-0
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DOI: https://doi.org/10.1038/s41596-024-00978-0
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