Pyridinic-N-Co single-atom catalysts unlock sustainable and efficient quinoline synthesis via hydrogen-transfer-coupled annulation

Abstract

Developing sustainable and atom-economical hydrogen transfer routes for constructing pharmacologically valuable quinoline scaffolds from abundant alcohol feedstocks remains a significant challenge. Herein, a tailored pyridinic-nitrogen-coordinated cobalt (Co) single-atom catalyst (Co-N/C-U) is showcased, enabling the efficient synthesis of quinoline derivatives from inexpensive and readily available 2-nitrobenzyl alcohol and various secondary or primary alcohols via a cascade hydrogen transfer process followed by annulation. Characterization confirmed that Co-N/C-U contains atomically dispersed Co centers and exhibits exceptional catalytic activity, accessing quinolines with up to 98% yield across a broad substrate scope (47 examples) with a turnover number of up to 30,808, outperforming state-of-the-art catalytic systems. This strategy demonstrates scalability to gram-scale reactions and enables the synthesis of the Cavosonstat derivative, while the pronounced stability and reusability of the catalyst further underscores its promising potential for practical implementation. Mechanistic studies revealed that the pyridinic-N-Co moiety plays a dual role, where the isolated Co sites facilitate efficient hydrogen transfer, and the neighboring pyridinic-N atoms act as basic sites to promote the key Friedländer cyclization step. Density functional theory calculations revealed that the enhanced catalytic performance of Co-N/C-U originates from its optimized pyridinic-N-Co coordination environment. This work establishes a sustainable route to a wide range of quinolines, providing a foundation for the precise design of next-generation SACs for complex organic transformations.

Keywords

Single-atom catalyst / 2-nitrobenzyl alcohol / quinolines / N-heterocycles / hydrogen transfer

References

[1] Garg N,Sundararaju B.Recent developments on methanol as liquid organic hydrogen carrier in transfer hydrogenation reactions.Coord. Chem. Rev.2021;433:213728

[2] Jafarzadeh M,Gajewski K.Recent advances in C/N-alkylation with alcohols through hydride transfer strategies.Org. Biomol. Chem.2022;20:7713-45

[3] Yan H,Chen Y.Photocatalytic metal hydride hydrogen atom transfer mediated allene functionalization by cobalt and titanium dual catalysis.Angew. Chem. Int. Ed.2023;135:e202302483

[4] Gao Y,Yang BM.Enantioconvergent transformations of secondary alcohols through borrowing hydrogen catalysis.Chem. Soc. Rev.2023;52:5541-62

[5] Reed-Berendt BG,Dambatta MB.Borrowing hydrogen for organic synthesis.ACS Cent. Sci.2021;7:570-85 PMCID:PMC8155478

[6] Cao H,Tang H,Wu J.Photoinduced intermolecular hydrogen atom transfer reactions in organic synthesis.Chem. Catal.2021;1:523-98

[7] Yang C,Maldonado S,Stephenson CRJ.The design of PINO-like hydrogen-atom-transfer catalysts.Nat. Rev. Chem.2023;7:653-66

[8] Ang HT,Ravelli D.Pyridine N-oxides as hydrogen atom transfer reagents for site-selective photoinduced Csp³-H functionalization.Nat. Synth.2024;3:568-75

[9] Nallagangula M,Kumar R.Transition metal-catalysis in interrupted borrowing hydrogen strategy.Chem. Commun.2023;59:7847-62

[10] Podyacheva E,Vasilyev DV.Borrowing hydrogen amination reactions: a complex analysis of trends and correlations of the various reaction parameters.ACS Catal.2022;12:7142-98

[11] Li J,Yao W,Wang D.Iridium supported on porous polypyridine-oxadiazole as high-activity and recyclable catalyst for the borrowing hydrogen reaction.Green Chem.2022;24:2602-12

[12] Muthukrishnan I,Menéndez JC.Progress in the chemistry of tetrahydroquinolines.Chem. Rev.2019;119:5057-191

[13] Prabagar B,Shi Z.Site-selective C-H functionalization to access the arene backbone of indoles and quinolines.Chem. Soc. Rev.2021;50:11249-69

[14] Jeanmart S,Lamberth C,Morris JA.Synthetic approaches to the 2015-2018 new agrochemicals.Bioorg. Med. Chem.2021;39:116162

[15] Yang GZ,Yin XD.Design, synthesis, and antifungal evaluation of novel quinoline derivatives inspired from natural quinine alkaloids.J. Agric. Food Chem.2019;67:11340-53

[16] Afzal O,Haider MR.A review on anticancer potential of bioactive heterocycle quinoline.Eur. J. Med. Chem.2015;97:871-910

[17] Kaur K,Reddy RP.Quinolines and structurally related heterocycles as antimalarials.Eur. J. Med. Chem.2010;45:3245-64

[18] Ma J,Bellotti P.Photochemical intermolecular dearomative cycloaddition of bicyclic azaarenes with alkenes.Science2021;371:1338-45 PMCID:PMC7610643

[19] Yang J,Zhao Y.Asymmetric dearomative [2 + 2] photocycloaddition of quinoline and indole derivatives with Bicyclo[1.1.0]butanes.J. Am. Chem. Soc.2025;147:35755-66

[20] Jia H,Zhang M.Reductive functionalization of pyridine-fused N-heteroarenes.Acc. Chem. Res.2024;57:795-813

[21] Kaur R.Synthetic and medicinal perspective of quinolines as antiviral agents.Eur. J. Med. Chem.2021;215:113220 PMCID:PMC7995244

[22] Patel A,Mehta M.A review on synthetic investigation for quinoline- recent green approaches.Green Chem. Lett. Rev.2022;15:337-72

[23] Batista VF,Silva AMS.Synthesis of quinolines: a green perspective.ACS Sustain. Chem. Eng.2016;4:4064-78

[24] Mandal A.Recent advancement in the synthesis of quinoline derivatives via multicomponent reactions.Org. Biomol. Chem.2024;22:2339-58

[25] Chelucci G.Synthesis of Quinolines via a metal-catalyzed dehydrogenative N-heterocyclization.Chem. Rec.2017;17:200-16

[26] Lu Y,Chen S.Single-atom Fe-catalyzed acceptorless dehydrogenative coupling to quinolines.J. Am. Chem. Soc.2024;146:23338-47

[27] Mastalir M,Pittenauer E,Kirchner K.Sustainable synthesis of quinolines and pyrimidines catalyzed by manganese PNP pincer complexes.J. Am. Chem. Soc.2016;138:15543-6

[28] Yu K,Liu W.Iron-catalysed quinoline synthesis via acceptorless dehydrogenative coupling.Org. Chem. Front.2022;9:6573-8

[29] Tian D,Yang LS,Wu H.Switchable skeletal editing of quinolines enabled by cyclizative sequential rearrangements.Nat. Chem.2025;17:952-60

[30] Trincado M,Grützmacher H.Homogeneously catalyzed acceptorless dehydrogenation of alcohols: a progress report.Coord. Chem. Rev.2021;443:213967

[31] Crabtree RH.Homogeneous transition metal catalysis of acceptorless dehydrogenative alcohol oxidation: Applications in hydrogen storage and to heterocycle synthesis.Chem. Rev.2017;117:9228-46

[32] Nguyen DH,Capet F,Dumeignil F.M Manganese pincer complexes for the base-free, acceptorless dehydrogenative coupling of alcohols to esters: development, scope, and understanding.ACS Catal.2017;7:2022-32

[33] Pal D,Sarmah R.Designing cobalt(II) complexes for tandem dehydrogenative synthesis of quinoline and quinazoline derivatives.Org. Lett.2024;26:514-8

[34] Paul B,Kundu S.Synthesis of N-heterocycles through alcohol dehydrogenative coupling.Nat. Protoc.2024;19:3640-76

[35] Chun S,Hong J,Oh DC.Iron‐catalyzed transfer hydrogenation: Divergent synthesis of quinolines and quinolones from ortho‐nitrobenzyl alcohols.Adv. Synth. Catal.2023;365:3367-74

[36] Xie F,Chen M,Jiang H.Convenient synthesis of quinolines from α‐2‐nitroaryl alcohols and alcohols via a ruthenium‐catalyzed hydrogen transfer strategy.ChemCatChem2014;7:349-53

[37] Sk M,Banerjee D.Nickel‐catalyzed sequential dehydrogenation and cyclization of 2‐amino (nitro)‐benzyl alcohols with alkyl alcohols: synthesis of C‐3‐substituted auinolines.ChemCatChem2023;15:e202300412

[38] Zhao L,Zhang C.Ru-CNP complex-catalyzed hydrogen transfer/annulation reaction of 2-nitrobenzylalcohol via an outer-sphere mechanism.J. Org. Chem.2025;90:4959-72

[39] Maji M,Panja D.Sustainable synthesis of N-heterocycles in water using alcohols following the double dehydrogenation strategy.J. Catal.2019;373:93-102

[40] Deshmukh G,Murugavel R.Dinuclear Ru(II) schiff base complex catalyzed one-pot synthesis of quinolines through acceptorless dehydrogenative coupling of secondary alcohols with 2-nitrobenzyl alcohol.Organometallics2024;43:1190-202

[41] Wang Q,Li H,Liu Y.Synthesis of quinolines via iron-catalyzed redox condensation of alcohols with 2-nitrobenzyl methyl ether/2-nitrobenzyl alcohols.Synthesis2016;48:3985-95

[42] Xi J,Xu Y,Bae JW.Synthesis strategies, catalytic applications, and performance regulation of single-atom catalysts.Adv. Funct. Mater.2021;31:2008318

[43] Guo W,Wang X.General design concept for single-atom catalysts toward heterogeneous catalysis.Adv. Mater.2021;33:e2004287

[44] Li X,Rabeah J.Cobalt single-atom catalysts with high stability for selective dehydrogenation of formic acid.Angew. Chem. Int. Ed.2020;59:15849-54 PMCID:PMC7540455

[45] Li B,Zeng G,Dong Z.Atomically dispersed Co on N-doped porous carbon for the highly efficient catalytic oxidation of aromatic alcohols to acids and nitriles.ACS Catal.2023;13:16286-99

[46] Ping K,Starkov P.M-N-C materials as heterogeneous catalysts for organic transformations.Coord. Chem. Rev.2023;497:215412

[47] Sun JL,Dixneuf PH.Reductive coupling of nitroarenes and HCHO for general synthesis of functional ethane-1,2-diamines by a cobalt single-atom catalyst.J. Am. Chem. Soc.2023;145:17329-36

[48] Li M,Wang B.Mechanism of hydrogen generation catalyzed by a single atom and its spin regulation.J. Am. Chem. Soc.2025;147:6193-202

[49] Levell Z,Wang R.What is the "other" site in M-N-C?.J. Am. Chem. Soc.2025;147:603-9

[50] Chen S,Li X.Identification of the highly active Co-N₄ coordination motif for selective oxygen reduction to hydrogen peroxide.J. Am. Chem. Soc.2022;144:14505-16 PMCID:PMC9389578

[51] Li W,Wang K,Cai D.Engineering pyridinic-N-Co sites for enhanced CO₂ hydrogenation to methanol.Appl.Catal. B Environ. Energy2025;365:124906

[52] Frisch M,Schlegel H. Gaussian 16, Revision C.01. Wallingford, CT: Gaussian, Inc.; 2016. Available from: https://gaussian.com/citation/ [Last accessed on 28 May 2026]

[53] Lu T.Multiwfn: a multifunctional wavefunction analyzer.J. Comput. Chem.2012;33:580-92

[54] Humphrey W,Schulten .VMD: visual molecular dynamics.J. Mol. Graph.1996;14:33-8

[55] Liang L,Zhou H.Cobalt single atom site isolated Pt nanoparticles for efficient ORR and HER in acid media.Nano Energy2021;88:106221

[56] Ha Y,Yan X.Atomically dispersed Co‐pyridinic N‐C for superior oxygen reduction reaction.Adv. Energy Mater.2020;10:2002592

[57] Chen M,Zhu L.Single-atom dispersed Co-N-C: a novel adsorption-catalysis bifunctional material for rapid removing bisphenol A.Catal. Today2020;348:187-93

[58] Zhang G,Cao F,Zheng X.N-doped graphene coupled with Co nanoparticles as an efficient electrocatalyst for oxygen reduction in alkaline media.J. Power Sources2016;302:114-25

[59] Yang T,Pu L.Hollow-spherical Co/N-C nanoparticle as an efficient electrocatalyst used in air cathode microbial fuel cell.Biosens. Bioelectron.2016;86:129-34

[60] Niu K,Cui J.Graphene-based non-noble-metal Co/N/C catalyst for oxygen reduction reaction in alkaline solution.J. Power Sources2013;243:65-71

[61] Liu X,Zhang Y.Atomically thick oxide overcoating stimulates low-temperature reactive metal-support interactions for enhanced catalysis.J. Am. Chem. Soc.2023;145:6702-9

[62] Zhang G,Wang X,Liu Y.Atomically dispersed Co-S-N active sites anchored on hierarchically porous carbon for efficient catalytic hydrogenation of nitro compounds.ACS Catal.2022;12:5786-94

[63] Lin X,Chen Y,Zhu R.Nitrogen-doped carbon cobalt grafted on graphitic carbon nitride catalysts with enhanced catalytic performance for ethylbenzene oxidation.J. Mol. Catal. A Chem.2016;420:11-7

[64] Zhu Q,Zhang F.Renewable chitosan-derived cobalt@N-doped porous carbon for efficient aerobic esterification of alcohols under air.Nanoscale2019;11:17736-45

[65] Gao J,Ma R.Cobalt single-atom catalysts for domino reductive amination and amidation of levulinic acid and related molecules to N-heterocycles.Chem. Catal.2022;2:178-94

[66] Wang C,Ren H,Chou S.Diminishing the uncoordinated N species in Co-N-C catalysts toward highly efficient electrochemical CO₂ reduction.ACS Catal.2022;12:2513-21

[67] Du Z,Hu W.Cobalt in nitrogen-doped graphene as single-atom catalyst for high-sulfur content lithium-sulfur batteries.J. Am. Chem. Soc.2019;141:3977-85

[68] Lu X,Huang L.Synergetic roles of pyridinic nitrogen and carbonyl sites in nitrogen-doped carbon for the metal-free transfer hydrogenation reactions.Appl. Catal. B Environ.2023;324:122277

[69] Yang H,Dai X,Shi F.Carbon-catalysed reductive hydrogen atom transfer reactions.Nat. Commun.2015;6:6478

[70] Luo Z,Nguyen VT.Transition metal-like carbocatalyst.Nat. Commun.2020;11:4091 PMCID:PMC7427970

[71] Yang X,Kang Y.Unveiling the axial hydroxyl ligand on Fe-N₄-C electrocatalysts and its impact on the pH-dependent oxygen reduction activities and poisoning kinetics.Adv. Sci.2020;7:2000176 PMCID:PMC7312417