C4-Selective Alkylation of Pyridines through Amidyl-Radical-Mediated 1,2-Hydrogen Atom Transfer

Abstract

Hydrogen atom transfer (HAT) reactions play a vital role in radical chemistry and biological systems, enabling selective C–H functionalization through bond dissociation energy and polarity effects. Whereas intramolecular 1,5-HAT is well established, 1,2-HAT processes remain relatively challenging, particularly for nitrogen-centered radicals, due to high activation barriers. Here, we report a successful 1,2-HAT of amidyl radicals generated from N-amidopyridinium salts, enabled by a frustrated Lewis pair system of t-Bu₃P and the pyridinium salt, without requiring an external photocatalyst. The phosphine serves dual roles: reducing the pyridinium salt through single-electron transfer and facilitating the 1,2-HAT process under mild conditions. Visible-light irradiation enhances the reaction efficiency, allowing late-stage functionalization of pyridine-containing pharmaceuticals. This method offers a new approach to selective pyridine C–H functionalization, broadening the scope of HAT chemistry in synthesis.

Key words

hydrogen atom transfer - pyridines - frustrated Lewis pair - late-stage functionalization - single-electron transfer - radical-chain reaction

Publikationsverlauf

Eingereicht: 23. Februar 2025

Angenommen nach Revision: 31. März 2025

Accepted Manuscript online:
31. März 2025

Artikel online veröffentlicht:
13. Mai 2025

• References and Notes

• 1a Capaldo L, Quadri LL, Ravelli D. Green Chem. 2020; 22: 3376
• 1b Guo W, Wang Q, Zhu J. Chem. Soc. Rev. 2021; 50: 7359
• 1c Rammal F, Gao D, Boujnah S, Gaumont A.-C, Hussein AA, Lakhdar S. Org. Lett. 2020; 22: 7671
• 1d Atriardi SR, Anita Y, Woo SK. Synthesis 2025; 57: 953
• 1e Koo J, Kim W, Jhun BH, Park S, Song D, You Y, Lee HG. J. Am. Chem. Soc. 2024; 146: 22874
• 1f Zhang X, MacMillan DW. C. J. Am. Chem. Soc. 2017; 139: 11353
• 2a Capaldo L, Ravelli D. Eur. J. Org. Chem. 2017; 2056
• 2b Mayer JM. Acc. Chem. Res. 2011; 44: 36
• 2c Yan X, Pang Y, Zhou Y, Chang R, Ye J. J. Am. Chem. Soc. 2025; 147: 1186
• 2d Short MA, Blackburn JM, Roizen JL. Synlett 2020; 31: 102
• 2e Capaldo L, Ravelli D, Fagnoni M. Chem. Rev. 2022; 122: 1875
• 3a Chen H, Fan W, Yuan X.-A, Yu S. Nat. Commun. 2019; 10: 4743
• 3b Wang C, Chen Z, Sun J, Tong L, Wang W, Song S, Li J. Nat. Commun. 2024; 15: 5087
• 3c Rand AW, Yin H, Xu L, Giacoboni J, Martin-Montero R, Romano C, Montgomery J, Martin R. ACS Catal. 2020; 10: 4671
• 3d Becker P, Duhamel T, Stein CJ, Reiher M, Muñiz K. Angew. Chem. Int. Ed. 2017; 56: 8004
• 3e Kweon B, Kim C, Kim S, Hong S. Angew. Chem. Int. Ed. 2021; 60: 26813
• 3f Procter RS. J, Chuentragool P, Colgan AC, Phipps RJ. J. Am. Chem. Soc. 2021; 143: 4928
• 3g Wang G.-Z, Fu M.-C, Zhao B, Shang R. Sci. China Chem. 2021; 64: 439
• 4a Che C, Qian Z, Wu M, Zhao Y, Zhu G. J. Org. Chem. 2018; 83: 5665
• 4b Jang J, Lee G, Cho EJ. Bull. Korean Chem. Soc. 2024; 45: 966
• 4c Zhong L.-J, Wang H.-Y, Ouyang X.-H, Li J.-H, An D.-L. Chem. Commun. 2020; 56: 8671
• 4d Liu D, Zhang J, Chen Y. Synlett 2021; 32: 356
• 4e Fu X, Ran T, Liu J. Org. Chem. Front. 2024; 11: 6760
• 4f Zhang J, Liu D, Liu S, Ge Y, Lan Y, Chen Y. iScience 2020; 23: 100755
• 5a Jiang Y, Liu D, Rotella ME, Deng G, Liu Z, Chen W, Zhang HB, Kozlowski MC, Walsh PJ, Yang X. J. Am. Chem. Soc. 2023; 145: 16045
• 5b Jiang Y, Li H, Tang H, Zhang Q, Yang H, Pan Y, Zou C, Zhang H, Walsh PJ, Yang X. Chem. Sci. 2025; 16: 962
• 6 Marshall CM, Federice JG, Bell CN, Cox PB, Njardarson JT. J. Med. Chem. 2024; 67: 11622
• 7a Kim N, Lee C, Kim T, Hong S. Org. Lett. 2019; 21: 9719
• 7b Lee W, Jung S, Kim M, Hong S. J. Am. Chem. Soc. 2021; 143: 3003
• 7c Choi W, Kim M, Lee K, Park S, Hong S. Org. Lett. 2022; 24: 9452
• 7d Vellakkaran M, Kim T, Hong S. Angew. Chem. Int. Ed. 2022; 61: e202113658
• 7e Kim M, Koo Y, Hong S. Acc. Chem. Res. 2022; 55: 3043
• 8 Tan C.-Y, Kim M, Park I, Kim Y, Hong S. Angew. Chem. Int. Ed. 2022; 61: e20221385
• 9 4-Methyl-N-[(2-phenylpyridin-4-yl)methyl]benzenesulfonamide (2a); Typical Procedure To an oven-dried 12 mL test tube equipped with a magnetic stirrer bar were added the N-amidopyridinium salt 1a (1.0 equiv, 0.05 mmol), t-Bu₃P·HBF₄ (1.5 equiv, 0.075 mmol), and NaHCO₃ (1.5 equiv, 0.075 mmol) under an Ar atmosphere. After evacuating the tube and back-filling with argon, anhyd DMSO (1.0 mL) was added from a syringe. The sealed test tube was immediately placed in a reaction bath equipped with a Kessil blue LED (λ = 440 nm, 25% intensity; distance from Kessil LED to test tube ~5 cm). The mixture was then irradiated and stirred at r.t. for 14 h. When the reaction was complete, the mixture was diluted with EtOAc (30 mL), washed with distilled water (3 × 20 mL), and extracted with EtOAc (×3). The organic layer was washed with brine (20 mL), dried (Na₂SO₄), and filtered. The resulting mixture was concentrated under reduced pressure and the residue was purified by flash column chromatography [silica gel, EtOAc–n-hexane (1:1)] to give a colorless oil; yield: 13.2 mg (0.05 mmol scale, 78%). ¹H NMR (500 MHz, CDCl₃): δ = 8.55 (d, J = 5.0 Hz, 1 H), 7.91–7.79 (m, 2 H), 7.73 (d, J = 8.3 Hz, 2 H), 7.48 (s, 1 H), 7.41 (dd, J = 9.2, 7.0 Hz, 3 H), 7.28–7.22 (m, 2 H), 7.08–7.02 (m, 1 H), 5.37 (s, 1 H), 4.20 (d, J = 6.5 Hz, 2 H), 2.37 (s, 3 H). ¹³C NMR (125 MHz, CDCl₃): δ = 157.8, 149.9, 146.6, 143.9, 138.9, 136.9, 129.9, 129.2, 128.8, 127.2, 127.0, 120.9, 119.3, 46.2, 21.6. HRMS (ESI): m/z calcd for C₁₉H₁₉N₂O₂S: 339.1162; found: 339.1168.