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

Publication History

Received: 23 February 2025

Accepted after revision: 31 March 2025

Accepted Manuscript online:
31 March 2025

Article published online:
13 May 2025

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• 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.