Mild, General, and Regioselective Synthesis of 2-Aminopyridines from Pyridine N-Oxides via N-(2-Pyridyl)pyridinium Salts

Abstract

A synthesis of 2-aminopyridines from pyridine N-oxides via their corresponding N-(2-pyridyl)pyridinium salts has been demonstrated and investigated. The reaction sequence features a highly regioselective conversion of the N-oxide into its pyridinium salt followed by hydrolytic decomposition of the pyridinium moiety to furnish the 2-aminopyridine product. The method is compatible with a wide range of functional groups, is scalable, and features inexpensive reagents. ¹⁵N-labeling results gave products consistent with a Zincke reaction mechanism.

Key words

aminopyridines - pyridine oxides - pyridylpyridinium compounds - isotopic labeling - Zincke reaction

Publication History

Received: 07 October 2021

Accepted after revision: 13 December 2021

Article published online:
11 January 2022

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• 15 1-(5-Phenylpyridin-2-yl)pyridinium Trifluoroacetate (3d); Typical Procedure TFAA (280 μL, 2.0 mmol, 2.0 equiv) was added to a stirred solution of 3-phenylpyridine 1-oxide (171 mg, 1.0 mmol) and pyridine (400 μL, 5.0 mmol, 5.0 equiv) in CH₂Cl₂ (5 mL, 0.2 M) at 0 °C, and the resulting mixture was stirred at r.t. until the reaction was complete (LCMS). The mixture was then concentrated, dissolved in a minimal amount of CH₂Cl₂, and triturated from rapidly stirred Et₂O. The crude pyridinium salt was isolated by filtration, washed with Et₂O, and purified by chromatography [silica gel (12 g), 0–40% MeOH–CH₂Cl₂] to give an off-white solid; yield: 312 mg (0.90 mmol, 90%). ¹H NMR (400 MHz, CDCl₃): δ = 10.15 (d, J = 5.6 Hz, 2 H), 8.73–8.62 (m, 2 H), 8.35 (t, J = 6.4 Hz, 2 H), 8.25 (t, J = 7.8 Hz, 1 H), 8.06–8.01 (m, 3 H), 7.54–7.50 (m, 3 H). ¹⁹F NMR (376.5 MHz, CDCl₃): δ = –75.2. ¹³C NMR (100 MHz, CDCl₃): δ = 158.1, 151.1, 147.9, 142.6, 142.5, 136.5, 130.8, 129.4, 129.0, 127.3, 123.5, 116.0, (F₃CCO₂ ^– signal not included). HRMS (ESI⁺): m/z [M]⁺ calcd for C₁₆H₁₃N₂: 233.1073; found: 233.1076. 5-Phenylpyridin-2-amine (4b); Typical Procedure TFAA (280 μL, 2.0 mmol, 2 equiv) was added to a stirred solution of 3-phenylpyridine 1-oxide (171 mg. 1.0 mmol) and pyridine (400 μL, 5.0 mmol, 5 equiv) in MeCN (5.0 mL, 0.2 M) at 0 °C, and the resulting mixture was stirred at r.t. until the reaction was complete (LCMS). The reaction was then concentrated, dissolved in a minimal amount of CH₂Cl₂, and triturated from rapidly stirred Et₂O. The crude pyridinium salt was isolated by filtration and washed with Et₂O. The off-white solid was treated with hydrazine monohydrate (240 μL, 5.0 mmol, 5 equiv) in EtOH (5.0 mL) at 80 °C for 2 h, The resulting mixture was concentrated over silica gel with excess solid NaHCO₃. The residue was purified by column chromatography (silica gel, 0–100% EtOAc–hexane) to give an off-white solid; yield:142 mg (0.84 mmol, 84%). ¹H NMR (400 MHz, DMSO-d ₆): δ = 8.25 (dd, J = 0.7, 2.5 Hz, 1 H), 7.69 (dd, J = 2.5, 8.6 Hz, 1 H), 7.56–7.54 (m, 2 H), 7.42–7.37 (m, 2 H), 7.28–7.24 (m, 1 H), 6.55 (dd, J = 0.7, 8.6 Hz, 1 H), 6.01 (br s, 2 H). ¹³C NMR (100 MHz, DMSO-d ₆) δ = 159.1, 145.6, 138.1, 135.2, 128.8, 126.1, 125.3, 123.9, 107.9. HRMS (ESI⁺) m/z [M + H]⁺ calcd for C₁₁H₁₁N₂: 171.0917; found: 171.0917.