Synthesis of 3-Substituted 2-Aminopyridines via Displacement of 3-Fluoro-2-nitropyridine

Abstract

An efficient method for the substitution of 3-fluoro-2-nitropyridine with a range of nitrogen-containing heterocycles and aliphatic amines is described. The reaction proceeds in a regioselective manner at moderate temperature and in reasonable yield.

Key words

nitrogen-containing heterocycles - 3-fluoro-2-nitropyridine - 3-substituted 2-aminopyridines - aliphatic amines

• References and Notes

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• 21 Typical Procedure for the Preparation of Nitropyridines Illustrated for Table 2, entry 1: K₂CO₃ (5.15 g, 37.23 mmol) was added in one portion to 3-fluoro-2-nitropyridine (2.65 g, 18.62 mmol) and 4-chloro-1H-pyrazole (2.00 g, 19.55 mmol) in MeCN (50 mL), and the resulting mixture was stirred at 50 °C for 5 h. The cooled reaction mixture was diluted with H₂O (100 mL) and extracted with EtOAc (2 × 50 mL). The combined extracts were washed with brine (100 mL), dried (MgSO₄), filtered, and evaporated. The crude product was purified by flash silica chromatography, elution gradient 30% to 60% CH₂Cl₂ in heptane. Pure fractions were evaporated to dryness to afford 3-(4-chloro-1H-pyrazol-1-yl)-2-nitropyridine (2.40 g, 57%) as a solid; mp 113–114 °C. ¹H NMR (400 MHz, CDCl₃): δ = 8.54 (1 H, dd, J = 4.6, 1.5 Hz), 8.07 (1 H, dd, J = 8.1, 1.5 Hz), 7.75 (1 H, s), 7.69–7.73 (2 H, m). ¹³C NMR (101 MHz, CDCl₃): δ = 114.28, 127.41, 128.00, 128.21, 134.85, 141.77, 147.32, 189.75. HRMS (ES): m/z calcd for (C₈H₅N₄O₂Cl)⁺: 224.0101; found: 224.0103. Typical Procedure for the Reduction of Nitropyridines Using Method A A suspension of the nitropyridine (2.06 mmol) and 10% Pd/C (0.03 mmol) in EtOH (20 mL)–EtOAc (3 mL) was stirred under an atmosphere of hydrogen at ambient temperature for 16 h. The reaction mixture was filtered through Celite, evaporated and the crude gum triturated with Et₂O–heptane to give a solid, which was collected by filtration and dried under vacuum to give the aminopyridine. Typical Procedure for the Reduction of Nitropyridines Using Method B Illustrated for Table 2, entry 1: NH₄Cl (2.70 g, 50.53 mmol) was added to 3-(4-chloro-1H-pyrazol-1-yl)-2-nitropyridine (2.27 g, 10.11 mmol) and iron (3.61 g, 64.64 mmol) in EtOH (30 mL) and H₂O (5 mL), and the resulting mixture was stirred at 80 °C for 3 h. The solvent was evaporated, and the crude product was slurried with MeOH and filtered through a Whatman No. 3 filter paper before purification by ion-exchange chromatography, using an SCX 2 column. The desired product was eluted from the column using 2 M NH₃–MeOH, and pure fractions were evaporated to dryness to afford crude product. The product was dissolved in CH₂Cl₂ and washed with H₂O (2×). The organic layer was dried over Mg₂SO₄, filtered, and evaporated to afford 3-(4-chloro-1H-pyrazol-1-yl)pyridin-2-amine (1.17 g, 59%) as a solid; mp 134–135.6 °C. ¹H NMR (400 MHz, DMSO): δ = 8.44 (1 H, s), 8.03 (1 H, dd, J = 4.8, 1.6 Hz), 7.89 (1 H, s), 7.62 (1 H, dd, J = 7.7, 1.6 Hz), 6.70 (1 H, dd, J = 7.7, 4.8 Hz), 6.32 (2 H, s). ¹³C NMR (101 MHz, DMSO, 30 °C): δ = 110.07, 112.24, 120.09, 128.98, 131.43, 138.69, 147.44, 152.81. HRMS (ES): m/z calcd for [C₈H₈N₄Cl]⁺: 195.0432; found: 195.0431