One Step Synthesis of Dihydropyridin-2-imines: Inhibitors of Inducible Nitric Oxide Synthase

Abstract

An exclusive one step synthesis of dihydropyridin-2-imines 2 or 3, both of which are potent inhibitors of inducible nitric oxide (iNOS), from the common starting material 2-aminopyridine 1 was successfully carried out using the Birch reduction followed by the appropriate work-up procedure. The application of this reduction to other substituted 2-aminopyridines 4-8 and 2-hydroxypyridine 9 are reported. The reaction mechanism is also discussed.

dihydropyridin-2-imine - Birch reduction - inhibitor of inducible nitric oxide - 2-aminopyridine - 4-methyl-3,6-dihydropyridin-2-one

References

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9

Kawanaka, Y.; Kobayashi, K.; Kusuda, S.; Tatsumi, T.; Murota, M.; Nishiyama, T.; Hisaichi, K.; Fujii, A.; Hirai, K.; Naka, M.; Komeno, M.; Nakai, H.; Toda, M. Bioorg. Med. Chem. Lett. under submission.

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13 Preparation of 2 from 1: To a stirred solution of 2-amino-4-methylpyridine 1 (2 g, 18.5 mmol) in THF (6.2 mL) and EtOH (2.2 mL) liquid NH₃ (60 mL) was added at -78 °C. Small pieces of lithium metal (320 mg, 46.2 mmol) were added to the reaction mixture and the solution stirred for an additional 1.5 h at -78 °C before quenched with solid NH₄Cl (75 g). The reaction mixture was slowly warmed up to r.t. removing the ammonia with a stream of nitrogen and then treated with aq NH₄Cl. The reaction mixture was extracted with CHCl₃ (100 mL × 4). The combined organic layers were dried (Na₂SO₄) and evaporated to afford 2 as a pale yellow oil, which was converted to its hydrochloride with 4 M HCl/EtOAc-EtOH at 0 °C and further purified by column chromatography on a silica gel using CHCl₃/MeOH = 5:1 as the eluent (pale yellow solid: 1.8 g, 66%): TLC R_f = 0.38 (CHCl₃/MeOH/HOAc = 10:1:1). IR (KBr): 3327, 3138, 1692, 1639, 1614, 1528, 1443, 1383, 1370, 1344, 1178, 1052, 987, 849, 785, 677 cm^-1. ¹H NMR (200 MHz, CDCl₃): δ = 9.30-9.15 (br, 1 H), 9.15-8.95 (br, 1 H), 8.65-8.50 (br, 1 H), 6.24 (s, 1 H), 3.50 (t, J = 7.5 Hz, 2 H), 2.43 (t, J = 7.6 Hz, 2 H), 2.05 (s, 3 H). MS (APCI, Pos.): m/z = 111 (M + H)⁺

14

Preparation of 3 from 1: To a stirred solution of 2-amino-4-methylpyridine 1 (1.0 g, 9.2 mmol) in THF (3.1 mL) and EtOH (1.1 mL) liquid NH₃ (30 mL) was added at -78 °C. Small pieces of lithium metal (210 mg, 30.3 mmol) were then added to the reaction mixture and the solution stirred for an additional 1.5 h at -78 °C before quenched with a small amount of water (4 mL). The reaction mixture was slowly warmed up to r.t. removing the ammonia with a stream of nitrogen and then treated with additional water (20 mL). The reaction mixture was extracted with CHCl₃ (20 mL × 3). The combined organic layers were dried (Na₂SO₄) and eva-porated to afford 3 as a pale yellow oil, which was converted to its hydrochloride with 4 M HCl/EtOAc-EtOH at 0 °C and further purified by column chromatography on a silica gel using CHCl₃/MeOH = 5/1 as the eluent (pale yellow solid: 860 mg, 64%): TLC R_f = 0.38 (CHCl₃/MeOH/HOAc = 10/1/1). IR (KBr): 3292, 3137, 2979, 2944, 2878, 1718, 1682, 1544, 1417, 1356, 1305, 1154, 1016, 946, 866, 812, 600
cm^-1. ¹H NMR (200 MHz, CDCl₃): δ = 10.15-9.95 (br, 1 H), 9.05-8.95 (br, 1 H), 8.90-8.65 (br, 1 H), 5.55 (br, 1 H), 4.05-3.90 (m, 2 H), 3.22 (t, J = 5.1 Hz, 2 H), 1.80 (s, 3 H). MS (APCI, Pos.): m/z = 111 (M + H)⁺.