Synthesis of N-Modified 4-Aminopyridine-3-carboxylates by Ring ­Transformation

Abstract

3-Methyl-5-nitropyrimidin-4(3H)-one reacted with enaminones to cause the ring transformation leading to functionalized 4-aminopyridines. Various kinds of amino groups can be introduced at the 4-position by modifying the enaminones. The modification of its vicinal positions was also possible. In addition, a bicyclic pyridine could be synthesized by making use of the ­vicinal functionality of a 4-aminopyridine-3-carboxylic acid.

amino alcohols - bicyclic compounds - heterocycles - ­pyridines

References and Notes

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6

Nitropyrimidinone 1 is readily prepared from 2-thiouracil by reduction, [12] methylation [12] and nitration [8] in 43% overall yield.

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9

To ethyl 3-oxobutanoate (127 µL, 1 mmol), propylamine (99 µL, 1.2 mmol) was added, and the resultant mixture was stirred without solvent at r.t. for 2 h. Excess amounts of amine and unreacted reagent were removed under reduced pressure to give enaminone 2a (170 mg, 1 mmol, quant.) as the residual yellow oil. Since enaminone 2a was sufficiently pure in the ¹H NMR, it was used for the following ring trans-formation without further purification. Other enaminones were prepared in a similar way changing amines or 1,3-dicarbonyl compounds. When the reaction did not reach completion, the mixture was heated at 60 °C for a long time.

10

Spectral data for 3a: yellow oil. IR (neat): 3346, 1687, 1219, 1105 cm^-1. ¹H NMR (400 MHz, CDCl₃, TMS): δ = 1.03 (t, J = 7.3 Hz, 3 H), 1.39 (t, J = 7.1 Hz, 3 H), 1.71 (tq, J = 7.3, 6.9 Hz, 2 H), 3.19 (dt, J = 6.9, 6.9 Hz, 2 H), 4.34 (q, J = 7.1 Hz, 2 H), 6.51 (d, J = 6.1 Hz, 1 H), 8.00-8.10 (br s, 1 H), 8.21 (d, J = 6.1 Hz, 1 H), 8.87 (s, 1 H). ¹³C NMR (100 MHz, CDCl₃, TMS): δ = 11.6 (q), 14.3 (q), 22.2 (t), 44.0 (t), 60.4 (t), 105.9 (d), 107.1 (s), 152.4 (d), 152.5 (d), 154.7 (s), 168.1 (s). Anal. Calcd for C₁₁H₁₆N₂O₂: C, 63.44; H, 7.74; N, 13.45. Found: C, 63.19; H, 7.90; N, 13.49.
Other APCA derivatives also showed satisfactory spectral data.

11

Spectral Data for 16.
To a solution of pyridine derivative 3h (210 mg, 1 mmol) in THF (10 mL), NaH (60 wt%, 80 mg, 2 mmol) was added, and the mixture was heated under reflux for 1 d. After quenching with 1 M HCl (2 mL, 2 mmol), the reaction mixture was evaporated under vacuo. The residue was washed with CHCl₃ (3 × 10 mL), and then extracted with EtOH (2 × 15 mL). After drying over MgSO₄, the solvent was removed under reduced pressure to give 3,4-dihydro-pyrido[4,3-e][1,4]oxazepin-1-one (16, 180 mg, 1 mmol, quant.) as a pale-yellow solid. IR (nujol): 1691, 1201, 1045 cm^-1. ¹H NMR (400 MHz, DMSO-d ₆, TMS): δ = 3.10-3.20 (m, 2 H), 3.50-3.80 (m, 2 H), 6.48 (d, J = 5.8 Hz, 1 H), 7.97 (d, J = 5.8 Hz, 1 H), 8.67 (s, 1 H), 9.50-9.60 (br s, 1 H). ¹³C NMR (100 MHz, DMSO-d ₆, TMS): δ = 45.3 (t), 60.8 (t), 106.1 (d), 126.9 (s), 151.5 (d), 153.7 (d), 155.6 (s), 173.2 (s).

12 Bauer L. Wright GE. Mikrut BA. Bell CE. J. Heterocycl. Chem.  1965,  2:  447