Efficient Synthesis of Functionalized 2-Pyridones from Malonyl Dichloride, Alkylamines and Dimethyl Acetylenedicarboxylate

Abstract

An efficient synthesis of dimethyl 1-alkyl-4-hydroxy-6-oxo-1,6-dihydropyridine-2,3-dicarboxylates is described. This involves a three-component reaction between primary alkylamines, malonyl dichloride, and dimethyl acetylenedicarboxylate.

Key word

malonyl dichloride - 2-pyridinone - acetylenic ester - multicomponent reaction

References and Notes

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8

Dimethyl 1-Benzyl-4-hydroxy-6-oxo-1,6-dihydro-2,3-pyridinedicarboxylate (4a): To a stirred solution of DMAD (0.34 g, 2.4 mmol) and benzyl amine (0.20 g, 2 mmol) in CH₂Cl₂ (10 mL) was added malonyl dichloride (0.19 mL, 2 mmol) at r.t. The reaction mixture was then stirred for 24 h. The solvent was removed under reduced pressure and the viscous residue was purified by flash column chromatography on silica gel (Merck 230-400 mesh) using n-hexane-EtOAc as eluent to give 4a as a white powder; mp 119-121 °C; yield: 0.53 g (85%). IR (KBr): 3445 (OH), 1732 (C=O), 1677, 1654, 1528, 1434 cm^-1. ¹H NMR (500.1 MHz, CDCl₃): δ = 3.69 (s, 3 H, OMe), 3.85 (s, 3 H, OMe), 5.19 (s, 2 H, CH₂), 6.05 (s, 1 H, CH), 7.16 (d, ³ J _HH = 6.9 Hz, 2 H, CH), 7.24-7.30 (m, 3 H, CH), 10.86 (s, 1 H, OH). ¹³C NMR (125.7 MHz, CDCl₃): δ = 48.9 (NCH₂), 53.0 (OMe), 53.2 (OMe), 97.8 (CH), 100.2 (C), 127.0 (2 × CH), 127.8 (CH), 128.5 (2 × CH), 135.4 (C), 147.4 (C), 162.3, 162.4, 165.3, 167.1 (COH, 3 × C=O). MS: m/z (%) = 317 (15) [M⁺], 241 (8), 211 (15), 196 (40), 179 (10), 91 (100), 77 (20), 57 (10). Anal. Calcd for C₁₆H₁₅NO₆ (317.29): C, 60.75; H, 4.76; N, 4.41. Found: C, 60.50; H, 4.70; N, 4.30. All other novel compounds isolated possessed spectroscopic and analytical data in agreement with their proposed structures.