Substituent-Dictated Concise Synthesis of 4,6-Disubstituted N-Alkyl-2-­pyridones and 2-Aminopyridines [1]

Abstract

Functionalized N-alkyl-2-pyridones and 2-aminopyridines are useful precursors for the synthesis of various heterocyclic compounds of therapeutic importance. In this paper we have delineated and illustrated a direct methodology for the synthesis of 6-aryl-N-hydroxyethyl-4-methylsulfanyl-2-pyridones through the ring transformation of 6-aryl-3-cyano-4-methylsulfanyl-2H-pyran-2-ones by ethanolamine. Surprisingly, the analogous reaction with 6-aryl-3-cyano-4-piperidin-1-yl-2H-pyran-2-ones afforded 2-aminopyridines in high yield instead of the corresponding 2-pyridones.

N-alkyl-2-pyridone - 2-aminopyridine - ethanolamine - pyran-2-one - ring transformation reaction

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30

Synthesis of 6-aryl- N -hydroxyethyl-4-methylsulfanyl-2 (1 H )-pyridones 3a-e and 6-aryl-3-carbomethoxy/cyano-4-(2-hydroxyethyl-amino)-2 H -pyran-2-ones 2a-e; General procedure: A mixture of 6-aryl-3-cyano-4-methylsulfanyl-2H-pyran-2-ones (1, 1 mmol) and ethanolamine (1.2 mmol) was refluxed in EtOH for 1-4 h. After completion, the reaction was cooled to r.t. and left overnight. The white crystalline solid 3 was filtered off and washed with EtOH. The filtrate was evaporated to dryness and pure compound 2 was isolated by column chromatography using CHCl₃ as an eluent.

31

Spectroscopic and elemental analyses data of selected compounds. 2a: white solid; mp 140-142 °C; IR (KBr): 1630 (CO), 3427 cm^-1 (OH); ¹H NMR (200 MHz, CDCl₃): δ = 2.44 (s, 3 H, SCH₃), 3.72-3.75 (m, 2 H, CH₂), 4.03 (t, J = 4.9 Hz, 2 H, CH₂), 4.16 (t, J = 4.9 Hz, 1 H, OH), 6.03 (d, J = 2.0 Hz, 1 H, CH), 6.33 (d, J = 2.0 Hz, 1 H, CH), 7.28-7.33 (m, 2 H, ArH), 7.43-7.48 (m, 3 H, ArH); MS (FAB): m/z = 262 (M⁺ + 1); Anal. Calcd for C₁₄H₁₅NO₂S: C, 64.34; H, 5.79; N, 5.36. Found: C, 64.07; H, 5.92; N, 5.25. 3a: white solid; mp 248-250 °C; IR (KBr): 1687 (CO), 2216 (CN), 3271 (NH), 3401 cm^-1 (OH); ¹H NMR (200 MHz, DMSO-d ₆): δ = 3.57 (s, 4 H, 2 CH₂), 4.90 (br s, 1 H, OH), 7.04 (s, 1 H, CH), 7.55-7.58 (m, 3 H, ArH), 7.93-7.97 (m, 2 H, ArH), 8.30 (br s, 1 H, NH); MS (FAB): m/z = 257 (M⁺ + 1); Anal. Calcd for C₁₄H₁₂N₂O₃: C, 65.62; H, 4.72; N, 10.93. Found: C, 65.65; H, 4.51; N, 10.83. 7: white solid; mp 236-237 °C; IR (KBr): 1657, 1688 (CO), 3403 cm^-1 (OH); ¹H NMR (200 MHz, DMSO-d ₆): δ = 3.63-3.66 (m, 4 H, 2 CH₂), 3.74 (s, 3 H, OCH₃), 5.08 (br s, 1 H, OH), 6.97 (s, 1 H, CH), 7.53-7.58 (m, 3 H, ArH), 7.96-8.00 (m, 2 H, ArH), 10.05 (br s, 1 H, NH); MS (FAB): m/z = 290 (M⁺ + 1); Anal. Calcd for C₁₅H₁₅NO₅: C, 62.28; H, 5.23; N, 4.84. Found: C, 62.31; H, 5.26; N, 4.48. 9a: white solid; mp 124-126 °C; IR (KBr): 3370 (NH), 3469 (NH) cm^-1; ¹H NMR (200 MHz, CDCl₃): δ = 1.56-1.60 (m, 4 H, 2 CH₂), 1.65-1.68 (m, 2 H, CH₂), 3.34-3.37 (m, 4 H, 2 CH₂), 4.51 (br s, 2 H, NH₂), 5.84 (d, J = 2.0 Hz, 1 H, PyH), 6.59 (d, J = 2.0 Hz, 1 H, PyH), 7.38-7.42 (m, 3 H, ArH), 7.84-7.88 (m, 2 H, ArH); MS (FAB): m/z = 254 (M⁺ + 1); Anal. Calcd for C₁₆H₁₉N₃: C, 75.85; H, 7.56; N, 16.59. Found: C, 75.38; H, 7.06; N, 16.37.