One-Pot, Three-Component Synthesis of 1,8-Naphthyridine Derivatives from Heterocyclic Ketene Aminals, Malononitrile Dimer, and Aryl Aldehydes

Abstract

An efficient and versatile method was developed for the access of multisubstituted 1,8-naphthyridine derivatives through a one-pot, three-component protocol from heterocyclic ketene animals, malononitrile dimer, and aryl aldehydes in high yields. The 1,8-naphthyridines were formed via Knoevenagel condensation, aza–ene reaction, imine–enamine tautomerization, and intramolecular cyclization.

Key words

one-pot - multicomponent reactions - heterocyclic ketene aminals - 1,8-naphthyridine - co-catalysts

• References and Notes

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• 17 Typical Procedure for the Synthesis of 4 Heterocyclic ketene aminals (1 mmol), aryl aldehydes (1.2 mmol), malononitrile dimer (1.5 mmol), AcOH (1 mmol), piperidine (1 mmol), and EtOH (10 mL) were stirred at refluxing for 1 h. After completion of the reaction (confirmed by TLC), the reaction mixture was filtered to afford the crude product, which was further washed with 95% EtOH to give pure product 4. The structures of the products were well characterized by NMR and HRMS studies. The characterization data of representative compounds 4a and 4u are given below. Compound 4a: light yellow solid; mp 300.9–302.0 °C. ¹H NMR (400 MHz, DMSO-d ₆): δ = 9.33 (s, 1 H), 7.37 (d, J = 7.6 Hz, 2 H), 7.25 (d, J = 7.6 Hz, 2 H), 6.41 (s, 2 H), 6.24 (s, 2 H), 5.40 (s, 1 H), 4.08 (t, 2 H), 3.89–3.73 (m, 2 H) ppm. ¹³C NMR (100 MHz, DMSO-d ₆): δ = 159.8, 154.2, 152.4, 149.1, 142.5, 130.9, 129.7, 127.6, 116.6, 106.6, 92.6, 69.9, 44.4, 43.3, 36.6 ppm. ESI-HRMS: m/z calcd for C₁₇H₁₄ ³⁵ClN₇O₂ [M – H]^–: 382.0898; found: 382.0811; calcd for C₁₇H₁₄ ³⁷ClN₇O₂ [M – H]^–: 384.0898; found: 384.0771 Compound 4u: light yellow solid; mp 281.4–282.0 °C. ¹H NMR (400 MHz, DMSO-d ₆): δ = 11.49 (s, 1 H), 8.07 (d, J = 8.4 Hz, 2 H), 7.61 (d, J = 8.4 Hz, 2 H), 6.50 (d, 4 H), 5.66 (s, 1 H), 4.08 (m, 2 H), 3.51 (m, 2 H), 2.04 (m, 2 H) ppm. ¹³C NMR (100 MHz, DMSO-d ₆): δ = 159.2, 154.8, 151.0, 150.6, 149.2, 146.1,128.9, 123.0, 116.3, 107.8, 91.9, 70.5 41.3, 38.7, 35.8, 19.5 ppm. ESI-HRMS: m/z calcd for C₁₈H₁₆N₈O₄ [M – H]^–: 407.1295; found: 407.1216.