An Efficient Strategy for the Synthesis of 1,6-Naphthyridine-2,5-dione Derivatives under Ultrasound Irradiation

Abstract

A flexible and efficient three-component reaction has been established for the synthesis of bioactive 1,6-naphthyridine-2,5-diones by using low-cost and readily accessible aminopyridinones, aromatic aldehydes, and Meldrum’s acid as starting materials. The main advantage of this synthetic method is that the yields of the resulting 1,6-naphthyridine-2,5-dione derivatives under ultrasound irradiation in water with acetic acid as catalyst are higher than those from the classical-heating method. The probable reaction mechanism indicates that the process involves a Knoevenagel condensation, Michael addition, and cyclization sequence.

Key words

aminopyridinones - naphthyridines - green chemistry - sonochemistry - multicomponent reaction - domino reaction

• References and Notes

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• 13 1,6-Naphthyridine-2,5-diones 4a–q; General Procedure A mixture of the appropriate aminopyridinone 1 (1.0 mmol), aldehyde 2 (1.0 mmol), Meldrum’s acid 3 (1.0 mmol), and HOAc (10 mol%) in H₂O (3.0 mL) was sonicated at 80 °C for about 1 h until the reaction was complete (TLC). The mixture was then diluted with H₂O (10 mL) and extracted with EtOAc (3 × 10 mL). The combined organic layers were dried (Na₂SO₄), filtered, and concentrated in a vacuum, and the resulting product was purified by column chromatography (silica gel). 7-Methyl-1,4,6-triphenyl-4,6-dihydro-1,6-naphthyridine-2,5(1H,3H)-dione (4a) Yellow powder; yield: 32.0 mg (79%); mp 160–162 °C. ¹H NMR (400 MHz, CDCl₃, TMS): δ = 7.43–7.53 (m, 8 H, ArH), 7.15–7.33 (m, 7 H, ArH), 5.38 (s, 1 H, CH), 4.66 (d, J = 6.0 Hz, 1 H, CH), 3.20–3.26 (m, 1 H, CH), 3.13 (dd, J = 20.0, 2.0 Hz, 1 H, CH), 1.82 (s, 3 H, CH₃). ¹³C NMR (100 MHz, CDCl₃, TMS): δ = 169.9, 162.6, 147.9, 145.4, 142.0, 138.5, 137.1, 129.8, 129.7, 128.8, 128.1, 127.8, 127.0, 110.6, 110.6, 98.7, 38.2, 35.0, 21.8. HRMS (ESI): m/z [M + H]⁺ calcd for C₂₇H₂₃N₂O₂: 407.1754; found: 407.1756. 3,3′-(2-Thienylmethylene)bis[4-(phenylamino)-6-methyl-1-phenylpyridin-2(1H)-one] (5) Yellow powder; yield: 29.1 mg (45%); mp 288–290 °C. ¹H NMR (400 MHz, CDCl₃, TMS): δ = 11.10 (s, 1 H, NH), 10.46 (s, 1 H, NH), 7.46–7.53 (m, 6 H, ArH), 7.08–7.27 (m, 15 H, ArH), 6.86 (s, 1 H, ArH), 6.78 (t, J = 4.0 Hz, 1 H, ArH), 6.62 (s, 1 H, ArH), 6.33 (s, 2 H, CH), 1.90 (s, 6 H, CH₃). ¹³C NMR (100 MHz, CDCl₃, TMS): δ = 145.3, 140.8, 129.0, 128.4, 126.0, 123.7, 123.3, 122.8, 122.5, 98.4, 35.1, 21.6. HRMS (ESI): m/z [M + H]⁺ calcd for C₄₁H₃₅N₄O₂S: 647.2475; found: 647.2477.
• 14 1′H-Spiro[indole-3,4′-[1,6]naphthyridine]-2,2′,5′(1H,3′H,6′H)-triones 7; General Procedure In a similar manner to the synthesis of 1,6-naphthyridine-2,5-diones 4, a mixture of the appropriate aminopyridinone 1 (1.0 mmol), isatin 6, (1.0 mmol), Meldrum’s acid (3; 1.0 mmol), and HOAc (10 mol%) in H₂O (3.0 mL) was sonicated at 80 °C for ~1 h until the reaction was complete (TLC). The mixture was then cooled to rt and the solid product was collected by filtration and purified by crystallization from 95% EtOH. 5,7′-Dimethyl-1′,6′-diphenyl-1′H-spiro[indole-3,4′-[1,6]naphthyridine]-2,2′,5′(1H,3′H,6′H)-trione (7a) White powder; yield: 39.2 mg (85%); mp >300 °C. ¹H NMR (400 MHz, CDCl₃, TMS): δ = 10.33 (s, 1 H, NH), 7.42–7.63 (m, 8 H, ArH), 6.97–7.12 (m, 4 H, ArH), 6.75 (s, 1 H, ArH), 5.38 (s, 1 H, ArH), 2.44–2.51 (m, 2 H, ArH), 2.26 (s, 3 H, CH₃), 1.75 (s, 3 H, CH₃). ¹³C NMR (100 MHz, CDCl₃, TMS): δ = 178.6, 168.0, 160.1, 149.5, 146.9, 139.9, 138.3, 137.4, 132.4, 130.7, 130.4, 129.8, 129.7, 129.4, 129.3, 129.0, 128.4, 123.4, 109.9, 107.4, 98.0, 48.3, 41.6, 40.6, 39.3, 21.7, 21.2. HRMS (ESI): m/z [M + H]⁺ calcd for C₂₉H₂₄N₃O₃: 462.1812; found: 462.1809.
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