An Efficient Strategy for the Synthesis of Naphtho[2,3-b][1,6]naphthyridines Promoted by Acetic Acid

Abstract

A three-component domino reaction for the synthesis of naphtho[2,3-b][1,6]naphthyridine derivatives has been established. Such strategy exhibited excellent substrate scope including various enaminones and aldehydes that afforded a series of multifunctionalized naphtho[2,3-b][1,6]naphthyridine derivatives with 70–86% yields. The advantages of bond-forming efficiency, accessibility of starting materials, and water as sole byproducts provide invaluable access to biological 1,6-naphthyridines.

Key words

aminopyridinone - 2-hydroxynaphthalene-1,4-dione - naphtho[2,3-b][1,6]naphthyridines - acetic acid - synthesis

Publication History

Received: 05 March 2021

Accepted after revision: 10 April 2021

Accepted Manuscript online:
10 April 2021

Article published online:
22 April 2021

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• 14 General Procedure for the Synthesis of 5,12-Dihydronaphtho[2,3-b][1,6]naphthyridine-1,6,11(2H)-triones 4a–vA mixture of aminopyridinone 1 (0.5 mmol), aldehyde 2 (0.5 mmol), 2-hydroxynaphthalene-1,4-dione 3 (0.5 mmol), and HOAc (3.0 mL) was stirred and heated at 100 °C for about 4 h. After completion of the reaction as indicated by TLC, the reaction mixture was diluted with cold water (10 mL). The crude products were filtered by Büchner funnel and further purified by recrystallization from hot 95% ethanol to afford the desired pure products 4 as red to red brown solid.3-Methyl-2,5-diphenyl-12-(p-tolyl)-5,12-dihydronaphtho[2,3-b][1,6]naphthyridine-1,6,11(2H)-trione (4a)Red brown solid; mp 290–292 °C. ¹H NMR (400 MHz, CDCl₃, TMS): δ = 8.03 (d, J = 8.0, 1.2 Hz, 1 H, ArH), 7.82 (d, J = 7.6, 0.8 Hz, 1 H, ArH), 7.63–7.66 (m, 5 H, ArH), 7.42–7.49 (m, 4 H, ArH), 7.51–7.53 (m, 3 H, ArH), 7.19 (d, J = 7.2 Hz, 1 H, ArH), 7.12 (d, J = 8.0 Hz, 2 H, ArH), 7.04–7.08 (m, 1 H, ArH), 5.77 (s, 1 H, CH), 5.58 (s, 1 H, CH), 2.30 (s, 3 H, CH₃), 1.82 (s, 3 H, CH₃). ¹³C NMR (100 MHz, CDCl₃, TMS): δ = 187.8, 182.1, 165.0, 161.6, 153.6, 145.5, 139.7, 138.1, 135.3, 134.2, 133.9, 133.1, 132.6, 131.2, 129.7, 129.6, 129.5, 129.1, 128.9, 128.3, 127.8, 126.6, 126.4, 124.6, 123.1, 99.5, 35.5, 21.6, 21.0. HRMS (ESI): m/z calcd for C₃₆H₂₇N₂O₃ [M + H]⁺: 535.2022; found: 535.2021
• 15 General Procedure for the Synthesis of 12-Aryl-2,3,4,12-tetrahydro-1H-benzo[b]xanthene-1,6,11-triones 6Similarly, the mixture of 3-(arylamino)cyclohex-2-en-1-one 1 (0.5 mmol), aldehyde 2 (0.5 mmol), 2-hydroxynaphthalene-1,4-dione (3, 0.5 mmol), and HOAc (3.0 mL) was stirred and heated at 100 °C for about 4 h. After completion of the reaction as indicated by TLC, the reaction mixture was diluted with cold water (10 mL). The crude products were filtered by Büchner funnel and further purified by recrystallization from hot 95% ethanol to afford the desired pure products 6 as red to red-brown solid. 3,3-Dimethyl-12-phenyl-2,3,4,12-tetrahydro-1H-benzo[b]xanthene-1,6,11-trione (6a)Red solid; mp 232–234 °C. ¹H NMR (400 MHz, CDCl₃, TMS): δ = 8.14 (t, J = 5.6 Hz, 1 H, ArH), 8.00–8.02 (m, 1 H, ArH), 7.71–7.73 (m, 2 H, ArH), 7.41 (d, J = 7.6 Hz, 2 H, ArH), 7.28 (t, J = 7.6 Hz, 2 H, ArH), 7.18 (t, J = 7.2 Hz, 1 H, ArH), 5.16 (s, 1 H, CH), 2.65–2.78 (m, 2 H, CH₂), 2.25–2.35 (m, 2 H, CH₂), 1.17 (s, 3 H, CH₃), 1.08 (s, 3 H, CH₃). ¹³C NMR (100 MHz, CDCl₃, TMS): δ = 196.2, 182.9, 178.0, 162.8, 149.0, 142.5, 134.5, 133.7, 131.6, 130.6, 128.7, 128.5, 127.2, 126.6, 126.5, 125.3, 114.3, 50.7, 40.7, 32.8, 32.4, 29.1, 27.4. HRMS (ESI): m/z calcd for C₂₅H₂₁O₄ [M + H]⁺: 385.1440; found: 385.1449
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