A Simple Approach for the Synthesis of Fused Quinazoline-Based Tetracyclic Compounds via a Multicomponent Reaction Strategy

Abstract

A simple method for the synthesis of tetracyclic quinazolinone derivatives via a multicomponent reaction strategy from isatoic anhydride and amine with ninhydrin has been developed.

Key words

isatoic anhydride - ninhydrin - tetracyclic quinazolinone - multicomponent reaction

• References and Notes

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• 14 Synthesis of 6-Substituted 6,6a-Dihydro-5H-isoquinolino[2,3-a]quinazoline-5,7,12-trione Derivatives 10a–p: General Procedure To a solution of isatoic anhydride (1.0 equiv) in 1,4 dioxane (4.0 mL) amine 8 (1.0 equiv) was added, and the reaction was heated to reflux for 3–4 h. The reaction progress was monitored by TLC. After completion of the reaction, the mixture was cooled to room temperature, then ninhydrin (1.0 equiv) followed by HCl in dioxane (3 M) solution (2.0 mL) were added, and the mixture was heated in a sealed tube for 8–10 h. After completion of the reaction, the solvent was evaporated under vacuum, and the residue was purified by column chromatography in EtOAc–hexane (3:7).
• 15 Representative Analytical Data 6-Butyl-6,6a-dihydro-5H-isoquinolino[2,3-a]quinazoline-5,7,12-trione (10a) Orange solid; yield 71%; mp 155–157 °C. ¹H NMR (400 MHz, DMSO-d ₆): δ = 8.19–8.14 (m, 3 H, ArH), 7.71 (d, J = 6.8 Hz, 1 H, ArH), 7.32 (t, J = 6.4 Hz, 1 H), 6.84 (t, J = 7.2 Hz, 1 H, ArH,), 6.61 (d, J = 8.0 Hz, 1 H), 3.07 (t, J = 7.2 Hz, 2 H), 1.34–1.28 (m, 2 H), 1.15–1.05 (m, 4 H), 0.69 (t, J = 7.2 Hz, 3 H). ¹³C NMR (100 MHz, DMSO-d ₆): δ = 194.84, 162.90, 144.97, 139.04, 138.10 (3 C), 133.54, 127.25, 124.47 (3 C), 118.38, 114.28, 113.75, 74.32, 43.28, 30.36, 19.42, 13.37. HRMS: m/z calcd for C₂₀H₁₉N₂O₃ [M + H]: 335.1396; found: 335.1400. 6-Cyclopropyl-6,6a-dihydro-5H-isoquinolino[2,3-a]quinazoline-5,7,12-trione (10d) Brown solid; yield 67%; mp 205–208 °C. ¹H NMR (400 MHz, DMSO-d ₆): δ = 8.18–8.14 (m, 4 H, ArH), 7.66 (d, J = 7.2 Hz, 2 H), 7.29–7.25 (m, 1 H, ArH), 6.77 (t, J = 7.2 Hz, 1 H), 6.57 (d, J = 8.0 Hz, 1 H, ArH), 2.29–2.23 (m, 1 H), 0.60–0.55 (m, 2 H), 0.39–0.35 (m, 2 H). ¹³C NMR (100 MHz, DMSO-d ₆): δ = 195.21, 163.89, 145.11, 139.14, 137.97 (3 C), 133.62, 127.34, 124.35 (3 C), 118.46, 114.91, 113.81, 74.71, 26.96, 8.27 (2 C). HRMS: m/z calcd for C₁₉H₁₅N₂O₃ [M + H]: 319.1083; found: 319.1068. 6-[(Tetrahydrofuran-2-yl)methyl]-6,6a-dihydro-5H-isoquinolino[2,3-a]quinazoline-5,7,12-trione (10e) Yellow solid; yield 68%; mp 194–197 °C. ¹H NMR (400 MHz, DMSO-d ₆): δ = 8.09–8.00 (m, 4 H, ArH), 7.76 (s, 1 H), 7.72 (d, J = 7.8 Hz, 1 H, ArH), 7.28–7.24 (m, 1 H, ArH), 6.80 (t, J = 7.2 Hz, 1 H, ArH), 6.59 (d, J = 8.0 Hz, 1 H, ArH), 4.01 (dd, J ₁ = 8.2 Hz, J ₂ = 1.6 Hz,1 H), 3.70–3.68 (m, 1 H), 3.40–3.36 (m, 1 H), 2.87–2.81 (m, 1 H), 2.68–2.62 (m, 1 H), 1.78–1.74 (m, 1 H), 1.56–1.50 (m, 2 H), 1.41–1.36 (m, 1 H). ¹³C NMR (100 MHz, DMSO-d ₆): δ = 192.88, 163.44, 144.68, 138.95, 138.79, 137.12 (2 C), 136.36, 133.44, 127.53, 124.14, 123.92, 118.76, 115.81, 114.33, 77.33, 73.67, 65.76, 43.98, 27.76, 24.57. HRMS: m/z calcd for C₂₁H₁₉N₂O₄ [M + H]: 363.1345; found: 363.1352. 6-(3,4-Dimethoxyphenethyl)-6,6a-dihydro-5H-isoquinolino[2,3-a]quinazoline-5,7,12-trione (10j) Orange solid; yield 74%; mp 159–161 °C. ¹H NMR (400 MHz, DMSO-d ₆): δ = 8.13–8.12 (m, 4 H, ArH), 7.73 (d, J = 8.0 Hz, 1 H, ArH), 7.66 (s, 1 H, ArH), 7.29 (t, J = 7.6 Hz, 1 H), 6.80 (t, J = 7.2 Hz, 1 H, ArH), 6.69 (d, J = 7.6 Hz, 1 H, ArH), 6.59 (d, J = 7.6 Hz, 1 H, ArH), 6.47 (s, 1 H), 6.43 (d, J = 8.0 Hz, 1 H, ArH), 3.63 (s, 6 H), 3.27 (t, J = 7.6 Hz, 2 H), 2.65 (t, J = 7.6 Hz, 2 H). ¹³C NMR (100 MHz, DMSO-d ₆): δ = 194.57, 162.88, 147.18, 145.03, 139.01 (2 C), 137.93 (3 C), 133.65, 130.54, 127.24, 124.39 (3 C), 120.19, 118.49, 114.36, 113.85, 112.01, 113.73, 74.36, 55.30, 55.17, 45.58, 34.01. HRMS: m/z calcd for C₂₆H₂₃N₂O₅ [M + H]: 443.1607; found: 443.1605. 3-Bromo-6-(3-methoxypropyl)-6,6a-dihydro-5H-isoquinolino[2,3-a]quinazoline-5,7,12-trione (10m) Orange solid; yield 74%; mp 205–207 °C. ¹H NMR (400 MHz, DMSO-d ₆): δ = 8.19–8.15 (m, 4 H, ArH), 7.94 (s, 1 H, ArH), 7.74 (d, J = 8.0 Hz, 1 H, ArH), 7.45 (dd, J ₁ = 8.8 Hz, J ₂ = 2.4 Hz, 1 H, ArH), 6.57 (d, J = 8.8 Hz, 1 H, ArH), 3.16 (t, J = 8.8 Hz, 2 H), 3.13–3.08 (m, 2 H), 3.02 (s, 3 H), 1.63–1.56 (m, 2 H). ¹³C NMR (100 MHz, DMSO-d ₆): δ = 194.31, 161.88, 144.15, 139.00, 138.24 (3 C), 136.09, 129.23, 124.60 (3 C), 116.21, 115.82, 109.37, 74.19, 69.10, 57.48, 41.46, 28.18. HRMS: m/z calcd for C₂₀H₁₈N₂O₄Br [M + H]: 429.0450; found: 429.0444. 3-Bromo-6-hexyl-6,6a-dihydro-5H-isoquinolino[2,3-a]quin-azoline-5,7,12-trione (10o) Orange solid; yield 74%; mp 145–147 °C. ¹H NMR (400 MHz, DMSO-d ₆): δ = 8.20–8.15 (m, 4 H, ArH), 7.92 (s, 1 H), 7.74 (d, J = 7.6 Hz, 1 H, ArH), 7.44 (dd, J ₁ = 8.4 Hz, J ₂ = 2.0 Hz, 1 H, ArH), 6.56 (d, J = 8.8 Hz, 1 H), 3.05 (t, J = 7.6 Hz, 2 H), 1.32–1.23 (m, 2 H), 1.13–1.05 (m, 6 H), 0.75 (t, J = 6.8 Hz, 3 H). ¹³C NMR (100 MHz, DMSO-d ₆): δ = 194.42, 161.71, 144.16, 138.96, 138.26 (3 C), 136.01, 129.27, 124.57 (3 C), 116.20, 115.97, 109.35, 73.98, 43.59, 30.48, 27.93, 26.79, 21.67, 13.71. HRMS: m/z calcd for C₂₂H₂₂N₂O₃Br [M + H]: 441.0814; found: 441.0805. 3-Bromo-6-phenethyl-6,6a-dihydro-5H-isoquinolino[2,3-a]quinazoline-5,7,12-trione (10p) Yellow solid; yield 76%; mp 211–213 °C. ¹H NMR (400 MHz, DMSO-d ₆): δ = 8.22–8.17 (m, 4 H, ArH), 7.98 (s, 1 H), 7.75 (d, J = 7.6 Hz, 1 H), 7.47 (dd, J ₁ = 8.4 Hz, J ₂ = 2.4 Hz, 1 H, ArH), 7.29–7.27 (m, 2 H, ArH), 7.21–7.10 (m, 1 H, ArH), 6.98 (d, J = 6.8 Hz, 2 H), 6.59 (d, J = 8.4 Hz, 1 H), 3.24 (t, J = 8.0 Hz, 2 H), 2.71 (t, J = 8.4 Hz, 2 H). ¹³C NMR (100 MHz, DMSO-d ₆): δ = 194.16, 161.78, 144.21, 139.09 (2 C), 138.22 (3 C), 136.17, 129.26, 128.38 (3 C), 128.22 (3 C), 126.33, 124.64, 116.31, 115.88, 109.51, 74.29, 45.53, 34.34. HRMS: m/z calcd for C₂₄H₁₈N₂O₃Br [M + H]: 461.0501; found: 461.0507.