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Synlett 2016; 27(16): 2362-2367
DOI: 10.1055/s-0035-1562465
DOI: 10.1055/s-0035-1562465
letter
A Simple Approach for the Synthesis of Fused Quinazoline-Based Tetracyclic Compounds via a Multicomponent Reaction Strategy
Weitere Informationen
Publikationsverlauf
Received: 02. April 2016
Accepted after revision: 03. Juni 2016
Publikationsdatum:
13. Juli 2016 (online)
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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.
Supporting Information
- Supporting information for this article is available online at http://dx.doi.org/10.1055/s-0035-1562465.
- Supporting Information
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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.