Synthesis of Unprecedented Benzofused [1,2,4]-Triazoloquinazolines via Benzyne Diels–Alder Reaction with 7-Vinyl-[1,2,4]triazolo[1,5-c]pyrimidines as Dienes

Abstract

The benzyne Diels–Alder reaction with 7-vinyl-[1,2,4]triazolo[1,5-c]pyrimidines as a kind of unusual acyclic dienes has been investigated. The transformation proceeded smoothly in the presence of CsF to afford the unprecedented partially hydrogenated benzo[f][1,2,4]triazolo[1,5-c]quinazolines in good yields. Treatment of benzo[f][1,2,4]triazolo[1,5-c]quinazolines with DDQ provided the respective dehydroaromatization products.

Key words

arynes - Diels–Alder reaction - heterocycles - triazolopyrimidines - benzotriazoloquinazolines

• References and Notes

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• 19 General Procedure for Kumada Coupling of 3a–u with Vinylmagnesium Bromide A flask charged with substrate 3 (1.0 mmol) and Pd(PPh₃)₂Cl₂ (35 mg, 0.05 mmol) was flushed with nitrogen. Anhydrous THF (10 mL) was added by syringe, and then vinylmagnesium bromide in THF (0.7 M in THF, 1.9 mL, 1.3 mmol) was added slowly by syringe over a period of about 30 min. The whole was further refluxed until the reaction was considered complete as determined by TLC analysis. The reaction solvent was removed under reduced pressure, and the residue was purified by flash column chromatography on silica gel to provide the corresponding 7-vinyl-[1,2,4]triazolo[1,5-c]pyrimidines 4. Spectral Data of 4a White powder; yield 77%; mp 187–188 °C. ¹H NMR (400 MHz, CDCl₃): δ = 8.28 (d, J = 4.0 Hz, 2 H, ArH), 7.48 (s, 3 H, ArH), 7.35 (s, 1 H, ArH), 6.75 (dd, J = 10.4, 16.8 Hz, 1 H, CH), 6.45 (d, J = 16.8 Hz, 1 H, CH₂), 5.59 (d, J = 10.4 Hz, 1 H, CH₂), 3.01 (s, 3 H, CH₃). ¹³C NMR (100 MHz, CDCl₃): δ = 165.3, 153.7, 150.8, 150.1, 134.5, 130.7, 130.3, 128.8, 127.7, 121.2, 106.0, 20.0. IR (KBr): ν_max = 3061, 3016, 1626, 1543, 1459, 1428, 1321, 1287, 1216, 925, 714, 690 cm^–1. ESI-HRMS: m/z calcd for C₁₄H₁₂N₄ [M + H]⁺: 237.1140; found: 237.1143.
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• 24 General Procedure for the Benzyne DA Cycloaddition of 7-Vinyl-[1,2,4]triazolo[1,5-c]pyrimidines 4a–k (Table 2) To the flask charged with a heterocyclic diene 4 (0.5 mmol), CsF (0.46 g, 3.0 mmol,) and o-(trimethylsilyl)phenyl triflate (5a, 0.45 g, 1.5 mmol) was carefully added degassed dry 1,4-dioxane (12 mL). The mixture was heated under reflux until complete consumption of the starting material (TLC monitoring – the time required was as indicated in Table 2). Concentration of the reaction mixture in vacuum followed by flash column chromatography over SiO₂ (hexane–EtOAc = 1:5) afforded 7a–k. Spectral Data of 7a (Table 2, Entry 1) Yellow powder; yield 76%; mp 164–165 °C. ¹H NMR (400 MHz, CDCl₃): δ = 9.09 (d, J = 8.0 Hz, 1 H, ArH), 8.42 (d, J = 6.8 Hz, 2 H, ArH), 7.53–7.43 (m, 4 H, ArH), 7.35–7.28 (m, 2 H, ArH), 3.13–3.05 (m, 7 H, 2 CH₂, CH₃). ¹³C NMR (100 MHz, CDCl₃): δ = 165.2, 152.2, 151.1, 148.3, 136.0, 130.6, 130.5, 129.7, 128.8, 128.6, 128.1, 127.9, 127.8, 127.2, 115.6, 30.5, 28.2, 20.1. IR (KBr): ν_max = 3061, 2944, 1614, 1599, 1576, 1533, 1484, 1457, 1433, 1333, 1278, 1246, 713, 687 cm^–1. ESI-HRMS: m/z calcd for C₂₀H₁₆N₄ [M + H]⁺: 313.1453; found: 313.1449.
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• 27 See also Supporting Information for computation details.
• 28 General Procedure for the Benzyne DA Cycloaddition of 7-Vinyl-[1,2,4]triazolo[1,5-c]pyrimidines 4n–u To the flask charged with 4 (1.0 mmol), CsF (0.91 g, 6.0 mmol), and o-(trimethylsilyl)phenyl triflate 5 (2.0 mmol) was carefully added degassed anhydrous MeCN (10 mL). The mixture was heated under reflux until complete consumption of the starting material (TLC monitoring). Concentration of the reaction mixture in vacuum followed by flash column chromatography over SiO₂ (hexane–EtOAc, 10:1) afforded 7n–y (Table 2). Spectral Data of 7n (Table 3, Entry 1) White solid; yield 56%; mp 155–156 °C. ¹H NMR (400 MHz, CDCl₃): δ = 9.19 (d, J = 7.8 Hz, 1 H), 8.80–8.71 (m, 2 H), 8.51–8.41 (m, 2 H), 7.64–7.60 (m, 3 H), 7.56–7.50 (m, 3 H), 7.47 (dd, J = 7.1, 0.8 Hz, 1 H), 7.38–7.33 (m, 1 H), 7.31 (d, J = 7.4 Hz, 1 H), 3.24 (t, J = 7.5 Hz, 2 H), 3.12 (t, J = 7.5 Hz, 2 H). ¹³C NMR (100 MHz, CDCl₃): δ = 165.2, 152.5, 152.4, 146.5, 136.3, 131.7, 131.6, 130.6, 130.4, 129.8, 128.8, 128.7, 128.4, 128.0, 127.8, 127.2, 115.9, 30.7, 28.3. ESI-HRMS: m/z calcd for C₂₅H₁₈N₄ [M + H]⁺: 375.1610; found: 375.1605.
• 29 Procedure for the DDQ-Mediated Dehydrogenation of 7b and 7n 7,8-Dihydrobenzo[f][1,2,4]triazolo[1,5-c]quinazoline 7b or 7n (0.3 mmol) and DDQ (136 mg, 0.6 mmol) were dissolved in CH₂Cl₂ (10 mL). The mixture was heated under reflux until complete consumption of the starting material (TLC monitoring). After filtration and removal of the solvent, the residue was purified by the flash column chromatography on SiO₂ with hexane–EtOAc (10:1) as eluent to afford, respectively, the dehydrogenated benzo[f][1,2,4]triazolo[1,5-c]quinazolines 8a and 8b. Spectral Data of 8a White solid; yield 90%; mp 177–178 °C. ¹H NMR (400 MHz, CDCl₃): δ = 10.17 (d, J = 8.5 Hz, 1 H), 8.31–8.14 (m, 2 H), 8.06–7.98 (m, 2 H), 7.93–7.83 (m, 1 H), 7.79–7.68 (m, 1 H), 7.66–7.55 (m, 1 H), 7.52–7.42 (m, 2 H), 3.20 (s, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 150.9, 148.1, 144.8, 143.29, 133.7, 133.1, 132.4, 132.1, 131.1, 131.0, 129.8, 129.7, 128.5, 128.3, 127.9, 127.5, 126.9, 126.1, 113.1, 20.2. ESI-HRMS: m/z calcd for C₂₀H₁₃ClN₄ [M + H]⁺: 345.0907; found: 345.0886. Spectral Data of 8b White solid; yield 60%; mp 192–193 °C. ¹H NMR (400 MHz, CDCl₃): δ = 10.32 (d, J = 8.4 Hz, 1 H), 8.82–8.70 (m, 2 H), 8.60–8.45 (m, 2 H), 8.19 (d, J = 8.9 Hz, 1 H), 8.11 (d, J = 8.9 Hz, 1 H), 8.03 (d, J = 7.9 Hz, 1 H), 7.96–7.86 (m, 1 H), 7.80–7.71 (m, 1 H), 7.69–7.63 (m, 3 H), 7.61–7.51 (m, 3 H).¹³C NMR (100 MHz, CDCl₃): δ = 156.1, 153.0, 146.7, 143.6, 133.2, 132.5, 132.1, 131.7, 130.8, 130.7, 128.9, 128.6, 128.5, 128.3, 128.1, 127.7, 126.8, 113.2, 107.0, 103.5, 101.9. ESI-HRMS: m/z calcd for C₂₅H₁₆N₄ [M + H]⁺: 373.1453; found: 373.1440.