Microwave-Assisted Synthesis of Benzo[4,5]imidazo[1,2-a]pyrimidines from β-Bromo-α,β-unsaturated Aldehydes and 2-Aminobenzimidazoles

Abstract

β-Bromo-α,β-unsaturated aldehydes react with 2-aminobenzimidazoles by microwave irradiation in the presence of a base and magnesium sulfate to give the corresponding benzo[4,5]imidazo[1,2-a]pyrimidines in moderate to good yields.

Key words

cyclization - heterocycles - aldehydes - fused-ring systems - coupling

• References and Notes

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For the synthesis of benzo[4,5]midazo[1,2-a]pyrimidine analogues, benzo[4,5]midazo[1,2-a]quinazolines, see:
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• 20 Lower molar ratio of [2a]/[1a] = 1.0 resulted in 43% yield of 3a.
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• 22 Similar treatment of 1a (0.3 mmol) with 2a (0.45 mmol) in N,N-dimethylformamide in the presence of triethylamine and magnesium sulfate under usual heating method (screw-capped vial, 150 °C for 24 h) afforded 3a in 40% yield.
• 23 As reported in reference 12a, it appears that base promotes intramolecular nucleophilic substitution reaction.
• 24 Benzo[4,5]imidazo[1,2-a]pyrimidines 3; General Procedure: A 10 mL microwave reaction tube was charged with the appropriate β-bromo-α,β-unsaturated aldehyde 1 (0.3 mmol) and 2-aminobenzimidazole 2 (0.45 mmol), together with Et₃N (0.6 mmol), MgSO₄ (0.6 mmol), and DMF (3 mL). After stirring at room temperature for 5 minutes, the reaction mixture was heated at 150 °C for 30 minutes by microwave irradiation (CEM Discover Microwave System) at 200 W initial power. The mixture was then cooled to r.t. and filtered through Celite (CH₂Cl₂–MeOH) to remove inorganic salts. Evaporation of the solvent gave a crude mixture that was purified by TLC [silica gel 60 GF₂₅₄ (Merck), CH₂Cl₂–MeOH]. All new products prepared by the above procedure were characterized spectroscopically as shown below. 1,2,3,4-Tetrahydrobenzo[4,5]imidazo[1,2-a]quinazoline (3a): Yield: 42 mg (63%); solid; mp 209–210 °C. ¹H NMR (400 MHz, CDCl₃): δ = 1.88–1.94 (m, 2 H), 2.04–2.10 (m, 2 H), 2.74–2.77 (m, 2 H), 3.27–3.30 (m, 2 H), 7.23–7.28 (m, 1 H), 7.47–7.51 (m, 1 H), 7.91 (d, J = 8.3 Hz, 1 H), 7.96 (d, J = 8.1 Hz, 1 H), 8.38 (s, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 21.38, 21.68, 24.88, 27.38, 115.25, 115.73, 120.23, 121.34, 125.54, 127.88, 144.69, 146.70, 151.06, 157.02. HRMS (EI): m/z [M⁺] calcd for C₁₄H₁₃N₃: 223.1109; found: 223.1108. 9,10-Dimethyl-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]quinazoline (3b): Yield: 42 mg (56%); solid; mp 212–213 °C. ¹H NMR (400 MHz, CDCl₃): δ = 1.89–1.94 (m, 2 H), 2.06–2.11 (m, 2 H), 2.41 (s, 3 H), 2.44 (s, 3 H), 2.78–2.80 (m, 2 H), 3.30–3.33 (m, 2 H), 7.70 (s, 1 H), 7.73 (s, 1 H), 8.39 (s, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 20.81, 21.00, 21.61, 21.85, 24.98, 27.48, 115.13, 115.32, 120.22, 126.53, 130.76, 135.13, 143.61, 146.32, 150.90, 156.13. HRMS (EI): m/z [M⁺] calcd for C₁₆H₁₇N₃: 251.1422; found: 251.1424. 3-Methyl-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]quinazoline (3c): Yield: 41 mg (58%); solid; mp 197–199 °C. ¹H NMR (400 MHz, CDCl₃): δ = 1.59–1.69 (m, 1 H), 1.17 (d, J = 6.6 Hz, 3 H), 1.92–2.04 (m, 1 H), 2.16–2.23 (m, 1 H), 2.36–2.43 (m, 1 H), 2.81–2.86 (m, 1 H), 3.24–3.32 (m, 1 H), 3.41–3.47 (m, 1 H), 7.25–7.29 (m, 1 H), 7.48–7.52 (m, 1 H), 7.94 (d, J = 8.4 Hz, 1 H), 7.97 (d, J = 8.1 Hz, 1 H), 8.39 (s, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 21.28, 27.44, 27.78, 29.62, 33.04, 115.23, 115.42, 120.31, 121.38, 125.59, 127.94, 144.77, 146.44, 151.15, 156.98. HRMS (EI): m/z [M⁺] calcd for C₁₅H₁₅N₃: 237.1266; found: 237.1263. 3-Phenyl-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]quinazoline (3d): Yield: 63 mg (70%); solid; mp 203–205 °C. ¹H NMR (400 MHz, CDCl₃): δ = 2.15–2.26 (m, 1 H), 2.44–2.50 (m, 1 H), 2.92–2.99 (m, 1 H), 3.08–3.15 (m, 2 H), 3.44–3.53 (m, 1 H), 3.58–3.64 (m, 1 H), 7.28–7.34 (m, 4 H), 7.37–7.42 (m, 2 H), 7.53–7.58 (m, 1 H), 8.03 (d, J = 8.8 Hz, 2 H), 8.49 (s, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 28.06, 28.74, 32.72, 38.97, 115.23, 115.48, 120.62, 120.69, 125.84, 126.98, 127.16, 128.07, 129.03, 144.35, 144.96, 146.16, 151.21, 156.86. HRMS (EI): m/z [M⁺] calcd for C₂₀H₁₇N₃: 299.1422; found: 299.1419. 2,3-Dihydro-1H-benzo[4,5]imidazo[1,2-a]cyclopenta[e]pyrimidine (3e): Yield: 35 mg (55%); solid; mp 174–175 °C. ¹H NMR (400 MHz, CDCl₃): δ = 2.41–2.48 (m, 2 H), 3.04–3.10 (m, 2 H), 3.54–3.57 (m, 2 H), 7.31–7.35 (m, 1 H), 7.51–7.56 (m, 1 H), 7.84 (d, J = 8.1 Hz, 1 H), 8.00 (d, J = 8.3 Hz, 1 H), 8.63 (s, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 22.60, 27.81, 31.44, 113.06, 120.15, 120.23, 121.08, 125.51, 125.96, 144.59, 150.98, 151.41, 152.65. HRMS (EI): m/z [M⁺] calcd for C₁₃H₁₁N₃: 209.0953; found: 209.0951. 2,3,4,5-Tetrahydro-1H-benzo[4,5]imidazo[1,2-a]cyclohepta[e]pyrimidine (3f): Yield: 46 mg (64%); solid; mp 200–202 °C. ¹H NMR (400 MHz, CDCl₃): δ = 1.80–1.83 (m, 2 H), 1.97–2.00 (m, 4 H), 2.89–2.92 (m, 2 H), 3.60–3.61 (m, 2 H), 7.27–7.31 (m, 1 H), 7.50–7.54 (m, 1 H), 7.98–8.03 (m, 2 H), 8.45 (s, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 23.68, 26.92, 29.48, 30.39, 30.85, 115.55, 120.60, 121.24, 121.61, 125.83, 127.83, 145.28, 151.56, 152.25, 157.18. HRMS (EI): m/z [M⁺] calcd for C₁₅H₁₅N₃: 237.1266; found: 237.1267. 1,2,3,4,5,6-Hexahydrobenzo[4,5]imidazo[1,2-a]cycloocta[e]pyrimidine (3g): Yield: 54 mg (72%); solid; mp 172–174 °C. ¹H NMR (400 MHz, CDCl₃): δ = 1.41–1.47 (m, 2 H), 1.55–1.60 (m, 2 H), 1.77–1.82 (m, 2 H), 2.06–2.12 (m, 2 H), 2.87–2.89 (m, 2 H), 3.47–3.52 (m, 2 H), 7.35–7.39 (m, 1 H), 7.54–7.58 (m, 1 H), 7.97–8.03 (m, 2 H), 8.53 (s, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 25.77, 26.44, 26.76, 27.14, 28.95, 32.00, 115.15, 119.75, 120.73, 121.77, 125.87, 127.41, 145.24, 149.11, 151.74, 157.33. HRMS (EI): m/z [M⁺] calcd for C₁₆H₁₇N₃: 251.1422; found: 251.1423. 1,2,3,4,5,6,7,8,9,10-Decahydrobenzo[4,5]imidazo[1,2-a]cyclododeca[e]pyrimidine (3h): Yield: 50 mg (54%); solid; mp 176–178 °C. ¹H NMR (400 MHz, CDCl₃): δ = 1.43–1.59 (m, 10 H), 1.62–1.66 (m, 2 H), 1.80–1.86 (m, 2 H), 1.97–2.03 (m, 2 H), 2.71–2.75 (m, 2 H), 3.38–3.42 (m, 2 H), 7.34–7.38 (m, 1 H), 7.52–7.56 (m, 1 H), 7.90 (d, J = 8.6 Hz, 1 H), 8.01 (d, J = 7.8 Hz, 1 H), 8.62 (s, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 21.72, 22.97, 24.28, 25.01, 25.59, 25.75, 26.02, 26.11, 26.36, 28.93, 115.38, 119.47, 120.71, 121.78, 125.68, 127.56, 145.08, 148.68, 151.41, 157.81. HRMS (EI): m/z [M⁺] calcd for C₂₀H₂₅N₃: 307.2048; found: 307.2052. 5,6-Dihydrobenzo[h]benzo[4,5]imidazo[1,2-a]quinazoline (3i): Yield: 55 mg (67%); solid; mp 180–182 °C. ¹H NMR (400 MHz, CDCl₃): δ = 2.79–2.87 (m, 2 H), 2.97–3.00 (m, 2 H), 7.17–7.22 (m, 1 H), 7.38–7.54 (m, 4 H), 7.94 (d, J = 8.6 Hz, 1 H), 8.01 (d, J = 8.3 Hz, 1 H), 8.14 (d, J = 7.6 Hz, 1 H), 8.65 (s, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 24.31, 28.80, 115.70, 118.83, 120.39, 120.90, 125.34, 126.08, 126.30, 126.63, 127.55, 128.79, 131.79, 140.06, 143.53, 145.36, 152.89, 155.46. HRMS (EI): m/z [M⁺] calcd for C₁₈H₁₃N₃: 271.1109; found: 271.1108. Benzo[f]benzo[4,5]imidazo[1,2-a]quinazoline (3j): Yield: 47 mg (58%); solid; mp 201–203 °C. ¹H NMR (400 MHz, CDCl₃): δ = 7.49–7.53 (m, 1 H), 7.57–7.61 (m, 1 H), 7.63–7.67 (m, 1 H), 7.77–7.81 (m, 1 H), 8.00 (d, J = 7.8 Hz, 1 H), 8.10 (d, J = 7.8 Hz, 1 H), 8.32–8.35 (m, 2 H), 8.55 (d, J = 9.1 Hz, 1 H), 8.65 (d, J = 8.4 Hz, 1 H), 9.96 (s, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 112.66, 113.94, 114.46, 121.38, 121.51, 123.22, 125.51, 127.02, 128.98, 129.47, 129.85, 129.88, 129.90, 136.50, 137.87, 144.53, 150.52, 153.12. HRMS (EI): m/z [M⁺] calcd for C₁₈H₁₁N₃: 269.0953; found: 269.0955. 3-Methyl-4-phenylbenzo[4,5]imidazo[1,2-a]pyrimidine (3k): Yield: 40 mg (52%); solid; mp 289–291 °C. ¹H NMR (500 MHz, CDCl₃): δ = 2.18 (s, 3 H), 6.22 (d, J = 8.5 Hz, 1 H), 6.94–6.97 (m, 1 H), 7.40–7.46 (m, 3 H), 7.68–7.74 (m, 3 H), 7.95 (d, J = 8.3 Hz, 1 H), 8.73 (s, 1 H). ¹³C NMR (125 MHz, CDCl₃): δ = 14.51, 114.64, 120.26, 121.20, 125.62, 127.51, 128.37, 130.03, 130.76, 131.46, 144.76, 146.08, 151.07, 158.08. Anal. Calcd for C₁₇H₁₃N₃: C, 78.74; H, 5.05; N, 16.20. Found: C, 78.61; H, 5.00; N, 16.28.
• 25 Ho SL. Cho CS. Appl. Organomet. Chem. 2013; 27: 507