Copper-Catalyzed Cascade Synthesis of [1,2,4]-Triazoloquinazolinones

Abstract

An efficient and practical method for the synthesis of 1,2,4-triazolo[5,1-b]quinazolin-9(3H)-ones has been developed via the copper-catalyzed domino reactions of readily available substituted N′-acetyl-2-bromobenzohydrazides with cyanamide. The protocol uses inexpensive CuI as the catalyst, and no other ligand or additive was required. The target products were prepared in good to excellent yields with tolerance of various functional groups.

Key words

copper - domino reactions - [1,2,4]-triazoloquinazolinones - cyanamide - synthetic method

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• 15 General Procedures for the Preparation of Compounds 3a–w: A Schlenk tube was charged with a mixture of CuI (0.03 mmol, 5.7 mg), Cs₂CO₃ (0.3 mmol, 98 mg), substituted N′-acetyl-2-bromobenzohydrazide 1 (0.3 mmol), cyanamide (2; 0.45 mmol, 19 mg) and anhyd DMF (3.0 mL). After being evacuated and recharged with Ar for three times, the tube was sealed and the mixture was allowed to stir at 120 °C for 10–15 h. After completion of the reaction, the mixture was cooled to r.t., and H₂O (20 mL) was added to the mixture. The solution was extracted with CH₂Cl₂–MeOH (10:1; 3 × 10 mL), and the combined organic layers were dried over anhyd Na₂SO₄. The solution was concentrated, and the residue was purified by silica gel column chromatography (CH₂Cl₂–MeOH = 30:1 or 20:1) providing the target product (3a–x). Three representative examples are shown as follows: 6-Methyl-2-phenyl-[1,2,4]triazolo[5,1-b]quinazolin-9(3H)-one (3e): eluent: CH₂Cl₂–MeOH = 30:1. Isolated yield: 85% (70.4 mg); white solid; mp 352–353 °C. ¹H NMR (400 MHz, DMSO-d ₆): δ = 8.16 (d, J = 6.5 Hz, 2 H), 8.11 (d, J = 8.2 Hz, 1 H), 7.54 (q, J = 6.4 Hz, 3 H), 7.27 (s, 1 H), 7.21 (d, J = 8.2 Hz, 1 H), 2.47 (s, 3 H). ¹³C NMR (151 MHz, DMSO-d₆ ): δ = 161.6, 155.4, 151.5, 145.9, 139.5, 130.4, 130.1, 128.9 (2 × CH), 127.4, 126.7 (2 × CH), 124.4, 116.3, 111.3, 21.6. ESI–HRMS: m/z [M + Na]⁺ calcd for C₁₆H₁₂N₄NaO: 299.0903; found: 299.0906. 7-Chloro-2-phenyl-[1,2,4]triazolo[5,1-b]quinazolin-9(3H)-one (3r): eluent: CH₂Cl₂–MeOH = 30:1. Isolated yield: 68% (60.4 mg); white solid; mp 281–283 °C. ¹H NMR (600 MHz, DMSO-d ₆): δ = 8.14–8.19 (m, 3 H), 7.88 (dd, J = 8.8, 2.4 Hz, 1 H), 7.51–7.58 (m, 4 H). ¹³C NMR (151 MHz, DMSO-d ₆): δ = 161.6, 155.0, 151.3, 139.1, 134.5, 131.1, 129.9, 128.3 (2 × CH), 127.9, 127.1, 126.5 (2 × CH), 122.4, 116.6. ESI–HRMS: m/z [M + H]⁺ calcd for C₁₅H₁₀ClN₄O: 297.0538; found: 297.0540. 2-Methyl-[1,2,4]triazolo[5,1-b]quinazolin-9(3H)-one (3w): eluent: CH₂Cl₂–MeOH = 30:1. Reaction time: 15 h. Isolated yield: 67% (40.3 mg); white solid; mp 312–314 °C. ¹H NMR (600 MHz, DMSO-d ₆): δ = 8.16 (d, J = 7.7 Hz, 1 H), 7.78 (t, J = 7.4 Hz, 1 H), 7.50 (d, J = 7.9 Hz, 1 H), 7.33 (t, J = 7.5 Hz, 1 H), 2.36 (s, 3 H). ¹³C NMR (151 MHz, DMSO-d ₆): δ = 161.9, 155.2, 151.0, 139.7, 134.8, 127.3, 122.6, 117.2, 113.3, 14.4. ESI–HRMS: m/z [M + H]⁺ calcd for C₁₀H₉N₄O: 201.0771; found: 201.0770.