Cu(I)–Pd(II)-Catalyzed Cycloaddition–Fusion of 1-Iodoalkynes and Azides: One-Pot Synthesis of Fused Tricyclic Heterosystems

Abstract

An unprecedented, one-pot regioselective synthesis of 1,2,3-triazole-fused heterocycles through Cu(I)–Pd(II) cycloaddition–fusion of 1-iodoalkynes and organic azides is described. The method presents a convenient heteroannulation approach towards the synthesis of polycyclic frameworks from easily accessible substrates.

Key words

heteroannulation - óaryl azides - 1,2,3-triazoles - polycyclic systems - regioselective reactions

• References and Notes

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• 21 Typical Procedure for the Synthesis of 3-Phenyl-8H-[1,2,3]triazolo[5,1-a]isoindole (3a, Table 1): The reagents [Pd(PPh₃)₂Cl₂] (24.6 mg, 0.035 mmol), CuI (13.3 mg, 0.07 mmol) and n-Bu₄NOAc (0.903 g, 3.0 mmol) were sequentially added to a solution of benzyl azide (2; 1.0 mmol) in anhyd NMP (7 mL) and the mixture was stirred at r.t. under an argon atmosphere for 30 min. (Iodoethynyl)benzene 1 (1.25 mmol) dissolved in anhyd NMP (1 mL) was added dropwise under argon. The reaction mixture was then heated at 125 °C for the requisite time (12–17 h, see Table 1). After completion of the reaction (TLC), the solvent was removed in vacuo, the residue was mixed with H₂O (30 mL) and extracted with EtOAc (2 × 25 mL). The combined organic extracts were dried with anhyd Na₂SO₄, filtered and concentrated under reduced pressure. The resulting residue was purified through silica gel (100–200 mesh) column chromatography (EtOAc–hexane) to afford the corresponding products 3a–e. Compound 3a was obtained as a pale brown solid; mp 152–154 °C. IR (KBr): 3058, 3034, 2964, 2922, 2850, 1609, 1448, 1359, 985, 760, 699, 668 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 5.35 (s, 2 H), 7.39–7.53 (m, 6 H), 7.89 (br d, J = 7.21 Hz, 1 H), 7.90–7.94 (m, 2 H). ¹³C NMR (400 MHz, CDCl₃): δ = 51.0, 121.3, 124.6, 126.8, 128.0, 128.4, 128.8, 129, 131.2, 139.1, 139.5, 141.2. MS (ESI): m/z [M + H]⁺ calcd for C₁₅H₁₂N₃: 234.28; found: 234.10.
• 22 Typical Procedure for the Synthesis of 3-Butyl-8H-[1,2,3]triazolo[5,1-a]isoindole (6a, Table 2): Similar procedure as given above for the synthesis of compound 3a was adopted for the synthesis of compound 6a–d except for the use of Pd(OAc)₂ (5 mol%) and Ph₃P (10 mol%) as the catalyst. Compound 6a was obtained as a brown solid; mp 74–75 °C. IR (KBr): 3054, 2935, 1634, 1234, 668 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 0.98 (t, J = 7.4 Hz, 3 H), 1.46 (sx, J = 7.4 Hz, 2 H), 1.80 (qn, J = 7.6 Hz, 2 H), 2.96 (t, J = 7.6 Hz, 2 H), 5.30 (s, 2 H), 7.35–7.54 (m, 3 H), 7.62 (d, J = 7.6 Hz, 1 H). ¹³C NMR (400 MHz, CDCl₃): δ = 13.9, 22.5, 25.8, 32.0, 51.1, 120.7, 124.3, 127.8, 128.6, 128.9, 139.3, 139.5. 140.8. MS (ESI): m/z [M + H]⁺ calcd for C₁₃H₁₆N₃: 214.28; found: 214.10.
• 23 Typical Procedure for the Synthesis of 1-Hexyl-1,4-dihydrochromeno[3,4-d][1,2,3]triazole (9a, Table 3 ): The reagents [Pd(PPh₃)₂Cl₂] (24.6 mg, 0.035 mmol), CuI (13.3 mg, 0.07 mmol) and Et₃N (0.71 mL, 5.0 mmol) were sequentially added to a solution of azide 8 (1.0 mmol) in anhyd NMP (8 mL) and the mixture was stirred at r.t. under an argon atmosphere for 20 min. Acetylenic compound 7 (1.25 mmol) dissolved in anhyd NMP (1 mL) was added dropwise under argon. The reaction mixture was then heated at 130 °C for the requisite time (12–20 h, see Table 3). Further procedure was the same as given above for the synthesis of compound 3a. The product 9a was obtained as a yellow oil. IR (KBr): 2954, 2859, 1522, 1467, 1447, 1336, 1229, 1197, 1125, 1041, 1023, 990, 841, 757 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 0.89 (t, J = 7.1 Hz, 3 H), 1.33 (m, 6 H), 1.96 (qn, J = 7.5 Hz, 2 H), 4.60 (t, J = 7.4 Hz, 2 H), 5.46 (s, 2 H), 7.06 (m, 2 H), 7.29 (m, 1 H), 7.42 (dd, J = 7.6 Hz, 1 H). ¹³C NMR (400 MHz, CDCl₃): δ = 14.2, 22.6, 26.4, 29.8, 31.3, 50.1, 64.7, 114.4, 118.4, 122.3, 122.4, 127.3, 131.0, 139.8, 153.7. MS (ESI): m/z [M + H]⁺ calcd for C₁₅H₂₀N₃O: 259.15; found: 259.16.