An Efficient Access to 4-Alkylidene-5,6-dihydro-4H-pyrrolo[1,2-c][1,2,3]triazoles

Abstract

From alkylidenecyclopropanes (MCPs), 4-alkylidene-5,6-dihydro-4H-pyrrolo-[1,2-c][1,2,3]triazoles 6 were prepared in moderate yields through diiodogenation, Cu(I)-catalyzed 1,3-di­polar cycloaddition and subsequent intramolecular Heck reaction.

Key words

1,2,3-trizaole - alkylidenecyclopropanes (MCPs) - 1,3-dipolar cycloaddition - Heck reaction

References and Notes

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8

Typical Procedure for the Synthesis of 5.
To a stirred 95% EtOH (2 mL) solution of NaN₃ (0.6 mmol), 2 (0.5 mmol) was added and the reaction mixture was stirred under reflux until the reaction was complete, as monitored by TLC. Then, H₂O (4 mL), ascorbic acid (0.1 g, 0.56 mmol), NaOH (0.022 g, 0.56 mmol), CuSO₄ (0.01 g, 0.04 mmol), and alkyne 4 (0.6 mmol) were added and heated together at 70 °C until the reaction was complete (monitored by TLC). Afterwards, the mixture was cooled to r.t. and H₂O (15 mL) was added. The aqueous layer was extracted with EtOAc (3 × 15 mL). The organic layer was dried over anhyd MgSO₄. After evaporation, the residue was subjected to preparative TLC (eluent: PE-EtOAc, 1:6 to 1:3) to afford 1,4-disub-stituted 1,2,3-triazoles 5.
Selected Spectral Data for 5a.
Solid, mp 70-72 °C. ¹H NMR (400 MHz, CDCl₃): δ = 0.95 (t, 3 H, J = 7.33 Hz), 1.39-1.44 (m, 2 H), 1.64-1.71 (m, 2 H), 2.74 (t, 2 H, J = 7.66 Hz), 3.08 (t, 2 H, J = 6.41 Hz), 4.58 (t, 2 H, J = 6.41 Hz), 6.75 (dd, 2 H, J = 1.75, 7.79 Hz), 7.10-7.32 (m, 9 H). ¹³C NMR (100 MHz, CDCl₃): δ = 152.17, 148.27, 146.08, 139.29, 128.50, 128.24, 127.91, 127.60, 127.56, 121.04, 102.68, 49.67, 42.45, 31.77, 25.32, 22.35, 13.85. IR: 2955, 2926, 1437, 1043, 701 cm^-1.

9

The temperature (70 °C) is required for the triazole synthesis step in our reaction by trial and error. At higher temperature 1,5-regioisomers can be formed and at lower temperature the reaction was not complete after several hours.

11

Typical Procedure for the Synthesis of 6.
Compound 5 (0.25 mmol), Pd(OAc)₂ (0.025 mmol), tetrabutylammonium chloride (TBAC, 0.25 mmol), NaHCO₃ (0.5 mmol), and N,N-dimethylformamide (DMF, 1 mL) were added into a Schlenk tube at r.t. The reaction mixture was stirred at 100 °C until the reaction was complete, as monitored by TLC. Then the reaction mixture was cooled and H₂O (15 mL) was added. The aqueous layer was extracted with EtOAc (3 ¥ 15 mL). The organic layer was dried over anhyd MgSO₄. After evaporation, the residue was subjected to preparative TLC (eluent: PE-EtOAc, 1:6 to 1:3) to afford 4-alkylidene-5,6-dihydro-4H-pyrrolo-[1,2-c][1,2,3]-triazoles 6.
Selected Data. Compound 6a: solid, mp 124-126 °C. IR: 2948, 2924, 1440, 764, 703 cm^-1. ¹H NMR (400 MHz, CDCl₃): δ = 0.74 (t, 3 H, J = 7.26 Hz), 0.92-1.00 (m, 2 H), 1.20-1.28 (m, 2 H), 1.49 (t, 2 H, J = 7.45 Hz), 3.51 (t, 2 H, J = 6.89 Hz), 4.36 (t, 2 H, J = 6.89 Hz), 7.18-7.38 (m, 10 H). ¹³C NMR (100 MHz, CDCl₃): δ = 141.97, 141.94, 141.30, 138.43, 137.67, 129.92, 129.18, 128.72, 128.21, 127.86, 127.70, 123.51, 45.24, 37.50, 31.62, 25.35, 22.28, 13.76. MS (EI, 70 eV): m/z (%) = 329 (19) [M⁺]. Anal. Calcd for C₂₂H₂₃N₃: C, 80.21; H, 7.04; N, 12.76. Found: C, 80.00; H, 7.16; N, 12.83.
Compound 7a: solid, mp 126-128 °C. IR: 2926, 1486, 1086, 828 cm^-1. ¹H NMR (400 MHz, CDCl₃): δ = 0.91 (t, 3 H, J = 7.33 Hz), 1.34-1.40 (m, 2 H), 1.61-1.68 (m, 2 H), 2.73 (t, 2 H, J = 7.58 Hz), 2.99 (t, 2 H, J = 6.71 Hz), 4.54 (t, 2 H, J = 6.71 Hz), 7.27 (s, 4 H), 7.40 (s, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 148.35, 134.24, 132.75, 128.61, 121.27, 120.96, 86.01, 82.23, 48.65, 31.55, 25.28, 22.22, 21.63, 13.78. MS (EI, 70 eV): m/z (%) = 287 (29.08) [M⁺]. Anal. Calcd for C₁₆H₁₈ClN₃: C, 66.78; H, 6.30; N, 14.60. Found: C, 66.90; H, 6.21; N, 14.65.