A New Synthesis of Pyrroles from Benzimidazolium N-Cyanomethyl Ylides and Alkyne Dipolarophiles

Abstract

A straightforward synthesis of highly functionalized pyrroles was achieved by a one-pot reaction between 3-(cyanomethyl)benzimidazolium salts and acetylenic dipolarophiles under reflux in 1,2-epoxybutane. The new pyrroles can also be obtained by a one-pot three-component reaction from substituted benzimidazoles, bromoacetonitrile, and activated acetylenes. The structures of the pyrroles were deduced by NMR spectroscopy and confirmed by X-ray crystal analysis.

Keywords

benzimidazolium ylides - 1,3-dipolar cycloaddition - pyrroles - multicomponent reaction - alkynes

• References and Notes

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• 7 Crystal data for 15a: C₁₆H₁₄BrN₃, M = 328.21, 0.16 × 0.12 × 0.07 mm³, orthorhombic, space group P2₁2₁2₁ (No. 19), a = 7.4389(6), b = 12.3635(10), c = 15.5553(13) Å, V = 1430.6(2) ų, Z = 4, D _c = 1.524 g/cm³, F ₀₀₀ = 664, MoKα radiation, λ = 0.71073 Å, T = 173(2)K, 2θ_max = 56.8°, 34401 reflections collected, 3571 unique (R_int = 0.0674). Final GooF = 1.049, R ₁ = 0.0281, wR ₂ = 0.0526, R indices based on 3251 reflections with I > 2σ(I) (refinement on F ²), 181 parameters, 0 restraints. Lp and absorption corrections applied, μ = 2.866 mm^–1. Absolute structure determined from diffraction data [Flack parameter = –0.026(8)]; CCDC 1528219.
• 8 Pyrroles 16; General Procedure Method A: Benzimidazolium bromide 15 (2 mmol) and the appropriate acetylenic dipolarophile (2.5 mmol) were refluxed with stirring in 1,2-epoxybutane (15 mL) for ~72 h. The solvent was evaporated under vacuum, and the residue was purified by column chromatography [Merck alumina (70–230 mesh), CH₂Cl₂]. Method B: 1-Benzylbenzimidazole 14a (R¹ = Ph; 2 mmol) and bromoacetonitrile (2.5 mmol) were refluxed for 2 h in 1,2-epoxybutane (15 mL). The appropriate acetylenic dipolarophile (2.5 mmol) was then added and the reaction was maintained under reflux for ~72 h. The reaction mixture was worked up as described for Method A. Methyl 1-[2-(Benzylamino)phenyl]-5-cyano-1H-pyrrole-3-carboxylate (16a) Colorless crystals (EtOH); yield: 358 mg (54%; Method A); 320 mg (48%) (Method B); mp 132–4 °C (EtOH). IR (ATR): 1701 (C=O); 2230 (C≡N), 3124 (CH), 3386 (NH) cm^–1. ¹H NMR (300 MHz, CDCl₃) δ = 3.76 (t, J = 5.5 Hz, 1 H, NH); 3.79 (s, 3 H, MeO); 4.30 (d, J = 5.5 Hz, 2 H, CH₂N); 6.68–6.76 (m, 2 H, Ar); 7.07–7.10 (m, 1 H, Ar); 7.22–7.29 (m, 6 H, Ar); 7.32 (d, J = 1.6 Hz, 1 H, H-3); 7.48 (d, J = 1.6 Hz, 1 H, H-5). ¹³C NMR (75 MHz, CDCl₃) δ = 47.6 (PhCH₂), 51.8 (MeO), 107.2, 112.0, 118.3, 122.7, 138.3, 143.6 (6 C, quaternary, CN), 112.7, 117.3, 121.8, 127.1, 127.5, 127.9, 128.9, 131.5, 131.8 (11 C, tertiary C-3, C-4, C-3′, C-4′, C-5′, C-6′), 163.2 (COOMe).
• 9 Crystal data for 16e: C₂₁H₁₉N₃O, M = 329.39, 0.38 × 0.10 × 0.05 mm³, monoclinic, space group P2₁/n (No. 14), a = 12.1900(14), b = 6.5597(7), c = 22.030(2) Å, β = 97.372(2)°, V = 1747.0(3) ų, Z = 4, D _c = 1.252 g/cm³, F ₀₀₀ = 696, MoKα radiation, λ = 0.71073 Å, T = 173(2)K, 2θ_max = 55.9°, 20252 reflections collected, 4185 unique (R_int = 0.0695). Final GooF = 1.017, R ₁ = 0.0485, wR ₂ = 0.1260, R indices based on 2757 reflections with I > 2σ(I) (refinement on F ²), 232 parameters, 0 restraints. Lp and absorption corrections applied, μ = 0.079 mm^–1; CCDC 1528481.
• 10 Crystal data for 16a: C₂₀H₁₇N₃O₂, M = 331.37, 0.21 × 0.20 × 0.17 mm³, monoclinic, space group P2₁/c (No. 14), a = 8.8205(8), b = 13.6840(13), c = 14.6271(14) Å, β = 104.423(2)°, V = 1709.8(3) ų, Z = 4, D _c = 1.287 g/cm³, F ₀₀₀ = 696, MoKα radiation, λ = 0.71073 Å, T = 173(2)K, 2θ_max = 56.6°, 20583 reflections collected, 4239 unique (R_int = 0.0539). Final GooF = 1.016, R₁  = 0.0448, wR₂  = 0.0964, R indices based on 2961 reflections with I >2σ(I) (refinement on F ²), 232 parameters, 0 restraints. Lp and absorption corrections applied, μ = 0.085 mm^–1; CCDC 1528223.