Mild Microwave-Assisted Synthesis of Dipyrromethanes and Their Analogues

Abstract

The Mannich reaction between pyrroles or indoles and ­Eschenmoser’s salt (dimethylmethylideneammonium iodide) forms N,N-dimethylamino-methylated derivatives in good to excellent yields. The reaction is highly regioselective, and for pyrroles both 2- and 3-substituted derivatives could be obtained. The N,N-dimethylaminomethylpyrroles and indoles underwent substitution with pyrrole under microwave irradiation, affording the appropriate dipyrromethanes, N-confused, and indolo-dipyrromethanes in moderate to excellent overall yield.

Key words

pyrroles - indoles - heterocycles - microwave synthesis - dipyrromethanes

• References and Notes

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• 16 General Procedure for the Mannich ReactionA sample of the heterocycle was dissolved in CH₂Cl₂ or MeCN (ca. 0.15–0.2 M). Eschenmoser’s salt (2 equiv) was added in a single portion. The reaction mixture was stirred at r.t. until TLC analysis indicated the complete consumption of the starting material (20 min to 26 h). The reaction mixture was diluted with CH₂Cl₂ or EtOAc (for MeCN as solvent) and sat. aq NaHCO₃. The phases were separated, and the aqueous layer was extracted once. The organic layer was dried (Na₂SO₄), filtered, and the solvent was evaporated. The crude product was used without further purification in the next step.Dipyrromethane SynthesisThe Mannich product was placed in a microwave vial. Pyrrole was added to afford a 0.2–0.3 M solution. The vial was capped. The vial was placed in a microwave reactor and was irradiated at 150 °C for 30 min. The reaction mixture was cooled to r.t., and the pyrrole was evaporated. The dark brown oily residue was purified by column chromatography (silica, PE–EtOAc) to afford the products.Compound 2e: yellow oil (62%); IR (thin film): ν = 3003, 2945, 2866, 2709, 1568, 1481, 1463, 1417, 1406, 1298, 1262, 1225, 1172, 1133, 1051, 1016 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 1.08 (d, J = 7.4 Hz, 18 H), 1.43 (sept, J = 7.4 Hz, 3 H), 2.25 (s, 6 H), 3.42 (s, 2 H), 6.23–6.27 (m, 1 H), 6.64–6.69 (m, 1 H), 6.70–6.74 (m, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 11.6, 17.8, 44.6, 56.2, 111.7, 121.4, 123.6, 124.3. ESI-HRMS: m/z calcd for C₁₆H₃₂N₂Si [M + H]⁺: 281.2363; found: 281.2406.Compound 3e: colorless oil (54%); IR (thin film): ν = 3676, 3341, 2959, 2867, 1563, 1534, 1464, 1407, 1394, 1383, 1272, 1258, 1236, 1210, 1116, 1067, 1016 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 1.19 (d, J = 7.6 Hz, 18 H), 1.50 (sept, J = 7.6 Hz, 3 H), 3.95 (s, 2 H), 5.97 (s, 1 H), 6.18–6.24 (m, 1 H), 6.25–6.29 (m, 1 H), 6.65–6.73 (m, 2 H), 6.79–6.87 (m, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 11.8, 17.9, 25.5, 105.0, 108.3, 111.3, 116.0, 122.2, 122.7, 124.7, 132.2. ESI-HRMS: m/z calcd for C₁₈H₃₀N₂Si [M + H]⁺: 303.2251; found: 303.2247.Compound 2f: colorless oil (quant.); ¹H NMR (400 MHz, CDCl₃): δ = 1.17 (t, J = 7.2 Hz, 3 H), 2.02 (s, 1.5 H), 2.17 (s, 4 H), 2.31 (s, 1.5 H), 3.33 (d, J = 11.9 Hz, 2 H), 4.12 (q, J = 7.6 Hz 1 H), 4.67 (s, 0.5 H), 7.01 (dd, J = 15.3, 8.2 Hz, 2 H), 7.38 (d, J = 10.6 Hz, 1 H), 7.66 (dd, J = 9.3, 7.7 Hz, 2 H). 10.4 (br, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 14.2, 14.4, 42.7, 44.8, 52.5, 54.0, 59.4, 70.4, 92.1, 114.2, 123.2, 124.4, 127.7, 128.1, 132.6, 132.8, 134.3, 136.4, 136.6, 164.6. ESI-HRMS: m/z calcd for C₁₆H₁₉N₂O₂I [M + MeOH + Na]⁺: 456.0888; found: 456.0894.Compound 3f: pale solid (52%); ¹H NMR (400 MHz, CDCl₃/ CD₃OD): δ = 1.14 (dt, J = 7.1, 1.2 Hz, 3 H), 3.76 (s, 1 H), 4.08 (q, J = 7. 2 Hz 2 H), 5.72–5.81 (m, 1 H), 5.94–6.05 (m, 1 H), 6.58–6.63 (m, 1 H), 7.04 (d, J = 8. 4 Hz, 2 H), 7.33–7.39 (m, 1 H), 7.61 (d, J = 8. 4 Hz, 2 H). ¹³C NMR (100 MHz, CDCl₃/CD₃OD): δ = 13.7, 24.0, 59.4, 91.3, 105.6, 107.5, 113.3, 116.8, 121.1, 124.1, 128.8, 129.0, 132.4, 134.8, 136.4, 165.8. ESI-HRMS: m/z calcd for C₁₆H₁₉N₂O₂I [M + MeOH + Na]⁺: 456.0888; found: 456.0894.