Synthesis of α,β′- and β,β′-Linked Dimethoxycarbonyldipyrromethanes by Rothemund-Type Condensation

Abstract

The Rothemund-type condensation of methoxycarbonylpyrrole with acetone produces mainly the α,β′-linked dipyrromethane, a building block for the synthesis of N-confused macrocycles. The influence of the reaction conditions on the regioselectivity of the process is reported. The X-ray structures of the α,α′-, α,β′- and β,β′-linked dipyrromethanes show an interesting discrimination of the structurally different types of hydrogen bonds.

Key words

heterocycles - condensation - regioselectivity - pyrroles - hydrogen bonds

• References and Notes

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• 9 Reactions monitored by GC
• 10 Typical Procedure for the Synthesis of Methyl 4-[2′-(5′-(Methoxycarbonyl)-1′H-pyrrol-2′-yl)propan-2′′-yl]-1H-pyrrole-2-carboxylate (2): Methyl 2-pyrrolecarboxylate (4; 2 g, 16 mmol) and acetone (10 equiv) in anhyd CH₂Cl₂ (200 mL; 0.08 M) were stirred at r.t. for 5 min. Then, methanesulfonic acid (10 equiv) was added at r.t. and stirred for further 40 min. After stirring, 10% Na₂CO₃ was added and the reaction mixture was extracted with CH₂Cl₂. The organic layer was washed successively with 10% Na₂CO₃ (2 ×) and sat. brine. The organic layer was dried with Na₂SO₄, and the solvents were removed under vacuum. The residue was purified by silica gel column chromatography with a mixture of cyclohexane–EtOAc–MeOH (80:18:2) as eluent. The first fraction (R_f = 0.36) afforded compound 1 (312 mg, 13%) as a colorless solid. The second fraction (R_f = 0.163) afforded compound 2 (1.12 g, 48%) as a colorless solid. The third fraction (R_f = 0.139) gave compound 3 (80 mg, 3.4%) as a colorless solid. Data of compound 2: mp 134 °C. ¹H NMR (CDCl₃, 298 K,): δ = 9.24 (br s, 1 H, 1′-NH), 8.73 (br s, 1 H, 1-NH), 6.82 (m, 1 H, 4′-CH), 6.77 (m, 1 H, 3-CH), 6.73 (m, 1 H, 5-CH), 6.07 (m, 1 H, 3′-CH), 3.83 (s, 3 H, 7′-OMe), 3.79 (s, 3 H, 7-OMe), 1.62 (s, 6 H, 1′′-Me, 3′′-Me). ¹³C NMR (CDCl₃): δ = 161.73 (C=O), 161.56 (C=O), 146.54 (C2′), 133.77 (C4), 122.76 (C2), 121.00 (C5′), 119.67 (C5), 115.71 (C4′), 113.22 (C3), 106.34 (C3′), 51.52 (C7 or C7′), 51.52 (C7 or C7′), 34.91 (C2′′), 30.14 (C1′′, C3′′). IR (KBr): 3355.0 (m), 3311.9 (m), 2947.0 (w), 1685.9 (s), 1568.3 (w), 1485.35 (m), 1440.3 (m), 1382.5 (m), 1236.0 (m), 766.3 (m) cm^–1 . HRMS: m/z [M⁺] calcd for C₁₅H₁₈N₂O₄H: 291.1339; found: 291.1336
• 11 Schmuck C. Synlett 2011; 1798