The Ugi Reaction of Cyanoacetic Acid as a Route to Tetramic Acid Derivatives

Abstract

Ugi adducts of cyanoacetic acid and aromatic aldehydes are readily cyclized under basic conditions leading to one-pot formation of aminopyrrolinone derivatives.

Key words

Ugi - isocyanide - cyanoacetic - aminopyrolidinones

• References and Notes


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• 8 Typical Procedure for 2a To a stirred solution of 3-nitrobenzaldehyde (305 mg, 2 mmol) in anhydrous MeOH (0.5 M) under argon at r.t. was added aniline (187 mg, 2 mmol). After 5 min, cyclohexylisocyanide (222 mg, 2 mmol) and cyanoacetic acid (171 mg, 2 mmol) were sequentially added. The resulting mixture was stirred at r.t. for 4 h. Subsequently, anhydrous MeOH was added to obtain a 0.2 M solution and K₂CO₃ (0.2 equiv) was added. The resulting mixture was stirred and heated at 65 °C for 1 h. Evaporation of the solvent under reduced pressure, addition of CH₂Cl₂ and extraction afforded the crude product that was purified by silica gel column chromatography (PE–Et₂O, 2:8). Compound 2a was obtained as a white solid (mp 231–233 °C) in 74% isolated yield (620 mg, 1.48 mmol); R_f  = 0.17 (PE–Et₂O, 2:8). ¹H NMR (400 MHz, DMSO): δ = 8.31 (t, J = 2.0 Hz, 1 H, ArH), 8.18 (d, J = 8.5 Hz, 1 H, NH), 8.10 (ddd, J = 0.9, 2.3, 8.2 Hz, 1 H, ArH), 7.70–7.68 (m, 1 H, ArH), 7.56–7.52 (m, 1 H, ArH), 7.13–7.12 (m, 4 H, ArH), 6.96–6.92 (m, 1 H, ArH), 6.60 (s, 2 H, NH₂), 4.87 (s, 1 H, CH), 3.76–3.67 (m, 1 H, CH), 1.66–1.65 (m, 3 H, CyH), 1.57–1.55 (m, 2 H, CyH), 1.35–1.17 (m, 4 H, CyH), 1.04–0.97 (m, 1 H, CyH) ppm. ¹³C NMR (100 MHz, DMSO): δ = 172.8 (CO), 165.9 (CO), 164.5 (CNH₂), 147.2 (ArC), 139.2 (ArC), 137.8 (ArC), 135.1 (ArC), 129.5 (ArC), 128.2 (ArC), 124.1 (ArC), 123.8 (ArC), 123.5 (ArC), 122.9 (ArC), 88.3 (CH), 75.0 (C_quat), 48.9 (CH), 31.7 (CyC), 25.1 (CyC), 25.0 (CyC), 25.0 (CyC) ppm. FTIR: ν = 1693 (CO), 1673 (CO), 1617 (NH₂), 1529 (NO₂), 1348 (NO₂) cm^–1. HRMS (ESI⁺/TOF): m/z calcd for C₂₃H₂₅N₄O₄ ⁺: 421.1870; found: 421.1886.
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