1,1'-Carbonyldiimidazole [Coupling Agent for Peptides Synthesis]

Used Chemicals

• N-Carbobenzoxyglycine [C0575]
• 1,1'-Carbonyldiimidazole [C0119]
• Anhydrous tetrahydrofuran
• L-Tyrosine ethyl ester [T0551]

Procedure

To a solution of N-carbobenzoxyglycine (2.10 g, 10 mmol) in anhydrous tetrahydrofuran (10 mL) was added 1,1'-carbonyldiimidazole (1.64 g, 10 mmol). The mixture was stirred at room temperature for 4 hours. L-tyrosine ethyl ester (2.10 g, 10 mmol) was added to the reaction mixture. The mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate (30 mL), treated with 1 mol/L HCl solution (50 mL), and stirred for 10 min. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (20 mL x 2). The combined organic layers were washed with saturated aqueous NaHCO₃ solution (30 mL), washed with brine (30 mL), dried over Na₂SO₄ and filtered. The solvent was removed under reduced pressure. The residue was purified by flash column chromatography (eluent: dichloromethane/ethyl acetate, 90/10→75/25→50/50) to obtain 1 as a white solid (3.54 g, 88%).

Experimenter's Comments

The reaction mixture was monitored by TLC (hexane/ethyl acetate = 5/1, Rf = 0.17) and ¹H NMR. After the reaction mixture was concentrated and quenched by 1 mol/L HCl solution, the recrystallization with ethanol was conducted. Sticky white solid was precipitated at low temperature but it can't be filtered.

Analytical Data（Compound 1）

¹H NMR (400 MHz, CDCl₃); δ 7.35 (m, 5H), 6.92 (d, J =8.24 Hz, 2H), 6.67(dd, ³J =8.24 Hz, ⁴J =1.83 Hz, 2H), 6.45(d, J =6.87 Hz, 1H), 5.69 (s, 1H), 5.40 (br s, 1H), 5.12 (s, 2H), 4.81(q, J =5.95 Hz, 1H), 4.18 (q, J =7.32 Hz, 2H), 3.84 (m, 2H), 3.03 (m, 2H), 1.27 (t, J=7.32 Hz, 4H)

¹³C NMR (101 MHz, CDCl₃); δ 171.55, 168.74, 156.61, 155.24, 135.99, 130.50, 130.39, 128.57, 128.29, 128.14, 126.93, 115.52, 115.37, 67.30, 61.78, 61.50, 53.16, 44.31, 36.95, 14.17, 14.07.

Lead Reference

• N,N'-Carbonyldiimidazole, a New Peptide Forming Reagent
  • R. Paul, G. W. Anderson, J. Am. Chem. Soc. 1960, 82, 4596.

References

• R. Paul, G. W. Anderson, J. Am. Chem. Soc. 1960, 82, 4596.