1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide Hydrochloride [Coupling Agent for Peptides Synthesis]

Used Chemicals

• N-Benzyloxycarbonyl-L-phenylalanine [C0660]
• 1-(2-Methoxyphenyl)piperazine [M0883]
• 1-Hydroxybenzotriazole Monohydrate (= HOBt·H₂O) [H0468]
• 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide Hydrochloride (= EDC·HCl) [D1601]
• DMF

Procedure

1-(2-methoxyphenyl)piperazine (500 mg, 2.60 mmol) was dissolved in DMF (15 mL). To this solution was added N-benzyloxycarbonyl-L-phenylalanine (770 mg, 2.60 mmol) and HOBt·H₂O (414 mg, 2.71 mmol). The reaction mixture was cooled to 0 °C, then EDC·HCl (515 mg, 2.71 mmol) was added. Reaction was allowed to warm to room temperature, then stirred for 20 h at room temperature. Complete of the reaction was confirmed by TLC. Reaction was quenched by adding H₂O (20 mL). Reaction mixture was extracted by EtOAc (30 mL). Organic phase was washed with H₂O (20 mL, twice) and brine (20 mL), dried over Na₂SO₄, concentrated under reduced pressure to afford the crude product (1.2 g) as pale yellow oil. The crude product was purified by column chromatography on silica gel (hexane : ethyl acetate = 40 : 60) to afford the product 1 as a white powder (1.10 g, 2.32 mmol, 90%).

Experimenter's Comments

The reaction mixture was monitored by TLC (hexane / ethyl acetate = 4 : 6, Rf = 0.40)

Analytical Data（Compound 1）

¹H NMR (400 MHz, CDCl₃); δ 7.39-7.16 (m, 10H), 6.99 (m, 1H), 6.91-6.84 (m, 2H), 6.78 (m, 1H), 5.73 (d, J = 8,2 Hz, 1H), 5.12-5.01 (m, 2H), 4.91 (dd, J= 7.7, 7.3 Hz, 1H), 3.82 (s, 3H), 3.71-3.63 (m, 2H), 3.51 (m, 1H), 3.31 (m, 1H), 3.07-2.78 (m, 5H), 2.51 (m, 1H).

References

• Dehydro-enkephalins: VIII. Attempted synthesis of dehydrotyrosine-enkephalins
  • Y. Shimohigashi, J. W. Dunning Jr., A. J. Kolar, C. H. Stammer, Int. J. Peptide Protein Res. 1983, 21, 202.


Application
Water-soluble Condensation Reagent



Typical Procedure: To a 50 mL round bottom flask equipped with a magnetic stir bar and septum is added 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride 2.54 g (13.3 mmol), 4-dimethylaminopyridine 1.62 g (13.3 mmol), carboxylic acid 1.02 g (2.46 mmol), alcohol 0.96 g (3.98 mmol) and CHCl3 (15 mL), and the reaction mixture is stirred at room temperature for 2.5 days. Acetic acid (0.5 mL) is added and the reaction mixture is stirred for 10 min to convert excess alcohol to a more easily separable acetate. The mixture is washed with saturated aqueous NH4Cl solution, diluted with Et2O, and the layers are dried, filtered and concentrated under reduced pressure. The crude material is chromatographed by silica gel column chromatography (hexane：ethyl acetate = 9：1) to give the desired product 1.25 g (1.96 mmol, 80%).

References

• Total Synthesis of (+)-Lithospermic Acid by Asymmetric Intramolecular Alkylation via Catalytic C−H Bond Activation
  • S. J. O’Malley, K. L. Tan, A. Watzke, R. G. Bergman, J. A. Ellman, J. Am. Chem. Soc. 2005, 127, 13496.


PubMed Literature