Products > TCI Topics Archives > TCI Topics 2021 >

TCI Practical Example: Peptide Coupling using Mukaiyama Condensation Reagent

We are proud to present the amidation using 2-chloro-1-methylpyridinium iodide called as Mukaiyama condensation reagent. 2-Chloro-1-methylpyridinium iodide is known to cause less racemization.

Used Chemicals

• Boc-Pro-OH [B1188]
• H-Phe-OMe·HCl [P1278]
• 2-Chloro-1-methylpyridinium Iodide [C0903]
• Triethylamine [T0424]
• Dichloromethane

Procedure

Boc-Pro-OH (1.65 g, 7.65 mmol), 2-chloro-1-methylpyridinium iodide (1.95 g, 7.65 mmol) were added to solution of H-Phe-OMe･HCl (1.50 g，6.95 mmol) in dichloromethane (30 mL) at room temperature and triethylamine (3.40 mL, 24.3 mmol) was added dropwise in 3 min at 5 to 10 °C. After stirring for 3 h, solvent was removed under reduced pressure and the residue was dissolved in ethyl acetate and washed with 10% citric acid aq. (30 mL × 3), 5% sodium bicarbonate solution aq. (30 mL × 3) and brine (30 mL). The organic layer was dried over anhydrous sodium sulfate and filtered. After the removal of solvent under reduced pressure, the given crude was purified by column chromatography (hexane : EtOAc = 2 : 1) to give Boc-Pro-Phe-OMe (2.37 g，91%) as a slightly yellowish solid.

Experimenter's Comments

Consumption of stating material and formation of product was monitored by LCMS.

Analytical Data

Boc-Pro-Phe-OMe

¹H NMR (400 MHz, DMSO-d6); δ 8.17–8.27 (m, 1H), 7.19–7.29 (m, 5H), 4.42–4.53 (m, 1H), 4.00–4.13 (m, 1H), 3.56–3.61 (m, 3H), 3.18–3.38 (m, 2H), 2.90–3.08 (m, 2H), 1.91–2.11 (m, 1H), 1.56–1.71 (m, 3H), 1.15-1.40 (m, 9H).

Lead Reference

• A facile synthesis of carboxamides by using 1-methyl-2-halopyridinium iodides as coupling reagents
• E. Bald, K. Saigo, T. Mukaiyama, Chem. Lett. 1975, 4, 1163.