Synthesis of Dipeptide, Amide, and Ester without Racemization by Oxalyl Chloride and Catalytic Triphenylphosphine Oxide

Ji-Wei Ren, Meng-Nan Tong, Yu-Fen Zhao and Feng Ni*

*Institute of Drug Discovery Technology, Ningbo University, Ningbo, Zhejiang 315211, P. R. China, Email: nifengnbu.edu.cn

J.-W. Ren, M.-N. Tong, Y.-F. Zhao, F. Ni, Org. Lett., 2021, 23, 7497-7502.

DOI: 10.1021/acs.orglett.1c02614

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Abstract

Triphenylphosphine oxide catalyzes amidation and esterification for an efficient synthesis of dipeptides, amides, and esters in good yields in less than 10 m without racemization. This reaction is applicable to challenging couplings of hindered carboxylic acids with weak nucleophiles amines or alcohols.

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proposed mechanism

General procedure for the synthesis of dipeptides

N-protected amino acids (1.0 mmol, 1.0 equiv.), amino acid esters (1.2 mmol, 1.2 equiv.) and triphenylphosphine oxide (55.7 mg, 0.2 mmol, 20 mol %) were well mixed in 1,2-dichloroethane (1.0 mL). Then oxalyl chloride (1.5 mmol, 1.5 equiv.) and triethylamine (2.0 mmol, 2.0 equiv.) were added in sequence at ambient temperature under argon atmosphere. The resulting mixture was stirred at room temperature for 10 min. Subsequently, the mixture was partitioned between EtOAc (100 mL) and H₂O (50 mL) at room temperature. The organic layer was washed with saturated aqueous solution of Na₂CO₃ (3×50 mL) and saturated brine (2×30 mL), dried over Na₂SO₄, and concentrated in vacuo. The resulting residue was purified via silica gel colunm chromatography (EtOAc/PE = 20%-40%) to yield dipeptides.

General procedure for the synthesis of amides

Carboxylic acids (1.0 mmol, 1.0 equiv.), amines (1.2 mmol, 1.2 equiv.) and triphenylphosphine oxide (55.7 mg, 0.2 mmol, 20 mol %) were well mixed in 1,2-dichloroethane (1.0 mL). Then oxalyl chloride (1.5 mmol, 1.5 equiv.) and triethylamine (2.0 mmol, 2.0 equiv.) were added in sequence at ambient temperature under argon atmosphere. The resulting mixture was stirred at room temperature for 10 min. Subsequently, the mixture was partitioned between EtOAc (100 mL) and H₂O (50 mL) at room temperature. The organic layer was washed with saturated aqueous solution of Na₂CO₃ (3×50 mL) and saturated brine (2×30 mL), dried over Na₂SO₄, and concentrated in vacuo. The resulting residue was purified via silica gel colunm chromatography (EtOAc/PE = 20%-40%) to yield amides.

General procedure for the synthesis of esters

Amino acids (1.0 mmol, 1.0 equiv.), alcohols (1.2 mmol, 1.2 equiv.) and triphenylphosphine oxide (55.7 mg, 0.2 mmol, 20 mol %) were well mixed in 1,2-dichloroethane (1.0 mL). Then oxalyl chloride (1.5 mmol, 1.5 equiv.) and triethylamine (2.0 mmol, 2.0 equiv.) were added in sequence at ambient temperature under argon atmosphere. The resulting mixture was stirred at room temperature for 10 min. Subsequently, the mixture was partitioned between EtOAc (100 mL) and H₂O (50 mL) at room temperature. The organic layer was washed with saturated aqueous solution of Na₂CO₃ (3×50 mL) and saturated brine (2×30 mL), dried over Na₂SO₄, and concentrated in vacuo. The resulting residue was purified via silica gel colunm chromatography (EtOAc/PE = 10%-20%) to yield esters.

Key Words

amidation, esterification, organocatalysis

ID: J54-Y2021