A Convenient Synthesis of Amino Acid Arylamides Utilizing Methanesulfonyl Chloride and N-Methylimidazole

Abstract

N-Cbz-protected amino acids reacted with various aryl­amines in the presence of methanesulfonyl chloride and N-methylimidazole in dichloromethane to give the corresponding arylamides in high yields. No obvious racemization was observed under the mild conditions.

amino acid arylamides - N-Cbz-protected amino acids - condensation - steric hindrance - enantioretention

References and Notes

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<A NAME="RW13010ST-13">13</A>

Typical Procedure for the Preparation of Amino Acid Arylamides: MeIm (25.0 mmol) was added to a stirred solution of Cbz-Phe (10.0 mmol) in CH₂Cl₂ (15 mL) at 0-5 ˚C, and the mixture was stirred for 10 min. MsCl (10.0 mmol) in CH₂Cl₂ (1.0 mL) was added to the mixture under
-5 ˚C. After the mixture was stirred under that temperature for 20 min, aniline (9.0 mmol) was added. Then the mixture was stirred at r.t. for 2 h. H₂O (100 mL) was added to the mixture, which was extracted with additional CH₂Cl₂ (100 mL). The organic layer was washed with sat. NaCl solution (3 × 50 mL) and dried with anhyd Na₂SO₄. The solvent was removed by evaporation under reduced pressure. Purification by chromatography on silica gel (CH₂Cl₂-MeOH) gave 3b as a white solid; mp 169-170 ˚C; [α]_D ^²5 46.0 (c = 0.2, DMSO); ee >99.5%. ^¹H NMR (400 MHz, DMSO): δ = 2.88 (dd, 1 H), 3.03 (dd, 1 H), 4.43 (m, 1 H), 4.99 (s, 2 H), 5.43 (br s, 1 H), 7.00-7.60 (m, 15 H), 10.04 (br s, 1 H). HRMS (ESI⁺): m/z [M + Na⁺] calcd for C₂₃H₂₂N₂O₃: 397.1528; found: 397.1530.