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.

Key words

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

References and Notes

• 1a Yin H. Frederick K. Liu D. Wand A. DeGrado W. Org. Lett.  2006,  8:  223 
• 1b Vinogradov S. Org. Lett.  2005,  7:  1761 
• 1c Yin H. Gerlach L. Miller M. Moore D. Liu D. Vilaire G. Bennett J. DeGrado W. Bioorg. Med. Chem. Lett.  2006,  16:  3380 
• 1d Kirkland T. Adler M. Bauman J. Chen M. Haeggstrm J. King B. Kochanny M. Liang A. Mendoza L. Phillips G. Bioorg. Med. Chem.  2008,  16:  4963 
• 1e Foss JF. Mathews T. Kharel Y. Kennedy P. Snyder A. Davis M. Lynch K. Macdonald T. Bioorg. Med. Chem.  2007,  15:  663 
• 2 Svendsen L. Blomback B. Blomback M. Olsson P. Thromb. Res.  1972,  1:  267 
• 3a Zimmerman M. Yurewicz E. Patel G. Anal. Biochem.  1976,  70:  258 
• 3b Fujiwara K. Tsuru D. J. Biochem.  1978,  83:  1145 
• 3c Sharma S. Castellino F. Thromb. Res.  1990,  57:  127 
• 4 Okada Y. Tsuda Y. Hirata A. Nagamatsu Y. Okamoto U. Chem. Pharm. Bull.  1982,  30:  4060 
• 5a Nedev H. Nabarisoa H. Haertle T. Tetrahedron Lett.  1993,  34:  4201 
• 5b Pozdnev V. Int. J. Peptide Protein Res.  1994,  44:  36 
• 5c Schutkowski M. Mrestani-Klaus C. Neubert K. Int. J. Peptide Protein Res.  1995,  45:  257 
• 5d Beniton N. Lee Y. Steinaur R. Chen F. Int. J. Peptide Protein Res.  1992,  40:  559 
• 6 Kato T. Nagatsu T. Kimura T. Sakakibara S. Experientia  1978,  19:  351 
• 7a Zimmerman M. Ashe B. Yurewicz E. Patel G. Anal. Biochem.  1977,  78:  47 
• 7b Teno N. Wanaka K. Okada Y. Tsuda Y. Okamoto U. Hijikata-Okunomiya A. Naito T. Okamoto S. Chem. Pharm. Bull.  1991,  39:  2340 
• 8a Haverback B. Dyce B. Bundy H. Edmondson H. Am. J. Med.  1960,  29:  424 
• 8b Bundy H. Arch. Biochem. Biophys.  1963,  102:  416 
• 9 Wu X. Hu L. J. Org. Chem.  2007,  72:  765 
• 10 Nicolaou K. Baran P. Zhong Y. Choi H. Fong K. He Y. Yoon W. Org. Lett.  1999,  1:  883 
• 11 Woo J. Fenster E. Dake G. J. Org. Chem.  2004,  69:  8984 
• 12a Wakasugi K. Iida A. Misaki T. Nishii Y. Tanabe Y. Adv. Synth. Catal.  2003,  345:  1209 
• 12b Nakatsuji H. Ueno K. Misaki T. Tanabe Y. Org. Lett.  2008,  10:  2131 

13

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.