Propylphosphonic Acid Anhydride (Cyclic Trimer) (48% in N,N-Dimethylformamide, ca. 1.6mol/L)

• N-Benzyloxycarbonyl-L-alanine [C0633]
• Aniline [A0463]
• Propylphosphonic Acid Anhydride Cyclic Trimer, 48 % in DMF [P1320]
• Pyridine
• Ethyl Acetate

To a 3-necked 100 mL round bottom flask equipped with an internal temperature probe was charged with N-benzyloxycarbonyl-L-alanine (3.01 g, 13.5 mmol, 1.0 eq.), aniline (1.53 g, 16.4 mmol, 1.2 eq.), pyridine (3.0 mL, 37 mmol) and ethyl acetate (12 mL). The heterogeneous mixture was cooled to –10 °C with EtOH/ice bath. Propylphosphonic acid anhydride cyclic trimer (48 % in DMF) (17.4 g, 26.3 mmol, 2.0 eq.) was slowly added while an internal temperature was kept below 0 °C. The reaction solution was stirred below 0 °C for 2 h. HCl aq. (0.5 mol/L, 6.0 mL) was added dropwise below 20 °C and ethyl acetate was removed under reduced pressure. H₂O (80 mL) was added into the residual crude mixture. The suspension was vigorous stirred for 2 hrs. The white precipitate was filtered, washed with H₂O (40 mL) and dried in vacuo for 16 h at 50 °C to obtain 1 (3.47 g, 85%) as a white solid.

The reaction mixture was monitored by HPLC.

¹H NMR (400 MHz, DMSO-d6); δ 9.99 (s, 1H), 7.69-7.53 (m, 3H), 7.42-7.10 (m, 7H), 7.03 (app t, J = 8 Hz, 1H), 5.02 (d, J = 4 Hz, 2H), 4.18 (dq J = 8 Hz, 8 Hz, 1H), 1.28 (d, J = 8 Hz, 3H).

¹³C NMR (101 MHz, DMSO-d6); δ 171.61, 155.81, 139.06, 137.03, 128.74, 128.38, 127.84, 127.80, 123.25, 119.14, 65.41, 50.79, 18.07.

• General and Scalable Amide Bond Formation with Epimerization-Prone Substrates Using T3P and Pyridine
  • J. R. Dunetz, Y. Xiang, A. Baldwin, J. Ringling, Org. Lett. 2011, 13, 5048.