Procedure:  250 mL 1-neck flask, stirbar, septum, N₂ inlet

                  Dissolved 6.280 g of I and 16.5 mL of a 2.0 M solution of II in THF in 100 mL of THF.  Stirred at rt.  Added 4.565 g of HOBT-H₂O followed by 6.2 mL of NMM.  Cooled to 0 C and added 6.498 g of EDC-HCl.  Let stir as bath warmed to rt.  After 16 h, TLC (50:50 EtOAc-hexanes, PMA) showed product spot at Rf 0.18.  The reaction mixture was poured into 1.0 M HCl and extracted with EtOAc.  The organic layer was washed with sat. aq. NaHCO₃, dried over MgSO₄ and filtered.  The solvent was removed by rotary evaporation.  The product was isolated by flash chromatography on silica gel using 50:50 EtOAc-hexanes as eluant. The product was a clear colorless oil. 

 

¹H NMR (CDCl₃, 300 MHz) d 7.35 (m, ArH, 5H), 5.82 (br, NH, 1H), 5.10 (s, ArCH₂, 2H), 4.68 (m, CH, 1H), 3.07 (s, NCH₃, 3H), 2.97 (s, NCH₃, 3H), 1.33 (d, J = 6.8 Hz, CH₃, 3H). 

 

notes

 

The use of HOBT in carbodiimide mediated amide bond forming reactions tends to enhance reaction rates and afford products with a lower degree of racemization than reactions involving carbodiimide alone.  The reaction appears to proceed through an HOBT ester intermediate which then reacts with amine to afford the desired product. 

 

The amount of racemization that occurs can be anywhere from ~0.08-3.01% depending on factors such as solvent, concentration and temperature (see Kemp, D.S.; Trangle, M.; Trangle, K.  Tetrahedron Lett.  1974, 2695).  More concentrated reactions tend to afford lower amounts of racemization. 

 

Other solvents such as CH₂Cl₂, DMF, CH₃CN or DMSO can also be employed.