A variety of phosphates and phosphoramides are also widely used in the condensation of amides. For example, dpp-cl, decp, DPPA, MPTA, BOP Cl, 2,4,6-tripropyl-1,3,5,2,4,6-trioxytriphosphate-2,4,6-trioxides (t3p), etc.
Among these phosphates and phosphoramides, decp is often used for the synthesis of small amount of polypeptides. Bop-cl is particularly suitable for the synthesis of amino acids. Its yield is high and it is not easy to racemize. However, when the reaction activity of amines is low, acylated oxazolidines are often obtained.
In addition, the solubility of bop-cl is poor, resulting in a long reaction time, sometimes up to four or five days. DMF is often used as the reaction solvent.
The yield of DCC is only 15%, but the yield of dpp-cl is 94%.
Reaction examples
Example of synthesis of amide with DPPA as condensation agent
To solution of this free amine 30 (0.270 g, 0.96 mmol) was added DMF (5 mL),(2-phthalimidoethoxy)acetic acid 29 (0.237 g, 0.96 mmol), DPPA (0.25 mL, 1.15mmol) and Et3N (0.29 mL, 2.11 mmol) at 0℃ while stirring. The ice bath was removed after two hours and the reaction was stirred at R.T. overnight. EtOAc (70 mL) was added and the solution wasextracted successively with 10% citric acid, H2O, saturated NaHCO3solution, H2O, and saturated NaCl solution (20 mL each), dried(anhydrous MgSO4) and finnaly evaporated in vacuo. The oily residue was purified by columnchromatography on silica gel, eluting with 7:1 CHCl3-MeOH to givethe desired product 31 as a white solid. Yield: 81% (two steps)。
2、 Example of synthesis of amide with bop-cl as condensation agent
To a solution of theacid 33 in dry CH2Cl2(5 ml / mmol) was added diisopropyl ethylamine (DIEA, 1 equiv) under nitrogen,and the mixture was stirred for 10 min. Then,BOP-Cl (1 equiv), amine 32 (1.1 equiv) and again DIPEA (2 equiv) wereadded. After it was stirred overnight, most of the DCM was removed under reduced pressure and ethyl acetate (100 ml)was added. The solution was washed threetimes with 5% NaHCO3 solution and once consecutively with water, 2M HCl solution, water and saturatedbrine (50 ml each). The organic layerwas dried over Na2SO4, and the solvent was evaporated to give the desired amide34.
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