Acid-Amine Coupling using NHS Esters

Acid-Amine Coupling using NHS ester route;

General Procedure:

To A stirred, cooled solution of acid (1 eq.) at 0 ^oC in DCM (10 Vol) at 0 ^oC is treated dropwise with N-Hydroxysuccinimide (NHS, 1 eq.) and DCC or EDCI (1 eq.) and stirred at 0 ^oC for one hour. A solution of amine (1.2 eq.) in DCM (60 ml) is added at 0 ^oC and stirred at room temperature for 2 h. The reaction is then brought to RT and stirred overnight. The reaction is monitored by TLC. The organic layer is diluted with CH₂Cl₂ (10 Vol) and then successively washed with water (15 ml x 2) and brine solution (15 ml). The resultant organic layer is dried using sodium sulphate, filtered and concentrated under reduced pressure. The crude product is purified by column chromatography.

Note:

• NHS (N-Hydroxysuccinimide) acts as an activating agent for -COOH, making it active ester for coupling reaction

• DCC is Dicyclohexylcarbodiimide and EDCI is 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide (also mentioned as EDC, EDAC)

• The most preferable solvent is DCM or EtOAc. Other solvents are DMF

• DCC (Dicyclohexylcarbodiimide), wherein the by-product (Dicyclohexylurea) is insoluble requires filtration. However, the byproduct from EDCI namely 1-Ethyl-3-(3-dimethylaminopropyl)urea is soluble in water. Hence, the work-up becomes much easier in case of EDCI

Typical Procedure:

• Condensation of piperidine with N-protected phenylalanine (ChemSpider)

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