[15580-20-8] · C13H23N3O · 1-Cyclohexyl-3-(2-morpholinoethyl)carbodiimide · (MW 237.34)
(coupling agent for peptide synthesis; used to make sulfate esters from alcohols)
Physical Data: bp 145 °C/0.2 mmHg.
Solubility: sol DMF, CH2Cl2, dioxane, xylene.
Preparative Methods: from cyclohexyl isothiocyanate and N-(2-aminoethyl)morpholine (67% yield);2 by dehydration of the corresponding urea with p-Toluenesulfonyl Chloride, Potassium Carbonate, and Benzyltriethylammonium Chloride (91% yield);3 or by the reaction of cyclohexyl isocyanate, 2-(4-morpholinyl)ethyl diethylphosphoramidate, and potassium carbonate (82% yield).4 The corresponding N-metho-p-toluenesulfonate salt is commercially available (see 1-Cyclohexyl-3-(2-morpholinoethyl)carbodiimide Metho-p-toluenesulfonate).
Amide bonds may be formed using carbodiimides but workup procedures are sometimes complicated by the presence of the urea byproduct. 1-Cyclohexyl-3-(2-morpholinoethyl)carbodiimide (1) carries a tertiary amine and has a urea derivative that is soluble in dilute acid, making product separation far easier. It has been used to couple glycine ethyl ester hydrochloride and phthaloyl-L-phenylalanine to give phthaloyl-L-phenylalanylglycine ethyl ester in 81% yield (eq 1).2
(1) has been found to be superior to 1,3-Dicyclohexylcarbodiimide (DCC) for the final cyclization step in the synthesis of a large-ring peptide lactone related to the antibiotic vernamycin Ba, with methylene chloride being the solvent of choice.5 Of all the other coupling reagents examined, only N,N´-Carbonyldiimidazole gave any cyclization product, although in lower yields.
1-Cyclohexyl-3-(2-morpholinoethyl)carbodiimide has been used to mediate the sulfation of 1-hexadecanol to give the corresponding monoalkyl sulfate in 56% yield (eq 2).6 DCC is superior in this reaction, giving the monoalkyl sulfate in 92% yield.
Andrew M. Griffin
University of Bristol, UK