[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).

Peptide Synthesis.

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.

Preparation of Sulfate Esters.

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.

1. For general reviews on the use of carbodiimides, see (a) Kurzer, F.; Douraghi-Zadeh, K. CRV 1967, 67, 107. (b) Williams, A.; Ibrahim, I. T. CRV 1981, 81, 589. (c) Mikolajczyk, M.; Kielbasinski, P. T 1981, 37, 233.
2. Sheehan, J. C.; Hlavka, J. J. JOC 1956, 21, 439.
3. Jászay, Z. M.; Petneházy, I.; Tőke, L.; Szajáni, B. S 1987, 520.
4. Jászay, Z. M.; Petneházy, I.; Tőke, L.; Szajáni, B. S 1988, 397.
5. Ondetti, M. A.; Thomas, P. L. JACS 1965, 87, 4373.
6. Mumma, R. O.; Hoiberg, C. P. CED 1971, 16, 492.

Andrew M. Griffin

University of Bristol, UK

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