1-Cyclohexyl-3-(2-morpholinoethyl)carbodiimide Metho-p-toluenesulfonate1

[2491-17-0]  · C21H33N3O4S  · 1-Cyclohexyl-3-(2-morpholinoethyl)carbodiimide Metho-p-toluenesulfonate  · (MW 423.58)

(used extensively in the activation of alcohols and carboxylic acids)

Alternate Name: morpho-CDI.

Physical Data: mp 113-115 °C.

Solubility: sol DMF, MeCN.

Form Supplied in: commercially available as a colorless solid.

Preparative Methods: prepared by quaternization of the corresponding carbodiimide (see 1-Cyclohexyl-3-(2-morpholinoethyl)carbodiimide) with methyl p-toluenesulfonate. The carbodiimide is obtained by dehydration of the thiourea.2

Handling, Storage, and Precautions: assumed to be harmful by ingestion and skin contact.

Peptide Synthesis.2

Phthaloyl-L-phenylalanyl-L-leucine ethyl ester has been prepared in 80% yield by the 1-cyclohexyl-3-(2-morpholinoethyl)carbodiimide metho-p-toluenesulfonate (1) mediated coupling of L-leucine ethyl ester hydrochloride to phthaloyl-L-phenylalanine (eq 1). Any excess of reagent and the corresponding urea were easily separated from the product by washing with aqueous solutions. The ease of separation of byproduct is the main advantage of this reagent over 1,3-Dicyclohexylcarbodiimide (DCC).

Macrocyclic Lactonization.3

Lactonization of secoacid (2) was effected with (1), and subsequent cleavage of the methoxymethyl ether results in the antibiotic milbemycin b3 (3) in 85% overall yield (eq 2).

Cyclodehydrations of N-Acyl-a-amino Acids.4

2-Oxazolin-5-ones are conveniently prepared by dehydration of N-acyl-a-amino acids with (1) (e.g. eq 3).

Modified Moffat-Type Oxidations.5

(1) used in conjunction with DMSO has been used to oxidize alcohols to ketones, as exemplified in the total synthesis of kopsanone (eq 4). This is another example where the advantage of the water solubility of (1) and the corresponding urea makes the use of this reagent more attractive than DCC as the diimide component.

Dehydration of a-Hydroxymethyl Lactones.6

a-Hydroxymethyl lactones can be dehydrated to the corresponding a-methylene lactone with the use of (1) in the presence of Copper(II) Chloride (eq 5). This procedure has been successfully demonstrated in the total synthesis of isolobophytolide.

1. For general reviews on 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. Williams, D. R.; Barner, B. A.; Nishitani, K.; Phillips, J. G. JACS 1982, 104, 4708.
4. Fieser, M. FF 1984, 11, 151.
5. Magnus, P.; Gallagher, T.; Brown, P.; Huffman, J. C. JACS 1984, 106, 2105.
6. Marshall, J. A.; Andrews, R. C.; Lebioda, L. JOC 1987, 52, 2378.

Peter Szeto

University of Bristol, UK

Copyright 1995-2000 by John Wiley & Sons, Ltd. All rights reserved.