2-Morpholinoethyl Isocyanide

[78375-48-1]  · C7H12N2O  · 2-Morpholinoethyl Isocyanide  · (MW 140.21)

(coupling reagent for amino acids; amide synthesis)

Physical Data: bp 72-73 °C/0.7 mmHg; d 1.017 g cm-3; nD 1.469.

Solubility: usually used in CH2Cl2.

Form Supplied in: liquid, >98% pure.

Analysis of Reagent Purity: comparison with literature boiling point; also nmax (liquid film) at 2150 cm-1 is indicative of isocyanide functionality.

Preparative Methods: by the reaction of 2-morpholinoethylamine with Formic Acid in boiling toluene with a water separator, to yield the formamide which is treated either with Phosgene and Triethylamine in CH2Cl2 or with Phosphorus Oxychloride and Diisopropylamine.1,2 The use of diisopropylamine as base is favored as yields are improved, typically to 68%. Trichloroacetic Anhydride has also been used as an alternative for COCl2, giving a yield of 74%.3

Purification: when phosphorus oxychloride and diisopropylamine are employed, purification is not required.2

Introduction.

The principal synthetic application of 2-morpholinoethyl isocyanide is as a coupling reagent of amino acids to yield peptides.2 It also reacts with aldehydes or ketones to yield amides,4 with acids to yield imidazolinium salts,5 and has been used as a ligand in spectroscopic studies to examine shielding effects.6

Coupling of Amino Acids.2

The coupling reaction is performed in CH2Cl2 with N-Hydroxysuccinimide or 1-Hydroxybenzotriazole and 2-morpholinoethyl isocyanide (1) to yield products in 61-95% yield (eq 1).

No racemization is observed, as determined by the coupling reaction of CF3CO-Phe-OH with H-Phe-O-t-Bu in the presence of HOSu.

Formation of Amides.4

The isocyanide moiety of 2-morpholinoethyl isocyanide reacts with aldehydes and ketones to form amides in good yields (eq 2).

Formation of Imidazolinium Salts by Cyclization.5

Treatment of the isocyanide with HZ (Z = Cl, TsO) gives 40-60% of the spiroimidazolium salt which on addition of excess HZ provides the imidazolinium salt in 70-95% yield (eq 3).

Use in Spectroscopic Studies.6

2-Morpholinoethyl isocyanide has been used to study the NMR 14N NMR signals of molybdenum (95Mo) and tungsten (183W) carbonyl isocyanide complexes M(CO)6 - n(CNR)n (n = 0-6). When isocyanide is coordinated to the metal center, the 14N signal is deshielded but, with further substitution, the N becomes more shielded again. With UV and IR studies, substitution of CO by isocyanide shifts the absorption toward longer wavelength so that the color of the complexes changes from white to orange-red.


1. Helmut, A.; Koch, G.; Marquarding, D. Chem. Pept. Proteins, Proc. USSR-FRG Symp. 3rd; 1982; p 209.
2. Obrecht, R.; Herrmann, R; Ugi, I. S 1985, 4, 400.
3. Eckert, H.; Forster, B. AG 1987, 99, 922.
4. Seebach, D.; Adam, G; Gees, T; Schiess, M; Wiegand, W. CB 1988, 121, 507.
5. Polyokov, A. I.; Baskakov, Y. A.; Artamonova, O. S.; Baranova, S. S. KGS 1983, 6, 843.
6. Minelli, M; Masley, W. J. IC 1989, 28, 2954.

Helen Osborn

University of Bristol, UK



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