[15263-20-4]  · C13H13NO5  · N-(t-Butoxycarbonyloxy)phthalimide  · (MW 263.25)

(reagent for protection of amino acids as t-butyl carbamates1)

Physical Data: mp 118 °C (dec).

Solubility: sol t-butanol and THF; insol water.

Form Supplied in: solid.

Handling, Storage, and Precautions: contact with the reagent may cause irritation. The toxicological properties of the reagent have not been thoroughly investigated.

Amine Protection.

N-(t-Butoxycarbonyloxy)phthalimide (1) has been utilized for the protection of amines as their t-butoxycarbonyl (Boc) derivatives, particularly for the N-protection of a-amino acids (eq 1).1

Equimolar amounts of (1), a base (NaOH or Na2CO3), and the amino acid in t-butanol-water (2:1) are heated to 90 °C for 2 h. Upon cooling, the byproduct sodium hydroxyphthalimide precipitates. The filtrate is then acidified to pH 3 with citric acid and extracted with chloroform. The extract is washed with water to obtain the Boc derivatives in moderate to good yield (Table 1). A related reagent where the phthalimide moiety is replaced by a succinimide can give comparable or superior yields (Table 1).1,2 The 9-fluorenylmethyloxycarbonyl (Fmoc) succinimide has also been prepared and can give good yields of Fmoc-protected amino acids.3

These reagents offer some advantage over t-Boc azide, which is thermally unstable and decomposes with apparent detonation at temperatures above 80 °C. However, 2-(t-Butoxycarbonyloxyimino)-2-phenylacetonitrile4,5 and Di-t-butyl Dicarbonate6 are generally the reagents of choice because the reactions are complete at ambient temperature within 2-4 h and because the yields are usually higher.

The reagent will selectively protect the amino group in the presence of alcohols, and may show selectivity for less hindered amines. The antibiotic sisomicin (eq 2) reacted with (1) to give a clean product by TLC. However, after silica gel chromatography the sole product isolated was obtained in only 26% yield, with the remainder of the starting material recovered. The authors suggest that while the reaction was remarkably selective and went to apparent completion, the product was unstable to silica gel.7

Related Reagents.

2-(t-Butoxycarbonyloxyimino)-2-phenylacetonitrile; N-(t-Butoxycarbonyloxy)succinimide; Di-t-butyl Dicarbonate; 9-Fluorenylmethyl Chloroformate.

1. Gross, H.; Bilk, L. LA 1969, 725, 212 (CA 1961, 71, 91 846k).
2. Frankel, M.; Ladkany, D.; Gilon, C.; Wolman, Y. TL 1966, 4765.
3. Paquet, A. CJC 1982, 60, 976.
4. Itoh, M.; Hagiwara, D.; Kamiya, T. TL 1975, 4393.
5. Itoh, M.; Hagiwara, D.; Kamiya, T. BCJ 1977, 50, 718.
6. Persio, G.; Piani, S.; De Castiglione, R. Int. J. Peptide Protein Res. 1983, 21, 227.
7. Daniels, P. J. L.; Jaret, R. S.; Nagabhushan, T. L.; Turner, W. N. J. Antibiotics 1976, 29, 488.

Michael S. Wolfe

National Institutes of Health, Bethesda, MD, USA

Jeffrey Aubé

University of Kansas, Lawrence, KS, USA

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