[22509-74-6]  · C11H9NO4  · N-Ethoxycarbonylphthalimide  · (MW 219.20)

(phthaloylating agent selective for amines;1 selective protection of amino acids2 and amino alcohols3)

Physical Data: mp 90-92 °C.

Solubility: sol DMF, benzene, THF, ether, chloroform; partially sol water, ethanol, isopropyl alcohol; insol petroleum ether.

Form Supplied in: crystalline (colorless).

Analysis of Reagent Purity: commercial material is >95% pure.

Preparative Methods: addition of Ethyl Chloroformate to a cold solution of Phthalimide and Triethylamine in DMF;4 alkylation of potassium phthalimide with ethyl chloroformate.5

Purification: commercial product can be purified by recrystallization from ethanol, although some loss of material occurs due to ring opening. Synthetic material should be purified by the method of McArthur.4 A 2 M solution of the crude material in chloroform is cooled overnight in a refrigerator and filtered to remove phthalimide. The solution is then concentrated to approximately 70% of the volume and an equal volume of petroleum ether is added. The crystals that form are collected and dried to give the desired N-ethoxycarbonylphthalimide.

Handling, Storage, and Precautions: no special handling conditions or precautions are required.

Phthaloylation of Amines.

The phthalimide protecting group has long been utilized for amines in organic synthesis.6 While this group can be introduced under a variety of conditions such as phthalic anhydride or Phthaloyl Dichloride, these generally require drastic conditions and are not typically selective. The use of N-ethoxycarbonylphthalimide allows the phthaloylation of primary amines under mild conditions (eq 1).7 Primary amines can be selectively protected in the presence of secondary amines (eq 2),8 as well as amides and carbamates (eq 3).9 The advantage of the phthalimido protecting group are its stability to both acid and mild base as well as the well known methods for selective removal with Hydrazine (eq 4)10 or Phenylhydrazine (eq 5).11

Selective Phthaloylation of Amino Acids.

In his attempt to develop a method for the selective amine protection of amino acids, Nefkens introduced N-ethoxycarbonylphthalimide.5 He reported the protection of a variety of amino acids without racemization (eq 6).2 These phthaloyl derivatives are typically highly crystalline, thereby facilitating purification. The phthaloylation of hindered amino acids such as valine could be achieved by initial deprotonation followed by protection in ethyl acetate (eq 7).12 Recently, McArthur has shown that the aqueous conditions initially developed by Nefkens lead to the formation of undesired side products.4 Heating N-ethoxycarbonylphthalimide in ethanol generates the corresponding carbamate (eq 8).4 He has developed an alternative method for the phthaloylation of amino acids in THF that occurs in exceptional yields without racemization (eq 9).1 These protections can be performed on amino acids with a variety of sensitive functionalities such as hydroxyl groups (eq 10)2 or halogens without reaction at these centers (eq 11).13

Phthaloylation of Amino Alcohols.

The use of N-ethoxycarbonylphthalimide to protect amino alcohols has also been demonstrated (eq 12).3

1. McArthur, C. R.; Worster, P. M.; Okon, A. U. SC 1983, 13, 393.
2. Nefkens, G. H. L.; Tesser, G. I.; Nivard, R. J. F. RTC 1960, 79, 688.
3. McArthur, C. R.; Worster, P. M.; Jiang, J.-L.; Leznoff, C. C. CJC 1982, 60, 1836.
4. Worster, P. M.; Leznoff, C. C.; McArthur, C. R. JOC 1980, 45, 174.
5. Nefkens, G. H. L. Nature (London) 1960, 185, 309.
6. Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic Synthesis; Wiley: New York, 1991; pp 358-362.
7. Krstenansky, J. L.; del Rosario-Chow, M.; Currie, B. L. JHC 1992, 29, 707.
8. Sosnovsky, G.; Lukszo, J. ZN(B) 1986, 41b, 122.
9. Funabashi, Y.; Tsubotani, S.; Koyama, K.; Katayama, N.; Harada, S. T 1993, 49, 13.
10. Greenstein, J. P.; Winitz, M. Chemistry of the Amino Acids; Wiley: New York, 1961; Vol. 2, p. 1249.
11. Schumann, I.; Boissonnas, R. A. HCA 1952, 35, 2235.
12. Adriaens, P.; Meesschaert, B.; Janssen, G.; Dumon, L.; Eyssen, H. RTC 1978, 97, 260.
13. Clarke, S.; Hider, R. C.; John, D. I. JCS(P1) 1973, 230.

James W. Leahy

University of California, Berkeley, CA, USA

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