[5801-58-5]  · C5H11NO  · N-Hydroxypiperidine  · (MW 101.17)

(acylation reactions; peptide synthesis)

Alternate Name: HOPip.

Physical Data: mp 39 °C; bp 110 °C/55 mmHg.

Form Supplied in: white solid; limited commercial availability.

Analysis of Reagent Purity: mp; should be a white solid; if it becomes discolored, it should be purified before use.

Preparative Method: prepared, in approximately 62% yield, by the oxidation of N-ethylpiperidine with Hydrogen Peroxide followed by Cope elimination in refluxing toluene.2

Purification: recrystallize from n-hexane or petroleum ether (40-60 °C fraction) at -60 °C.

Handling, Storage, and Precautions: best stored in a stoppered vessel at 0 °C or below; avoid contact with reducing agents; toxicity not fully investigated so should be treated with caution.

Acylation Reactions.

N-Hydroxypiperidine has been coupled with carboxylic acids using 1,3-Dicyclohexylcarbodiimide (DCC) to give an activated ester which is capable of reacting directly with amines under acid catalysis (eqs 1-3).3 This has proved of particular interest in the preparation of peptides because the activated ester intermediates are usually stable crystalline materials, and their coupling reactions have been demonstrated to proceed without racemization.4 Unfortunately this procedure has not found widespread application because, as can be seen from eq 3, the reaction rate is rather sensitive to steric hindrance.5

The lack of reactivity of the activated ester systems towards sterically hindered amines can be useful if selective acylation of an amine is required.3a For example, the activated ester (1) will benzoylate primary amines such as n-butylamine at rt over 48 h, whereas more hindered amines such as t-butylamine are untouched (eq 4). There is also no reaction with less nucleophilic amines such as aniline or with hydroxy groups under these conditions.

Peptide Synthesis using the Kaiser Resin.

Perhaps the most common use of N-hydroxypiperidine today is in conjunction with solid-phase peptide synthesis using the Kaiser resin.1,4,6 This involves the use of a polystyrene or polyamide (PA) based resin support on which peptides (up to about 40 residues) can be synthesized, the peptide being attached to the support by means of a hydroxylamine ester linkage. Once the desired peptide has been constructed on the support, it can be released under mild conditions by reaction with N-hydroxypiperidine (eq 5). The resulting N-hydroxypiperidine ester can then be cleaved by the action of Zinc-Acetic Acid, to give the peptide free at the carboxyl terminus. This two-step operation proceeds in good overall yields and without racemization of the peptide unit. It is also compatible with a wide range of common amino acid protecting groups,6 making this a useful method for peptide synthesis.

1. Kaiser, E. T. ACR 1989, 22, 47.
2. Sabel, W. CI(L) 1966, 1216.
3. (a) Handford, B. O.; Jones, J. H.; Young, G. T.; Johnson, T. F. N. JCS 1965, 6814; (b) Jones, J. H.; Liberek, B.; Young, G. T. JCS(C) 1967, 2371; (c) Jones, J. H.; Young, G. T. JCS(C) 1968, 53.
4. Weygand, F.; Prox, A.; König, W. CB 1966, 99, 1451.
5. Nakagawa, S. H.; Kaiser, E. T. JOC 1983, 48, 678.
6. (a) &OOuml;sapay, G.; Taylor, J. W. JACS 1992, 114, 6966; (b) Sasaki, T.; Findeis, M. A.; Kaiser, E. T. JOC 1991, 56, 3159; (c) Findeis, M. A.; Kaiser, E. T. JOC 1989, 54, 3478.

Barry Lygo

Salford University, UK

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