2-Hydroxypyridine1

(-ol form)

[72762-00-6]  · C5H5NO  · 2-Hydroxypyridine  · (MW 95.11) (-one form)

[142-08-5]

(acylating agent; nitrile formation; peptide coupling)

Alternate Names: 2-pyridinol; 2(1H)-pyridone.

Physical Data: mp 105-107 °C; bp 181-185 °C/24 mmHg.

Form Supplied in: off-white solid; widely available commercially.

Analysis of Reagent Purity: mp; should be an off-white solid; if it becomes discolored it should be purified before use.

Purification: distill under vacuum then recrystallize from ethanol.

Handling, Storage, and Precautions: best stored in a stoppered vessel at 0 °C or below; avoid contact with strong acids and oxidizing agents; it is toxic and an irritant and so appropriate precautions should be taken.

Introduction.

The pyridone tautomer is treated separately (see 2-Pyridone), where cycloaddition chemistry is discussed. This entry deals with uses of the reagent as an acylating and activating agent.

Bifunctional Catalysis.

2-Hydroxypyridine has been used as a bifunctional catalyst2 in a number of reactions,3 most notably in the formation of amides. In this context the addition of 2-hydroxypyridine to the reaction between methyl ester (1) and amine (2) significantly enhances the yield of the amide product (eq 1).

Acyl Derivatives of 2-Hydroxypyridine.

The coupling of 2-hydroxypyridine with amino acids has been used as a means of activating the carboxyl function for peptide synthesis. The active esters can then be readily reacted with the amino function of another amino acid with minimal epimerization of any chiral centers (eq 2).4

The reaction rates for these coupling reactions decrease considerably in polar solvents such as DMF, which means that this method is only really useful for small peptide units which are soluble in less polar solvent systems such as dichloromethane. For larger peptides, it has been shown that good reaction rates can be achieved if this coupling reaction is used in conjunction with a Merrifield resin.

These active esters will also acylate a range of carbon nucleophiles including Grignard reagents,5 organocopper reagents,6 and ester enolates.7 This chemistry has been used to prepare keto derivatives of amino acids as illustrated in eq 3.

O-Acyl derivatives of 2-hydroxypyridine have also been employed as general acylating agents;3b,8 for example, the benzyloxycarbonate derivative will readily react with amino acids to give the corresponding benzyloxycarbamate. In the case of free amino acids such as serine, this reagent shows high chemoselectivity for the amino function (eq 4).

2-Trifluoroacetoxypyridine (TFAP), which is readily prepared from 2-hydroxypyridine, will trifluoroacetylate both amines and alcohols, as illustrated in eq 5.

As well as being a simple trifluoroacetylation agent, TFAP is also capable of effecting the dehydration of oximes and amides to give nitriles, as exemplified in eq 6.


1. Kim, S. OPP 1988, 20, 145.
2. Swain, C. G; Brown, J. F., Jr. JACS 1952, 74, 2538.
3. (a) Openshaw, H. T.; Whittaker, N. JCS(C) 1969, 89. (b) Kametani, T; Kanaya, N; Ihara, M. JCS(P1) 1981, 959. (c) Jägers, E; Steglich, W. AG(E) 1981, 20, 1016. (d) Radüchel, B. TL 1983, 24, 3229. (e) Hoffmann, R. W; Endesfelder, A. LA 1986, 1823.
4. (a) Dutta, A. S; Morley, J. S. JCS(C) 1971, 2896. (b) Effenberger, F; Brodt, W. CB 1985, 118, 468.
5. (a) Araki, M; Sakata, S; Takei, H; Mukaiyama, T. BCJ 1974, 47, 1777. (b) Hagiwara, D; Miyake, H; Morimoto, H; Murai, M; Fujii, T; Matsuo, M. JMC 1992, 35, 3184.
6. Kim, S; Lee, J. I. JOC 1983, 48, 2608.
7. Kim, H. O; Olsen, R. K; Choi, O. S. JOC 1987, 52, 4531.
8. (a) Ueno, Y; Takaya, T.; Imoto, E. BCJ 1964, 37, 864. (b) Nakamizo, N. BCJ 1969, 42, 1071. (c) Carson, J. F. S 1979, 24. (d) Keumi, T; Shimada, M; Morita, T; Kitajima, H. BCJ 1990, 63, 2252.

Barry Lygo

Salford University, UK



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