Picolinic Acid

[98-98-6]  · C6H5NO2  · (MW 123)

(reagent used as a partner in the Mitsunobu reaction. The resulting esters can be hydrolyzed under mild conditions using Cu(OAc)2 in methanol. Used as a substrate in the Hammick reaction)

Physical Data: crystalline solid, mp 139-142 °C.

Solubility: soluble in water and alcoholic solvents. Partially soluble in polar organic solvents such as THF, ethyl acetate, chloroform, and dichloromethane. Not soluble in hexanes.

Form Supplied in: crystalline solid.

Purification: crystallized from water or benzene.1

Handling, Storage, and Precautions: no special instructions for storage and handling are mentioned in the literature. Use in a fume hood.

Partner in the Mitsunobu Reaction

Picolinic acid has been used as a partner in the Mitsunobu reaction2,3 and offers the advantage that the resulting picolinate ester can be cleaved under very mild conditions. Recent advances in understanding the mechanism of the Mitsunobu reaction have led to the use of acids that are more acidic than benzoic acid as partners, and p-nitrobenzoic acid has emerged as the reagent of choice, especially for less reactive systems.4 Cleavage of the resulting p-nitrobenzoate ester is most commonly accomplished by alkaline hydrolysis, and for base-sensitive substrates this can be problematic. Picolinic acid exhibits comparable, and at times superior, reactivity to p-nitrobenzoic acid in the Mitsunobu reaction, and the resulting p-nitrobenzoate esters can be cleaved with copper acetate in methanol. Notable examples of the use of picolinic acid in the Mitsunobu reaction include the hindered alcohols 1 and 2, which proceed in 80 and 94% yields, respectively (eqs 1 and 2).5 Attempted Mitsunobu reaction on alcohol 3 by using p-nitrobenzoic acid provided only the elimination products; however, using picolinic acid, the desired inversion product could be isolated in 36-39% yield (3).6

Notable examples of the methanolysis of picolinate esters include substrates 4 and 5, which can be cleaved in 79% and 95% yields, respectively, using copper acetate in methanol (eqs 4 and 5)5. For compound 5, which is somewhat hindered, the authors utilized 2 equiv of copper acetate and allowed the reaction to stir for 24 h. The cleavage of compound 4 was complete in 2 d using 1 equiv of copper acetate. Substrate 6 is prone to elimination, and attempted cleavage of other esters under basic hydrolysis conditions provided predominant or exclusive elimination. However, using 1/2 equiv of copper acetate in methanol, the picolinate ester could be cleaved in 85% yield in 6 h (6).5

Substrate in the Hammick Reaction

Picolinic acid has been used as a substrate in the Hammick reaction.7 The Hammick reaction consists of heating a 2-pyridyl, quinolyl or isoquinolyl carboxylic acid in the presence of an aldehyde. Decarboxylation of the heterocycle occurs and produces a nucleophilic species, which undergoes addition to the aldehyde and competitive protonation. The reaction was originally run in neat aldehyde. However, subsequent studies showed that p-cymene is an effective solvent and that near-stiochiometric quantities of aldehyde can be employed (eqs 7 and 8).8 Yields are usually moderate, and are typically around 50%. Substituted picolinic acids (alkoxy and alkyl) can be used as can aliphatic and aromatic aldehydes (8).9 The carboxylate group has to be at the 2-position (ortho to the nitrogen); 3- and 4-picolinic acid undergo no reaction when subjected to these conditions. Thiazoles and benzaldehyde derivatives failed to undergo decarboxylation and are not suitable partners in the reaction.8

A modification of the Hammick reaction has been reported that provides significantly higher yields.10 In this reaction, the trimethylsilyl ester is used in place of the free acid. This procedure minimizes protonation of the nucleophilic intermediate, and funnels the reaction pathway to the addition product (9). Using this procedure, diazines, pyrazines, pyrimidines, and picolinic acid N-oxides have been used. Unfortunately, intramolecular variants of this reaction provide low yields and are not synthetically useful.11

Related Reagents.

p-Nitrobenzoic acid; benzoic acid.

1. Perrin, D. D.; Armarego, W. L. F., Purification of Laboratory Chemicals; Pergamon: Oxford, 1998.
2. Hughes, D. L., Org. Prep. and Proc. Int. 1996, 28, 127.
3. Hughes, D. L., In Organic Reactions; Paquette, L. A., Ed.; Wiley: New York, 1992, Chapter 2.
4. Martin, S. F.; Dodge, J. A., Tetrahedron Lett. 1991, 32, 3017.
5. Sammakia, T.; Jacobs, J. S., Tetrahedron Lett. 1999, 40, 2685.
6. Achmatowicz, B.; Gorobets, E.; Marczak, S.; Przezdziecka, A.; Steinmeyer, A.; Wicha, J.; Zügel, U., Tetrahedron Lett. 2001, 42, 2891.
7. Dyson, P.; Hammick, D. L., J. Chem. Soc. 1937, 1724.
8. Cantwell, N.; Brown. E. V., J. Am. Chem. Soc. 1953, 75, 1489.
9. Rapoport, H.; Volcheck, E. J., J. Am. Chem. Soc. 1956, 78, 2451.
10. Effenberger, F.; Konig, J., Tetrahedron 1988, 44, 3281.
11. Bohn, B.; Heinrich, N.; Vorbruggen, H., Heterocycles 1994, 37, 1731.

Tarek Sammakia

University of Colorado, Boulder, CO, USA

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