[142-08-5]  · C5H5NO  · 2-Pyridone  · (MW 95.11) (iminol tautomer)


(ambident nucleophile,2 diene for [4 + 2] cycloaddition;3 used to form active esters in peptide synthesis4)

Alternate Name: a-pyridone.

Physical Data: mp 105-107 °C; bp 280-218 °C; lmax 293 nm (ε 5900, H2O).

Solubility: sol H2O, EtOH, CHCl3; moderately sol Et2O, C6H6; sparingly sol ligroin, hexane.

Form Supplied in: crystalline; widely available.

Purification: commercial material is distilled under vacuum (181-185 °C/24 mmHg) to remove colored impurities. The distillate is recrystallized from EtOH, CHCl3/ether, C6H6, C6H6/hexane, or CCl4.5 Alternatively, high purity material can be prepared by sequential recrystallization,2 sublimation,6 or a combination of both techniques.7

Handling, Storage, and Precautions: store refrigerated, preferably under an inert atmosphere. Uses of the iminol tautomer of this reagent as a coupling agent are considered under 2-Hydroxypyridine.

General Considerations.

2-Pyridone (1) is a classical substrate for the study of iminol-amide tautomerism (eq 1). In polar media the pyridone form is favored;6 the tautomeric equilibrium shifts to the hydroxypyridine form as solvent polarity decreases. In the vapor phase the hydroxypyridine form predominates.8 Consequently, nucleophilic substitution reactions using various electrophilic reagents can and sometimes do provide mixtures of isomeric products. In the case of simple alkylation, N-alkylation is most commonly observed when the conjugate base of (1) is used as nucleophile,2,9,10 as illustrated by the conjugate addition-elimination product (2) (eq 2) formed by addition of (1) to 3-chloro-5,5-dimethyl-2-cyclohexenone in the presence of Potassium Carbonate.11

Regiospecific N-alkylation also is observed with Pt- and Pd-catalyzed allylations12 and with sulfenium ions generated from a Pummerer reaction of tetramethylene sulfoxide.13 Solvent and counterion effects are substantial: polar solvents favor N-alkylation, while the Ag salt of (1) is highly biased towards O-alkylation.2 Silyl ethers form when Trimethylsilyl Trifluoromethanesulfonate is used as electrophile with Triethylamine present;13 similarly, the dimethylphosphinite is the sole product when (1) is reacted with chlorodimethylphosphine.7a Kinetically controlled methylation of (1) with Diazomethane provides ~60:40 ratio of N-methyl and O-methyl products,7b while hard electrophiles such as 2-methoxybiphenyl-2-yldiazonium fluoroborate provide exclusive O-methylation.14 Other things being equal, substrate identity can influence the regiospecificity of alkylation (eq 3).15

Acylations of (1) are less well known: acetylation at cold temperatures results in a mixture of products; the N-acetyl derivative rearranges to the thermodynamically preferred O-acetyl isomer upon warming to room temperature (eq 4).16 Benzoylation17 and triflation18 provide only ester products from attack at the oxygen of (1).

[4 + 2] Cycloaddition reactions of (1) usually are difficult to achieve.3 2-Pyridone itself is prone to undergo conjugate addition reactions with dienophiles,19 but N-alkyl derivatives, especially N-methyl and N-alkenyl derivatives, are found to form N-alkylated isoquinuclidine adducts with highly reactive dienophiles such as Dimethyl Acetylenedicarboxylate (eq 5),19,20 Maleic Anhydride, and benzyne21 under thermal or high pressure conditions. When heated, the adducts can aromatize via alkyl isocyanate extrusion. Related N-arylsulfonyl-3-(p-toluenesulfonyl)-2-pyridones are relatively good dienes in inverse electron demand Diels-Alder reactions with vinyl ether dienophiles;3 these cycloadditions are facilitated by high pressure.

Although intramolecular [4 + 2] cycloadditions of N-(o-alkenyl)-2-pyridones have been unsuccessful,21a photosensitized intramolecular [2 + 2] cycloadditions of these substrates provide a simple route to stereochemically defined tricyclic lactams.10 A unique intramolecular 1,3-dipolar cycloaddition between DMAD and an azomethine ylide generated from N-(3-diazoacetonyl)-2-pyridone provides indolizinone products.9

2-Pyridone is useful in the preparation of active esters for solid-phase peptide synthesis;4 these esters are considerably more reactive than the corresponding p-nitrophenyl esters when peptide coupling is performed in CH2Cl2. In one application to peptide synthesis, 2-pyridyl esters serve as intermediates in the preparation of 2,2,2-trichloroethyl esters of amino acids (eq 6).22

Other uses of 2-pyridone include that as a ligand in transition metal complexes, such as the preparation of complexes derived from chloro-bridged RuIV bis(allyl) dimers23 and triruthenium carbonyl complexes from Ru3(CO)12.24 N-Hydroxy-2-pyridone can be used to effect radical decarboxylation: N-dihydrocinnamyloxy-2-pyridone is reduced by Tri-n-butylstannane with Azobisisobutyronitrile initiation to provide ethylbenzene in 73% yield.25 Finally, 2-hydroxypyridinium tosylate acts as an acid catalyst in the dimerization of a-aminoacrylonitrile.26

Related Reagents.

Methanesulfonic Anhydride.

1. Smith, D. M. In Comprehensive Organic Chemistry, Barton, D. H. R.; Ollis, W. D., Eds.; Pergamon: New York, 1979; Vol. 4, p 55.
2. Hopkins, G. C.; Jonak, J. P.; Minnemeyer, H. J.; Tieckelmann, H. JOC 1967, 32, 4040.
3. Posner, G. H.; Switzer, C. JOC 1987, 52, 1642.
4. Dutta, A. S.; Morley, J. S. JCS(C) 1971, 2896.
5. Perrin, D. D.; Armarego, W. L. F. Purification of Laboratory Chemicals, 3rd ed.; Pergamon: New York, 1988; p 200.
6. Frank, J.; Katritzky, A. R. JCS(P2) 1976, 1428.
7. (a) DePue, R. T.; Collum, D. B.; Ziller, J. W.; Churchill, M. R. JACS 1985, 107, 2131. (b) Kornblum, N.; Coffey, G. P. JOC 1966, 31, 3447.
8. Beak, P.; Fry, F. S., Jr.; Lee, J.; Steele, F. JACS 1976, 98, 171.
9. Padwa, A.; Austin, D. J.; Precedo, L.; Zhi, L. JOC 1993, 58, 1144.
10. Somekawa, K.; Okuhira, H.; Sendayama, M.; Suishu, T.; Shimo, T. JOC 1992, 57, 5708.
11. Mariano, P. S.; Krochmal, E.; Beamer, R.; Huesmann, P. L.; Dunaway-Mariano, D. T 1978, 34, 2609.
12. Moreno-Mañas, M.; Pleixats, R.; Villarroya, M. T 1993, 49, 1457.
13. O'Neil, I. A.; Hamilton, K. M. SL 1992, 791.
14. Downie, I. M.; Heaney, H.; Kemp, G.; King, D.; Wosley, M. T 1992, 48, 4005.
15. Raddatz, P.; Jonczyk, A.; Minck, K.-O.; Rippmann, F.; Schittenhelm, C.; Schmitges, C. J. JMC 1992, 35, 3525.
16. McKillop, A.; Zelesko, M. J.; Taylor, E. C. TL 1968, 4945.
17. Singgih, P. A.; Janssem, M. J. TL 1971, 4223.
18. Meyers, A. I.; Robichaud, A. J.; McKennon, M. J. TL 1992, 33, 1181.
19. Acheson, R. M.; Tasker, P. A. JCS(C) 1967, 1542.
20. Matsumoto, K.; Ikemi-Kono, Y.; Uchida, T.; Acheson, R. M. CC 1979, 1091.
21. (a) Gisby, G. P.; Royall, S. E.; Sammes, P. G. JCS(P1) 1982, 169. (b) Mariano, P. S.; Huesmann, P. L.; Beamer, R. L.; Dunaway-Mariano, D. T 1978, 34, 2617. (c) Tomisawa, H.; Hongo, H.; Kato, H.; Fujita, R.; Sato, A. CPB 1978, 26, 2312. (d) Tomisawa, H.; Fujita, R.; Noguchi, K.; Hongo, H. CPB 1970, 18, 941. (e) Tomisawa, H.; Hongo, H. TL 1969, 2465.
22. Carson, J. F. S 1979, 24.
23. Steed, J. W.; Tocher, D. A. JCS(D) 1992, 2765.
24. Lugan, N.; Laurent, F.; Lavigne, G.; Newcomb, T. P.; Liimatta, E. W.; Bonnet, J.-J. OM 1992, 11, 1351.
25. Barton, D. H. R.; Blundell, P.; Jaszberenyi, J. C. TL 1989, 30, 2341.
26. Ksander, G.; Bold, G.; Lattmann, R.; Lehmann, C.; Früh, T.; Xiang, Y.-B.; Inomata, K.; Buser, H.-P.; Schreiber, J.; Zass, E.; Eschenmoser, A. HCA 1987, 70, 1115.

Martin Hulce

Creighton University, Omaha, NE, USA

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