[496-64-0]  · C5H4O3  · 3-Hydroxy-2-pyrone  · (MW 112.09)

([4 + 2] cycloaddition vinylketene diene equivalent2,3)

Physical Data: white, crystalline solid; mp 92 °C; mp (dihydrate) 80-85 °C; bp 112 °C/20 mmHg; sublimes at 50 °C/4 mmHg; lmax 294 nm (H2O).

Solubility: 4-5 g/100 mL H2O; sol EtOH, Et2O, CHCl3, hot C6H6; slightly sol CS2, petroleum ether.

Preparative Methods: acid-catalyzed decarboxylation-dehydration of mucic acid provides 3-hydroxy-2-pyrone in 20-40% yield: a three-neck round-bottom flask equipped with an overhead stirrer, thermometer, and distillation head is charged with a 1:1 mixture of mucic acid and powdered KHSO4. The mixture is heated at 160-165 °C while ca. 1 mL of a light brown distillate per 2 g of mucic acid used is collected. The distillate is filtered and the pH adjusted to 7 using 6 N HCl. Continuous extraction with ether for ca. 12 h is followed by drying of the ether extract; concentration by rotary evaporation provides the crude product as a yellow solid. Recrystallization from petroleum ether or sublimation provides pure white crystalline material.3,4 3-Hydroxy-2-pyrone also has been prepared by oxidation of 2-Pyrone.5

A degradation product commonly formed in nonenzymic browning of fruits, 3-hydroxy-2-pyrone and its analogs are useful synthetic reagents. When used in Diels-Alder reactions, bicyclic lactone adducts result and these can be elucidated into a variety of highly functionalized, stereochemically defined cyclohexenes, cyclohexadienes, and benzenes.

Although unreactive towards simple alkenes, 3-hydroxy-2-pyrone undergoes slow [4 + 2] cycloadditions with reactive dienophiles, including maleates, maleic anhydride, acrylates, acrylonitriles, methacrylates, crotonates, benzoquinone, and acetylenedicarboxylates.3,6-8 Reaction temperatures and times required for cycloaddition are in the range 80-200 °C for 2-72 h, so that pyrolytic decarboxylation of the adduct is common. Typical is the regio- and stereospecific synthesis of tricyclic ketones using the hydroxypyrone and indene (eq 1);9 isolated chemical yields usually are good. Similarly, chloronaphthazarin (1) (eq 2) undergoes cycloaddition with 3-hydroxy-2-pyrone with in situ extrusion of CO2 and dehydrochlorination to provide digitopurpone diacetate (3), a model compound for anthracyclinone construction.10

Inhibition of adduct decarboxylation can be achieved using high-pressure cycloaddition conditions, which proceed at temperatures 50-180 °C lower than the corresponding thermal conditions.11 Eq 3 compares the results of thermal3 and high-pressure11 addition of methyl crotonate to 3-hydroxy-2-pyrone. Esterification of the 3-hydroxy group allows for asymmetric inverse electron demand, high-pressure Diels-Alder reactions, providing a stereoselective route to highly oxygenated cyclohexanes when vinyl ethers are used as dienophiles (eq 4).12

Both thermal and high-pressure Diels-Alder dimerizations of 3-acetoxy-2-pyrone lead to a normal endo dimer (4a), which reverts to the monomer upon heating at the melting point. Photodimerization, on the other hand, leads to regioisomeric exo dimers, (5) and (6). The parent hydroxypyrone appears to polymerize under thermal or high-pressure conditions, but does yield a single photodimer (4b).13 At very high temperatures, substituted 2-pyrones are known to undergo rearrangements through reversible ring opening to vinylketene aldehydes, which undergo a [1,5]-sigmatropic hydrogen shift before reclosing to the isomeric pyrone form.14 These rearrangements normally are observed at temperatures exceeding 350 °C, and so should not lead to rearrangement adducts under typical thermal Diels-Alder reaction conditions.

A series of reagents based upon the sulfur analog 3-mercapto-2-pyrone have been introduced2 and are excellent alternatives to 3-hydroxy-2-pyrone. 3-p-Tolylthio-2-pyrone acts as a classical Diels-Alder diene; lactone adducts from reaction with acrylates, acrylonitrile, and methacrylates form in 42-70% yields at temperatures <=90 °C.2 Inverse electron demand thermal Diels-Alder reactions of 3-p-tolylsulfinyl-15 and 3-p-tolylsulfonyl-2-pyrone16 with vinyl ethers or vinyl thioethers are highly efficient; cycloaddition proceeds at sufficiently mild temperatures so that decarboxylation of the lactone does not compete. These pyrones have been used in formal total syntheses of chorismic acid,15,16 vitamin D3 analogs,17 and shikimates.18 For example, 3-p-tolylsulfonyl-2-pyrone19 undergoes highly diastereoselective, Lewis acid promoted,20,21 inverse electron demand [4 + 2] cycloaddition with (S)-2-methyl-1-phenylpropyl vinyl ether to provide a sulfonyl lactone (eq 5),22 which can be used to prepare (-)-methyl triacetyl-4-epishikimate.18 Diastereoselectivity is considerably enhanced compared to cycloadditions using 3-acetoxy-2-pyrone12 (e.g. eq 4).

Related Reagents.

2-Pyridone; 2-Pyrone.

1. Staunton, J. In Comprehensive Organic Chemistry; Barton, D. H. R.; Ollis, W. D., Eds; Pergamon: New York, 1979; Vol. 4, p 629.
2. Posner, G. H.; Nelson, T. D.; Kinter, C. M.; Johnson, N. JOC 1992, 57, 4083.
3. Corey, E. J.; Kozikowski, A. P. TL 1975, 2389.
4. Wiley, R. H.; Jarboe, C. H. JACS 1956, 78, 2398.
5. Mayer, R. CB 1957, 90, 2369.
6. Ziegler, T.; Layh, M.; Effenberger, F. CB 1987, 120, 1347.
7. Kozikowski, A. P.; Floyd, W. C.; Kuniak, M. P. CC 1977, 582.
8. Profitt, J. A.; Jones, T.; Watt, D. S. SC 1975, 5, 457.
9. Middlemiss, D. S 1979, 987.
10. Cano, P.; Echavarren, A.; Prados, P.; Fariña, F. JOC 1983, 48, 5373.
11. Galdysz, J. A.; Lee, S. J.; Tomasello, J. A. V.; Yu, Y. S. JOC 1977, 42, 4170.
12. Prapansiri, V.; Thornton, E. R. TL 1991, 32, 3147.
13. Pirkle, W. H.; Eckert, C. A.; Turner, W. V.; Scott, B. A.; McKendry, L. H. JOC 1976, 41, 2495.
14. Pirkle, W. H.; Turner, W. V. JOC 1975, 1617.
15. Posner, G. H.; Haces, A.; Harrison, W.; Kinter, C. M. JOC 1987, 52, 4836.
16. Posner, G. H.; Nelson, T. D. T 1990, 46, 4573.
17. Posner, G. H.; Nelson, T. D. JOC 1991, 56, 4339.
18. Posner, G. H.; Wettlaufer, D. G. JACS 1986, 108, 7373.
19. Posner, G. H.; Harrison, W.; Wettlaufer, D. G. JOC 1985, 50, 5041.
20. Forman, M. A.; Dailey, W. P. JACS 1991, 113, 2761.
21. Maruoka, K.; Itoh, T.; Sakurai, M.; Nonoshita, K.; Yamamoto, H. JACS 1988, 110, 3588.
22. Posner, G. H.; Kinter, C. M. JOC 1990, 55, 3967.

Martin Hulce

Creighton University, Omaha, NE, USA

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