Conversion of α,β-epoxyketones to diosphenols using 6-methyl-2-pyridone anion as an hydroxide equivalent

Article abstract of DOI:10.1016/S0040-4039(00)01691-9

Treatment of α,β-epoxyketones with 6-methyl-2-pyridone anion gives diosphenol (6-methyl-2-pyridyl) ethers that can be cleaved to diosphenols under mild basic conditions. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)01691-9

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 9031–9035
Conversion of a,b-epoxyketones to diosphenols using
6-methyl-2-pyridone anion as an hydroxide equivalent
Anthony A. Ponaras* and M. Younus Meah
Department of Chemistry, The Catholic University of America, Washington, DC 20064, USA
Received 4 September 2000; accepted 22 September 2000
Abstract
Treatment of a,b-epoxyketones with 6-methyl-2-pyridone anion gives diosphenol (6-methyl-2-pyridyl)
ethers that can be cleaved to diosphenols under mild basic conditions. © 2000 Elsevier Science Ltd. All
rights reserved.
Keywords: diosphenols; a-diketones; diosphenol ethers; a,b-epoxyketones; 6-methyl-2-pyridone; 2-pyridones; hydrox-
ide equivalent.
The diosphenol (enolized a-diketone) array is found in diverse natural products,1–5 and has
synthetic utility for Claisen rearrangements,6 aldol and Michael additions,7 Wittig reactions,8
ring-cleavage reactions,9 ring-contraction reactions,10 and photochemical reactions.11 a,b-
Epoxyketones have been used as precursors of diosphenols via isomerization with strong acid in
a hydroxylic solvent.12 This procedure, however, gives variable results13 and is incompatible with
many functional groups. Treatment of a,b-epoxyketones with methoxide often gives acceptable
yields of diosphenol methyl ethers,14 but hydrolysis to the parent diosphenols requires harsh
conditions.15 The apparently simpler route, namely treatment of an a,b-epoxyketone with
hydroxide ion,16 is unsatisfactory since any diosphenol produced undergoes benzilic acid
rearrangement.17 We now report that treatment of a,b-epoxyketones with 6-methyl-2-pyridone
Scheme 1. (a) 2 Equiv. 6-methyl-2-pyridone, 0.1 equiv. KH, Bu2O–HMPA 9:1, 140°C, 6 h (conditions ‘A’), 66%; (b)
MeOTf, CH2Cl2, 25°C, 3 h, 95%; (c) 1 M aq. Na2CO3–acetone 1:1, 25°C, 12 h, 88% (of 4) Overall: 54% yield
* Corresponding author.
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01691-9

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anion gives diosphenol (6-methyl-2-pyridyl) ethers that can be cleaved to diosphenols under mild
basic conditions (Scheme 1).
Other N-hindered18 2-hydroxyazaarenes such as 2-hydroxyquinoline and 6-phenyl-2-pyridone
may be used in this sequence but, save crystallinity of the diosphenol ether, offer no advantage
over the readily-available19 6-methyl-2-pyridone. Table 1 shows results for the transformation of
six racemic a,b-epoxyketones into diosphenols.20 Vigorous epoxide opening conditions ‘A’
(Bu2O–HMPA, 140°C)21 are required for some substrates; for 1a–c, conditions ‘B’ (2 equiv.
6-methyl-2-pyridone, 1 equiv. NaOH, s-BuOH, 100°C, 4–12 h) suffice. Complete experimental
details (including spectral data) for the preparation of 4d from 1d are provided as a footnote.22
Table 1
Step synthesis of diosphenols. P=6-methyl-2-pyridyl; P+=N,6-dimethyl-2-pyridinium

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The ability of 2-pyridolates to function as hydroxide equivalents requires pyridine-oxygen
fission during hydrolysis of the quaternized ethers, presumably via decomposition of the
tetrahedral intermediate 8 (Scheme 2).
Scheme 2.
Our reaction sequence fails in the case of either 10a or 10b, when the major product is 11
(Scheme 3).
Scheme 3.
6-Methyl-2-pyridone and related compounds may be used in the Mitsunobu reaction to invert
alcohols (including those sensitive to acid and/or strong base). We will give details of this
procedure shortly.
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Taylor, D. A. H. Prog. Chem. Org. Nat. Prod. 1984, 45, 1 (see p. 61).

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5. Steroids. Solanudine alkaloid: (a) Usubillaga, A. Phytochemistry 1988, 27, 3031. Bufadienolides and cardenolides:
(b) Chen, R. F.; Abe, F.; Yamauchi, T.; Taki, M. Phytochemistry 1987, 26, 2351. (c) Spengel, S.; Linde, H. H.
A.; Meyer, K. Helv. Chim. Acta 1973, 56, 2827. 4-Hydroxy-3-keto-D4 steroids are inhibitors of aromatase: (d)
Brodie, A. M. H.; Garrett, W. M.; Hendrickson, J. R.; Tsai-Morris, C.-H.; Marcotte, P. A.; Robinson, C. H.
Steroids 1981, 38, 693. (e) Martin, M. B.; Mateos, A. F.; Gonzalez, R. R. J. Chem. Soc., Perkin Trans. 1 1995,
569.
6. (a) Ponaras, A. A. J. Org. Chem. 1983, 48, 3866 and previous papers cited therein. (b) Trost, B. M.; Schroeder,
G. M. J. Am. Chem. Soc. 2000, 122, 3785. (c) Hunt, D. A. US Patent, US 4,463,184; Chem. Abstr. 1986, 102,
6182g. See also: (d) Koreeda, M.; Luengo, J. I. J. Am. Chem. Soc. 1985, 107, 5572.
7. Utaka, M.; Kuriki, H.; Sakai, T.; Takeda, A. J. Org. Chem. 1986, 51, 935 and references therein.
8. Saalfrank, R. W.; Schierling, P.; Schatzlein, P. Chem. Ber. 1983, 116, 1463.
9. Beckmann fragmentation of a-ketooximes: (a) Conley, R. T.; Ghosh, S. Mech. Mol. Migr. 1971, 4, 233ff. (b)
Hassner, A.; Wentworth, W. A.; Pomerantz, I. H. J. Org. Chem. 1963, 28, 304. Fission of a-diketone
monothioketals: (c) Takano, S.; Hatakeyama, S.; Ogasawara, K. J. Am. Chem. Soc. 1979, 101, 6414. Oxidative
cleavages: (d) Payne, G. B. J. Org. Chem. 1959, 24, 719. See, also, Ref. 7.
10. Benzilic acid rearrangement: Inter alia (a) Dunlap, N. K.; Gross, R. S.; Watt, D. S. Synth. Commun. 1988, 18,
13. Wolff rearrangement of a-diazoketones: (b) Gill, G. R. In Comprehensive Organic Synthesis; Trost, B. M.;
Fleming, I., Eds.; Pergamon Press: New York, 1991; Vol. 3, pp. 887–912. (c) Stetter, H.; Kiehs, K. Chem. Ber.
1965, 98, 1181. (d) Blomquist, A. T.; Schlaefer, F. W. J. Am. Chem. Soc. 1961, 83, 4547.
11. (a) Feigenbaum, A.; Fort, Y.; Pete, J.-P.; Scholler, D. J. Org. Chem. 1986, 51, 4424 and references cited therein.
(b) Matoba, K.; Karibe, N.; Yamazaki, T. Bull. Chem. Soc. Jpn. 1984, 32, 2639. (c) Tonari, K.; Ichimoto, I.;
Ueda, H. Agric. Biol. Chem. 1980, 44, 2185. (d) Matsumoto, T.; Shirahama, H.; Ichihara, A.; Kagawa, S.;
Matsumoto, S. Tetrahedron Lett. 1969, 4103.
12. Reaction conditions are very important. Isophorone oxide, for example, gives moderate yields of 2-hydroxy-
isophorone when treated with (a) 2% aq. sulfuric acid (Langin-Lanteri, M. T.; Huet, J. Synthesis 1976, 541) or
with (b) 37% aq. HCl (Ref. 9d) but only a 3% yield of diosphenol when treated with (c) BF3·Et2O in benzene (in
this non-basic solvent the major products result from ring-contraction—House, H. O.; Wasson, R. L. J. Am.
Chem. Soc. 1959, 79, 1488).
13. The isomerization involves regiospecific epoxide fission to generate partial positive charge at the b-carbon atom.
Thus, it is not surprising that b-unsubstituted-a,b-epoxyketones (such as 1c) give poor yields of diosphenols and
that verbenone oxide or 2,3-epoxy-3-t-butylcycloalkanones give mainly skeletally-rearranged products: (a)
Ponaras, A. A. unpublished. Acid treatment of 4b,5b-epoxy-3-ketosteroids gives mainly 2a-hydroxy-3-keto-D4
steroids, probably via the alternative regiochemical sense of epoxide fission: (b) Camerino, B.; Patelli, B.;
Vercellone, A. J. Am. Chem. Soc. 1956, 78, 3540. (c) Burnett, R. L.; Kirk, D. N. J. Chem. Soc., Perkin Trans.
1 1973, 1830.
14. Inter alia: (a) Reusch, W. R.; LeMahieu, R. J. Org. Chem. 1963, 28, 2443. (b) Gianturco, M. A.; Friedel, P.
Tetrahedron 1963, 19, 3980. (c) Tobias, M. A.; Strong, J. G.; Napier, R. P. J. Org. Chem. 1970, 35, 1709.
15. Typical conditions are hydrochloric acid in boiling ethanol (see, for example, Ref. 14a). Treatment of diosphenol
methyl ethers with trimethylsilyl iodide gives reduction of the CꢀC double bond as well as demethylation:
Kawada, K.; Kim, M.; Watt, D. S. Tetrahedron Lett. 1989, 30, 5985.
16. Some common hydroxide equivalents are either insufficiently reactive (acetate) or give ring cleavage (superoxide).
17. Dawson, T. M.; Littlewood, P. S.; Medcalfe, T.; Moon, M. W.; Tompkins, P. M. J. Chem. Soc. C 1971, 1292.
18. 2-Pyridone itself is unsatisfactory because its anion shows greater reactivity at nitrogen than at oxygen.
19. Commercially available from Acros, Alfa Aesar, ICN, Kingchem, Lancaster, Pfaltz and Bauer, and Sigma-
Aldrich.
20. All new substances were characterized by IR, NMR, MS and elemental analysis or HRMS.
21. Epoxide opening in boiling N-methyl- or N-ethylmorpholine (no added HMPA) is also satisfactory. Reaction in
THF–HMPA at 67°C (cf. Schultz, A. G.; Lucci, R. D.; Fu, W. Y.; Berger, M. H.; Erhardt, J.; Hagmann, W. K.
J. Am. Chem. Soc. 1978, 100, 2150) requires many days, confirming that 2-pyridolates are less nucleophilic than
phenolates.
22. Two drops of 30% KH oil suspension were added, under N2, to a stirred solution of 2.20 g (20 mmol) of
6-methyl-2-pyridone in 1.3 mL of dry HMPA and 10 mL of dry Bu2O. Then a solution of 1.54 g (10 mmol) of

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isophorone oxide in 2 mL Bu2O was added rapidly, the mixture was heated at reflux for 6 h, cooled, diluted with
100 mL of ether and washed successively with 3×50 mL of water and 50 mL of brine. Evaporation of the
MgSO4-dried extract, followed by evacuation at the oil pump gave 4.5 g of a residue which was chromatographed
on 180 g of silica gel (Davison, 235–400 mesh) packed in cyclohexane/EtOAc (4:1) to afford 1.72 g (70%) of 2d.
IR 1680, 1599 cm−1; 60 MHz NMR l 1.05 (s, 6H), 1.85 (s, 3H), 2.3–2.5 (m, 7H), 6.49 (d, J=4.5 Hz, 1H), 6.61
(d, J=4.5 Hz, 1H), 7.35 (t, J=4.5 Hz, 1H). Anal. calcd for C15H19NO2: C, 73.04; H, 7.08. Found: C, 72.79; H,
7.18. A 2.45 g (10 mmol) portion of 2d was added at 0°C, under N2, to a stirred solution of 1.5 mL (11 mmol)
of methyl triflate in 10 mL of dry CH2Cl2 and kept at this temperature for 0.5 h and then at room temperature
for 2.5 h. The solvent was evaporated, then 10 mL of tetrachloroethylene was added and evaporated, ultimately
at the oil pump, giving 3.74 g (91%) of 3d as a solid. IR 1685, 1636, 1586, 1497 cm−1; 60 MHz NMR l 1.14 (s,
6H), 1.98 (s, 3H), 2.35 (s, 2H), 2.55 (s, 2H), 2.70 (s, 3H), 4.05 (s, 3H), 7.00 (d, J=8 Hz, 1H), 7.30 (d, J=8 Hz,
1H), 8.00 (t, J=8 Hz, 1H). This solid was added to a mixture of 5 mL of a 1 M aq. Na2CO3 solution and 5 mL
of acetone and stirred overnight. The solvent was evaporated and the residue was suspended in 50 mL of ether
and extracted with 3×50 mL of an ice-cold 1 M NaOH solution in MeOH/water 1:1. The comb. aq. methanolic
extracts were neutralized with ice-cold 3 M aq. HCl (about 50 mL) and extracted with 3×50 mL of CH2Cl2. The
comb. organic extracts were washed successively with a 50 mL satd NaHCO3 solution and 50 mL of brine. The
MgSO4-dried extract was evaporated to give 1.3 g of crude product which, after filtration in 5 mL of CH2Cl2
through a 1 g plug of silica gel, concentration and crystallization from hexane, gave 1.21 g (86%) of 4d, mp
91–92°C, mp, mixed mp and spectra identical to an authentic sample prepared according to Ref. 9d. Triflate salt
3d could be converted to the highly-crystalline hexafluorophosphate by adding a 0.411 g (1 mmol) portion of it
to a stirred solution of 1.0 g of NaPF6 in 5 mL of MeOH, then evaporating. The residue was suspended in 50
mL of CH2Cl2 and washed with 3×25 mL of water. Evaporation of the MgSO4-dried extract gave a solid which
was crystallized from abs. EtOH, to give 0.36 g (90%) of white plates, mp 168–170°C. Anal. calcd for
C16H22F6NO2P: C, 47.40; H, 5.50. Found: C, 47.20; H, 5.54.
.