C O M M U N I C A T I O N S
Scheme 2. Proposed Reaction Pathways
stabilize the aromatic enol tautomer of the oxazolone appear to
promote the reaction much more readily than those that do not.
For example, acylated oxazolones (Table 2, entries 9 and 10) reacted
readily to provide the ene-products in excellent yields at room
temperature. Aryl substituted oxazolones also provided ene-products
in excellent yields (Table 2, entries 11 and 12), albeit at higher
temperatures (reflux in toluene). On the other hand, oxazolones
containing alkyl substituents did not produce any desired product
and resulted in the isolation of starting materials under the current
reaction conditions (Table 2, entry 13).
In summary, we report a new intermolecular ene reaction using
oxazolones and enol ethers. These reactions occur under very mild
reaction conditions and in most cases result in near quantitative
yields. The overall transformation of the reaction complements the
intramolecular Conia-ene cyclization and makes ene reactions a
useful alternative to enolate alkylation chemistry. Further studies
are currently under investigation to determine the reaction scope
and synthetic utility.
Table 2. Substituted Oxazolones
Acknowledgment. The authors gratefully acknowledge the
financial support provided by the American Cancer Society (Grant
RSG CDD-106972) and Michigan State University.
entry
R2
temp (
°
C)
time
% yield
9
CO2Me
COCH3
Ph
1-naphthyl
Me
room temp
room temp
110
110
110
20 min
24 h
8 h
26 h
24 h
99
10
11
12
13
98a
95
Supporting Information Available: Full experimental protocols;
IR, 1H NMR, 13C NMR, and HRMS data for all new compounds. This
99a
0b
References
a Yield based on the crude oxazolone intermediate. b Reaction resulted
in recovery of starting materials.
(1) For reviews on the ene reaction see: (a) Hoffman, H. M. R. Angew. Chem.,
Int. Ed. 1969, 8, 556. (b) Mikami, K.; Shimizu, M. Chem. ReV. 1992, 92,
1021-1050. (c) Dias, L. C. Curr. Org. Chem. 2000, 4, 305-342.
(2) For a review on the Conia-ene reaction see: Conia, J. M.; Le Perchec, P.
Synthesis 1975, 1-19.
(3) Paderes, G. D.; Jorgensen, W. L. J. Org. Chem. 1992, 57, 1904-1916.
(4) (a) Balme, G.; Bouyssi, D.; Faure, R.; Gore, J.; Vanhemelryck, B.
Tetrahedron 1992, 48, 3891-3902. (b) McDonald, F. E.; Olson, T. C.
Tetrahedron Lett. 1997, 38, 7691-7692. (c) Bouyssi, D.; Monteiro, N.;
Balme, G. Tetrahedron Lett. 1999, 40, 1297-1300. (d) Kitagawa, O.;
Suzuki, T.; Inoue, T.; Watanabe, Y.; Taguchi, T. J. Org. Chem. 1998,
63, 9470-9475.
(5) Boaventura, M. A.; Drouin, J.; Conia, J. M. Synthesis 1983, 801-804.
(6) (a) Cruciani, P.; Stammler, R.; Aubert, C.; Malacria, M. J. Org. Chem.
1996, 61, 2699-2708. (b) Cruciani, P.; Aubert, C.; Malaria, M.
Tetrahedron Lett. 1994, 35, 6677-6680. (c) Renaud, J. L.; Petit, M.;
Aubert, C.; Malacria, M. Synlett 1997, 931. (d) Renaud, J. L.; Aubert,
C.; Malacria, M. Tetrahedron 1999, 55, 5113-5128.
(7) (a) Kennedy-Smith, J. J.; Staben, S. T.; Toste, F. D. J. Am. Chem. Soc.
2004, 126, 4526-4527. (b) Kennedy-Smith, J. J.; Toste, F. D. Angew.
Chem., Int. Ed. 2004, 43, 5350-5352.
(8) Gao, Q.; Zheng, B.; Li, J.; Yang, D. Org. Lett. 2005, 7, 2185-2188.
(9) Corkey, B. K.; Toste, F. D. J. Am. Chem. Soc. 2005, 127, 17168-17169.
(10) (a) Koen, M. J.; Morgan, J.; Pinhey, J. T. J. Chem. Soc., Perkins Trans.
I 1993, 2383-2384. (b) Morgan, J.; Pinhey, J. T.; Sherry, C. J. J. Chem.
Soc., Perkin Trans. I 1997, 613-618. (c) Pinhey, J. T.; Xuan, P. T. Aust.
J. Chem. 1988, 41, 69-80.
(11) (a) Cativiela, C.; Diaz-de-Villegas, M. D. Tetrahedron: Asymmetry 1999,
9, 3517-3599. (b) Liu, X.; Hartwig, J. F. Org. Lett. 2003, 5, 1915-
1918. (c) Ruble, J. C.; Fu, G. C. J. Am. Chem. Soc. 1998, 120, 11532-
11533. (d) Shaw, S. A.; Aleman, P.; Vedejs, E. J. Am. Chem. Soc. 2003,
125, 13368-13369.
(12) (a) Dejersey, J.; Willadse, P.; Zerner, B. Biochemistry 1969, 86, 1959-
1967. (b) Goodman, M.; Levine, L. J. Am. Chem. Soc. 1964, 86,
2918-2922.
reaction resulting in isolation of only starting materials after several
hours (Table 1, entry 8). This may be in part due to the need to
stabilize positive charge accumulation on the carbon adjacent to
the oxygen atom.
Insight into the mechanistic nature of the reaction was obtained
when the ester substituted oxazolone was reacted with 5-deutero-
3,4-dihydro-2H-pyran (Scheme 2). Protonation of the enol ether
by the acidic oxazolone12 followed by condensation on to the
resulting oxonium ion (path A) would result in a mixture of
diastereomers, whereas a more concerted reaction (path B) would
be stereospecific and result in the formation of one single
diastereomer. Treatment of the oxazolone with a large excess of
deuterium labeled enol ether provided the product in near quantita-
tive yields as a single diastereomer after methanol workup as
determined by NOE. The stereospecific nature of this reaction
argues against the possibility that mere protonation of the enol ether
induces an aldol-type reaction and supports a more concerted
mechanism.
In order to further expand the scope of this reaction, the nature
of the substituent at the R2 position of the oxazolone was explored
(Table 2). Various oxazolones were reacted with tert-butyl vinyl
ether and evaluated for ene-product formation. The data supports
the hypothesis that increased enol character of the oxazolone is
helpful for the induction of this ene-reaction. Substituents that
JA0627904
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J. AM. CHEM. SOC. VOL. 129, NO. 11, 2007 3059