bonds of 2 did not occur). Additional features of interest in
this route are the short reaction time and the easy workup
procedure, which are important for the preparation of the
labile products 2 to avoid decomposition. After decantation
to remove the excess metal and extraction with hexane, the
crude products 2 were of sufficient purity (>90%) to be used
directly in the next reaction without further purification.
In particular, the synthetically useful application of difluoro
Danishefsky’s dienes 2 has been made for the hetero Diels-
Alder reaction.12 As shown in Table 1, the reaction of 2b
Scheme 1. Preparation of Difluorinated Danishefsky’s Dienes
fashion. The starting ketones 3 were easily prepared from
the reaction of trifluoroacetic anhydride (TFAA) with vinyl
ethers in 80-90% yields.6,7 Upon treatment with 8 equiv of
Mg and Me3SiCl in DMF, defluorinative silylation of
trifluoromethyl ketones 3 proceeded to afford difluorobuta-
dienes 2 in 80-85% yield (19F NMR).8 The reactions were
completed within 3 min at 50 °C. Compounds 2 are thermally
unstable, moisture-sensitive, and less reactive than non-
fluorinated Danishefsky’s diene, so 2 was used for next step
without further purification.
Table 1. Lewis Acid Catalyzed Hetero Diels-Alder Reactions
of 2b with Aldehydes
In general, the cleavage of a C-F bond is not easy because
of the large bond energy (ca. 552 kJ mol-1). However, the
bond breaking does rather easily occur when a CF3 group is
attached to the π-electron system, because electron ac-
ceptance into the π-system and subsequent extrusion of a
fluoride ion may make large contributions to the driving force
of the reaction.9 Electrochemical methods have hitherto been
developed for reductive defluorination of a trifluoromethyl
group, and they can be successfully applied to the preparation
of difluoromethylene building blocks.10 Very recently, we
have found that Mg(0) metal proves useful for the C-F
bond-breaking process of trifluoromethyl ketones to provide
a highly efficient access to silyl difluoroenol ethers.11
The defluorinative silylation route for the preparation of
difluoro Danishefsky’s dienes 2 has several advantages: (i)
the starting materials 3 are readily available directly from
TFAA; (ii) Mg as a reducing agent is inexpensive and easy
to handle; and (iii) formation of 2,2-difluoroenol silyl ethers
is highly selective (further reduction of the C-C double
a Isolated yields from R,â-unsaturated ketone 3b.
with benzaldehyde in the presence of ZnBr2, followed by
treatment with catalytic trifluoroacetic acid gave the fluori-
nated dihydropyrone 4a in total yield of 64% from 3b (entry
1). This procedure worked well for both aromatic (entries
1-3) and aliphatic (entry 4) aldehydes to afford the corre-
sponding dihydropyrones 4 in moderate yields (from tri-
fluoromethyl ketone 3b).
Instead of aldehydes, aldimines were used as a dienophile
in this reaction providing the nitrogen-containing adducts.
ZnI2-promoted hetero Diels-Alder reaction of 2b worked
well with various N-aryl- and N-alkyl-substituted imines 5
to give the corresponding difluoro dihydropyridones 6 (Table
2). Interestingly, the reaction of N-p-methoxyphenyl imine
of ethyl glyoxylate 5d13 gave, upon aqueous acidic hydrolysis
of the intermediate cycloadduct, difluorinated cyclic amino
acid precursor 6d in 54% yield (entry 4). The reaction of
cyclic imine 5e afforded the mono-fluorinated cycloadduct
6e in 52% yield by a sequence of the cycloaddition followed
by dehydrofluorination of the corresponding difluorinated
cycloadduct (entry 5). The arylquinolizine ring system is
common in many naturally occurring alkaloids.14,15 The
interesting biological activities of many of these compounds
(6) Hojo, M.; Masuda, R.; Kokuryo, Y.; Shioda, H.; Matsuo, S. Chem.
Lett. 1976, 499.
(7) Colla, A.; Martins, M. A. P.; Clar, G.; Krimmer, S.; Fischer, P.
Synthesis 1991, 483.
(8) Compounds 2 decompose at room temperature for several hours.
Because of the instability of 2, the yields were estimated by 19F NMR using
4, 4′-difluoro diphenylmethane as an internal standard.
(9) (a) Chaussard, J.; Folest, J.-C.; Nedelec, J.-Y.; Pe´richon, J.; Sibille,
S.; Troupel, M. Synthesis 1990, 369. (b) Saboureau, C.; Troupel, M.; Sibille,
S.; Pe´richon, J. J. Chem. Soc., Chem. Commun. 1989, 1138. (c) Cavel, P.;
Legar-lambert, M. P.; Biran, C.; Serein-Spirau, F.; Bordeau, M.; Roques,
N.; Marzouk, H. Synthesis 1999, 829. (d) Andrieux, C. P.; Combellas, C.;
Kanoufi, F.; Save´ant, J.-M.; Thie´bault, A. J. Am. Chem. Soc. 1997, 119,
9527.
(10) Electrochemical preparation of difluoromethyl compounds: (a)
Uneyama, K.; Maeda, K.; Kato, T.; Katagiri, T. Tetrahedron Lett. 1998,
39, 3741. (b) Uneyama, K.; Kato, T. Tetrahedron Lett. 1998, 39, 587. (c)
Uneyama, K.; Mizutani, G. Chem. Commun. 1999, 613. (d) Uneyama, K.;
Mizutani G.; Maeda, K.; Kato, T. J. Org. Chem. 1999, 64, 6717.
(11) Mg(0)-promoted preparation of difluoro silyl enol ethers: (a) Amii,
H.; Kobayashi, T.; Hatamoto, Y.; Uneyama, K. Chem. Commun. 1999, 1323.
(b) Amii, H.; Kobayashi, T.; Uneyama, K. Synthesis 2000, 2001. (c) Mae,
M.; Amii, H.; Uneyama, K. Tetrahedron Lett. 2000, 41, 7893.
(12) Hetero Diels-Alder reaction of fluorinated aldimines: Crousse, B.;
Begue, J.-P.; Bonnet-Delpon, D. J. Org. Chem. 2000, 65, 5009.
(13) Preparation of iminoester 5d: Tietze, L. F.; Bratz, M. Synthesis
1989, 439.
(14) Monteiro, H. J. The Alkaloids; Manske, R. H. F., Ed.; Academic
Press: New York, 1968; Vol. XI, p 145.
3104
Org. Lett., Vol. 3, No. 20, 2001
Amii, Hideki
