1690
LETTER
Efficient Dehydration of Hydroxyenals and -enones: HfCl4 (THF)2 as an
effective Catalyst for Di-, Tri- and Tetraene Formation
Efficient
D
ehy
u
dration of
H
s
ydroxyena
u
ls and -enon
m
es u Saito, Takashi Nagahara, Hisashi Yamamoto*
Graduate School of Engineering, Nagoya University, SORST, Japan Science and Technology Corporation (JST), Chikusa, Nagoya
464-8603, Japan
Received 26 July 2001
H2O, Cu(OTf)2, and Eu(OTf)3. These screening studies
Abstract: Polyenes were easily obtained from hydroxy(tri, di)ene-
(10 mol% metal) indicated that the Hf, Zr, and Ti salts
provide higher levels of reactivity in conjunction with a
proper solvent. With the remaining metal salts, low con-
containing carbonyl compounds in good to excellent yields in the
presence of catalytic HfCl4 (THF)2.
Key words: aldol reactions, carbonyl, catalysis, eliminations,
version (mostly < 5%) was detected (in MeCN). The use
Lewis acids
of a less polar solvent, toluene or ClCH2CH2Cl, did not
give desired dehydration, while MeCN and EtNO2 gave
excellent results. Further examination indicated that
HfCl4 (THF)2 was superior to ZrCl4, which was more ef-
fective than TiCl4 (e.g., 2c: 83%, 27%, and 11% yields, re-
spectively (10 mol% metal, MeCN, reflux, 24 hours)).
Considerable effort has recently been devoted to the syn-
thesis of polyene-macrolide antibiotics.1 Wittig–Horner
and Peterson reagents, and their respective variants, have
found the broadest use in this regard, and allow for the for-
Several hydroxy(tri, di)ene-containing carbonyl com-
pounds with varying steric and electronic demands re-
garding the carbonyl were subjected to the same
conditions to investigate the generality of the results (Ta-
ble). The high E-geometry (> 20:1) of new double bonds
was consistently observed for all reactions we tested. The
best solvent in terms of the isolated yield of the dehydrat-
ed products depends on the structure of the hydroxy car-
bonyl compound used. A smaller amount of the catalyst (<
5 mol%) substantially lowered the yield of 2c (< 25%),
and gave an unknown complex mixture. Although alde-
hydes with elongated conjugation reacted less effectively
(entries 8 and 9), -unbranched aldehydes were dehydrat-
ed in good to excellent yields (entries 1–8 and 10–12). -
Hydroxyenones 1k and 1l were also compatible with these
conditions (entries 15–18), while dienone 1m favored the
intramolecular conjugate addition to give 4 as a major
product (entry 19). The ene-reaction/double-dehydration/
redox (aromatization-hydrogenation)-reaction took place
with -branched aldehyde 1j to give p-cymene-like prod-
uct 3 in < 58% yield (entry 14).6 These results suggest that
HfCl4 (THF)2 acted not only as a dehydrating agent but
also as a Lewis acid to activate carbonyl groups.7 Unfor-
tunately, ester 1n was inert under otherwise identical con-
ditions (entry 20).
mation of two to six consecutive double bonds at one
time.2 Recently, we reported a highly efficient direct viny-
logous aldol reaction using a bulky aluminum reagent as
a key technology.3a–c Unfortunately, however, an efficient
dehydration of the resulting hydroxy unsaturated carbonyl
compounds to give polyenes is still needed, although indi-
rect and direct dehydration of this class of compounds was
recently investigated by us,3b Hoffmann et al.4a and
others4b–h using a stoichiometric amount of dehydrating
agents. We report here that catalytic HfCl4 (THF)25 facil-
itates direct dehydration from hydroxy(tri, di)enals and -
enones to give polyene derivatives (Scheme).
HfCl4•(THF)2
(10 mol%)
O
O
OH
R1
R1
R
R
n
n
MeCN
or
EtNO2
reflux
Scheme
A vast array of hydroxy(tri, di)ene-containing carbonyl
compounds 1a–n was readily obtained by the vinylogous
direct aldol reaction using aluminum tris(2,6-diphe-
nylphenoxide) (ATPH).3 A MeCN solution of hydroxye-
nal 1a and HfCl4 (THF)2 (10 mol%) was heated at reflux
for 24 hours to give, after column chromatography on sil-
ica gel, dienal 2a in 99% yield, with the resulting double
bond in an absolute E-geometry. The following metal
salts were also screened: Hf(Ot-Bu)4, ZrCl4, Zr(OEt)4,
TiCl4, Ti(OEt)4, FeCl3, ScCl3, Sc(OTf)3, Yb(OTf)3,
YbCl3 6 H2O, Y(OTf)3, CeCl3 7 H2O, Zn(OTf)2, CuSO4 8
In conclusion, this work represents an efficient approach
to polyenes, which may be useful for the synthesis of piv-
otal fragments of complex natural products. An array of
carbonyl compounds with elongated conjugation can be
obtained in only two steps, involving the ATPH-mediated
aldol reaction/Hf(IV)-catalyzed dehydration sequence,
from commercially available molecules. Elucidation of
the mechanism and broader applicability through im-
provement of the present catalysis are currently under in-
vestigation.
Synlett 2001, No. 11, 26 10 2001. Article Identifier:
1437-2096,E;2001,0,11,1690,1692,ftx,en;G16401ST.pdf.
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