Iron(III) chloride-catalyzed convenient one-pot synthesis of homoallyl benzyl ethers starting from aldehydes

Article abstract of DOI:10.1021/ol035019w

(Matrix presented) Iron(III) chloride-catalyzed effective allylation reactions of acetals with allyltrimethylsilane proceeded smoothly in high to excellent yields. In addition, this method could be applied to the one-pot synthesis of homoallyl benzyl ethe

Full text of DOI:10.1021/ol035019w

ORGANIC
LETTERS
2003
Vol. 5, No. 17
3045-3048
Iron(III) Chloride-Catalyzed Convenient
One-Pot Synthesis of Homoallyl Benzyl
Ethers Starting from Aldehydes
Tsutomu Watahiki, Yusuke Akabane, Seiji Mori, and Takeshi Oriyama*
Department of EnVironmental Sciences, Faculty of Science, Ibaraki UniVersity,
2-1-1 Bunkyo, Mito 310-8512, Japan
tor@mx.ibaraki.ac.jp
Received June 6, 2003
ABSTRACT
Iron(III) chloride-catalyzed effective allylation reactions of acetals with allyltrimethylsilane proceeded smoothly in high to excellent yields. In
addition, this method could be applied to the one-pot synthesis of homoallyl benzyl ethers by a combination of dibenzyl acetalization of
aldehydes and consecutive allylation of dibenzyl acetals.
Lewis acid-catalyzed allylations of carbonyl compounds with
allyltrimethylsilane (Hosomi-Sakurai reaction) are important
carbon-carbon bond-forming reactions, since they afford
synthetically useful homoallyl alcohol derivatives.1 Allylation
of acetals is also well documented, and the corresponding
products are homoallyl alkyl ethers. Several Lewis acids have
been used to perform this reaction efficiently. In particular,
traditional Lewis acids such as TiCl4, BF3‚OEt2, and AlCl3
have been generally utilized,2 though stoichiometric or near-
stoichiometric amounts of Lewis acid were required to
accomplish the reaction completely. Other Lewis acids, such
as trityl perchlorate,3 TMSI,4 TMSOTf,5 TMSNTf2,6
acetals. However, these methods involve some annoying
problems. (1) Homoallyl methyl ethers obtained by the
reaction of dimethyl acetals with allylsilane cannot readily
lead to further manipulation due to the inactivity of the
aliphatic ether linkage. (2) The preparation of homoallyl
methyl ethers from aldehyde requires a two-step conver-
sion comprising acetalization of aldehydes and subsequent
allylation of acetals. On the other hand, we have recently
developed a highly efficient method for the allylation of
aldehydes with allyltrimethylsilane catalyzed by FeCl3.9 This
reaction took place smoothly using only 5 mol % FeCl3 and
could be applied to a broad range of aldehydes, and in
particular, hindered aliphatic aldehydes could be allylated
efficiently at room temperature. Therefore, we planned to
elaborate the one-pot synthesis of homoallyl benzyl ethers
from aldehydes in order to overcome the above problems. I.
E. Marko´ et al. reported one-pot synthesis of homoallylic
ethers from aldehydes catalyzed by TMSOTf; however, the
scope and limitations were not described at all.10 In this
communication, we wish to report a convenient procedure
8
Sc(OTf)3,7 and Bi(OTf)3 were reported to be utilized as
Lewis acid catalysts to promote the allylation reaction of
(1) For leading reviews, see: (a) Sakurai, H. Pure Appl. Chem. 1982,
54, 1. (b) Yamamoto, Y.; Asao, N. Chem. ReV. 1993, 93, 2207. (c) Masse,
C. E.; Panek, J. S. Chem. ReV. 1995, 95, 1293. (d) Marshall, J. A. Chem.
ReV. 1996, 96, 31. (e) Fleming, I.; Barbero, A.; Walter, D. Chem. ReV.
1997, 97, 2063.
(2) (a) Hosomi, A.; Endo, M.; Sakurai, H. Chem. Lett. 1976, 941. (b)
Hosomi, A.; Endo, M.; Sakurai, H. Chem. Lett. 1978, 499. (c) Hosomi, A.;
Ando, M.; Sakurai, H. Chem. Lett. 1986, 365.
(3) Mukaiyama, T.; Nagaoka, H.; Murakami, M.; Ohsima, M. Chem.
Lett. 1985, 977.
(9) Watahiki, T.; Oriyama, T. Tetrahedron Lett. 2002, 43, 8959. We have
also investigated the effect of Lewis acid catalysts for allylation of
benzaldehyde under the optimal conditions: FeCl3 (92%), FeCl3‚6H2O
(14%), FeCl2 (0%), TiCl4 (13%), BF3‚OEt2 (10%), AlCl3 (5%), SnCl4 (73%),
Cu(OTf)2 (4%), ZnCl2 (0%).
(10) (a) Mekhalfia, A.; Marko´, I. E. Tetrahedron Lett. 1991, 32, 4779.
(b) Wang, M. W.; Chen, Y. J.; Wang, D. Synlett 2000, 385.
(4) Sakurai, H.; Sasaki, K.; Hosomi, A. Tetrahedron Lett. 1981, 22, 745.
(5) Tsunoda, T.; Suzuki, M.; Noyori, R. Tetrahedron Lett. 1980, 21, 71.
(6) Ishii, A.; Kotera, O.; Saeki, T.; Mikami, K. Synlett 1997, 1145.
(7) Yadav, J. S.; Subba, B. V.; Srihari, P. Synlett 2001, 673.
(8) Wieland, L. C.; Zerth, H. M.; Mohan, R. S. Tetrahedron Lett. 2002,
43, 4597.
10.1021/ol035019w CCC: $25.00 © 2003 American Chemical Society
Published on Web 07/24/2003

for the allylation of various acetals and dibenzyl acetalization
of various aldehydes catalyzed by FeCl3 and, additionally,
an efficient procedure for the one-pot synthesis of homoallyl
benzyl ethers directly from the parent aldehydes.
substrate instead of dimethyl acetal, the corresponding
homoallyl ethyl ether and homoallyl benzyl ether could be
similarly obtained in 95 and 87% yields, respectively (runs
13 and 14).
Next, we attempted FeCl3-catalyzed one-pot synthesis of
homoallyl benzyl ether directly from aldehyde. Homoallyl
methyl ethers obtained by the reaction of dimethyl acetals
with allylsilane do not readily lead to further manipulation
as mentioned above. From the synthetic viewpoint, it is very
significant to prepare homoallyl benzyl ethers starting from
dibenzyl acetals, which are more suitable for further ma-
nipulation. However, dibenzyl acetals are not so widely used
in comparison with dimethyl acetals because of their lability
to acidic conditions.11 Therefore, we attempted at first the
synthesis of dibenzyl acetals from aldehydes catalyzed by
FeCl3.
Initially, we investigated the reaction conditions of allyla-
tion of acetals in detail. The reaction of benzaldehyde
dimethyl acetal with 1.2 equiv of allyltrimethylsilane in the
presence of 2 mol % anhydrous FeCl3 (MeNO2, -20 °C)
afforded the corresponding homoallyl methyl ether in 97%
yield (Table 1, run 1). It was found that the reaction
Table 1. Allylation of Various Dimethyl Acetals
The reaction of benzaldehyde with 2.4 equiv of benzyl-
oxytrimethylsilane (BnOTMS) in the presence of 2 mol %
FeCl3 without a solvent at 0 °C afforded the desired dibenzyl
acetal in 92% yield (Table 2, run 1). We examined the
run
R
yielda (%)
1
2
3
4
5
6
7
8
9
10
11b
12b
13c
14d
Ph-
97
97
91
92
93
4-BrC6H4-
4-AcOC6H4-
4-MeC6H4-
3-MeC6H4-
2-MeC6H4-
2,4,6-Me3C6H2-
4-MeOC6H4-
1-Naphtho-
(E)-PhCHdCH-
Ph(CH2)2-
PhCH(Me)-
Ph-
Table 2. Dibenzyl Acetalization of Various Aldehydes
86
100
100
77
93
95
96
95
87
run
RCHO
PhCHO
p-BrC6H4CHO
m-MeC6H4CHO
p-MeOC6H4CHO
Ph(CH2)2CHO
c-C6H11CHO
methoda
yieldb (%)
1
2
3
4
5
6
7
8
A
A
A
A
B
B
B
B
92
97
44
20
87
60
92
60
Ph-
a Isolated yields of purified product. b Reaction was performed for 15
min at room temperature. c Diethyl acetal was used as a starting substrate.
d Dibenzyl acetal was used as a starting substrate.
PhCH(Me)CHO
t-BuCHO
a Method A: FeCl3 (2 mol %), 0 °C. Method B: FeCl3 (5 mol%),
CH2Cl2, rt. b Isolated yields of purified product.
proceeded smoothly under similar conditions for allylation
of aldehydes as reported in our previous paper.9 Additional
experimental results of this allylation are summarized in
Table 1. Electron-deficient aromatic dimethyl acetals having
halogen or acyloxy substituents were allylated in excellent
yields (runs 2 and 3). Likewise, reaction of electron-rich
aromatic dimethyl acetals having methyl or methoxy sub-
stituents on the benzene ring with allylsilane proceeded
efficiently (runs 4-8), and over-allylation products, obtained
in the case of allylation of p-tolualdehyde or p-anisaldehyde
were not observed. Also, R,â-unsaturated dimethyl acetal was
transformed into the corresponding homoallyl methyl ether
in 93% yield (run 10), while over-allylation occurred mainly
in TiCl4-induced allylation of acetal.2b In general, it is
anticipated that the allylation of an aliphatic dimethyl acetal
is more difficult than that of an aromatic dimethyl acetal
because of the higher electron density of the acetal carbon
center. Fortunately, aliphatic dimethyl acetals could be also
allylated in high yields in shorter reaction time at room
temperature (runs 11 and 12). Furthermore, when benz-
aldehyde diethyl acetal and dibenzyl acetal were used as a
reaction of various aldehydes with BnOTMS. Dibenzyl
acetalization of p-bromobenzaldehyde took place smoothly
in excellent yield (run 2). In contrast, m-tolualdehyde and
p-anisaldehyde, such as electron-rich aromatic aldehydes,
showed lower reactivity and the corresponding dibenzyl
acetals were obtained in only 44 and 20% yields, respectively
(runs 3 and 4). In the case of aliphatic aldehydes, CH2Cl2
was necessary as a reaction solvent because the FeCl3 catalyst
was insoluble under neat condition. Various aliphatic alde-
hydes were transformed into the corresponding dibenzyl
acetals at room temperature in high yields (runs 5-8). Thus,
it was demonstrated that FeCl3 was also a very effective
catalyst for dibenzyl acetalization of aldehydes as well as
allylation of dialkyl acetals.
Considering the above-mentioned successful results, we
speculated that one-pot synthesis of homoallyl benzyl ether
(11) Tsunoda, T.; Suzuki, M.; Noyori, R. Tetrahedron Lett. 1980, 21,
1357.
3046
Org. Lett., Vol. 5, No. 17, 2003

from aldehyde could be accomplished by a combination of
dibenzyl acetalization and subsequent allylation. Actually,
after dibenzyl acetalization of benzaldehyde with 2.4 equiv
of BnOTMS, allylation of in situ-formed dibenzyl acetal with
allylsilane catalyzed by FeCl3 was performed very smoothly,
and the desired homoallyl benzyl ether could be isolated
quantitatively (Scheme 1).
from aromatic and aliphatic aldehydes are listed in Tables 3
and 4. Aromatic aldehydes having an electron-withdrawing
Table 4. One-Pot Synthesis of Homoallyl Benzyl Ethers from
Various Aliphatic Aldehydes
Scheme 1. One-Pot Synthesis of Homoallyl Benzyl Ether
Using 2.4 Equiv of BnOSiMe3
run
RCHO
yielda (%)
1
2
3
4
Ph(CH2)2CHO
c-C6H11CHO
PhCH(Me)CHO
t-BuCHO
80
83
81
87
a Isolated yields of purified product.
In this reaction, 1 equiv of BnOTMS is supposed to be
reproduced after completion of the reaction. From the
viewpoint of atom economy, decreasing the number of
equivalents of BnOTMS used in the one-pot synthesis would
be favorable. So we tried the one-pot synthesis of homoallyl
benzyl ether using 1.2 equiv of BnOTMS. This was also
proven to be successful, and the corresponding homoallyl
benzyl ether was given in 100% yield directly from benz-
aldehyde (Table 3, run 1). Other representative examples for
the one-pot syntheses of various homoallyl benzyl ethers
or an electron-donating group were transformed smoothly
into the homoallyl benzyl ethers (Table 3). In the case of
using methallyltrimethylsilane as an allyl nucleophile, the
yield of the corresponding homoallyl benzyl ether was
decreased to 66% (run 2). When the reaction was carried
out with p-methoxybenzyloxytrimethylsilane, no reaction
occurred (run 3). As depicted in Table 2, while dibenzyl
acetalization of m-tolualdehyde and p-anisaldehyde pro-
ceeded in lower yield (44 and 20%, respectively), the
corresponding homoallyl benzyl ethers could be obtained in
100 and 81% yields from the parent aldehydes, respectively
(runs 5 and 6). These results can be explained by the mobile
equilibrium of dibenzyl acetalization. That is, shifting the
equilibrium of acetalization toward dibenzyl acetal by the
allylation of acetal would improve the yield of homoallyl
benzyl ether. In the presence of other functional groups such
as ketone and ester, desired one-pot reaction of aldehydes
also proceeded chemoselectively with these functional groups
unaffected (runs 7 and 8). Moreover, aliphatic aldehydes had
a slightly lower reactivity in comparison with aromatic ones,
but these reactions were also successfully performed in high
yields (Table 4). In particular, it should be noted that
sterically hindered trimethylacetaldehyde transformed smoothly
into the corresponding homoallyl benzyl ether in 87% yield
(run 4).
In conclusion, we have presented an efficient and conve-
nient procedure for the one-pot synthesis of homoallyl benzyl
ethers starting from a variety of parent aldehydes and
demonstrated that FeCl3 is a very effective catalyst for both
acetalization and allylation. This convenient one-pot reaction
took place smoothly using very low loading (2-5 mol %)
of FeCl3 at nearly ambient temperature and could be applied
to a broad range of aldehydes. Furthermore, this procedure
is quite promising in the case of synthesis of unstable
homoallyl alcohol derivatives because no protection proce-
dure is required. Additionally, FeCl3 is a very cheap Lewis
Table 3. One-Pot Synthesis of Homoallyl Benzyl Ethers from
Various Aromatic Aldehydes
run
ArCHO
PhCHO
PhCHO
PhCHO
p-BrC6H4CHO
m-MeC6H4CHO
p-MeOC6H4CHO
p-MeCOC6H4CHO
p-MeO2CC6H4CHO
yielda (%)
1
100
66
0
99
100
81
85
95
2b
3c
4
5
6
7d
8
a Isolated yields of purified product. b Methallyltrimethylsilane was used
instead of allyltrimethylsilane. c p-Methoxybenzyloxytrimethylsilane was
used instead of BnOSiMe3. d Reaction was performed for 1 h at the second
step.
Org. Lett., Vol. 5, No. 17, 2003
3047

acid. These valuable features show that this new method is
very practical and will be applicable to the synthesis of
various complex natural products.
Supporting Information Available: Experimental pro-
cedures and 1H NMR, 13C NMR, and IR spectra for
homoallyl methyl ethers, dibenzyl acetals, and hoallyl benzyl
ethers. This material is available free of charge via the
Internet at http://pubs.acs.org.
Acknowledgment. T.W. thanks the Sasakawa Scientific
Research Grant from The Japan Science Society for generous
financial support.
OL035019W
3048
Org. Lett., Vol. 5, No. 17, 2003