Lewis acid-catalyzed reductive etherification of carbonyl compounds with alkoxyhydrosilanes

Article abstract of DOI:10.1055/s-2002-19779

The TMSI-catalyzed reaction of aldehydes and ketones with alkoxydimethylsilanes gave unsymmetrical ethers in good to high yields. This reductive etherification is superior to the conventional method using two kinds of silicon reagents in terms of atom eff

Full text of DOI:10.1055/s-2002-19779

LETTER
313
Lewis Acid-catalyzed Reductive Etherification of Carbonyl Compounds with
Alkoxyhydrosilanes1
L
ewis Acid-cataly
a
ze
d
Reducti
t
ve
E
th
s
erificationukiyo Miura, Kazunori Ootsuka, Shuntaro Suda, Hisashi Nishikori, Akira Hosomi*
Department of Chemistry, Graduate School of Pure and Applied Science, University of Tsukuba, Tsukuba, Ibaraki 305-8571, Japan
Fax +81(298)536503; E-mail: hosomi@chem.tsukuba.ac.jp
Received 5 November 2001
Table 1 Reductive Etherification of Benzaldehyde with 1aa
Abstract: The TMSI-catalyzed reaction of aldehydes and ketones
with alkoxydimethylsilanes gave unsymmetrical ethers in good to
high yields. This reductive etherification is superior to the conven-
tional method using two kinds of silicon reagents in terms of atom
efficiency and ease of operation.
cat. Lewis acid
+
+
+
Bn2O BnOH
PhCHO
BuOSiHMe2
BnOBu
2a
CH2Cl2, 0 °C to rt
1a
Entry LA (equiv)
Time (h) Yield (%)
Key words: Lewis acids, reductive etherifications, ethers, alde-
hydes, bifunctional silicon reagents
2a
Bn2O
BnOH
1
TiCl4 (0.2)
16
96
70
2
64
13
< 1
4
20
0
2b
3
TiCl4 (0.2)
91
Reductive etherification of aldehydes and ketones, that is,
reduction of in situ-generated acetals and oxocarbenium
ions provides a convenient route to a variety of ethers.2–6
Particularly, the Lewis acid-catalyzed reaction with
alkoxysilanes and hydrosilanes is valuable for the highly
efficient synthesis of unsymmetrical ethers.6 In the course
of our studies on tandem reactions using bifunctional sili-
con reagents,7,8 we have recently reported the Lewis acid-
catalyzed reductive amination of aldehydes and ketones
with aminohydrosilanes.9 Thus, our interest was focused
on reductive etherification with alkoxyhydrosilanes. Such
a tandem reaction is expected to be advantageous in terms
of atom efficiency and ease of operation in comparison
with the conventional method using two kinds of silicon
reagents.6 We herein disclose that alkoxydimethylsilanes
(ROSiHMe2) efficiently work for the Lewis acid-cata-
lyzed reductive etherification of various aldehydes and
ketones.
ZnI2 (0.2)
12
71
0
4
TMSI (0.05)
TMSOTf (0.05)
Ph3CClO4 (0.05)
quant.
94
0
5
2
0
0
6
2
97
0
0
a The reactions were carried out with 1.2 (entries 1–3) or 1.1 equiv
(entries 4–6) of 1a. For general procedure, see ref.12
b At –50 °C.
the para substituent affected the reactivity to 1a. Introduc-
tion of an electron-donating group decelerated the reduc-
tive etherification (entries
2
and 3), while 4-
halobenzaldehydes as well as benzaldehyde exhibited
high reactivity (entries 4 and 5). The reactions of 4-nitro-
and 4-cyanobenzaldehyde resulted in comparably low
yields of 2 (entries 7 and 8), which is probably due to de-
activation of the Lewis acid by the polar functionalities.
The unsatisfactory yields could be improved by increased
amounts of 1a and TMSI (method B). Aromatic ketones
were much less reactive than aromatic aldehydes (entries
9 and 10). Particularly, the reductive etherification of ben-
zophenone was quite slow even under the conditions of
method B. Cinnamaldehyde smoothly reacted with 1a to
give 2 in high yield (entry 11). In contrast, the reaction of
, -unsaturated ketones such as (E)-4-phenyl-3-buten-2-
one and 2-cyclohexen-1-one did not form the desired allyl
ethers. Aliphatic aldehydes and ketones were not as reac-
tive as benzaldehyde, but they could be efficiently con-
verted into 2 by method B (entries 12–14).
Initially, the reaction of benzaldehyde with butoxydime-
thylsilane 1a was run to screen Lewis acids (Table 1).10
The use of TiCl4, which is effective in the reductive ami-
nation with aminodimethylsilanes,9 gave the desired ether
2a in moderate yield along with dibenzyl ether and benzyl
alcohol (entry 1).11 Lowering the reaction temperature
completely suppressed the formation of these by-products
to improve the yield of 2a (entry 2). The ZnI2-catalyzed
reaction with 1a resulted in selective formation of benzyl
alcohol (entry 3). In contrast, 5 mol% of TMSI, TMSOTf,
and Ph3CClO4 effectively promoted the reductive etherifi-
cation at 0 °C to room temperature to give 2a in high
yields (entries 4–6).
As shown in Table 2, the TMSI-catalyzed reductive ether-
ification with 1 was applicable to various aldehydes and
ketones.12 In the reaction of substituted benzaldehydes,
We also examined the reaction of other alkoxydimethylsi-
lanes 1b–d. As a result, 1b and 1c were successfully uti-
lized for the TMSI-catalyzed reductive etherification
(entries 15–18). Unfortunately, the etherification with 1d
was too slow to attain satisfactory results (entries 19 and
20). In entry 20, the low reactivity caused reductive
Synlett 2002, No. 2, 01 02 2002. Article Identifier:
1437-2096,E;2002,0,02,0313,0315,ftx,en;Y21901ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

314
K. Miura et al.
LETTER
Table 2 Reductive Etherification of Aldehydes and Ketonesa
O
OR
cat. TMSI
+
ROSiHMe2
R1
R2
R1
R2
CH2Cl2, 0 °C to rt
1a: R = Bu
2
1b: R = Ph(CH2)2
1c: R = c-Hex
1d: R = Bn
Entry
Carbonyl Compound
R1
1
Methoda
Time
(h)
Yield
R2
H
(%)
1
2
Ph
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1b
1b
1c
1c
1d
1d
A
2
quant.
84 (88)
65 (67)
96
4-MeC6H4
4-MeOC6H4
4-ClC6H4
4-BrC6H4
4-MeO2CC6H4
4-O2NC6H4
4-NCC6H4
Ph
H
A (B)
A (B)
A
18 (2)
18 (12)
2
3
H
4
H
5
H
A
2
98
6
H
A
12 (2)
18 (3)
36 (3)
18 (18)
24
90 (90)
69 (82)
74 (96)
24 (73)
21
7
H
A (B)
A (B)
A (B)
B
8
H
9
Me
Ph
H
10
11
12
13
14
15
16
17
18
19
20
Ph
(E)-PhCH=CH
Ph(CH2)2
Ph(CH2)2
-(CH2)2CHt-Bu(CH2)2-b
Ph
A
3
88
H
A (B)
A (B)
A (B)
A
18 (2)
24 (2)
18 (3)
2
79 (95)
68 (96)
85 (96)
92
Me
H
-(CH2)5-c
Ph
A (B)
A
2
91 (94)
quant.
80 (85)
35 (45)
41 (48)d
H
H
H
H
2
Ph(CH2)2
Ph
A (B)
A (B)
A (B)
2 (2)
24 (24)
24 (24)
Ph(CH2)2
a Method A: 1 (1.1 equiv), TMSI (0.05 equiv). Method B: 1 (1.2 equiv), TMSI (0.2 equiv). For general procedure, see ref.12.
b 4-t-Butylcyclohexanone.
c Cyclohexanone.
d Di(3-phenylpropyl) ether was obtained in ca. 40% yield in both cases of methods A and B.
dimerization to di(3-phenylpropyl) ether as a side reac- amount of TMSI (Scheme 2). As a result, the expected
tion.
ether 2a was not obtained at all. The reaction of 5 was car-
ried out in the presence of an equimolar amount of 1a, but
it resulted in no formation of 2a again. Thus path b is un-
likely in the present reductive etherification.
Judging from the report by Olah et al.,6b the present reduc-
tive etherification would pass through nucleophilic attack
of the alkoxy group of 1 or an alkoxysilane arising from 1
and the subsequent reduction with a hydride species (path We further performed the TMSI-catalyzed reaction of
a in Scheme 1). Another possible mechanism is that the benzaldehyde with an equimolar mixture of 1a and deute-
substrate undergoes hydride reduction in the initial step, riosilane 1e to gain mechanistic insight into the reaction
then the resultant silyl ether 4 is converted into 2 by nu- (Scheme 3). GC-MS analysis of the reaction mixture re-
cleophilic substitution of the alkoxy group (path b). To ex- vealed that the reductive etherification formed all of the
amine the latter possibility, dialkoxysilane 5 was prepared four possible benzyl ethers with no selectivity
from dimethyldichlorosilane and subjected to a catalytic (Scheme 3). This result shows that a hydrogen atom and
Synlett 2002, No. 2, 313–315 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Lewis Acid-catalyzed Reductive Etherification
315
+
O
References
Si
O
ISi
Si = silyl group
HSi
(1) Studies on Organosilicon Chemistry. No. 156.
(2) (a) Miura, K.; Hosomi, H. In Lewis Acid Reagents;
R1
R2
R1
R2
ROSi
Yamamoto, H., Ed.; Oxford University Press: Oxford, 1999,
159. (b) Brewster, J. H. In Comprehensive Organic
Synthesis, Vol. 8; Trost, B. M.; Fleming, I., Eds.; Pergamon
Press: Oxford, 1991, 211.
path a
path b
Si
Si
+
O
+
O
Si
OR
Si
H
(3) Reductive etherification by catalytic hydrogenation in
alcoholic acidic media: Verzele, M.; Acke, M.; Anteunis, M.
J. Chem. Soc. 1963, 5598.
R1
R2
R1
R2
3
4
HSi
ROSi
(4) Reductive etherification with alcohols and hydrosilanes:
(a) Doyle, M. P.; DeBruyn, D. J.; Kooistra, D. A. J. Am.
Chem. Soc. 1972, 94, 3659. (b) Loim, N. M.; Parnes, Z. N.;
Vassilyeva, S. P.; Kursanov, D. N. Zh. Org. Khim. 1972, 8,
896. (c) Nicolaou, K. C.; Hwang, C.-K.; Nugiel, D. A. J. Am.
Chem. Soc. 1989, 111, 4136.
+
+
ISi
Si2O
2
Scheme 1
(5) Reductive dimerization of carbonyl compounds with
hydrosilanes: (a) Doyle, M. P.; DeBruyn, D. J.; Donnelly, S.
J.; Kooistra, D. A.; Odubela, A. A.; West, C. T.; Zonnebelt,
S. M. J. Org. Chem. 1974, 39, 2740. (b) Doyle, M. P.;
West, C. T.; Donnelly, S. J.; McOsker, C. C. J. Organomet.
Chem. 1976, 117, 129. (c) Sassaman, M. B.; Prakash, G. K.
S.; Olah, G. A. Tetrahedron 1988, 44, 3771; and ref.6b.
(6) Lewis acid-catalyzed reductive etherification with
alkoxysilanes and hydrosilanes (Lewis acid): (a) Kato, J.;
Iwasawa, N.; Mukaiyama, T. Chem. Lett. 1985, 743;
(Ph3CClO4). (b) Sassaman, M. B.; Kotian, K. D.; Prakash,
G. K. S.; Olah, G. A. J. Org. Chem. 1987, 52, 4314; (TMSI).
(c) Hatakeyama, S.; Mori, H.; Kitano, K.; Yamada, H.;
Nishizawa, M. Tetrahedron Lett. 1994, 35, 4367;
(TMSOTf). (d) Komatsu, N.; Ishida, J.; Suzuki, H.
Tetrahedron Lett. 1997, 38, 7219; (BiBr3).
an alkoxy group introduced into a substrate molecule by
the present reaction are not originated from the same mol-
ecule of 1. Accordingly, the reduction of 3 to 2 may pro-
ceed intermolecularly rather than by the action of an
internal hydride species.
TMSI (0.05 equiv)
SiMe3
(1a (1 equiv))
+
Me2(BuO)Si
O H
BnOSi(OBu)Me2
2a
CH2Cl2
0 °C to rt, 2 h
5
Ph
4'
H
Scheme 2
(7) Miura, K.; Nakagawa, T.; Suda, S.; Hosomi, A. Chem. Lett.
2000, 150.
(8) Review on tandem reactions: Tietze, L. F. Chem. Rev. 1996,
96, 115.
TMSI (0.05 equiv)
+
+
HexOSiDMe2
PhCHO
BuOSiHMe2
CH2Cl2, 0 °C to rt, 2 h
1a
1e
(9) Miura, K.; Ootsuka, K.; Suda, S.; Nishikori, H.; Hosomi, A.
Synlett 2001, 1617.
PhCHO : 1a : 1e = 1 : 0.55 : 0.55
+
+
+
PhCHDOHex
(10) Alkoxydimethylsilanes 1 were prepared from alcohols,
chlorodimethylsilane, and triethylamine (50–60% yield) or
from alcohols and(diethylamino)dimethylsilane (50–70%
yield).
PhCH2OBu
PhCHDOBu
PhCH2OHex
1 : 1 : 1 : 1
Scheme 3
(11) For the formation of dibenzyl ether (reductive dimerization),
see ref.5c and ref.6b
In summary, we have demonstrated that alkoxydimethyl-
silanes 1 work as bifunctional silicon reagents to enable
the Lewis acid-catalyzed reductive etherification of alde-
hydes and ketones. The present reaction is superior to the
conventional method using two kinds of silicon reagents
in terms of atom efficiency and ease of operation.
(12) General Procedure for the TMSI-catalyzed Reductive
Etherification (Method A): To a solution of 1 (1.10 mmol)
and a carbonyl compound (1.00 mmol) in CH2Cl2 (1.0 mL)
at 0 °C was added TMSI (1.0 M in CH2Cl2, 0.05 mL, 0.05
mmol). The mixture was stirred for 10 min and warmed to
r.t. After a given reaction time, the reaction mixture was
poured into water (20 mL) and extracted with t-BuOMe (3
10 mL). The combined organic layer was dried over Na2SO4
and evaporated. The residual oil was purified by silica gel
column chromatography.
Acknowledgement
This work was partly supported by CREST, Science and Technolo-
gy Corporation (JST). We thank Dow Corning Toray Silicone Co.
Ltd. and Shin-Etsu Chemical Co. Ltd. for a gift of organosilicon
compounds.
Synlett 2002, No. 2, 313–315 ISSN 0936-5214 © Thieme Stuttgart · New York