InCl3/Me3SiBr-catalyzed direct coupling between silyl ethers and enol acetates

Article abstract of DOI:10.1021/ol200875m

A combined Lewis acid catalyst of InCl₃ and Me₃SiBr promoted the direct use of enol acetates in the coupling with low-reactive silyl ethers, in which functional groups including ketones and aldehydes survived. Sterically hindered silyl ethers such as ROSiEt₃, ROSiPh₃, ROSit-BuMe₂, and ROSii-Pr₃ were also applicable.

Full text of DOI:10.1021/ol200875m

ORGANIC
LETTERS
2011
Vol. 13, No. 10
2762–2765
InCl3/Me3SiBr-Catalyzed Direct Coupling
between Silyl Ethers and Enol Acetates
Yoshiharu Onishi, Yoshihiro Nishimoto, Makoto Yasuda, and Akio Baba*
Department of Applied Chemistry, Graduate School of Engineering, Osaka University,
2-1 Yamadaoka, Suita, Osaka 565-0871, Japan
baba@chem.eng.osaka-u.ac.jp
Received April 4, 2011
ABSTRACT
A combined Lewis acid catalyst of InCl3 and Me3SiBr promoted the direct use of enol acetates in the coupling with low-reactive silyl ethers, in
which functional groups including ketones and aldehydes survived. Sterically hindered silyl ethers such as ROSiEt3, ROSiPh3, ROSit-BuMe2, and
ROSii-Pr3 were also applicable.
The coupling reactions between metal enolates and
alkylating electrophiles such as alkyl halides, alcohols, alkyl
ethers, and alkyl carboxylates have been extensively inves-
tigated to produce R-alkylated carbonyl compounds.1À3
Thereaction system using silylethersasalkylatingreagents,
however, has not been sufficiently established,4 because
silyl ethers are used for the typical protection of alcohols
and they have such a high tolerance to nucleophilic sub-
stitution. In fact, they do not react with even strong
nucleophiles like Grignard reagents. Gevorgyan et al. also
reported that no allylation using silyl ethers took place
while other protected alcohols easily gave allylated
products.5 On the other hand, if the replacement of the
metal enolates by metal-free enol acetates were achieved, it
would be a great advantage in reducing metal waste. More-
over, enol acetates are easily available and handled, stable,
and storable.6 Thus, the coupling reaction between enol
acetates and silyl ethers is a challenging and practical
subject. Herein we report the direct coupling catalyzed by
an InCl3/Me3SiBr combined system.7 To the best of our
knowledge, this is the first successful direct substitution of
bulkier siloxy groups rather than a trimethylsiloxy one.
Furthermore, the direct coupling of silyl ethers enables
skipping the deprotection process, which often requires a
multistep synthesis.
(1) For a review, see: Caine, D. In Comprehensive Organic Synthesis;
Trost, B. M., Fleming, I., Eds.; Elsevier: Oxford, U.K., 1991; Vol. 9, pp
1À63.
(2) For reviews, see: (a) Reetz, M. T.; Maier, W. F.; Chatziiosifidis, I.;
We first screened various Lewis acids in the reaction of
silyl ether 1a with enol acetate 2a (Table 1). Neither InCl3 nor
Me3SiBr gave an adduct in their sole use (entries 1 and 2).
Gratifyingly, when Me3SiI or Me3SiBr was combined with
€
Giannis, A.; Heimbach, H.; Lowe, U. Chem. Ber. 1980, 113, 3734–3757.
(b) Reetz, M. T. Angew. Chem., Int. Ed. 1982, 21, 96–108.
(3) For recent works on R-alkylation of carbonyl compounds using
alcohols or protected alcohols, see: (a) Nishibayashi, Y.; Wakiji, I; Ishii,
Y.; Uemura, S.; Hidai, M. J. Am. Chem. Soc. 2001, 123, 3393–3394. (b)
Noji, M.; Ohno, T.; Fuji, K.; Futaba, N.; Tajima, H.; Ishii, K. J. Org.
Chem. 2003, 68, 9340–9347. (c) Shirakawa, S.; Kobayashi, S. Org. Lett.
2007, 9, 311–314. (d) Vicennati, P.; Cozzi, P. G. Eur. J. Org. Chem. 2007,
2248–2253. (e) Rubenbauer, P.; Bach, T. Tetrahedron Lett. 2008, 49,
1305–1309. (f) Yoshimatsu, M.; Otani, T.; Matsuda, S.; Yamamoto, T.;
Sawa, A. Org. Lett. 2008, 10, 4251–4254. (g) Cozzi, P. G.; Benfatti, F.;
Zoli, L. Angew. Chem., Int. Ed. 2009, 48, 1313–1316. (h) Nishimoto, Y.;
Onishi, Y.; Yasuda, M.; Baba, A. Angew. Chem., Int. Ed. 2009, 48, 9131–
9134.
(4) For reports using silyl ethers as alkylating reagents, see: (a) Kira,
M.; Hino, T.; Sakurai, H. Chem. Lett. 1992, 21, 555–558. (b) Yokozawa,
T.; Furuhashi, K.; Natsume, H. Tetrahedron Lett. 1995, 36, 5243–5246.
(c) Braun, M.; Kotter, W. Angew. Chem., Int. Ed. 2004, 43, 514–517. (d)
Saito, T.; Nishimoto, Y.; Yasuda, M.; Baba, A. J. Org. Chem. 2007, 72,
8588–8590.
(5) (a) Schwier, T; Rubin, M.; Gevorgyan, V. Org. Lett. 2004, 6,
1999–2001. (b) Rubin, M; Gevorgyan, V. Org. Lett. 2001, 3, 2705–2707.
(6) (a) Mukaiyama, T.; Izawa, T.; Saigo, K. Chem. Lett. 1974, 323–
326. (b) Shono, T.; Nishiguchi, I.; Komamura, T.; Sasaki, M. J. Am.
Chem. Soc. 1979, 101, 984–987. (c) Yanagisawa, M.; Shimamura, T.;
Iida, D.; Matsuo, J.; Mukaiyama, T. Chem. Pharm. Bull. 2000, 48, 1838–
1840. (d) See ref 3h. (e) Song, C.-X.; Cai, G.-X.; Farrell, T. R.; Jiang, Z.-
P.; Li, H.; Gan, L.-B.; Shi, Z.-J. Chem. Commun. 2009, 6002–6004. (f)
Liu, L.; Floreancig, P. E. Angew. Chem., Int. Ed. 2010, 49, 3069–3072.
(7) (a) Onishi, Y.; Ito, T.; Yasuda, M.; Baba, A. Eur. J. Org. Chem.
2002, 1578–1581. (b) Saito, T.; Yasuda, M.; Baba, A. Synlett 2005, 1737–
1739. (c) Nishimoto, Y.; Yasuda, M.; Baba, A. J. Org. Chem. 2006, 71,
8516–8522. (d) See ref 4d.
r
10.1021/ol200875m
Published on Web 04/28/2011
2011 American Chemical Society

Table 1. Screening of Catalytic Systema
Table 2. Reactions of Various Silyl Ethers with Enol Acetate 2aa
yield/ %b
entry
catalyst
additive
3aa
4
5
1c
InCl3
À
À
0
0
0
0
0
2c
Me3SiBr
Me3SiI
0
10
15
14
64
65
76
43
90
8
3
InCl3
InCl3
InCl3
InBr3
InI3
68
65
22
27
11
13
35
0
22
20
18
6
4
Me3SiBr
Me3SiCl
Me3SiBr
Me3SiBr
Me3SiBr
Me3SiBr
Me3SiBr
Me3SiBr
Me3SiBr
Me3SiBr
Me3SiBr
Me3SiBr
Me3SiBr
Me3SiBr
5
6
7
0
8
FeBr3
GaBr3
Sc(OTf)3
ZnCl2
0
9
14
10
8
10
11c
12c
13c
14c,d
15c,e
16f
17c,g
0
BF3 OEt2
0
7
0
3
AlCl3
InCl3
InCl3
InCl3
InCl3
0
0
21
7
0
9
0
12
26
5
26
50
0
12
0
a Reaction conditions: 1a (1 mmol), 2a (2 mmol), catalyst (0.05
mmol), additive (0.1 mmol), CH2Cl2 (2 mL), rt, 2 h. b 1H NMR yield.
c 1a and the corresponding alcohol were considerably recovered. d Hex-
ane (2 mL). e Toluene (2 mL). f MeCN (2 mL). g THF (2 mL).
InCl3, the desired R-alkylated ketone 3aa was furnished at
room temperature in 68 or 65% yields, respectively, while
the combination with Me3SiCl was less effective (entries
3À5).8 InBr3 and InI3 were decidedly inferior to InCl3 to
producedimerized ether5 asa major product(entries 6 and
7). These results indicate that the subtle control of Lewis
acidity by the combined ingenuity is essential. FeBr3 and
GaBr3 provided unsatisfactory results even in the presence
of Me3SiBr while they were reported to be effective cata-
lysts in the direct coupling between alcohols and enol
acetates (entries 8 and 9).9 Representative Lewis acids such
a Reaction conditions: 1 (1 mmol), 2a (2 mmol), InCl3 (0.05 mmol),
Me3SiBr (0.1 mmol), CH2Cl2 (2 mL), rt, 2 h. b 1H NMR yield. Values in
parentheses are isolated yields. c ClCH2CH2Cl (2 mL), 83 °C, 2 h.
d CH2Cl2 (2 mL), 0 °C, 2 h. e Me3SiBr (0.2 mmol), CH2Cl2 (2 mL),
0 °C, 2 h. f MeCN (2 mL), 2 h. g 2a (5 mmol), MeCN (2 mL), 81 °C, 2 h
as Sc(OTf)3, ZnCl2, BF3 OEt2, and AlCl3 gave no desired
3
primary ones gave lower yields (entries 1À6). Allylic and
propargylic silyl ethers effectively produced the ketones
3ga and 3ha, respectively (entries 7 and 8). Silyl ether 1i
with a ferrocene moiety produced 3ia in 82% yield (entry
9). The reaction using 1-adamantyl trimethylsilyl ether 1j
proceeded effectively (entry 10). These results indicate the
incorporation of a cationic mechanism.10 Gratifyingly,
even the siloxy groups such as OSiEt3, OSiPh3, OSit-
ketone (entries 10À13). CH2Cl2 was found to be the choice
of solvent because both noncoordinative solvents such as
hexane and coordinative ones (e.g., THF) were ineffective
(entries 14À17). The combination of InCl3 and Me3SiBr at
room temperature in CH2Cl2 was employed as practically
optimal conditions because of the instability of Me3SiI.
The scope of silyl ethers was investigated (Table 2).
Secondary benzylic silyl ethers bearing electron-withdraw-
ing and -donating groups provided excellent yields while
(10) Several reports suggest the generation of a adamantyl cation as
an intermediate; see: (a) Sasaki, T.; Usuki, A.; Ohno, M. J. Org. Chem.
1980, 45, 3559–3564. (b) Laali, K. K.; Sacra, V. D.; Okazaki, T.; Brock,
A.; Der, P. Org. Biomol. Chem. 2005, 3, 1034–1042. (c) Nishimoto, Y.;
Kajioka, M.; Saito, T.; Yasuda, M.; Baba, A. Chem. Commun. 2008,
6396–6398.
(8) Other combinations of indium halides and trimethylsilyl halides
were investigated; see Supporting Information.
(9) See ref 3h.
Org. Lett., Vol. 13, No. 10, 2011
2763

BuMe2, and OSii-Pr3, which are bulkier than OSiMe3,
could be easily substituted without deprotection (entries
11À14).
Scheme 1. Competitive Reaction between Silyl Ether 1c and
Aldehyde 6
Various enol acetates effectively reacted with silyl ether
1b as summarized in Table 3. Enol acetates derived from
aromatic and aliphatic ketones gave the corresponding R-
alkylated ketones in excellent yields (entries 1À3). Also,
unsymmetrical ketone-derived 2e was applicable without
isomerization (entry 4). Stericallyhindered 2f furnishedthe
product 3bf in a moderate yield (entry 5). The production
of an R-alkylated aldehyde without overreaction demon-
strates the mildness of our system (entry 6). This result
prompted us to examine a competitive reaction between
aldehyde 6 and silyl ether 1c, as illustrated in Scheme 1. As
expected, silyl ether 1c was exclusively consumed irrespec-
tive of the aldehyde to furnish R-alkylated ketone 3ca in
99% yield. It is apparent that the combined catalyst
predominantly activates a silyl ether more than it does an
aldehyde.11 On the other hand, the addition of tri-n-
butyltin methoxide 8 leads to a generation of a tin enolate
in situ to give only the aldol adduct 7 in 65% yield.12
Equations 1À3 demonstrate a high chemoselective pro-
motion toward a siloxy moiety. Ketone, ester, and halogen
moieties survived the dichloroethane refluxing conditions
for direct coupling at siloxy moieties. In
Table 3. Reactions of Various Enol Acetates with Silyl Ether 1ba
particular, it was noteworthy that silyl ether 1q provided a
relatively higher yield of the desired product 3qb than our
previous InI3-catalyzed coupling reaction between alco-
hols and enol acetates [eq 4].3h,13 This example shows the
practical advantage of the direct substitution of silyl
ethers without deprotection.
Figure 1 shows a plausible mechanism. First, the gen-
eration of a combined Lewis acid 10 is followed by the
interaction between the silicon center of 10 and silyl ether 1
as illustrated. Then, the carbocation species 11 is generated
along with the elimination of Me3SiOSiMe3 12.14 Enol
(11) Lewis acid catalyzed aldol-type reaction of aldehydes with enol
acetates; see ref 6a.
(12) For recent works, see: (a) Yasuda, M.; Chiba, K.; Baba, A.
J. Am. Chem. Soc. 2000, 122, 7549–7555. (b) Yanagisawa, A.; Matsumoto,
Y.; Asakawa, K.; Yamamoto, H. Tetrahedron 2002, 58, 8331–8339. (c)
Yanagisawa, A.; Sekiguchi, T. Tetrahedron Lett. 2003, 44, 7163–
7166.
a Reaction conditions: 1b (1 mmol), 2 (2 mmol), InCl3 (0.05 mmol),
Me3SiBr (0.1 mmol), CH2Cl2 (2 mL), rt, 2 h. b 1H NMR yield. Values in
parentheses are isolated yields. c dr
= = 54:46.
63:37. d dr
e ClCH2CH2Cl (2 mL), 83 °C, 2 h. f 2g (5 mmol), Me3SiCl (0.1 mmol),
ClCH2CH2Cl (2 mL), 83 °C, 1 h. g dr = 63:37.
(13) The results using other alcohols are shown in the Supporting
Information.
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Org. Lett., Vol. 13, No. 10, 2011

13 reacts with 12 to regenerate the combined Lewis acid
InCl3/Me3SiBr with the formation of byproduct 14. The
elimination of stable 12 may be a driving force of this
catalytic cycle, and the weak interaction between InCl3
and oxygen have caused the selective activation of silyl
ether.
In conclusion, we have reported the direct coupling
between enol acetates and silyl ethers, which is achieved
by chemoselective activation of siloxy moieties by the
combined Lewis acids of InCl3 and Me3SiBr.
Acknowledgment. This work was supported by a
Grant-in-Aid for Scientific Research on Innovative Areas
(No. 22106527, “Organic Synthesis Based on Reaction
Integration. Development of New Methods and Creation
of New Substances”) and Scientific Research (No.
21350074) from the Ministry of Education, Culture,
Sports, Science and Technology, Japan. Y.O. thanks the
Global COE Program of Osaka University.
Supporting Information Available. Experimental pro-
cedures and characterization. This material is available
free of charge via the Internet at http://pubs.acs.org.
Figure 1. Tentative mechanism.
(14) The reaction of optically active silyl ether 1b with enol acetate 2a
gave the racemized product 3ba. The details are shown in the Supporting
Information.
acetate 2 reacts with the generated cation to produce the
R-alkylated carbonyl compound 3. Finally, acid bromide
Org. Lett., Vol. 13, No. 10, 2011
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