InI3/me3sii-catalyzed direct alkylation of enol acetates using alkyl acetates or alkyl ethers

Article abstract of DOI:10.1246/cl.2011.1223

A combined Lewis acid of InI₃ and Me₃SiI was used to catalyze the direct coupling reactions of enol acetates with alkyl acetates or alkyl ethers without generating metal waste. The easily-handled alkylating reagents enlarged the application area of this coupling reaction. 2011 The Chemical Society of Japan.

Full text of DOI:10.1246/cl.2011.1223

doi:10.1246/cl.2011.1223
Published on the web October 1, 2011
1223
InI3/Me3SiI-catalyzed Direct Alkylation of Enol Acetates
Using Alkyl Acetates or Alkyl Ethers
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
(Received August 4, 2011; CL-110654; E-mail: baba@chem.eng.osaka-u.ac.jp)
Table 1. Screening of catalystsa
A combined Lewis acid of InI3 and Me3SiI was used to
Catalyst (5 mol%)
Additive (10 mol%)
catalyze the direct coupling reactions of enol acetates with alkyl
acetates or alkyl ethers without generating metal waste. The
easily-handled alkylating reagents enlarged the application area
of this coupling reaction.
O
OAc
+
Ph
OAc
1a
CH2Cl2, rt, 2 h
Ph
2a
3
Entry
Catalyst
Additive
Yield/%b
1
2
3
4
5
6
7
8
9
InI3
InI3
®
InCl3
InBr3
Sc(OTf)3
ZnCl2
BF3¢OEt2
AlCl3
®
54
quant.
0
72
87
27
0
Me3SiI
Me3SiI
Me3SiI
Me3SiI
Me3SiI
Me3SiI
Me3SiI
Me3SiI
The ¡-alkylation of carbonyl compounds is one of the most
fundamental carbon-carbon bond-forming reactions in organic
synthesis. In particular, the coupling reaction between alkyl
electrophiles and metal enolates is a useful protocol,1-4 but metal
enolates often lead to problems with handling, poor chemo-
selectivity, and the generation of metal wastes. Therefore, we
focused on the displacement of metal enolates to enol acetates,
which are helpful metal-free enol derivatives in terms of
availability, easy handling, and stability.5 We recently developed
the direct coupling between enol acetates and either alcohols or
silyl ethers.5e,5g However, these couplings have some disadvan-
tages, as alcohols often cause alcoholysis of substrates, and silyl
ethers bring silyl compounds as a side product. Therefore, we
wish to report the direct coupling of enol acetates with either
alkyl acetates or alkyl ethers, which were activated by a
combined Lewis acid of InI3 and Me3SiI.6
The effects of Lewis acid catalysts were evaluated in the
reaction of secondary benzylic acetate 1a with enol acetate 2a
(Table 1). The use of InI3, which is based on our previous work,
gave the desired ¡-alkylated ketone 3 in unsatisfying yield of
54% (Entry 1).5e,5g However, the addition of Me3SiI increased
the yield to a quantitative value (Entry 2). No catalytic attribute
of Me3SiI indicated a high plausibility for the cooperation of InI3
with Me3SiI (Entry 3).7 Although the reaction between Me3SiI
and ester moieties had been expected,8 the combination catalyst
selectively promoted the desired coupling. Combinations using
either InCl3 or InBr3 were inferior to that using InI3 (Entries 4
and 5). Representative Lewis acids such as Sc(OTf)3, ZnCl2,
BF3¢OEt2, and AlCl3 provided unsatisfying results even in the
presence of Me3SiI (Entries 6-9).
With the optimized conditions in hand, we investigated the
scope and limitations of alkyl acetates 1 and enol acetates 2
(Table 2). Enol acetate 2b derived from acetophenone gave the
¡-alkylated aromatic ketone 4 quantitatively (Entry 1). The
reactions using aliphatic enol acetates 2c and 2d furnished the
corresponding products effectively (Entries 2 and 3). Unsym-
metrical ketone-derived 2e was applicable without isomerization
(Entry 4). Sterically hindered 2f also provided the desired
product 8 and led to the constitution of a quaternary carbon
center at the ¡-position of the carbonyl group (Entry 5).
Unexpectedly, in the reaction using aldehyde-derived enol
acetate 2g, geminal diacetate 9 was obtained instead of the ¡-
alkylated aldehyde product (Entry 6). This result indicates that
0
0
aReaction conditions: alkyl acetate 1a (1 mmol), enol acetate
2a (2 mmol), Lewis acid (0.05 mmol), Me3SiI (0.1 mmol),
CH2Cl2 (2 mL), rt, 2 h. Yields were determined by H NMR
analysis using an internal standard for crude products.
b
1
the ¡-alkylated aldehyde reacted with acetic anhydride which
was generated as a side product.9,10 Although primary benzylic
acetate 1b did not produce the desired ¡-alkylated ketone, allylic
and propargylic acetates effectively gave the corresponding
products 11 and 12, respectively (Entries 7-9).
To our delight, we found that alkyl ethers instead of alkyl
acetates were also applicable in the reaction conditions using the
InI3/Me3SiI combined system, and the results are summarized
in Table 3. Secondary benzylic and benzhydryl methyl ethers
provided the corresponding ¡-alkylated ketones 3 and 14 in 89
and 98% yields, respectively (Entries 1 and 2). Gratifyingly,
benzyl methyl ether (13c) furnished 10 in 41% yield despite the
inertness of benzyl acetate (1b), as shown in Entry 7, Table 2
(Entry 3). Although the reason for this result cannot yet be
explained, alkyl methyl ethers could be used in a supplemental
fashion. The reactions using methyl ethers 13d proceeded to
give desired products effectively (Entry 4). Unfortunately,
tert-butyl methyl ether and diisopropyl ether did not provide
the corresponding ¡-alkylated ketones at all, but 1-methoxy-
adamantane (13e) furnished 15 quantitatively (Entry 5). Not
only methyl ether but n-butyl ether 13f produced the desired
ketone quantitatively (Entry 6). These results, as shown in
Table 3, are noteworthy because there have been few reports
on the ¡-alkylation of carbonyl compounds by the direct use of
alkyl ethers as an alkyl electrophile.3 In addition, the generation
of alkyl acetate as a side product is an advantage of this system
in terms of preventing side reactions.
Figure 1 shows a plausible mechanism. First, InI3 and
Me3SiI form a combined Lewis acid 16, and the silicon center of
Chem. Lett. 2011, 40, 1223-1225
© 2011 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/

1224
Table 2. Reactions of alkyl acetate 1 with various enol
acetates 2a
Table 3. Reactions of various alkyl ethers 13 with enol
acetate 2aa
InI3 (5 mol%)
Me3SiI (10 mol%)
InI3 (5 mol%)
OAc Me3SiI (10 mol%)
OAc
R3
O
O
R1
R
R
OMe
+
+
R
R3
OAc
R
CH2Cl2, rt, 2 h
CH2Cl2, rt, 2 h
R2
4-12
R1
R2
13
2a
1
2
Yield
/%b
OAc
Entry
1
Alkyl ether
13
Product
OAc
OAc
OAc
OAc
Ph
2b
OAc
C5H11
OAc
O
O
O
(E/Z = 69:31)
(E/Z = 67:33)
H
89
13a
3
2a
2c
2d
2e
2f
2g
Ph
OMe
(68)
Ph
Yield
/ %b
Entry
Alkyl acetate
1
2
Product
Ph
Ph
98
2
13b
13c
13d
13e
13f
14
10
11
15
14
O
Ph
O
quant.
(58)
(84)
Ph
Ph
OMe
Ph
Ph
1a
1a
1a
1a
1a
1a
1b
1c
1d
1
2
3
4
2b
2c
2d
2e
2f
4
Ph
OAc
Ph
Ph
41
3c
4d
5c
6
quant.
(68)c
OMe
(35)
5
6
7
8
9
O
O
58
O
77
(59)d
Ph
(40)
OMe
O
98
(60)e
quant.
(74)
Ph
OMe
C5H11
O
51
Ph
On-Bu
Ph
f
O
quant.
(90)
5
Ph
(36)
Ph
Ph
OAc
OAc
53
6g
7f
8h
9i
2g
2a
2a
2a
aReaction conditions: alkyl ether 13 (1 mmol), enol acetate 2a
(2 mmol), InI3 (0.05 mmol), Me3SiI (0.1 mmol), CH2Cl2
(2 mL), rt, 2 h. Yields were determined by H NMR analysis
using an internal standard for crude products. Values in the
(45)
Ph
b
1
O
10
11
12
0
Ph
OAc
Ph
c
parenthesis are isolated yields. ClCH2CH2Cl (2 mL), 83 °C,
d
2 h. 0 °C, 2 h.
74
O
(45)
OAc
Ph
InI3
Ph
O
O
Me3SiI
67
OAc
OR'
δ−
I3In
δ+
(48)
Ph
I
SiMe3
Ph
R
OR'
17
22
16
aReaction conditions: alkyl acetate 1 (1 mmol), enol acetate 2
(2 mmol), InI3 (0.05 mmol), Me3SiI (0.1 mmol), CH2Cl2
b
1
(2 mL), rt, 2 h. Yields were determined by H NMR analysis
using an internal standard for crude products. Values in
parentheses are isolated yields. cdr 64:36. ddr 59:41. edr 55:45.
O
I3In
I
SiMe3
OR'
I3In
I
R
fClCH2CH2Cl (2 mL), 83 °C, 2 h. 2g (5 mmol), ClCH2CH2Cl
g
Me3Si OR'
21
h
i
19
(2 mL), 83 °C, 1 h. 0 °C, 2 h. MeCN (2 mL), rt, 2 h.
O
R
16 interacts with the leaving group (OR¤) of 17, as illustrated.
Then, cationic species 18 is generated along with the elimination
of Me3SiOR¤ 19. Enol acetate 2 reacts with 18 to produce
¡-alkylated carbonyl compound 20. Finally, acyl cationic
species 21 reacts with 19 to regenerate the combined Lewis
acid InI3/Me3SiI with the formation of a metal-free side product
22.11
20
I3In
I
O
R
18
O
2
Figure 1. Reaction mechanism.
In conclusion, the direct coupling between enol acetates and
alkyl electrophiles, such as alkyl acetates and alkyl ethers, was
catalyzed via the combination catalyst InI3/Me3SiI. This
reaction system is environmentally benign, as it produces no
metal waste.
This work was supported by a Grant-in-Aid for Scientific
Research on Innovative Areas (No. 22106527, “Organic Syn-
thesis Based on Reaction Integration. Development of New
Methods and Creation of New Substances” and No. 23105525,
Chem. Lett. 2011, 40, 1223-1225
© 2011 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/

1225
“Molecular Activation Directed toward Straightforward Syn-
thesis”) and Challenging Exploratory Research (No. 23655083)
from the Ministry of Education, Culture, Sports, Science and
Technology (Japan). Y.O. thanks the Global COE Program of
Osaka University.
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11 Acetic anhydride and methyl acetate were observed in situ
1
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12 Supporting Information is available electronically on the
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Chem. Lett. 2011, 40, 1223-1225
© 2011 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/