Double nucleophilic addition to acrolein with ketene silyl acetals and allylborolanes catalyzed by proline

Article abstract of DOI:10.1246/cl.2011.862

In the presence of a catalytic amount of proline and silica gel, a mixture of ketene silyl acetals and 2-allyl-4,4,5,5-tetramethyl- 1,3,2-dioxaborolane underwent 1,4- and subsequently 1,2-addition with acrolein to give ω-hydroxyesters in good yields in a

Full text of DOI:10.1246/cl.2011.862

doi:10.1246/cl.2011.862
862
Published on the web July 16, 2011
Double Nucleophilic Addition to Acrolein with Ketene Silyl Acetals
and Allylborolanes Catalyzed by Proline
Makoto Shimizu,* Mami Kawanishi, Akinori Itoh, Isao Mizota, and Iwao Hachiya
Department of Chemistry for Materials, Graduate School of Engineering, Mie University, Tsu, Mie 514-8507
(Received June 6, 2011; CL-110473; E-mail: mshimizu@chem.mie-u.ac.jp)
In the presence of a catalytic amount of proline and silica gel,
and pipecolic acid examined were not as effective as proline
(Entries 4-10).3
In order to find the optimum reaction conditions additives and
the amounts of reagents were examined, and Table 2 summarizes
the results.
a mixture of ketene silyl acetals and 2-allyl-4,4,5,5-tetramethyl-
1,3,2-dioxaborolane underwent 1,4- and subsequently 1,2-addi-
tion with acrolein to give ¤-hydroxyesters in good yields in a
highly diastereoselective manner.
As can be seen from Table 2, in the absence of silica gel and
added acids the reaction gave the adduct in low yield (Entry 1),
whereas the acids promoted the addition reaction in the presence
of silica gel (1.5 g mmol¹1) (Entries 2, 3, 5, and 6). However,
when increased amounts of silica gel were used, the presence of
Although acrolein is one of the most useful three-carbon units
in organic synthesis, it is not always easy to use this particular
compound as a conjugate addition acceptor of carbon nucleo-
philes.1 This is due in part to the high reactivity of the carbonyl
and olefin functional groups to induce 1,2-addition and/or
polymerization. We have recently reported that N-allylidene-1,1-
diphenylethanamine (1) is successfully used as a latent acrolein in
the presence of silica gel and a limited amount of water to effect
the 1,4- and 1,2- double nucleophilic addition of two different
kinds of nucleophiles (eq 1 in Scheme 1).2a Since under similar
conditions, double addition reactions do not proceed (eqs 2-4 in
Scheme 1),2 this procedure has opened a new entry into an easy
use of an acrolein equivalent. However, there still remains an
important problem of the waste of a 1,1-diphenylethanamine
moiety, and therefore, in an effort to find an efficient system for
the use of acrolein itself, catalytic use of an appropriate amine was
examined. We have now found that the use of proline and silica
gel enables the desired catalytic system.
Table 1. Double addition to acrolein in the presence of aminea
SiO2 (1.5 gmmol−1
)
OTMS
Bpin
Catalyst
PhCOOH (5.0 mol%)
H2O (2.80 equiv)
OEt
(1.25 equiv) (1.10 equiv)
(20 mol%)
O
EtO2C
DMF/CH2Cl2=1/5, -78 °C to rt, 24 h
OH
3
2a
Entry
Catalyst
2a/%b
24
Entry
Catalyst
2a/%b
TBSO
1c,d
2
i-Pr2NH
6c
7
16
26
32
24
COOH
N
H
Ph
OH
OH
Bn2NH
35
N
H
Ph
Ph
COOH
3
60
8c
9
N
N
H
Ph
H
HO
Ph
OTMS
COOH
COOH
4
24
As summarized in Table 1, the initial examination was
carried out using diisopropylamine as a catalyst in the presence of
silica gel and water, and the double addition product was obtained
in low yield (Entry 1). Among the amines examined proline gave
the best result, and the desired adduct was obtained in moderate
yield, when the addition was conducted in the presence of silica
gel, benzoic acid, and water (Entry 3). Other proline derivatives
N
N
H
Ph
H
TBSO
5
56
10
25
N
COOH
N
H
H
aSee a typical procedure in the Supporting Information; SI.4 bIsolated
c
d
yields. In CH2Cl2. In the absence of benzoic acid.
Table 2. Double addition reaction using proline and additivesa
SiO2 (X gmmol−1
)
OTMS
COOH
Bpin
N
OTMS
O
Additive
OEt
H
SiO2
(20 mol%),
H2O (5.60 equiv),
(1.25 equiv),
(1.10 equiv)
B
H2O
OEt
O
O
EtO2C
(2.50 gmmol−1), (1.25 equiv), (1.10 equiv)
N
O
Ph
Ph
(2.80 equiv)
rt, 15.5 h
OH
EtO2C
DMF/CH2Cl2 =1/5, -78 °C to rt, 24 h
(1)
(2)
2a
3
CH2Cl2, -78 °C, 1.5 h
OH
Yield 81%
2a
1
Entry
Additive (mol %)
SiO2/g mmol
2a/%b
¹1
OTMS
Bpin
SiO2
(2.50 gmmol−1),
1
2
3
4
5
6
7
8
9c
10
11
®
®
0
21
45
60
38
56
54
55
70
75
58
61
OEt
(1.50 equiv), (1.10 equiv)
1.5
1.5
1.5
1.5
1.5
2.5
5.0
5.0
5.0
7.5
2a
CH2Cl2, -78 °C to rt, 17 h
PhCO2H (5)
PhCO2H (20)
B(OH)3 (5)
Salicylic acid (5)
®
3
3
Yield 5%
SnCl4 5H2O
(0.25 equiv)
OTMS
Bpin
OEt
(1.50 equiv), (1.10 equiv)
SiO2
(2.50 gmmol−1),
(3)
(4)
2a
CH2Cl2, -78 °C, 17 h
trace
SnCl4 5H2O
(0.25 equiv)
®
®
OTMS
Bpin
OEt
(1.50 equiv), (1.10 equiv)
SiO2
(2.50 gmmol−1),
PhCO2H (5)
®
3
2a
CH2Cl2, -78 °C to rt, 17 h
Yield 19%
aSee a typical procedure in the SI.4 bIsolated yields. cKetene silyl
acetal (1.50 equiv) was used.
Scheme 1. Double addition to acrolein.
Chem. Lett. 2011, 40, 862-863
© 2011 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/

863
Table 3. Double addition reaction to acroleina
H2O
N
R1
OTMS
OTMS
OEt
COOH
R4
Bpin
O
SiO2
(5.0 gmmol−1
)
N
4
R2
R3
COO
R5
R5
R4
H
R1 R2
3
(1.5 equiv),
(20 mol%),
H2O (5.6 equiv),
(1.1 equiv)
R3
O
DMF/CH2Cl2=1/5, -78 °C to rt, 24 h
O
OH
3
2
N
EtO2C
COOH
Entry R1 R2 R3
R4 R5
2/%b
a: 75d
anti:sync
5
N
COOTMS
(H)
H
1
2
3
Me Me OEt
Me Me OBn
Me Me OMe
Me Me OCy
H
H
H
H
H
H
H
H
H
Me
H
H
H
H
H
H
H
H
H
H
H
®
®
b: 40
c: 58 (61)e
d: 61
e: 0
®
®
H2O
O
B
4
O
5
6
7
8
H
H
H
H
H
Me SPh
Me OCy
Me SCy
®
®
O
EtO2C
EtO2C
f: trace
g: 27f
h: 0
i: 0
j: 52
OH
2a
6
®
®
H
H
OCy
SCy
Scheme 2. A possible reaction pathway.
9
®
10
11
12
Me Me OEt
Me Me OEt
Me Me OEt
>99:<1
<1:>99
®
In conclusion, we have developed an efficient system for the
double nucleophilic addition to acrolein employing a proline
catalyst and silica gel as promoters. Although there is a limitation
for the 1,4-nucleophiles, this study opens a direct use of acrolein
as an acceptor of plural nucleophiles in a one-pot procedure.
Regarding the efficiecy of the proline catalyst as compared with
other amines, we have not yet obtained a definite idea, however a
sort of double activation of the unsaturated aldehyde by forming
the iminium salt coupled with that of the ketene silyl acetal by the
attack of the carboxylate anion may be involved in the present
system.
Me k: 58
Me Me l: 60
aSee a typical procedure in the SI.4 bIsolated yields. cRatio regarding
C5/C6 diastereomers.5 dEnantiopurity of the product was 10% ee. eIn
the presence of proline (100 mol %). A 55:45 ratio of diastereomers
f
was obtained.
added acids was not necessary (Entries 7 and 8), indicating that an
appropriate acidity of the silica gel would facilitate the formation
of the iminium salt. The best conditions were found when the
reaction was carried out with ketene silyl acetal (1.50 equiv) and
2-allyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.10 equiv) in
the presence of proline (20 mol %) and silica gel (5.0 g mmol¹1),
and the 1,4- and 1,2-adduct was obtained in 75% yield (Entry 9).
Under the optimum conditions a variety of ketene silyl acetals and
allylborolanes were subjected to the double addition reaction, and
Table 3 summarizes the results.4
Among tetrasubstituted ketene silyl acetals ethoxy derivatives
recorded the best result, whereas benzyloxy and methoxy
derivatives gave moderate yields of the product. However, in
contrast to the results using N-allylidene-1,1-diphenylethanamine
(1) previously reported,2a trisubstituted ketene silyl thioacetal
gave the adduct in only low yield, where the diastereoselectivity
regarding the C2-C5 carbons was not high (Entry 7), and
disubstituted derivatives were not successfully employed (Entries
8 and 9). Competing hydrolysis of tri- and disubstituted ketene
silyl (thio)acetals may account for the low yields. Use of one
equivalent of proline did not noticeably improve the yields of
the desired adducts (Entry 3). When crotylborolanes were used as
the second nucleophile, the reaction proceeded with excellent
diastereoselectivity with respect to the C5-C6 carbons, where the
(E)-derivative gave anti-adducts and the (Z)-isomer effected the
formation of the syn-isomers (Entries 10 and 11). 3-Methylcrotyl
derivative could also be employed (Entry 12).
This work was supported by Grant-in-Aids for Scientific
Research (B) and on Innovative Areas from JSPS and MEXT.
References and Notes
1
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2
3
a) M. Shimizu, M. Kawanishi, I. Mizota, I. Hachiya, Org. Lett. 2010,
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For recent reviews dealing with conjugate addition to iminium ions,
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For more detailed examination of reaction conditions, see the
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Journal Web site, http://www.csj.jp/journals/chem-lett/index.html.
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N. Asao, Chem. Rev. 1993, 93, 2207, and references cited therein.
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4
Regarding the reaction pathway, the following Scheme 2 may
account for the present reaction. First, the iminium salt 46 is
formed from acrolein 3 and proline, and undergoes 1,4-addition
with ketene silyl acetal to give the enamine intermediate 5.
Hydrolysis with water present in the reaction system generates the
aldehyde 6, which is attacked by allylborolane to give the double
addition product 2a. Regarding the enantiopurity of the product
2a, low ee values (8 to 10% ee) were usually obtained, indicating
that a major pathway of the 1,2-addition might not include the
proline catalysis.
5
6
Chem. Lett. 2011, 40, 862-863
© 2011 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/