Enantioselective Morita-Baylis-Hillman reaction catalyzed by a chiral phosphine oxide

Article abstract of DOI:10.1016/j.tetlet.2013.09.067

An application of a hypervalent silicon complex, generated from a chiral phosphine oxide catalyst and silicon tetrachloride, to the enantioselective organocatalytic Morita-Baylis-Hillman reaction is described. A chloride anion liberated from the hypervalent silicon complex smoothly generated a γ-chloro silyl enol ether that subsequently reacted with an aldehyde to afford the Baylis-Hillman adducts in good yields and with good enantioselectivities.

Full text of DOI:10.1016/j.tetlet.2013.09.067

Tetrahedron Letters 54 (2013) 6430–6433
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Enantioselective Morita–Baylis–Hillman reaction catalyzed
by a chiral phosphine oxide
Shunsuke Kotani a, , Masaya Ito , Hirono Nozaki , Masaharu Sugiura , Masamichi Ogasawara ,
Makoto Nakajima
a
⇑
b
b
b
c
b,
⇑
Priority Organization for Innovation and Excellence, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan
Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan
Catalysis Research Center and Graduate School of Life Science, Hokkaido University, Kita-ku, Sapporo 001-0021, Japan
b
c
a r t i c l e i n f o
a b s t r a c t
Article history:
An application of a hypervalent silicon complex, generated from a chiral phosphine oxide catalyst and sil-
icon tetrachloride, to the enantioselective organocatalytic Morita–Baylis–Hillman reaction is described. A
chloride anion liberated from the hypervalent silicon complex smoothly generated a c-chloro silyl enol
ether that subsequently reacted with an aldehyde to afford the Baylis–Hillman adducts in good yields
and with good enantioselectivities.
Received 3 August 2013
Revised 9 September 2013
Accepted 12 September 2013
Available online 21 September 2013
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Enantioselective
Hypervalent silicon complex
Morita–Baylis–Hillman reaction
Organocatalysis
Phosphine oxide
Considerable interest over the last decade has focused on the
versatility of hypervalent silicon complexes formed from a chloros-
ilane and a Lewis base catalyst in the context of preparative meth-
ods in organic synthesis.1 In some cases, chloride anions can play
an important role in realizing useful asymmetric transformations;
however, the utility of chloride anions from hypervalent silicon
complexes has not been extensively studied.2 This report de-
scribes the use of a chloride anion released from a hypervalent sil-
icon complex toward the efficient mediation of the
enantioselective Morita–Baylis–Hillman (MBH) reaction in the
presence of a chiral phosphine oxide.
chalcogenide promoted the MBH reaction to give the products in
8
good yields. Shi et al. reported that amines or ammonium salts
9
were effective for the Lewis acid-mediated MBH reaction. The
chloride anion liberated from the Lewis acid added to a vinyl ke-
tone, and then the chloride-adduct subsequently reacted with an
aldehyde to afford the MBH adduct.
–4
Hypervalent silicon complexes that were formed by a reaction
of a chlorosilane with a Lewis base enhanced both the electrophi-
licity of the silicon atom and the nucleophilicity of the substituents
1
b
attached thereto (Fig. 1).
A ligand may be liberated from the
hypervalent silicon complex. The chloride anion liberated from sil-
icon tetrachloride (L = Cl) was found to enable several asymmetric
The MBH reaction is a powerful and efficacious method in or-
ganic synthesis for producing adducts having a variety of func-
2
synthetic reactions, such as the ring-opening of a meso-epoxide,
5
,6
3
tional groups that may be subjected to further transformations.
the phosphonylation of an aldehyde, or the halo aldol reaction
4
The MBH reaction is typically catalyzed by a tertiary amine or a
tertiary phosphine, although the slow reaction rate of the MBH
has presented a major drawback. Efforts have been applied toward
remedying the inherent low reactivity of the amines and phos-
phines that form the center of the nucleophilic activation of the
of an
a
,b-ynone. From this perspective, chloride anions may be
effective toward activating substrates. By focusing on the nucleo-
philicity of the chloride anion generated from the hypervalent sil-
icon complex (L = Cl), we achieved the enantioselective MBH
1
1,12
reaction catalyzed by a chiral phosphine oxide.
a,b-unsaturated carbonyls. On the other hand, there are a few re-
ports for Lewis acid-mediated MBH reaction, though this approach
has not been extensively tested.7–10 In 1998, Kataoka and co-work-
ers reported that the combination of titanium tetrachloride and a
⇑
Corresponding authors.
E-mail addresses: skotani@gpo.kumamoto-u.ac.jp (S. Kotani), nakajima@gpo.ku-
mamoto-u.ac.jp (M. Nakajima).
Figure 1. Hypervalent silicon complexes.
0
040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.09.067

S. Kotani et al. / Tetrahedron Letters 54 (2013) 6430–6433
6431
0
0
0
Figure 3. Equilibrium among syn-3au , anti-3au , and 4au .
Figure 2. Nucleophilic activation of a,b-enone 1a by a chloride anion.
Table 1
Optimization studiesa
Figure 4. Screening of chiral phosphine oxides.
Entry Ketone 1 Amine
Solvent Time (h)
Product 4
Yieldb (%) Eec (%)
aldehyde in the presence of a chiral phosphine oxide then permit-
ted the development of an enantioselective MBH reaction of ,b-
enones.
Phenyl vinyl ketone (1a) and benzaldehyde (2u) were reacted
with silicon tetrachloride in dichloromethane in the presence of
a
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1a
1a
1b
1b
1b
1b
1b
1b
1b
1b
1b
1b
1b
1b
None
CH
CH
CH
CH
CH
CH
EtCN
THF
EtOAc
2
2
2
2
2
2
Cl
Cl
Cl
Cl
Cl
Cl
2
2
2
2
2
2
4
1
1
1
30d
59
88
—
86
77
85
66
17
15
44
63
76
92
30
32
77
—
1
3
i
Pr
2
Pr
2
Pr
2
Pr
2
Pr
2
Pr
2
Pr
2
Pr
2
NEt
NEt
NEt
NEt
NEt
NEt
NEt
NEt
i
i
i
i
i
i
i
e
f
1
70
73
55
75
77
38
69
78
78
76
1
0 mol % of BINAP dioxide (BINAPO). In the absence of diisopropyl-
g
16
13
6
16
1.5
2
2
1
1
ethylamine, chloro aldol adduct 3au and MBH adduct 4au were
obtained in 39% and 30% yields, respectively, both of which were
determined to be 30% ee (Table 1, entry 1). Since the asymmetric
induction in both syn-3au and anti-3au was same magnitude with
that in 4au, these products were thought to be in equilibrium in
the reaction mixture as shown in Figure 3. The use of a stoichiom-
etric amount of diisopropylethylamine converted aldol adducts
syn- and anti-3au into MBH adduct 4au, thereby increasing the
yield of 4au to 59% (entry 2). The reaction was conducted with
ketone 1b bearing a p-nitro group, revealing a remarkable increase
in both the reactivity and enantioselectivity (entry 3). In the ab-
sence of Lewis base, no product was obtained (entry 4). Therefore,
the chiral phosphine oxide was essential for the MBH reaction. Shi
et al. also reported that silicon tetrachloride alone was ineffective
0
1
2
3
4
3
Et N
CH
CH
CH
2
2
2
2
2
Cl
2
Cl
2
Cl
2
Cl
2
Cl
2
Cy
Cy
2
NMe
N Bu
i
2
2,6-Lutidine CH
h
i
Pr
2
NEt
CH
a
Unless otherwise noted, reactions were carried out by adding silicon tetra-
chloride (1.2 equiv) to a solution of ketone 1a or 1b (1.1 equiv), aldehyde 2u
1.0 mmol or 0.5 mmol), an amine (1.3 equiv), and BINAPO (10 mol %) in a solvent at
20 °C under argon atmosphere.
Isolated yield.
The ee was determined by HPLC.
Aldol adduct 3au was obtained (39% yield, syn/anti = 1.8/1, 30% ee (syn), 30% ee
anti) (see the text for additional discussion).
Without catalyst.
(
ꢀ
b
c
d
(
e
9d
with respect to enabling the MBH reaction.
f
At 0 °C.
At ꢀ40 °C.
Next, the conditions for the reaction of 1b, 2u, and (S)-BINAPO
were optimized. The reaction proceeded well at 0 °C, but gave
slight lower selectivity (entry 5), whereas lower temperature than
g
h
i
4 2
The reaction was performed by using SiCl (1.5 equiv) and Pr NEt (1.6 equiv).
ꢀ
20 °C decreased both reactivity and enantioselectivity (entry 6).
Among the solvents tested, dichloromethane provided the best
1
4
In an initial step, we searched for a suitable substrate for the
nucleophilic addition of a chloride anion from a hypervalent silicon
complex. We found that phenyl vinyl ketone (1a) and SiCl gave
the b-chlorinated ketone in 88% yield in the presence of triphenyl-
phosphine oxide (20 mol %) (Fig. 2). This result suggested that
phosphine oxide significantly catalyzed the nucleophilic addition
of the chloride anion to the a,b-enone, and that the c-chloro silyl
enol ether was generated as an intermediate in the reaction media.
The subsequent direct reaction of the silyl enol ether with an
reactivity and enantioselectivity (entries 7–9). Triethylamine
dramatically reduced both the reactivity and the enantioselectivity
due to the deactivation of silicon tetrachloride by the coordination
to the silicon atom (entry 10). Therefore, the use of sterically hin-
dered amines having sufficient Brønsted basicity but low nucleo-
philicity was crucial for promoting the reaction (entries 3 and
11–13). Increasing the amounts of diisopropylethylamine and
silicon tetrachloride slightly improved the product yield without
significantly decreasing the enantioselectivity (entry 14).
4

6
432
S. Kotani et al. / Tetrahedron Letters 54 (2013) 6430–6433
Table 2
Enantioselective MBH reaction catalyzed by SEGPHOSOa
Entry
Ketone 1
Ar
Aldehyde 2
Time (h)
Product 4
R
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
9
Ph, 1a
Ph, 2u
Ph, 2u
Ph, 2u
Ph, 2u
Ph, 2u
Ph, 2u
Ph, 2u
Ph, 2u
24
2
24
4
2
3
24
24
6
12
24
4
4au
4bu
4cu
4du
4eu
4fu
4gu
4hu
4bv
4bw
4bx
4by
4bz
66
93
32
82
89
87
61
76
87
86
82
94
49
81
8
4-NO
2
C
6
H
4
, 1b
, 1c
, 1d
, 1e
, 1f
4-MeOC
6
H
4
4-CF
2-CF
3-CF
3
C
3
C
3
C
6
6
6
H
H
H
4
4
4
70
63
64
56
41
72
81
73
81
9
1-Naphthyl, 1g
2-Naphthyl, 1h
4-NO
4-NO
4-NO
4-NO
4-NO
2
2
2
2
2
C
C
C
C
C
6
H
6
H
6
H
6
H
6
H
4
, 1b
4
, 1b
4
, 1b
4
, 1b
4
, 1b
4-BrC
6
H
4
, 2v
, 2w
10
11
12
13
4-MeOC
6
H
4
1-Naphthyl, 2x
2-Naphthyl, 2y
PhCH@CH, 2z
d
16
29
a
All the reactions were carried out by adding silicon tetrachloride (1.5 equiv) to a solution of ketone 1 (1.1 equiv), aldehyde 2 (0.5 mmol), and diisopropylethylamine
(
1.6 equiv), and (S)-SEGPHOSO (10 mol %) in CH
2
Cl
2
(0.75 mL) at ꢀ20 °C.
b
Isolated yield.
Determined by HPLC.
c
d
2
-(Chloromethyl)-1-(4-nitrophenyl)-5-phenylpenta-2,4-dien-1-one was produced in 52% yield.
We next screened several chiral phosphine oxide catalysts
stereoselectivity and exploration of the precise reaction mecha-
nism are in progress.
for the reaction between 1b and 2u under the optimal condi-
tions in an effort to increase the enantioselectivity (Fig. 4). Cat-
alysts bearing biaryl structures mostly gave enantioselectivities
similar to that obtained using BINAPO,15 whereas DIOP dioxide
Acknowledgments
(
DIOPO) afforded a racemate. SEGPHOS dioxide (SEGPHOSO)
was found to be the most effective catalyst affording 4bu with
1% ee.
With the optimal conditions and the catalyst in hand, the asym-
metric MBH reaction with various substrates was examined
This work was partially supported by JSPS KAKENHI Grant
Number 25860008 and a Grant-in-Aid for Scientific Research on
Innovative Areas ‘Advanced Molecular Transformations by Organ-
ocatalysts’ from The Ministry of Education, Culture, Sports, Science
and Technology, Japan. This work was performed under the Coop-
erative Research Program: Network Joint Research Center for
Materials and Devices (Institute for Materials Chemistry and Engi-
neering, Kyushu University). Chiral phosphines ((S)-H8-BINAP, (S)-
tol-BINAP, and (S)-SEGPHOS) were donated by Takasago Perfumery
Co. Ltd.
8
1
6
(Table 2). The electronic effects on the aromatic ring of ketone
1
1
remarkably affected both the reactivity and selectivity (entries
–3). Ketone 1c, which included an electron-donating group, dis-
played a dramatically lower enantioselectivity (entry 3). On the
other hand, ketones 1d–f, bearing electron-withdrawing groups
at any position on the aromatic ring, gave moderate selectivities
1
7
(
entries 4–6). Steric hindrance at the ketones slightly affected
Supplementary data
the enantioselectivities of the products (entries 7 and 8). These re-
sults suggested that the rate-determining step was the addition of
the chloride anion to the ketone 1, and that the enantioselectivity
was subject to the nucleophilicity of the resulting silyl enol ether.
Ketone 1b was used as a substrate to investigate the reactions with
various aldehydes 2 (entries 9–13). Although the reaction with 1-
naphthaldehyde (2x) was relatively slow (entry 11), the aryl alde-
hydes gave good enantioselectivities. Cinnamaldehyde (2z) mainly
produced the dehydrated product of the chlorinated intermediate
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2013.
0
9.067.
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with good enantioselectivities. Further improvements of the

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16. Representative procedure for the MBH reaction of ketone 1b and aldehyde 2u:
Silicon tetrachloride (0.068 mL, 0.75 mmol, 1.5 equiv) was slowly added to a
solution of ketone 1b (97.4 mg, 0.55 mmol, 1.1 equiv), aldehyde 2u (0.051 mL,
0.50 mmol, 1.0 equiv), diisopropylethylamine (0.14 mL, 0.80 mmol, 1.6 equiv),
9
.
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2 2
and (S)-SEGPHOSO (32.1 mg, 0.05 mmol, 10 mol %) in CH Cl (0.75 mL) at
ꢀ20 °C. After being stirred for 2 h, the reaction was quenched with sat. NaHCO
3
5
1
7, 7343; (d) Shi, M.; Jiang, J.-K.; Cui, S.-C.; Feng, Y.-S. J. Chem. Soc., Perkin Trans.
2001, 390; (e) Shi, M.; Feng, Y.-S. J. Org. Chem. 2001, 66, 406; (f) Shi, M.; Li, C.-
(5.0 mL), and then the slurry was stirred for 1 h. The two-layers mixture was
filtered through a cotton pad to remove the silicon precipitates and the
aqueous layer was extracted with EtOAc (3 ꢁ 20 mL). The combined organic
Q.; Jiang, J.-K. Chem. Commun. 2001, 833.
1
1
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1. Papers on phosphine oxide-catalyzed reactions from our group, see: (a)
Nakajima, M.; Kotani, S.; Ishizuka, T.; Hashimoto, S. Tetrahedron Lett. 2005, 46,
3
layers were washed with 10% HCl (20 mL), sat. NaHCO (20 mL), and brine
(20 mL), and dried over Na
crude product was purified by column chromatography (hexane/EtOAc = 6:1,
SiO 10 g) to give the product 4bu (131.0 mg, 93% yield). The enantiomeric
2 4
SO . After filtration and concentration, the obtained
2
1
57; (b) Kotani, S.; Hashimoto, S.; Nakajima, M. Tetrahedron 2007, 63, 3122; (c)
excess was determined to be 81% ee by HPLC analysis with Daicel Chiralpak
AD-H column [eluent: 4:1 = hexane/IPA; flow rate: 1.0 mL/min; detection:
254 nm; t : 13.1 min (major), 14.9 min (minor)].
R
Sugiura, M.; Sato, N.; Kotani, S.; Nakajima, M. Chem. Commun. 2008, 4309; (d)
Kotani, S.; Shimoda, Y.; Sugiura, M.; Nakajima, M. Tetrahedron Lett. 2009, 50,
4
(
2
602; (e) Sugiura, M.; Kumahara, M.; Nakajima, M. Chem. Commun. 2009, 3585;
f) Kotani, S.; Aoki, S.; Sugiura, M.; Nakajima, M. Tetrahedron Lett. 2011, 52,
834; (g) Shimoda, Y.; Kotani, S.; Sugiura, M.; Nakajima, M. Chem. Eur. J. 2011,
17. Electron-donating groups on the aromatic ketones may retard chlorination of
enones decreasing the chemical yield, and enhance the nucleophilicity of the
resulting enol ethers promoting the non-catalytic process.