Dibutyltin dimethoxide and BINAP · silver(I) complex-catalyzed asymmetric aldol reaction of alkenyl trichloroacetates with aldehydes

Article abstract of DOI:10.1016/j.jorganchem.2006.08.048

A catalytic asymmetric aldol reaction of alkenyl trichloroacetates with aldehydes was achieved using dibutyltin dimethoxide and BINAP · silver(I) complex as catalysts in a mixed solvent consisting of THF and MeOH. Various optically active β-hydroxy ketone

Full text of DOI:10.1016/j.jorganchem.2006.08.048

Journal of Organometallic Chemistry 692 (2007) 550–553
www.elsevier.com/locate/jorganchem
Dibutyltin dimethoxide and BINAP Æ silver(I) complex-catalyzed
asymmetric aldol reaction of alkenyl trichloroacetates with aldehydes
a,
b
a
Akira Yanagisawa *, Toshikazu Ichikawa , Takayoshi Arai
a
Department of Chemistry, Faculty of Science, Chiba University, Inage, Chiba 263-8522, Japan
Graduate School of Science and Technology, Chiba University, Inage, Chiba 263-8522, Japan
b
Received 28 February 2006; accepted 20 March 2006
Available online 30 August 2006
Abstract
A catalytic asymmetric aldol reaction of alkenyl trichloroacetates with aldehydes was achieved using dibutyltin dimethoxide and
BINAP Æ silver(I) complex as catalysts in a mixed solvent consisting of THF and MeOH. Various optically active b-hydroxy ketones were
diastereoselectively obtained not only from aromatic and a,b-unsaturated aldehydes but also from an aliphatic aldehyde with good
enantioselectivity up to 92% ee.
ꢀ 2006 Elsevier B.V. All rights reserved.
Keywords: Asymmetric catalysis; Aldol reaction; Tin alkoxide; BINAP; Silver; Alkenyl esters; Aldehydes
1. Introduction
products in high yield [5]. An asymmetric version of the
catalytic aldol process has been also achieved by addition
of a BINAP Æ Ag(I) catalyst. Although various aldehydes
are applicable to the asymmetric reaction, aliphatic alde-
hydes are less reactive under the standard reaction condi-
tions [5]. To solve the problem on the reactivity, we
further studied the catalytic activity of several tin alkoxides
and found that dibutyltin dimethoxide is more reactive
than tributyltin methoxide, and aliphatic aldehydes show
high reactivity under the influence of the former tin catalyst
[6]. We report here the asymmetric process of the Bu2Sn-
(OMe)2-catalyzed aldol reaction of alkenyl trichloroace-
tates with aldehydes using the BINAP Æ AgOTf complex
as a chiral catalyst (Scheme 1).
The b-hydroxy carbonyl group is an important synthon
for natural products and biologically active organic mole-
cules. In order to construct the functionality, various trans-
formations have been developed and among them, aldol
reaction is recognized as the most efficient and convenient
method [1]. Numerous asymmetric catalytic aldol processes
have so far been reported; however, most of these are the
chiral Lewis acid- or chiral Lewis base-catalyzed Mukaiy-
ama type-aldol reactions using silyl enolates as nucleo-
philes [2–4] and there have been no examples using
alkenyl esters as masked enolates. We have previously
found that alkenyl trichloroacetates react with trialkyltin
methoxide to afford the corresponding trialkyltin enolates,
which have sufficient reactivity toward aldehydes. In addi-
tion, in the presence of a catalytic amount of trialkyltin
methoxide and a stoichiometric amount of methanol, the
aldol reaction takes place smoothly to give the desired
2. Results and discussion
First, we studied the amounts of (R)-BINAP and AgOTf
in the reaction of 1-trichloroacetoxy cyclohexene [7] with
benzaldehyde. As we have reported before, a chiral silver(I)
catalyst prepared from BINAP and an excess amount of
silver(I) salt shows reactivity higher than that of the corre-
*
Corresponding author. Fax: +81 43 290 2789.
E-mail address: ayanagi@faculty.chiba-u.jp (A. Yanagisawa).
0022-328X/$ - see front matter ꢀ 2006 Elsevier B.V. All rights reserved.
doi:10.1016/j.jorganchem.2006.08.048

A. Yanagisawa et al. / Journal of Organometallic Chemistry 692 (2007) 550–553
551
cat. Bu2Sn(OMe)2
cat. BINAP·AgOTf
MeOH (5 eq)
BINAP and 17 mol% of AgOTf was the most effective in
obtaining high yield and high enantioselectivity in combi-
nation with 6 mol% of Bu2Sn(OMe)2. For example, the
reaction using these catalysts in the presence of 5 equiv.
of MeOH at ꢀ20 ꢁC for 24 h provided the aldol adduct
in 98% yield with an anti/syn ratio of 86/14. The anti-iso-
mer showed 92% ee (Scheme 2). In the reaction, molecular
sieves 3A (MS 3A) was indispensable and the isolated yield
was drastically decreased unless the additive was present.
Under the optimized reaction conditions we performed
the asymmetric aldol reaction of various combinations of
alkenyl trichloroacetates and aldehydes. Selected exam-
ples are shown in Table 1. In the reaction of cyclohexa-
none-derived alkenyl trichloroacetate, aromatic and a,b-
OCOCCl3
O
OH
R3
R3CHO
R1
R1
*
R2
+
*
THF, MS 3A, -20 oC
R2
Scheme 1.
sponding 1:1 mixture, because a significant amount of a
less reactive 2:1 complex of BINAP and Ag(I) salt is
formed in addition to the desired 1:1 complex from the
1:1 mixture [8]. So we tested various ratios of (R)-BINAP
and AgOTf in the present reaction and found that the chi-
ral silver(I) complex prepared by mixing 8 mol% of (R)-
(R)-BINAP (8 mol%)
AgOTf (17 mol%)
Bu2Sn(OMe)2 (6 mol%)
OCOCCl3
+
O
OH
Ph
O
OH
Ph
+
PhCHO
MeOH (5 equiv), THF, -20 oC
anti
syn
1.5 equiv
With MS 3A (24 h):
98%, anti/syn = 86 (92% ee)/14
Without MS 3A (22 h): 15%, anti/syn = 71 (69% ee)/29
Scheme 2.
Table 1
Enantioselective aldol reaction of alkenyl trichloroacetates with aldehydes catalyzed by Bu2Sn(OMe)2 and (R)-BINAP Æ AgOTfa
(R)-BINAP (8 mol%), AgOTf (17 mol%)
Bu2Sn(OMe)2 (6 mol%), MeOH (5 eq)
OCOCCl3
O
OH
R3
O
OH
R3
R1
R3CHO
R1
R1
+
+
THF, MS 3A, -20 oC, time
R2
anti
R2
syn
R2
Entry
Alkenyl trichloroacetate
Aldehyde
Time/h
Yield/%b
anti/sync
ee/%d
1
2
3
4
5e
PhCHO
4-MeOC6H4CHO
1-C10H7CHO
(E)-PhCH@CHCHO
Ph(CH2)2CHO
24
25
24
24
48
98
92
90
90
52
86/14
86/14
94/6
77/23
67/33
92
91
90
82
55
OCOCCl3
6
7
8
9
PhCHO
24
24
24
96
84
58
71
27
93/7
92/8
79/21
82/18
84
84
72f
64
OCOCCl3
4-MeOC6H4CHO
(E)-PhCH@CHCHO
Ph(CH2)2CHO
10
11
12
PhCHO
4-MeOC6H4CHO
Ph(CH2)2CHO
44
53
72
62
77
60
22/78
17/83
14/86
58
70
26
OCOCCl3
E/Z = 1/4
a
Unless otherwise noted, the reaction was carried out using (R)-BINAP (8 mol%), AgOTf (17 mol%), dibutyltin dimethoxide (6 mol%), alkenyl
trichloroacetate (1.5 equiv.), and aldehyde (1 equiv.) in THF containing MeOH (5 equiv.) at ꢀ20 ꢁC for 24–96 h.
b
Isolated yield.
c
Determined by 1H NMR analysis.
d
The value corresponds to the major diastereomer. Determined by HPLC analysis (Daicel Chiralcel OD-H, OJ-H, or Chiralpak AD-H, AS-H).
(R)-BINAP (9 mol%), AgOTf (19 mol%), and dibutyltin dimethoxide (7 mol%) were used.
Determined by HPLC analysis (Daicel Chiralpak AD-H) of the corresponding saturated b-hydroxy ketone derived from the aldol adduct by
e
f
hydrogenation (H2, Pd–C, EtOAc, ꢀ20 ꢁC).

552
A. Yanagisawa et al. / Journal of Organometallic Chemistry 692 (2007) 550–553
unsaturated aldehydes gave the aldol adducts in high
yield with anti-selectivity. The anti-isomers indicated high
enantioselectivity up to 92% ee (entries 1–4). As for the
a,b-unsaturated aldehyde, exclusive 1,2-selectivity was
observed (entry 4). Aliphatic aldehydes also showed
moderate reactivity and for example, hydrocinnamalde-
hyde afforded the desired product in 52% yield but with
lower diastereo- and enantioselectivities (entry 5). Use
of 1-tetralone-derived alkenyl trichloroacetate as a reac-
tion partner resulted in a better anti/syn selectivity and
enantioselectivity (entry 9). Not only cyclic alkenyl tri-
chloroacetates but acyclic ones such as a 3-pentanone
derivative also underwent the asymmetric aldol reaction.
Noteworthy was the fact that the opposite syn-selectivity
was observed for the reaction of the acyclic substrate
(entries 10–12).
A plausible catalytic mechanism of the asymmetric aldol
reaction is shown in Fig. 1. First, an alkenyl trichloroace-
tate 1 reacts with Bu2Sn(OMe)2 generating the dibutyl-
methoxytin enolate 2 and methyl trichloroacetate. Then,
addition of the tin enolate 2 to an aldehyde occurs enanti-
oselectively under the influence of the (R)-BINAP Æ AgOTf
catalyst to produce the nonracemic aldol adduct 3. Proton-
ation of 3 by MeOH affords the final product 4 and
regenerates the tin dimethoxide.
3. Experimental
3.1. General
Analytical TLC was done on precoated (0.25 mm) silica
gel plates. Column chromatography was conducted with
70–230 mesh silica gel. Infrared (IR) spectra were recorded
on an FTIR spectrometer. 1H NMR spectra were recorded
1
on 400 MHz spectrometers. Chemical shifts of H NMR
spectra were reported relative to tetramethylsilane (d 0).
Splitting patterns are indicated as s, singlet; d, doublet;
m, multiplet; br, broad. 13C NMR spectra were recorded
on 100 MHz spectrometers. Chemical shifts of 13C NMR
spectra were reported relative to CDCl3 (d 77.0). Analytical
high-performance liquid chromatography (HPLC) was
done using a chiral column (4.6 mm · 25 cm, Daicel Chi-
ralcel OD-H, OJ-H, or Chiralpak AD-H, AS-H). All exper-
iments were carried out under an atmosphere of standard
grade argon gas (oxygen <10 ppm). Alkenyl trichloroace-
tates were prepared by treatment of the corresponding
ketones with trichloroacetic anhydride in the presence of
a catalytic amount of p-toluenesulfonic acid and purified
by distillation before use [7]. Other chemicals were used
as purchased.
In summary, we have demonstrated a novel example of
asymmetric aldol reaction of alkenyl trichloroacetates
with aldehydes catalyzed by dibutyltin dimethoxide and
BINAP Æ AgOTf. The procedure is operationally simple
employing readily available chemicals and can produce
various optically active b-hydroxy ketones with enantiose-
lectivity up to 92% ee not only from aromatic and
a,b-unsaturated aldehydes but also from an aliphatic alde-
hyde. This process is environmentally benign because the
amount of the toxic organotin compound is a catalytic
amount. Further work is now in progress on the asym-
metric reaction.
3.2. A typical procedure for the asymmetric aldol reaction of
benzaldehyde with 1-trichloroacetoxy cyclohexene catalyzed
by (R)-BINAP Æ AgOTf complex and dibutyltin
dimethoxide: synthesis of (2S,10R)-2-
(hydroxyphenylmethyl)cyclohexanone (anti-isomer,
Scheme 2 and entry 1 in Table 1) [9]
A mixture of AgOTf (43.2 mg, 0.167 mmol), (R)-BINAP
(49.8 mg, 0.080 mmol), and MS 3 A (0.8 g) was dissolved in
dry THF (5 mL) under argon atmosphere and with direct
light excluded, and stirred at 20 ꢁC for 10 min. To the
resulting solution were added dropwise benzaldehyde
(102 lL, 1.00 mmol), 1-trichloroacetoxy cyclohexene
(365.3 mg, 1.50 mmol), dibutyltin dimethoxide (13.8 lL,
0.060 mmol), and MeOH (202 lL, 5.00 mmol) successively
at ꢀ20 ꢁC. After being stirred for 24 h at this temperature,
the mixture was treated with MeOH (2 mL). The mixture
was then treated with brine (2 mL) and solid KF (ca. 1 g)
at ambient temperature for 30 min. The resulting precipitate
was filtered off with a glass filter funnel filled with Celiteꢂ
and silica gel. The filtrate was dried over Na2SO4 and con-
centrated in vacuo after filtration. The residual crude prod-
uct was purified by column chromatography on silica gel to
afford a mixture of the aldol adducts (200.7 mg, 98% yield)
as a colorless oil. The anti/syn ratio was determined to be
O
OH
R3
OCOCCl3
Bu2Sn(OMe)2
R1
R1
R2
1
R2
4
MeOCOCCl3
MeOH
O
OSnBu2(OMe)
R3
OSnBu2(OMe)
1
R1
R1
86/14 by H NMR analysis. The enantioselectivity of the
R2
2
R2
anti isomers was determined to be 92% ee by HPLC analysis
using a chiral column (Daicel Chiralcel OD-H, hexane/
3
R3CHO
i-PrOH = 9/1, flow rate = 0.5 mL/min): tsyn-minor
13.3 min (2S,10S), tsyn-major = 14.5 min (2R,10R), tanti-major
=
=
(R)-BINAP·AgOTf
15.8 min (2S,10R), tantiꢀminor = 22.1 min (2R,10S). The abso-
Fig. 1. A suggested catalytic cycle for the asymmetric aldol reaction
catalyzed by Bu2Sn(OMe)2 and (R)-BINAP Æ AgOTf.
lute configurations of all stereoisomers were unambiguously

A. Yanagisawa et al. / Journal of Organometallic Chemistry 692 (2007) 550–553
553
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18
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Acknowledgements
We gratefully acknowledge financial support from the
Ministry of Education, Science, Sports, Culture and Tech-
nology of the Japanese Government. We thank Dr. T. Ooi
(Kyoto University) for valuable data on an aldol product.
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