Highly enantioselective 1,4-addition of arylzinc reagents to 3-arylpropenals catalyzed by a rhodium-binap complex in the presence of chlorotrimethylsilane

Article abstract of DOI:10.1016/j.tetasy.2006.01.036

Asymmetric 1,4-addition of arylzinc chlorides to (E)-3-arylpropenals proceeded with high enantioselectivity in the presence of a rhodium/(R)-binap catalyst and chlorotrimethylsilane to give, after hydrolysis, high yields of the corresponding 3,3-diarylpro

Full text of DOI:10.1016/j.tetasy.2006.01.036

Tetrahedron: Asymmetry 17 (2006) 607–613
Highly enantioselective 1,4-addition of arylzinc reagents
to 3-arylpropenals catalyzed by a rhodium–binap complex
in the presence of chlorotrimethylsilane
Norihito Tokunaga and Tamio Hayashi*
Department of Chemistry, Graduate School of Science, Kyoto University, Sakyo, Kyoto 606-8502, Japan
Received 15 December 2005; accepted 31 January 2006
Available online 28 February 2006
Abstract—Asymmetric 1,4-addition of arylzinc chlorides to (E)-3-arylpropenals proceeded with high enantioselectivity in the pres-
ence of a rhodium/(R)-binap catalyst and chlorotrimethylsilane to give, after hydrolysis, high yields of the corresponding 3,3-diaryl-
propanals of 98–99% ee. The presence of the chlorosilane is essential for high yields of the 1,4-addition products.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
2. Results and discussion
Catalytic asymmetric 1,4-addition of organometallic
reagents to electron-deficient olefins is a powerful tool
for asymmetric carbon–carbon bond formation.1
Among the olefins activated by electron-withdrawing
groups, a,b-unsaturated aldehydes are one of the most
challenging substrates, because the aldehyde carbonyls
are so reactive that undesired 1,2-addition takes place.
In the rhodium-catalyzed asymmetric 1,4-addition,
which has been growing very rapidly,2,3 aryl- and
alkenylboronic acids have been widely used for various
types of electron-deficient olefins, but the reaction sys-
tems, which realize both high chemoselectivity and
enantioselectivity in the asymmetric addition of boronic
acids to a,b-unsaturated aldehydes have not been
reported,4,5 until very recently. One solution to this
problem is to use chiral diene ligands for the rhodium-
catalyzed 1,4-addition of arylboronic acids,6–8 where
exclusive 1,4-addition was observed although the enantio-
selectivity was not always high (around 90% ee). Here-
in, we report another approach to the asymmetric 1,4-
addition to a,b-unsaturated aldehydes. High enantio-
selectivity of not lower than 98% ee was realized by
use of arylzinc reagents and chlorotrimethylsilane in
the rhodium-catalyzed asymmetric 1,4-addition to 3-
arylpropenals.
Several phenyl-metal reagents were examined for the
asymmetric addition to (E)-3-(4-methoxyphenyl)pro-
penal 1a in the presence of a rhodium catalyst coordi-
nated with (R)-binap. The best result was obtained
with PhZnCl in the presence of ClSiMe3 (Scheme 1).
Thus, to a solution of 1a, ClSiMe3 (1.3 equiv to 1a),
and [RhCl((R)-binap)]2 (3 mol % Rh) in THF was added
PhZnCl (1.1 equiv to 1a), which was generated from
PhLi and ZnCl2, and the mixture stirred at 20 °C for
1 h. Volatile materials were removed under reduced
pressure, and then the mixture hydrolyzed by addition
of a solution of potassium carbonate in methanol and
water. Silica gel chromatography gave 80% yield of
1,4-addition product, (S)-3-(4-methoxyphenyl)-3-phen-
ylpropanal 2a together with 17% yield of 1,2-addition
product, (E)-3-(4-methoxyphenyl)-1-phenyl-2-propenol
3a (Table 1, entry 1). NMR analysis of the reaction mix-
ture before hydrolysis showed that the primary 1,4-addi-
tion product is silyl enol ether 4a, consisting of Z- and
E-isomers in a ratio of 7:1. The enantiomeric purity of
2a was determined to be 99% ee by HPLC analysis of
3-(4-methoxyphenyl)-3-phenyl-1-propanol, which was
obtained by reduction with NaBH4. The reaction in
the absence of ClSiMe39 did not provide the 1,4-addition
product 2a, starting enal 1a being recovered in a high
yield (entry 2). The high performance of the zinc reagent
in combination with ClSiMe3 has been observed in the
asymmetric 1,4-addition to 4-quinolones10 and 1,6-addi-
tion to dienones.11 Other phenyl-metal reagents, which
*
Corresponding author. Tel.: +81 75 753 3983; fax: +81 75 753
3988; e-mail: thayashi@kuchem.kyoto-u.ac.jp
0957-4166/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2006.01.036

608
N. Tokunaga, T. Hayashi / Tetrahedron: Asymmetry 17 (2006) 607–613
13
MeO
ClSiMe3 were not suitable for the present substrate
PhZnCl
(1.1 equiv)
[RhCl((R)-binap)]2
(3 mol % Rh)
1a. Selective 1,2-addition giving allylic alcohol 3a was
observed with PhTi(Oi-Pr)3 (entry 4), and PhTi(Oi-
Pr)4Li/ClSiMe3 gave a low yield (9%) of 1,4-addition
product 2a in addition to 28% yield of 3a (entry 5).
+
H
THF
20 ˚C, 1 h
ClSiMe3
(1.3 equiv)
1a
O
MeO
MeO
Table 2 illustrates the scope of the present asymmetric
1,4-addition to a,b-unsaturated aldehydes containing
aryl substituents at b-position. In general, the 1,4-addi-
tion proceeded with very high enantioselectivity (98–
99% ee) via the use of a combination of arylzinc reagents
(1.1 equiv) and ClSiMe3 (1.3 equiv), although the yields
of 1,4-addition products 2 are not always high (55–80%
yield) due to competitive 1,2-addition giving allylic alco-
hols. The enantioselectivity was high for the addition of
PhZnCl to cinnamaldehydes substituted on the phenyl
group at the b-position (entries 1–4) and in the addition
of substituted arylzinc reagents to unsubstituted cinna-
maldehyde (entries 5–10). Various aryl groups possess-
ing both electron-donating and -withdrawing groups
were introduced in a 1,4-fashion into cinnamaldehyde
with high enantioselectivity to give 3,3-diaryl-substi-
tuted propanals of 98–99% ee. Both enantiomers can
be obtained with a single enantiomer of the binap ligand
by varying the zinc reagent and cinnamaldehyde (entries
1 and 5). It should be noted that the aryl moieties with
electron-withdrawing groups can be used for this asym-
metric 1,4-addition process, because their introduction
is difficult in the amine-catalyzed reactions.14
K2CO3
H
MeOH/H2O
rt, 1 h
Ph
O
Ph OSiMe3
2a
80% yield, 99% ee
(Z)-4a
MeO
MeO
OSiMe3
Ph
OH
Ph
(E)-4a
3a
17% yield, 36% ee
(Z)-4a/(E)-4a = 7/1
PPh2
PPh2
(R)-binap
Scheme 1.
have successfully been used for the rhodium-catalyzed
asymmetric 1,4-addition to some other electron-deficient
olefins,2 were much less reactive or selective for the pres-
ent 1,4-addition to a,b-unsaturated aldehydes. The reac-
tion conditions and results obtained are included in
Table 1. Phenylboronic acid, which is a standard phen-
yl-metal reagent for the rhodium-catalyzed 1,4-addi-
tion,2 was not reactive towards enal 1a resulting in a
low yield of the 1,4-addition product 2a. Thus, the reac-
tion of PhB(OH)2 catalyzed by a rhodium–binap com-
plex at 50 °C for 3 h only gave 19% yield of 2a (90%
The stereochemical outcome of the 1,4-addition reaction
catalyzed by Rh/(R)-binap can be rationalized by the
asi face attack of the enal to avoid a steric repulsion
between the phenyl group on the phosphorous atom of
(R)-binap and the carbonyl group of the enal (Fig. 1).3b
The role of chlorotrimethylsilane in the present asym-
metric 1,4-addition remains to be clarified. It is likely
that the chlorosilane activates the enone as a Lewis acid
to facilitate the insertion step.
ee), 67% of enal 1a being recovered (entry 3). Titanium
12
reagents, either PhTi(Oi-Pr)3
or PhTi(Oi-Pr)4Li/
Table 1. Rhodium-catalyzed asymmetric 1,4-addition to enal 1aa
Entry
[Ph–M] (equiv)
Conditionsb
Yield (%) of 2ac
ee (%) of 2ad
99 (S)
1
2
3
4
5
PhZnCle/ClSiMe3 (1.1/1.3)
PhZnCle (1.1)
PhB(OH)2 (5.0)
PhTi(Oi-Pr)3 (1.1)
A
B
C
D
E
80f
0g
19h
0i
90 (S)
82 (S)
PhTi(Oi-Pr)4Li/ClSiMe3 (1.1/1.3)
9j
a The reaction was carried out with 0.20 mmol of 1a in the presence of 3 mol % of the rhodium catalyst.
b Condition A: [RhCl((R)-binap)]2, THF, 20 °C, 1 h; then hydrolysis with K2CO3 in MeOH/H2O. Condition B: [RhCl((R)-binap)]2, THF, 20 °C, 1 h;
then hydrolysis with H2O. Condition C: [RhCl(C2H4)]2/(R)-binap, KOH (10 mol %), MeOH/THF/H2O (12/3/2), 50 °C, 3 h. Condition D:
[Rh(OH)((R)-binap)]2, THF, 20 °C, 1 h; then hydrolysis with H2O. Condition E: [RhCl((R)-binap)]2, THF, 20 °C, 1 h; then hydrolysis with K2CO3
in MeOH/H2O.
c Isolated yields by column chromatography on silica gel (hexane/Et2O = 8/1–4/1).
d Determined by HPLC analysis with a chiral stationary phase column (Chiralpak AD-H: hexane/2-propanol = 90/10) after reduction into 3-(4-
methoxyphenyl)-3-phenyl-1-propanol. The absolute configuration (S) was determined by comparison of its specific rotation with that of authentic
sample (Ref. 7).
e Generated from PhLi and ZnCl2.
f A 1,2-addition product 3a was formed in 17% yield with 36% ee.
g Enal 1a was recovered (63%).
h Enal 1a was recovered (67%).
i A 1,2-addition product 3a was formed in 70% yield with 0% ee, and enal 1a was recovered (6%).
j A 1,2-addition product 3a was formed in 28% yield with 0% ee, and enal 1a was recovered (31%).

N. Tokunaga, T. Hayashi / Tetrahedron: Asymmetry 17 (2006) 607–613
Table 2. Rhodium-catalyzed asymmetric 1,4-addition to enal 1a
609
[RhCl((R)-binap)]2
(3 mol % Rh)
Ar2ZnCl
ClSiMe3
Ar1
H
Ar1
H
K2CO3
+
PPh2
PPh2
THF
20 ˚C, 1 h
MeOH/H2O
rt, 1 h
O
Ar2
O
1
2
(R)-binap
OMe
MeO
OMe
H
F
H
H
O
H
O
Me
O
O
(S)-2a
(S)-2b
(S)-2c
(S)-2d
H
H
H
H
H
H
O
O
O
O
O
O
(R)-2e
(R)-2f
(R)-2g
(R)-2h
(R)-2i
(R)-2j
Cl
Me
Me
OMe
Cl
OMe
Entry
Ar1 on substrate
Ar2 on Zn
Yield (%) of 2b
eec (%) of 2d
1e
2e
3e
4e
5f
4-MeOC6H4
2-MeOC6H4
2-MeO-5-MeC6H3
4-FC6H4
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
4-MeOC6H4
3-MeOC6H4
3,5-Me2C6H3
2-Naphthyl
4-ClC6H4
80 2a
74 2b
66 2c
80 2d
55 2e
75 2f
68 2g
75 2h
79 2i
79 2j
99 (S)
99 (S)
99 (S)
98 (S)
99 (R)
99 (R)
99 (R)
99 (R)
99 (R)
98 (R)
6f
7f
8f
9f
10f
C6H5
3-ClC6H4
a The reaction conditions: 1 (0.20 mmol), [RhCl((R)-binap)]2 (3 mol % Rh), THF, 20 °C, 1 h; then hydrolysis with K2CO3 in MeOH/H2O.
b Isolated yields by column chromatography on silica gel (hexane/Et2O).
c Determined by HPLC analysis with a chiral stationary phase column Chiralpak AD-H (2a, 2b, 2e, 2f, 2h, 2i), Chiralpak AS (2c, 2d, 2g), Chiralcel
OD-H (2j) after reduction into the corresponding 3,3-diaryl-1-propanol.
d The absolute configuration was assigned by analogy with (S)-2a.
e Reaction with 0.22 mmol of ArZnCl and 0.26 mmol of ClSiMe3.
f Reaction with 0.44 mmol of ArZnCl and 0.52 mmol of ClSiMe3.
zinc reagents and chlorotrimethylsilane. The asymmetric
addition proceeded with high enantioselectivity to give
1,3-diarylpropanals of 98–99% ee, some of which are
key intermediates to pharmaceutically interesting
compounds.15
Ar1
Rh
Ar1
insertion
P
P
P
P
Rh
Ar2
Ar2
O
O
H
H
H
H
α si face [(R)-binap]
4. Experimental
4.1. General
Ar1
H
Ar2
O
All anaerobic and moisture-sensitive manipulations
were carried out with standard Schlenk techniques
under predried nitrogen or glovebox techniques under
prepurified argon. NMR spectra were recorded on a
JEOL JNM LA-500 spectrometer (500 MHz for 1H,
and 125 MHz for 13C). Chemical shifts are reported in
Figure 1. The stereochemical pathway in the rhodium-catalyzed
asymmetric 1,4-addition.
3. Conclusions
1
d ppm referenced to an internal SiMe4 standard for H
NMR and chloroform-d (d 77.05) for 13C NMR. Optical
We have demonstrated that the asymmetric 1,4-aryla-
tion of 3-arylpropenals can be efficiently catalyzed by
a rhodium–binap complex by the combination of aryl-
rotations were measured on
a JASCO DIP-370
polarimeter.

610
N. Tokunaga, T. Hayashi / Tetrahedron: Asymmetry 17 (2006) 607–613
4.2. Materials
tered and washed with Et2O. The filtrate was washed
with 5% NaOH aq, and the organic layer was dried over
MgSO4. Evaporation of the solvent followed by silica gel
column chromatography (hexane/Et2O = 2/1) gave 61%
yield (0.67 g, 3.8 mmol) of (E)-3-(2-methoxy-5-methyl-
phenyl)propenal as pale yellow oil.
THF, Et2O, dioxane, and benzene were distilled from
benzophenone-ketyl under nitrogen prior to use. MeOH
was distilled from Mg under nitrogen prior to use. DMF
was distilled from CaH2 under nitrogen prior to use.
[RhCl(C2H4)2]2,16 [RhCl((S)-binap)]2,3b ArZnCl,9 PhTi-
(OPr-i)3,12 PhTi(OPr-i)4Li,13 were prepared according to
the reported procedures.
1H NMR (CDCl3): d 2.31 (s, 3H), 3.89 (s, 3H), 6.78 (dd,
J = 16.0, 7.9 Hz, 1H), 6.85 (d, J = 8.4 Hz, 1H), 7.21 (d,
J = 8.4 Hz, 1H), 7.35 (s, 1H), 7.81 (d, J = 16.0 Hz, 1H),
9.68 (d, J = 7.9 Hz, 1H). 13C{1H} NMR (CDCl3): d
20.42, 55.71, 111.32, 122.71, 128.97, 129.26, 130.14,
133.31, 148.37, 156.44, 194.61. Anal. Calcd for
C11H12O2: C, 74.98; H, 6.86. Found: C, 74.90; H, 6.90.
4.3. Synthesis of (E)-3-(2-methoxy-5-methylphenyl)-
propenal from 2-bromo-1-methoxy-4-methylbenzene
4.3.1. (E)-3-(2-Methoxy-5-methylphenyl)propenoic acid
from 2-bromo-1-methoxy-4-methylbenzene. To Mg
(0.38 g, 16 mg atom, dried by heat gun under vacuum)
in THF (10 mL) was added dibromoethane (ca.
100 lL) as an activator. To the mixture was added drop-
wise at 0 °C, a solution of 2-bromo-1-methoxy-4-meth-
ylbenzene (2.0 mL, 14 mmol) in THF (10 mL). After
3.5 h stirring at room temperature, DMF (1.7 mL,
21 mmol) was added. This was stirred at room tempera-
ture for 14 h, before the mixture was quenched with 10%
HCl aq and extracted with Et2O. The combined organic
layers were dried over MgSO4 and concentrated under
reduced pressure to give 2-methoxy-5-methyl-
benzaldehyde. The crude product was used for the next
reaction without further purification (>95% pure, a
quantitative yield).
4.4. Rhodium-catalyzed asymmetric 1,4-addition of
PhZnCl to (4-methoxyphenyl)propenal 1a in the
presence of chlorotrimethylsilane
To a solution of enal 1a (32.4 mg, 0.20 mmol), [RhCl-
((R)-binap)]2 (4.6 mg, 0.0030 mmol, 3 mol % Rh), and
ClSiMe3 (33 lL, 0.26 mmol) in THF (0.50 mL) was
added PhZnCl (0.44 mL, 0.22 mmol; 0.50 M in THF
solution), and the mixture stirred at 20 °C for 1 h. Vol-
1
atile materials were removed by evaporation, and H
NMR measurement of the residue indicated the forma-
tion of silyl enol ethers (Z)-4a and (E)-4a ((Z)-4a/(E)-
4a = 7/1) as 1,4-addition products.
4.4.1. (R)-(Z)-3-(4-Methoxyphenyl)-3-phenyl-1-trimeth-
ylsilyloxy-1-propene (Z)-4a. 1H NMR (CDCl3): d
0.15 (s, 9H), 3.77 (s, 3H), 5.01 (dd, J = 9.6, 5.8 Hz,
1H), 5.22 (d, J = 9.6 Hz, 1H), 6.30 (d, J = 5.8 Hz, 1H),
6.81 (d, J = 8.7 Hz, 2H), 7.12 (d, J = 8.7 Hz, 2H),
7.13–7.28 (m, 5H).
A mixture of 2-methoxy-5-methylbenzaldehyde (ca.
14 mmol, a crude compound), malonic acid (2.89 g,
28 mmol), pyridine (5.4 mL, 67 mmol), and piperidine
(0.21 mL, 2.0 mmol) was stirred at room temperature
for 1 h and then at 160 °C for 3 h. After cooling to room
temperature, 20% NaOH aq was added to the solution
until pH 14. The mixture was washed with Et2O, and
the water layer was acidified with concd HCl until
pH 1. The resulting water layer was extracted with
Et2O and the combined organic layers were dried over
MgSO4. Evaporation of the solvent gave 86% yield in
two steps (2.37 mg, 12 mmol) of (E)-3-(2-methoxy-5-
methylphenyl)propenoic acid as pale yellow solid.
4.4.2. (R)-(E)-3-(4-Methoxyphenyl)-3-phenyl-1-trimeth-
ylsilyloxy-1-propene (E)-4a. 1H NMR (CDCl3): d 0.17
(s, 9H), 3.77 (s, 3H), 4.56 (d, J = 8.6 Hz, 1H), 5.48
(dd, J = 12.0, 8.6 Hz, 1H), 6.19 (d, J = 12.0 Hz, 1H),
6.81 (d, J = 8.7 Hz, 2H), 7.12 (d, J = 8.7 Hz, 2H),
7.13–7.28 (m, 5H).
1
[CAS: 103986-76-1]: H NMR (CDCl3): d 2.29 (s, 3H),
4.4.3. Hydrolysis of the silyl enol ethers 4. To the resi-
due obtained above, which contained the silyl enol
ethers 4 were added K2CO3 (276 mg, 2.0 mmol), MeOH
(1.0 mL), and H2O (0.70 mL). After 1 h stirring at 20 °C,
the mixture was extracted with Et2O three times, and the
combined organic layers dried over MgSO4. Evapora-
tion of the solvent followed by silica gel column chroma-
tography (hexane/Et2O = 8/1–4/1) gave 80% yield
(38.4 mg, 0.160 mmol) of 2a as a 1,4-addition product
and 17% yield (8.2 mg, 0.034 mmol) of 3a as a 1,2-addi-
tion product. The enantiomeric excess of 2a was 99% ee,
which was determined by HPLC analysis with a chiral
stationary column (Chiralpak AD-H, hexane/2-propan-
ol = 90/10) after reduction into (S)-3-(4-methoxyphen-
yl)-3-phenyl-1-propanol (with NaBH4 in CH2Cl2 and
EtOH).
3.85 (s, 3H), 6.53 (d, J = 16.0 Hz, 1H), 6.81 (d,
J = 8.4 Hz, 1H), 7.16 (d, J = 8.4 Hz, 1H), 7.32 (s, 1H),
8.07 (d, J = 16.0 Hz, 1H), 11.20 (br s, 1H).
4.3.2. (E)-3-(2-Methoxy-5-methylphenyl)propenal from
(E)-3-(2-methoxy-5-methylphenyl)propenoic
acid.
A
solution of (E)-3-(2-methoxy-5-methylphenyl)propenoic
acid (1.20 g, 6.3 mmol) and SOCl2 (0.64 mL, 8.7 mmol)
in benzene (10 mL) was stirred at 120 °C for 10 h. Evap-
oration of the solvent gave the corresponding acyl chlo-
ride, which was used immediately for the next reduction
step without further purification.
To a solution of the acyl chloride in THF (20 mL) was
added dropwise a solution of LiAlH(OBu-t)3 (1.59 g,
6.3 mmol) in THF (10 mL) at ꢀ78 °C. The mixture was
stirred at the same temperature for 0.5 h and warmed
to room temperature over a period of 1 h. After addition
of crushed ice (ca. 30 g), the precipitates formed were fil-
4.4.4. (S)-3-(4-Methoxyphenyl)-3-phenylpropanal 2a.
[CAS:92804-32-5]: 80% Yield (colorless oil; column
20
eluent: hexane/Et2O = 8/1–4/1). ½aꢁD ¼ þ4:4 (c 0.77,

N. Tokunaga, T. Hayashi / Tetrahedron: Asymmetry 17 (2006) 607–613
611
20
CHCl3) for (S) isomer of 99% ee {lit.7 ½aꢁD ¼ ꢀ3:1 (c
0.88, CHCl3) for (R) isomer of 90% ee}. 1H NMR
(CDCl3): d 3.11 (dd, J = 7.7, 1.9 Hz, 2H), 3.75 (s, 3H),
4.56 (t, J = 7.7 Hz, 1H), 6.82 (d, J = 8.6 Hz, 2H), 7.13
(d, J = 8.6 Hz, 2H), 7.16–7.22 (m, 3H), 7.28 (t,
J = 7.7 Hz, 2H), 9.71 (t, J = 1.9 Hz, 1H). 13C{1H}
NMR (CDCl3): d 44.23, 49.58, 55.23, 114.12, 126.61,
127.63, 128.70, 135.31, 143.62, 158.31, 201.19. The ee
of 3-(4-methoxyphenyl)-3-phenyl-1-propanol was 99%
ee (Chiralpak AD-H, hexane/2-propanol = 90/10, flow =
1.0 mL/min, wavelength = 224 nm. Retention times:
12.7 min [(R)-enantiomer], 14.3 min [(S)-enantiomer]).
times: 23.0 min [(S)-enantiomer], 26.5 min [(R)-enan-
tiomer]).
4.5.2. (S)-3-(2-Methoxy-5-methylphenyl)-3-phenylprop-
anal 2c. [CAS:857288-55-2]: 66% Yield (colorless oil;
20
column eluent: hexane/Et2O = 16/1–8/1). ½aꢁD ¼ ꢀ16:2
(c 1.4, CHCl3) for (S)-isomer of 99% ee. 1H
NMR (CDCl3): d 2.22 (s, 3H), 3.08 (dd, J = 7.9,
2.3 Hz, 2H), 3.76 (s, 3H), 4.99 (t, J = 7.9 Hz, 1H), 6.74
(d, J = 8.3 Hz, 1H), 6.86 (d, J = 1.9 Hz, 1H), 6.97 (dd,
J = 8.3, 1.9 Hz, 1H), 7.18 (tt, J = 8.5, 1.8 Hz, 1H),
7.22–7.30 (m, 4H), 9.69 (t, J = 2.3 Hz, 1H). 13C{1H}
NMR (CDCl3): d 20.68, 38.33, 48.50, 55.56, 110.87,
126.39, 128.02, 128.10, 128.47, 128.87, 129.88, 131.37,
142.99, 156.62, 201.95. The ee of 3-(2-methoxy-5-meth-
ylphenyl)-3-phenyl-1-propanol was 99% ee (Chiralpak
AS, hexane/2-propanol = 90/10, flow = 0.5 mL/min,
wavelength = 224 nm. Retention times: 14.1 min [(S)-
enantiomer], 18.2 min [(R)-enantiomer]).
4.4.5. (E)-3-(4-Methoxyphenyl)-1-phenylprop-2-en-1-ol
3a. [CAS:3906-07-8]: 17% Yield (colorless oil; column
eluent: hexane/Et2O = 8/1–4/1), 36% ee. The ee was
determined on a Chiralcel OD-H, hexane/2-propa-
nol = 80/20, flow = 0.5 mL/min, wavelength = 224 nm.
Retention times: 18.8 min [minor enantiomer],
20
20.8 min [major enantiomer]. ½aꢁD ¼ ꢀ7:7 (c 0.25,
1
CHCl3) for 36% ee. H NMR (CDCl3): d 2.18 (s, 1H),
4.5.3.
(S)-3-(4-Fluorophenyl)-3-phenylpropanal
2d.
3.78 (s, 3H), 5.33 (d, J = 6.7 Hz, 1H), 6.23 (dd,
J = 15.7, 6.7 Hz, 1H), 6.60 (d, J = 15.7 Hz, 1H), 6.83
(d, J = 8.8 Hz, 2H), 7.28 (t, J = 7.3 Hz, 1H), 7.31 (d,
J = 8.8 Hz, 2H), 7.35 (t, J = 7.3 Hz, 2H), 7.41 (d,
J = 7.3 Hz, 2H). 13C{1H} NMR (CDCl3): d 55.29,
75.28, 114.01, 126.32, 127.69, 127.83, 128.58, 129.31,
129.45, 130.25, 143.04, 159.39.
[CAS:86397-22-3]: 80% Yield (colorless oil; column elu-
20
ent: hexane/Et2O = 16/1–8/1). ½aꢁD ¼ þ3:3 (c 1.8,
1
CHCl3) for (S) isomer of 98% ee. H NMR (CDCl3): d
3.13 (ddd, J = 17.1, 7.9, 1.8 Hz, 1H), 3.17 (ddd,
J = 17.1, 7.7, 1.8 Hz, 1H), 4.61 (t, J = 7.7 Hz, 1H),
6.97 (t, J = 8.6 Hz, 2H), 7.16–7.23 (m, 5H), 7.30 (t,
J = 7.8 Hz, 2H), 9.73 (t, J = 1.8 Hz, 1H). 13C{1H}
NMR (CDCl3): d 44.16, 49.53, 115.52 (d, J = 21 Hz),
126.82, 127.60, 128.80, 129.19 (d, J = 7.8 Hz), 139.01,
143.03, 161.56 (d, J = 245 Hz), 200.58. The ee of 3-(4-
fluorophenyl)-3-phenyl-1-propanol was 98% ee (Chir-
alpak AS, hexane/2-propanol = 90/10, flow = 0.5 mL/
min, wavelength = 224 nm. Retention times: 16.9 min
[(S)-enantiomer], 19.1 min [(R)-enantiomer]).
4.5. General procedure for Table 2
The reaction conditions and results are summarized in
Table 2. To
a solution of enal 1 (0.20 mmol),
[RhCl((R)-binap)]2 (4.6 mg, 0.0030 mmol, 3 mol %
Rh), and ClSiMe3 (33 lL, 0.26 mmol) in THF
(0.50 mL) was added ArZnCl (0.22 mmol; THF solu-
tion), and the mixture was stirred at 20 °C for 1 h. To
the reaction solution were added K2CO3 (276 mg,
2.0 mmol), MeOH (1.0 mL), and H2O (0.70 mL). After
1 h stirring at 20 °C, the mixture was extracted with
Et2O three times. The combined organic layers were
dried over MgSO4 and concentrated under reduced pres-
sure. The residue was chromatographed on silica gel
(hexane/Et2O) to give the 1,4-addition product. Enan-
tiomeric excess of the product was determined by HPLC
analysis with a chiral stationary column after reduction
into the corresponding alcohol (with NaBH4 in CH2Cl2
and EtOH).
4.5.4. (R)-3-(4-Methoxyphenyl)-3-phenylpropanal 2e.
[CAS:92804-32-5]: the enantiomer of 2a. 55% yield
20
(colorless oil). ½aꢁD ¼ ꢀ4:2 (c 0.80, CHCl3) for (R)-iso-
mer of 99% ee. The ee of 3-(4-methoxyphenyl)-3-phe-
nyl-1-propanol was 99% ee.
4.5.5. (R)-3-(3-Methoxyphenyl)-3-phenylpropanal 2f.
Yield 75% (colorless oil; column eluent: hexane/
20
Et2O = 8/1–4/1). ½aꢁD ¼ ꢀ0:5 (c 1.9, CHCl3) for (R)
1
isomer of 99% ee. H NMR (CDCl3): d 3.13 (ddd, J =
17.3, 7.8, 1.9 Hz, 1H), 3.15 (ddd, J = 17.3, 7.7, 1.9 Hz,
1H), 3.75 (s, 3H), 4.58 (t, J = 7.8 Hz, 1H), 6.73 (dd,
J = 8.2, 2.5 Hz, 1H), 6.77 (t, J = 1.8 Hz, 1H), 6.82 (dt,
J = 7.7, 1.0 Hz, 1H), 7.16–7.24 (m, 4H), 7.28 (t,
J = 7.2 Hz, 2H), 9.72 (t, J = 1.9 Hz, 1H). 13C{1H}
NMR (CDCl3): d 44.99, 49.32, 55.15, 111.60, 114.03,
120.06, 126.73, 127.69, 128.73, 129.72, 143.07, 144.84,
159.83, 200.96. Anal. Calcd for C16H16O2: C, 79.97; H,
6.71. Found: C, 79.69; H, 6.85. The ee of 3-(2-methoxy-
phenyl)-3-phenyl-1-propanol was 99% ee (Chiralpak
AD-H, hexane/2-propanol = 90/10, flow = 0.5 mL/
min, wavelength = 224 nm. Retention times: 35.7 min
[(R)-enantiomer], 38.9 min [(S)-enantiomer]).
4.5.1. (S)-3-(2-Methoxyphenyl)-3-phenylpropanal 2b.
[CAS:92804-31-4]: 74% Yield (colorless oil; column
20
eluent: hexane/Et2O = 8/1–4/1). ½aꢁD ¼ ꢀ54:3 (c
1.4, CHCl3) for (S) isomer of 99% ee. 1H NMR
(CDCl3): d 3.09 (dd, J = 7.9, 2.3 Hz, 2H), 3.79 (s, 3H),
5.02 (t, J = 7.9 Hz, 1H), 6.85 (d, J = 8.2 Hz, 1H), 6.88
(td, J = 7.5, 1.0 Hz, 1H), 7.07 (dd, J = 7.5, 1.6 Hz,
1H), 7.15–7.21 (m, 2H), 7.23–7.29 (m, 4H), 9.69 (t,
J = 2.3 Hz, 1H). 13C{1H} NMR (CDCl3): d 38.28,
48.45, 55.36, 110.79, 120.69, 126.41, 127.81, 128.04,
128.10, 128.45, 131.61, 142.85, 156.63, 201.78. The ee
of 3-(2-methoxyphenyl)-3-phenyl-1-propanol was 99%
ee (Chiralpak AD-H, hexane/2-propanol = 90/10,
flow = 0.5 mL/min, wavelength = 224 nm. Retention
4.5.6. (R)-3-(3,5-Dimethylphenyl)-3-phenylpropanal 2g.
Yield 68% (colorless oil; column eluent: hexane/
20
Et2O = 16/1–8/1). ½aꢁD ¼ ꢀ6:2 (c 1.6, CHCl3) for (R)

612
N. Tokunaga, T. Hayashi / Tetrahedron: Asymmetry 17 (2006) 607–613
isomer of 99% ee. 1H NMR (CDCl3): d 2.26 (s, 6H), 3.10
(ddd, J = 18.4, 8.3, 1.8 Hz, 1H), 3.12 (ddd, J = 18.4, 7.7,
1.8 Hz, 1H), 4.52 (t, J = 7.8 Hz, 1H), 6.83 (s, 3H), 7.18
(t, J = 7.3 Hz, 1H), 7.22 (d, J = 7.3 Hz, 2H), 7.28 (t,
J = 7.3 Hz, 2H), 9.70 (t, J = 1.8 Hz, 1H). 13C{1H}
NMR (CDCl3): d 21.37, 44.99, 49.39, 125.55, 126.60,
127.70, 128.42, 128.70, 138.21, 143.07, 143.46, 201.29.
Anal. Calcd for C17H18O: C, 85.67; H, 7.61. Found:
C, 85.94; H, 7.90. The ee of 3-(2,6-dimethylphenyl)-3-
phenyl-1-propanol was 99% ee (Chiralpak AS, hexane/
2-propanol = 90/10, flow = 0.3 mL/min, wavelength =
224 nm. Retention times: 19.5 min [(R)-enantiomer],
21.2 min [(S)-enantiomer]).
Acknowledgements
This work was partially supported by a Grant-in-Aid for
Scientific Research, the Ministry of Education, Japan.
N.T. thanks the Japan Society for the Promotion of
Science, for the award of a fellowship for graduate
students.
References
1. For recent reviews on catalytic asymmetric 1,4-additions,
see: (a) Krause, N.; Hoffmann-Roder, A. Synthesis 2001,
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Wiley-VCH: Weinheim, 2005, Chapter 3, p 55.
4.5.7. (R)-3-(2-Naphthyl)-3-phenylpropanal 2h. Yield
75% (white solid; column eluent: hexane/Et2O = 8/1–
20
4/1). ½aꢁD ¼ ꢀ36:9 (c 2.0, CHCl3) for (R) isomer of
99% ee. 1H NMR (CDCl3): d 3.24 (ddd, J = 17.0, 7.8,
1.8 Hz, 1H), 3.27 (ddd, J = 17.0, 7.8, 1.8 Hz, 1H), 4.78
(t, J = 7.8 Hz, 1H), 7.18 (tt, J = 6.8, 1.6 Hz, 1H), 7.23–
7.34 (m, 5H), 7.44 (quintd, J = 6.8, 1.0 Hz, 2H), 7.68
(s, 1H), 7.73–7.81 (m, 3H), 9.77 (t, J = 1.8 Hz, 1H).
13C{1H} NMR (CDCl3):
d 45.05, 49.25, 125.80,
125.82, 126.25, 126.44, 126.78, 127.61, 127.79, 127.87,
128.54, 128.77, 132.31, 133.46, 140.61, 143.09, 200.93.
Anal. Calcd for C19H16O: C, 87.66; H, 6.19. Found:
C, 87.93; H, 6.46. The ee of 3-(2-naphthyl)-3-phenyl-1-
propanol was 99% ee (Chiralpak AD-H, hexane/2-
propanol = 90/10, flow = 0.3 mL/min, wavelength =
224 nm. Retention times: 39.8 min [(R)-enantiomer],
43.1 min [(S)-enantiomer]).
3. (a) Takaya, Y.; Ogasawara, M.; Hayashi, T.; Sakai, M.;
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Hayashi, T.; Takahashi, M.; Takaya, Y.; Ogasawara, M.
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4.5.8.
(R)-3-(4-Chlorophenyl)-3-phenylpropanal
2i.
4. As a reference containing the results obtained for the
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5. As a reference reporting the palladium-catalyzed asym-
metric 1,4-addition to enals: Nishikata, T.; Yamamoto,
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[CAS:13243-64-6]: 79% Yield (white solid; column
20
eluent: hexane/Et2O = 16/1–8/1). ½aꢁD ¼ ꢀ5:7 (c 2.0,
1
CHCl3) for (R) isomer of 99% ee. H NMR (CDCl3):
d 3.13 (ddd, J = 17.2, 8.1, 1.7 Hz, 1H), 3.15 (ddd,
J = 17.2, 7.6, 1.7 Hz, 1H), 4.59 (t, J = 7.7 Hz, 1H),
7.15 (d, J = 8.5 Hz, 2H), 7.17–7.23 (m, 3H), 7.25 (d,
J = 8.5 Hz, 2H), 7.29 (t, J = 7.2 Hz, 2H), 9.72 (t,
J = 1.7 Hz, 1H). 13C{1H} NMR (CDCl3): d 44.26,
49.34, 126.92, 127.65, 128.86, 129.11, 132.51, 141.82,
142.75, 200.41. The ee of 3-(4-chlorophenyl)-3-phenyl-
1-propanol was 99% ee (Chiralpak AD-H, hexane/2-
propanol = 90/10, flow = 0.5 mL/min, wavelength =
224 nm. Retention times: 18.1 min [(R)-enantiomer],
19.2 min [(S)-enantiomer]).
4.5.9. (R)-3-(3-Chlorophenyl)-3-phenylpropanal 2j. Yield
79% (yellow oil; column eluent: hexane/Et2O = 16/1–8/
20
1). ½aꢁD ¼ ꢀ4:9 (c 1.6, CHCl3) for (R) isomer of
1
98% ee. H NMR (CDCl3): d 3.14 (ddd, J = 17.4, 7.7,
1.6 Hz, 1H), 3.16 (ddd, J = 17.4, 7.6, 1.6 Hz, 1H), 4.59
(t, J = 7.7 Hz, 1H), 7.11 (d, J = 7.5 Hz, 1H), 7.15–7.27
(m, 6H), 7.30 (t, J = 7.8 Hz, 2H), 9.72 (t, J = 1.6 Hz,
1H). 13C{1H} NMR (CDCl3): d 44.56, 49.21, 125.97,
126.94, 127.00, 127.70, 127.91, 128.89, 129.99, 134.56,
142.46, 145.39, 200.41. Anal. Calcd for C15H13ClO: C,
73.62; H, 5.35. Found: C, 73.87; H, 5.62. The ee of 3-(3-
chlorophenyl)-3-phenyl-1-propanol was 98% ee (Chiralcel
OD-H, hexane/2-propanol = 90/10, flow = 0.5 mL/min,
wavelength = 224 nm. Retention times: 23.1 min [(R)-
enantiomer], 27.5 min [(S)-enantiomer]).
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