Highly active and enantioselective rhodium-catalyzed asymmetric 1,4-addition of arylboronic acid to α,β-unsaturated ketone by using electron-poor MeO-F12-BIPHEP

Article abstract of DOI:10.1002/adsc.201000339

The asymmetric 1,4-addition of phenylboronic acid to cyclohexenone were performed by using a low amount of rhodium/(R)-(6,6′-dimethoxybiphenyl-2, 2′-diyl)bis[bis(3,4,5-trifluorophenyl)phosphine] (MeO-F ₁₂-BIPHEP) catalyst. Because the catalyst

Full text of DOI:10.1002/adsc.201000339

FULL PAPERS
DOI: 10.1002/adsc.201000339
Highly Active and Enantioselective Rhodium-Catalyzed
Asymmetric 1,4-Addition of Arylboronic Acid to a,b-
Unsaturated Ketone by using Electron-Poor MeO-F -BIPHEP
1
2
a,
a
a
a,
Toshinobu Korenaga, * Ryota Maenishi, Keigo Hayashi, and Takashi Sakai *
a
Division of Chemistry and Biochemistry, Graduate School of Natural Science and Technology, Okayama University,
3-1-1 Tsushima-naka, Kita-ku, Okayama 700-8530, Japan
Fax : (+81)-86-251-8092; phone: (+81)-86-251-8092; e-mail: korenaga@cc.okayama-u.ac.jp
Received: May 2, 2010; Revised: October 8, 2010; Published online: December 7, 2010
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.201000339.
ꢀ
1
¼6
ꢀ1 ꢀ1
Abstract: The asymmetric 1,4-addition of phenylbor- 0.1 kcalmol
onic acid to cyclohexenone were performed by using indicating that the entropy contribution is relatively
low amount of rhodium/(R)-(6,6’-dimethoxy- small. Both the result and consideration of the tran-
biphenyl-2,2’-diyl)bis[bis(3,4,5-trifluorophenyl)phos- sition state in the insertion step at the B3LYP/6-
phine] (MeO-F -BIPHEP) catalyst. Because the cat- 31G(d) [LANL2DZ for rhodium] levels indicated
and DDS =ꢀ1.3ꢁ0.3 calmol K ),
a
A
C
H
T
U
N
G
T
R
E
N
N
U
N
G
ACHTUNGTRENNUNG
12
alyst shows thermal resistance at 1008C, up to that the less s-donating electron-poor (R)-MeO-F -
12
0.00025 mol% Rh catalyst showed good catalytic ac- BIPHEP could be creating a rigid chiral environ-
tivity. The highest turnover frequency (TOF) and ment around the rhodium catalyst even at high tem-
ꢀ
1
turnover number (TON) observed were 53,000 h
and 320,000, respectively. The enantioselectivities of
perature.
the products were maintained at a high level of 98% Keywords: asymmetric catalysis; density function
ee in these reactions. The Eyring plots gave the fol- theory (DFT) calculations; fluorinated ligands; phos-
¼6
lowing
kinetic
parameters
(DDH =ꢀ4.0ꢁ phane ligands; rhodium
Introduction
lysts, Hayashiꢀs chiral diene ligand shows outstanding
catalytic activity with a turnover frequency (TOF)
ꢀ
1
The catalytic asymmetric conjugate addition of organ- reaching 1,900 h at 308C for the asymmetric 1,4-ad-
ometallic reagents to a,b-unsaturated carbonyl com- dition of phenylboronic acid (1a) to cyclohexenone
pounds is an important method for the preparation of (2a).
[
3e]
However, the 1,4-addition product was not
chiral b-aryl-substituted carbonyl compounds. In par- formed when the catalyst loading was reduced to
ticular, the Rh-catalyzed asymmetric 1,4-addition re- 0.01 mol%. The reason for this unsuccessful result is
action of arylboron reagents has been studied inten- the small amount of phenol present in 1a, which was
[1]
sively. Recently, the kilogram scale Rh-catalyzed not removed by recrystallization, and therefore, led to
asymmetric 1,4-addition of arylboronic acid was re- the deactivation of the catalyst. Therefore, Hayashi
[2]
ported. Although 27 kg of substrate were used in et al. used 2,4,6-triphenylboroxin excluding the con-
the presence of 2 mol% Rh catalyst in that study, the taminant to give [3ea] n impressive result (TOF=
ꢀ
1
amount of Rh precursor ([RhCl ACHTUNGTERNNN(UG COD)] ) was equiva- 14,000 h at 308C). Because of its high catalytic ac-
2
lent to ca. 480 g. Using less rhodium is highly desira- tivity, the Rh/chiral diene catalyst system is one of the
ble because it is very expensive. If the catalyst loading best catalytic systems for Rh-catalyzed asymmetric
for the asymmetric catalysis is reduced to, for exam- 1,4-addition. However, use of the commercially avail-
ple, 0.01% or less, the asymmetric catalysis would in- able 1a without modification in a highly active cata-
crease in value. However, even though over one hun- lytic reaction would be more convenient for the Rh-
dred studies of the asymmetric catalytic reaction have catalyzed 1,4-addition. Recently, we reported that the
been reported, most of the chiral catalysts for the re- highly electron-poor chiral ligand (R)-MeO-F -
1
2
[
3f]
action require 1 to 3% Rh and those requiring 0.1% BIPHEP (3), an electronically unique chiral diphos-
Rh or less are scarce. Among the highly active cata- phane relative to the known chiral diphosphanes
[
3]
Adv. Synth. Catal. 2010, 352, 3247 – 3254
ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3247

Toshinobu Korenaga et al.
FULL PAPERS
this reaction, the complex is usually generated in situ
[
3f,5]
from [RhCl
A
H
U
G
R
N
N
(C H ) ] and diphosphane,
followed by
2
4
2 2
the conversion to [RhOH(diphosphane)] as the
2
[
6]
active (or resting) species with base and H O. If the
2
[
RhCl{(R)-3}] complex can be stored as a pre-catalyst
2
and used directly for the catalysis, handling in the ex-
periment will be facilitated. Therefore, we checked
the air stability of the [RhCl{(R)-3}] complex. Un-
2
fortunately, [RhCl{(R)-3}] was very air-sensitive and
2
decomposed readily even after careful weighing.
When the solid state of [RhCl{(R)-3}] was allowed to
2
stand in the air for 2 min, diphosphane dioxide (R)-5
3
1
was observed by P NMR in toluene-d (Figure 2).
8
The dioxide (R)-5 would be generated via oxidation
of Rh. This result is unexpected because electron-
poor (R)-3 and its ligated metal should be resistant to
Figure 1. Electronic properties of BINAP-type chiral ligands
by measurement of carbonyl stretching frequencies of
[
7]
[RhCl(diphosphane)(CO)] complexes.
air oxidation. Interestingly, [RhCl{(R)-BINAP}] is air
2
stable, although (R)-BINAP is a more electron-donat-
ing diphosphane than (R)-3. When these crystal struc-
[
3f,7]
tures
were compared, the difference was con-
firmed in the Rh···Rh distance [Figure 3; 3.511 ꢂ for
Rh/(R)-3 vs. 3.287 ꢂ for Rh/(R)-BINAP]. The elonga-
tion of Rh···Rh in [RhCl{(R)-3}] results from the
2
2
z
weak interaction between filled d and empty p orbi-
tals in the two Rh atoms, because the interaction is
[9]
unfavorable for the less s-donating (R)-3 (Figure 3).
This weak interaction between Rh atoms suggests
2
z
that the filled d orbital of Rh did not achieve stabili-
zation by interaction with the empty p orbital of the
2
other Rh; in other words, the orbital energy of dz is
maintained at a high level. Therefore, [RhCl{(R)-3}]2
would be susceptible to oxidation with O in the air.
2
Because [RhCl{(R)-3}] cannot be weighed in air, it is
2
difficult to use the complex as a storble precatalyst.
Scheme 1. Asymmetric 1,4-addition by using Rh/(R)-3.
The active species of [Rh(OH){(R)-3}] are also unsta-
2
ble in air. Therefore, the rhodium species are required
to be prepared in situ in our catalytic system.
[
4]
(
Figure 1), is highly effective for Rh-catalyzed asym-
[
3f]
metric 1,4-additions (Scheme 1). Although its TOF
ꢀ
1
value reached 750 h with high enantioselectivity
>99% ee) at 208C in the asymmetric 1,4-addition of
a to 2a, the reaction conditions were not fully opti-
(
1
mized. Therefore, we studied the appropriate reaction
conditions required to achieve a highly effective
asymmetric 1,4-addition in the presence of 0.01 mol%
or less Rh/(R)-3, even with the use of commercially
available 1a. Firstly, the stability of Rh complexes
bearing (R)-3 was investigated to obtain relevant in-
formation for the catalysis. It is also beneficial to un-
derstand the highly electron-poor chiral diphosphane-
metal complexes that are not well-known.
Results and Discussion
The [RhCl(diphosphane)] complex is a catalyst pre-
2
cursor for the asymmetric 1,4-addition of 1a to 2a. In Figure 2. Air unstable [RhCl{(R)-3}]2.
3248
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ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2010, 352, 3247 – 3254

Highly Active and Enantioselective Rhodium-Catalyzed Asymmetric 1,4-Addition of Arylboronic Acid
complex. The complex was allowed to stir in toluene-
d8 solution at 1008C for 12 h. Although an ultra-low
volume of black precipitate was generated, only the
[
Rh(OH){(R)-3}] (d=56.6) signal was observed by
2
3
1
P NMR. Hence, the [Rh(OH){(R)-3}] catalyst was
2
found to have a thermal stability up to 1008C in tolu-
ene. Furthermore, the RhꢀP bond possibly does not
show weakening at such high temperatures because
the coupling constant remained at JRh,P =186 Hz at
temperatures between 20 and 1008C. Although the
thermal stability of the other labile species in the cat-
alysis could not be ascertained, improvement in the
catalytic activity may be possible by increasing the re-
action temperature without the addition of a large
amount of (R)-3.
Following the successful investigation of the stabili-
ty of Rh complexes bearing (R)-3, optimization of the
reaction conditions for the asymmetric 1,4-addition of
1a to 2a was performed. Previously, the reaction cata-
lyzed by Rh/(R)-3 was found to be accelerated by
[3f]
changing the solvent from 1,4-dioxane to toluene.
Therefore, we first investigated the solvent effect. The
Rh-catalyzed asymmetric 1,4-addition to 2a was opti-
mized by using 1.0 equivalent of 1a, without purifica-
tion, in the presence of 0.05 mol% [RhCl ACHTGNUTRNEUNG( C H ) ]
2 4 2 2
with 0.1 mol% (R)-3 (3/Rh=1.0) and 40% KOH in
solvent/H O at 308C for 30 min. Although several sol-
2
vents containing 1,4-dioxane were used for the cata-
lytic reaction, a solvent system exceeding the perfor-
mance of toluene was not found (Table 1). The sol-
Figure 3. Comparison of oxidative resistance between
RhCl{(R)-3}] and [RhCl{(R)-binap}] .
[3c]
[
2
2
vent effect did not affect the enantioselectivities of
(
R)-4aa.
Next, we investigated the thermal stability of the
Next, we optimized the added base (Table 2), which
Rh complex bearing (R)-3. Although catalytic activity mainly plays a role in the transformation of [RhCl-
[
5]
is generally improved by increasing the reaction tem-
ACTHUNGERTNNUN(G ligand)] into [Rh(OH) AHCTUNGTRENNNU(G ligand)] . The addition of
2
2
perature, thermal decomposition of the catalyst into 10 or 40 mol% KOH to the reaction of 1a and 2a in
metal and ligand sometimes occurs, especially in the the presence of 0.05 mol% Rh/(R)-3 catalyst at 308C
case of a less electron-donating ligand. For example, for 30 min gave 79% (R)-4aa with over 99.5% ee (en-
the 1,5-cyclooctadiene (COD) ligand in the achiral
[
RhCl ACHTUNGTRENNUNG( COD)] complex is dissociated at temperatures
2
[9]
higher than 908C. Therefore, an additional 45,000- Table 1. Solvent effect of asymmetric 1,4-addition.
fold amount of COD ligand was required for rhodium
to achieve high turnover numbers (TON=375,000) in
the 1,4-addition of p-tolylboronic acid to 2a at 1008C
[
9]
for 36 h catalyzed by [RhCl ACTHUNGTRNEUNG( COD)] with NaHCO .
2 3
Such thermal decomposition of the catalyst and corre-
sponding addition of a large quantity of ligand repre-
sent a great disadvantage for asymmetric catalysis be-
cause the decomposed achiral metal catalyst may
reduce the enantioselectivity of the reaction product.
Also, a large quantity of the expensive chiral ligand is
required. In the case of Rh/(R)-3 catalyst, a lack of
the thermal stability is suspected because the elec-
tron-poor (R)-3 has a weak s-donating ability, show-
ing a relatively weak RhꢀP bond in BINAP-like di-
Entry
Solvent
Yield [%]
% ee
1
2
3
4
5
6
7
8
toluene
1,4-dioxane
hexane
79
24
18
23
15
12
24
5
>99
>99
99
>99
>99
>99
>99
99
CH Cl
2
2
Et O
2
THF
DMF
EtOH
[10]
phosphanes.
Therefore, we confirmed the thermal
stability of the active species of [Rh(OH){(R)-3}]2
Adv. Synth. Catal. 2010, 352, 3247 – 3254
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asc.wiley-vch.de
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Toshinobu Korenaga et al.
FULL PAPERS
Table 2. Study of additional base for asymmetric 1,4-addi- KOH and NaHCO , no tendency was observed. Inter-
3
tion.
estingly, the yield of (R)-4aa in the presence of
[
Rh(OH){(R)-3}] with Et N was similar to that ach-
2 3
ieved by using [RhCl{(R)-3}] /Et N (entry 20 vs. 19),
2
3
and the result also showed that the addition of Et N
3
dramatically decreased the catalytic activity of
[
Rh(OH){(R)-3}] (entry 20 vs. 2). These results sug-
2
gest that Et N deactivated the catalytic cycle rather
3
than inhibited the formation of [Rh(OH){(R)-3}]2.
Entry
1
Base
A
T
N
T
E
N
N
Yield [%]
% ee
From the results of these experiments, we chose
none
none
KOH
KOH
KOH
KOH
NaHCO3
NaHCO3
NaHCO3
NaHCO3
20
78
79
79
16
0
80
86
86
82
82
76
52
32
36
62
30
18
16
20
98
4
0 mol% of NaHCO as the additional base for fur-
3
[
a]
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
>99
>99
>99
–
ther studies.
(10)
(40)
(70)
We studied the asymmetric 1,4-addition of 1a to 2a
in the presence of Rh/(R)-3 catalyst under the opti-
mized conditions (toluene solvent with 40 mol%
A
H
U
G
R
N
U
G
–
aqueous NaHCO ) to decrease the catalyst loading
(10)
(40)
(40)
(70)
>99
>99
>99
>99
>99
>99
>99
>99
99
99
99
>99
98
99
3
(
Table 3). The asymmetric 1,4-addition of 1a to 2a in
the presence of 0.02 mol% Rh catalyst, prepared
from 0.01 mol% [RhCl(C H ) ] and 0.02 mol% (R)-3,
gave a 41% yield of product (R)-4aa with >99% ee,
[
a]
0
1
2
3
4
5
6
7
8
9
0
ACHTUNGTRENNUNG
2
4 2 2
NaHCO3
ACHTUNGTNERNUNG( 100)
ꢀ
1
Na CO3
(40)
(40)
(40)
(40)
(40)
(40)
(40)
(40)
(40)
2
indicating that the TOF is 2,100 h (entry 1). Under
similar conditions, the reaction using Rh/(R)-BINAP
or Rh/(R)-MeO-BIPHEP catalyst did not proceed
K CO3
2
K PO4
3
KO-t-Bu
KF
LiOH
[
3f]
(
entries 2 and 3). Additionally, the use of presyn-
thesized [RhOH{(R)-BINAP}] did not yield a prod-
2
uct under these conditions (entry 4). The reason for
the very high catalytic activity of Rh/(R)-3 is the ach-
ievement of optimized reaction conditions for this cat-
alyst and its acceleration of the transmetalation and
insertion steps of the asymmetric 1,4-addition by the
A
C
H
T
U
N
G
T
R
E
N
N
U
N
G
(i-Pr) NEt
2
Et N
3
[
a]
Et N
3
[
a]
[
(
Rh(OH){(R)-3}]2 was used instead of [RhCl
R)-3.
ACHTUNGTRENNGU( C H )] /
2 4 2
[
3f,12,13]
electronic effect of (R)-3.
perature to 508C and using the same quantity of Rh/
tries 3 and 4). However, when the amount of KOH (R)-3, the yield was improved to 92% (TOF=
By increasing the tem-
ꢀ
1
was increased to 70 or 100 mol%, the yield of (R)-4aa 4,600 h ) without any loss of enantioselectivity
decreased (16%, 0%) because of hydrolysis of 1a or (entry 5). The reaction at 808C could reduce the cata-
[
9,11]
the [RhꢀPh] species with KOH (entries 5 and 6).
lyst loading to 0.005% Rh/(R)-3. Although only a sto-
The use of NaHCO as a base gave (R)-4aa in yields ichiometric amount of 1a was used at 808C, (R)-4aa
3
of 80% and higher with >99% ee (entries 7–11, was obtained in 90% yield with 99% ee and a TOF
ꢀ
1
except for 9). In particular, addition of 40 mol% value of 18,000 h (entry 6). Increasing the reaction
NaHCO gave the best result (86%, entry 8). It is in- temperature to 1008C could reduce the catalyst load-
3
teresting to note that the decrease in the yield of (R)- ing down to 0.0025% Rh/(R)-3. Under these condi-
4
aa was not observed when using 100 mol% tions, a slight excess of PhB(OH) was required to
2
NaHCO , suggesting that hydrolysis of 1a or the [Rhꢀ provide a high yield of (R)-4aa. The product was ob-
3
ꢀ
1
Ph] species under harsher conditions such as high re- tained in 96% yield with a TOF of 38,000 h
action temperatures is avoidable with this base. It is (entry 7).
[
14]
When Rh/(R)-3 catalyst was reduced to
clear that the role of the added base is to form 0.001%, the TOF value further increased up to
ꢀ
1
[
Rh(OH){(R)-3}] , because the reaction without the 53,000 h with 98% ee (entry 8). To the best of our
2
base in the presence of [RhCl
ACHTUNGRTNNGE(U C H )] /(R)-3 gave a knowledge, the highest TOF value was established in
2 4 2
poor yield (entry 1) and in the presence of the catalytic asymmetric carbon-carbon bond forming
[
3d,e,15]
[
Rh(OH){(R)-3}]2 afforded 78% yield of (R)-4aa reactions.
As a result, although boronic acid 1a
(
entry 2). The latter reaction was slightly improved by was used, the amount of Rh/(R)-3 catalyst could be
the addition of NaHCO (entry 9), suggesting that the reduced below 0.01 mol%, raising its high catalytic
added base somewhat accelerated the transmetalation activity up to a TOF of 53,000 h in the asymmetric
of 1a to the Rh catalyst.
3
ꢀ
1
[
3f,9]
The other bases, Na CO , 1,4-addition by increasing the reaction temperature.
2 3
K CO , K PO , KO-t-Bu, KF, LiOH, Et N and (i- The TOF values in the case of other substrates were
2
3
3
4
3
Pr) NEt, were less effective relative to NaHCO (en- estimated. An electron-donating or electron-with-
2
3
tries 12–19). From the viewpoint of basicity, including drawing functional group on the phenylboronic acid
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Adv. Synth. Catal. 2010, 352, 3247 – 3254

Highly Active and Enantioselective Rhodium-Catalyzed Asymmetric 1,4-Addition of Arylboronic Acid
Table 3. Low catalyst loading and high TOF of Rh/(R)-3 catalyst for asymmetric 1,4-addition of 1 to 2.
ꢀ
1
Entry
1
Rh [%]
2
1 [equiv.]
Temperature [8C]
Yield [%]
TOF [h ]
% ee
0.02
0.02
0.02
0.02
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2b
1a [1.0]
1a [1.0]
1a [1.0]
1a [1.0]
1a [1.0]
1a [1.0]
1a [1.3]
1a [1.3]
1b [1.3]
1c [1.3]
1d [1.3]
1a [1.3]
30
30
30
30
50
80
100
100
100
100
100
100
41
0
0
2,100
–
–
>99
–
–
[
[
[
a]
b]
c]
2
3
4
5
6
7
8
9
1
1
1
0
–
–
0.02
92
90
96
53
79
55
54
52
4,600
18,000
38,000
53,000
32,000
22,000
22,000
10,000
99
99
98
98
97
98
96
95
0.005
0.0025
0.001
0.0025
0.0025
0.0025
0.005
0
1
2
[
[
[
a]
[
[
[
RhCl
RhCl
A
C
H
T
U
N
G
T
R
E
N
N
U
N
G
(C H ) ] /(R)-MeO-BIPHEP was used.
2
4
2
2
b]
c]
A( C H ) ] /(R)-BINAP was used.
C
H
T
U
N
G
T
R
E
N
N
U
N
G
2
4
2
2
RhOH{(R)-BINAP}] was used.
2
(
1b–1d) slightly diminished the catalytic activity of 27.9 g (R)-4aa (80%) with 98% ee. The TON reached
Rh/(R)-3 (entries 9–11). Although Rh/(R)-3 show rel- 320,000.
atively low catalytic activity in the case of straight-
In the asymmetric 1,4-addition, our catalyst
chain a,b-unsaturated ketone 2b (entry 12), the TOF achieved both high activity and high enantioselectivi-
ꢀ
1
value exceeded 10,000 h .
ty. Performing the reaction at several temperatures
The catalytic system was applicable to a larger
scale of asymmetric 1,4-addition in the presence of a
small quantity of Rh/(R)-3 catalyst (Scheme 2). A
mixture of 19.4 mL (0.2 mol) 2a and 36.6 g
(
{
(
1.5 equiv.) 1a in the presence of 0.00025% Rh/(R)-3
97 mg (0.25 mmol) [RhCl(C H ) ] and 400 mg
0.50 mmol) (R)-3} catalyst in toluene with 40% aque-
ACHTUNGTRENNUNG
2
4 2 2
ous NaHCO was stirred at 1008C for 24 h to give
3
Scheme 2. Asymmetric 1,4-addition of 1a to 2a on a gram-
scale.
Figure 4. Eyring plotꢀs of the reaction of 2a with 1a cata-
lyzed by Rh/(R)-3.
Adv. Synth. Catal. 2010, 352, 3247 – 3254
ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
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Toshinobu Korenaga et al.
FULL PAPERS
Figure 5. DFT calculations at insertion step.
enabled us to evaluate kinetic parameters in the tran-
[
16]
sition state. Figure 4 shows the Eyring plots of ln-
ACHTUNGTRENNUNG( k /k ), whose enantioselectivities were average
R
S
values of three times experiments, as a function of 1/
T for the Rh/(R)-3-catalyzed asymmetric 1,4-addition
of 1a to 2a. The Eyring plots show a straight line with
2
a high correlation coefficient (r >0.99), indicating
that the decreasing % ee of (R)-4aa is followed by
the theory of kinetics. Therefore, the slight decrease
in % ee of (R)-4aa with increasing reaction tempera-
ture is not attributed to decomposition of the catalyst.
¼
6
ꢀ1
The kinetic parameters DDH (ꢀ4.0ꢁ0.1 kcalmol ) Figure 6. Transition state in insertion step.
¼6
ꢀ1 ꢀ1
and DDS (ꢀ1.3ꢁ0.3 calmol K ) were obtained
from the Eyring plots. The entropy contribution is rel-
¼6
atively small because TDDS at 373 K is calculated to
ꢀ
1 [17]
be ꢀ0.47 kcalmol ,
suggesting that the electron-
poor (R)-3 ligand coordinates relatively more tightly tion state was sustained even under high-temperature
to the Rh and creates a rigid chiral environment conditions.
around the Rh, as explained above. The asymmetric
introduction occurs in the insertion of 2a to the (R)-3-
RhꢀPh complex. We calculated the insertion step, in- Conclusions
cluding the transition states, by DFT calculations
[18,19]
(
Figure 5).
The favorable transition state, which In conclusion, we have developed a highly active and
gave (R)-enantiomer of 4aa, was more stable by enantioselective Rh-catalyzed asymmetric 1,4-addi-
ꢀ
1
1
.9 kcalmol than the unfavorable one, which gave tion of phenylboronic acid to cyclohexenone using the
the (S)-enantiomer of 4aa (Figure 6). Although the electron-poor MeO-F -BIPHEP. Because of its pro-
1
2
relative energy is estimated incompletely as compared nounced catalytic activity, the Rh/(R)-3 catalyst is
¼6
ꢀ1
to the experimental DDH value (ꢀ4.0 kcalmol ), suitable for practical use as a catalyst for asymmetric
the difference in their characters becomes very appar- 1,4-additions. In fact, we have already reported the ef-
ent. In the favorable transition state, 2a coordinated ficient reaction of a less reactive coumarin substrate
[
20]
to an open space at the lower part of the vacant coor- using Rh/(R)-3 catalyst.
In the near future, we
dination site in Figure 6a, as expected from the pre- would like to synthesize a biologically active agent
[11]
ceding paper. In contrast, the steric repulsion arises using Rh/(R)-3 catalyst.
from the aromatic rings on phosphorous and 2a coor-
We also studied the properties of the electron-poor
dinated to the upper part being blocked in the unfav- diphosphane-ligated Rh complex. We found that the
orable transition state (Figure 6b). Although the elec- chiral electron-poor diphosphane acts effectively even
tron-poor (R)-3 has lower s-donating ability for a at high temperatures and promises to exceed the use
metal catalyst, this chiral environment in the transi- of other related asymmetric catalysts.
3252
asc.wiley-vch.de
ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2010, 352, 3247 – 3254

Highly Active and Enantioselective Rhodium-Catalyzed Asymmetric 1,4-Addition of Arylboronic Acid
Experimental Section
General Procedure of Asymmetric 1,4-Addition
A 20-mL Schlenk flask was flushed with argon and charged
General Experimental Methods
with (R)-MeO-F -BIPHEP (3) (400 mg, 0.501 mmol), m-di-
1
2
chlorotetraethylenedirhodium(I) (97 mg, 0.25 mmol; 0.001%
Rh for 2a) and 0.1 mL of deoxygenated toluene. The mix-
ture was stirred at room temperature for 5 min, and then
the solvent was removed under vacuum. To the Schlenk
flask were added sodium hydrogen carbonate (1.68 g,
All reactions were carried out under an argon atmosphere
with dry solvents under anhydrous conditions, unless other-
wise noted. Solvents, which were purchased as dehydrated
solvents grade commercial products from Kanto Chemical
Co., Inc., were stored in Schlenk tubes under an argon at-
2
0.0 mmol), phenylboronic acid (1a) (7.93 g, 65.0 mmol), 2-
mosphere after argon bubbling. m-Dichlorotetraethylenedi-
ꢃ
cyclohexen-1-one (2a) (4.8 mL, 50 mmol), 7.5 mL of deoxy-
genated toluene, and 5.0 mL of deoxygenated water. The re-
sulting mixture was then stirred at 1008C for 1 h. To the so-
A
C
H
T
U
N
G
T
R
E
N
N
U
N
G
rhodium(I) was purchased from Sigma–Aldrich and was
used without purification. 2-Cyclohexenone was purchased
ꢃ
from Sigma–Aldrich and was stored under argon atmos-
lution was added saturated aqueous NaHCO solution. The
phere after a degassing operation. Phenylboronic acid was
purchased from Tokyo Chemical Industry Co., Ltd. and was
used without purification. Other reagents were purchased at
the highest commercial quality and used without further pu-
rification, unless otherwise noted. Preparative column chro-
matography was carried out by using silica gel (Fuji Silysia
3
resulting mixture was extracted with EtOAc (three times).
The organic layer was dried over MgSO , filtrated with suc-
4
tion, and then concentrated under vacuum. The residue was
purified by silica gel column chromatography (hexane/
EtOAc=5/1) to give (R)-3-phenylcyclohexanone (4aa) as a
ꢀ
1
1
13
colorless oil; yield: 4.57 g (53%); 98% ee; TOF=53,000 h .
BW-127 ZH, 100–270 mesh). H NMR and C NMR spectra
were measured at 300 MHz or 500 MHz and 75 MHz or
1
H NMR (300 MHz, CDCl ): d=1.74–1.92 (m, 2H), 2.07–
3
2
7
.19 (m, 2H), 2.32–2.63 (m, 4H), 2.96–3.06 (m, 1H), 7.20–
.25 (m, 3H), 7.31–7.36 (m, 2H); C NMR (75 MHz,
1
25 MHz or 150 MHz, respectively, and chemical shifts are
13
19
given relative to tetramethylsilane (TMS). F NMR spectra
were measured at 282 or 376 HzMHz, and chemical shifts
are given relative to CCl F using C F as a secondary refer-
CDCl ): d=25.4, 32.7, 41.1, 44.6, 48.8, 126.4, 126.6, 128.6,
3
1
1
7
44.2, 211.0; IR (neat): n=3061, 3028, 2937, 2866, 1713,
3
6
6
3
1
603, 1497, 1452, 1421, 1344, 1315, 1250, 1223, 1030, 756,
ence (ꢀ162.9 ppm). P NMR spectra were measured at
21 MHz, and chemical shifts are given relative to 85%
H PO as an external standard.
ꢀ
1
23:5
D
00, and 538 cm ; [a] : +19.98 (c 1.0, CHCl ); HPLC
1
3
(
0
Daicel Chiralcel OD-H, hexane/i-PrOH=100/1, flow rate=
3
4
ꢀ
1
.7 mLmin ): t of (S)-4aa; 20.0 min (0.86%), t of (R)-4aa;
R
R
2
1.3 min (99.14%).
Synthesis of [RhCl{(R)-3}]2
Asymmetric 1,4-Addition for TON Experiment
A 20-mL Schlenk flask was flushed with argon and charged
with (R)-3 (9.6 mg, 12 mmol), m-dichlorotetraethylenedirho-
dium(I) (2.3 mg, 6.0 mmol), and 0.50 mL of deoxygenated di-
chloromethane. The mixture was stirred at room tempera-
A 20-mL Schlenk flask was flushed with argon and charged
with (R)-MeO-F -BIPHEP (3) (400 mg, 0.501 mmol), m-di-
1
2
chlorotetraethylenedirhodium(I)
(97 mg,
0.25 mmol;
0
.00025% Rh for 2a) and 0.1 mL of deoxygenated toluene.
ture for 5 min. Removal of the solvent under vacuum gave
1
The mixture was stirred at room temperature for 5 min, and
then the solvent was removed under vacuum. To the
Schlenk flask were added sodium hydrogen carbonate
[
RhCl{(R)-3}] as a red solid: H NMR (300 MHz, CDCl ):
2
3
d=3.52 (s, 12H), 6.52–6.58 (m, 8H), 7.04–7.61 (m, 20H);
1
9
F NMR (282 MHz, CDCl ): d=ꢀ157.8 to ꢀ157.7 (m, 4F),
3
(
6.72 g, 80.0 mmol), phenylboronic acid (1a) (36.6 g,
ꢀ
157.3 to ꢀ157.1 (m, 4F), ꢀ134.6 to ꢀ134.5 (m, 8F),
3
1
300 mmol), 2-cyclohexen-1-one (2a) (19.4 mL, 200 mmol),
30 mL of deoxygenated toluene, and 20 mL of deoxygenated
water. The resulting mixture was then stirred at 1008C for
ꢀ
134.3 (br s, 8F); P NMR (121 MHz, CDCl ): d=50.0 (d,
3
1
J
=196 Hz).
Rh,P
2
4 h. To the solution was added saturated aqueous NaHCO3
solution. The resulting mixture was extracted with EtOAc
Synthesis of [RhOH{(R)-3}]2
(three times). The organic layer was dried over MgSO , fil-
4
trated with suction, and then concentrated under vacuum.
The residue was purified by silica gel column chromatogra-
phy (hexane/EtOAc=5/1) to give (R)-4aa as a colorless oil;
A 20-mL Schlenk flask was flushed with argon and charged
with (R)-3 (4.1 mg, 5.1 mmol), m-dichlorotetraethylenedirho-
dium(I) (1.0 mg, 2.5 mmol), KOH (0.9 mg) and 1.0 mL of de-
oxygenated dioxane with 0.5 mL of water. The mixture was
stirred at room temperature for 10 min. After removal of
the solvent under vacuum, the resulting orange solid was
dissolved in toluene, and then the solution was filtered
ꢀ
1
yield: 27.9 g (80%); 98% ee; TON=320,000 h .
Acknowledgements
ꢃ
through Celite to give a yellowish-orange solution. Remov-
al of the solvent under vacuum gave [RhOH{(R)-3}] as an
2
This work was supported by JSPS KAKENHI (20550099).
We thank the SC NMR Laboratory of Okayama University
for H, C, F, and P NMR measurements.
1
orange solid: H NMR (300 MHz, toluene-d ): d=ꢀ2.84 (s,
8
2
4
8
H), 3.01 (s, 12H), 5.94 (d, J=7.85 Hz, 4H), 6.29–6.35 (m,
H), 6.56 (t, J=7.85 Hz, 4H), 7.28–7.36 (m, 8H), 7.78 (br,
1
13
19
31
19
H); F NMR (282 MHz, toluene-d ): d=ꢀ157.6 to ꢀ157.4
8
(
ꢀ
m, 4F), ꢀ156.7 to ꢀ156.5 (m, 4F), ꢀ134.5 (br s, 8F),
3
1
132.4 to ꢀ132.3 (m, 8F); P NMR (121 MHz, toluene-d ):
8
1
d=56.6 (d, J =186 Hz).
Rh,P
Adv. Synth. Catal. 2010, 352, 3247 – 3254
ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
3253

Toshinobu Korenaga et al.
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