4,4′ and 5,5′-DiamBINAP as a hydrosoluble chiral ligand: Syntheses and use in Ru(II) asymmetric biphasic catalytic hydrogenation

Article abstract of DOI:10.1016/j.tetasy.2003.12.033

4,4′ and 5,5′-DiaminomethylBINAP were prepared in five steps from enantiomerically pure BINAP. Their synthesis involves, as key steps, the regioselective bromination of BINAP and the chemoselective efficient reduction of a dicyano, diphosphine oxide into the corresponding dicyano, diphosphine by a mixture of HSiCl₃/PhSiH₃. The ruthenium complexes of these new ligands were tested for the homogeneous and water/organic solvent biphasic asymmetric hydrogenation of β-ketoesters leading to 100% conversion with an enantiomeric excess greater than 97% in water. Catalysts can be recycled several times by extraction of the product with pentane.

Full text of DOI:10.1016/j.tetasy.2003.12.033

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 15 (2004) 639–645
0
0
4
,4 and 5,5 -DiamBINAP as a hydrosoluble chiral ligand: syntheses
and use in Ru(II) asymmetric biphasic catalytic hydrogenation
a
a
b
a,
*
Mika €e l Berthod, Christine Saluzzo, Gerard Mignani and Marc Lemaire
a
Laboratoire de Catalyse et de Synth ꢀe se Organique, UMR 5181, UCBL, CPE Bat. 308, 43, Boulevard du 11 Novembre 1918,
9622 Villeurbanne Cedex, France
6
b
Rhodia, Centre de recherches de Lyon, 85, avenue des Fr ꢀe res-Perret, BP 62, 69192 Saint-Fons Cedex, France
Received 21 October 2003; revised 10 December 2003; accepted 11 December 2003
0
0
Abstract—4,4 and 5,5 -DiaminomethylBINAP were prepared in five steps from enantiomerically pure BINAP. Their synthesis
involves, as key steps, the regioselective bromination of BINAP and the chemoselective efficient reduction of a dicyano, diphosphine
3 3
oxide into the corresponding dicyano, diphosphine by a mixture of HSiCl /PhSiH . The ruthenium complexes of these new ligands
were tested for the homogeneous and water/organic solvent biphasic asymmetric hydrogenation of b-ketoesters leading to 100%
conversion with an enantiomeric excess greater than 97% in water. Catalysts can be recycled several times by extraction of the
product with pentane.
ꢀ
2004 Elsevier Ltd. All rights reserved.
1
. Introduction
water-soluble chiral catalysts for biphasic applications.
Most of the reported water-soluble chiral ligands have
been prepared by the incorporation of anionic groups
such as sulfonate or carbonate cationic groups such as
quaternary ammonium ions, or neutral hydrophilic
groups such as polyethers. In many cases, chiral cata-
lysts in aqueous or organic two-phase systems led to a
lower stereoselectivity and/or reactivity than in the
homogeneous organic phase, due to several factors such
as the solvent effect, the reaction kinetics and mass
Although asymmetric catalysis is without doubt one of
the most promising methods for the synthesis of chiral
compounds, its industrial applications remain rare, even
if a wide variety of reactions have been performed with
1
2
both high enantioselectivities and conversions. The lack
of employment of asymmetric catalysis is partly due to
the problems of separation and recovering of the
expensive chiral catalyst. To overcome this drawback,
two types of enantioselective heterogeneous catalysts
have emerged: heterogeneous catalysts with demon-
strated catalytic activities that are rendered chiral by
modification with a chiral auxiliary and homogeneous
catalysts with demonstrated enantioselectivity and
activity modified in such a way as to become hetero-
7
transport in the two solvents.
Recently, we reported the synthesis of a BINAP deriv-
0
3
ative bearing two amine functions: 6,6 -dimethylamino-
8
BINAP (diamBINAP). This modified BINAP was then
involved in the synthesis of insoluble catalysts and
4
9
geneous. Thus, the catalyst can be recovered from the
reaction mixture by filtration, precipitation or extraction.
water-soluble catalysts, which were shown to be as
efficient and selective as BINAP itself for the hydro-
genation of b-ketoesters. Nevertheless, the synthesis
of 6,6 -diamBINAP equates careful chromatographic
0
Since the industrial application of the rhodium-TPPTS
system by Hoechst AG in Oberhausen, Germany, the
development of water-soluble organometallic catalysis
has expanded significantly. The recovery of catalysts
from products by phase separation has become a very
purification, which rendered its manufacture difficult.
Thus in order to overcome these drawbacks, we chose to
functionalize directly and regioselectively BINAP at the
0
0
4,4 - and 5,5 -positions.
5
;6
active field of research. In the case of asymmetric
catalysis, substantial efforts have been made to prepare
2. Results and discussion
*
Corresponding author. Tel.: +33-4-7243-1407; fax: +33-4-7243-1408;
e-mail: marc.lemaire@univ-lyon1.fr
Most of the BINAP derivatives were usually prepared
from BINOL or protected BINOL with a phosphination
0
957-4166/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2003.12.033

640
M. Berthod et al. / Tetrahedron: Asymmetry 15 (2004) 639–645
Br
CN
CN
O
PPh2
PPh2
O
O
CuCN, DMF
PPh2
PPh2
O
1
65°C
60%
Br2, Pyridine
CH2Cl2, rt..
O
PPh2 H2O2
3
Br
5
PPh2
PPh2
O
80%
PPh2
CH2Cl2
>99%
1
2
80%
Br
CN
Fe, Br2
,2-Dichloroethane
0°C
1
O
CuCN, DMF
O
8
165°C
PPh2
PPh2
O
PPh2
PPh2
O
60%
4
6
Br
CN
0
0
Scheme 1. Synthesis of 4,4 and 5,5 -dicyanoBINAPO (5 and 6).
1
0
reaction at the end of the synthesis. In order to prepare
0 0
CN
O
NH2
CN
CN
4
,4 - and 5,5 -diamBINAP 9 and 10, we chose a five step
synthesis strategy starting from optically active BINAP.
As depicted in Scheme 1, (R)- or (S)-BINAP were
transformed into their corresponding dioxide 2 followed
by a regioselective bromination. The 4,4 -positions were
brominated in the presence of pyridine according to
PPh2
PPh2
PPh2
O
PhSiH3
HSiCl3
LiAlH4
PPh2
PPh2 THF/ toluene
PPh2
0
1
quantitative
quantitative
5
CN
7
1
9
NH2
0
K o€ ckritz and co-workers while the 5,5 -positions were
NH2
brominated in the presence of iron as catalyst. In both
cases, brominations were regioselective, with only a
trace of monobrominated by-products being detected.
The dibrominated phosphines 3 and 4 were obtained in
0% isolated yield. The 4,4 - and 5,5 -positions were
brominated with an electron withdrawing group, with a
phosphine oxide group at the 2,2 -position. In the lit-
erature the only way (except cross-coupling reactions) to
reach the 5,5 -position is by nitration and sulfona-
tion. Our method was not as acidic but required a
strong Lewis acid. Phosphine oxides are Lewis bases
and may be complexed during electronic substitution in
presence of Lewis acid. Although the 4,4 -position was
the most reactive, the presence of a Lewis acid seemed to
deactivate this position by complexing the phosphine
oxide; Br (activated by the presence of Fe) would
0
brominate the less deactivated 5,5 -position. To our
knowledge, this method is the first report, which leads to
CN
CN
O
PPh2
PPh2
PPh2
O
PhSiH3
HSiCl3
LiAlH4
PPh2
PPh2
THF/ toluene
0
0
PPh2
8
quantitative
quantitative
10
CN
6
8
0
12
CN
NH2
0
0
0
13
Scheme 2. Synthesis of 4,4 and 5,5 -diamBINAP.
14
15
0
0
Thus, with this method 4,4 and 5,5 -dicyanoBINAP 7
and 8 were obtained with up to 98% yield (Scheme 2).
This efficient procedure permitted the chemoselective
reduction of the phosphine oxide without reducing the
cyano groups of 5 and 6. Moreover, at the end of the
reaction, products 7 or 8 crystallized from the reaction
mixture and could be isolated in their pure form by fil-
tration. Finally, the cyano groups were subsequently
0
2
0
a dibrominated BINAP at the 5,5 -position.
0 0
reduced with LiAlH to give (S)- or (R)-4,4 and 5,5 -
4
Dicyanation of these molecules with CuCN in DMF at
diamBINAP, 9 and 10, in 47% overall yield, starting
from the enantiopure BINAP.
0
0
1
6
50 ꢁC gave 4,4 and 5,5 -dicyanoBINAPO 5 and 6 in
0% yield after recrystallization from ethanol. This key
0
step is much easier than the same one for the 6,6 -diam-
BINAP synthesis, where a difficult chromatographic
purification was involved.
In order to evaluate ligands 9 and 10, their corre-
sponding ruthenium complexes were prepared via reac-
tion of [(COD)Ru(2-methylallyl) ] according to the
2
19
general procedures described by Gen ^e t et al. The cat-
alytic activities of these ruthenium complexes in the
hydrogenation of methyl or ethyl acetoacetate were
tested in methanol and ethanol, respectively, with a
substrate/catalyst ratio (S/C) of 1000, at 50 ꢁC and under
40 bar of hydrogen (Scheme 3). The same ruthenium
complexes were prepared with the (R)-BINAP in order
to compare the activity and selectivity of ligands
(Table 1).
Reduction of the phosphine oxide did not succeed using
16
normal reducing agents, such as HSiCl
PhSiH ,
3
3
,
LiAlH
which gave partly reduced phosphine oxide
and numerous nondetermined by-products. More com-
4
and
17
18
plex methods such as ImamotoÕs (MeOTf + LiAlH
4
)
failed too. For that reason, we optimized a new reducing
system consisting of a mixture of PhSiH and HSiCl
3 3
at 120 ꢁC.

M. Berthod et al. / Tetrahedron: Asymmetry 15 (2004) 639–645
641
Br
Br
Table 2. Recycling of hydrosoluble catalysts in the hydrogenation of
NH2
NH3
NH3
ethyl acetoacetate
H2 (40 bar)
Ph2
O
O
catalyst
OH O
P
PPh2 aq.HBr
PPh2
Ru(II)
Br
Br
PPh2
PPh2
OEt
Ru
OEt
Water
0°C; 15 hours
acetone
aq.HBr
CH2Cl2
P
5
Ph2
a
a
Entry Reuse
1
Catalyst Substrate/
catalyst
Conversion
(%)
Ee (%)
quantitative
13
NH2
NH3
Br
NH3
9
Br
13
13
1000
1000
1000
1000
1000
1000
100
100
100
100
100
100
99
98
97
99
98
Br
Br
2
3
4
5
6
First
Eight
First
Sixth
NH3
13
14
NH2
NH3
Ph2
P
14
Ru(II)
Br
b
PPh2 aq.HBr
PPh2
BINAP
98
Ru
PPh2
PPh2 acetone
Br
P
a
CH2Cl2
Conversion and enantioselectivity were determined by GC on a
lipodex A (25 m · 0.25 mm) column.
Hydrogenation was performed in homogeneous conditions in ethanol
aq.HBr
Ph2
quantitative
14
b
NH3
NH2
NH3
10
2
H (40 bar), 50 ꢁC, 15 h.
Br
Br
Scheme 3. Hydrosoluble catalysts from 9 and 10.
conversion was obtained in all cases under 40 bar of
hydrogen after 15 h at 50 ꢁC. At the end of the reaction,
the mixture was cooled down and the homogeneous
solution obtained, extracted three times with pentane.
Fresh substrate was added to the resulting aqueous
phase the hydrogenation could be repeated under these
conditions, 13 was recycled eight times with always more
than 97% ee. Compound 14 was recycled six times with
more than 97% ee (Table 2).
Ligands 9 and 10 (Table 1, entries 2 and 4) were shown
to be almost as efficient as the BINAP complex, which
gave for the reduction of ethyl acetoacetate, total con-
version and 98% ee (Table 1, entry 5). As we have
0
10
already observed with 6,6 -diamBINAP the amino-
methyl groups do not have any influence either on the
0
0
activity or on the selectivity. Moreover 4,4 and 5,5 -
0
diamBINAP exhibited the same efficiency as 6,6 -diam-
BINAP, which means that we do not change the
geometry of the metal–ligand complex with the positions
of the aminomethyl groups. Excellent conversions and
ees were also observed for the reduction of methyl ace-
toacetate (Table 1, entries 1 and 3). The HBr salts of 9
and 10 and the corresponding Ru(II)-catalysts were
In the catalytic hydrogenation of this substrate our
biphasic system was as good as BINAP itself with the
advantage of recycling. As observed in homogeneous
conditions, the presence of the two ammonium bromo-
hydrate groups of hydrosoluble 4,4 and 5,5 -diam-
BINAP had no influence on the catalytic activity and
selectivity, which were similar to those of BINAP itself.
The decrease in activity and selectivity observed after six
or eight runs was due to the catalysts oxidation despite
the utmost care taken.
0
0
prepared in situ from [Ru(COD)(2-methylallyl)
aqueous hydrobromic acid according to the usual pro-
2
] and
20
cedure.
obtained in quantitative yields (Scheme 3).
Hydrosoluble catalysts 13 and 14 were
To evaluate these two hydrosoluble catalysts, hydroge-
nation was carried out using ethyl acetoacetate 11 as the
standard substrate (Table 1). Water and ethyl acetoac-
etate were added to obtain a biphasic mixture where the
catalysts were only in the aqueous phase. Complete
In order to extend the validity of our system, other b-
ketoesters were tested in the same conditions of hydro-
genation (Table 3). Methyl acetoacetate 12 and ethyl
benzoylacetate 15 were both hydrogenated with excel-
lent activity and ee.
0
Table 1. Ruthenium catalyzed reduction of ketoesters with 4,4 and
0
5,5 -diamBINAP
H2 (40 bar)
catalyst
O
O
OH
O
3
. Conclusion
Me
OR
Me
OR
MeOH or EtOH
0°C; 15 hours
5
11 R= Et
2 R= Me
Herein, we have reported that ruthenium complexes of
0 0
,4 and 5,5 -diamBINAP exhibit excellent efficiency in
the catalytic hydrogenation of b-ketoesters (total con-
versions and ees greater than 96%). As with 6,6 -diam-
BINAP, the presence of the two aminomethyl groups of
0 0
,4 and 5,5 -diamBINAP had no influence on the cata-
lytic activity, which was similar to those of the BINAP
itself. Moreover, an efficient regioselective synthesis
1
4
Entry
Ligand
R
Conversion (%) Ee (%)
0
1
2
3
4
5
(R)-9
(R)-9
Me
Et
100
100
100
100
100
99
98
99
96
98
(R)-10
(R)-10
(R)-BINAP
Me
Et
4
Et

642
M. Berthod et al. / Tetrahedron: Asymmetry 15 (2004) 639–645
Table 3. Biphasic heterogeneous hydrogenation of 12 and 15
H2 (40 bar)
catalyst
O
O
OH
O
R
OMe
Water
0°C; 15 hours
R
OMe
5
1
1
2 R= CH3
5 R= C6H5
a
a
Entry
Reuse
First
Substrate
Catalyst
Substrate/catalyst Conversion (%)
Ee (%)
1
2
3
4
5
6
12
12
12
15
15
15
13
13
1000
1000
1000
1000
1000
1000
100
100
100
100
100
100
99
98
b
BINAP
13
13
98
98
99
First
b
BINAP
97
a
Conversion and enantioselectivity were determined by GC on a lipodex A (25 m · 0.25 mm) column.
b
Hydrogenation was performed in homogeneous conditions in ethanol H (40 bar), 50 ꢁC, 15 h.
2
0
from BINAPO have been developed to reach 4,4 and
0
stirred for 4 h. Then 100 mL of water was added.
Aqueous phases were extracted with 50 mL of CH Cl .
5
,5 -diaminomethylBINAP. This synthesis is easier than
0
2
2
WITH 6,6 -diamBINAPs and can be performed on a
larger scale. Moreover, we have demonstrated that
The organics phases were washed with 50 mL of aque-
ous sodium hydrogen sulfite solution, dried over
Na SO and evaporated to obtained a white solid
0
0
quaternarization of 4,4 and 5,5 -diamBINAP provides a
water-soluble BINAP analogue, suitable for asymmetric
biphasic catalytic hydrogenation of several b-ketoesters.
The use of such a ligand is interesting because high
conversions and attractive enantioselectivities were
obtained. In addition, it allows easy separation of the
catalyst from the reaction product by extraction. The
reuse of the ruthenium complex is effective without any
loss of either conversion or enantioselectivity.
2
4
1
(3.14 g, 4.8 mmol, quantitative yield). H NMR (300
MHz, CDCl
): 6.80 (d, 4H, J ¼ 3:7), 7.2–7.3 (m, 8H),
7.3–7.5 (m, 12H), 7.6–7.7 (m, 4H), 7.8–7.9 (m, 4H).
3
31
P
NMR (81 MHz, CDCl ): 28.67. Mp: 256–258 ꢁC
3
½aꢀ ¼ +198.1 (c 1, Benzene).
D
0
4.3. (S)-4,4 -DibromoBINAPO 3
In a 250 mL round-bottomed flask were placed (S)-BI-
NAPO (5 g, 7.64 mmol) and 150 mL of CH
2
Cl
0.62 mL, 7.64 mmol) and bromine (1.2 mL, 22.92 mmol,
2
. Pyridine
(
4. Experimental
3
equiv) were added. The mixture was stirred at room
temperature for 20 h. The organic phase was extracted
successively with 1 M aqueous sodium hydrogen sulfite
solution, brine and saturated sodium hydrogen car-
bonate solution, dried and evaporated. To obtain the
bis-brominated product 3, the above described bro-
mination procedure was repeated twice and the crude
product of the preceding bromination used as starting
materials. A white solid (4.74 g, 5,8 mmol, 76%) was
4
.1. General methods
ꢁ
Solvents were dried with 4 A molecular sieves and dis-
tilled under an argon stream on LiAlH or purchased
4
anhydrous (Aldrich or Acros). For catalytic use, sol-
vents were deoxygenated by repeated evacuation and
argon purging. NMR spectra were recorded on a Bruker
AC 200 and DRX 300. Chemical shifts are given in ppm
1
1
obtained after recrystallization from ethanol. H NMR
using tetramethylsilane as the internal standard for H
31
13
(
300 MHz, CDCl ): 6.80 (d, 2H, J ¼ 8:3), 6.85 (ddd, 2H,
and C NMR spectra, and P NMR from H
3
PO
4
.
3
J ¼ 0:9; 6.7; 15.1), 7.2–7.5 (m, 18H), 7.6–7.7 (m, 4H),
Coupling constants are reported in Hz. Optical rotations
were measured on a Perkin–Elmer 241 polarimeter. For
the air-sensitive compounds, elemental analyses were
not performed. Mass spectra were recorded on LCQ
Advantage Thermofinnigan. Conversions and enantio-
selectivities were determined by GC on a lipodex A
13
7
.75 (s, 2H), 8.23 (d, 2H, J ¼ 8:4). C NMR (75 MHz,
CDCl ): 123.3, 123.5, 127.1, 127.5, 127.8, 128.3, 128.5,
28.7, 129.0, 130.3, 131.6, 131.7, 131.8, 131.8, 131.9,
31.9, 132.3, 132.4, 132.7, 132.8, 132.9, 133.0, 133.1,
3
1
1
1
31
33.3, 134.4, 134.7, 134.9, 142.2, 142.3, 142.4. P NMR
25
(
81 MHz, CDCl ): 27.60. ½aꢀ ¼ )96.4 (c 1, DMF).
(25 m · 0.25 mm) column. All the yields are isolated
yields.
3
D
þ þ
ESI : MH ¼ 813.33. Mp: >300 ꢁC. Calcd. C 65.05, H
3
1
.72, P 7.62, Br 19.67; found C 65.13, H 3.82, P 7.81, Br
9.42.
4
.2. (R) or (S)-BINAPoxide 2
0
In a 250 mL round-bottomed flask were placed either
R)- or (S)-BINAP (3 g, 4.81 mmol) and 100 mL of
CH Cl
. The mixture was cooled to 0 ꢁC and 10 mL of
hydrogen peroxide (35%) then added. The mixture was
4.4. (S)-4,4 -DicyanoBINAPO 5
(
In a 50 mL round-bottomed flask fitted with a reflux
0
2
2
condenser were placed (S)-4,4 dibromoBINAPO

M. Berthod et al. / Tetrahedron: Asymmetry 15 (2004) 639–645
643
(
0
200 mg, 0.25 mmol) and copper cyanide (63 mg,
.7 mmol, 2.8 equiv) in 3 mL of DMF. The mixture
(3.71 g, 5.5 mmol, 90.8%). The product was recrystal-
lized from ethanol to yield 2.52 g, 61.7% of a white
product. H NMR (200 MHz, CDCl ): 6.85 (dd, 2H,
3
1
refluxed overnight then cooled. 1 mL of ethylenediamine
and 1 mL of water were added. After stirring for 5 min,
5
aqueous phase was then extracted with 10 mL of tolu-
ene. The organic phases were washed with 5 mL of
water, 5 mL of HCl (0.5 M, four times) 5 mL of brine
and 5 mL of saturated sodium carbonate solution. The
mixture was dried and evaporated and the residue
recrystallized from methanol. A white solid was ob-
J ¼ 7:0, 7.1), 6.97 (d, 2H, J ¼ 9:0), 7.2–7.5 (m, 20H),
mL of water and 10 mL of toluene were added. The
7.6–7.7 (m, 2H), 7.8 (dd, 2H, J ¼ 1:1, 6.1), 8.33 (dd, 2H,
1
3
J ¼ 1:9, 7.1). C NMR (75 MHz, CDCl ): 110.4, 110.9,
3
117.8, 125.3, 125.4, 125.7, 128.5, 128.6, 128.7, 128.8,
128.9, 129.1, 129.4, 131.0, 131.2, 131.6, 131.9, 132.1,
132.2, 132.4, 132.8, 132.9, 133.0, 133.1, 133.3, 133.6,
31
3
134.2, 134.5, 138.3, 143.0. P NMR (81 MHz, CDCl ):
2
D
5
þ
þ
29.1. ½aꢀ ¼ +95.3 (c 1, DMF). ESI : MH ¼ 705. Mp:
1
tained (100 mg, 0.15 mmol, 60% yield). H NMR
(
>300 ꢁC. Calcd. C 78.40, H 4.29, N 3.98, P 8.79; found C
78.12, H 4.35, N 3.84, P 8.45.
200 MHz, CDCl ): 6.73 (d, 2H, J ¼ 8:4), 6.90 (ddd, 2H,
3
J ¼ 1:0; 7.0; 14.3), 7.2–7.8 (m, 22H), 7.85 (d, 2H,
13
J ¼ 11:3), 8.28 (d, 2H, 8.3). C NMR (75 MHz,
CDCl ): 110.8, 111.0, 117.9, 125.8, 127.6, 128.0, 128.6,
3
0
4
.7. (S)-4,4 -DicyanoBINAP 7
1
1
1
28.8, 129.0, 129.2, 129.7, 130.3, 130.7, 131.0, 132.1,
32.2, 132.3, 132.6, 132.8, 132.9, 133.0, 133.9, 134.5,
In a 25 mL round-bottomed flask under an inert atmo-
sphere fitted with a reflux condenser was placed, (S)-
31
34.7, 147.3.
P NMR (81 MHz, CDCl ): 27.77.
3
25
þ
þ
½
aꢀ ¼ )94.3 (c 1, DMF). ESI : MH ¼ 705.2. Mp:
0
D
4
,4 -dicyanoBINAPO (420 mg, 0.6 mmol). Degassed
>
300 ꢁC. Calcd. C 78.40, H 4.29, N 3.98, P 8.79; found C
7.99, H 4.33, N 3.74, P 8.2.
phenylsilane (8 mL, 64.8 mmol) was added. The mixture
was heated to 130 ꢁC after which trichlorosilane was
added in three portions (3 · 1 mL) after 1, 3 and 15 h.
The solution was then stirred for 2 h, cooled and evap-
orated till a white solid was obtained. This latter was
washed with cyclohexane, filtered on Millipore and
7
0
4
.5. (R)-5,5 -DibromoBINAPO 4
A solution of (R)-BINAPO (4.8 g, 7.4 mmol) in 1,2-
dichloroethane (45 mL) was added dropwise to a stirred
refluxing solution of 1,2-dichloroethane (65 mL), Br2
(
1
mixture was left at reflux overnight and then filtered to
remove any iron. The organic layer was washed
2
sequentially with H O, aqueous 1 M sodium hydrogen
dried. White crystals were obtained in quantitative
1
yields (402 mg, >99%). H NMR (300 MHz, CDCl
3
):
6
7
.64 (d, 2H, J ¼ 9), 6.93–6.97 (m, 2H), 7.1–7.3 (m, 20H),
7.6 mL, 148 mmol, 20 equiv) and Fe (622 mg,
1.1 mmol, 1.5 equiv). After addition was completed, the
13
.54 (t, 2H), 7.98 (s, 2H), 8.23 (d, 2H, J ¼ 8; 3).
): 111.6, 118.2, 125.4, 125.6,
27.8, 128.0, 128.8, 128.9, 129.0, 129.1, 129.12, 129.16,
C
NMR (75 MHz, CDCl
3
1
1
1
1
1
29.2, 129.5, 129.8, 132.2, 132.8, 132.9, 133.0, 133.1,
33.2, 133.4, 134.6, 134.8, 134.9, 135.0, 135.1, 135.15,
35.2, 136.0, 136.1, 136.2, 136.7, 136.8, 136.9, 137.1,
48.3, 148.6, 148.9. P NMR (81 MHz, CDCl ): )13.30.
D
73.1884, found 673.1879.
sulfite, saturated sodium hydrogen carbonate solution
and brine. After drying over Na SO the solvent was
removed to obtain a white solid (4.85 g, 6 mmol, 80.7%).
2
4
31
3
25
þ
½
aꢀ ¼ )96.3 (c 1, DMF). HRLSIMS: MH . Calcd
1
H NMR (200 MHz, CDCl
.72 (d, 2H, J ¼ 9:0), 7.2–7.5 (m, 20H), 7.55 (dd, 2H,
J ¼ 3:0, 1.0), 7.6–7.8 (m, 2H), 8.3 (dd, 2H, J ¼ 1:7, 9.0).
3
): 6.62 (t, 2H, J ¼ 15:0),
6
6
13
C NMR (75 MHz, CDCl
3
): 123.2, 126.5, 127.1, 127.3,
0
1
1
2
28.5, 128.7, 129.9, 131.6, 131.8, 132.1, 132.3, 132.5,
4.8. (R)-5,5 -DicyanoBINAP 8
31
3
32.8, 132.9, 133.4, 135.0. P NMR (81 MHz, CDCl ):
2
5
þ
þ
9.20. ½aꢀ ¼ +97.7 (c 1, DMF). ESI : MH ¼ 813.32.
In a 25 mL round-bottomed flask under an inert
0
D
Mp: >300 ꢁC. Calcd. C 65.05, H 3.72, P 7.62, Br 19.67;
found C 65.34, H 4.05, P 7.46, Br 19.44.
atmosphere and reflux condenser was placed (R)-5,5 -
dicyanoBINAPO (420 mg, 0.6 mmol). Degassed phenyl-
silane (8 mL, 64.8 mmol) was then added. The mixture
was heated to 130 ꢁC and trichlorosilane was added in
three portions (3 · 1 mL) after 1, 3 and 15 h. The
solution was stirred for 2 h, cooled and evaporated till a
white solid was obtained. It was washed with cyclo-
hexane, filtered on Millipore and evaporated. The
0
4
.6. (R)-5,5 -DicyanoBINAPO 6
In a 250 mL round-bottomed flask fitted with a reflux
0
condenser were placed (R)-5,5 dibromoBINAPO (4.7 g,
5
2
.8 mmol) and copper cyanide (1.04 g, 16.24 mmol,
.8 equiv) in 3 mL of DMF. The mixture was heated to
product was obtained in quantitative yields (400 mg,
1
>99%). H NMR (300 MHz, CDCl ): 6.6–6.8 (m, 4H),
7.04–7.3 (m, 20H), 7.4 (d, 2H, J ¼ 7:14), 7.5 (d, 2H,
3
reflux overnight. The mixture was then cooled and
5 mL of ethylenediamine and 25 mL of water added.
13
2
J ¼ 8:85), 8.3 (d, 2H, J ¼ 9:03). C NMR (75 MHz,
After stirring for 5 min, 100 mL of water and 200 mL
of toluene were added, the aqueous phase was then
extracted with 100 mL of toluene. The organic phases
were washed with 100 mL of water, 100 mL of HCl
CDCl ): 110.2, 117.7, 124.9, 125.7, 128.3, 128.4, 128.5,
3
128.54, 128.6, 128.65, 129.1, 131.8, 132.4, 132.5, 132.6,
132.65, 132.7, 132.8, 132.9, 133.0, 133.1, 134.3, 134.5,
3
1
134.7, 135.0, 135.5, 136.5, 136.6, 139.1, 143.2, 143.6.
P
25
(
0.5 M, four times) 100 mL of brine and 100 mL of sat-
NMR (81 MHz, CDCl ): )13.99. ½aꢀ ¼ +98.6 (c 1,
3
D
þ
urated sodium carbonate solution. The mixture was
dried and evaporated. A white solid was obtained
DMF). HRLSIMS: MH . Calcd 673.1884, found
673.1881.

644
M. Berthod et al. / Tetrahedron: Asymmetry 15 (2004) 639–645
0
4
.9. (S)-4,4 -DiaminomethylBINAP 9
4.12. Formation of the catalysts 13 and 14 (according to
9
the literature )
In a 100 mL round-bottomed flask, under an inert
0
atmosphere, (S)-4,4 -dicyanoBINAP (400 mg, 0.6 mmol)
was dissolved in a mixture of 23 mL of toluene and
Under Ar, at 25 ꢁC, 8.4 lL of an aqueous HBr solution
(48%) (0.05 mmol) was added to a stirred solution of (R)
0
0
2
was then added portionwise. The mixture was heated to
3 mL of tetrahydrofuran. LiAlH (227.7 mg, 6 mmol)
or (S)-4,4 or 5,5 -diamBINAP (17 mg, 0.025 mmol) in
CH Cl (1 mL). The reaction mixture was allowed to stir
4
2
2
1
0
05 ꢁC and stirred for 2 h. The product was cooled and
.5 mL of water and 0.5 mL of a 10 M sodium hydroxide
for 1 h after which the solvent was then removed. To the
residue was added Ru[(2-methylallyl)2(COD)] (7.5 mg,
0.024 mmol) and 1 mL of acetone. Then 8.4 lL of an
aqueous HBr solution (48%) (0.05 mmol) was added.
The reaction mixture was allowed to stir for 0.5 h after
which the solvent was removed. Catalysts were used
immediately for the hydrogenation.
solution were added and stirred for 5 min. Celite (1.5 g)
was added and stirred for 5 min. Then the solution was
filtered. The filtrate was dried and the solvent evapo-
rated to yield a white solid (407 mg, 0.6 mmol, 100%).
1
H NMR (200 MHz, CDCl
3
): 1.56 (s, 4H), 4.33 (s, 4H),
6
.7–7.0 (m, 4H), 7.1–7.3 (m, 20H), 7.4–7.5 (m, 4H), 8.08
31
(
d, 2H, J ¼ 8:5)). P NMR (81 MHz, CDCl ): )14.62.
3
1
3
C NMR (50 MHz, CDCl
27.6, 128.0, 128.1, 128.4, 128.6, 128.8, 129.1, 131.3,
3
): 44.3, 123.1, 125.6, 126.9,
4.13. Typical biphasic reduction procedure of b-ketoesters
1
1
1
25
D
32.7, 132.9, 133.0, 134.0, 134.4, 138.9. ½aꢀ ¼ )102.4 (c
Under Ar, to the preceding catalysts dissolved in H O
2
2
D
5
þ
, DMF). ½aꢀ ¼ +101.7 (c 1, DMF). HRLSIMS: MH .
(1 mL), the water-insoluble b-ketoesters were added
(substrate/catalyst: 1000). This biphasic mixture was
allowed to stir and then stand overnight in a stainless
Calcd 681.2588, found 681.2581.
steel hydrogenation vessel at 50 ꢁC under 40 bar H
2
. The
resulting water-soluble reduced product was extracted
three times with pentane. The aqueous phase containing
the catalyst was reused as previously described.
0
4
.10. (R)-5,5 -DiaminomethylBINAP10
In a 100 mL round-bottomed flask under an inert
0
atmosphere, (R)-5,5 -dicyanoBINAP (400 mg, 0.6 mmol)
was dissolved in a mixture of 23 mL of toluene and
GC conditions
Substrate
Conditions
Lipodex A
Retention time
2
3 mL of tetrahydrofuran. LiAlH
was then added portionwise. The mixture was heated to
4
(227.7 mg, 6 mmol)
Methyl
acetoacetate
Starting material:
5.3 min
1
05 ꢁC and stirred for 2 h. The reaction mixture was
4
5 ꢁC (5 min)–1 ꢁC/
Enantiomers: 7.13;
7.93 min
cooled and 0.5 mL of water and 0.5 mL of a 10 M
sodium hydroxide solution were added and stirred for
min–60 ꢁC (5 min)
Lipodex A
Ethyl
acetoacetate
Starting material:
10.17 min
Enantiomers: 26.3;
5 min. Celite (1.5 g) was added and stirred for 5 min.
Then the solution was filtered. The filtrate was dried and
the solvent evaporated to yield a white solid (405 mg,
4
0 ꢁC (30 min)
Ethyl benzoylacetate Lipodex A
90 ꢁC (1 min)–1 ꢁC/
2
7.4 min
1
0
4
7
2
.6 mmol, 100%). H NMR (200 MHz, CDCl ): 1.6 (s,
3
Starting material:
12.3 min
H), 4.37 (s, 4H), 6.8–7.0 (m, 4H), 7.1–7.3 (m, 20H),
.36 (d, 2H, J ¼ 6:58), 7.5 (d, 2H, J ¼ 8; 82), 8.15 (d,
Enantiomers: 14.5;
15.2 min
31
13
H, J ¼ 8; 82). P NMR (81 MHz, CDCl ): )15.50.
C
min–150 ꢁC (1 min)
3
3
NMR (50 MHz, CDCl ): 44.3, 122.2, 125.6, 125.9, 127.3,
1
1
28.1, 128.3, 128.4, 128.7, 129.0, 129.3, 130.0, 132.6,
25
D
32.9, 133.2, 133.8, 135.2, 139.4. ½aꢀ ¼ )100.3 (c 1,
25
þ
DMF). ½aꢀ ¼ +101.4 (c 1, DMF). HRLSIMS: MH .
D
Calcd 681.2588, found 681.2587.
References and notes
1
2
3
. Noyori, R. Asymmetric Catalysis in Organic Synthesis;
Wiley Intersciences: New York, 1994.
. Kumobayashi, H.; Miura, T.; Sayo, N.; Saito, T.; Zhang,
X. Synlett 2001, 1055.
. Nakagawa, S.; Sugimura, T.; Tai, A. Chem. Lett. 1997,
859; Kukula, P.; Cerveny, L. J. Mol. Catal. A. 2002, 185,
195–202; Welton, T. Chem. Rev. 1999, 99, 2071; Dupont,
J.; de Souza, R. F.; Suarez, P. A. Z. Chem. Rev. 2002, 102,
4
.11. Typical reduction procedure of b-ketoesters
All experiments were performed under argon and all
solvents were degassed by argon bubbling followed by
three vacuum/argon cycles. Catalysts were prepared
9;10
3
667–3692; Olivier-Bourbigou, H.; Magna, L. J. Mol.
according to literature procedures.
A calculated
Catal. A. 2002, 182–183, 419–437; Jessop, P. G.; Ikaria, T.;
Noyori, R. Chem. Rev. 1999, 99, 475–493.
amount of b-ketoesters in 2 mL of MeOH or EtOH was
added to the above catalysts obtained in situ. This
solution was put in a stainless steel hydrogenation ves-
sel. After purging three times with argon and three times
with hydrogen, the pressure was raised to 40 bar and the
reaction mixture stirred at 50 ꢁC for 15 h. The reaction
mixture was filtered on Celite and analyzed by GC to
determine both conversion and ee.
4
5
. For example see: Fan, Q. H.; Li, Y. M.; Chan, A. S. C.
Chem. Rev. 2002, 102, 3385–3466.
. Kuntz, E. G. CHEMTECH 1987, 570; Herrmann, W. A.;
Kohpaintner, C. W. Angew. Chem., Int. Ed. Engl. 1993,
32, 1524.
6. Aqueous-phase Organometallic Catalysis; Cornils, B.,
Herrmann, W. A., Eds.; Wiley-VCH: Weinheim, 1998.

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9
. Lamouille, T.; Saluzzo, C.; ter Halle, R.; Le guyader, F.;
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1
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1