A hybrid phosphorus ligand for highly enantioselective asymmetric hydroformylation

Article abstract of DOI:10.1021/ja057065s

A new hybrid phosphorus ligand has been prepared starting from chiral NOBIN (2-amino-2-hydroxy-1,1-binaphthyl). Excellent enantioselectivities (up to 99% ee) have been achieved in the Rh-catalyzed asymmetric hydroformylations of styrene derivatives and vinyl acetate.

Full text of DOI:10.1021/ja057065s

Published on Web 05/12/2006
A Hybrid Phosphorus Ligand for Highly Enantioselective
Asymmetric Hydroformylation
Yongjun Yan and Xumu Zhang*
Contribution from the Department of Chemistry, The PennsylVania State UniVersity,
UniVersity Park, PennsylVania 16802
Received October 17, 2005; E-mail: xumu@chem.psu.edu.
Abstract: A new hybrid phosphorus ligand has been prepared starting from chiral NOBIN (2-amino-2′-
hydroxy-1,1′-binaphthyl). Excellent enantioselectivities (up to 99% ee) have been achieved in the
Rh-catalyzed asymmetric hydroformylations of styrene derivatives and vinyl acetate.
Introduction
benchmark ligands for the asymmetric hydroformylation of
vinylarenes. For example, up to 94% ee has been achieved for
Hydroformylation is the reaction of alkenes with carbon
monoxide and hydrogen to form aldehydes, which provides a
versatile method for the functionalization of C-C double bonds
the hydroformylation of styrene with Rh-Binaphos catalyst.
However, racemization remains a major problem for Binaphos,2
and the enantioselectivity can be further improved. The devel-
opment of ligands for highly enantioselective hydroformylation
without the racemization of chiral products is highly desirable.
Herein, we would like to report the synthesis of a new hybrid
b,4a
[eq 1].
5
phosphine-phosphoramidite ligand 1 and its applications in
asymmetric hydroformylation. With (R,S)-1 as the ligand,
unprecedented high enantioselectivities (up to 99% ee) have
been achieved for hydroformylation, and significant performance
Today, hydroformylation is the largest industrially homoge-
neous catalytic process. Over 6 million tons of oxo products
are being produced worldwide per year. Because chiral alde-
hydes can be easily converted into a variety of enantiomerically
1
(2) (a) Sakai, N.; Mano, S.; Nozaki, K.; Takaya, H. J. Am. Chem. Soc. 1993,
pure compounds, asymmetric hydroformylation is potentially
1
15, 7033-7034. (b) Nozaki, K.; Sakai, N.; Nanno, T.; Higashijima, T.;
useful for the preparation of pharmaceutical products. Despite
its importance, asymmetric hydroformylation is underdeveloped.
Achieving high ee’s (g98% ee) remains a challenging goal due
to the following reasons: First, hydroformylation reactions are
often carried out at elevated temperature to achieve an acceptable
reaction rate. However, high enantioselectivities are generally
observed at low temperature with relatively low reaction rate
and low conversion. This limits the utilities of this important
transformation. Second, the aldehyde products, especially for
those hydroformylated from styrene derivatives, can undergo
Mano, S.; Horiuchi, T.; Takaya, H. J. Am. Chem. Soc. 1997, 119, 4413-
4423. (c) Clark, T. P.; Landis, C. R.; Freed, S. L.; Klosin, J.; Abboud, K.
A. J. Am. Chem. Soc. 2005, 127, 5040-5042. (d) Breeden, S.; Cole-
Hamilton, D. J.; Foster, D. F.; Schwarz, G. J.; Wills, M. Angew. Chem.,
Int. Ed. 2000, 39, 4106-4108. (e) Babin, J. E.; Whiteker, G. T. Patent
WO 9303839, 1992. (f) Dieguez, M.; Pamies, O.; Ruiz, A.; Castillon, S.;
Claver, C. Chem.-Eur. J. 2001, 7, 3086-3094. (g) Axtell, A. T.; Cobley,
C. J.; Klosin, J.; Whiteker, G. T.; Zanotti-Gerosa, A.; Abboud, K. A. Angew.
Chem., Int. Ed. 2005, 44, 5834-5838. (h) Huang, J.; Bunel, E.; Allgeier,
A.; Tedrow, J.; Storz, T.; Preston, J.; Correll, T.; Manley, D.; Soukup, T.;
Jensen, R.; Syed, R.; Moniz, G.; Larsen, R.; Martinelli, M.; Reider, P.
Tetrahedron Lett. 2005, 46, 7831-7834.
(3) (a) Ewalds, R.; Eggeling, E. B.; Hewat, A. C.; Kamer, P. C. J.; van Leeuwen,
P. W. N. M.; Vogt, D. Chem.-Eur. J. 2000, 6, 1496-1504. (b) Lot, O.;
Suisse1, I.; Mortreux, A.; Agbossou, F. J. Mol. Catal. A: Chem. 2000,
164, 125-130. (c) Deerenberg, S.; Kamer, P. C. J.; van Leeuwen, P. W.
N. M. Organometallics 2000, 19, 2065-2072. (d) Franci o` , G.; Faraone,
F.; Leitner, W. Angew. Chem., Int. Ed. 2000, 39, 1428-1430. (e) Kless,
A.; Holz, J.; Heller, D.; Kadyrov, R.; Selke, R.; Fischer, C.; B o¨ mer, A.
Tetrahedron: Asymmetry 1996, 7, 33-36.
1b
racemization under certain hydroformylation reaction conditions.
This racemization results in lower ee’s at high conversion in
some catalytic systems. To the best of our knowledge, only a
few ligands2 are capable of affording over 90% ee’s in
asymmetric hydroformylation. Recent reports have shown that
mixed phosphorus ligands bearing two different phosphorus
(4) (a) Solinas, M.; Gladiali, S.; Marchetti, M. J. Mol. Catal. A: Chem. 2005,
226, 141-147. (b) Nozaki, K.; Matsuo, T.; Shibahara, F.; Hiyama, T. AdV.
Synth. Catal. 2001, 343, 61-63. (c) Horiuchi, T.; Ohta, T.; Shirakawa, E.;
Nozaki, K.; Takaya, H. J. Org. Chem. 1997, 62, 4285-4292. (d) Nozaki,
K.; Hidemasa, T.; Tamejiro, H. Top. Catal. 1998, 4, 175-185. (e) Horiuchi,
T.; Shirakawa, E.; Nozaki, K.; Takaya, H. Organometallics 1997, 16, 2981-
2986. (f) Nozaki, K.; Nanno, T.; Takaya, H. J. Organomet. Chem. 1997,
2
a,b,3
groups are effective in asymmetric hydroformylation.
Binaphos,2
a,b,4
a hybrid phosphine-phosphite ligand developed
5
27, 103-108. (g) Nozaki, K.; Li, W.-G.; Horiuchi, T.; Takaya, H.
by Takaya and co-workers, has been proved to be one of the
Tetrahedron Lett. 1997, 38, 4611-4614. (h) Horiuchi, T.; Ohta, T.;
Shirakawa, E.; Nozaki, K.; Takaya, H. Tetrahedron 1997, 53, 7795-7804.
(i) Nozaki, K.; Li, W.-G.; Horiuchi, T.; Takaya, H.; Saito, T.; Yoshida,
A.; Matsumura, K.; Kato, Y.; Imai, T.; Miura, T.; Kumobayashi, H. J.
Org. Chem. 1996, 61, 7658-7659. (j) Horiuchi, T.; Ohta, T.; Nozaki, K.;
Takaya, H. Chem. Commun. 1996, 155-156. (k) Nanno, T.; Sakai, N.;
Nozaki, K.; Takaya, H. Tetrahedron: Asymmetry 1995, 6, 2583-2591. (l)
Sakai, N.; Nozaki, K.; Takaya, H. J. Chem. Soc., Chem. Commun. 1994,
395-396.
(
1) For recent reviews, see: (a) Claver, C.; van Leeuwen, P. W. N. M. In
Rhodium Catalyzed Hydroformylation; Claver, C., van Leeuwen, P. W. N.
M., Eds.; Kluwer Academic Publishers: Dordrecht, The Netherlands, 2000.
(
b) Agbossou, F.; Carpentier, J.; Mortreux, A. Chem. ReV. 1995, 95, 2485-
2
506. (c) Gladiali, S.; Bay o¨ n, J. C.; Claver, C. Tetrahedron: Asymmetry
995, 6, 1453-1474. (d) Breit, B.; Seiche, W. Synthesis 2001, 1-36. (e)
1
Di e´ guez, M.; P a` mies, O.; Claver, C. Tetrahedron: Asymmetry 2004, 15,
2
113-2122.
(5) We named this new hybrid phosphine-phosphoamidite ligand as YanPhos.
7198
9
J. AM. CHEM. SOC. 2006, 128, 7198-7202
10.1021/ja057065s CCC: $33.50 © 2006 American Chemical Society

A Hybrid Phosphorus Ligand for Hydroformylation
A R T I C L E S
Figure 1. Space-filling and stick models for Rh[(R,S)-1]H(CO)2 and Rh[(R,S)-Binaphos]H(CO)2 based on CAChe MM2 calculation.
enhancements have been obtained as compared to the benchmark
ligand, Binaphos.
Scheme 1. Synthesis of (R,S)-1
Results and Discussion
Takaya and co-workers have demonstrated that configuration
matched (R,S and S,R) Binaphos led to better enantioselectivity
than mismatched (R,R and S,S) Binaphos.2b As the phosphine-
phosphoramidite analogue of Binaphos, we anticipated that
phosphine oxide amide 3 was easily obtained in high yield.
Reduction of both phosphine oxide and amide groups with
excess BH3, followed by treatment with diethylamine, gave 4
in 49% yield. After deprotonation with n-BuLi and quenching
with phosphorochloridite 5, the desired ligand (R,S)-1 was
obtained in 37% yield as an air-stable solid (Scheme 1).
(R,S)-1 and its enantiomer are the configuration matched
isomers. We thus synthesized (R,S)-1 for the current study.
Despite the similarity, there is a significant difference between
Binaphos and ligand 1, both electronically (phosphoramidites
are more electron-donating than phosphites because the elec-
tronegativity of nitrogen (3.04) is less than that of oxygen (3.44))
and sterically. Hence, replacing the phosphite group in Binaphos
with the N-substituted phosphoramidite group in ligand 1
represents substantial change. Figure 1 shows the space-filling
and stick models (based on CAChe MM2 calculation) for Rh-
Using the chiral ligand (R,S)-1, rhodium-catalyzed asymmetric
hydroformylation has been explored. Styrene was selected as
the standard substrate for the optimization of reaction conditions.
The catalyst was prepared in situ by mixing Rh(acac)(CO)2 with
4
equiv of ligand 1. Hydroformylation reactions were performed
using 1:1 CO/H2 gas with 0.1 mol % of the catalyst. The
chemoselectivities of the hydroformylation reactions were
[(R,S)-1]H(CO)2 and Rh[(R,S)-Binaphos]H(CO)2 complexes,
which are presumed to be the active intermediates in hydro-
formylation reactions.2 As shown in Figure 1, in the presence
of the crowded N-substituent, Rh[(R,S)-1]H(CO)2 complex can
provide a deeper and more closed chiral pocket than the
corresponding Rh[(R,S)-Binaphos]H(CO)2 complex. Molecular
dynamics simulation based on the CAChe program also indicates
that the Rh complex of ligand 1 is more conformationally rigid
than the analogous Binaphos complex due to the presence of
N-substituent of the phosphoramidite part in ligand 1. We
envision that a more closed rigid chiral pocket provided by Rh-
1
excellent, and no hydrogenation product was detected via H
a,b
NMR. The regioselectivities were moderate with a branch/linear
ratio generally over 85:15, which were comparable to the results
2
a,b
obtained with Binaphos.
The enantioselectivities strongly
depended on reaction conditions. Significant solvent effect was
observed (Table 1, entries 1-4). High enantioselectivities were
obtained when the reactions were run in nonpolar solvents such
as methylene chloride and benzene, while low ee values were
observed in THF and EtOAc. The competition for coordination
sites between polar solvents and substrates may account for this
[
(R,S)-1]H(CO)2 complex could lead to high asymmetric induc-
tion.
Ligand 1 was prepared from chiral 2-amino-2′-hydroxy-1,1′-
1
b
solvent effect. Increasing reaction temperature led to faster
(
6) Vyskocil, S.; Smrcina, M.; Hanus, V.; Polasek, M.; Kocovsky, P. J. Org.
6
binaphthyl (NOBIN) 2. Following the literature procedure, the
Chem. 1998, 63, 7738-7748.
J. AM. CHEM. SOC.
9
VOL. 128, NO. 22, 2006 7199

A R T I C L E S
Yan and Zhang
Table 1. Optimization of Asymmetric Hydroformylation of Styrene with Rh-(R,S)-1 Catalysta
entry
solvent
T (°
C)
H
2
/CO (atm)
time (h)
conv. (%)b
b/lc
ee (%)d
1
2
3
4
5
6
7
8
9
C6H6
CH2Cl2
THF
EtOAC
C6H6
C6H6
C6H6
C6H6
C6H6
C6H6
60
60
60
60
40
80
60
60
60
60
10/10
10/10
10/10
10/10
10/10
10/10
20/20
30/30
10/10
10/10
24
24
24
24
24
24
24
24
12
36
>99
93
95
98
25
>99
91
83
87
88/12
91/9
88/12
89/11
91/9
85/15
89/11
88/12
89/11
88/12
98(R)
97(R)
78(R)
84(R)
99(R)
81(R)
98(R)
98(R)
99(R)
97(R)
1
0
>99
a
All reactions were carried out with L:Rh ) 4:1, substrate:Rh ) 1000. Conversions were determined on the basis of H NMR. c (b/l) branched-linear
b
l
l
d
ratio. Determined on the basis of H NMR. Determined by converting the aldehyde to the corresponding alcohol with NaBH4 followed by GC analysis
Supelco’s Beta Dex 225). The absolute configuration (R) was assigned by comparing the sign of the optical rotation of the resulting alcohol with (R)-2-
(
phenylpropan-1-ol.
Table 2. Asymmetric Hydroformylations with Rh-L Catalystsa
entry
R
ligand
S/Cb
T (
°C)
H
2
/CO (atm)
time (h)
conv. (%)c
b/ld
ee (%)e
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
Ph 6a
Ph 6a
Ph 6a
(R,S)-1
1000
1000
2000
1000
1000
1000
2000
1000
2000
1000
1000
1000
1000
1000
300
60
60
60
60
60
60
40
60
40
60
60
60
60
60
60
60
60
60
10/10
10/10
50/50
10/10
50/50
10/10
50/50
10/10
50/50
10/10
50/50
10/10
50/50
10/10
50/50
10/10
50/50
10/10
24
24
43
24
20
24
39
24
30
24
34
24
34
24
66
24
36
24
>99
>99
>99
98
97
>99
43
99
52
>99
>99
97
>99
98
>99
75
88/12
83/17
88/12
87/13
86/14
88/12
89/11
91/9
98(R)
84(S)
94(S)
99(R)
95(S)
98(R)
92(R)
98(R)
95(R)
98(R)
93(S)
98(R)
88(S)
98(R)
92(S)
96(S)
92(S)
98(R)
(S,R)-Binaphos
(S,R)-Binaphos
(R,S)-1
(S,R)-Binaphos
(R,S)-1
(R,S)-Binaphos
(R,S)-1
(R,S)-Binaphos
(R,S)-1
(S,R)-Binaphos
(R,S)-1
(S,R)-Binaphos
(R,S)-1
(S,R)-Binaphos
(R,S)-1
(R,S)-Binaphos
(R,S)-1
f
p-Me-Ph 6b
p-Me-Ph 6b
p-F-Ph 6c
f
g
p-F-Ph 6c
o-F-Ph 6d
o-F-Ph 6d
p-Cl-Ph 6e
p-Cl-Ph 6e
p-Meo-Ph 6f
p-Meo-Ph 6f
g
91/9
1
1
1
1
1
1
1
1
1
87/13
87/13
86/14
87/13
89/11
88/12
93/7
f
f
f
f
i
p- Bu-Ph 6g
i
p- Bu-Ph 6g
OAc 6h
OAc 6h
Ph 6a
1000
400
10 000
>99
89
86/14
88/12
a
All reactions were carried out with L:Rh ) 4:1 in benzene. Substrate-catalyst ratio. c Conversions were determined on the basis of H NMR. (b/l)
b
1
d
1
e
f
g
branched-linear ratio. Determined on the basis of H NMR. See Supporting Information for details. Data taken from ref 2a for comparison. Data taken
from ref 2b for comparison.
reaction rate and lower ee (Table 1, entries 1, 5, and 6).
Enantiomeric excess of 99% was achieved when the reaction
was run at 40 °C with 25% conversion. Up to 98% ee was
achieved in asymmetric hydroformylation with 100% conversion
at 60 °C, while the enantioselectivity dropped to 81% ee at 80
It has also been reported that significant racemization may occur
even before full conversion was reached in the hydroformylation
4
a
of styrene with Binaphos. After reaction conditions were
screened, hydroformylation of styrene with the Rh-(R,S)-1
catalyst was performed under 20 atm of 1:1 CO/H2 at 60 °C in
benzene. Optimized conversion, regioselectivity, and enanti-
oselectivity were achieved under this condition.
°
C. No significant influence of the CO/H2 pressure on regio-
and enantioselectivity was observed. The total pressure dramati-
cally affected the reaction rate (Table 1, entries 1, 7, and 8).
Under low CO/H2 pressure, the reaction was fast and complete
conversion was achieved in 24 h under 20 atm of CO/H2. The
pressure effect on the reaction rate can be explained by the lower
dissociation rate of CO from the Rh center at high pressure. It
is worth noting that the racemization of the hydroformylation
product was significantly lower with ligand 1 than with
Binaphos.2b For example, elongation of the reaction time after
the reaction was complete only slightly lowered the enantiomeric
excess of the chiral product with ligand 1 (Table 1, entries 1,
A series of styrene derivatives were hydroformylated using
the Rh-(R,S)-1 catalyst under the optimized reaction condition
(Table 2). Under the same reaction condition, 98% ee (Table
2, entry 1) in the hydroformylation of styrene was achieved
with ligand 1, while only 84% ee (Table 2, entry 2) was obtained
with Binaphos. The result with Binaphos under current reaction
condition is much lower than the literature reported result (Table
2a,b
2, entry 3, 94% ee). Because optimized reaction conditions
for Binaphos and ligand 1 are very different due to different
steric and electronic properties of two ligands, direct comparison
of ligand 1 with Binaphos under the same reaction condition is
not appropriate. To demonstrate the utilities of this new ligand,
9
, and 10). With Binaphos as the ligand, a dramatic decrease
2b
of enantiomeric excess after full conversion has been observed.
7200 J. AM. CHEM. SOC.
9
VOL. 128, NO. 22, 2006

A Hybrid Phosphorus Ligand for Hydroformylation
A R T I C L E S
we have selected the best reported results with Binaphos for a
side-by-side comparison. With ligand 1, up to 99% ee was
obtained for the hydroformylation of para-methyl styrene (Table
obtained on a Perkin-Elmer 241 polarimeter. MS spectra were recorded
on a KRATOS mass spectrometer MS 9/50. GC analysis was carried
out on Hewlett-Packard 6890 gas chromatography using chiral capillary
columns. Compound 3 was synthesized according to known literature
procedure.6
2
, entry 4). Halogen-substituted styrene derivatives were also
hydroformylated with excellent enantioselectivities with ligand
(Table 2, entries 6, 8, and 10). It is worth noting that high
Synthesis of Compound 4. To a solution of 3 (3.70 g, 7.24 mmol)
in THF (200 mL) was added dropwise a 10 M borane-dimethyl sulfide
complex in THF (7.24 mL, 72.4 mmol) at 0 °C. The mixture was
refluxed for 18 h. After being cooled to room temperature, the mixture
was diluted with EtOAc (200 mL) and poured into ice water. The
mixture was stirred for 30 min, and the organic layer was separated
and washed with brine. The organic phase was dried over Na SO and
1
enantioselectivities at high conversions were achieved for
fluorinated styrene derivatives (Table 2, entries 6 and 8). For
comparison, the reactions with Binaphos needed to be terminated
at moderate conversions to obtain high enantioselectivities due
to the racemization of the chiral products (Table 2, entries 7
and 9).2b With ligand 1, para-methoxy styrene was hydroformy-
lated with high enantioselectivity (98% ee) (Table 2, entry 12),
which is significantly higher than the result (88% ee) reported
with Binaphos.2a,b Up to 98% ee for the hydroformylation of
para-isobutyl styrene was achieved with ligand 1 (Table 2, entry
2
4
concentrated under reduced pressure. To the residue was added 270
mL of diethylamine, and the reaction mixture was stirred at room
temperature for 30 min. After removal of diethylamine, the residue
was chromatographed on silica gel (eluted with hexane/EtOAc, 16:1)
1
to give 4 (1.71 g) in 49% yield. H NMR (360 MHz, CDCl
2
) δ: 7.91
(t, J ) 8.92 Hz, 3H), 7.77 (d, J ) 8.01 Hz, 1H), 7.54-7.7.44 (m, 2H),
14). Oxidation of the aldehyde product affords the corresponding
7
6
2
.33-7.16 (m, 11H), 7.12 (t, J ) 7.40 Hz, 1H), 7.07-7.01 (m, 3H),
acid, ibuprofen, one of the most widely used nonsteroidal
antiinflammatory agents. (S)-Ibuprofen is the biological active
form of two enantiomers. With Binaphos, only 92% ee was
obtained (Table 2, entry 15), and the turnover frequency was
very low (300 turnover after 66 h).2 Hydroformylation of vinyl
acetate was also tested with ligand 1. The hydroformylation
product 2-acetoxypropanal is a precursor for the Strecker
.65 (d, J ) 8.47 Hz, 1H), 3.21 (m, 1H), 3.07-3.00 (m, 1H), 2.81-
13
.72 (m, 1H), 0.76 (t, J ) 7.11 Hz, 3H). C NMR (91 MHz, CD
2
Cl
2
)
δ: 144.81, 144.78, 142.62, 142.24, 138.65, 138.50, 138.10, 137.65,
134.79, 134.18, 133.96, 133.63, 133.42, 133.35, 131.34, 129.91, 128.97,
128.91, 128.90, 128.81, 128.66, 128.59, 128.56, 128.47, 128.31, 127.60,
127.34, 127.19, 126.77, 126.74, 126.57, 124.31, 121.79, 116.24, 116.14,
a,b
1
13.92, 38.68, 15.17. 31P NMR (146 MHz, CH
HRMS (ES+) (m/z): calcd for C34 29NP, 482.2038; found, 482.2029.
2 2
Cl ) δ: -14.235 (s).
7
H
synthesis of the amino acid threonine. The hydroformylation
Synthesis of Ligand 1. To a solution of 4 (0.24 g, 0.5 mmol) in
THF (5 mL) at 0 °C was added dropwise n-BuLi (0.65 mmol, 0.26
mL of 2.5 M hexane solution). The reaction mixture was allowed to
warm to room temperature and stirred for 30 min to give a deep red
solution. The reaction mixture was then recooled to 0 °C, and 5 (262
mg, 0.75 mmol) in THF (5 mL) was added dropwise. After addition,
the cooling bath was removed and the mixture was stirred at room
temperature overnight. The volatiles were evaporated under reduced
was performed under the identical reaction condition for styrene.
After 24 h, 75% of the starting material was converted to
aldehyde with 96% ee and with a 13:1 branch/linear ratio (Table
2
, entry 16). The enantioselectivity with ligand 1 was higher as
2
a,b
compared to Binaphos ligand (Table 2, entry 17, 92% ee)
and matched the previous best result using chiral diazaphos-
pholane ligand (96% ee).2c To demonstrate the catalytic ef-
ficiency of Rh-(R,S)-1 catalyst, hydroformylation of styrene was
carried out with substrate/catalyst molar ratio of 10 000:1 (Table
2 2
pressure. To the residue was added CH Cl (10 mL), and the mixture
was filtered to remove the salt. The filtration was concentrated and
subjected to chromatography on silica gel (eluted with hexane/EtOAc
2
, entry 18). With this low catalyst loading, Rh-(R,S)-1 catalyst
1
9
:1) to afford pure ligand 1 (145 mg) in 37% yield. H NMR (300
still showed high reactivity (89% conversion after 24 h) and
maintained high enantioselectivity (98% ee) for the hydro-
formylation reaction.
MHz, CD
(
(
2
Cl
d, J ) 8.20 Hz, 2H), 7.67-7.55 (m, 4H), 7.41-7.05 (m, 16H), 6.99
t, J ) 6.75 Hz, 2H), 6.87 (t, J ) 7.08 Hz, 2H), 6.57 (t, J ) 7.68 Hz,
2
) δ: 8.10-8.01 (m, 3H), 7.93 (t, J ) 7.28 Hz, 2H), 7.81-
Conclusion
1H), 6.41-6.32 (m, 2H), 2.74 (m, 1H), 2.35 (m, 1H), 0.66 (t, J ) 7.01
Hz, 1H). 13C NMR (75 MHz, CD
Cl ) δ: 150.30, 150.21, 149.92,
42.36, 141.94, 138.59, 138.39, 138.27, 138.20, 135.44, 135.14, 134.10,
33.57, 133.36, 131.68, 130.51, 129.88, 129.11, 128.66, 128.58, 128.55,
128.49, 128.46, 128.42, 128.30, 128.12, 127.56, 127.19, 127.12, 127.03,
126.66, 126.29, 126.18, 125.71, 125.54, 125.06, 124.75, 122.49, 122.23,
2
2
In conclusion, a new hybrid phosphine-phosphoramidite
ligand 1 has been developed. Unprecedented high enantiose-
lectivities have been achieved for Rh-catalyzed asymmetric
hydroformylations. The high reactivity and excellent enanti-
oselectivity of this new ligand make the catalyst system
potentially useful for industrial applications. Further structural
variation of N-substituted phosphoramidite ligands will be
developed in the future for asymmetric hydroformylation and
other metal-catalyzed transformations.
1
1
122.19, 41.03, 14.98. 31P NMR (146 MHz, CD
5
C H40NO P
54 2 2
Cl
3.3 Hz), -13.57 (d, J ) 53.3 Hz). HRMS (ES+) (m/z): calcd for
, 796.2534; found, 796.2552.
General Procedure for Asymmetric Hydroformylation. In a
glovebox filled with nitrogen, to a 2 mL vial equipped with a magnetic
) δ: 141.63 (d, J )
2
2
8
2
bar were added ligand 1 (0.004 mmol), Rh(acac)(CO) (0.001 mmol
Experimental Section
in 0.10 mL of benzene), and substrate (1.0 mmol), and additional
benzene was charged to bring the total volume of the reaction mixture
to 1.0 mL. After the mixture was stirred for 10 min, the vial was
transferred into an autoclave and taken out of the glovebox. Carbon
monoxide (10 atm) and dihydrogen (10 atm) were charged in sequence.
General Methods. All reactions and manipulations were performed
in a nitrogen-filled glovebox or using standard Schlenk techniques,
unless otherwise noted. Solvents were dried with standard procedures
and degassed with N
00-400 mesh silica gel supplied by Natland International Corp. Thin-
layer chromatography (TLC) was performed on EM reagents 0.25 mm
2
. Column chromatography was performed using
9
The reaction mixture was stirred (60 rpm) at 60 °C (oil bath) for 24
2
(
8) Hydroformylation at lower ligand/metal ratio resulted in decreased enan-
tioselectivity. For example, when the ligand/metal ) 2, enantiomeric excess
dropped to 54% (branch/linear ratio ) 85/15).
1
13
31
silica 60-F plates. H, C NMR, and P spectra were recorded on
Bruker AM-300 and AMX-360 spectrometers. Optical rotation was
(
9) This is sufficient for good stirring due to the small volume of the reaction
mixture. Stirring at 160 rpm gave the same results. However, further
increasing the stirring rate (260 rpm) caused the reaction mixture to spill
out of the reaction vessel.
(
7) Chibata, I. In Synthetic Production and Utilization of Amino Acids; Kaneoko,
T., Izumi, Y., Chibata, I., Itoh, T., Eds.; Wiley: New York, 1974.
J. AM. CHEM. SOC.
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VOL. 128, NO. 22, 2006 7201

A R T I C L E S
Yan and Zhang
h. The reaction was cooled, and the pressure was carefully released in
a well-ventilated hood. The conversion and regioselectivity were
determined by H NMR spectroscopy from the crude reaction mixture.
Acknowledgment. This work was supported by a grant from
the National Institutes of Health (5R01GM058832-07).
1
For styrene derivatives, the enantiomeric excesses of the hydroformy-
lation products were determined by reduction with NaBH or oxidation
4
with Jones reagent to the corresponding alcohols or carboxylic acids,
and then analyzed by GC. For the hydroformylation product of vinyl
acetate, the enantiomeric excess was determined directly by GC analysis
of the crude reaction mixture.
Supporting Information Available: Determination of the
enantiomeric excess of hydroformylation products and ligand
NMR spectra. This material is available free of charge via the
Internet at http://pubs.acs.org.
JA057065S
7202 J. AM. CHEM. SOC.
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VOL. 128, NO. 22, 2006