Rhodium-catalyzed asymmetric hydrogenation of functionalized olefins using monodentate spiro phosphoramidite ligands

Article abstract of DOI:10.1021/jo049655z

Novel chiral monodentate phosphorus ligands, SIPHOS, were conveniently synthesized from 1,1′-spirobiindane-7,7′-diol. The Rh complexes of SIPHOS can catalyze the hydrogenation of α-dehydroamino esters in mild conditions, providing α-amino acid derivatives

Full text of DOI:10.1021/jo049655z

Rh od iu m -Ca ta lyzed Asym m etr ic Hyd r ogen a tion of F u n ction a lized
Olefin s Usin g Mon od en ta te Sp ir o P h osp h or a m id ite Liga n d s
Yu Fu,† Xun-Xiang Guo,‡ Shou-Fei Zhu,† Ai-Guo Hu,† J ian-Hua Xie,† and Qi-Lin Zhou*,†
State Key Laboratory and Institute of Elemento-organic Chemistry, Nankai University,
Tianjin 300071, China, and Institute of Fine Chemicals, East China University of Science
and Technology, Shanghai 200237, China
qlzhou@nankai.edu.cn
Received March 2, 2004
Novel chiral monodentate phosphorus ligands, SIPHOS, were conveniently synthesized from 1,1′-
spirobiindane-7,7′-diol. The Rh complexes of SIPHOS can catalyze the hydrogenation of R-dehy-
droamino esters in mild conditions, providing R-amino acid derivatives in up to 99% ee. Enamides
and â-dehydroamino esters can also be hydrogenated in good to excellent enantioselectivities (up
to 99% and 94% ee, respectively). The SIPHOS ligand with smaller alkyl groups on the N-atom
afforded higher enantioselectivity. The X-ray analysis of single crystal showed that the structure
of Rh/SIPHOS catalyst is [Rh(COD)((S)-SIPHOS-Me)2]+, which clarified the configuration of the
catalyst with the monodentate chiral phosphorus ligand in Rh-catalyzed asymmetric hydrogenation.
A positive nonlinear effect in the relationship of the optical purities of ligand and product was
observed in the hydrogenation of dehydroamino acid derivatives. The kinetic study of hydrogenation
showed that the reaction is zero order in the concentration of substrate and first order in the
concentration of Rh catalyst and the hydrogenation pressure. The rate of hydrogenation decreased
when the Rh/L ratio changed from 1:1 to 1:4.
In tr od u ction
Monodentate phosphorus ligands have been neglected
for a long period owing to the great success of biphosphine
ligands. The main advantage of the application of biden-
tate ligands is that their catalysts are more rigid, which
reduces the number of conformations of catalyst and
subsequently provides a higher enantioselectivity.8 Using
monodentate ligands, the catalyst has much more con-
formational freedom, so that a lower chiral induction was
expected. However, easy synthesis and modification of
ligands are good features of monophosphorus ligands.
Furthermore, monodentate ligands might be good choices
for the catalytic asymmetric reactions where bidentate
ligands are unfavorable, especially as the catalytic cycle
involves one or more steps in which the ligand can only
occupy one coordination site. Therefore, monodentate
ligands are gaining more attention.9
The increasing demand of enantiomerically pure chemi-
cals has expedited the development of asymmetric syn-
thesis. Significant progress has been made in Rh-
catalyzed hydrogenation in the past 2 decades.1 Both the
scope of substrate and the class of chiral ligands have
been rapidly extended. For example, a great number of
chiral phosphorus ligands have been synthesized and
applied to the Rh-catalyzed asymmetric hydrogenation
of functionalized olefins such as R-dehydroamino acid
derivatives, â-dehydroamino acid derivatives, and ena-
mides.2 Among them, most are bidentate phosphine
ligands, such as DIOP,3 BINAP,4 and DuPhos,5 though
the first utilization of a chiral ligand is monodentate
P-chiral phosphines by Knowles6 and Horner.7
In 1999, Fiaud10 reported a rhodium complex of mono-
dentate ligand 1,2,5-triphenylphospholane (1), achieving
82% ee in the hydrogenation of (Z)-2-acetaminocin-
namic ester. Only 1 year later, several efficient chiral
monophosphorus ligands including phosphonites (2),
phosphites (3), and phosphoramidites (4) were applied
in asymmetric hydrogenation of functionalized olefins
with high enantioselectivities by Pringle,11 Reetz,12 and
de Vries and Feringa,13 respectively (Figure 1). It is
noteworthy that all of the reported monodentate ligands
† Nankai University.
‡ East China University of Science and Technology.
(1) (a) Noyori, R. Asymmetric Catalysis in Organic Synthesis; Wiley
& Sons: New York, 1994. (b) Catalytic Asymmetric Synthesis; Ojima,
I., Ed.; Wiley & Sons: New York, 2000. (c) Comprehensive Asymmetric
Catalysis; J acobsen, E. N., Pfaltz, A., Yamamoto, H., Eds; Springer:
Berlin, 1999.
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Kagan, H. B.; Dang, T. P. J . Am. Chem. Soc. 1972, 94, 6429. (c) Kagan,
H. B.; Langlois, N.; Dang, T. P. J . Organomet. Chem. 1975, 90, 353.
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10.1021/jo049655z CCC: $27.50 © 2004 American Chemical Society
Published on Web 06/05/2004
4648
J . Org. Chem. 2004, 69, 4648-4655

Monodentate Phosphorus Ligands
SCHEME 1
F IGURE 1.
SCHEME 2. Syn th eses of SIP HOS Liga n d s
that induced high enantioselectivity are phosphorus
derivatives of binaphthol.14
In asymmetric catalysis, chiral C2-symmetric biaryls,
such as 1,1′-binaphthalene, were widely used as back-
bones of ligands.2,15 By contrast, chiral spiranes, another
class of C2-symmetric molecules, which also possess an
axial chirality, have not been paid much attention.16 The
rigidity of the spiro cyclic framework should decrease the
flexibility of ligands and their related complexes and
consequently benefit asymmetric induction in catalysis.
Spiro[4,4]nonane itself is not a chiral molecule. Substitu-
tions on the spiro cycles introduced more than one chiral
center into the molecule and increased the difficulty in
the synthesis of optically pure ligands. However, spiro-
biindane, which can be regarded as a benzo derivative
of sprio[4,4]nonane, has only axial chirality and its rigid
spiro structure makes it a potential backbone of chiral
ligands. By using 1,1′-spirobiindane backbone we have
developed novel monodentate chiral phosphoramidite
ligands SIPHOS (5) (Scheme 1). The ligands 5 were found
to be highly efficient in Rh-catalyzed asymmetric hydro-
genations of R-dehydroamino acid derivatives17 and N-(R-
arylethenyl)acetamides.18 Here we report the results of
our detailed studies on these reactions with emphasis on
the kinetics of the reaction, structures of the catalysts,
and the new application of SIPHOS ligands in asym-
metric hydrogenation of â-dehydroamino acid derivatives.
TABLE 1. Rh /SIP HOS-Ca ta lyzed Asym m etr ic
Hyd r ogen a tion of Meth yl (Z)-2-Aceta m id ocin n a m a tea
entry solvent cat. (mol %) PH (atm) time (h)b ee (%)c config
2
1
2
3
4
5
6
7
8
MeOH
EtOAc
toluene
acetone
THF
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
1
1
1
1
1
1
1
1
1
1
1
1
1
1
5
20
1
50
1
8
10
12
12
10
10
4
94
97
97
96
97
97
97
96
96
97
98
S
S
S
S
S
S
S
S
S
S
S
1
9
10
0.5
0.1
1
16
24
20
11d CH2Cl2
a
The reaction was performed at room temperature with 0.5
mmol of substrate in 5 mL of solvent, [Rh(COD)2BF4]/(S)-5a )
b
1:2.1 unless otherwise mentioned. Time for complete conversion.
Yields were quantitative. c Determined by chiral HPLC using a
d
CHIRACEL-OJ column. Performed at 0 °C.
Resu lts a n d Discu ssion
Liga n d P r ep a r a tion . SIPHOS represent a new class
of chiral monodentate ligands. It can be conveniently
synthesized from enantiomerically pure 1,1′-spirobiin-
dane-7,7′-diol (SPINOL).19 Ligands SIPHOS-Me (5a ) and
SIPHOS-Et (5b), which have small amino groups, were
prepared by the reaction of SPINOL with hexameth-
ylphosphorus triamide or hexaethylphosphorus triamide
in good yields. The SIPHOS ligands with larger amino
groups, such as pyrrolidinyl (SIPHOS-Pyr, 5c) and di-
isopropylamino (SIPHOS-Pri, 5d ), however, were pre-
pared in moderate yields by the reaction of SPINOL with
PCl3, followed by treatment with two equivalent corre-
sponding amines (Scheme 2).20
Asym m etr ic Hyd r ogen a tion of r-Deh yd r oa m in o
Acid Der iva tives w ith Rh /SIP HOS. Rhodium-cata-
lyzed asymmetric hydrogenation of R-dehydroamino acid
derivatives has been extensively studied and afforded a
model reaction to test the effectiveness of new chiral
ligands.2 The hydrogenation of methyl (Z)-2-acetamido-
cinnamate was first performed using 1 mol % Rh/
SIPHOS catalyst in different solvents. It was found that
the reaction, under 1 atm H2 at room temperature, is not
very sensitive to the solvent used (Table 1). In aprotic
solvents, such as CH2Cl2, toluene, and EtOAc, the
hydrogenation product was obtained in high ee. The
hydrogen pressure has no influence on the enantioselec-
tivity, but the reaction rate was accelerated when the
hydrogen pressure was increased (entries 6-8). Lowering
the catalyst loading from Rh/substrate ratio 1:100 to
1:200 decreased reaction rate but did not change the ee
(11) Claver, C.; Fernandez, E.; Gillon, A.; Heslop, K.; Hyett, D. J .;
Martorell, A.; Orpen, A. J .; Pringle, P. G. Chem. Commun. 2000, 961.
(12) (a) Reetz, M. T.; Mehler, G. Angew. Chem, Int. Ed. 2000, 39,
3889. (b) Reetz, M. T.; Sell, T.; Meiswinkel, A.; Mehler, G. Angew.
Chem., Int. Ed. 2003, 42, 790. (c) Reetz, M. T.; Sell, T. Tetrahedron
Lett. 2000, 41, 6333.
(13) (a) van den Berg, M.; Minnaard, A. J .; Schudde, E. P.; van Esch,
J .; de Vries, A. H. M.; de Vries, J . G.; Feringa, B. L. J . Am. Chem. Soc.
2000, 122, 11539. (b) Pen˜a, D.; Minnaard, A. J .; de Vries, J . G.; Feringa,
B. L. J . Am. Chem. Soc. 2002, 124, 14552. (c) van den Berg, M.;
Minnaard, A. J .; Haak, R. M.; Leeman, M.; Schudde, E. P.; Meetsma,
A.; Feringa, B. L.; de Vries, A. H. M.; Maljaars, C. E. P.; Willans, C.
E.; Hyett, D.; Boogers, J . A. F.; Henderickx, H. J . W.; de Vries, J . G.
Adv. Synth. Catal. 2003, 345, 308.
(14) Komarov, I. V.; Bo¨rner, A. Angew. Chem., Int. Ed. 2001, 40,
1197.
(15) Chen, Y.; Yekta, S.; Yudin, A. K. Chem. Rev. 2003, 103, 3155.
(16) Chan, A. S. C.; Hu, W.-H.; Pai, C.-C.; Lau, C.-P.; J iang, Y.-Z.;
Mi, A.-Q.; Yan, M.; Sun, J .; Lou, R.-L.; Deng, J .-G. J . Am. Chem. Soc.
1997, 119, 9570.
(17) Fu, Y.; Xie, J .-H.; Hu, A.-G.; Zhou, H.; Wang, L.-X.; Zhou, Q.-
L. Chem. Commun. 2002, 480.
(18) Hu, A.-G.; Fu, Y.; Xie, J .-H.; Zhou, H.; Wang, L.-X.; Zhou, Q.-
L. Angew. Chem., Int. Ed. 2002, 41, 2348.
(19) (a) Birman, V. B.; Rheingold, A. L.; Lam, K.-C. Tetrahedron:
Asymmetry 1999, 10, 125. (b) Zhang, J .-H.; Liao, J .; Cui, X.; Yu, K.-B.;
Deng, J .-G.; Zhu, S.-F.; Wang, L.-X.; Zhou, Q.-L.; Chung, L.-W.; Ye, T.
Tetrahedron: Asymmetry 2002, 13, 1363.
J . Org. Chem, Vol. 69, No. 14, 2004 4649

Fu et al.
TABLE 2. Asym m etr ic Hyd r ogen a tion of Meth yl
TABLE 3. Asym m etr ic Hyd r ogen a tion of
r-P h en ylen a m id e Ca ta lyzed by Rh /SIP HOS Com p lexesa
(Z)-2-Aceta m id ocin n a m a te w ith Differ en t Ca ta lystsa
entry
[Rh]
ligand
ee (%)
config
1
2
[Rh(COD)Cl]2
Rh(COD)2BF4
Rh(COD)2PF6
Rh(COD)2SbF6
Rh(COD)2BF4
Rh(COD)2BF4
Rh(COD)2BF4
(S)-5a
(S)-5a
(S)-5a
(S)-5a
(S)-5b
(S)-5c
(S)-5d
98
98
98
94
87
83
S
S
S
S
S
S
entry solvent
[Rh] (mol %)
L
PH (atm) ee (%)b
2
3
4b
5
1
2
MeOH
EtOAc
Rh(COD)2BF4 (1)
Rh(COD)2BF4 (1)
5a
5a
5a
5a
5a
5a
5a
10
10
10
10
10
10
100
50
100
50
10
10
10
10
nr
50
90
83
83
81
96
96
96
84
99
57
38
96
95
6
7
3
4
acetone Rh(COD)2BF4 (1)
CH2Cl2 Rh(COD)2BF4 (1)
5
THF
Rh(COD)2BF4 (1)
a
Reaction conditions: 1 mol % catalyst, [Rh]/L ) 1:2.1, PH
1 atm, CH2Cl2, 0 °C, 24 h, unless mentioned otherwise. Conv2er-
)
6
7
toluene Rh(COD)2BF4 (1)
toluene Rh(COD)2BF4 (1)
b
sions are 100%. 70% conversion.
8
9
toluene Rh(COD)2BF4 (0.5) 5a
toluene Rh(COD)2BF4 (0.1) 5a
10c
11
12
13d
14d
15
toluene Rh(COD)2BF4 (1)
toluene Rh(COD)2BF4 (1)
toluene Rh(COD)2BF4 (1)
toluene Rh(COD)2PF6 (1)
toluene Rh(COD)2SbF6 (1)
toluene [Rh(COD)Cl]2 (1)
5a
5b
5c
5a
5a
5a
of product. When the Rh/substrate ratio of 1:1000 was
employed, the reaction could not complete unless the
hydrogen pressure was increased to 50 atm (entry 10).
In the optimal conditions, a variety of R-amino acid
derivatives were prepared in excellent enantiomerically
excesses.17
a
The reaction was performed using 1 mol % catalyst at room
temperature with 0.5 mmol of substrate in 5 mL of solvent, PH
)
Different catalyst precursors were compared in the
asymmetric hydrogenation of methyl (Z)-2-acetamido-
cinnamate catalyzed by Rh/(S)-5a complex. All ionic
rhodium complexes can catalyze the hydrogenation,
although Rh(COD)2SbF6 provided a slow reaction and
neutral catalyst precursor [Rh(COD)Cl]2 gave no reaction
since Cl- coordinates to Rh tightly so that the catalyst
cannot provide enough coordinate sites to accept ligand
or substrate. Using ionic Rh precursors, the reactions had
the same level of enantioselectivity (Table 2).
In a previous paper, we reported that small alkyl
groups on the nitrogen atom of SIPHOS ligands are
necessary for obtaining high enantioselectivity in the
asymmetric hydrogenation of R-arylenamides.18 It was
the same in the Rh-catalyzed hydrogenation of methyl
(Z)-2-acetamidocinnamate. Ligand SIPHOS-Me (5a), which
has the smallest methyl groups at the nitrogen atom,
provided the highest enantioselectivity (98% ee). Replac-
ing the methyl groups of ligand 5a by other bulkier alkyl
groups produced ligands SIPHOS-Et (5b), SIPHOS-Pyr
(5c), and SIPHOS-Pri (5d ) and led to a continuous
decrease of ee of hydrogenation product (Table 2, entries
5-7). A similar trend was also observed in the asym-
metric hydrogenation of â-(acetylamino)acrylates with
MonoPhos ligands.13b However, the substitutions on the
4,4′-positions of the spirobiindane backbone have almost
no impact on the enantioselectivity of reaction.21
2
10 atm, [Rh]/L ) 1:2.2, unless otherwise mentioned. Complete
conversions were achieved within 12 h. Yields were quantitative.
b
Determined by chiral capillary GC on a Varian Chirasil-L-Val
column (25 m). Configurations were S. c T ) 5 °C. Reaction time
was 48 h.
d
drogenation of enamides provides a direct and convenient
route to chiral amine derivatives. Encouraged by the high
enantioselectivities of Rh/SIPHOS catalysts in the asym-
metric hydrogenation of R-dehydroamino acid derivatives,
we therefore investigated the utility of Rh/SIPHOS in the
asymmetric hydrogenation of enamides.
The results in Table 3 showed that the enantioselec-
tivity of the reaction was quite sensitive to the solvent
used. Toluene appeared to be the best solvent of choice
(Table 3, entry 1-6). However, the hydrogen pressure
has influence only on the reaction rate and not on the
enantioselectivity. For example, in the hydrogenation of
R-phenylenamide using SIPHOS-Me in toluene at room
temperaturee, the ee values of product at both 10 and
100 atm H2 were 96% (entries 6 and 7). The investigation
of catalyst loading showed that 0.5 mol % of catalyst was
sufficient to give a high enantioselectivity, while the ee
value of the product dropped drastically when 0.1 mol %
catalyst was used (entry 9). The effect of ligand structure
on the enantioselectivity of the catalysts was also exam-
ined. When the alkyl groups on the N-atom of SIPHOS
ligands changed from methyl (5a ) to ethyl (5b) and
isopropyl (5c), the enantioselectivities of the catalysts
greatly decreased from 96% to 57% and 38% ee (entries
11 and 12 vs 6). Catalysts prepared in situ from different
ionic Rh complexes were active in the asymmetric
hydrogenation of enamides and provided a similar level
of enantiocontrol, though the catalysts with bulkier
counteranions needed a longer time for completion of
reaction (entries 13 and 14). However, the catalyst
prepared from the neutral complex [Rh(COD)Cl]2 was
inert (entry 15). Various R-arylenamides can be hydro-
genated under the optimal conditions to produce chiral
amines in excellent enantioselectivities.18
Asym m et r ic H yd r ogen a t ion of E n a m id es w it h
Rh /SIP HOS. Optically active R-arylalkylamines are an
important class of compounds that are widely used in
organic and pharmaceutical synthesis, and much effort
has been made in developing efficient asymmetric syn-
theses of these compounds.22 Asymmetric catalytic hy-
(20) (a) Zhou, H.; Wang, W.-H.; Fu, Y.; Xie, J .-H.; Shi, W.-J .; Wang,
L.-X.; Zhou, Q.-L. J . Org. Chem. 2002, 41, 1582. (b) Shi, W.-J .; Wang,
L.-X.; Fu, Y.; Zhu, S.-F.; Zhou, Q.-L. Tetrahedron: Asymmetry 2003,
14, 3768.
(21) Zhu, S.-F.; Fu, Y.; Xie, J .-H.; Liu, B.; Xing, L.; Zhou, Q.-L.
Tetrahedron: Asymmetry 2003, 14, 3219.
(22) (a) No´gra´di, M. Steroselective Synthesis, 2nd ed.; Wiley-VCH:
Weinheim, 1995. (b) Denmark, S. E.; Weber, T.; Piotrowski, D. W. J .
Am. Chem. Soc. 1987, 109, 2224. (c) Gawley, R. E.; Rein, K.; Chem-
burkar, S. J . Org. Chem. 1989, 54, 3002. (d) Pridgen, L. N.; Mokhal-
lalati, M. K.; Wu, M.-J . J . Org. Chem. 1992, 57, 1237. (e) J acqueline,
H.-P. Chiral Auxiliaries and Ligands in Asymmetric Synthesis; Wiley
& Sons: New York, 1995.
Chiral 1-aminoindanes are key intermediates for drugs
such as rasagiline for Parkinson’s disease.23 Asymmetric
hydrogenation of N-(1,2-dehydro-1-indanyl)acetamide is
a potential method for the production of enantioenriched
4650 J . Org. Chem., Vol. 69, No. 14, 2004

Monodentate Phosphorus Ligands
TABLE 4. Asym m etr ic Hyd r ogen a tion of Meth yl
3-Acetyla m in ocin n a m a tea
entry
solvent
PH (atm)
conv (%)
ee (%) b
configc
2
F IGURE 2. Chiral 1-aminoindanes.
1
2
3
4
5
6
7
8
CH2Cl2
CH2Cl2
CH2Cl2
EtOAc
THF
20
50
73
90
100
92
55
63
90
90
90
48
81
80
76
85
65
75
S
S
S
S
S
S
S
S
S
S
1-aminoindane. Using the Rh/SIPHOS catalyst, N-(1,2-
dehydro-1-indanyl)acetamide was hydrogenated in tolu-
ene at 0 °C under 100 atm H2, providing 1-aminoindane
in 100% yield with 94% ee. Under the same reaction
conditions, 5-Br- and 6-MeO-substituted 1-aminoindanes
were also prepared in 88% and 95% ee, respectively
(Figure 2).
100
100
100
100
100
100
100
100
toluene
acetone
MeOH
EtOH
90
100
100
100
9
10
iPrOH
Asym m etr ic Hyd r ogen a tion of â-Deh yd r oa m in o
Acid Der iva tives w ith Rh /SIP HOS. Enantiomerically
pure â-amino acid derivatives are important building
blocks in the synthesis of many chiral drugs.24 Asym-
metric hydrogenation of â-(acylamino)acrylate derivatives
has attracted much attention recently because it provides
a convenient method for the synthesis of â-amino acid
derivatives. Among the ligands used in the Rh-catalyzed
hydrogenation of â-(acylamino)acrylate derivatives, the
diphosphines have been most effective.25 Recently,
monophosphoramidites13b were also successfully em-
ployed in the Rh-catalyzed asymmetric hydrogenation of
â-(acylamino)acrylates, providing excellent enantioselec-
tivities. However, for most catalytic systems, high enan-
tioselectivity can only be obtained when pure Z- or
E-isomers of â-(acylamino)acrylate substrates are used
in the hydrogenation. Very few catalysts have been
reported to be efficient for the hydrogenation of Z/E
mixtures of â-(acylamino)acrylates. The exceptional ex-
amples include Rh/TangPhos25d and Ru/o-BINAPO25e
catalysts in the hydrogenations of Z/E mixtures of â-aryl
â-(acylamino)acrylates, achieving high enantioselectivi-
ties.26 Because the â-(acylamino)acrylates are normally
formed as a mixture of Z- and E-isomers, the develop-
ment of a new efficient catalyst that can hydrogenate the
mixture of the two isomers is significantly important. It
is our delight that the Rh/SIPHOS complexes can cata-
a
Reactions were carried out in 5 mL of solvent using 2 mol %
b
catalyst at room temperature for 48 h. Rh/L ) 1:2.1. Determined
by chiral capillary GC on a Varian Chirasil-L-Val column (25 m).
c Determined by comparing the optical rotations with reported
values.
TABLE 5. Hyd r ogen a tion of â-Deh yd r oa m in o Ester sa
substrate
ee (%)b
configc
R1 ) Ph, R2 ) Me
90
91
92
94
91
91
93
87d
89d
S
S
S
S
S
S
S
R
R
R1 ) 2-BrPh, R2 ) Me
R1 ) 3-BrPh, R2 ) Me
R1 ) 4-BrPh, R2 ) Me
R1 ) 4-ClPh, R2 ) Me
R1 ) 4-MePh, R2 ) Me
R1 ) 4-CH3OPh, R2 ) Me
R1 ) CH3, R2 ) Et
R1, R2 ) Me
a
Reactions were carried out under 100 atm H2 in 5 mL of
CH2Cl2 using 2 mol % catalyst at room temperature for 48 h. Rh/L
b
) 1:2.1. Conversions are 100%. Determined by chiral capillary
GC on a Varian Chirasil-L-Val column (25 m). c Determined by
d
comparing the optical rotations with reported values. Determined
by chiral capillary GC on a Supelco â-dex 120 column (30 m).
lyze asymmetric hydrogenations of Z/E mixtures of â-aryl
â-(acylamino)acrylate derivatives, which cannot be sepa-
rated by silica gel column chromatography, providing
â-amino acid derivatives in high enantioselectivities.
Methyl (Z/E)-3-(acylamino)cinnamate (Z/E ) 88:12) was
chosen as the substrate for optimizing the reaction
condition. Screening of solvents showed that CH2Cl2 was
the best solvent for obtaining high enantioselectivity.
Increasing hydrogen pressure led to higher reaction rates,
while the enantiomeric excesses remain the same (Table
4).
Under the optimal conditions, a variety of â-(acylami-
no)acrylate (Z/E ) 98:2 to 50:50) can be hydrogenated in
high enantioselectivities, and the results are summarized
in Table 5. In the hydrogenations of â-aryl â-(acylamino)-
acrylates, the electronic nature of the aryl group in the
substrate had little influence on the ee of product. The
hydrogenations of â-methyl â-(acylamino)acrylates, how-
ever, had slightly lower enantioselectivities compared to
the hydrogenations of â-aryl â-(acylamino)acrylates.
Mech an istic Con sider ation . The mechanism of rhod-
ium-catalyzed asymmetric hydrogenation of functional-
ized olefins using diphosphine ligands has been well-
established by Halpern,27 Brown,28 Gridnev and Ima-
moto,29 and others.30 However, the investigation into the
(23) (a) Youdim, M. B. H.; Finberg, J . P. M.; Levy, R.; Sterling, J .;
Lerner, D.; Berger-Paskin, T.; Yellin, H.; Veinberg, A. U.S. Patent 5,-
786,390, J une, 1995. (b) Cohen, S.; Herzig, Y.; Levy, R.; Speiser, T.;
Sterling, J .; Veinberg, A.; Youdim, M. B. H.; Finberg, J . P. M. U.S.
Patent 5,994,408, October, 1997.
(24) (a) Enantioselective Synthesis of â-Amino Acids; J uaristi, E.,
Ed.; Wiley-VCH: New York, 1997. (b) Drexler, H.-J .; You, J .; Zhang,
S.; Fischer, C.; Baumann, W.; Spannenberg, A.; Heller, D. Org. Process
Res. Dev. 2003, 7, 355.
(25) (a) Zhu, G.; Chen, Z.; Zhang, X. J . Org. Chem. 1999, 64, 6907.
(b) Heller, D.; Holz, J .; Drexler, H.-J .; Lang, J .; Drauz, K.; Krimmer,
H.-P.; Bo¨rner, A. J . Org. Chem. 2001, 66, 6816. (c) Yasutake, M.;
Gridnev, I. D.; Higashi, N.; Imamoto, T. Org. Lett. 2001, 3, 1701. (d)
Tang, W.; Zhang, X. Org. Lett. 2002, 4, 4159. (e) Zhou, Y.-G.; Tang,
W.; Wang, W.-B.; Li, W.; Zhang, X. J . Am. Chem. Soc. 2002, 124, 4952.
(f) Lee, S.-G.; Zhang, Y. J . Org. Lett. 2002, 4, 2429. (g) Tang, W.; Wu,
S.; Zhang. X. J . Am. Chem. Soc. 2003, 125, 9570. (h) Tang, W.; Wang,
W.; Chi, Y.; Zhang, X. Angew. Chem., Int. Ed. 2003, 42, 3509. (i) Holz,
J .; Monsees, A.; J iao, H.; You, J .; Komarov, I. V.; Fischer, C.; Drauz,
K.; Bo¨rner, A. J . Org. Chem. 2003, 68, 1701. (j) Wu, J .; Chen, X.; Guo,
R.; Yeung, C.-H.; Chan, A. S. C. J . Org. Chem. 2003, 68, 2490. (k)
J erphagnon, T.; Renaud, J .-L.; Demonchaux, P.; Ferreira, A.; Bruneau,
C. Tetrahedron: Asymmetry 2003, 14, 1973. (l) Dubrovina, N. V.;
Tararov, V. I.; Monsees, A.; Kadyrov, R.; Fischer, C.; Bo¨rner, A.
Tetrahedron: Asymmetry 2003, 14, 2739.
(26) Moderate to good enanstioselectivities were also reported in the
hydrogenation of mixtures of â-alkyl â-(acylamino)acrylates; see ref
25f, 25k, 25l and J erphagnon, T.; Renaud, J .-L.; Demonchaux, P.;
Ferreira, A.; Bruneau, C. Adv. Synth. Catal. 2004, 346, 33.
J . Org. Chem, Vol. 69, No. 14, 2004 4651

Fu et al.
F IGURE 3. Dependency of conversion versus reaction time
F IGURE 4. Dependency of TOF versus catalyst concentration
(T ) 25 °C, PH ) 1 atm, [sub]0 ) 0.1 M, [Rh] ) 1.0 mM).
2
(T ) 25 °C, PH ) 1 atm, [sub]0 ) 0.1 M, [Rh] ) 0.5-1.5 mM).
2
mechanism of asymmetric hydrogenation using mono-
phosphorus ligands is still in its infancy. To collect more
information about the mechanism of Rh(I)-catalyzed
hydrogenation using monophosphorus ligands, we made
a kinetic study of the Rh/5a -catalyzed hydrogenation of
methyl (Z)-2-acetamidocinnamate. The kinetic features
tested include substrate and catalyst concentration,
hydrogen pressure. Using ligand (S)-5a , all reactions
gave the hydrogenation product with the same (S)-
configuration and the same level of enantioselectivity.
The substrate concentration dependency of reaction
was obtained by following the conversion of substratevs
reaction time. The graph in Figure 3 suggests a zero-
order dependency of reaction rate on the substrate
concentration. The effect of the catalyst concentration on
the reaction rate was studied. When the reactions were
performed with a catalyst concentration between 0.5 and
1.5 mM, the rate (TOF) of hydrogenation is linear to the
catalyst concentration (Figure 4), suggesting a first-order
dependency of reaction rate on the catalyst concentration.
The hydrogen pressure was varied between 0.25 and 1.0
atm. The graph of TOF vs hydrogen pressure in Figure
5 also shows a first-order dependency of reaction rate on
the hydrogen pressure.31 Temperature is another condi-
tion that can affect the reaction result. We also examined
the temperature effect of reaction by following conversion
F IGURE 5. Dependency of TOF versus hydrogen pressure
(T ) 25 °C, PH ) 0.25-1 atm, [sub]0 ) 0.1 M, [Rh] ) 1.0 mM).
2
(27) (a) Halpern, J . Science 1982, 217, 401. (b) Halpern, J . In
Asymmetric Synthesis; Morrison, J . D., Ed.; Academic: Orlando, FL,
1985. (c) Chan, A. S. C.; Pluth, J . J .; Halpern, J . Inorg. Chim. Acta
1979, 37, L477. (d) Chan, A. S. C.; Pluth, J . J .; Halpern, J . J . Am.
Chem. Soc. 1980, 102, 5952. (e) Chan, A. S. C.; Halpern, J . J . Am.
Chem. Soc. 1980, 102, 838. (f) Landis, C. R.; Halpern, J . J . Am. Chem.
Soc. 1987, 109, 1746.
(28) (a) Brown, J . M.; Chaloner, P. A. Tetrahedron Lett. 1978, 21,
1877. (b) Brown, J . M.; Chaloner, P. A. J . Chem. Soc., Chem. Commun.
1980, 344. (c) Brown, J . M.; Parker, D. Organometallics 1982, 1, 950.
(d) Brown, J . M.; Canning, L. R.; Downs, A. J .; Forster, A. M. J .
Organomet. Chem. 1983, 255, 103.
(29) (a) Gridnev, I. D.; Higashi, N.; Asakura, K.; Imamoto, T. J . Am.
Chem. Soc. 2000, 122, 7183. (b) Gridnev, I. D.; Yamanoi, Y.; Higashi,
N.; Tsuruta, H.; Yasutake, M.; Imamoto, T. Adv. Synth. Catal. 2001,
343, 118. (c) Gridnev, I. D.; Yasutake, M.; Higashi, N.; Tsuruta, H.;
Imamoto, T. J . Am. Chem. Soc. 2001, 123, 5268.
(30) (a) Rossen, K. Angew. Chem., Int. Ed. 2001, 40, 4611. (b)
Pa`mies, O.; Die´guez, M.; Net, G.; Ruiz, A.; Claver, C. J . Org. Chem.
2001, 66, 8364.
F IGURE 6. Dependency of reaction rate versus temperature
(T ) 0-30 °C, PH ) 1 atm, [sub]0 ) 0.1 M, [Rh] ) 1.0 mM).
2
vs time at 0, 20, and 30 °C. As shown in Figure 6, the
reaction became faster at higher temperature, while a
higher enantioselectivity was obtained at lower temper-
ature. The kinetic features of Rh/SIPHOS-catalyzed
hydrogenation clearly show that the oxidative addition
(31) The difference of activities of catalysts shown in Figures 4 and
5 might be attributed to the difference in morphology in the catalysts
used from different batches.
4652 J . Org. Chem., Vol. 69, No. 14, 2004

Monodentate Phosphorus Ligands
F IGURE 7. NLE in Rh/SIPHOS-catalyzed hydrogenation (T
) 25 °C, PH ) 1 atm, [sub] ) 0.1 M, [Rh] ) 1.0 mM, Rh/5a )
2
F IGURE 8. Dependency of conversion vs time at 0 °C.
1:2.1).
SCHEME 3
of hydrogen to the Rh complex is the rate-determining
step, which is similar to that of using diphosphine
ligands.
The true structure of the Rh catalyst in the asymmetric
hydrogenation with monophosphorus ligand was un-
known before we were able to grow a single crystal of
the Rh/(S)-5a complex. The single crystal was obtained
by mixing Rh(COD)2BF4 and 2 equiv of (S)-5a (Rh/L )
1:2) in a mixed solvent of CH2Cl2 and Et2O, and its
structure was determined by X-ray diffraction to be a C2-
symmetric [Rh(COD)((S)-5a )2]+.32 It is surprising that the
structure of a single crystal obtained by mixing equal
molar Rh(COD)2BF4 and (S)-5a (Rh/L ) 1:1) was also
[Rh(COD)((S)-5a )2]+. In the crystal of the catalyst, two
(S)-5a ligands coordinate to Rh through the P-atom and
two CdC double bonds of COD occupy the other two
coordination sites of Rh. The P-Rh bond lengths (2.286
Å) are close to those reported in Rh-biphosphine com-
plexes. However, the P-Rh-P angle (95.6°) is distinctly
larger than those in the Rh complexes of bidentate
phosphines.27c,d
Although the crystal structure shows that there are
two ligands in the solid state of the catalyst, we still do
not know the real composition of the active catalyst in
the reaction. Nonlinear effect (NLE) of the ee of the
product on the ee of ligand provides useful information
to determine whether two or more ligands are contained
in the active catalyst.33 In Rh/5a -catalyzed hydrogenation
of methyl (Z)-2-(acetamido)cinnamate, we found a posi-
tive NLE (Figure 7), which implies that there are more
than one ligand bonded to the Rh in the active catalyst.34
Reetz12a reported that 1:1 and 1:2 Rh/ligand ratios have
no significant difference on the conversion and enantio-
selectivity in the asymmetric hydrogenation of itaconic
ester using chiral monophosphite ligands. Minnaard,
Feringa, and de Vries13c found that reaction rate in-
creased when the Rh/L ratio was lowered from 1:2 to 1:1
and the ee of product remained the same in the asym-
metric hydrogenation of methyl (Z)-2-(acetamido)cin-
namate using MonoPhos ligands. We compared the rates
of reactions with different Rh/L ratios in the Rh/(S)-5a -
catalyzed asymmetric hydrogenation of methyl (Z)-2-
(acetamido)cinnamate at 0 °C (Figure 8). The reaction
with 1:1 Rh/L ratio was found to be faster than the
reaction with 1:2 Rh/L ratio, the reaction with 1:3 Rh/L
ratio was much slower, and the catalyst with 1:4 Rh/L
ratio has almost no activity. This seems to suggest that
only one monophosphorus ligand is bonded to rhodium
in the active catalyst.
On the basis of the results we so far gained from the
experiments, it is reasonable to presume that the Rh-
catalyst in hydrogenation using SIPHOS ligand contains
two ligands and losses one to generate the active catalyst
during hydrogenation. The positive NLE of reaction could
be attributed to the fact that the heterochiral complex
RhLSLR is more stable than homochiral complex Rh(LS)2
or Rh(LR)2 in the dissociation step, namely, K2 > K1 in
Scheme 3.33b Having these analyses, we propose a mech-
anism for the Rh-catalyzed asymmetric hydrogenation
of R-(acylamino)acrylate derivatives using chiral mono-
phosphorus ligands with activation of H2 being the rate-
determination step, which is similar to Halpern’s mech-
anism with diphosphine ligand (Scheme 4).27 However,
it is obvious that this mechanism did not give a clear
picture about the real catalytic cycle. A complete under-
standing of the mechanism in this type of asymmetric
hydrogenation using monodentate phosphorus ligands
needs more detailed information.
(32) For the structure of the crystal, see ref 18. For the crystal data,
structure refinement, and selected bond lengths and angles, see
Supporting Information.
(33) (a) Puchot, C.; Samuel, O.; Dunach, E.; Zhao, S.; Agami, C.;
Kagan, H. B. J . Am. Chem. Soc. 1986, 108, 2353. (b) Girard, C.; Kagan,
H. B. Angew. Chem., Int. Ed. 1998, 37, 2922. (c) Kagan, H. B. Synlett
2001, 888.
(34) A positive NLE was reported in the asymmetric hydrogenation
using MonoPhos ligand; see ref 13c.
Con clu sion
The SIPHOS were demonstrated to be excellent ligands
in the Rh-catalyzed hydrogenation of functionalized
olefins, such as R-dehydroamino acid derivatives, â-de-
J . Org. Chem, Vol. 69, No. 14, 2004 4653

Fu et al.
2-a ceta m id o-3-(4-n itr op h en yl)p r op ion a te: HPLC (Chiral-
cel OD column, iPrOH/Hex (15/85), 1.0 mL/min) tR ) 17.13 min,
tS ) 19.74 min. Meth yl 2-a ceta m id o-bu tyr a te: GC (Supelco
γ-dex 225 column 30 m × 0.25 mm × 0.25 µm; N2 1.4 mL/min;
100 °C then 2 °C/min to 160 °C) tR ) 20.88 min, tS ) 21.27
min. Meth yl 2-a ceta m id op r op ion a te: GC (Supelco γ-dex
225 column; N2 1.0 mL/min; 100 °C then 2 °C/min to 160 °C)
tR ) 19.60 min, tS ) 20.33 min.
SCHEME 4. P r op osed Mech a n ism of Rh -Ca ta lyzed
Asym m etr ic Hyd r ogen a tion Usin g
Mon op h osp h or u s Liga n d
Ar yla m in es. N-Acetyl-1-p h en yleth yla m in e: GC (Varian
Chirasil-L-Val column; N2 1.0 mL/min; 130 °C) tR ) 10.36 min,
tS ) 10.93 min. N-Acetyl-1-(3-m eth ylp h en yl)eth yla m in e:
GC (Varian Chirasil-L-Val column; N2 1.0 mL/min; 140 °C) tR
) 15.37 min, tS ) 16.73 min. N-Acetyl-1-(4-m eth ylp h en yl)-
eth yla m in e: GC (Varian Chirasil-L-Val column; N2 1.0 mL/
min; 130 °C) tR ) 15.81 min, tS ) 16.78 min. N-Acetyl-1-(4-
tr iflu or om eth ylp h en yl)eth yla m in e: GC (Varian Chirasil-
L-Val column; N2 1.0 mL/min; 140 °C) tR ) 9.35 min, tS ) 9.94
min. N-Acetyl-1-(2-flu or op h en yl)eth yla m in e: GC (Varian
Chirasil-L-Val column; N2 1.0 mL/min; 130 °C) tR ) 8.34 min,
tS ) 8.67 min. N-Acetyl-1-(4-flu or op h en yl)eth yla m in e: GC
(Varian Chirasil-L-Val column; N2 1.0 mL/min; 140 °C) tR
)
8.00 min, tS ) 8.37 min. N-Acetyl-1-(4-ch lor op h en yl)-
eth yla m in e: GC (Varian Chirasil-L-Val column; N2 1.0 mL/
min; 150 °C) tR ) 11.27 min, tS ) 11.87 min. N-Acet yl-1-
(4-br om op h en yl)eth yla m in e: GC (Varian Chirasil-L-Val
column; N2 1.0 mL/min; 150 °C) tR ) 17.19 min, tS ) 18.22
min. 1-Acetyla m in oin d a n e: GC (Supelco γ-dex-225 column;
N2 1.8 mL/min, 150 °C then 2 °C/min to 180 °C, constant 5
min) tR ) 15.8 min, tS ) 16.1 min. 1-Acetyla m in o-7-m eth -
oxyin d a n e: GC (Supelco γ-dex-225 column; N2 1.8 mL/min,
150 °C then 2 °C/min to 180 °C, constant 20 min) tR ) 30.46
min, tS ) 31.56 min. 1-Acetyla m in o-6-br om oin d a n e: GC
(Varian Chirasil-L-Val column; N2 1.8 mL/min, 100 °C then 1
°C/min to 160 °C) tR ) 58.01 min, tS ) 58.88 min.
â-Am in o Ester s. Meth yl 3-a cetyla m in o-3-p h en ylp r o-
p ion a te: GC (Varian Chirasil-L-Val column; N2 1.8 mL/min,
120 °C then 1 °C/min to 150 °C) tR ) 27.57 min, tS ) 28.24
min. Meth yl 3-a ceta m id o-3-(2-br om op h en yl)-p r op ion a te:
GC (Varian Chirasil-L-Val column; N2 1.8 mL/min, 120 °C then
1 °C/min to 150 °C) tR ) 27.26 min, tS ) 27.96 min. Meth yl
3-a ceta m id o-3-(3-br om op h en yl)-p r op ion a te: GC (Varian
Chirasil-L-Val column; N2 2.0 mL/min, 120 °C then 1 °C/min
to 160 °C) tR ) 26.28 min, tS ) 26.93 min. Meth yl 3-a cet-
a m id o-3-(4-br om op h en yl)-p r op ion a te: GC (Varian Chira-
sil-L-Val column; N2 2.0 mL/min, 120 °C then 1 °C/min to 160
°C) tR ) 32.08 min, tS ) 32.67 min. Meth yl 3-a ceta m id o-3-
(4-ch lor op h en yl)-p r op ion a te: GC (Varian Chirasil-L-Val
hydroamino acid derivatives, and R-arylenamides. Higher
enantioselectivity was achieved as the alkyl groups on
the N-atom of the SIPHOS ligand became smaller. The
X-ray analysis of the crystal structure of the Rh-SIPHOS
catalyst showed that there were two monophosphorus
ligands in the catalyst, which was also probed by a
positive nonlinear effect in the asymmetric hydrogenation
of (Z)-2-(acetamido)cinnamate. The rate of hydrogenation
with 1:1 Rh/L ratio is faster than that with 1:2 Rh/L ratio,
which implied that only one monophosphorus ligand is
bonded to Rh in the active catalyst. A possible explana-
tion of the experimental results is that the catalyst
preferably contains two ligands but loses one to generate
the active catalyst during hydrogenation. Kinetic studies
showed that the reaction rate is zero order to the
concentration of substrate and first order to the concen-
tration of the Rh catalyst and hydrogen pressure, sug-
gesting that the mechanism of Rh-catalyzed hydrogena-
tion using monodentate phosphorus ligand is similar to
the use of diphosphine ligands. Further investigations
on the application scope of the SIPHOS ligands and the
reaction mechanism are in progress.
column; N2 1.8 mL/min, 120 °C then 1 °C/min to 170 °C) tR
)
44.35 min, tS ) 45.28 min. Meth yl 3-a ceta m id o-3-(4-m eth -
ylp h en yl)-p r op ion a te: GC (Varian Chirasil-L-Val column; N2
2.0 mL/min, 120 °C then 1 °C/min to 160 °C) tR ) 33.07 min,
tS ) 33.97 min. Meth yl 3-a ceta m id o-3-(4-m eth oxylp h en yl)-
p r op ion a te: GC (Varian Chirasil-L-Val column; N2 1.8 mL/
Exp er im en ta l Section
The ligands were synthesized according to the literature:
5a ,20a 5b,20a 5c,20b 5d .20a For general procedures for asymmetric
hydrogenations, see Supporting Information.
min, 100 °C then 1 °C/min to 170 °C) tR ) 67.03 min, tS
)
Deter m in a tion of Con ver sion a n d En a n tioselectivity.
r-Am in o E st er s. Met h yl 2-a cet a m id o-3-p h en ylp r op i-
on a te: GC (Varian Chirasil-L-Val column 25 m × 0.25 mm ×
67.82 min. Meth yl 3-a ceta m id o-bu tyr a te: GC (Supelco â-dex
120 column; N2 1.0 mL/min, 70 °C then 1 °C/min to 140 °C) tS
) 63.10 min, tR ) 64.54 min. Eth yl 3-a ceta m id o-bu tyr a te:
GC (Supelco â-dex 120 column; N2 1.0 mL/min, 70 °C then 1
°C/min to 140 °C) tS ) 63.13 min, tR ) 64.73 min.
0.25 µm; N2 1.8 mL/min; 90 °C then 4 °C/min to 160 °C) tR
)
17.54 min, tS ) 18.40 min, tsub ) 23.40 min. Or HPLC
(Chiralcel OJ , iPrOH/Hex (10/90), 1.0 mL/min) tR ) 12.76 min,
tS ) 19.45 min. Meth yl 2-a ceta m id o-3-(2-ch lor op h en yl)-
Mech a n ist ic St u d y. Kin et ic St u d y on t h e Su b st r a t e
Con cen tr a tion Dep en d en cy. To a Schlenk tube equipped
with a septum and a stirring bar were added 2.0 mg (5 µmol)
of Rh(COD)2BF4 and 3.4 mg (10.5 µmol) of 5a . Another Schlenk
tube was added with 110 mg (0.5 mmol) of methyl (Z)-2-
acetamidocinnamate. After three vacuum/hydrogen cycles, 5.0
mL of CH2Cl2 was added by a syringe to the catalyst Schlenk
tube and stirred for 0.5 h at 0 °C. The resulting catalyst
solution was transferred into the substrate Schlenk tube. The
reaction was left stirring under ambient hydrogen pressure
at 0 °C. A sample of reaction mixture (0.2 mL) was taken at
regular time intervals, filtered through a short silica column,
and then submitted to analysis for conversion and ee values.
i
p r op ion a te: HPLC (Chiralcel OJ column, 25 cm, PrOH/Hex
(10/90), 1.0 mL/min) tR ) 11.17 min, tS ) 13.89 min. Meth yl
2-acetam ido-3-(4-ch lor oph en yl)pr opion ate: HPLC (Chiral-
cel OJ column, iPrOH/Hex (10/90), 1.0 mL/min) tR ) 12.86 min,
tS ) 17.21 min. Meth yl 2-a ceta m id o-3-(4-m eth ylp h en yl)-
p r op ion a te: HPLC (Chiralcel OJ column, iPrOH/Hex (10/90),
1.0 mL/min) tR ) 9.33 min, tS ) 15.34 min. Meth yl 2-a cet-
a m id o-3-(4-m eth oxyp h en yl)p r op ion a te: HPLC (Chiralcel
i
OJ column, PrOH/Hex (10/90), 1.0 mL/min) tR ) 6.42 min, tS
) 11.43 min. Meth yl 2-a ceta m id o-3-(3-n itr op h en yl)p r o-
p ion a te: HPLC (Chiralcel OD column, 25 cm, iPrOH/Hex (15/
85), 1.0 mL/min) tR ) 13.76 min, tS ) 17.20 min. Met h yl
4654 J . Org. Chem., Vol. 69, No. 14, 2004

Monodentate Phosphorus Ligands
Kin etic Stu d y on th e Ca ta lyst Con cen tr a tion Dep en -
d en cy. To a Schlenk tube equipped with a septum and a
stirring bar were added 12.0 mg (30 µmol) of Rh(COD)2BF4
and 21.0 mg (61 µmol) of 5a . Another Schlenk tube was
charged with 660 mg (3 mmol) of methyl (Z)-2-acetamidocin-
namate. After three vacuum/hydrogen cycles, 12 mL of CH2-
Cl2 was charged by a syringe to the catalyst tube. The two
Schlenk tubes were stirred for 0.5 h at 0 °C under ambient
hydrogen pressure. The reactions with different catalyst
concentration were performed by mixing the proper amount
of the above catalyst solution, substrate solution, and CH2Cl2
(saturated with H2) and allowing the mixture to stir at 0 °C
under ambient hydrogen pressure. A sample of reaction
mixture (0.2 mL) was taken at regular time intervals, filtered
through a short silica column, and then submitted to analysis
for conversion and ee values. 0.5 m M [Rh ]: 2.0 mL of CH2-
Cl2, 2.0 mL of substrate solution and 1.0 mL of catalyst
solution. 0.8 m M [Rh ]: 1.4 mL of CH2Cl2, 2.0 mL of substrate
solution and 1.6 mL of catalyst solution. 1.0 m M [Rh ]: 1.0
mL of CH2Cl2, 2.0 mL of substrate solution and 2.0 mL of
catalyst solution. 1.2 m M [Rh ]: 0.6 mL of CH2Cl2, 2.0 mL of
substrate solution and 2.4 mL of catalyst solution. 1.5 m M
[Rh ]: 2.0 mL of substrate solution and 3.0 mL of catalyst
solution.
Kin etic Stu d y on th e Tem p er a tu r e Dep en d en cy. To a
Schlenk tube equipped with a septum and a stirring bar were
added 2.0 mg (5 µmol) of Rh(COD)2BF4 and 3.4 mg (10.5 µmol)
of 5a . After three vacuum/hydrogen cycles, 5.0 mL of CH2Cl2
was added by a syringe to the catalyst Schlenk tube and stirred
under ambient hydrogen for 0.5 h at request temperature.
Another Schlenk tube was charged with 110 mg (0.5 mmol) of
methyl (Z)-2-acetamidocinnamate and filled with ambient
hydrogen at corresponding temperature. The catalyst solution
was transferred into the substrate Schlenk tube and left
stirring under ambient hydrogen pressure at the same tem-
perature. A sample of reaction mixture (0.2 mL) was taken at
regular time intervals, filtered through a short silica column,
and then submitted to analysis for conversion and ee values.
P r ep a r a tion a n d Cr ysta l Str u ctu r e of [Rh (COD)((S)-
SIP HOS-Me)2] Ca ta lyst. To a Schlenk tube were added 10
mg (25 µmol) of Rh(COD)2BF4, 16.5 mg (51 µmol) of ligand,
and 1.0 mL of CH2Cl2 to form a solution; 2.0 mL of Et2O was
then added slowly while keeping the two-phase interface clear.
The single crystal was collected after the mixture stood
overnight and was subjected to X-ray analysis. The X-ray
structure was described in a previous communication,18 and
the crystal data in CIF format are in the Supporting Informa-
tion.
Kin etic Stu d y on th e Hyd r ogen P r essu r e Dep en d en cy.
Under 0.25 atm H2 (PH ) 0.25 atm, PN ) 0.75 atm), to a
Schlenk tube equipped with a septum and2 a stirring bar were
added 2.0 mg (5 µmol) of Rh(COD)2BF4, 3.4 mg (10.5 µmol) of
5a , and 2 mL of CH2Cl2. Another Schlenk tube was charged
with 110 mg (0.5 mmol) of methyl (Z)-2-acetamidocinnamate
and 3 mL of CH2Cl2. The two Schlenk tubes were stirred for
0.5 h at 0 °C under 0.25 atm H2 pressure. Then the substrate
solution was transferred to the catalyst solution, and the
reaction was left stirring at 0 °C. A sample of reaction mixture
(0.2 mL) was taken at regular time intervals, filtered through
a short silica column, and then submitted to analysis for
conversion and ee values. Other reactions under different
hydrogen pressure were performed similarly by using different
2
Ack n ow led gm en t. We thank professor Yun-Dong
Wu, Department of Chemistry, Hong Kong University
of Scince and Technology, Hong Kong, China, for helpful
discussions. We also thank the National Natural Science
Foundation of China, the Major Basic Research Devel-
opment Program (Grant G2000077506), and the Min-
istry of Education of China for financial support.
Su p p or tin g In for m a tion Ava ila ble: General remarks
and general procedures for asymmetric hydrogenations; crystal
data in CIF format. This material is available free of charge
via the Internet at http://pubs.acs.org.
hydrogen pressure. 0.50 a tm H2: (PH ) 0.5 atm, PN ) 0.5
2
atm). 0.75 a tm H2: (PH ) 0.75 atm,2 PN ) 0.25 atm). 1.00
2
2
a tm H2: (PH ) 1.00 atm, PN ) 0 atm).
J O049655Z
2
2
J . Org. Chem, Vol. 69, No. 14, 2004 4655