Development of a continuous-flow system for asymmetric hydrogenation using self-supported chiral catalysts

Article abstract of DOI:10.1002/chem.200900899

Well-designed, self-assembled, metal-organic frameworks were constructed by simple mixing of multitopic MonoPhos-based ligands (3; MonoPhos = chiral, monodentate phosphoramidites based on the 1,1′-bi-2naphthol platform) and [Rh(cod)₂]BF₄

Full text of DOI:10.1002/chem.200900899

FULL PAPER
DOI: 10.1002/chem.200900899
Development of a Continuous-Flow System for Asymmetric Hydrogenation
Using Self-Supported Chiral Catalysts
Lei Shi, Xingwang Wang, Christian A. Sandoval, Zheng Wang, Hongji Li, Jiang Wu,
Liting Yu, and Kuiling Ding*[a]
Dedicated to Professor Youcheng Liu on the occasion of his 90th birthday
Abstract: Well-designed, self-assem-
bled, metal–organic frameworks were
constructed by simple mixing of multi-
topic MonoPhos-based ligands (3;
MonoPhos=chiral, monodentate phos-
phoramidites based on the 1,1’-bi-2-
98% and 90–98%, respectively. The
linker moiety in 4 influenced the reac-
tivity significantly, albeit with slight
impact on the enantioselectivity. Ac-
quisition of reaction profiles under
steady-state conditions showed 4h and
4i to have the highest reactivity (turn-
over frequency (TOF)=95 and 97 hÀ1
at 2 atm, respectively), whereas appro-
priate substrate/catalyst matching was
needed for optimum chiral induction.
The former was recycled 10 times with-
out loss in ee (95–96%), although a
drop in TOF of approximately 20%
per cycle was observed. The estimation
of effective catalytic sites in self-sup-
ported catalyst 4e was also carried out
by isolation and hydrogenation of cata-
lyst–substrate complex, showing about
37% of the RhI centers in the self-sup-
ported catalyst 4e are accessible to
substrate 5c in the catalysis. A continu-
ous flow reaction system using an acti-
vated C/4h mixture as stationary-phase
catalyst for the asymmetric hydrogena-
tion of 5b was developed and run con-
tinuously for a total of 144 h with
>99% conversion and 96–97% enan-
tioselectivity. The total Rh leaching in
the product solution is 1.7% of that in
original catalyst 4h.
naphthol platform) and [RhACHTUNGRTENUNG(cod)2]BF4
(cod=cycloocta-1,5-diene). This self-
supporting strategy allowed for simple
and efficient catalyst immobilization
without the use of extra added support,
giving well-characterized, insoluble (in
toluene) polymeric materials (4). The
resulting self-supported catalysts (4)
showed outstanding catalytic perfor-
mance for the asymmetric hydrogena-
tion of a number of a-dehydroamino
acids (5) and 2-aryl enamides (7) with
enantiomeric excess (ee) ranges of 94–
Keywords: asymmetric catalysis
·
continuous flow system · heteroge-
neous catalysis · hydrogenation ·
self-supported catalysts
Introduction
tems offer the advantages of high enantioselectivity and cat-
alytic activity under mild reaction conditions, the difficulties
associated with recovery and reuse of expensive (toxic)
chiral catalysts, and catalyst–product separation have ham-
pered their more widespread application. A promising solu-
tion to such limitations is the immobilization and subse-
quent recycling of the chiral catalysts employed.[2] Due to
the significant importance of asymmetric hydrogenation
(AH), this endeavor has attracted a great deal of interest
from both academic and industrial societies in recent
years.[2,3]
Presently, the most common and successful strategy for
heterogeneous asymmetric catalysis has been the immobili-
zation of well-developed and understood homogeneous cat-
alysts. Several major heterogenization approaches have
been utilized:[2,4] covalent attachment to inorganic and or-
ganic (soluble and insoluble) polymers, dendrimers, and
The use of homogeneous asymmetric hydrogenation cata-
lysts to provide enantiomerically enriched products is of
central importance in modern synthetic chemistry and a
core technology in the pharmaceutical, agrochemical, and
fine chemical industries.[1] Although such homogeneous sys-
[a] L. Shi, Dr. X. Wang, Prof. Dr. C. A. Sandoval, Prof. Dr. Z. Wang,
H. Li, J. Wu, L. Yu, Prof. Dr. K. Ding
State Key Laboratory of Organometallic Chemistry
Shanghai Institute of Organic Chemistry
Chinese Academy of Sciences
345 Lingling Road, Shanghai 200032 (P.R. China)
Fax : (+86)21-6416-6128
E-mail: kding@mail.sioc.ac.cn
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200900899.
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membrane supports; noncovalent catalyst adhesion (ion ex-
change, electrostatic attraction); encapsulation of catalyst;
and use of biphasic systems (aqueous/organic solvent, ionic
liquid). Such immobilization strategies have inherent advan-
tages and disadvantages, although no method has thus far
proven to be general. Moreover, despite some noteworthy
exceptions in which the immobilized system outperforms
the homogeneous counterparts,[5] support-anchored hetero-
geneous catalysts have generally displayed reduced activity
and/or enantioselectivity. This can mostly be attributable to
disruption of the optimum metal–ligand relationship crucial
for catalysis (geometric and chemical) and/or undesired in-
teractions between the metal–ligand unit and the support
employed.
A recently reported promising immobilization strategy for
heterogeneous asymmetric catalysis is the “self-supporting”
approach[6] inspired by recent development of coordination
polymer chemistry[7] and its application in catalysis.[7b,e,8,9] In
the self-supporting strategy for chiral catalyst immobiliza-
tion, heterogenization of the catalysts is achieved by the
self-assembly of chiral multitopic ligands and reactive metal
ions to give homochiral metal–organic coordination poly-
mers or networks (Figure 1). The high dimensionality of ob-
tained microstructures in the coordination polymers may
result in extremely low solubility in common organic sol-
vents, rendering the system heterogeneous in nature and
thus providing an excellent opportunity for heterogeneous
asymmetric catalysis. Furthermore, such structures can repli-
cate the key features of a homogeneous molecular catalyst
and thus exhibit a somewhat predictable catalytic behavior,
since the stereochemical properties of the chiral ligands and
corresponding catalysts are expected to remain intact by
virtue of the mild synthesis employed. The isolation of the
reactive sites to prevent the interaction of catalytically
active centers can be readily achieved by tuning the struc-
ture of the spacer in the multitopic ligand. Since the first
report on the use of self-assembled microporous homochiral
organic–metal material for enantioselective catalysis (with
8% enantioselectivity for a kinetic resolution of racemic 1-
phenyl-2-propanol) in 2000,[10] several types of homogeneous
chiral catalysts have been effectively immobilized based on
this strategy without the use of any extra supports. The re-
sulting homochiral assemblies have met with notable success
in the heterogeneous catalysis of asymmetric catalytic car-
bonyl-ene reaction,[11] Michael addition,[11a] alkylation,[12]
olefin epoxidation,[13] sulfoxidation,[11c] cyclopropanation,[14]
ring-opening of epoxide,[15] and hydrogenation.[16] These self-
supported chiral catalysts can usually be recycled for several
consecutive runs, and in some cases the product enantiose-
lectivities were comparable to or even better than the ho-
mogeneous counterparts (up to 99.9%).
Previously in a communication[16c] we have reported the
preliminary results on the development of the self-support-
ing strategy for immobilization of Feringa and co-workersꢁ
MonoPhos (1, Scheme 1)/RhI catalyst[17a] in asymmetric hy-
drogenation of a-dehydroamino acids and enamides.[17] The
approach was inspired by the generally accepted under-
standing that the catalytically active species involved in the
reactions should contain two monodentate phosphorous li-
gands coordinatively bonded to one RhI cation.[18] Thus,
through assembly of a polytopic monodentate phosphorus
ligand with an appropriate RhI precursor, a catalytically
active P-Rh-P motif could be incorporated into the back-
bone of the resulting coordination polymer. The thus immo-
bilized MonoPhos/Rh catalysts showed good reactivity (>
99% conversion) and excellent enantioselectivities (94–97%
ee) in the asymmetric hydrogenation of a-dehydroamino
acid and enamide derivatives. For the catalyst reuse test, the
conversion remained quantitative during seven runs under
the experimental conditions (1 mol% cat., 40 atm of H2,
10 h); however, a gradual loss of enantioselectivity was ob-
served with recycling (95–89% ee). To overcome such a
problem commonly seen in a heterogenized catalyst, it is
necessary to carry out a comprehensive study for under-
standing the inherent properties of the immobilized cata-
lysts, including the structure-catalytic performance correla-
tion of these metal–organic coordination polymers.
Herein we describe the details on the synthesis, character-
ization, and catalytic performance of a series of self-support-
ed catalysts built up from variably linked multitopic Mono-
Phos ligands and a RhI metal salt. The efficient heterogene-
ous asymmetric hydrogenation of a-dehydroamino acids and
enamides catalyzed by the resultant assemblies are detailed.
Presentation and discussion of comprehensive studies of the
inherent properties and recyclable nature of such metal–or-
ganic polymers, and differences in their catalytic perfor-
Figure 1. Schematic representation of self-supported heterogeneous cata-
lysts from the reaction of metal ions with a) ditopic, b) tritopic (planar),
and c) tetratopic (tetrahedral) chiral ligands.
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Self-Supported Chiral Catalysts
FULL PAPER
Results and Discussion
For a self-supported chiral catalyst constructed on the con-
ceptual base shown in Figure 1, the stereochemical charac-
teristics of the multitopic ligand should exhibit some impact
on the microstructure of the resulting assembly, and thus
may exert significant influence on its catalytic performance
in a given reaction. Such an effect of the bridging spacer in
the multitopic ligand, for example, has been observed in the
heterogenization of Shibasakiꢁs BINOL/La (BINOL=1,1’-
bi-2-naphthol) catalyst for enantioselective epoxidation of
a,b-unsaturated ketones.[13a] In the present work, four types
of multitopic MonoPhos ligands (3a–3i; Scheme 1) with dif-
ferent bridging linkers, including linear (3a–b, 3d,e), bent
(3c, 3 f,g), trigonal-planar (3h), and tetrahedral (3i) spacers,
were synthesized to investigate the potential impact of the
spatial arrangement of chiral units ((S)-MonoPhos) in the li-
gands on the catalytic properties of the self-supported
MonoPhos/Rh catalysts in asymmetric hydrogenation. Ac-
cording to the principle shown in Figure 1 for generation of
self-supported heterogeneous catalysts, these structurally di-
verse ligands are expected to result in a variety of heteroge-
neous chiral catalysts with different spatial arrangement
when they react with a RhI cation.
Multitopic ligand synthesis: Ligand 2a was prepared by
Suzuki coupling of (S)-6-bromo-2,2’-di(methoxymethoxy)-
1,1’-binaphthyl with (S)-6-(MeO)2B-2,2’-di(methoxyme-
thoxy)-1,1’-binaphthyl, followed by acidic deprotection of
methoxymethyl groups.[11b] In similar fashion, ligands 2b,c
were obtained by the reaction of para- and meta-phenylene-
diboronic acid with (S)-6-bromo-2,2’-di(methoxymethoxy)-
1,1’-binaphthyl, followed by acidic deprotection of methoxy-
methyl groups. The syntheses of other ligands (2d–i) were
achieved by the Pd-catalyzed Sonogashira reactions of me-
thoxymethyl
(MOM)-protected,
6-ethynyl-substituted
BINOL derivatives with the corresponding aryl bromides or
a MOM-protected, 6-bromo-substituted BINOL derivative
with the corresponding aryl acetylene, followed by deprotec-
tion of the MOM groups of the Sonogashira coupling prod-
ucts by acidic hydrolysis.[13a] The linker-bridged poly-Mono-
Phos ligands 3a–i were prepared by the reaction of hexame-
thylphosphorus triamide (HMPT) with corresponding multi-
topic BINOL ligands 2a–i in good yields (64–85%,
Scheme 1).[16c] All multitopic ligands have been character-
ized by standard H and 31P NMR spectroscopy, optical rota-
1
Scheme 1. Synthesis of MonoPhos (1)-based multitopic phosphoramide li-
gands 3a–i. In the case of ligand 3i, (R)-BINOL was used as the starting
material.
tion, FTIR, mass spectroscopy (MS), and high-resolution
mass spectroscopic (HRMS) analysis. They are soluble in
common organic solvents, air stable, and may be stored in-
definitely under argon.
mance are provided. Furthermore, the development and per-
formance of a three-phase (gas–liquid–solid) continuous
flow reactor for asymmetric hydrogenation is described,
which has provided a useful approach for stabilizing the
self-supported catalyst.
Catalyst synthesis and characterization: The self-supported
catalysts 4a–i were synthesized by assembly of Rh metal
ions with the MonoPhos-based multitopic ligands 3a–i, as
outlined in Scheme 2. The multitopic phosphoramidite
ligand 3 and catalyst precursor [Rh
ACHTUNGTREN(NUNG cod)2]BF4 (cod=cyclo-
octa-1,5-diene) were dissolved in dichloromethane. The ad-
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K. Ding et al.
cordingly, toluene was selected
as the reaction medium for the
heterogeneous hydrogenation
of olefin derivatives.
Elemental analysis results
showed that the composition
of the resulting solids (4a–i)
were consistent with their cor-
responding expected structures.
In each case, the ratio of the
MonoPhos unit(s) to that of
Rh centers was calculated to
be closely equal to two. The sa-
lient features of the self-sup-
porting strategy include the
high overall ligand content and
well-isolated coordinating units
by linking spacers, and accord-
ingly high density of active
sites in the resulting materials.
This should be easily under-
standable since no extra carrier
(mass) was introduced during
the catalyst generation. As-
suming
a perfect alternating
copolymerization of the metal
with the ligand has occurred
during polymer formation, the
maximum density of the cata-
lytically active Rh units was
expected to range from 0.39 to
0.98 mmolgÀ1 (mmol of Rh per
gram of the polymer) for 4a–
i.[19] Such an assumption is rea-
sonable
considering
that
metal–ligand
coordination
(binding) is essential for poly-
mer formation and that such a
structural motif persists during
and after hydrogenation itself,
that is, no hydrogenation is ob-
served with filtrate alone after
catalyst filtration following hy-
drogenation (discussed below).
A comparison of the chemi-
cal shifts in the solid-state 31P
cross-polarization magic-angle-
Scheme 2. Synthesis of self-supported catalysts 4a–i.
spinning (CP-MAS) NMR
spectra of multitopic ligand
dition of a solution of 3 to that of [Rh
(cod)2]BF4 afforded a
3h,i and their assembled polymers 4h,i (see the Supporting
Information) with those of 1 and its RhI complex clearly
demonstrated a similar coordination pattern in the solid
state. 31P CP-MAS NMR spectroscopy of 1 shows a broad
peak centered at d=148.6 ppm, which moves upfield to d=
135.3 ppm upon formation of the Rh–12 complex (see Fig-
ure S3 in the Supporting Information). Similarly, resonances
for 3h and 3i shift from d=148.8 ppm to d=137.3 and
suspension or a precipitate immediately. After stirring for
30 min, the solvent was removed to give the orange self-sup-
ported catalyst 4 in almost quantitative yields. The orange
solids 4a–g were sparingly soluble in CH2Cl2, whereas 4h
and 4i were insoluble in the same solvent. All self-supported
catalysts (4a–i) were completely insoluble in toluene, fulfill-
ing the basic prerequisites of heterogeneous catalysis. Ac-
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Self-Supported Chiral Catalysts
FULL PAPER
137.0 ppm, respectively, after the formation of 4h,i. These
data in combination with the ratio of MonoPhos units to Rh
centers discussed above suggests the occurrence of the re-
peating units of [P2RhACHTUNTGRENUNG(cod)]BF4, a well-known structural
I
À
motif often encountered in Rh P complex-catalyzed hydro-
genations.[18]
The self-supported catalysts are composed of micrometer-
sized particles as evidenced from SEM microscopy. Figure 2
shows SEM images for 4h and 4i, respectively. Furthermore,
these materials display no crystallinity in respective XRD
powder patterns indicating their amorphous nature (see Fig-
ure S2 in the Supporting Information).
Figure 3. Typical reaction profile for asymmetric hydrogenation of 5b cat-
~
alyzed by 4d: a) consumption of 5b ( ) and production of 6b (&); b) ob-
tained enantioselectivity in 6b.
Table 1. Asymmetric hydrogenation of a-dehydroamino acid methyl
esters (5) catalyzed by self-supported catalysts (4).[a]
Figure 2. SEM images for self-supported catalysts: a) 4h with 2 mm scale
bar; b) 4i with 100 nm scale bar.
Catalyst
Enantiomeric excess [%][b]
6a
6b
6c
4a
4b
4c
4d
4e
4 f
4g
4h
4i
95
94
95
95
94
96
93
95
97[c]
95
94
95
96
96
97
95
96
98[c]
96
94
96
95
96
97
96
96
95[c]
Hydrogenation with self-supported catalysts: Hydrogena-
tions were conducted either in a standard steel autoclave, or
in a glass autoclave equipped with a sampling needle con-
nected to a stop valve.[17a,20] The latter allowed for aliquots
to be taken from the active hydrogenation mixture and ana-
lyzed by chiral GC so as to provide valuable information
about the steady-state reduction process. Figure 3 shows a
typical reaction profile obtained under standard conditions
([4d]=1 mm (based on [Rh]), [5b]=0.1m, P(H2)=2 atm,
T=258C, in 5 mL of toluene) for asymmetric hydrogenation
of (Z)-methyl 2-acetamidobut-2-enoate (5b, Table 1) cata-
lyzed by 4d. Hydrogenation of 5b proceeds efficiently with-
out the appearance of side products with substrate consump-
tion showing pseudo-first-order dependence. There is no ap-
parent incubation period and the initial rate is maintained
until approximately 70% conversion (TOF=82 hÀ1 at
2 atm).[21] Importantly, the observed enantiomeric excess
[a] Conditions: [5]=0.2m, [4]=2 mm (1 mol% based on the (Mono-
Phos)2/RhI unit), T=258C, P(H2)=40 atm, t=10 h, toluene as solvent.
Conversion is always >99%. [b] 6a and 6b were determined by GC (Su-
pelco BETA-DEX 225 column). The ee of 6c was determined by HPLC
(Chiralcel AD column). [c] (S)-6a–c were obtained with 4i.
(ee) was found to be independent of the substrate concen-
tration, remaining constant throughout the reaction at the
high value of 97%. To test the heterogeneous nature of the
above catalyst system, the supernatants of 4d in toluene was
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K. Ding et al.
Table 2. Asymmetric hydrogenation of 2-aryl-substituted enamides (7)
catalyzed by self-assembled catalyst (4).[a]
employed for the catalysis of the hydrogenation of 5b under
the same experimental conditions. No product was observed.
Furthermore, inductively coupled plasma (ICP) atomic
emission spectroscopy (AES) analyses indicated no detecta-
ble rhodium (detection limit of ICP-AES for Rh is 1 ppm)
had leached into the organic solution (<0.85% of the sup-
ported rhodium in 4d). Thus, the present systems are unam-
biguously heterogeneous without metal and/or ligand leach-
ing into the liquid phase.
As can be envisioned from Figure 1, when using the self-
supporting strategy for heterogenization of homogeneous
chiral catalysts, the stereochemical characteristics of the
multitopic ligands should in principle have a substantial in-
fluence on the microstructures of the resulting homochiral
metal–organic polymers. This, in turn, is expected to exert
an impact on the enantioselectivity and activity of the catal-
ysis. In fact, catalysts 4 prepared in the same way, with the
only difference lying in their spacer moieties, displayed dif-
ferent catalytic performance for the asymmetric hydrogena-
tion of a-dehydroamino acid methyl esters (5) under the
standard conditions ([4]=2 mm, [5]=0.2m, P(H2)=40 atm,
T=258C, t=10 h, toluene solvent) shown in Table 1. The
obtained ee values for products 6 were comparable to the
homogeneous Rh–12 catalyst, consistently giving values be-
tween 94 and 98%. Interestingly, the ee values were found
to be subtly influenced by the linker used in the multitopic
ligand and the particular substrate structure. Thus, although
the highest enantioselectivity for 6a and 6b was obtained
with the catalyst 4i generated from tetratopic 3i (97 and
98%, respectively), ditopic-ligand-based catalyst 4 f yielded
the highest ee value for 6c (97%).
Under the same conditions, asymmetric hydrogenations of
2-aryl-substituted enamides (7) were similarly conducted,
and the results are summarized in Table 2. For the simple
phenyl derivative 7a the highest chiral induction (98% ee)
was obtained with 4 f catalyst, whereas some other ditopic-
ligand-based catalysts (4a, 4d, and 4e) similarly gave high
enantioselectivity (97%). In contrast, tetratopic-ligand-
based catalyst 4i promotes the hydrogenation of 7a in only
93% ee. In general, the performance of self-supported cata-
lysts was comparable to the homogeneous MonoPhos-based
(Rh–12) system that yields 8a in 95% ee under the same
conditions. Overall, the observed enantioselectivities for a
number of aryl enamides were found to also be dependent
on catalyst-linker/substrate-structure matching. For example,
catalyst 4a gave 8c in 96% ee, whereas 4c gave the same
product in 90% ee. The catalysis was not obviously influ-
enced by electron-donating or -withdrawing groups on the
aryl substituent in 7. Interestingly, the observed differences
in enantioselectivity are only marginal for a number of
ligand types, while noting that all catalysts provide respecta-
ble chiral induction. This suggests that the actual environ-
ment about the metal-coordinating moiety (P ligand) is not
detrimentally affected by the self-supporting process itself.
This is in contrast to some other immobilization techniques
employed in which a consequent large drop in enantioselec-
tivity may occur.[4] This constitutes an attractive feature of
Entry Catalyst Substrate ee
[%][b]
Entry Catalyst Substrate ee
[%][b]
1
2
3
4
5
6
7
8
4a
4a
4a
4a
4a
4a
4b
4b
4b
4b
4b
4c
7a
7b
7c
7d
7e
7g
7a
7b
7c
7d
7g
7a
97
13
14
15
16
17
18
19
20
21
22
23
24
4c
4c
4c
4c
4c
4c
4d
4e
4 f
4g
4h
4i
7b
7c
7d
7e
7 f
7g
7a
7a
7a
7a
7a
7a
95
93
96
93
95
93
95
95
94
96
90
95
90
95
93
93
90
97
97
98
95
96
93[c]
9
10
11
12
[a] Conditions: [7]=0.2m, [4]=2 mm (1 mol% based on the (Mono-
Phos)2/RhI unit), T=258C, P(H2)=40 atm, t=10 h, toluene as solvent.
Conversion is always >99%. [b] Determined by HPLC (Chiral AD
column). [c] (S)-8a was obtained in this case.
the gentle self-supporting strategy for chiral catalyst immo-
bilization.
Figure 4 shows the reaction profiles for selected self-sup-
ported catalysts and comparison to the homogeneous Mono-
Phos-based system (Rh–12) under the same conditions.[22]
Notably, the catalytic activity observed for 4h and 4i
(TOF=95 and 97 hÀ1 at 2 atm, respectively) is actually
higher than that for the homogeneous counterpart.[23] Thus,
heterogeneous catalyst 4h yields 6b in >95% conversion at
60 min (>99% after 90 min) with a constant ee value of
97%. Slightly lower reactivities were observed for 4b–g
(TOF range=71–87 hÀ1 at 2 atm), whereas catalyst 4b re-
Figure 4. Comparison of the catalytic performance of selected self-sup-
ported catalysts (4) with homogeneous MonoPhos/Rh in the hydrogena-
tion of 5b ([4]=1 mm, [5b]=0.1m, P(H2)=2 atm, T=258C, toluene as
I
~
*
^
solvent). Key: & =4h; =4i; =Rh –12; =4e; ꢂ=4g; +=4b.
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Self-Supported Chiral Catalysts
FULL PAPER
quired considerably longer reaction times by comparison
(TOF=51 hÀ1 at 2 atm). In all cases the obtained enantiose-
lectivity for 6b was constant for each profile with all cata-
lysts providing product in the range of 95–98% ee. This rate
enhancement is considered to result from favorable structur-
al changes inherent in the metal–organic polymerization
process. For example, effects on ligand rigidity and/or
pseudo-bite angle for the two component MonoPhos units
about the Rh metal may provide a positive influence on the
catalysis. In addition, site isolation due to heterogenization
may minimize unwanted saturation of reactive metal centers
by irreversible clustering and aggregation during catalysis.[24]
In fact, for a homogeneous hydrogenation catalyst prepared
in situ with RhI salt and a monophosphorus ligand L, a dy-
namic mixture of RhI complexes composed of species such
as ML1, ML2, ML3, and ML4 may exist, among which the
ML2 species is usually held responsible for the catalysi-
s.[17e, g,18] In the present work, the self-supported catalysts
4a–i were generated on the basis of the ML2 coordination
pattern, which seems to fit the structural requirement of the
active species. The use of sterically bulky tritopic or tetra-
topic ligands 3h and 3i to generate a self-supported Rh cat-
alyst can minimize the possibility of forming ML3 or ML4
species, and this presumably can be one reason why catalysts
4h and 4i demonstrated superior catalytic activity over
other ditopic-ligand-based catalysts. In any event, the com-
parable reactivity to analogous homogeneous systems ren-
ders the self-supporting approach an outstanding strategy
for catalyst immobilization. These results clearly show that
modifications in the linker moieties of the bridging ligands
may alter the supramolecular structures of the assemblies,
and as a result, have an impact on the catalysis. Coupled
with the fact that the coordinatively unsaturated reactive
metal centers of the resulting polymers remain relatively un-
compromised by the self-supporting process, such subtle in-
fluences can result in better catalyst performance in terms
of enantioselectivity and/or reactivity. Thus, the heterogene-
ous catalyst may be fine-tuned to optimize the overall catal-
ysis for the reaction of a given substrate, outperforming
their homogeneous counterparts as a result.
Hydrogenation by a gas–liquid–solid reaction has the in-
herent disadvantage of slow mass transfer. Accordingly, the
reaction is typically performed under high pressure to mini-
mize such (and related) issues. Alternatively, increasing the
interfacial area between gas (H2), liquid (solvent and sub-
strate), and solid (catalyst) will also result in better reaction
rates. For this reason, an understanding of the nature of the
self-supported catalyst during hydrogenation is extremely
important. Although BET measurements suggest a nonpo-
rous material for the present self-assembled metal–organic
polymers, this precatalyst condition might very well change
in solution under hydrogenation conditions. As observed in
a number of polymer (cross-linked) or resin-bound catalyst
systems,[3b,4a,g,i] a nonporous polymer would be expected to
undergo swelling in the reaction solvent. However, as can
be seen in Figure 5, changing the stirring (and mixing) time
prior to H2 activation did not result in any significant
Figure 5. Catalyst 4h performance in catalyst formation with a variation
~
*
of stirring time ( =<3 min; & =10 h; =10 min).
change to the overall reaction profile shape. For a swelling
process, notable incubation periods result from limited cata-
lyst turnover due to hidden active sites prior to swelling.
Nevertheless, there is a definite difference in the TOF for
the differently made precatalysts, with longer precatalyst
stirring times resulting in increases in catalyst activity. We
consider this to be due to an increase in the overall available
surface as a result of mechanical stirring, which causes a re-
duction in the average particle size (see Figure S1b,c in the
Supporting Information). This effect acts in two major ways:
1) it increases direct exposure of active sites on the surface
of the catalyst to the substrate, and 2) it increases the availa-
bility and access of substrate (solvent) to interstitial active
sites within the catalyst/polymer matrix. In addition, it may
be expected that polymer units may break and come togeth-
er during catalysis to similarly expose “new” active sites.
This is particularly likely since metal coordination involves
nonchelating monodentate ligand types. However, current
mechanistic data on analogous homogeneous monodentate
P ligands suggest that a 2:1 ligand/Rh complex is involved in
the active catalyst. Thus, considering the exceptionally high
enantioselectivity obtained with the self-supported catalysts,
2:1 ligand/Rh units should predominate in these systems.
Estimation of effective catalytic sites in the self-supported
catalyst: It has been generally accepted that in the RhI-cata-
lyzed asymmetric hydrogenation of a-dehydroamino acid
derivatives, the active catalyst first reacts with substrate in a
pre-equilibrium to form the catalyst–substrate complex. In
the rate-determining step, this complex finally reacts to
form the product and regenerate the catalyst. The NMR
spectroscopic technique and X-ray molecular structure de-
terminations of the catalyst–substrate complexes have pro-
vided a wide range of evidence for the formation and the in-
volvement of these species in the catalysis.[25] On the basis
of this mechanistic understanding, we decided to measure
the ratio of accessible active sites in our self-supported RhI
catalysts by isolating the solid-catalyst–substrate complex
and performing their hydrogenation. Assuming that the
complexed substrate in the solid catalyst can be completely
converted to the product in a stoichiometric manner, the
amount of the product obtained corresponds to the sum of
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9861

K. Ding et al.
catalyst–substrate complex, and thus provides a rough esti-
mation of how much accessible active site is present in the
solid catalyst.
As shown in Scheme 3, the self-supported catalyst 4e
(0.18 mmol) was first treated with H2 (10 atm) to remove
the coordinated cycloocta-1,5-diene around the RhI center,
and the resultant catalyst was reacted with a-dehydroamino
~
*
Figure 6. Reaction profiles ( =first run; =second run) for the recy-
cling of self-supported catalyst 4h in the hydrogenation of a-dehydroami-
no acid derivative 5b.
the hydrogenation drops from 95 to 54 hÀ1 (2 atm) for the
first and second run, respectively, however, the enantioselec-
tivity remained the same for both runs (97% ee).
Results for an analogous hydrogenation recycled a total
of 10 times are given in Table 3. Here, the hydrogenation
Scheme 3. Isolation and hydrogenation of the catalyst–substrate complex
for the estimation of effective catalytic sites in the self-supported catalyst
4e.
Table 3. Determination of turnover frequency (TOF) during recycling of
catalyst 4h for the asymmetric hydrogenation of 5b.[a]
Run
t [min][b]
Conversion [%]
TOF[c]
ee [%][d]
1
2
3
4
5
6
7
8
25
30
30
30
40
60
70
90
115
130
71
75
72
67
73
85
81
81
81
68
170
152
145
135
111
86
69
54
42
31
96
95
96
97
97
97
97
97
96
96
acid derivative 5c (4.6 equiv, 0.82 mmol) in toluene. The
mixture was stirred for 1 h and the resulting solid was sepa-
rated by filtration and washed with toluene (3ꢂ5 mL) to
ensure the complete removal of the uncomplexed 5c. Final-
ly, the isolated self-supported catalyst (4e) saturated by sub-
strate 5c was recharged with toluene and H2; 14.6 mg
(0.066 mmol) of hydrogenated product 6c was obtained with
96% ee. Based on these experimental data, it can be de-
duced that approximately 37% of the RhI centers in the
self-supported catalyst 4e are accessible to the large-size
substrate 5c. This high ratio of effective catalytic sites in the
self-supported catalyst may provide a rationale for its rela-
tively high activity in the heterogeneous catalysis.
9
10
[a] Conditions: [5b]=0.4m, [4h]=4 mm (1 mol% based on the (Mono-
Phos)2/RhI unit), T=258C, P(H2)=3 atm, toluene as solvent. [b] Re-
action was stopped at approximately >70% conversion. [c] For definition
see ref. [21]. [d] Determined by GC (Supelco BETA-DEX 225 column).
was stopped after approximately >70% conversion so that
the TOF could be calculated for each consecutive run. Al-
though no significant loss in enantioselectivity was observed
(96–97% ee), the TOF for each successive run (recycle)
drops by a significant, near-constant amount (ca. 20%). This
highlights an important issue when discussing the recyclabili-
ty of catalysts, since such a drop in reactivity (TOF) may go
unnoticed if conversion is used to quantify catalyst activity.
This decrease in reactivity with recycling can be attributed
to a number of reasons,[2–4] some inherent to the method of
catalyst immobilization and recycling. Presently, we suggest
that partial catalyst decomposition during the recycling pro-
cess due to instability of intermediate catalyst species might
be responsible. Importantly, the leaching of Rh metal in
each cycle during recycling of the catalyst was less than
1 ppm, as determined by ICP spectroscopy. Although the
presence of adventitious air or moisture cannot be ruled
Catalyst recycling: The tremendous advantage of the self-
supported heterogeneous catalysts over their homogeneous
counterparts, notwithstanding their comparable reactivity
and enantioselectivity, was exemplified by the facile recov-
ery and recycling of 4h during the asymmetric hydrogena-
tion of 5b. Following the completion of hydrogenation,
simple cannula filtration of the reaction mixture under an
N2 atmosphere in a glove box allowed the separation of the
solid-state catalyst from the product-containing solution.
The isolated solids were recharged with toluene and sub-
strate, and reloaded into the glass autoclave for the next
run. Figure 6 shows the reaction profiles for the first and
second run for a single reuse ([4h]=1 mm (based on (Mono-
Phos)2/RhI unit), [5b]=0.1m, P(H2)=2 atm, T=258C, tolu-
ene solvent). It is evident that the system experiences a sig-
nificant drop in the reactivity upon recycling. The TOF for
9862
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Chem. Eur. J. 2009, 15, 9855 – 9867

Self-Supported Chiral Catalysts
FULL PAPER
out, we suggest that the removal of the H2 atmosphere
during recycling is obviously unfavorable for the stability of
the catalytically active species. For a set reaction time of
10 h, catalyst 4c has previously been recycled up to 7 times
(here, filtration of the catalyst was carried out using a stan-
dard Schlenk technique under an argon atmosphere, but not
in a glove box) with quantitative conversion (>99%), but
yielding 6a with a noticeable drop in enantioselectivity (95–
89%).[16c] This again demonstrated that the instability of in-
termediate catalyst species is a problematic issue during re-
cycling in the absence of H2.
Figure 7. Schematic representation of the continuous flow reactor using
self-supported catalyst.
Development of a continuous flow system: To further en-
hance the performance of a heterogeneous catalyst for hy-
drogenation, various continuous flow reactors have been de-
veloped using different strategies for stationary-phase cata-
lyst immobilization.[26,27] Such processes offer several advan-
tages over existing batch techniques, particularly when using
an anchored catalyst phase.[28] Primarily, the reaction param-
eters like flow rate, system pressure, reaction stoichiometry,
and temperature can be readily controlled and monitored,
leading to well-defined and reproducible reaction condi-
tions. Moreover, such systems are readily scalable by appli-
cation of multichannel, parallel reactors, or extended run-
ning times. These factors thus allow for a large product-to-
catalyst output without the need for repeated catalyst recy-
cling, which typically suffers from a progressive loss in cata-
lyst performance.[4] Particularly for the hydrogenation cata-
lyst, the stability may be also enhanced by avoiding the de-
composition of unstable metal species during the separation
of catalyst in the absence of H2 atmosphere.
As we mentioned above, a decrease in reactivity with con-
secutive recycling is a general problem for hydrogenation
using immobilized catalysts.[4] Accordingly, continuous flow
reactors may provide a good opportunity to overcome this
limitation and improve overall process capacity and produc-
tivity.[26–28] On the other hand, the high TOF of the self-sup-
ported MonoPhos/Rh catalyst system in batch heterogene-
ous hydrogenation can meet the basic requirement for the
development of a continuous flow reaction system due to
the short interaction time between immobilized catalyst and
flowing substrate in the flow reaction system. Presently, a
continuous flow reactor was designed and developed for
asymmetric hydrogenation using the self-supporting strategy
for stationary-phase catalyst immobilization. The principle
design elements are illustrated in Figure 7. The reactor
setup allows for a continuous flow of the substrate solution
and hydrogen gas through a tube reactor packed with the
heterogenized catalyst. The gas–liquid mixture is pumped
through a T-shaped mixer to ensure efficient gas dispersion,
while the flow of the substrate solution was controlled by an
HPLC pump and the flow of the hydrogen gas was regulat-
ed by a gas flow controller. The mixed hydrogen–substrate
solution flow stream formed within the T-shaped cross was
driven to flow continuously through a 4.6 mm inner diame-
ter and 2 cm stainless steel column that was prepacked with
the solid catalyst. At the outlet of the column, the product
solution was collected for GC analysis and the excess
amount of the hydrogen gas came out at atmospheric pres-
sure.
Initially, self-supported catalyst 4b was packed into the
column and used as the stationary heterogeneous catalyst
phase. However, use of this metal–organic polymer alone or
a 4b/MgSO4 (with an average diameter of 15 mm) (120 mg/
170 mg) mixture quickly resulted in system blockage. In-
creasing the loading of the inorganic salt (4b/MgSO4 =
60 mg/230 mg) allowed for the flow system to function con-
tinuously following an initial stabilization period (ca. 3 h).
Under standardized conditions (4b=60 mg, MgSO4 =
230 mg; [5b]=1 g/100 mL; flow rate=0.1 or 0.05 mLminÀ1
;
H2 flow rate=3 mLminÀ1; toluene as solvent), the conver-
sion could be continuously maintained at 55–76% for a
period of 52 h, yielding product 6b in 94–96% ee. However,
possibly due to temporary blockage of the continuous flow,
the pressure for this system was observed to be unstable.
To improve the productivity and flow properties of the
packed column, other packing materials were tested. Reac-
tion profiles under the same standard conditions for hetero-
geneous asymmetric hydrogenation of 5b by catalysts com-
prised of 4b and MgSO4, TiO2 (with an average diameter of
0.1 mm and a specific surface area of 90 m2 gÀ1), or activated
carbon (with an average diameter of 30 mm and a specific
surface area of 1000 m2 gÀ1) are shown in Figure 8. The 4b/
~
Figure 8. Reaction profiles for mixtures of 4b with added support ( =no
*
^
support; =TiO2; & =MgSO4; =carbon) under the following condi-
tions: [4b]=1 mm, [5b]=0.1m, P(H2)=2 atm, T=258C, toluene as sol-
vent.
Chem. Eur. J. 2009, 15, 9855 – 9867
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9863

K. Ding et al.
MgSO4 system shows slightly lower but comparable reactivi-
ty to 4b alone, whereas mixing with TiO2 clearly results in a
less active catalyst. Most notably, the reactivity when acti-
vated carbon was used as added support significantly in-
creased the reactivity beyond that of the self-supported cata-
lyst 4b alone. This is somewhat surprising but may be attrib-
utable to the improved dispersion of 4b in the reaction mix-
ture in the presence of activated carbon. For all systems,
however, the obtained enantioselectivity in 6b for mixed
systems is relatively constant (96–97% ee) when compared
to 4b alone (97% ee) or the homogeneous 1–Rh catalyst
(97% ee). This indicates that the delicate local multitopic
ligand/Rh metal electronic and steric properties are not in-
fluenced by the addition of an added support.
Since reaction profiles (see Figure 4) of the various het-
erogenized catalysts (4) showed that 4h and 4i give an out-
standing result both in activity and enantioselectivity, even
under low H2 pressure (2 atm), 4h was selected for catalyst
column loading because of its easy preparation. (For SEM
images of 4h, activated carbon, the mixture of catalyst 4h,
and activated carbon, see Figures S1a and S1d in the Sup-
porting Information.) Under the experimental conditions,
product 6b could be continuously obtained in >99% con-
version (93–94 mmolhÀ1) in 97% ee for a total of 144 h
(Figure 9). This corresponds to a constant daily production
of 0.36 g (2.25 mmol), giving an overall yield of 2.52 g
(15.75 mmol) of 6b after 144 h. The leaching of Rh into the
product solution in toluene was 0.13 ppm, corresponding to
1.7% of that in the original catalyst 4h (determined by ICP
spectroscopy). Thus, the self-supporting strategy provides a
viable means for chiral catalyst immobilization in continu-
ous flow reactors.
centers comprises a simple and efficient means of chiral cat-
alyst immobilization. The resulting self-supported catalysts
are stable and well behaved under catalytic conditions; they
show outstanding reactivity and selectivity, comparable to or
even better than their analogous homogeneous counterparts.
Variation of the linker (or spacer) adjoining the coordinat-
ing groups allows for fine-tuning of the catalytic perfor-
mance. The resultant homochiral metal–organic coordina-
tion polymers are easily recycled without significant loss in
enantioselectivity, although a drop in reactivity is apparent.
The latter can be overcome by employment of a continuous
flow reactor, which allows for high efficiency for extended
periods without loss in reactivity or enantioselectivity. Thus,
the self-supported approach is a reliable (and general)
method for immobilization of MonoPhos/Rh catalyst in
asymmetric hydrogenation. The immobilized catalyst is ap-
plicable in both batch recycling and continuous flow pro-
cesses, constituting a very competitive heterogenization
strategy in asymmetric catalysis.
Experimental Section
All the experiments sensitive to moisture or air were carried out under
an argon atmosphere using standard Schlenk techniques. Dichlorome-
thane and chloroform were freshly distilled from calcium hydride; and
THF, diethyl ether, and toluene from sodium benzophenone ketyl. Com-
mercial reagents were used as received without further purification
unless otherwise noted. Compounds 2a–c,[16c] 2d–i,[13a] 3a–c,[16c] and
4a–c[16c] were prepared as previously reported.
1H NMR and 13C NMR spectroscopy were conducted using a Varian Mer-
cury 300 (1H: 300 MHz; 13C: 75 MHz) spectrometer. Chemical shifts are
reported in ppm relative to the internal standard SiACHTNUGTRNEG(UN CH3)4 (d=0.0 ppm)
for 1H NMR spectroscopy and CDCl3 (d=77.0 ppm) for 13C NMR spec-
troscopy. Coupling constants, J, are listed in Hertz. 31P NMR spectra
were referenced with an external 85% H3PO4 sample. 31P NMR CP-
MAS spectra were measured using a Bruker DSX300 NMR spectrometer
(125 MHz). Chemical shifts were referenced from 70% H3PO4 (d=
0.0 ppm) as external standard. EI (70 eV) and ESI mass spectra (MS)
were conducted using HP5989A and Mariner LC-TOF spectrometers, re-
spectively. HRMS spectra were determined using a Q-Tof micro instru-
ment or APEXIII 7.0 TESLA FTMS. Elemental analysis was performed
using an Elemental VARIO EL apparatus. Optical rotations were mea-
sured using a Perkin–Elmer 341 automatic polarimeter. Infrared (IR)
spectra were obtained using a BIO-RAD FTS-185 Fourier transform
spectrometer using KBr pellets. Scanning electron micrographs were
taken using a Hitachi S-570 scanning electron microscope. Powder X-ray
diffraction (XRD) spectroscopy was conducted using a Bruker-AXS D8
Advance spectrometer. ICP analysis was performed using a Varian spec-
tra AA. Liquid chromatographic (LC) analyses were conducted using a
JASCO 1580 system. GC analyses were conducted using an Agilent
6890N network system.
~
Figure 9. Catalytic performance (& =ee; =yield) of the continuous flow
reactor in the asymmetric hydrogenation of 5b (reaction column: 4.6 mm
inner diameter and 2 cm in length; 4h=60 mg; activated carbon=90 mg;
reaction conditions: [5b]=1 g/200 mL, flow rate=0.05 mLminÀ1, H2 flow
rate=3 mLminÀ1, toluene as solvent).
General procedure for the synthesis of compounds 3d–i: The correspond-
ing bis-BINOL (2) derivative (1.0 mmol) and hexamethylphosphorous
triamide (0.46 mL, 2.5 mmol) were heated at reflux for 9 h in anhydrous
toluene (3.0 mL) under an argon atmosphere. After cooling to room tem-
perature, the solvent was removed under reduced pressure and the crude
pale yellow residue was purified by flash chromatography on silica gel
using petroleum ether/ethyl acetate (10:1) for 3d–h or petroleum ether/
dichloromethane (2:1) for 3i as eluent. Recrystallization from diethyl
ether afforded pure product as a white (3d–g,i) or pale yellow (3h) solid.
Conclusion
Compound 3d: Yield: 526 mg (76%); m.p. 164–1678C; [a]2D0 =+620.7
Construction of self-assembled metal–organic frameworks
using well-designed multitopic ligands and reactive metal
(c=0.5 in CHCl3); 1H NMR (300 MHz, CDCl3): d=8.14 (d, J=3.0 Hz,
9864
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Self-Supported Chiral Catalysts
FULL PAPER
2H), 7.87–7.99 (m, 6H), 7.49–7.53 (m, 2H), 7.29–7.45 (m, 12H), 2.53–
2.57 ppm (m, 12H); 31P NMR (121 MHz, CDCl3): d=149.98, 150.06 ppm;
FTIR (KBr pellet): n˜ =3055, 2964, 2922, 2844, 2800, 2205, 1619, 1589,
1506, 1469, 1461, 1361, 1334, 1292, 1262, 1233, 1207, 1187, 1072, 1027,
984, 944, 922, 888, 836, 820, 796, 791, 780, 749, 693, 677, 637 cmÀ1; MS
(MALDI-DHB): m/z: 741.20 [M+H]+; HRMS (MALDI-DHB): m/z:
calcd for C46H35N2O4P2 [M+H]+: 741.2066; found: 741.2093.
calcd (%) for {[RhACHTUNGTERNNU(G cod)CAHTNUGTREN(NUNG 3e)]BF4·CH2Cl2}n: C 61.84, H 4.28, N 2.29;
found: C 61.77, H 5.08, N 1.90.
Compound 4 f: FTIR (KBr pellet): n˜ =2924, 1620, 1591, 1508, 1464, 1330,
1262, 1226, 1178, 1157, 1070, 989, 964, 946, 890, 828, 791, 752, 698,
581 cmÀ1; elemental analysis calcd (%) for {[Rh
H 4.43, N 2.46; found: C 65.79, H 5.69, N 2.01.
ACHUTNGTRENUNG(cod)AHCTUNGTREN(NUGN 3 f)]BF4}n: C 65.39,
Compound 4g: FTIR (KBr pellet): n˜ =3061, 2925, 1621, 1590, 1508, 1463,
Compound 3e: Yield: 621 mg (74%); m.p. 169–1728C; [a]2D0 =+610.2
(c=0.5 in CHCl3); 1H NMR (300 MHz, CDCl3): d=8.13 (d, J=3.3 Hz,
2H), 7.86–7.99 (m, 6H), 7.54 (s, 4H), 7.25–7.52 (m, 14H), 2.53–2.57 ppm
(m, 12H); 31P NMR (121 MHz, CDCl3): d=149.98, 150.10 ppm. FTIR
(KBr pellet): n˜ =3057, 2922, 2845, 2800, 2202, 1588, 1509, 1463, 1334,
1292, 1234, 1207, 1188, 1070, 984, 944, 913, 888, 836, 820, 796, 790, 751,
1328, 1261, 1226, 1179, 1071, 1008, 990, 948, 864, 828, 791, 753, 699, 662,
587 cmÀ1; elemental analysis calcd (%) for {[Rh
H 4.43, N 2.46; found: C 64.45, H 5.39, N 2.01.
ACHUTNGTRENUNG(cod)AHCTUNGTREN(NUGN 3g)]BF4}n: C 65.39,
Compound 4h: 31P NMR CP-MAS: d=137.30 ppm; FTIR (KBr pellet):
n˜ =3443, 2923, 2852, 1619, 1589, 1466, 1327, 1226, 1180, 1083, 987, 947,
828, 744, 692 cmÀ1
(cod)(3h)]BF4}1.5 A
;
elemental analysis calcd (%) for ({[Rh-
693, 677, 635 cmÀ1 MS (MALDI-DHB): m/z: 840.20 [M]+; HRMS
;
N
·CHTUGNERTN(NGNU CH2Cl2)2)n: C 60.09, H 4.17, N 2.29, Rh 8.39; found: C
(MALDI-DHB): m/z: calcd for C54H39N2O4P2 [M+H]+: 841.2379; found:
60.05, H 4.61, N 2.14, Rh 7.77.
Compound 4i: 31P NMR CP-MAS: d=137.04 ppm; FTIR (KBr pellet):
841.2385.
Compound 3 f: Yield: 663 mg (79%); m.p. 214–2178C; [a]2D0 =+597.4 (c=
0.5 in CHCl3); 1H NMR (300 MHz, CDCl3): d=8.13 (d, J=3.3 Hz, 2H),
7.90–7.96 (m, 6H), 7.76 (s, 1H), 7.49–7.54 (m, 4H), 7.25–7.45 (m, 13H),
2.53–2.57 ppm (m, 12H); 31P NMR (121 MHz, CDCl3): d=150.02,
150.11 ppm; FTIR (KBr pellet): n˜ =3057, 2953, 2924, 2845, 2800, 2207,
1591, 1506, 1463, 1334, 1293, 1233, 1207, 1188, 1071, 984, 945, 889, 822,
790, 750, 694, 637 cmÀ1; MS (MALDI-DHB): m/z: 841.10 [M+H]+;
HRMS (MALDI-DHB): m/z: calcd for C54H39N2O4P2 [M+H]+: 841.2379;
found: 841.2378.
Compound 3g: Yield: 537 mg (64%); m.p. 210–2138C; [a]2D0 =+679.5
(c=0.5 in CHCl3); 1H NMR (300 MHz, CDCl3): d=8.17 (d, J=9.9 Hz,
2H), 7.90–7.99 (m, 4H), 7.67–7.79 (m, 2H), 7.58–7.61 (m, 2H), 7.23–7.52
(m, 16H), 2.53–2.56 ppm (m, 12H); 31P NMR (121 MHz, CDCl3): d=
149.92, 150.09 ppm; FTIR (KBr pellet): n˜ =3056, 2923, 2845, 2801, 2199,
1619, 1587, 1505, 1462, 1355, 1334, 1294, 1230, 1207, 1070, 985, 944, 822,
790, 756, 694, 636 cmÀ1; MS (MALDI-DHB): m/z: 841.10 [M+H]+;
HRMS (MALDI-DHB): m/z: calcd for C54H39N2O4P2 [M+H]+: 841.2379;
found: 841.2383.
Compound 3h: Yield: 855 mg (70%); m.p. 279–2818C; [a]2D0 =+614.2
(c=0.5 in CHCl3); 1H NMR (300 MHz, CDCl3): d=8.13 (d, J=3.6 Hz,
3H), 7.87–7.99 (m, 10H), 7.70 (s, 2H), 7.27–7.54 (m, 22H), 2.52–2.58 ppm
(m, 18H); 31P NMR (121 MHz, CDCl3): d=150.00, 150.11 ppm; 31P NMR
CP-MAS: d=148.80 ppm; FTIR (KBr pellet): n˜ =3055, 2922, 2887, 2844,
2800, 2208, 1619, 1589, 1506, 1469, 1332, 1293, 1233, 1207, 1188, 1071,
983, 945, 887, 829, 796, 790, 780, 749, 693, 648 cmÀ1; MS (MALDI-DHB):
m/z: 1222.30 [M+H]+; HRMS (MALDI-DHB): m/z: calcd for
C78H55N3O6P3 [M+H]+: 1222.3298; found: 1222.3294.
n˜ =3430, 2930, 1589, 1513, 1465, 1336, 1226, 1070, 948, 828, 756, 697,
592 cmÀ1
;
elemental analysis calcd (%) for ({[RhACHTUGNTRENNU(G cod)ACHTUNGTRENNUNG(3i)]BF4}2·
(CH2Cl2)3)n: C 63.60, H 4.63, N 1.98; found: C 63.09, H 5.00, N 1.91.
Representative hydrogenation procedure: Self-supported catalyst 4d
(0.01 mmol based on [Rh] unit) was placed in toluene (5 mL, 2 mm)
under an argon atmosphere and stirred for 3 h. To this mixture was then
added 5a (1 mmol) under an argon atmosphere. The test tube was trans-
ferred into a stainless steel autoclave that was then sealed. After purging
with hydrogen (3 times), the H2 pressure was adjusted to 40 atm and stir-
ring commenced. Following the designated reaction time (10 h), the H2
was released to stop hydrogenation. The product was obtained by chro-
matography (petroleum ether/ethyl acetate, 2:1 v/v), followed by the re-
moval of solvents under reduced pressure. Conversion was determined
by 1H NMR spectroscopy and enantiomeric excess (ee) values were de-
termined by chiral GC (Supelco BETA-DEX225 column) or chiral
HPLC (Chiralcel AD column).
Recycling experiments: Polymeric solid 4h (0.02 mmol based on [Rh])
was placed in toluene (2.5 mL) under an argon atmosphere and stirred
for 3 h. To this mixture was then added a solution of 5b (2 mmol, 2.5 mL,
0.8m) in toluene under an argon atmosphere. The test tube was trans-
ferred into a stainless steel autoclave that was then sealed. After purging
with hydrogen (3 times), the H2 pressure was adjusted to 3 atm and stir-
ring commenced. Following a calculated reaction time during which
>70% conversion had been reached, the H2 was slowly released. The
product and the solid catalyst were separated by cannula filtration under
an argon atmosphere. The autoclave was recharged with a new batch of
5b (2 mmol, 5 mL, 0.4m) in toluene, purged with hydrogen (3 times), the
H2 pressure was adjusted to 3 atm, and stirring commenced. This proce-
dure was repeated 9 times (10 cycles). Conversion was determined by
1H NMR spectroscopy and enantiomeric excess (ee) values were deter-
mined by chiral GC (Supelco BETA-DEX225 column). The data are
given in Table 3.
Compound 3i: Yield: 1277 mg (65%); m.p. >3108C; [a]2D0 =À271.7 (c=
0.5 in DMF); 1H NMR (300 MHz, CDCl3): d=8.12 (d, J=2.4 Hz, 4H),
7.85–7.98 (m, 12H), 7.23–7.57 (m, 44H), 2.52–2.58 (m, 24H), 2.18 ppm (s,
12H); 31P NMR (121 MHz, CDCl3): d=150.09, 150.16 ppm; 31P NMR
CP-MAS: d=148.75 ppm; FTIR (KBr pellet): n˜ =3055, 2922, 2887, 2844,
2800, 2208, 1619, 1589, 1506, 1469, 1332, 1293, 1233, 1207, 1188, 1071,
983, 945, 887, 829, 796, 790, 780, 749, 693, 648 cmÀ1; MS (MALDI-DHB):
m/z: 1920.5 [MÀNMe2]+; HRMS (MALDI-DHB): m/z: calcd for
Representative procedure for reaction profile measurement: Self-sup-
ported catalyst 4d (0.005 mmol based on [Rh] unit) and anhydrous tolu-
ene (5.0 mL, 1 mm) were added to a glass autoclave equipped with a sam-
pling needle and a magnetic stirrer bar under an argon atmosphere. The
mixture was stirred for at least 3 h. Substrate (5b, 0.5 mmol) was then in-
troduced into the autoclave under an argon atmosphere. Following purg-
ing with H2 (3 times), the pressure was adjusted to 2 atm and stirring
commenced (t=0 min). Sample aliquots were taken at regular intervals.
Conversion and enantiomeric excess (ee) values were determined by GC
(Supelco BETA-DEX225 column). 1H NMR spectral analysis was used
to double-check the conversion for each sample aliquot.
C
128H90N3O8P4 [MÀNMe2]+: 1920.5672; found: 1920.5726.
General procedure for the synthesis of catalysts 4d–i: Compound 3 (a–g)
(0.011 mmol), 3h (0.0073 mmol), or 3i (0.0055 mmol) in dichloromethane
(1.0 mL) was added to a solution of [RhACHTNUTRGNEUNG(cod)2]BF4 (4.06 mg, 0.01 mmol)
in dichloromethane (0.5 mL). The solution was stirred at room tempera-
ture for 30 min, ultimately affording an orange precipitate. After removal
of the solvents at 508C under reduced pressure, the residue was dried in
vacuo (2 h). The resulting orange powder was washed with toluene to
remove any trace amount of soluble low molecular weight species to give 4.
With a different catalyst: The same conditions were used for each self-
supported catalyst: [4h]=1 mm, [5b]=0.1m, P(H2)=2 atm, T=258C, tol-
uene solvent (5 mL). Data are given in Figure 4.
Compound 4d: FTIR (KBr pellet): n˜ =2924, 2853, 1620, 1590, 1508, 1465,
1432, 1361, 1261, 1226, 1178, 1072, 1009, 990, 964, 947, 865, 827, 687,
590 cmÀ1; elemental analysis calcd (%) for {[Rh
N
ACHTUGNTNER(UNNG 3d)]BF4·CH2Cl2}n:
With different added supports: a) Carbon: 4b=6 mg, activated C=10 mg,
[5b]=0.1m, P(H2)=2 atm, T=258C, toluene solvent (5 mL); b) MgSO4:
4b=6 mg, MgSO4 =20 mg, [5b]=0.1m, P(H2)=2 atm, T=258C, toluene
solvent (5 mL); c) TiO2: 4b=6 mg, TiO2 =20 mg, [5b]=0.1m, P(H2)=
Compound 4e: FTIR (KBr pellet): n˜ =2924, 2855, 1621, 1589, 1508, 1464,
1328, 1261, 1226, 1071, 990, 948, 864, 699, 569 cmÀ1; elemental analysis
Chem. Eur. J. 2009, 15, 9855 – 9867
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
9865

K. Ding et al.
2 atm, T=258C, toluene solvent (5 mL). All these data are given in
Figure 8.
[3] a) C. Saluzzo, M. Lemaire, Adv. Synth. Catal. 2002, 344, 915–928;
b) P. Barbaro, Chem. Eur. J. 2006, 12, 5666–5675; c) R. Somanathan,
N. A. Cortez, M. Parra-Hake, D. Chavez, G. Aguirre, Mini-Rev. Org.
Chem. 2008, 5, 313–322.
Swelling experiments: [4h]=1 mm, [5b]=0.1m, P(H2)=2 atm, T=258C,
toluene solvent (5 mL). Self-supported catalyst 4 h (0.005 mmol based on
[Rh], 1 mm) was placed in toluene (5 mL) under an argon atmosphere
and stirred for a designated time prior to use as precatalyst in hydrogena-
tion. Data are given in Figure 5.
[4] a) C. Saluzzo, R. terHalle, F. Touchard, F. Fache, E. Schulz, M. Lem-
aire, J. Organomet. Chem. 2000, 603, 30–39; b) C. Bianchini, P. Bar-
baro, Top. Catal. 2002, 19, 17–32; c) S. Brꢃse, F. Lauterwasser, R. E.
Ziegert, Adv. Synth. Catal. 2003, 345, 869–929; d) P. Mastrorilli,
C. F. Nobile, Coord. Chem. Rev. 2004, 248, 377–395; e) P. McMorn,
G. J. Hutchings, Chem. Soc. Rev. 2004, 33, 108–122; f) C. E. Song,
Annu. Rep. Prog. Chem. Sect. C 2005, 101, 143–173; g) B. M. L.
Dioos, I. V. J. Vankelecom, P. A. Jacobs, Adv. Synth. Catal. 2006,
348, 1413–1446; h) D. E. Bergbreiter, S. D. Sung, Adv. Synth. Catal.
2006, 348, 1352–1366; i) M. Heitbaum, F. Glorius, I. Escher, Angew.
Chem. 2006, 118, 4850–4881; Angew. Chem. Int. Ed. 2006, 45, 4732–
4762.
[5] For reviews with selected examples therein, see: a) C. Li, Catal. Rev.
Sci. Eng. 2004, 46, 419–492; b) C. E. Song, D. H. Kim, D. S. Choi,
Eur. J. Inorg. Chem. 2006, 2927–2935; c) C. Li, H. D. Zhang, D. M.
Jiang, Q. H. Yang, Chem. Commun. 2007, 547–558; d) J. M.
Thomas, R. Raja, Acc. Chem. Res. 2008, 41, 708–720. See also
ref. [4e].
Continuous flow system
Typical mixing strategy for packing the catalysts and the support material:
a) After being heated at 1008C under vacuo for 10 h and cooled down to
RT, the activated carbon (90 mg) was mixed with catalyst 4h (60 mg) in
anhydrous toluene (5 mL) in a container in a glove box. The mixture was
stirred at RT for 10 h, and the resulting slurry was introduced using a sy-
ringe into a stainless steel tube (4.6 mm inner diameter, 2 cm length)
with a filter at one end. The solvent was vacuumed with a pump. After
completion, the column was capped with another filter and mounted
onto the reaction setup. b) The substrate (5b) solution was mixed with
the hydrogen gas in the T-shaped mixer. To maintain this condition, at
the inlet of the column, the flow of the substrate solution was controlled
to 0.05 mLminÀ1 by an HPLC pump and the flow of the hydrogen gas
was adjusted to 3.0 mLminÀ1 using a gas mass-flow controller. This re-
sulted in an overall system pressure of 3 atm. At the outlet of the
column, the product solution and the excess amount of the hydrogen gas
came out at atmospheric pressure. Therefore, the pressure drop between
the inlet and the outlet of the column was 2 atm. The product was ana-
lyzed by chiral GC (Supelco BETA-DEX225 column) to determine the
conversion of the substrate and enantiomeric excess (ee) values of the
product. 1H NMR spectral analysis was used to double-check the conver-
sion.
[6] For reviews, see: a) L.-X. Dai, Angew. Chem. 2004, 116, 5846–5850;
Angew. Chem. Int. Ed. 2004, 43, 5726–5729; b) K. Ding, Z. Wang,
X. Wang, Y. Liang, X. Wang, Chem. Eur. J. 2006, 12, 5188–5197;
c) L. Shi, Z. Wang, X. Wang, M. Li, K. Ding, Chin. J. Org. Chem.
2006, 26, 1444–1456; d) K. Ding, Z. Wang, L. Shi, Pure Appl. Chem.
2007, 79, 1531–1538; e) Z. Wang, G. Chen, K. Ding, Chem. Rev.
2009, 109, 322–359.
[7] For reviews, see: a) S. L. James, Chem. Soc. Rev. 2003, 32, 276–288;
b) S. Kitagawa, R. Kitaura, S. Noro, Angew. Chem. 2004, 116, 2388–
2430; Angew. Chem. Int. Ed. 2004, 43, 2334–2375; c) O. M. Yaghi,
M. OꢁKeeffe, N. W. Ockwig, H. K. Chae, M. Eddaoudi, J. Kim,
Nature 2003, 423, 705–714; d) A. Y. Robin, K. M. Fromm, Coord.
Chem. Rev. 2006, 250, 2127–2157; e) G. Fꢄrey, Chem. Soc. Rev.
2008, 37, 191–214.
Acknowledgements
[8] For reviews, see: a) C. Janiak, Dalton Trans. 2003, 2781–2804;
b) P. M. Forster, A. K. Cheetham, Top. Catal. 2003, 24, 79–86; c) F.
Schuth, Annu. Rev. Mater. Res. 2005, 35, 209–238; d) W. Lin, J.
Solid State Chem. 2005, 178, 2486–2490.
Financial support from the National Natural Science Foundation of
China (nos. 20532050, 20632060, 20620140429), the Chinese Academy of
Sciences, the Major Basic Research Development Program of China
(grant no. 2006CB806106), the Science and Technology Commission of
Shanghai Municipality, and Merck Research Laboratories are gratefully
acknowledged.
[9] For selected examples, see: a) A. Efraty, I. Feinstein, Inorg. Chem.
1982, 21, 3115–3118; b) R. Tannenbaum, Chem. Mater. 1994, 6,
550–555; c) M. Fujita, Y. J. Kwon, S. Washizu, K. Ogura, J. Am.
Chem. Soc. 1994, 116, 1151–1152; d) T. Sawaki, T. Dewa, Y.
Aoyama, J. Am. Chem. Soc. 1998, 120, 8539–8540; e) S. Naito, T.
Tanibe, E. Saito, T. Miyao, W. Mori, Chem. Lett. 2001, 1178–1179;
f) J. M. Tanski, P. T. Wolczanski, Inorg. Chem. 2001, 40, 2026–2033;
g) B. Gomez-Lor, E. Gutierrez-Puebla, M. Iglesias, M. A. Monge, C.
Ruiz-Valero, N. Snejko, Inorg. Chem. 2002, 41, 2429–2432; h) J.
Perles, M. Iglesias, C. Ruiz-Valero, N. Snejko, Chem. Commun.
2003, 346–347; i) S. K. Yoo, J. Y. Ryu, J. Y. Lee, C. Kim, S. J. Kim,
Y. Kim, Dalton Trans. 2003, 1454–1456; j) K. Schlichte, T. Kratzke,
S. Kaskel, Microporous Mesoporous Mater. 2004, 73, 81–88; k) T.
Arai, H. Takasugi, T. Sato, H. Noguchi, H. Kanoh, K. Kaneko, A.
Yanagisawa, Chem. Lett. 2005, 34, 1590–1591; l) S. Ishida, T.
Hayano, H. Furuno, J. Inanaga, Heterocycles 2005, 66, 645–649;
m) W. Chen, R. Li, Y. Wu, L. S. Ding, Y. C. Chen, Synthesis 2006,
3058–3062; n) Y. M. A. Yamada, Y. Maeda, Y. Uozumi, Org. Lett.
2006, 8, 4259–4262; o) H. Han, S. Zhang, H. Hou, Y. Fan, Y. Zhu,
Eur. J. Inorg. Chem. 2006, 1594–1600; p) K. H. Park, K. Jang, S. U.
Son, D. A. Sweigart, J. Am. Chem. Soc. 2006, 128, 8740–8741; q) L.
Alaerts, E. Seguin, H. Poelman, F. Thibault-Starzyk, P. A. Jacobs,
D. E. De Vos, Chem. Eur. J. 2006, 12, 7353–7363; r) U. Mueller, M.
Schubert, F. Teich, H. Puetter, K. Schierle-Arndt, J. Pastre, J. Mater.
Chem. 2006, 16, 626–636; s) P. Horcajada, S. Surble, C. Serre, D. Y.
Hong, Y. K. Seo, J. S. Chang, J. M. Greneche, I. Margiolaki, G.
Fꢄrey, Chem. Commun. 2007, 2820–2822; t) F. X. L. I. Xamena, A.
Abad, A. Corma, H. Garcia, J. Catal. 2007, 250, 294–298; u) S. Ha-
segawa, S. Horike, R. Matsuda, S. Furukawa, K. Mochizuki, Y. Ki-
[1] a) T. Ohkuma, R. Noyori in Comprehensive Asymmetric Catalysis,
Vol. 1 (Eds.: E. N. Jacobsen, A. Pfaltz, H. Yamamoto), Springer,
Berlin, 1999, pp. 199–246; b) T. Ohkuma, M. Kitamura, R. Noyori
in Catalytic Asymmetric Synthesis, 2nd ed. (Ed.: I. Ojima), Wiley-
VCH, Weinheim, 2000, pp. 1–110; c) J. M. Brown in Comprehensive
Asymmetric Catalysis, Vol. 1 (Eds.: E. N. Jacobsen, A. Pfaltz, H. Ya-
mamoto), Springer, Berlin, 1999, pp. 119–182; d) T. Ohkuma, R.
Noyori in Transition Metals for Organic Synthesis, Vol. 2 (Eds.: M.
Beller, C. Bolm), Wiley, New York, 1998, pp. 25–69; e) The Hand-
book of Homogeneous Hydrogenation (Eds.: J. G. de Vries, C. J.
Elsevier), Wiley-VCH, Weinheim, 2007; f) H.-U. Blaser, R. Han-
reich, H.-D. Schneider, F. Spindler, B. Steinacher in Asymmetric Cat-
alysis on Industrial Scale (Eds.: H.-U. Blaser, E. Schmidt), Wiley-
VCH, Weinheim, 2004, p. 55–70; g) W. S. Knowles, Angew. Chem.
2002, 114, 2096–2107; Angew. Chem. Int. Ed. 2002, 41, 1998–2007;
h) R. Noyori, Angew. Chem. 2002, 114, 2108–2123; Angew. Chem.
Int. Ed. 2002, 41, 2008–2022; i) H.-U. Blaser, C. Malan, B. Pugin, F.
Spindler, H. Steiner, M. Studer, Adv. Synth. Catal. 2003, 345, 103–
151.
[2] a) Chiral Catalyst Immobilization and Recycling (Eds.: D. E. de Vos,
I. F. Vankelecom, P. A. Jacobs), Wiley-VCH, Weinheim, 2000;
b) Handbook of Asymmetric Heterogeneous Catalysis (Eds.: K.
Ding, Y. Uozumi), Wiley-VCH, Weinheim, 2008; c) For special
issues on recoverable catalysts and reagents, see: Chem. Rev. 2002,
102, 3215–3892; d) Chem. Rev. 2009, 109, 257–838.
9866
www.chemeurj.org
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Chem. Eur. J. 2009, 15, 9855 – 9867

Self-Supported Chiral Catalysts
FULL PAPER
noshita, S. Kitagawa, J. Am. Chem. Soc. 2007, 129, 2607–2614; v) S.
Horike, M. Dinka, K. Tamaki, J. R. Long, J. Am. Chem. Soc. 2008,
130, 5854–5855; w) U. Ravon, M. E. Domine, C. Gaudillꢅre, A.
Desmartin-Chomel, D. Farrusseng, New J. Chem. 2008, 32, 937–940;
x) D. Jiang, T. Mallat, F. Krumeich, A. Baiker, J. Catal. 2008, 257,
390–395; y) A. Henschel, K. Gedrich, R. Kraehnert, S. Kaskel,
Chem. Commun. 2008, 4192–4194.
mund, M. Graf, W. Thiel, R. Mynott, D. G. Blackmond, J. Am.
Chem. Soc. 2005, 127, 10305–10313; b) I. D. Gridnev, C. Fan, P. G.
Pringle, Chem. Commun. 2007, 1319–1321, and references therein.
See also ref. [17g].
[19] The coordinating ligand has been included as part of the polymer
mass used. Possible enclathration of the solvent in the polymer was
not considered in the calculation for simplicity.
[10] J. S. Seo, D. Whang, H. Lee, S. I. Jun, J. Oh, Y. J. Jeon, K. Kim,
Nature 2000, 404, 982–986.
[20] M. van den Berg, A. J. Minnaard, R. M. Haak, M. Leeman, E. P.
Schudde, A. Meetsma, B. L. Feringa, A. H. M. de Vries, C. E. P.
Maljaars, C. E. Willans, D. Hyett, J. A. F. Boogers, H. J. W. Hender-
ickx, J. G. de Vries, Adv. Synth. Catal. 2003, 345, 308–323.
[21] Turnover number (TON) is defined as moles of product per mole of
catalyst, and turnover frequency (TOF) is defined as TON per hour
or second.
[11] a) S. Takizawa, H. Somei, D. Jayaprakash, H. Sasai, Angew. Chem.
2003, 115, 5889–5892; Angew. Chem. Int. Ed. 2003, 42, 5711–5714;
b) H. Guo, X. Wang, K. Ding, Tetrahedron Lett. 2004, 45, 2009–
2012; c) X. Wang, X. Wang, H. Guo, Z. Wang, K. Ding, Chem. Eur.
J. 2005, 11, 4078–4088.
[12] a) H. L. Ngo, A. G. Hu, W. Lin, J. Mol. Catal. A 2004, 215, 177–186;
b) C.-D. W. A. Hu, L. Zhang, W. Lin, J. Am. Chem. Soc. 2005, 127,
8940–8941; c) C. D. Wu, W. Lin, Angew. Chem. 2007, 119, 1093–
1096; Angew. Chem. Int. Ed. 2007, 46, 1075–1078.
[13] a) X. Wang, L. Shi, M. Li, K. Ding, Angew. Chem. 2005, 117, 6520–
6524; Angew. Chem. Int. Ed. 2005, 44, 6362–6366; b) S. H. Cho, B.
Ma, S. T. Nguyen, J. T. Hupp, T. E. brecht-Schmitt, Chem. Commun.
2006, 2563–2565; c) S. H. Cho, T. Gadzikwa, M. Afshari, S. T.
Nguyen, J. T. Hupp, Eur. J. Inorg. Chem. 2007, 4863–4867.
[14] J. I. Garcꢆa, B. Lꢇpez-Sꢈnchez, J. A. Mayoral, Org. Lett. 2008, 10,
4995–4998.
[15] K. Tanaka, S. Oda, M. Shiro, Chem. Commun. 2008, 820–822.
[16] a) A. Hu, H. L. Ngo, W. Lin, J. Am. Chem. Soc. 2003, 125, 11490–
11491; b) A. Hu, H. L. Ngo, W. Lin, Angew. Chem. 2003, 115, 6182–
6185; Angew. Chem. Int. Ed. 2003, 42, 6000–6003; c) X. Wang, K.
Ding, J. Am. Chem. Soc. 2004, 126, 10524–10525; d) Y. Liang, Q.
Jing, X. Li, L. Shi, K. Ding, J. Am. Chem. Soc. 2005, 127, 7694–
7695; e) L. Shi, X. Wang, C. A. Sandoval, M. Li, Q. Qi, Z. Li, K.
Ding, Angew. Chem. 2006, 118, 4214–4218; Angew. Chem. Int. Ed.
2006, 45, 4108–4112.
[17] For leading references of AH by using monodentate phosphorous li-
gands, see: a) M. van den Berg, A. J. Minnaard, E. P. Schudde, J. va-
n Esch, A. H. M. de Vries, J. G. de Vries, B. L. Feringa, J. Am.
Chem. Soc. 2000, 122, 11539–11540; b) M. T. Reetz, G. Mehler,
Angew. Chem. 2000, 112, 4047–4049; Angew. Chem. Int. Ed. 2000,
39, 3889–3890; c) C. Claver, E. Fernandez, A. Gillon, K. Heslop,
D. J. Hyett, A. Martorell, A. G. Orpen, P. G. Pringle, Chem.
Commun. 2000, 961–962; d) I. V. Komarov, A. Bçrner, Angew.
Chem. 2001, 113, 1237–1240; Angew. Chem. Int. Ed. 2001, 40, 1197–
1200; e) A.-G. Hu, Y. Fu, J.-H. Xie, H. Zhou, L.-X. Wang, Q.-L.
Zhou, Angew. Chem. 2002, 114, 2454–2456; Angew. Chem. Int. Ed.
2002, 41, 2348–2350; f) S. Wu, W. Zhang, Z. Zhang, X. Zhang, Org.
Lett. 2004, 6, 3565–3567; g) Y. Liu, K. Ding, J. Am. Chem. Soc.
2005, 127, 10488–10489.
[22] The reaction profiles for 4c,d,f under analogous conditions are
given in the Supporting Information, Figure S4.
[23] However, the same homogeneous catalyst is faster (TOF=190 hÀ1
at 2 atm) when CH2Cl2 is used as solvent, whereas the ee for 6b is
96% (Supporting Information, Figure S4).
[24] a) B. Pugin, J. Mol. Catal. A 1996, 107, 273–279; b) K. Mashima, T.
Hino, H. Takaya, Tetrahedron Lett. 1991, 32, 3101–3104.
[25] a) J. M. Brown, P. A. Chaloner, J. Chem. Soc. Chem. Commun. 1978,
321; b) J. Halpern, A. S. C. Chan, J. J. Pluth, J. Am. Chem. Soc. 1980,
102, 5952–5954; c) I. D. Gridnev, T. Imamoto, Acc. Chem. Res. 2004,
37, 633–644; T. Schmidt, W. Baumann, H.-J. Drexler, A. Arrieta, D.
Heller, H. Buschmann, Organometallics 2005, 24, 3842–3848; d) H.-
J. Drexler, W. Baumann, T. Schmidt, S. Zhang, A. Sun, A. Spannen-
berg, C. Fischer, H. Buschmann, D. Heller, Angew. Chem. 2005, 117,
1208–1212; Angew. Chem. Int. Ed. 2005, 44, 1184–1188.
[26] a) S. Saaby, K. R. Knudsen, M. Ladlow, S. C. Ley, Chem. Commun.
2005, 2909–2911; b) N. Yoswathananont, K. Nitta, Y. Nishiuchi, M.
Sato, Chem. Commun. 2005, 40–42; c) J. Kobayashi, Y. Mori, K.
Okamoto, R. Akiyama, M. Ueno, T. Kitamori, S. Kobayashi, Science
2004, 304, 1305–1308; d) J. Kobayashi, Y. Mori, S. Kobayashi, Adv.
Synth. Catal. 2005, 347, 1889–1892.
[27] Other hydride sources: a) A. J. Sandee, D. G. I. Petra, J. N. H. Reek,
P. C. J. Kamer, P. W. N. M. van Leewen, Chem. Eur. J. 2001, 7, 1202–
1208; b) W. Solodenko, H. Wen, S. Leue, F. Stuhlmann, G. Sourkou-
ni-Argirusi, G. Jas, H. Schçnfeld, U. Kunz, A. Kirschning, Eur. J.
Org. Chem. 2004, 3601–3610.
[28] For selected reviews on continuous flow reactors and processes, see:
a) A. Kirschning, W. Solodenko, K. Mennecke, Chem. Eur. J. 2006,
12, 5972–5990; b) C. Wiles, P. Watts, Eur. J. Org. Chem. 2008, 1655–
1671. For recent examples, see: c) Y. Uozumi, Y. M. A. Yamada, T.
Beppu, N. Fukuyama, M. Ueno, T. Kitamori, J. Am. Chem. Soc.
2006, 128, 15994–15995; d) C. D. Smith, I. R. Baxendale, S. Lanners,
J. J. Hayward, S. C. Smith, S. V. Ley, Org. Biomol. Chem. 2007, 5,
1559–1561.
[18] This has been borne out in some case studies using monodentate
phosphorus ligands for RhI-catalyzed hydrogenation reactions. See,
for example: a) M. T. Reetz, A. Meiswinkel, G. Mehler, K. Anger-
Received: April 5, 2009
Published online: August 15, 2009
Chem. Eur. J. 2009, 15, 9855 – 9867
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www.chemeurj.org
9867