A new class of tunable dendritic diphosphine ligands: Synthesis and applications in the Ru-catalyzed asymmetric hydrogenation of functionalized ketones

Article abstract of DOI:10.1002/chem.201402709

A series of tunable G₀-G₃ dendritic 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (BINAP) ligands was prepared by attaching polyaryl ether dendrons onto the four phenyl rings on the P atoms. Their ruthenium complexes were employed in the asymmetric hydrogenation of β-ketoesters, α-ketoesters, and α-ketoamides to reveal the effects of dendron size on the catalytic properties. The second- and third-generation catalysts exhibited excellent enantioselectivities, which are remarkably higher than those obtained from the small molecular catalysts and the first-generation catalyst. Molecular modeling indicates that the incorporation of bulky dendritic wedges can influence the steric environments around the metal center. In addition, the ruthenium catalyst bearing a second-generation dendritic ligand could be recycled and reused seven times without any obvious decrease in enantioselectivity.

Full text of DOI:10.1002/chem.201402709

DOI: 10.1002/chem.201402709
Full Paper
&
Dendrimers
A New Class of Tunable Dendritic Diphosphine Ligands: Synthesis
and Applications in the Ru-Catalyzed Asymmetric Hydrogenation
of Functionalized Ketones
Baode Ma,[a] Tingting Miao,[a] Yihua Sun,[b] Yanmei He,[a] Ji Liu,[a] Yu Feng,[a] Hui Chen,*[b] and
Qing-Hua Fan*[a]
Abstract: A series of tunable G0–G3 dendritic 2,2’-bis(diphe-
nylphosphino)-1,1’-binaphthyl (BINAP) ligands was prepared
by attaching polyaryl ether dendrons onto the four phenyl
rings on the P atoms. Their ruthenium complexes were em-
ployed in the asymmetric hydrogenation of b-ketoesters, a-
ketoesters, and a-ketoamides to reveal the effects of den-
dron size on the catalytic properties. The second- and third-
generation catalysts exhibited excellent enantioselectivities,
which are remarkably higher than those obtained from the
small molecular catalysts and the first-generation catalyst.
Molecular modeling indicates that the incorporation of bulky
dendritic wedges can influence the steric environments
around the metal center. In addition, the ruthenium catalyst
bearing a second-generation dendritic ligand could be recy-
cled and reused seven times without any obvious decrease
in enantioselectivity.
Introduction
more catalytic sites at the periphery or an isolation effect of
catalytic site at the core.
Dendrimers are fascinating man-made macromolecules owing
to their unique physical and chemical properties,[1] and have
been served as a new class of catalyst supports.[2] Unlike the
traditional cross-linked polymer-supported catalysts, dendrimer
catalysts possess well-defined molecular architectures with
nanoscale size.[3] They catalyze the reaction under homogene-
ous manner, and can be easily recycled at the end of reaction
by solvent precipitation or nanofiltration. Therefore, the den-
drimer catalyst offers a unique potential to combine the ad-
vantages of both homogeneous catalysis and conventional
heterogeneous catalysis. To date, lots of organometallic den-
drimers bearing catalytically active units at the core and/or at
the periphery have been described.[2,4–6] However, only a few
dendrimer catalysts, particularly, chiral dendrimer catalysts
have shown a “positive dendrimer effect”, which is referred to
when the reactivity and/or stereoselectivity of the dendritic
catalyst increases in comparison with the parent catalyst.[3,7,8]
This can be attributed to a cooperative interaction of two or
For asymmetric catalysis, subtle changes in conformational,
steric and/or electronic properties of the chiral ligands can
often lead to dramatic variations of reactivity and enantioselec-
tivity.[9] Thus, attachment of the well-defined and bulky den-
dritic wedges onto the framework of a chiral catalyst is expect-
ed to provide a unique tool for fine-tuning the enantioselectiv-
ity.[10] For example, we recently reported chiral dendritic mono-
dentate phosphoramidite ligands by replacing both methyl
groups on the N atom of the phosphoramidite ligand with dif-
ferent generation polyether dendritic wedges.[8f] Their rhodium
complexes exhibited unprecedentedly increased enantioselec-
tivity upon using higher-generation dendrimers in the asym-
metric hydrogenation of a-dehydroamino acid derivatives and
enamides. As an extension of our research on chiral dendrimer
catalysts and our continued interests in the development of re-
cyclable catalysts,[3,11] here we wish to report a new class of
tunable and recylable dendritic chiral diphosphine ligands.
The design and synthesis of chiral diphosphine ligands have
played a significant role in the development of efficient transi-
tion-metal-catalyzed asymmetric hydrogenations.[12] Among
the reported various chiral diphosphine ligands, most of them
involve a chiral skeleton bearing two diphenylphosphine che-
lating units. The chiral information is transferred from the
chiral skeleton to the catalytically active metal center through
the chiral array of the four phenyl rings at the P atoms.[13] Fur-
ther modifications to the chiral skeleton and/or the chelating
units by introducing small molecular substituents with differ-
ent steric and/or electronic properties are often used strategy
to fine-tune the chiral microenvironment around the metal
center. On the basis of this method, some conformationally
[a] Dr. B. Ma, T. Miao, Y. He, Dr. J. Liu, Dr. Y. Feng, Prof. Dr. Q.-H. Fan
Beijing National Laboratory for Molecular Sciences
and CAS Key Laboratory of Molecular Recognition and Function
Institute of Chemistry, Chinese Academy of Sciences (CAS)
Beijing 100190 (P.R. China)
E-mail: fanqh@iccas.ac.cn
[b] Y. Sun, Prof. Dr. H. Chen
Beijing National Laboratory for Molecular Sciences
and CAS Key Laboratory of Photochemistry
Institute of Chemistry, CAS, Beijing 100190 (P.R. China)
E-mail: chenh@iccas.ac.cn
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201402709.
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rigid and yet tunable ligands have been reported and demon-
strated excellent asymmetric induction in transition-metal-cata-
lyzed asymmetric hydrogenation reactions.[14] However, most
homogeneous catalytic systems suffer from difficulty in separa-
tion and recycling of the expensive chiral catalyst.[11,15] It is still
a big challenge to develop ideal chiral catalysts possessing ex-
cellent catalytic ability and easy recyclability.[3]
tioselectivities with higher-generation catalysts were observed
compared with those of the small molecular and the low-gen-
eration catalysts. In addition, the dendrimer catalyst could be
easily recycled several times by solvent precipitation without
obvious decrease of enantioselectivity.
Considering the well-defined and nanoscale dendritic archi-
tectures, here we report a new general method to modify the
chiral diphosphine ligands by attaching sterically demanding
dendritic wedges onto the four phenyl rings at the P
atoms.[16,17] In addition to the specific microenvironment creat-
ed by the branched dendritic shell, the increasing steric repul-
sion between the four larger dendritic wedges with the in-
crease of generation can influence the chiral array of the four
phenyl rings, and consequently modulate and improve the cat-
alytic behavior of the core. To exemplify our approach, we
chose BINAP as the model diphosphine ligand for this study.[18]
A series of dendritic BINAP ligands bearing polyether dendrons
at the para position of the four phenyl rings on the P atoms
were synthesized. Their ruthenium complexes proved to be ef-
fective catalysts in the asymmetric hydrogenation of b-ketoest-
ers, a-ketoesters, as well as the less-explored a-ketoamides.
The size of the dendritic wedges was found to be crucial in
achieving high asymmetric induction. Remarkably higher enan-
Results and Discussion
Synthesis of dendritic BINAP ligands and their ruthenium
complexes
Frꢁchet-type polyaryl ether dendrons were chosen for this
study due to their inertness to reaction and inability to coordi-
nate metal, as well as easy preparation.[19] The synthesis and
structures of the dendritic ligands are shown in Scheme 1. By
using a convergent strategy, the first to third generation
BINAP-cored dendrimers were synthesized by coupling (R)-OH-
BINAPO with the corresponding dendritic wedges Gn-Br fol-
lowed by reduction of Gn-BINAPO with HSiCl3/N(n-Bu)3,[20] pro-
viding the target dendritic ligands (R)-Gn-BINAP in quite good
yields. It is worth mentioning that all the dendritic intermedi-
ates and final ligands could be purified by solvent precipitation
method without the use of column chromatography. For com-
parison, two small molecular BINAP derivatives MeO-BINAP
and G0-BINAP were also synthesized. All these BINAP ligands
Scheme 1. Synthesis and molecular structures of chiral dendritic BINAP ligands.
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1
were well characterized by H, 13C, and 31P NMR spectroscopy,
MALDI-TOF mass spectrometry and elemental analysis. All the
results were consistent with the compounds synthesized.
With these dendritic BINAP ligands in hand, we prepared
their ruthenium complexes by mixing the corresponding den-
dritic ligands with [RuI2(p-cymene)] in a mixture of CH2Cl2 and
CH3OH at room temperature for 60 min under nitrogen atmos-
phere. The solvent was then removed under reduced pressure
to give the in situ dendritic catalysts as orange powders. The
chemical shifts of all these ruthenium complexes were very
similar (dꢀ36 and ꢀ19 ppm, Jpp =ꢀ60 Hz), indicating that the
introduction of sterically demanding dendritic wedges could
not influence the coordination of ruthenium with the phos-
phorus atoms at the core of the dendrimer, as shown in
Figure 1. Notably, all dendritic catalysts are well soluble in
CH2Cl2, THF, and toluene, whereas the second- and third-gener-
ation catalysts are practically insoluble in methanol. The differ-
ent solubility of the dendritic catalysts thus offered a reliable
method for subsequent separation and recycling of the ruthe-
nium catalysts.
Figure 1. 31P NMR spectra of dendritic [Ru(Gn-BINAP)] complexes and corre-
sponding small molecular Ru catalysts.
Asymmetric hydrogenation of b-ketoesters
observed. For example, the hydrogenation of methyl 4-(benzy-
loxy)-3-oxobutanoate proceeded smoothly in the presence of
0.2 mol% catalyst. The size of substituents on phenyl rings of
the P atoms was found to influence the enantioselectivity re-
markably (entry 1, Table 1). The zeroth- and first-generation
catalysts gave the reduced product with enantiomeric excesses
Asymmetric hydrogenation of b-alkyl- and b-aryl b-ketoesters
provides a direct approach to optically active b-hydroxy acids
and their derivatives,[12,21] which are very important structural
motifs in numerous biologically compounds.[22] Accordingly,
a number of chiral diphosphine ligands have been developed
for the Ru-catalyzed asymmetric
hydrogenation of b-ketoesters.
However, only a few of them ex-
hibited high asymmetric induc-
tion for the hydrogenation of b-
aryl b-ketoesters.[14c,23] As an ex-
ample, Noyori and co-workers
pioneeringly reported a highly
asymmetric hydrogenation of b-
alkyl b-ketoesters by using the
Ru-BINAP system, but much
more inferior enantioselectivities
were obtained for analogous b-
aryl ketoester substrates.[24] To
evaluate the efficiency of the
dendritic [Ru(Gn-BINAP)] com-
plexes and to established the re-
lationship between the size of
the dendrimer and its catalytic
properties, the Ru-catalyzed
asymmetric hydrogenation of b-
ketoesters was chosen as the
model reaction.
Table 1. Asymmetric hydrogenation of b-ketoesters with dendritic [Ru(BINAP)].[a]
Entry
Substrate
Conversion [%];[b] ee [%][c]
MeO-BINAP
G0-BINAP
G1-BINAP
G2-BINAP
G3-BINAP
1
2
>95; 84
>95; 66
>95; 67
>95; 44
>95; 92
>95; 95
>95; 97
>95; 83
>95; 82
>95; 54
>95; 42
>95; 97
67; 92
3
>95; 69
>95; 92
4
>95; 82
>95; 80
>95; 92
>95; 64
>95; 62
>95; 91
>95; 50
>95; 41
>95; 91
67; 93
33; 94
75; 91
>95; 92[d]
36; 94
>95; 95[d]
5
6[e]
>95; 91
80; 91
As shown in Table 1, all these
ruthenium catalysts were effec-
tive in the asymmetric hydroge-
nation of both b-alkyl- and b-aryl
b-ketoester substrates, and an
unusual dendrimer effect was
[a] Reaction conditions: Substrate (0.2 mmol) in solvent (CH2Cl2/MeOH=2:1, v/v; 1.5 mL), substrate/catalyst=
500 (entries 1) and 200 (entries 2–6), 50 atm H2, 608C, 24 h. [b] Based on 1H NMR spectroscopic analysis of the
crude product. [c] Determined by HPLC with chiral OD-H (2a and 2e) and OB-H (2b–d) columns. [d] 5 mol%
TsOH·H2O was added as additive. [e] Dendritic [Ru(Gn-DenBINAP)] catalysts were used, which were generated
in situ from [RuCl2(p-cymene)] and Gn-DenBINAP (n=0–4).[8b, e]
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(ee) of 66 and 44%, respectively, which were lower than that
obtained from the parent MeO-BINAP catalyst. In contrast,
when the higher-generation G2-BINAP and G3-BINAP catalysts
were used, the enantioselectivity increased gradually, giving b-
hydroxyl acid ester with 92 and 97% ee, respectively, which
were obviously superior to the parent catalyst. To further inves-
tigate the synthetic utility of our dendritic catalyst, hydrogena-
tion of some b-aryl b-ketoester substrates were studied. As
shown in Table 1 (entries 2–5), quite a similar tendency of var-
iation in enantioselectivity among different generation dendrit-
ic catalysts was observed. Excellent enantioselectivities (up to
97% ee) for all four substrates were obtained when using
higher-generation catalysts. Notably, low conversions were ob-
served in some cases, suggesting that the reactivity decreased
with increasing generation of catalyst. This was probably due
to the steric effect of the more bulky dendritic wedges, and
similar phenomena were observed for other core-functional-
ized dendrimer catalysts. It is worth mentioning that full con-
versions and the same enantioselectivityies could be achieved
in the presence of 5 mol% TsOH (entry 5, Table 1).[25] For com-
parison, ruthenium complexes of Gn-DenBINAP ligands, which
contain dendritic wedges at the 5,5’-positions of the binaphth-
yl backbone instead of on the P atoms were employed in this
reaction (Scheme 2). It was found that the generation number
(i.e., the size of the dendritic wedges) did not influence the
enantioselectivity at all (entry 6, Table 1). Thus, these results
suggested that the sterically demanding dendritic wedges at-
tached on the P atoms could fine-tune the chiral array of the
four phenyl rings around the metal center, which are consis-
tent with the rationale of designing such chiral dendritic cata-
lysts.
Table 2. Asymmetric hydrogenation of a-ketoesters with dendritic [Ru-
(BINAP)].[a]
Entry
Ligand
Substrate (R)
Conv.
[%][b]
ee
[%][c]
1
2
3
4
5
6
7
8
MeO-BINAP
G0-BINAP
G1-BINAP
G2-BINAP
G3-BINAP
G2-BINAP
G2-BINAP
G2-BINAP
G2-BINAP
G2-BINAP
G2-BINAP
G2-BINAP
G2-BINAP
G2-BINAP
G2-BINAP
G2-BINAP
G2-BINAP
C6H5 (3a)
C6H5 (3a)
C6H5 (3a)
C6H5 (3a)
C6H5 (3a)
C6H5 (3a)
C6H5 (3a)
4-Me-C6H4 (3b)
4-F-C6H4 (3c)
4-Cl-C6H4 (3d)
3-MeO-C6H4 (3e)
3-Cl-C6H4 (3 f)
2-MeO-C6H4 (3g)
2-Cl-C6H4 (3h)
3,5-diMe-C6H3 (3i)
2-naphthyl (3j)
phenethyl (3k)
>95
>95
>95
>95
>95
>95
>95
>95
>95
>95
>95
>95
>95
>95
>95
>95
>95
84 (96)[d]
70 (96)[d]
59 (96)[d]
93 (94)[d]
95 (94)[d]
93
91
91
94
94
94
92
86
83
9
10
11
12
13
14
15
16
17
94
93
83
[a] Reaction conditions: Substrate (1.0 mmol) in solvent (CH2Cl2/EtOH=
2:1, 3.0 mL v/v), substrate/catalyst=1000 (except for entries 6 and 7, sub-
strate/catalyst=5000 and 10000), 15 mol% FeCl2, 50 atm H2, 608C, 24 h.
[b] Based on 1H NMR spectroscopic analysis of the crude product. [c] De-
termined by HPLC with chiral AD-H (4a–h and 4j), OD-H (4i and 4k) col-
umns. [d] Data in brackets were obtained with 0.2 mol% dendritic [Ru(Gn-
DenBINAP)] (n=0–4) catalysts under otherwise identical conditions.
our catalytic system in the asymmetric hydrogenation of a-ke-
toesters, and the results are summarized in Table 2. It was
found that hydrogenation reactions catalyzed by these rutheni-
um catalysts proceeded smoothly in the presence of 15 mol%
FeCl2.[28] Notably, a remarkable dendrimer effect was also ob-
served in such transformations, which is similar to that ob-
served in the hydrogenation of b-ketoesters (entries 1–5,
Table 2). The highest ee value of 95% was obtained with the
third-generation catalyst. It is worth mentioning that with even
the use of 0.01 mol% G2-BINAP catalyst, full conversion with
91% ee was obtained (entry 7, Table 2). In addition, various a-
aryl ketoesters bearing electron-donating- or electron-with-
drawing substituents were successfully hydrogenated by using
0.1 mol% G2-BINAP catalyst, providing chiral a-hydroxyl esters
in full conversions with quite good enantioselectivities (en-
tries 8–16, Table 2). Only the substrates bearing substituents at
the ortho position of the phenyl ring gave relatively low enan-
tioselectivities (entries 13 and 14, Table 2). Substrate a-alkyl ke-
toester 3k could also be hydrogenated to give the reduced
product with good enantioselectivity (entry 17, Table 2). Nota-
bly, ruthenium complexes of Gn-DenBINAP ligands were also
effective for such transformation, but the generation number
did not obviously influence the enantioselectivity (entries 1–5,
Table 2).
Scheme 2. Molecular structures of chiral dendritic Gn-DenBINAP ligands.
Asymmetric hydrogenation of a-ketoesters
Optically pure a-hydroxyl esters and their derivatives are im-
portant building blocks for the synthesis of pharmacologically
active and naturally occurring compounds.[26] In contrast to the
great progress made in the asymmetric hydrogenation of b-ke-
toesters, the success in the homogeneous asymmetric hydro-
genation of a-ketoesters, particularly, a-aryl ketoesters has
been quite limited.[14d,25a,27] Thus, the development of new ef-
fective catalytic systems is still of great importance. On the
basis of the excellent performance of our dendritic ruthenium
catalysts in the hydrogenation of b-ketoesters, we then applied
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Asymmetric hydrogenation of a-ketoamides
Table 3. Asymmetric hydrogenation of a-ketoamides with dendritic [Ru-
(BINAP)].[a]
Optically active a-hydroxyl amides are important chiral build-
ing blocks for the synthesis of biologically active compounds
and chiral ligands for enantioselective addition reaction.[26a,29]
Accordingly, many efforts have been devoted to their prepara-
tion through asymmetric synthesis. Among the various meth-
ods for synthesizing chiral a-hydroxyl amides, including enan-
tioselective Passerini-type reaction,[30a] ring opening of chiral
a,b-epoxy amides,[30b] and asymmetric oxidation of racemic a-
hydroxy amides,[30c] the asymmetric hydrogenation of the cor-
responding prochiral a-ketoamides represents one of the most
direct and efficient approaches for attaining such chiral com-
pounds. However, in sharp contrast to the b-ketoester and a-
ketoester substrates, asymmetric hydrogenation of a-ketoa-
mides has been less studied. Only a few examples were report-
ed on the asymmetric hydrogenation of a-ketoamides, which
still suffered from low efficiency and limited substrate scope.[31]
Encouraged by the excellent performance of our dendritic cat-
alysts in the asymmetric hydrogenation of both b-ketoester
and a-ketoester substrates, we further applied our catalytic
system to the asymmetric hydrogenation of these less studied
a-ketoamides.
Entry
Ligand
Substrate (R/R1/R2)
Conv.
[%][b]
ee
[%][c]
1
2
3
4
5
6
7
8
MeO-BINAP
G0-BINAP
G1-BINAP
G2-BINAP
G3-BINAP
G2-BINAP
G2-BINAP
G2-BINAP
G2-BINAP
G2-BINAP
G2-BINAP
G2-BINAP
G2-BINAP
G2-BINAP
G2-BINAP
G2-BINAP
G2-BINAP
Et/Me/Ph (5a)
Et/Me/Ph (5a)
Et/Me/Ph (5a)
Et/Me/Ph (5a)
Et/Me/Ph (5a)
Me/Me/Ph (5b)
PhCH2CH2/Me/Ph (5c)
PhCH2CH2/Me/Me (5d)
PhCH2CH2/Et/Et (5e)
PhCH2CH2/-(CH2)4- (5 f)
PhCH2CH2/OMe/Me (5g)
PhCH2CH2/H/iPr (5h)
PhCH2CH2/H/Ph (5i)
Ph/Me/Ph (5j)
>95
>95
>95
>95
>95
>95
>95
>95
>95
>95
>95
>95
>95
<5
85 (98)[d]
70 (98)[d]
52 (98)[d]
95 (97)[d]
98 (96)[d]
89
95
94
95
93
94
85
80
–
9
10
11
12
13
14
15
16
17
Ph/H/Ph (5k)
Ph/H/Bn (5l)
Ph/H/n-Pr (5m)
>95
>95
>95
73
73
78
[a] Reaction conditions: Substrate (0.1 mmol) solvent (CH2Cl2/EtOH=2:1,
v/v, 1.5 mL), substrate/catalyst=100 (mol/mol), 15 mol% FeCl2, 50 atm H2,
608C, 24 h. [b] Based on 1H NMR spectroscopic analysis of the crude
product. [c] Determined by HPLC with chiral OJ-H (6a–f), OD-H (6g), and
AD-H (6h–m) columns. [d] Data in brackets were obtained with 1.0 mol%
dendritic [Ru(Gn-DenBINAP)] (n=0–4) catalysts under otherwise identical
conditions.
Under the optimized conditions for the asymmetric hydroge-
nation of a-ketoester substrates, a wide range of a-ketoamides
were smoothly hydrogenated in the presence of 1.0 mol%
ruthenium catalyst. As shown in Table 3, the dendritic wedges
played an important role in achieving high enantioselectivity,
the same phenomena was observed in the hydrogenation of
b-ketoesters and a-ketoesters (entries 1–5, Table 3). Excellent
enantioselectivities were achieved by using high-generation
catalysts, which are much better than those obtained from the
small molecular catalysts. Notably, the enantioselectivity was
found to be sensitive to the substituent number on the N
atom. All a-alkyl ketoamides bearing two substituents gave
very good enantioselectivities by using the second-generation
catalyst (entries 4–11, Table 3). Hydrogenation of a-alkyl Wein-
reb amide 5g also proceeded smoothly to give the product
with 94% ee. To the best of our knowledge, these represent
the highest enantioselectivities for the asymmetric hydrogena-
tion of a-alkyl ketoamides. In addition, several a-aryl ketoa-
mides were also tested, and the substituents on the N atom
had an obvious influence on the reactivity (entries 14–17,
Table 3). Substrate 5j bearing methyl and phenyl groups on
the N atom could not be reduced at all (entry 14, Table 3). Full
conversions and moderate enantioselectivities for other sub-
strates bearing only one substituent were observed (en-
tries 15–17, Table 3). For comparison, ruthenium complexes of
Gn-DenBINAP ligands were also applied for this reaction and
exhibited excellent enantioselectivities (entries 1–5, Table 3).
However, the generation number did not obviously influence
the enantioselectivity. Finally, the absolute configuration of the
a-hydroxyl amide product 6a was determined to be R based
on single-crystal X-ray analysis (for details, see the Supporting
Information).[32] Thus, the hydride was supposed to attack the
si-face of the a-ketoamides, which was the same as that for a-
ketoesters.
Catalyst recycling
As mentioned above, the dendritic catalysts could be easily
precipitated quantitatively by adding protonic solvent. The re-
cyclability of the dendritic catalyst was then investigated by
using the G2-BINAP catalyst, and the hydrogenation of a-aryl
ketoester 1e was chosen as the standard reaction (Table 4).
Upon the completion of the reaction, degassed methanol was
Table 4. Catalyst recycling.[a]
Run
t [h]
Conv. [%]
ee [%]
1
2
3
4
5
6
7
8
24
24
40
40
40
40
40
40
>95
>95
>95
>95
>95
93
92
91
92
90
88
87
88
89
87
76
[a] Reaction conditions: Substrate (0.6 mmol) in (CH2Cl2/MeOH=2:1, v/v,
4.5 mL), substrate/catalyst=200, 5 mol% TsOH, 50 atm H2, 608C.
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added to the reaction mixture, and the precipitated catalyst
was collected by filtration and used for the next catalytic run.
Gratifyingly, the catalyst could be reused at least 7 times with
no obvious decrease in enantioselectivity (entries 1–8, Table 4).
Notably, the reaction rate decreased slightly, but full conver-
sions were still obtained before run 6 upon prolonging the re-
action time. The decrease in reactivity was probably due to the
oxidation of catalyst during the recycling process.
Computational study of the tunable dendritic [Ru(BINAP)]
complexes
It has been well known that coordination of BINAP ligand to
RuII species makes a conformationally unambiguous seven-
membered chelate complex. Its dissymmetric structure deter-
mines the chiral array of the four phenyl rings on the P atoms,
which form the chiral pocket of the catalyst at which the enan-
tioselective reaction occurs.[18] For the dendritic BINAP ligands,
we envision that the increasing steric repulsion between the
four larger dendritic wedges with the increase of generation
can influence the chiral array of the four phenyl rings, and con-
sequently modulate the catalytic behavior of the core. To fur-
ther understand this unusual “dendritic effect” observed, theo-
retical calculations were carried out.
Figure 2. The optimized structure of dendritic [Ru(Gn-BINAP)] complex with
the dendritic wedges omitted for clarity (X is the center of the p-cymene
ring, “Z” is the axis passing through Ru and meeting at right angles with P1-
P2).
By employing the semi-empirical PM6 method[33] in the
Gaussian 09 program,[34] we fully optimized the molecular
structures of the four dendritic [Ru(Gn-BINAP)] complexes and
[Ru(MeO-BINAP)]. To confirm that semi-empirical PM6 method
is reliable here, we also performed first principle DFT calcula-
tions for the smallest complexes from MeO-BINAP, the larger
congeners of which are too large to be done with DFT calcula-
tions. The geometric results of DFT calculations are similar with
PM6 results as shown in the Supporting Information (Table S1),
which indicates that PM6 is the appropriate method here. The
optimized structure of dendritic [Ru(Gn-BINAP)] complex with
the numbering scheme is schematically shown in Figure 2.
We list several geometric parameters of the optimized struc-
tures in Table 5 and Table 6. The results show that the dihedral
angle (D1) between the two naphthalene rings of BINAP unit
and the P1-Ru-P2 angle are almost unchanged in this series of
complexes (Table 5), which were proven to play an important
role in achieving high enantioselectivity for other types of tun-
able chiral biaryl diphosphine ligands.[14a,d,20b] To further explore
the effect of bulky dendritic wedges on chiral environment
around the metal center, we employed an atom-to-plane dis-
tance analysis as used in a previous study.[35] The distances of
carbon atoms in the phenyl ring on P2-atom from the plane
(labeled by a dotted oval in Figure 2) passing through the Ru
atom and perpendicular to the axis (labeled as “Z” in Figure 2),
which passes through Ru and meets at right angles with P1-P2
show apparent disparity in the BINAP ligands (Table 6). These
distances in MeO-BINAP, G2-BINAP, and G3-BINAP systems are
larger than the corresponding ones in G0-BINAP and G1-BINAP
systems, indicating that the phenyl rings of high-generation li-
gands and MeO-BINAP protrude to the other P-Ru-P in-plane
coordination sites to a greater extent as compared with those
of low generation ligands. This distance trend, which reflects
Table 5. Calculated dihedral angles D1 (between the two naphthalene
rings of BINAP unit), D2 (between the C45-X-Ru plane and the X-Ru-I
plane), and the P1-Ru-P2 angle of [Ru(MeO-BINAP)] and [Ru(Gn-BINAP)]
complexes, all in degrees.[a]
Ligand
MeO-BINAP G0-BINAP G1-BINAP G2-BINAP G3-BINAP
D1
D2
76.5
57.7
76.9
51.8
96.7
76.6
51.7
96.3
76.8
56.3
96.7
76.2
55.9
96.4
P1-Ru-P2 96.4
[a] Atomic numberings are shown in Figure 2, X is the center of the p-
cymene ring.
Table 6. Distances [ꢂ] of carbons in the phenyl rings of [Ru(Gn-BINAP)]
complexes from the plane passing through the Ru atom and perpendicu-
lar to the axis that passes through Ru and meets at right angles with P1-
P2.[a]
C atom No. MeO-BINAP G0-BINAP G1-BINAP G2-BINAP G3-BINAP
C39
C40
C41
C42
C43
C44
1.76
0.66
3.05
0.83
3.25
2.13
1.63
0.46
2.88
0.52
2.97
1.78
1.64
0.47
2.90
0.54
2.99
1.80
1.78
0.68
3.08
0.86
3.29
2.17
1.75
0.63
3.04
0.80
3.24
2.11
[a] The atom-numbering scheme of [Ru(Gn-BINAP)] complexes is shown
in Figure 2.
the difference in steric environments around the metal center,
is in agreement with that of enantioselectivity observed in the
asymmetric hydrogenation of all three kinds of ketones.
Chem. Eur. J. 2014, 20, 9969 – 9978
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Considering that the co-ligand p-cymene will be replaced by
ketone substrates in the hydrogenation process, we further
choose this co-ligand as a probe to measure the chiral pocket
of these dendritic Ru catalysts. The dihedral angle (D2) be-
tween the plane C45-X-Ru (X is the center of the p-cymene
ring) and the plane X-Ru-I, which represents the rotation of p-
cymene, is listed in Table 5. Clearly, the dihedral angles of G0-
BINAP and G1-BINAP systems are different from those of MeO-
BINAP, G2-BINAP and G3-BINAP systems. Notably, both the di-
hedral angle trend and the distance trend discussed above are
in accord. All these results suggest that the attachment of
bulky dendritic wedges on the four phenyl rings at P atoms
will fine-tune the steric environments around the metal center.
The increasing steric repulsion interaction between dendritic
wedges might be responsible for the different array of the four
phenyl rings, and consequently modulate the catalytic behav-
ior of the [Ru(Gn-BINAP)] complexes, as shown in Figure 3.
wedges on the naphthalene rings do not significantly interact
with one another, and consequently do not influence the
chiral pocket of the catalyst where the hydrogenation reaction
occurs, which is consistent with the experiment results.
Conclusion
We have developed a new family of tunable dendritic BINAP li-
gands by attaching polyaryl ether dendrons onto the four
phenyl rings on the P atoms. These dendritic ligands were ap-
plied to the ruthenium-catalyzed asymmetric hydrogenation of
b-ketoesters, a-ketoesters, as well as the less-studied a-ketoa-
mides. It was found that the size of the dendritic wedges
played important roles in catalytic performance. The unusual
enantioselectivity profile of G3-BINAP>G2-BINAP>MeO-
BINAP>G0-BINAP>G1-BINAP was observed in the hydrogena-
tion of all three kinds of substrates. The high-generation cata-
lysts exhibited excellent enantioselectivities, which are superior
to those obtained from the small molecular catalysts. On the
other hand, the larger dendrons led to decreased reactivity
due to the steric effect of the more bulky dendritic wedges.
Further molecular modeling indicates that the attachment of
bulky dendritic wedges on the four phenyl rings at P atoms
can fine-tune the steric environments around the metal center.
The increasing steric repulsion interaction between dendritic
wedges might be responsible for the different array of the four
phenyl rings, and consequently modulate and improve the
enantioselectivity. In addition, the second-generation catalyst
could be easily recovered by solvent precipitation and reused
at least seven times without obvious decrease in enantioselec-
tivity. Since most phosphorus ligands contain “PPh2” units, this
method can be extended to other synthetically useful chiral
phosphorus-containing dendritic catalysts. The use of these
tunable and recyclable chiral dendritic diphosphines to other
asymmetric catalytic reactions is in progress.
Figure 3. Optimized structure of the [Ru(G2-BINAP)] complex.
Experimental Section
General
For comparison, we also investigate the three parameters
described above for similar dendritic [Ru(Gn-DenBINAP)] cata-
lysts, in which the dendritic wedges are attached at the 5,5’-
positions of binaphthyl backbone of BINAP unit as shown in
Scheme 2. The data are summarized in Table 7. Expectedly,
both dihedral angles (D1 and D2) and P1-Ru-P2 angles in this
series of [Ru(Gn-DenBINAP)] complexes do not show apparent
variation. These results indicate that the bulky dendritic
All chemicals were obtained from Aldrich, Alfa, or Acros and used
as received unless otherwise mentioned. The organic solvents used
were dried according to published methods. Unless otherwise
noted, all reactions were performed under an atmosphere of dini-
trogen employing standard Schlenk techniques. H NMR, 13C NMR,
1
and 31P NMR spectra were recorded on Bruker AMX 300 Spectrom-
eter (1H: 300 MHz; 13C: 75 MHz; 31P: 121 MHz) or Bruker AMX-600
spectrometers (1H: 600 MHz; 13C: 150 MHz; 31P: 243 MHz) at 298 K.
Chemical shifts are reported in parts per million (ppm)
relative to the internal standards, partially deuterated
solvents or tetramethylsilane (TMS). Coupling constants
Table 7. Calculated dihedral angles D1, D2, and BINAPÀRu binding angle (P1-Ru-P2)
for the five [Ru(Gn-DenBINAP)] molecular structures, all in degrees.[a]
(J) are denoted in Hz and chemical shifts (d) in ppm.
Multiplicities are denoted as follows: s=singlet, d=dou-
blet, m=multiplet, br=broad. Matrix-assisted laser de-
sorption-ionization (time of flight) mass spectrometry
(MALDI-TOF) was performed on a Bruker Biflex III MALDI-
TOF spectrometer with a-cyano-4-hydroxylcinnamic acid
(CCA) as the matrix. HRMS-FAB spectra were carried out
on a Bruker APEX 47E FTMS spectrometer. HRMS-ESI
Ligand
G0-DenBINAP G1-DenBINAP G2-DenBINAP G3-DenBINAP G4-DenBINAP
D1
D2
76.6
51.7
76.6
52.4
96.3
76.6
52.9
96.2
76.5
52.5
96.1
77.9
52.1
96.1
P1-Ru-P2 96.3
[a] The three parameters are same as ones described in Table 5.
Chem. Eur. J. 2014, 20, 9969 – 9978
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mass spectra were obtained on a Bruker APEX IV instrument. Ele-
mental analyses were performed on a Carlo–Erba-1106 instrument.
The detailed spectroscopic and analytical data of all known and
new compounds is provided in the Supporting Information.
stirred at 808C until the organic layer became clear. The organic
layer was separated at room temperature, washed with water,
dried over Na2SO4, and concentrated under reduced pressure. The
residue was further purified by precipitation into methanol and/or
by silica column chromatography, giving the desired chiral dendrit-
ic Gn-BINAP ligands as an off-white powder.
General procedure for the synthesis of chiral dendritic di-
phosphine oxides Gn-BINAPO
G0-BINAP: Treatment of G0-BINAPO (1.08 g, 1 mmol) with trichloro-
silane (1 mL, 10 mmol) in toluene as the above procedure giving
G0-BINAP (0.77 g, 80%). 1H NMR (300 MHz, CDCl3): d=7.86–7.89
(m, 2H), 7.80–7.82 (m, 2H), 7.29–7.46 (m, 24H), 6.85–7.06 (m, 10H),
6.69–6.79 (m, 10H), 4.94–4.98 ppm (m, 8H); 13C NMR (75 MHz,
CDCl3): d=144.7, 144.4, 137.0, 137.0, 136.3, 136.0, 135.9, 135.7,
135.6, 134.5, 134.3, 134.2, 133.5, 133.4, 133.4, 133.2, 130.2, 129.3,
129.2, 129.1, 129.0, 128.9, 128.6, 128.6, 128.4, 128.1, 128.0, 127.7,
127.6, 127.5, 127.1, 127.0, 126.4, 125.8, 114.7, 114.7, 113.3, 70.6,
69.9, 69.8 ppm; 31P NMR (121 MHz, CDCl3): d=À20.0 ppm; MS
(MALDI-TOF): m/z calcd for C72H56O4P2: 1048.2 [M+H]+; found:
1045.5; elemental analysis calcd (%) for [C72H56O4P2]: C, 82.58; H,
5.39; found: C, 82.43; H, 5.68.
A mixture of OH-BINAPO, Gn-Br (6.0 equiv), K2CO3 (6.0 equiv), KI
(1.0 equiv), and a catalytic amount of 18-crown-6 in acetone was
stirred at 808C for 20 h. After being cooled to room temperature,
the organic solvent was evaporated under reduced pressure. The
residue was further purified by precipitation into methanol and/or
by silica column chromatography, giving the desired chiral dendrit-
ic Gn-BINAPO as an off-white powder.
G0-BINAPO: Treatment of OH-BINAPO (0.15 g, 0.2 mmol) and G0-Br
(0.21 g, 1.2 mmol) in acetone as the above procedure to give G0-
1
BINAPO (0.19 g, 70%). H NMR (300 MHz, CDCl3): d=7.75–7.78 (m,
4H), 7.51–7.58 (m, 4H), 7.30–7.40 (m, 28H), 6.75–6.83 (m, 12H),
5.03 (s, 4H), 4.96 ppm (s, 4H); 13C NMR (75 MHz, CDCl3): d=160.9,
136.5, 134.5, 134.3, 133.9, 133.7, 128.7, 128.6, 128.3, 128.1, 128.1,
127.7, 127.6, 127.5, 127.3, 127.1, 125.8, 114.4, 114.2, 69.9 ppm;
31P NMR (121 MHz, CDCl3): d=27.3 ppm. MS (MALDI-TOF): m/z
calcd (%) for C72H56O6P2: 1080.2 [M+H]+; found: 1079.2.
G1-BINAP: Treatment of G1-BINAPO (0.97 g, 0.5 mmol) with tri-
chlorosilane (0.5 mL, 5 mmol) in toluene as the above procedure
1
giving G1-BINAP (0.78 g, 82%). H NMR (300 MHz, CDCl3): d=7.84–
7.87 (m, 2H), 7.77–7.80 (m, 2H), 7.24–7.45 (m, 44H), 6.84–7.02 (m,
10H), 6.52–6.76(m, 22H), 4.86–5.02 ppm (m, 24H); 13C NMR
(75 MHz, CDCl3): d=160.2, 159.1, 158.6, 1445.0, 144.7, 144.3, 139.5,
136.9, 136.8, 136.5, 135.9, 135.8, 135.6, 134.5, 134.3, 134.2, 133.5,
133.4, 133.2, 130.3, 129.4, 129.4, 129.1, 129.1, 128.7, 128.6, 128.1,
128.1, 127.6, 127.5, 126.4, 125.8, 114.8, 106.4, 101.7, 101.6, 70.2,
70.1, 69.9, 69.8 ppm; 31P NMR (121 MHz, CDCl3): d=À19.2 ppm. MS
(MALDI-TOF): m/z calcd for C128H104O12P2: 1897.1 [M+H]+, found:
1896.1; elemental analysis calcd (%) for [C128H104O12P2]: C 81.08; H
5.53; found: C 80.53; H 5.66.
G1-BINAPO: Treatment of OH-BINAPO (0.15 g, 0.2 mmol) and G1-Br
(0.46 g, 1.2 mmol) in acetone as the above procedure giving G1-
1
BINAPO (0.33 g, 85%). H NMR (300 MHz, CDCl3): d=7.72–7.84 (m,
4H), 7.60–7.67 (m, 4H), 7.25–7.41 (m, 44H), 7.14–7.21 (m, 4H),
6.82–6.94 (m, 6H), 6.56–6.67 (m, 18H), 4.94–5.03 ppm (m, 24H);
13C NMR (75 MHz, CDCl3): d=161.1, 161.0, 160.3, 160.3, 139.1,
139.0, 136.9, 136.8, 134.6, 134.4, 134.1, 133.8, 128.7, 128.7, 128.2,
128.1, 127.7, 127.4, 114.6, 106.5, 101.8, 101.7, 70.3, 70.2, 69.9 ppm;
31P NMR (121 MHz, CDCl3): d=26.8 ppm. MS (MALDI-TOF): m/z
calcd for C128H104O14P2: 1929.1: [M+H]+; found:1928.0.
G2-BINAP: Treatment of G2-BINAPO (1.82 g, 0.5 mmol) with tri-
chlorosilane (0.5 mL, 5 mmol) in toluene as the above procedure
1
giving G2-BINAP (1.49 g, 83%). H NMR (300 MHz, CDCl3): d=7.83–
G2-BINAPO: Treatment of OH-BINAPO (0.15 g, 0.2 mmol) and G2-Br
(0.97 g, 1.2 mmol) in acetone as the above procedure giving G2-
7.86 (m, 2H), 7.76–7.79 (m, 2H), 7.26–7.39 (m, 84H), 6.89–7.02 (m,
10H), 6.48–6.87 (m, 46H), 4.84–5.02 ppm (m, 56H); 13C NMR
(75 MHz, CDCl3): d=160.8, 160.1, 160.0, 160.0, 159.0, 159.5, 144.9,
144.7, 144.4, 139.4, 139.2, 139.1, 138.9, 136.7, 136.7, 136.3, 135.8,
135.5, 134.2, 133.3, 133.1, 130.7, 130.6, 130.2, 129.0, 128.5, 127.9,
127.7, 127.5, 127.1, 126.4, 125.8, 114.7, 106.3, 101.5, 69.9 ppm;
31P NMR (121 MHz, CDCl3): d=À19.2 ppm; MS (MALDI-TOF): m/z
calcd for C240H200O28P2: 3595.1 [M+H]+; found: 3596.3; elemental
analysis calcd (%) for [C240H200O28P2]: C 80.20; H 5.61; found: C
80.15; H 5.67.
1
BINAPO (0.65 g, 90%). H NMR (300 MHz, CDCl3): d=7.62–7.68 (m,
4H), 7.43–7.50 (m, 4H), 7.07–7.34 (m, 90H), 6.64–6.70 (m, 10H),
6.43–6.55 (m, 36H), 4.75–4.86 ppm (m, 56H); 13C NMR (75 MHz,
CDCl3): d=160.9, 160.3, 160.2, 160.1, 160.0, 144.2, 143.0, 139.5,
139.3, 139.2, 139.1, 139.0, 136.9, 136.8, 134.6, 133.9, 133.8, 133.6,
130.1, 128.6, 128.6, 128.3, 128.1, 128.0, 127.8, 127.6, 127.2, 125.9,
114.5, 114.3, 106.5, 105.6, 101.7, 101.2, 70.1, 70.1, 70.0, 69.8 ppm;
31P NMR (121 MHz, CDCl3): d=28.3 ppm; MS (MALDI-TOF): m/z
calcd for C240H200O30P2: 3627.1 [M+H]+; found: 3626.1.
G3-BINAP: Treatment of G3-BINAPO (1.76 g, 0.25 mmol) with tri-
G3-BINAPO: Treatment of OH-BINAPO (0.08 g, 0.1 mmol) and G3-Br
(0.99 g, 0.6 mmol) in acetone as the above procedure giving G3-
BINAPO (0.60 g, 86%). H NMR (300 MHz, CDCl3): d=7.70–7.74 (m,
chlorosilane (0.25 mL, 2.5 mmol) in toluene as the above procedure
1
1
giving G3-BINAP (1.31 g, 75%). H NMR (300 MHz, CDCl3): d=7.80–
7.82 (m, 2H), 7.74–7.77 (m, 2H), 7.23–7.38 (m, 164H), 6.77–7.05 (m,
12H), 6.44–6.68(m, 92H), 4.75–5.01 ppm (m, 120H); 13C NMR
(75 MHz, CDCl3): d=160.2, 160.2, 159.2, 158.6, 158.5, 143.7, 139.31,
137.2, 136.9, 136.5, 136.2, 135.8, 134.3, 133.3, 130.4, 128.7, 128.3,
128.1, 127.6, 126.5, 125.9, 114.7, 106.5, 105.8, 101.7, 70.2, 70.1 ppm;
31P NMR (121 MHz, CDCl3): d=À20.1 ppm. MS (MALDI-TOF): m/z
calcd for C464H392O60P2: 7029.1 [M+K]+; found: 7025; elemental
analysis calcd (%) for [C464H392O60P2]: C 79.73; H 5.65; found: C
79.87; H 5.69.
4H), 7.42–7.56 (m, 4H), 7.15–7.37 (m, 170H), 6.46–6.86 (m, 94H),
4.65–5.00 ppm (m, 120H); 13C NMR (75 MHz, CDCl3): d=160.2,
160.1, 160.1, 160.0, 139.3, 139.2, 139.0, 136.8, 128.6, 128.6, 128.0,
128.0, 127.6, 114.4, 106.4, 101.6, 70.1, 70.0, 69.9 ppm; 31P NMR
(121 MHz, CDCl3): d=27.7 ppm. MS (MALDI-TOF): m/z calcd for
C464H392O62P2: 7023.0 [M+H]+; found: 7025.
General procedure for the synthesis of chiral dendritic di-
phosphine ligands Gn-BINAP
Trichlorosilane (10 equiv) was added carefully at 08C to a mixture
of Gn-BINAPO and N(n-Bu)3 (20 equiv) in degassed toluene under
nitrogen atmosphere. The mixture was then stirred at 1208C for
24 h. After being cooled to room temperature, degassed NaOH so-
lution (4m, 20 equiv) was added carefully. Then, the mixture was
General procedure for asymmetric hydrogenation and cata-
lyst recycling
In situ catalyst preparation: A 25 mL flask was charged with Gn-
BINAP (0.11 mmol), [RuI2(cymene)]2 (0.05 mmol) and degassed sol-
Chem. Eur. J. 2014, 20, 9969 – 9978
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vent (CH2Cl2/EtOH=2:1, v/v, 6 mL). The mixture was stirred at 508C
for 2 h under nitrogen atmosphere. After cooling to room temper-
ature, the solvent was evaporated under reduced pressure. A
brown powder was obtained that was used directly in the catalytic
asymmetric hydrogenation without further purification. All in situ-
generated ruthenium catalysts were characterized by using
31P NMR spectroscopy.
Asymmetric hydrogenation and catalyst recycling: A 10 mL
glass-lined stainless steel reactor with a magnetic stirring bar was
charged with ketoester substrate, the above prepared catalyst
[Ru(Gn-BINAP)], additive if necessary and suitable solvent. The au-
toclave was closed and was pressurized with H2 to 50 atm. The
mixture was stirred at 608C for 24 h. After carefully venting of hy-
drogen, excess cold methanol was added to the reaction mixture
to precipitate the dendritic catalyst. The recovered catalyst was
then reused in the next catalytic cycle. The organic layer was used
to determine the conversion and enantioselectivity of the reduced
product, which were obtained by GC or HPLC analysis with a chiral
column.
[10] To the best of our knowledge, only four examples reported a remark-
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Acknowledgements
The authors thank the National Natural Science Foundation of
China (No. 21232008, 21290194, 21221002), the National Basic
Research Program of China (973 program, No. 2010CB833300),
and ICCAS (Institute of Chemistry), Chinese Academy of Scien-
ces for financial support.
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dendritic wedges attached to the four phenyl rings at the P atoms was
first reported by Brunner, see: H. Brunner, J. Organomet. Chem. 1995,
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Keywords: asymmetric
hydrogenation · ligands · ruthenium
catalysis
·
dendrimers
·
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Received: March 21, 2014
Published online on July 10, 2014
Chem. Eur. J. 2014, 20, 9969 – 9978
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