Synthesis and application of peripherally alkyl-functionalized dendritic pyrphos ligands: Homogeneous-supported catalysts for enantioselective hydrogenation

Article abstract of DOI:10.1016/j.molcata.2009.09.004

A new series of dendritic ligands with a chiral diphosphine located at the focal point have been synthesized through coupling of (R,R)-3,4-bis(biphenylphosphino)pyrrolidine (pyrphos) with peripherally alkyl-functionalized benzoic acid dendrons. These ligands were employed in the Rh-catalyzed asymmetric hydrogenation of prochiral dehydroamino acids, exhibiting excellent catalytic activities and enantioselectivities. The second-generation dendritic catalyst could be recovered by simple liquid-liquid biphasic separation and reused four times without serious loss of its activity and selectivity.

Full text of DOI:10.1016/j.molcata.2009.09.004

Journal of Molecular Catalysis A: Chemical 315 (2010) 82–85
Contents lists available at ScienceDirect
Journal of Molecular Catalysis A: Chemical
journal homepage: www.elsevier.com/locate/molcata
Synthesis and application of peripherally alkyl-functionalized dendritic pyrphos
ligands: Homogeneous-supported catalysts for enantioselective hydrogenation
Bing Yia,b,∗, Hua-Ping Heb, Qing-Hua Fanc
a College of Chemistry and Chemical Engineering, Hunan Institute of Engineering, Xiangtan 411104, PR China
b College of Chemistry, Xiangtan University, Xiangtan 411105, PR China
c CAS Key Laboratory of Molecular Recognition and Function, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 7 February 2009
Received in revised form 9 September 2009
Accepted 10 September 2009
Available online 16 September 2009
A new series of dendritic ligands with a chiral diphosphine located at the focal point have been syn-
thesized through coupling of (R,R)-3,4-bis(biphenylphosphino)pyrrolidine (pyrphos) with peripherally
alkyl-functionalized benzoic acid dendrons. These ligands were employed in the Rh-catalyzed asym-
metric hydrogenation of prochiral dehydroamino acids, exhibiting excellent catalytic activities and
enantioselectivities. The second-generation dendritic catalyst could be recovered by simple liquid–liquid
biphasic separation and reused four times without serious loss of its activity and selectivity.
© 2009 Elsevier B.V. All rights reserved.
Keywords:
Dendritic ligands
Homogeneous catalysis
Asymmetric hydrogenation
Biphasic separation
1. Introduction
of the specific microenvironment created by the branched shell
could modulate the catalytic behavior of the core. Recently, Fan and
Dendrimer chemistry has been extremely popular in the past
decades, and several potential applications of dendrimers have
been explored and are well documented in various reviews [1–6].
Unlike traditionary polymers, dendrimers can be characterized by
their elaborate structure, which allows us to precisely control their
molecular size, shape, and the numbers and positions of functional
groups. Recently, dendrimers as ideal scaffolds employed in catal-
ysis have received considerable attention. The dendrimer catalysts
are soluble in most common organic solvents, allowing the cat-
alytic reactions to be carried out in a homogeneous manner under
appropriate reaction conditions. On the other hand, such novel
nano-sized catalyst can be easily recycled via supra-filtration or
solvent precipitation methods. Thus, dendritic catalysts may bridge
the gap between homogeneous and heterogeneous catalysis. So
far, a number of organometallic dendrimers with catalytic sites at
either their core or their periphery have been reported [7–10]. For
the immobilization of chiral catalysts, even subtle conformational
changes may significantly influence the catalytic behavior of the
active sites [11–23]. In the case of the core-functionalized den-
drimers, it is expected that the steric shielding or blocking effect
co-workers reported a kind of BINAP-cored dendrimers for asym-
metric catalytic reaction of prochiral substrates. It was found that
the rate of the reaction increased by using the high-generation
dendritic catalysts [11,16]. In contrast, dendritic catalysts with
a chiral diphosphine pyrphos located at the focal point showed
a dramatic decrease in catalytic activity on going from genera-
tion 3 to generation 4. This negative effect might be due to the
steric shielding effect of the dendritic shell [22]. In addition, the
solubility and physical properties of dendrimers can be altered
by peripheral modification, which may facilitate the recycling
of catalysts [9,24–26]. For example, introduction of hydrophilic
groups to the peripheral layer of a hydrophobic dendron can
result in water-soluble dendritic unimolecular micelles [27–29].
Most recently, Fan and co-workers reported a new kind of apo-
lar dendritic Ru-BINAP catalysts functionalized with alkyl chain
at the periphery. These catalysts were employed for the homo-
geneous asymmetric hydrogenation by using ethanol–hexane as
solvent, and could be easily recycled at the end of reaction via
a liquid–liquid biphasic separation method [30]. Inspired by this
finding, in this paper, we designed and synthesized a new kind
of dendritic pyrphos ligands (Scheme 1) bearing alkyl chains at
the periphery for the Rh-catalyzed asymmetric hydrogenation of
dehydroamino acids. In contrast to the poly(benzyl ether) dendron-
supported catalysts [22], excellent catalytic performance (100%
conversion and up to 97.8% ee) and facile catalyst recycling have
been achieved.
∗
Corresponding author at: College of Chemistry and Chemical Engineering,
Hunan Institute of Engineering, Xiangtan 411104, PR China. Tel.: +86 732 58680393;
fax: +86 732 58680125.
E-mail address: bingyi2004@126.com (B. Yi).
1381-1169/$ – see front matter © 2009 Elsevier B.V. All rights reserved.
doi:10.1016/j.molcata.2009.09.004

B. Yi et al. / Journal of Molecular Catalysis A: Chemical 315 (2010) 82–85
83
Scheme 1. Synthesis of chiral dendritic pyrphos ligands. (1) DCC, DMAP, CH2Cl2, r.t.
2. Results and discussions
The rhodium catalysts were prepared from the correspond-
ing ligands and [Rh(COD)2]+BF4 (COD = 1,5-cyclooctadiene) at an
−
The preparation of new dendritic chiral pyrphos ligands was
conducted according to the recently reported procedure [22].
Condensation reaction of pyrphos [31] with peripherally alkyl-
functionalized dendritic wedges with carboxyl groups located at
the focal point in the presence of 1,3-dicyclohexylcarbodiimine
(DCC) and 4-(dimethylamino)pyridine (DMAP) in dichloromethane
at room temperature gave the chiral dendritic ligands with good
reaction yields (Scheme 1). All these ligands were purified by flash
column chromatography and characterized by 1H, 13C and 31P NMR
spectroscopy, elemental analyses and/or HRMS, and MALDI-TOF
mass spectrometry. All results are in full agreement with the pro-
posed structures.
equal molar ratio in dichloromethane at room temperature. The
metalation was complete within minutes, which was evident from
the change of their colour from brown red to orange-yellow. The
above metallodendrimers can be directly used in the hydrogenation
reactions without further purification.
With these chiral dendritic catalysts in hand, we chose the
asymmetric hydrogenation of acetamido cinnamic acid 1a as a stan-
dard reference system for comparing their catalytic performance.
Methanol was initially chosen as the solvent for this reaction. The
preliminary results are summarized in Table 1. As we expected, the
number and length of the alkyl end groups of the dendritic wedges
influenced the reaction performance and the results depended on
Table 1
Asymmetric hydrogenation of dehydroamino acids catalyzed by the dendritic pyrphos-Rh(I) catalystsa.
.
Entry
Substrate (R)
Ligand
Solvent (v/v)
T/h
bConv./%
bE.e./%
1
2
3
4
5
6
7
8
1a (C6H5)
1a (C6H5)
1a (C6H5)
1a (C6H5)
1a (C6H5)
1a (C6H5)
1a (C6H5)
1a (C6H5)
10C-G1
16C-G1
10C-G2
10C-G1
16C-G1
10C-G2
10C-G2
10C-G2
10C-G2
10C-G2
10C-G2
10C-G2
10C-G2
10C-G2
10C-G2
MeOH
MeOH
MeOH
4
4
4
2
2
2
2
2
1
3
2
3
3
2
2
100
94.0
65.0
100
100
100
98.2
100
86.7
100
100
100
100
100
100
95.6
95.2
95.2
97.3
97.1
97.2
97.0
97.1
97.2
96.8
96.1
96.7
96.4
97.5
97.8
MeOH/cyclohexane (1/1)
MeOH/cyclohexane (1/1)
MeOH/cyclohexane (1/1)
MeOH/cyclohexane (2/3)
MeOH/cyclohexane (3/2)
MeOH/cyclohexane (1/1)
MeOH/cyclohexane (1/1)
MeOH/cyclohexane (1/1)
MeOH/cyclohexane (1/1)
MeOH/cyclohexane (1/1)
MeOH/cyclohexane (1/1)
MeOH/cyclohexane (1/1)
9c
10
11
12
13
14
15
1a (C6H5)
1b (2-Cl–C6H4)
1c (3-Cl–C6H4)
1d (4-Cl–C6H4)
1f (4-NO2–C6H4)
1g (4-CH3O–C6H4)
1h (4-CH3–C6H4)
a
Hydrogenations were carried out in 0.032 M solution of substrate 1 (0.0975 mmol) under the following conditions: substrate/catalyst = 200:1; 60 atm hydrogen pressure;
20 ◦C.
b
Based on GC analysis with a 25 m × 0.25 mm Chrompack Chirasil L-Val column. The absolute configuration of product is (S), which were determined by comparison of
the optical rotation with the literature value.
c
0.975 mmol of substrate 1a and 30 ml of reaction solvent with a substrate/catalyst molar ratio of 800 were used under otherwise identical conditions.

84
B. Yi et al. / Journal of Molecular Catalysis A: Chemical 315 (2010) 82–85
the solubility of the dendrimer in solvent. Full conversion and
high enantioselectivity (up to 95.6% ee) for the first generation
dendrimer ligand 10C-G1 was observed (entry 1), which are sim-
ilar to those for the soluble polymer-supported catalyst (95.5%
ee) [32]. However, the dendritic ligand 16C-G1, which linked with
hexadecoxy chain at the periphery, gave lower conversion and
slightly lower enantioselectivity (entry 2). Much lower activity
was obtained with the second-generation dendritic ligand 10C-
G2 (entry 3). The low reactivity was due to the poor solubility of
the latter two catalysts in methanol. Thus, a binary solvent system
was chosen as the reaction medium in order to sustain homoge-
neous reaction conditions for all generation/size dendritic catalysts.
In comparison with those in methanol, utilizing an equal volume
mixture of methanol and cyclohexane as solvent gave better reac-
tivity and higher enantioselectivity (100% conversion and up to
97.3% ee) for all of the dendritic pyrphos Rh(I)-catalysts among
the chosen binary solvent system (entries 4–6), which were much
higher than those of the soluble MeO-PEG-supported pyrphos-
rhodium(I) catalyst [32]. This confirmed the value of catalysts
with a well-defined dendritic wedge. The further experimen-
tal results showed that similar conversion and enantioselectivity
were obtained in the Rh(10C-G2) catalyzed hydrogenation when a
mixture of methanol/cyclohexane was used in different ratios as
solvent (entries 7–8). Notably, the dendritic catalyst was found to
be highly effective even under low catalyst loading. For example,
the hydrogenation of 1a with a substrate/catalyst molar ratio of
800 and under 60 atm H2 pressure at 20 ◦C gave 86.7% conversion
and 97.2% ee in 1 h with TOF of 694 h−1 (entry 9). Encouraged by
these excellent results, we decided to further investigate the appli-
cations of the dendritic catalyst in the asymmetric hydrogenation of
other dehydroamino acid derivatives using 10C-G2 as the ligand. In
all cases, full conversion and high enantioselectivities (96.1–97.8%)
were observed (entries 10–15).
An important feature of the design of peripherally alkyl-
modified dendritic ligands was the easy and reliable catalyst
recycling via liquid–liquid biphasic separation technique. It was
found that these dendrimer-based catalysts with alkyl tailed at the
periphery preferred to dissolve in a non-polar solvent system. In the
case of the second-generation dendritic ligand 10C-G2, more than
99% of its Rh complex could be extracted to the non-polar cyclohex-
ane phase in a methanol/cyclohexane (2.0% H2O) biphasic system.
For example, upon completion of the catalytic hydrogenation reac-
tion, a small amount of water (2.0%) was added to the reaction
mixture to induce phase separation. The cyclohexane layer, which
contained the catalyst 10C-G2-Rh(I), was separated and reused in
the next run of reaction. The recovered catalyst was reused five
times with similar enantioselectivity, albeit decreased activity until
the fourth cycle (Table 2, entry 4). To the methanol layer, which
contained the reduced product, was added some new substrate,
and then subjected to hydrogenation under otherwise identical
conditions. No hydrogenation of the newly added substrate was
observed. However, when this reaction was carried out for 24 h,
some of substrate was found to be reduced, indicating that a small
amount of the catalyst might remain dissolved in the methanol
layer. Further determination of the Rh content in the product by
using inductively coupled plasma (ICP) spectroscopy showed that
less than 0.35% Rh was leached into the methanol layer.
3. Conclusions
A practical protocol for the effective asymmetric hydrogenation
of prochiral dehydroamino acids and the recycling of catalyst by
simple liquid–liquid biphasic separation has been developed, as
summarized as follows: (1) peripherally alkyl-functionalized den-
dritic Rh(pyrphos) catalysts have been synthesized and applied in
the asymmetric hydrogenation of acetamido cinnamic acids using
a mixture of methanol/cyclohexane as reaction medium, afford-
ing better enantioselectivity and catalytic activity than those of the
soluble polymer-supported catalyst; (2) the combination of chiral
dendritic catalyst and organic biphasic system provided facile cat-
alyst recycling. The recovered catalyst could be recycled four times
without significant loss of catalytic activity and enantioselectiv-
ity. No obvious Rh leaching was observed during the recycling of
catalyst via liquid–liquid biphasic separation.
4. Experimental
Unless otherwise noted, all experiments were carried out
under an inert atmosphere by using standard Schlenk-type tech-
niques, or performed in a nitrogen-filled glovebox. All solvents
were dried using standard, published methods and were dis-
tilled under a nitrogen atmosphere before use. Pyrphos was
synthesized according to the reported procedures [31]. Peripher-
ally alkyl-functionalized Fréchet-type dendrimers with carboxyl
groups at the focal points were prepared by using the convergent
approach according to literature [33,34]. [Rh(COD)2]BF4 [35] and
[Rh(COD)Cl]2 [36] were synthesized according to the literature.
1H NMR, 31P NMR and 13C NMR spectra were recorded on a
Bruker Model Avance DMX 300 Spectrometer (1H 300 MHz, 31P
121 MHz and 13C 75 MHz, respectively). Chemical shift (␦) is given
in ppm and is referenced to residual solvent peaks (1H and 13C
NMR) or to an external standard (85% H3PO4, 31P NMR). Infrared
spectra were recorded on a Bruker Tensor 27 spectrophotometer.
MALDI-TOF mass spectra were obtained on a BIFLEX III instrument
with ␣-cyano-4-hydroxycinnamic acid (CCA) as the matrix. High
resolution mass spectra were recorded on a GCT or a APEX II spec-
trometer. Elemental analyses were performed on a Flash EA 1112
Elemental Analyzer. Optical rotations were measured on an AA-10R
automatic polarimeter in the solvent indicated. All enantiomeric
excess values were obtained from GC analysis on a Varian-6000
chromatograph with a Chrompack Chirasil L-VAL chiral column.
4.1. General procedure for the synthesis of dendritic pyrphos
ligands
Table 2
Recycling of the catalyst 10C-G2-Rh(I) in the asymmetric hydrogenation of
acetamido cinnamic acid (1a)a.
Typical procedure: 3,4,5-tri(decoxy)benzoic acid (36 mg,
Entry
Cycle
bConv./%
bE.e./%
0.061 mmol),
(3R,4R)-pyrphos
hydrochloride
(34.3 mg,
1
2
3
4
5
First
100
99
97
83
56
97.0
97.1
97.0
96.8
96.5
0.072 mmol), DCC (20 mg, 0.097 mmol), and DAMP (15 mg,
0.122 mmol) were combined in dry, degassed CH2Cl2 (5 ml) at
ambient temperature. The mixture was stirred for 12 h at the same
temperature (TLC monitoring), and the hydrated DCC adduct dicy-
clohexylurea (DCU) precipitate was removed by filtration through
celite. After a usual work-up, the crude product was purified
by column chromatography on silica gel (petroleum ether:ethyl
acetate 2:1,v/v) to afford 10C-G1 as white grease. (58 mg, 94%);
Rf = 0.27 (4:1 petroleum ether/ethyl acetate); [␣]D20 = +60.0 (C
Second
Third
Fourth
Fifth
a
Hydrogenations were carried out in 0.032 M solution of substrate 1a (20 mg)
under the following conditions: solvent = MeOH/cyclohexane (1/1, v/v); sub-
strate/catalyst = 100:1; 60 atm hydrogen pressure; 20 ◦C; 2 h for cycles 1–2, 6 h for
cycles 3–4, 24 h for cycle 5.
b
Based on GC analysis with a 25 m × 0.25 mm Chrompack Chirasil L-Val column.

B. Yi et al. / Journal of Molecular Catalysis A: Chemical 315 (2010) 82–85
85
1, CH2Cl2); 1H NMR (300 MHz, CDCl3): ı 7.74–7.10 (m, 18H),
7.02–6.99 (m, 2H), 6.55 (s, 2H), 4.19–4.07 (m, 1H), 3.94–3.90
(m, 1H), 3.89–3.78 (m, 6H), 3.59 (pseudo-t, J = 13.5 Hz, 1H), 3.32
(pseudo-t, J = 11.4 Hz, 1H), 2.90–2.85 (m, 1H), 2.76–2.71 (m, 1H),
1.72–1.61 (m, 6H), 1.38–1.31 (m, 42H), 0.81 (t, J = 7.1 Hz, 9H); 13C
NMR (75 MHz, CDCl3):ı 168.8, 151.9, 138.3, 134.5 (m), 132.7 (m),
132.4 (m), 130.6, 128.4, 128.2, 127.6 (m), 104.6, 72.4, 68.1, 50.4
(m), 47.4 (m), 38.7 (m), 36.3 (m), 30.9, 29.3, 28.7, 28.6, 28.5, 28.4,
28.3, 25.0, 21.7, 13.1; 31P NMR (121 MHz, CDCl3): ı −11.7, −12.4
(J = 7 Hz); IR (KBr): v (cm−1) 1635.5, 1580.0; MALDI-TOF MS: m/z
1012.8 (M+); HRMS (ESI) m/z found: 1012.6508, C65H91NO4P2
([M+H]+) requires: 1012.6522.
reaction mixture under inert atmosphere to induce complete phase
separation. The cyclohexane layer, which contained the catalyst,
was separated, and reused in the next catalytic cycle after dried
with anhydrous MgSO4. The conversion and ee value of product
were determined by chromatography using a 25 m Chiralsi L-Val
capillary column after the acids had been transformed into the
corresponding methyl esters.
Acknowledgements
We are grateful to the National Natural Science Foundation of
China (20972045), Provincial Natural Science Foundation of Hunan
(No. 06JJ5017), and the foundation for the Returned Overseas Chi-
nese Scholars of Ministry of Education (20071108) for financial
supports.
Compound 10C-G2:
a procedure similar to that for the
preparation of 10C-G1 was used to prepare 10C-G2 from periph-
erally decyl-functionalized generation 2 acid and (3R,4R)-pyrphos
hydrochloride. The resulting residue was purified by column chro-
matography on silica gel (petroleum ether:ethyl acetate 2:1) to
afford 10C-G2 as white grease. Yield 80%; Rf = 0.34 (1:1 petroleum
ether/dichloromethane); [␣]D20 = +49.0 (C 1, CH2Cl2); 1H NMR
(300 MHz, CDCl3): ı 7.47–7.18 (m, 18H), 7.08–7.04 (m, 2H), 6.73
(s, 2H), 6.62 (s, 5H), 4.89 (m, 4H), 4.27–4.02 (m, 2H), 4.01–3.94 (m,
12H), 3.68 (pseudo-t, J = 13.2 Hz, 1H), 3.38 (pseudo-t, J = 11.7 Hz,
1H), 2.98–2.96 (m, 1H), 2.84–2.80 (m, 1H), 1.86–1.72 (m, 12H),
1.49–1.28 (m, 84H), 0.89 (t, J = 6.6 Hz, 18H); 13C NMR (75 MHz,
CDCl3):ı 169.4, 159.8, 153.4, 138.7, 138.0, 136.3 (m), 135.5 (m),
133.6 (m), 131.4, 129.5, 129.2 (m), 129.0 (m), 106.2, 103.7, 73.5,
70.7, 69.2, 51.4 (m), 48.6 (m), 39.4 (m), 37.5 (m), 32.0, 30.4, 29.8,
29.7, 29.5, 26.2, 22.8, 14.1; 31P NMR (121 MHz, CDCl3): ı −12.1,
−12.3 (J = 7 Hz); IR (KBr): v (cm−1) 1636.7, 1591.2; MALDI-TOF MS:
m/z 1693.3 (M+); HRMS (ESI) m/z found: 1665.1536, C107H159NO9P2
(M+) requires: 1665.1524.
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In a glovebox under a nitrogen atmosphere, a 45 ml glass-lined
stainless steel reactor with a magnetic stirring bar was charged
with substrate (0.0975 mmol), the calculated amount of catalyst
and methanol–cyclohexane (1:1, v/v, 3 ml). The inert gas in the
autoclave was displaced with hydrogen. The pressure was set at
60 atm and the reaction started by stirring. The temperature was
kept constant at about 20 ◦C with an oil-bath. After carefully vent-
ing hydrogen, 0.06 ml degassed distilled-water was added to the