Asymmetric hydroformylation with highly crosslinked polystyrene-supported (R,S)-BINAPHOS-Rh(I) complexes: the effect of immobilization position.

Article abstract of DOI:10.1016/S0960-894X(02)00267-6

A new class of polymer-supported (R,S)-BINAPHOS 1e in which the parent BINAPHOS has two alkoxy-substituents at the 3-positions of the phenyls, has been synthesised. Using its Rh(I) complex, asymmetric hydroformylation of olefins proceeded with higher enantioselectivity in some cases compared to the conventional polymer-supported 1c.

Full text of DOI:10.1016/S0960-894X(02)00267-6

Bioorganic & Medicinal Chemistry Letters 12 (2002) 1825–1827
Asymmetric Hydroformylation with Highly Crosslinked
Polystyrene-Supported (R,S )-BINAPHOS–Rh(I) Complexes:
The Effect of Immobilization Position
Fumitoshi Shibahara,a Kyoko Nozaki,a,b,* Takeshi Matsuob and Tamejiro Hiyamab
aDepartment of Chemistry and Biotechnology, Graduate School of Engineering, The University of Tokyo, Hongo Bunkyo-ku,
113-8656 Tokyo, Japan
bDepartment of Material Chemistry, Graduate School of Engineering, Kyoto University, Yoshida,
Sakyo-ku, Kyoto 606–8501, Japan
Received 13 December 2001; accepted 4 February 2002
Abstract—A new class of polymer-supported (R,S)-BINAPHOS 1e in which the parent BINAPHOS has two alkoxy-substituents at
the 3-positions of the phenyls, has been synthesised. Using its Rh(I) complex, asymmetric hydroformylation of olefins proceeded
with higher enantioselectivity in some cases compared to the conventional polymer-supported 1c. # 2002 Elsevier Science Ltd. All
rights reserved.
Asymmetric hydroformylation of olefins serves as a
direct route to optically active aldehydes which are valu-
able precursors for various pharmaceuticals and agro-
Here, we report the synthesis of a new class of polymer-
supported (R,S)-BINAPHOS 1e in which the parent
BINAPHOS has two alkoxy-substituents at the 3-posi-
tions of the phenyls, as was so for the homogeneous
ligand 1b (Fig. 1). Using a Rh(I) complex of 1e, asym-
metric hydroformylation of styrene, vinyl acetate, and
(Z)-2-butene were examined.
chemicals.1 Previously, we developed
a
chiral
phosphinephosphite ligand (R,S)-BINAPHOS (1a) and
demonstrated its Rh(I) complex as the first example of a
truly efficient catalyst for asymmetric hydroformylation
of various olefins.2 Recently, Leitner3 and we4 found that
introduction of a substituent on each of the two phenyls
at their 3-positions (e.g., methoxy-substituted 1b) sig-
nificantly improved the catalytic activity and regio- and
enantio-selectivities of asymmetric hydroformylation.
Synthesis of 1e was accomplished in several steps start-
ing from the methoxy-substituted phosphine oxide 24
Immobilization of homogeneous chiral catalysts onto
insoluble support is one of the current trends in organic
synthesis due to the easy separation and recycling of the
catalyst.5 In 1998, we immobilized Rh(I)-(R,S)-BINA-
PHOS onto a highly crosslinked polystyrene support at
the 6-position of one of the naphthalenes (1c), without
reducing the excellent performance of the catalyst.6 One
of the unique features of this immobilization is the
extremely high content of divinylbenzene (over
50 mol%) to prepare polystyrene, whose pore size and
surface area were precisely studied by Gagne, recently.7
*Corresponding author. Fax: +81-3-5841-7261; e-mail: nozaki@
chembio.t.u-tokyo.ac.jp
Figure 1. Chiral phosphinephoshite ligand (R,S)-BINAPHOS (1a)
and its derivatives.
0960-894X/02/$ - see front matter # 2002 Elsevier Science Ltd. All rights reserved.
PII: S0960-894X(02)00267-6

1826
F. Shibahara et al. / Bioorg. Med. Chem. Lett. 12 (2002) 1825–1827
Scheme 1. Synthesis of a new polystyrene-supported Rh(I)–(R,S)-BINAPHOS complex 7 [=Rh(acac)(1e)].
(Scheme 1). After cleavage of the methoxy ethers, the
two hydroxyl groups of 3 were alkylated with meta-
bromobenzyl bromide followed by hydrolysis of the tri-
flate and reduction of the phosphine oxide. Two vinyl
groups were introduced via Suzuki–Miyaura coupling.
The phosphine part 4 thus obtained was coupled with
chlorophosphite 5 to afford divinyl-(R,S)-BINAPHOS 6.
CO=1/1) at 60 ꢀC [Eq. (1)]. The reaction was carried
out in benzene and the polymer-supported catalyst 7
was scattered in the solution by stirring. The result is
compared with the ones having homogeneous parent
ligand 1a, methoxy-substituted 1b, and the previous
polymer-supported 1c (Table 1). With 1e, the corre-
sponding aldehydes were obtained with 85% iso-selec-
tivity and in 92% ee (entry 1). The values are
comparable to the data with homogeneous 1a (entry 2),
slightly higher than supported 1c (entry 3), and a little
lower than that with methoxy-substituted homogeneous
1b (entry 4). On the other hand, the use of 1e diminished
the % ee in hydroformylation of vinyl acetate (compare
entry 4 with 5 and 6).
For the preparation of polystyrene-supported Rh com-
plex from 6, two approaches are available: (i) copoly-
merization of ligand 6 with styrene/divinylbenzene first
and then Rh-complex formation with the resulting
polymeric ligand, and (ii) Rh-complex formation with
ligand 6 first and then copolymerization of the resulting
Rh-6 complex with styrene/divinylbenzene. In this
work, the latter method, complexation-then-polymeri-
zation, was employed due to the following reason. Pre-
viously, we compared the two methods with two
BINAPHOS derivatives 1c and 1d.8 No difference in
catalytic performance was observed between the two
methods with ligand 1c which is immobilized at a single
point. On the other hand, three-point attached 1d
showed significant loss of %ee when the polymeri-
zation-then-complexation method was employed. The
difference between 1c and 1d was attributed to the flex-
ibility of the ligand conformation. Apparently, the
multipoint-attached 1d has less flexibility, and by the
polymerization-then-complexation method, the fixed
ligand conformation was not always suitable for the
Rh-coordination. In the complexation-then-polymeri-
zation method, however, Rh atom seems to have
behaved as a template to order the ligand conformation
which fits to the Rh-coordination. Considering its mul-
tipoint-attachment nature, ligand 6 was first mixed with
Rh(acac)(CO)2 in toluene to form complex Rh(acac)(6)
and then copolymerized with divinylbenzene (55% con-
tent, the rest is ethylstyrene) initiated by V-65 (=azo-
bis(2,4-dimethylvaleronitrile)) to form 7 [=Rh(acac)(1e)].
ð1Þ
Unlike most of the asymmetric hydrogenation, hydro-
formylation with Rh-1a does not require the use of
polar solvents. Taking advantage of this point, we
Table 1. Asymmetric hydroformylation of styrene and vinylacetate
catalyzed by Rh(I)–(R,S)-BINAPHOS complexes
Entry
Olefin
R=
Ligand
S/C
Conv
(%)
i/n
% ee of
iso-
1a
Ph
1e
1a
1b
1c
1e
1a
1c
2000
2000
2000
2000
500
>99
>99
>99
>99
87
85/15
89/11
93/7
85/15
84/16
84/16
87/13
92
92
95
90
86
92
92
2a,d
3a,e
3a,d
4b
AcO
5c,d
6c,d
500
500
98
67
aH2/CO=10 atm/10 atm, 12ꢁ13 h.
bH2/CO=40 atm/40 atm, 25 h.
cH2/CO=50 atm/50 atm, 42 h.
dRef 6.
The polymer supported catalyst 7 was subjected to
asymmetric hydroformylation of styrene under hydro-
gen and carbon monoxide (total pressure of 20 atm, H2/
eRef 4.

F. Shibahara et al. / Bioorg. Med. Chem. Lett. 12 (2002) 1825–1827
1827
ð2Þ
In conclusion, we have demonstrated that immobili-
zation of Rh-(R,S)-BINAPHOS is also possible at the
phosphine phenyls. Although the active Rh-center in 1e
is located closer to the polymer backbone compared to
1c, the loss in catalytic activity was less significant and
enantioselectivities were improved in some cases. How-
ever, the effect of 3-alkoxy-substituent in 1e was not
always as remarkable as homogeneous ligand 1b.
Figure 2. Vapor-phase asymmetric hydroformylation apparatus.
Table 2. Asymmetric hydroformylation of (Z)-2-butene catalyzed by
Rh(I)–(R,S)-BINAPHOS complexes in several systemsc,d
Entry
System
Ligand
TOF (hÀ1
)
ee (%)
1a
2b
3
Dispersion (A)
1e
1c
1b
1a
1e
1c
14
24
7.6
23
18
27
82
80
90
82
81
80
References and Notes
Homogeneous
1. (a) Agbossou, F.; Carpentier, J.-F.; Mortreux, A. Chem.
Rev. 1995, 95, 2485. (b) Nozaki, K.; Ojima, I. In Catalytic
Asymmetric Synthesis, 2nd ed.; Ojima, I., Ed.; VCH: New
York, 2000; p 429. (c) Nozaki, K. In Comprehensive Asym-
metric Catalysis; Jacobsen, E., Pfaltz, A., Yamamoto, H.,
Eds.; Springer: Berlin, 2000; p 381.
4
5a
6b
Fixed bed (B)
aH2/CO=1/1; 40 atm, 3 h.
bH2/CO=1/1; 32 atm, 4 h.
cH2/CO=1/1; 32 atm, 9 h.
dH2/CO=1/1; 32 atm, 8 h.
2. Nozaki, K.; Takaya, H.; Hiyama, T. Top. Catal. 1997, 4, 175.
3. Leitner, W.; Francio, G. Chem. Commun. 1999, 1663.
`
4. Nozaki, K.; Matsuo, T.; Shibahara, F.; Hiyama, T. Adv.
Synth. Cat. 2001, 343, 61.
5. (a) De Vos, D. E.; Vankelecom, I. F. J.; Jacobs, P. A. Chiral
Catalyst Immobilization and Recycling; Wiley-VCH: Weinheim,
2000. (b) Clapham, B.; Reger, T. S.; Janda, K. D. Tetrahedron
2001, 57, 4637. (c) Kragl, U.; Dwars, T. Trends Biotech. 2001,
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Ohta, T.; Takaya, H.; Hiyama, T. J. Am. Chem. Soc. 1998,
120, 4051. (b) Nozaki, K.; Shibahara, F.; Itoi, Y.; Ohta, T.;
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reported the vapor–solid two-phase asymmetric
hydroformylation.8 Using a fixed bed, substrates with
high vapor pressure were successfully converted to the
corresponding aldehydes with high % ee’s (Fig. 2).
Asymmetric hydroformylation of (Z)-2-butene was also
examined with the new ligand 1e both with the disper-
sion in benzene solution (A) and with the fixed bed sys-
tem (B) (Table 2). As shown, the enantioselectivities
with 1e (entries 1 and 5) were higher that that with 1c
(entries 2 and 6), but the difference is almost negligible
compared to the significant improvement with 1b (entry 3)
from 1a (entry 4). With 1e, the turnover frequencies
were slightly lower than those with 1c.
8. Nozaki, K.; Shibahara, F.; Hiyama, T. Chem. Lett. 2000, 694.