Continuous flow system with a polymer-supported dirhodium(II) catalyst: Application to enantioselective carbonyl ylide cycloaddition reactions

Article abstract of DOI:10.1002/chem.201102733

The immobilization of [Rh₂(S-PTTL)(S-TCPTTL)₃] (PTTL = N-phthaloyl-tert-leucinate, TCPTTL=N-tetrachlorophthaloyl-tert-leucinate) has been accomplished by copolymerization of the Rh^II-complex-containing monomer with 2-(trif

Full text of DOI:10.1002/chem.201102733

DOI: 10.1002/chem.201102733
Continuous Flow System with a Polymer-Supported Dirhodium(II) Catalyst:
Application to Enantioselective Carbonyl Ylide Cycloaddition Reactions
Koji Takeda, Tadashi Oohara, Naoyuki Shimada, Hisanori Nambu, and
Shunichi Hashimoto*[a]
Dedicated to Professor Albert Padwa
Over the past two decades,
the exceptional power of chiral
dirhodium(II) carboxylate and
carboxamidate catalysts has
been demonstrated in a diverse
array of enantioselective metal
carbene transformations of di-
azocarbonyl compounds, in-
À
cluding cyclopropanation, C H
insertion, and rearrangement
or cycloaddition via ylide gen-
eration.[1] Although such reac-
tions frequently proceed in
high yield and with high levels
of asymmetric induction, their
practical applications in phar-
maceutical production were
often hindered due to high
costs of both rhodium[2] and
chiral ligands as well as the dif-
ficulty in catalyst recovery and
recycling. To address this issue,
several approaches toward im-
Scheme 1. Immobilization of chiral dirhodium(II) complex.
mobilization[3] of chiral dirhodium(II) complexes have been
explored, including covalent attachment to soluble[4] and in-
soluble supports,[5–8] use of biphasic systems,[9] and novel
noncovalent immobilization using the combination of ligand
coordination and encapsulation.[10] However, further im-
provements in catalyst activity, selectivity, recyclability, and
rhodium leaching are still needed.[11]
Continuous flow reactors have found use as powerful syn-
thetic tools enabling operational flexibility, reduced reaction
times and system automation, resulting in a technique that
is suitable for a high-throughput synthesis.[12] The applica-
tion of heterogeneous catalysts in continuous flow mode
offers advantages of suppressing the mechanical degradation
of catalyst supports as well as easy catalyst separation and
large-scale production.[13] Despite these potential benefits,[14]
to the best of our knowledge, there is no immobilized dirho-
dium(II) catalyst available for a continuous flow process.[15]
Recently, we reported an effective immobilization of
[Rh2ACTHGNUTERNNUG
(S-PTTL)4] (1a)[16,17] (Figure 1) composed of four inde-
pendent chiral ligands,[18,19] which relied on preparation of a
dirhodium(II)-complex-containing monomer 2a followed by
copolymerization with styrene (4a) and 1,6-bis(4-vinylben-
zyloxy)hexane
(5)
as
a
flexible
cross-linker
(Scheme 1).[8,20–22] The polymer-supported complex 6 with no
[a] Dr. K. Takeda, T. Oohara, Dr. N. Shimada, Dr. H. Nambu,
Prof. Dr. S. Hashimoto
unreacted linkers or free ligands[23] catalyzed asymmetric C
À
Faculty of Pharmaceutical Sciences
Hokkaido University
Sapporo 060-0812 (Japan)
Fax : (+81)11-706-4981
E-mail: hsmt@pharm.hokudai.ac.jp
H insertions even at À788C with high enantioselectivities
similar to those found with homogeneous 1a and could be
used for up to 100 sequential applications with a low leach-
ing level (0.28 ppm),[8] a feature that results from the combi-
nation of good swelling properties and uniform dispersion of
catalytic sites in the polymer matrix.[24] Given that the com-
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201102733.
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Chem. Eur. J. 2011, 17, 13992 – 13998

COMMUNICATION
Table 1. Enantioselective intermolecular cycloaddition of 2-diazo-3,6-di-
plex 6 was a remarkably effective catalyst for intramolecular
ketoester 7 with styrene (4a) catalyzed by dirhodium(II) complexes.[a]
À
C H insertion reactions, we were intrigued by the applica-
bility of a polymer-supported dirhodium(II) complex to in-
termolecular metal–carbene transformations. We previously
reported that [Rh2ACHTUNGTRENNUNG
(S-TCPTTL)4] (1b),[25–27] the chlorinated
analogue of 1a, is an exceptionally effective catalyst for
enantioselective tandem carbonyl ylide formation-1,3-dipo-
lar cycloaddition reactions of 2-diazo-3,6-diketoesters with
arylacetylene, alkoxyacetylene, and styrene dipolarophiles,
in which high levels of asymmetric induction (up to 99% ee)
as well as perfect exo diastereoselectivity for styrenes were
achieved.[26a,28,29] Herein, we report the immobilization of a
chiral chlorinated dirhodium(II) complex and its use for
enantioselective carbonyl ylide cycloaddition reactions
under continuous flow conditions.
Entry Catalyst
T
Yield
7
ee of 8
[8C] [%][b]
[%][d]
1[e]
2
3
4
5
N
G
23
85
80
50
88
86
36
>99:1
>99:1
95:5
>99:1
>99:1
99
99
90
95
93
ACHTUNGTRENNUNG
23
60
ACHTUNGTRENNUNG
6
73:27 52
[a] All reactions were carried out as follows: a solution of 7 (61 mg,
0.2 mmol) and 4a (3 equiv) in CF3C6H5 (1 mL) was added over 1 h to a
solution of RhII catalyst (1 mol%) in CF3C6H5 (1 mL). [b] Combined
yield of 8 and 9. [c] Determined by 1H NMR analysis of the crude prod-
uct. [d] Determined by HPLC. [e] See ref. [26a].
On the basis of our previous work, we considered that
[Rh2ACHTUNGTRENNUNG(S-TCPTTL)4] (1b) could be immobilized by copoly-
merization of dirhodium(II)-complex-containing monomer
2b, the chlorinated analogue of 2a. However, all attempts
to synthesize monomer 2b were unsuccessful. At this point,
we turned our attention to the catalytic performance of a
also proposed that [Rh
benefit from halogen-bonding interactions,[35] might be even
more rigid in solution than [Rh2A
(S-PTTL)4] (1a).[33] Al-
though one of the four ligands in [Rh2A(S-PTTL)(S-
TCPTTL)3] (3) is not chlorinated, variable temperature
13C NMR experiments in C6D6 carried out on 3 indicated
the rigid nature of such a chlorinated complex in solution as
demonstrated by Charette[36] (see the Supporting Informa-
tion for details). This observation, together with the great
catalytic performance of 3, had important implications for
the design of a polymer-supported catalyst based on copoly-
merization of monomer 2c.
2ACHTUNGRTEN(NUNG S-TCPTTL)4] (1b), which could
mixed dirhodium(II) tetracarboxylate,[30] [Rh
2ACTHNUTRGENNU(G S-PTTL)ACHTUNTGREN(NUGN S-
TCPTTL)3] (3), as a surrogate for 2b. As a model reaction,
intermolecular cycloaddition of carbonyl ylide derived from
2-diazo-3,6-diketoester 7 with styrene (4a) in a,a,a-trifluor-
otoluene (CF3C6H5) was examined (Table 1).[26a] The reac-
tion using 1 mol% of catalyst 3 afforded cycloadduct 8[31] in
high yield and asymmetric induction (99% ee) with perfect
CHTUNGTRENNUNG
C
ACHTUNGTRENNUNG
exo diastereoselectivity as found with [Rh2ACTHUNTRGNEU(GN S-TCPTTL)4]
(1b) (entries 1 and 2). Examination of the temperature pro-
file demonstrated that catalysis with 1b or 3 performed well
even at 608C (entries 4 and 5), in stark contrast to that with
[Rh
Charette[33] independently determined the X-ray crystal
structure of [Rh2A(S-PTTL)4] (1a) and other phthalimido-de-
C
Dirhodium(II)-complex-containing monomer 2c was pre-
pared according to the procedure developed for 2a
C
(Scheme 2).[8] Treatment of [Rh
2ACHTNGURETNNU(G S-TCPTTL)4] (1b) with N-
rived catalysts and showed that the four phthalimido groups
are projected on the same face of the catalyst, thus provid-
ing a chiral crown conformation.[34] Charette and co-workers
4-hydroxyphthaloyl-(S)-tert-leucine (10) in refluxing chloro-
benzene gave an equilibrium mixture of dirhodium(II) com-
plex 11 and 1b, which were readily separable by column
chromatography on silica gel.
The desired complex 11 was
isolated in 39% yield; 1b was
recovered in 50% yield.
A
three-cycle sequence of ligand-
exchange reaction of recovered
1b and 10 furnished complex
11 in 72% overall yield. O-Al-
kylation of complex 11 with 6-
(4-vinylbenzyloxy)iodohexane
(12) afforded monomer 2c in
94% yield.
At the outset, we performed
AIBN-initiated and acacia
gum-stabilized suspension co-
polymerization[37] of 2c with
styrene (4a) and 5 as a cross-
linker to give a polymer-sup-
ported complex 13a in 80%
Figure 1. Chiral dirhodium(II) catalysts. PTTL=N-phthaloyl-tert-leucinate, TCPTTL=N-tetrachlorophthaloyl-
tert-leucinate.
Chem. Eur. J. 2011, 17, 13992 – 13998
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13993

S. Hashimoto et al.
yl moieties to polymer sup-
ports could be used as an alter-
native methodology. Thus, we
conducted
copolymerization
with 4- or 2-trifluoromethyl-
substituted styrenes 4b and 4c
to provide resins 13b and 13c
in 88 and 83% yield, respec-
tively (entries 2 and 3).[39]
Pleasingly, both resins 13b and
13c showed a significant in-
crease of swelling in CF3C6H5
(13b,
10.7 mLgÀ1
;
13c,
11.8 mLgÀ1). Toluene was
a
better swelling solvent than
CF3C6H5 for 13a, whereas
Scheme 2. Preparation of dirhodium(II)-complex-containing monomer 2c.
CF3C6H5 was a better solvating
medium for 13b, although both
yield (Table 2, entry 1). The swelling volumes of resin 13a
were 7.8 mLgÀ1 in CF3C6H5 and 11.3 mLgÀ1 in toluene (vol-
umes were measured in syringes equipped with a filter; see
the Supporting Information for details). An important gen-
eral consideration for successful heterogeneous catalysis is
swelling of the resin in the reaction medium.[24] In an at-
tempt to achieve good swelling of 13a in CF3C6H5, the opti-
mal solvent for enantioselective carbonyl ylide cycloaddition
reaction,[38] we considered that attachment of trifluorometh-
were exceptionally effective swelling solvents for 13c. Ele-
mental analysis of 13a–c indicated that incorporation of dir-
hodium(II) complex in resin was close to the theoretical
value in all cases, as also confirmed by inductively coupled
plasma atomic emission spectroscopy (ICP-AES) analysis.
The polymer-supported complexes 13a–c were evaluated
for their catalytic performance in the reaction of diazodike-
toester 7 with styrene (4a) (Table 3). The reactions with
Table 3. Enantioselective intermolecular cycloaddition of 2-diazo-3,6-di-
ketoester 7 with styrene (4a) catalyzed by polymer-supported dirho-
dium(II) complexes 13a–c.[a]
Table 2. Preparation of polymer-supported complexes 13.
Entry
Catalyst
Yield [%][b]
ee [%]
1
2
3
13a
13b
13c
56
64
69
99
99
99
[a] All reactions were carried out as follows: a solution of 7 (61 mg,
0.2 mmol) and 4a (3 equiv) in CF3C6H5 (1 mL) was added over 3 h to a
solution of RhII catalyst (3 mol%) in CF3C6H5 (1 mL). [b] Isolated yield.
[c] Determined by HPLC.
three types of complexes (3 mol%) resulted in high enantio-
selectivity (99% ee) and perfect exo diastereoselectivity as
found with [Rh2ACHTUNRGTENNUG(S-PTTL)HCATUNGTERN(NUGN S-TCPTTL)3] (3), though the
yields of cycloadduct 8 were diminished to 56, 64 and 69%,
respectively (entries 1–3). These results indicate that the
present method of immobilization had very little effect on
the chiral environment around the immobilized catalyst.
This is the first example of carbonyl ylide cycloaddition with
heterogeneous dirhodium(II) complexes. The reaction using
13a was less efficient as reflected by the lower yield; this
suggests that swelling of trifluoromethyl-substituted poly-
mers 13b and 13c in CF3C6H5 is important for the catalytic
performance.
We next explored the possibility of performing the reac-
tion with catalysts 13b and 13c under continuous flow con-
ditions, with particular emphasis on improvement in product
yield and reduction in reaction times. The principal design
of our flow reactor featured the need to make optimum use
Entry Polymer Yield Loading
Volume
[mLgÀ1
Dry in CF3C6H5 in toluene
[%]
A
]
E
]
1
2
3
13a
13b
13c
80
88
83
0.24
0.18
0.18
1.7
1.9
1.9
7.8
10.7
11.8
11.3
8.0
14.7
AIBN=2,2’-azobisisobutyronitrile.
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Chem. Eur. J. 2011, 17, 13992 – 13998

Continuous Flow System with a Polymer-Supported Dirhodium(II) Catalyst
COMMUNICATION
Another illustration of prac-
tical advantages of the flow re-
actor packed with 13c was pre-
sented in the reaction of diazo-
diketoester 14 and phenylace-
tylene
(Table 5), in which the use of 1
mol% of [Rh2A(S-TCPTTL)4]
(15)
in
CF3C6H5
CTHUNGTRENNUNG
(1b) produced cycloadduct
16[43] in 82% yield with 97%
ee (entry 1).[26a] When the
amount of 1b was reduced
from the standard
1
to
0.1 mol%, 27 and 6% drops in
yield and enantioselectivity, re-
Figure 2. Schematic set up of the flow reactor.
Table 5. Enantioselective intermolecular cycloaddition of 2-diazo-3,6-di-
ketoester 14 with phenylacetylene (15) under continuous flow conditions.
of the cavity for operating without any pressurization.
Toward this goal, a reaction vessel (80 mm in length and
11 mm in diameter)[13l] equipped with a filter was packed by
injecting a slurry of catalyst (0.006 mmol of RhII catalyst)
and sea sand (4 g)[40] in CF3C6H5 (Figure 2). A solution of di-
azodiketoester 7 (0.2m) and styrene (4a) (3 equiv) in
CF3C6H5 was passed through the flow reactor (0.34 mLhÀ1,
3 h, 3 mol% of catalyst with respect to 7) using a syringe
pump (Table 4, entries 1 and 2). The continuous flow experi-
ments gave higher yields than the reaction under batch con-
ditions (cf. Table 3). A greatly improved yield of 80% was
obtained when the catalyst 13c was used. It seems likely
that the polymer matrix of 13c has a high affinity for reac-
tants as 13c exhibited superior swelling characteristics not
Entry
Catalyst
[mol%]
t
Yield
[%][a]
ee
G
[h]
[%][b]
1[c]
2
1b: 1
1b: 0.1
13c: 1
13c: 0.1
13c: 0.0067
1
1
0.1
1
15
82
55
75
74
78
97
91
98
97
97
3[d]
4[d]
5[d]
[a] Isolated yield. [b] Determined by HPLC. [c] See ref. [26a]. [d] The re-
action was carried out as follows: a solution of 14 (0.2m) and 15 (3 equiv)
in CF3C6H5 was pumped through the flow reactor at a flow rate of
only in CF3C6H5 but also in toluene (cf. Table 2).[41]
A
30 mLhÀ1
.
survey of flow rates revealed that full conversion with no
apparent loss of product yield could be achieved at flow
rates of up to 0.5 mLhÀ1, whereby the reaction time was
substantially reduced (entry 3). This result can be attributed
to the close contact of the catalyst with the reactants and
the high local concentration of the catalyst.[42] The leaching
level of rhodium atom was examined by ICP-mass spectrom-
etry. The reaction mixture contained only 2.1 ppm rhodium,
which corresponds to 0.013% of the initial catalyst charge.
Indeed, the flow reactor could be operated under a steady
state for a period of 60 h (entry 4). It is noteworthy that the
extrusion of nitrogen gas from diazodiketoester had no dele-
terious effect on this continuous flow process.
spectively, were observed (entry 2). In stark contrast, the
flow reactor (0.1 mol% of catalyst with respect to 14) pro-
vided 16 with virtually no drop in product yield or enantio-
selectivity at a flow rate of 30 mLhÀ1 (entries 3 and 4). To
demonstrate the preparative utility of this process, the reac-
tion was conducted on a 90 mmol scale (22 g of 14) with the
flow reactor (32 mg of 13c) to afford 22 g (78% yield) of 16
in 97% ee, in which turnover numbers as high as 11700
were achieved (entry 5). These results demonstrate that op-
timized reaction parameters developed on a small scale in
the flow reactor could be transferred directly to large-scale
production without the need for substantial further optimi-
zation.
Table 4. Enantioselective intermolecular cycloaddition of 2-diazo-3,6-di-
ketoester 7 with styrene (4a) under continuous flow conditions.[a]
Entry
Catalyst
[mol%]
Flow rate
[mLhÀ1
t
Yield
[%][b]
ee
In conclusion, we have accomplished the immobilization
of [Rh2ACHTUNTRGENNUG(S-PTTL)ACHTUGNTNER(NUGN S-TCPTTL)3] (3) by copolymerization of
G
G
]
[h]
[%][c]
1
2
3
4
13b: 3
13c: 3
13c: 3
13c: 0.1
0.34
0.34
0.5
3
3
2
71
80
80
78
99
99
99
99
dirhodium(II)-complex-containing monomer 2c with styr-
enes 4 and the flexible cross-linker 5. The polymer-support-
ed dirhodium(II) complex 13c derived from 2-(trifluorome-
thyl)styrene (4c) as a comonomer was successfully applied
in tandem carbonyl ylide formation-cycloaddition reactions
of 2-diazo-3,6-diketoesters with styrene (4a) and phenylace-
tylene (15) dipolarophiles in CF3C6H5 under continuous
0.5
60
[a] All reactions were carried out as follows: a solution of 7 (0.2m) and
4a (3 equiv) in CF3C6H5 was pumped through the flow reactor using a sy-
ringe pump at the indicated flow rate. [b] Isolated yield. [c] Determined
by HPLC.
Chem. Eur. J. 2011, 17, 13992 – 13998
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
13995

S. Hashimoto et al.
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metric induction (up to 99% ee) similar to those found with
[Rh2ACHTUNGTRENNUNG(S-TCPTTL)4] (1b) were achieved. The efficiency of
13c is considered to be due to the combination of excellent
swelling in CF3C6H5 and good accessibility of the soluble re-
actants to the catalytic sites in the polymer matrix. The
robust nature of the flow reactor was demonstrated by the
retention of full activity and enantioselectivity for a number
of hours (up to 60 h) with a low leaching level (2.1 ppm).
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turnover numbers (up to 11700) relative to the homogene-
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first example of a continuous flow system with heterogene-
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continuous flow method to other metal carbene transforma-
tions of diazocarbonyl compounds is currently in progress.
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Typical procedure for enantioselective carbonyl ylide cycloaddition under
continuous flow conditions (Table 5, entry 5): A solution of diazodike-
toester 14 (21.6 g, 90 mmol, 0.2m) and phenylacetylene (15) (27.6 g,
270 mmol, 3 equiv) in CF3C6H5 was passed through the flow reactor
packed with polymer-supported dirhodium(II) complex 13c (32 mg,
0.006 mmol of RhII catalyst) and sea sand (4 g) at 30 mLhÀ1 for 15 h.
After complete addition, the flow reactor was washed with an additional
CF3C6H5 (2 mL). After evaporation of the solvent in vacuo, the residue
was purified by column chromatography on silica gel (6:1 hexane/
EtOAc) to provide cycloadduct 16 (22.0 g, 78%) as a white solid. The
enantiomeric excess of 16 was determined to be 97% by HPLC with a
Chiralpak OD column [9:1 hexane/iPrOH; flow: 1.0 mLminÀ1; retention
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Acknowledgements
This research was supported by a Grant-in Aid for Scientific Research on
Innovative Areas “Organic Synthesis Based on Reaction Integration. De-
velopment of New Methods and Creation of New Substances” (No. 2105)
from the Ministry of Education, Culture, Sports, Science and Technology,
Japan. We thank S. Oka and M. Kiuchi from The Center For Instrumen-
tal Analysis at Hokkaido University for technical assistance with mass
spectrometry and elemental analysis.
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Keywords: asymmetric catalysis · continuous flow system ·
heterogeneous catalysis · immobilization · rhodium
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Continuous Flow System with a Polymer-Supported Dirhodium(II) Catalyst
COMMUNICATION
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À
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À
fluence stereoselectivity in cyclopropanation and C H insertion re-
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À
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Chem. Eur. J. 2011, 17, 13992 – 13998
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www.chemeurj.org
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S. Hashimoto et al.
[40] A major issue encountered in packing flow reactor with polymer-
supported catalysts is the pressure drop across the reactor caused by
the swelling of packing material. Sea sand does not swell in
CF3C6H5, and the use of sea sand thus allows swelling of polymer
beads and maintenance of acceptable flow characteristics in the
column, see ref. [13d].
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[43] The preferred absolute stereochemistry of 16 was not determined.
[41] The swelling volumes of resin 13b and 13c were 7.6 and 13.8 mLgÀ1
respectively, in styrene (4a).
,
Received: September 1, 2011
Published online: November 17, 2011
13998
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Chem. Eur. J. 2011, 17, 13992 – 13998