Toward efficient asymmetric carbon-carbon bond formation: Continuous flow with chiral heterogeneous catalysts

Article abstract of DOI:10.1002/chem.201202896

A chiral Ca catalyst based on CaCl₂ with a chiral ligand was developed and applied to the asymmetric 1,4-addition of 1,3-dicarbonyl compounds to nitroalkenes as a model system. To address product inhibition issues, the Ca catalyst was applied t

Full text of DOI:10.1002/chem.201202896

COMMUNICATION
DOI: 10.1002/chem.201202896
Toward Efficient Asymmetric Carbon–Carbon Bond Formation: Continuous
Flow with Chiral Heterogeneous Catalysts
Tetsu Tsubogo, Yasuhiro Yamashita, and Shu Kobayashi*[a]
¯
Preparation of optically active compounds, which are
often observed in pharmaceuticals, liquid crystals, agrochem-
Table 1. 1,4-Addition reaction catalyzed by Pybox-Ca(OR)2 and air-stable
Pybox-CaCl2.
icals, etc., is among the most important tasks in synthetic or-
ganic chemistry.[1] Catalytic asymmetric synthesis provides
one of the most efficient methods for their preparation, be-
cause desired optically active compounds are obtained by
using small amounts of chiral sources.[2] Accordingly, while
many chiral catalysts for asymmetric reactions have been
developed in the past two decades, the efficiency of the cat-
alysts has also been intensively pursued because it is a key
factor for applications in industry. For example, turnover
number (TON) is an index to evaluate efficiency of cata-
Entry
Ca
Et3N
x
Temp
[8C]
Yield
[%]
ee
[%]
TON
lysts. Whereas high TONs have been attained in some reac-
tions such as asymmetric hydrogenation,[3] TONs of asym-
1[a]
2[a]
3[b]
4[b]
CaN
0
0
5
5
10
10
5
0
0
0
À20
84
94
90
92
91
91
87
94
8.4
9.4
18.0
18.4
À
metric C C bond forming reactions, which construct basic
Ca(OAr)2
T
carbon skeletons of target molecules, are generally lower.[4]
To achieve high TONs, not only are fast catalytic cycles re-
quired, but also issues of catalyst destruction and product in-
hibition have to be addressed. To prevent the catalyst de-
struction, development of robust catalysts that are tolerant
of both water and oxygen is required. As for product inhibi-
tion, we thought that the issue might be solved by using con-
tinuous flow with chiral heterogeneous catalysts, if the inhib-
ition occurred under coordination equilibrium. Herein, we
describe the development of robust catalysts and their use
in continuous flow systems using chiral calcium (Ca)-cata-
lyzed asymmetric 1,4-addition of malonates to nitroalkenes
as examples.
CaCl2·2H2O
CaCl2·2H2O
5
[a] Reaction was conducted under Ar. [b] Reaction was conducted under
air. Ar=p-MeOC6H4
tries 1, 2).[7] The Ca(OR)2 catalysts were relatively unstable
under air (moisture) because of hydrolysis. In addition,
product inhibition occurred in this asymmetric 1,4-addition
because starting materials and products have 1,3-dicarbonyl
and nitro functional groups.[8] To address these issues, we
first focused on calcium chloride (CaCl2). CaCl2 is a
common and abundant salt; it has low toxicity and is mois-
ture tolerant and inexpensive. It is familiar as a desiccant, as
a deicing and freezing point depressing agent, and as an ad-
ditive to food and medicines. Although CaCl2 is also a very
common compound in laboratories and is employed as a
drying agent for liquid or gas materials in desiccators or
drying tubes, use of CaCl2 as a reagent, in particular as a
catalyst in organic synthesis, is very rare.[9] After screening
several reaction conditions, it was found that CaCl2 with an
amine worked quite well for the reaction of methyl malo-
nate (1a) with b-trans-nitrostyrene (2a) under air. At this
stage, TONs were increased to around 18 (Table 1, entries 3,
4). It is noted that the CaCl2-Pybox complex is more stable
than the Ca(OR)2 catalysts and can be handled in air. Fur-
thermore, this is the first example of a CaCl2 complex with a
chiral ligand being successfully used as a chiral catalyst.
Next, we examined an application of the chiral CaCl2
system to continuous flow with a chiral heterogeneous cata-
lyst to address the product inhibition issue and to further in-
Asymmetric 1,4-addition of 1,3-dicarbonyl compounds to
nitroalkenes is one of the most important methods for the
preparation of chiral g-nitro compounds, which can be con-
verted to chiral g-amino acids and other derivatives.[5] We
have recently reported chiral calcium alkoxide (phenoxide)
(Ca(OR)2)-pyridinebisoxazoline (Pybox) complex-catalyzed
asymmetric 1,4-addition reactions of 1,3-dicarbonyl com-
pounds with nitroalkenes to afford the desired adducts in
high yields with high enantioselectivities (ees).[6] In these re-
actions, TONs were around nine in most cases (Table 1, en-
[a] Dr. T. Tsubogo, Dr. Y. Yamashita, Prof. Dr. S. Kobayashi
Department of Chemistry, School of Science
The University of Tokyo
7-3-1 Hongo, Bunkyo-ku, Tokyo (113-0033) Japan
Fax : (+81)3-5684-0634
E-mail: shu_kobayashi@chem.s.u-tokyo.ac.jp
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201202896.
Chem. Eur. J. 2012, 00, 0 – 0
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Table 2. 1,4-Addition reaction catalyzed by PS-Pybox-calcium.
crease the TON. Continuous flow systems have several ad-
vantages over batch systems in terms of space, energy and
time savings, and facility and safety in large-scale synthe-
sis.[10] Furthermore, in continuous flow with a heterogeneous
catalyst, a product is removed from a catalyst if a product–
catalyst interaction occurs under coordination equilibrium;
that is, inhibition of catalytic turnover by a product may be
avoided to attain a higher TON compared with that in a
batch system. From this point of view, continuous flow with
chiral heterogeneous catalysts is a promising method to real-
ize high performance of chiral catalysts; indeed, several in-
vestigations have been conducted for over 10 years in labo-
ratory-scale experiments,[11] successful examples are limited.
In chiral metal complex-catalyzed continuous flow reactions,
a serious problem, especially in pharmaceuticals, is the
leaching of precious metals, leading not only to loss of ex-
pensive metals but also to contamination of metals in prod-
ucts.[12] Because of this, use of ubiquitous and nontoxic
metals such as Ca is highly de-
Entry
Ca
Ca
Et3N
[mol%]
Yield
[%]
ee
[%]
TON
U
1
2
(OiPr)2
0
5
88
91
74
91
17.6
18.2
CaCl2·2H2O
sirable.[13]
Because chiral heterogeneous
catalysts are needed for the
flow systems, we then synthe-
sized polymer-supported Pybox
(PS-Pybox, loading of Pybox:
0.72–0.85 mmolgÀ1) according
to conventional transforma-
tions.[14] PS-Pybox was first
tested in the reaction of 1a
with 2a in
a batch reactor.
When Ca(OiPr)2 was used, the
ACHTUNGTRENNUNG
desired product was obtained in
high yield with good enantiose-
lectivity (88%, 74% ee, Table 2,
entry 1). In addition, the de-
sired 1,4-addition reaction pro-
Figure 1. 1,4-Addition reaction using a flow reactor.
ceeded smoothly using 5 mol% of CaCl2·2H2O with PS-
Pybox (5 mol%) and triethylamine (5 mol%) to afford the
product in higher yield with higher enantioselectivity
(Table 2, entry 2).
Table 3. 1,4-Addition reaction using a flow reactor.
Encouraged by these results, we then tried the 1,4-addi-
tion reaction using a flow reactor (Figure 1).[15] Two glass
columns (f 1.0 cm ꢁ 10 cm)[16] were filled with a mixed cata-
lyst powder, which contained PS-Pybox (750 mg, loading of
Pybox: 0.72–0.85 mmolgÀ1), CaCl2·2H2O (375 mg), and
Celite (1.4 g) in each column. A precolumn (f 0.5 cm x
5.0 cm) containing activated MS 4 A (500 mg) was attached
to dry the substrate solution.[17] The substrate toluene solu-
tion (1a: 0.25m, 2a: 0.30m (1.2 equiv), Et3N: 0.005m
(0.02 equiv)) was passed through the system. Initially, the
flow rate was 50 mLminÀ1 (3 mLhÀ1), and it was found that
Entry
Flow rate
[mLminÀ1
Temp
[8C]
Duration of
experiment
[h]
Yield
[%]
ee
[%]
G
]
1
2
3
4
50
50
50
100
RT
0
13
13
13
61
95–96
93–96
69–71
91–93
85–87
92–93
94
À20
0
92–93
a
lower temperature showed better enantioselectivity
(Table 3, entries 1–3), although the yield was moderate at
À208C. To increase the flow rate, we chose 08C, and con-
ducted this flow reaction at the rate of 100 mLminÀ1
(6 mLhÀ1) at 08C (Table 3, entry 4). After stabilizing the
flow system (12 h), fractions each corresponding to 30 min
of flow (theoretically 0.75 mmol of the product included in
each fraction) were collected; each fraction was quenched
with solid NH4Cl and diluted with dichloromethane. After
filtration, the filtrate was evaporated to remove the solvents
under reduced pressure, and the crude product was purified
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Asymmetric Carbon–Carbon Bond Formation
COMMUNICATION
by preparative TLC. We monitored 12 fractions during the
61 h-continuous flow. In each fraction, the desired 1,4-addi-
tion product was obtained in high yield (av. 92.4%) with
high enantioselectivity (av. 92.8% ee), and minimal deacti-
vation of the flow system was observed during 12–61 h.
Under these conditions, we obtained a total amount of
67.9 mmol of the product and the TON was 62.6. Then, we
further prolonged the reaction time. During analysis of 11
fractions, we found no deactivation of the catalyst after
216 h. The product was obtained in high yield with high
enantioselectivity (av. 95.5% yield, 92.0% ee) during 204 h
(8.5 days). The total amount of the product was 291.4 mmol
and the TON reached 228 (Table 4). When we stopped the
system after 216 h, the catalyst was not deactivated (the cat-
alyst was still “living”). Furthermore, when the flow rate
was increased to 200 mLminÀ1 (12 mLhÀ1), high yield and
high enantioselectivity were still obtained (86–90%, 91%
ee).
Table 4. Long-period experiment.
Scheme 1. Substrate scope of the 1,4-addition reactions using a flow reac-
tor. [a] Malonate (0.1m) was used. [b] Malonate (0.5m) was used. Flow
rate was 50 mLminÀ1. Yields were determined by 1H NMR spectroscopy
using an internal standard.
Time [h]
Yield [%]
ee [%]
Time [h]
Yield [%]
ee [%]
12–12.5
24–24.5
36–36.5
60–60.5
84–84.5
88
91
97
98
97
93
93
92
92
92
92
132–132.5
156–156.5
180–180.5
204–204.5
216–216.5
98
96
97
95
95
92
92
92
91
91
first successful example of asymmetric 1,4-addition reactions
of 1,3-dicarbonyl compounds with nitroalkenes using a con-
tinuous flow system and a chiral heterogeneous catalyst.
In summary, we have developed an asymmetric 1,4-addi-
tion of 1,3-dicarbonyl compounds to nitroalkenes affording
the synthetically useful g-nitro carbonyl compounds in high
yields with high enantioselectivities by using a chiral Ca cat-
alyst based on CaCl2 with a chiral ligand that is tolerant of
moisture and can be handled in air. The catalyst is more
robust than the previous Ca(OR)2 catalysts, and the TON of
the catalyst was improved from about 9 to about 18. More-
over, the catalyst was applied to continuous flow with a
chiral heterogeneous catalyst to solve the issue of product
inhibition. A polymer-supported Pybox was synthesized and
was successfully used in a flow system, which worked well
for 8.5 days without loss of activity. The TON reached 228,
the catalyst was still “living,” and wide substrate scope of
this continuous flow system was shown. Thus, it has been
demonstrated that development of robust catalysts and con-
tinuous flow with chiral heterogeneous catalysts is effective
in increasing TONs of the catalyst. Further investigations to
108–108.5 98
Finally, the substrate scope of the 1,4-addition reaction
using the continuous flow system was surveyed. Several sub-
stituted nitroalkenes bearing either electron-withdrawing or
electron-donating groups and heteroaromatic and aliphatic
nitroalkenes were examined. The collection, isolation, and
analysis were conducted the same as in the previous experi-
ments. We monitored the reactor from 12 h to 18 h for each
substrate (Scheme 1). For nitroalkenes with p-, m-tolyl, and
p-anisyl groups, high yields and high enantioselectivities
were obtained (3b, 3c, 3d). In particular, the m-tolyl sub-
strate gave the highest enantioselectivity (3c). p-Bromo-
and p-fluoro-substituted aromatic nitroalkenes also reacted
smoothly to afford the desired compounds (3e, 3 f) in high
yields with high enantioselectivities. Nitroalkenes bearing
heteroaromatics were also good substrates for this flow
system (3g, 3h). For a nonaromatic nitroalkene, the yield
was lower while good enantioselectivity was obtained (3i).
We also examined a nonsubstituted b-ketoester, which af-
forded the desired product 3j in high yield with high enan-
tioselectivity. It should also be noted that wide substrate
generality was confirmed in this system, and that this is the
À
develop more efficient chiral catalysts for asymmetric C C
bond forming reactions are now in progress.
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S. Kobayashi et al.
Chem. Int. Ed. 2005, 44, 6367; g) M. Terada, H. Ube, Y. Yaguchi, J.
Am. Chem. Soc. 2006, 128, 1454; h) S. L. Poe, M. Kobaslija, D. T.
McQuade, J. Am. Chem. Soc. 2007, 129, 9216; i) Q. Zhu, H. Huang,
D. Shi, Z. Shen, C. Xia, Org. Lett. 2009, 11, 4536; j) D. Almasi,
D. A. Alonso, E. Gomez-Bengoa, C. Najera, J. Org. Chem. 2009, 74,
6163; k) L. Zhang, M.-M. Lee, S.-M. Lee, J. Lee, M. Cheng, B.-S.
Jeong, H. Park, S. Jew, Adv. Synth. Catal. 2009, 351, 3063; l) H. Y.
Bae, S. Some, J. S. Oh, Y. S. Leea, C. E. Song, Chem. Commun.
2011, 47, 9621; m) K. Wilckens, M.-A. Duhs, D. Lentz, C. Czekelius,
Eur. J. Org. Chem. 2011, 5441; n) F. Li, Y.-Z. Li, Z.-S. Jia, M.-H. Xu,
P. Tian, G.-Q. Lin, Tetrahedron 2011, 67, 10186; o) O. Gleeson, G.-L.
Davies, A. Peschiulli, R. Tekoriute, Y. K. Gun’ko, S. J. Connon, Org.
Biomol. Chem. 2011, 9, 7929; p) Y.-F. Wang, R.-X. Chen, K. Wang,
B.-B. Zhang, Z.-B. Lib, D.-Q. Xu, Green Chem. 2012, 14, 893; q) S.
Mortezaei, N. R. Catarineu, J. W. Canary, J. Am. Chem. Soc. 2012,
134, 8054.
Experimental Section
Catalytic asymmetric 1,4-addition reaction of malonate with trans-b-ni-
trostyrene in a flow system: Two glass columns (f 1.0 cm ꢁ 10 cm) were
used. Celite (1.4 g), calcium chloride dihydrate (375 mg), and polymer-
supported Pybox (0.85 mmolgÀ1
, 750 mg) were charged into each
column. For drying substrates and Et3N solution, a precolumn (f 0.5 cm
ꢁ 5 cm), which contained dried activated MS 4 A (500 mg), was connect-
ed between an HPLC pump and the reaction columns. Malonic acid
methyl ester (1a, 0.25 molLÀ1), trans-b-nitroalkene (2a, 0.30 molLÀ1) and
Et3N (0.005 molLÀ1) in toluene was passed through the reaction columns
(flow rate: 100 mLminÀ1) at 08C. After 12 h, several fractions (Table 4)
were collected during flow of the substrate solution, which contained the-
oretically 0.75 mmol of the product in each fraction. The solid NH4Cl
was added to the fraction and the mixture was diluted with CH2Cl2 and
was filtered. The obtained solution was evaporated under vacuum and
purified by preparative TLC. The enantioselectivity of the obtained prod-
uct was determined by HPLC analysis.
[6] T. Tsubogo, Y. Yamashita, S. Kobayashi, Angew. Chem. 2009, 121,
9281; Angew. Chem. Int. Ed. 2009, 48, 9117.
[7] The reaction was also conducted in the presence of 1.0 mol% of the
catalyst to obtain the product quantitatively with 94% ee after 18
days under strictly anhydrous conditions. However, other substrates
did not work under these conditions.
[8] To date, although there have been several reports on catalytic asym-
metric 1,4-addition reactions of malonates with nitroalkenes using
metal or non-metal catalysts, attaining high TONs, for example,
>100 is still difficult to achieve in this reaction except for some spe-
cial cases. For metal catalysis, Mg-,[5a] Ru-,[5d] Ni-,[5e,h,i,m] Cu-,[5q] and
Ca-based[6] catalysts have been developed, and TONs are 9–50 in
most cases (exception: Ru, one example, 99% yield using 1 mol%
catalyst for 2 days; Ni, one example, 87% yield using 0.1 mol% cat-
alyst for 6 days, and Ref. [7]). Other examples are based on chiral
organobase catalysis. While reactions proceeded relatively slowly
and relatively high loadings of catalysts are required in most cases,
the improvement of TONs by using a designed catalyst,[5h] a special
Acknowledgements
This work was partially supported by a Grant-in-Aid for Scientific Re-
search from the Japan Society for the Promotion of Science (JSPS), the
Global COE Program (Chemistry Innovation through Cooperation of
Science and Engineering), the University of Tokyo, and MEXT (Japan).
T. T. thanks the JSPS Research Fellowship for Young Scientists.
Keywords: asymmetric catalysis · calcium · environmental
chemistry · Michael addition · supported catalysts
medium (brine),[5l] or special conditions (solvent-free in
mill)[5p] has been challenged.
a ball
[9] Examples of reactions using CaCl2: a) K. Miura, T. Nakagawa, A.
Hosomi, J. Am. Chem. Soc. 2002, 124, 536; b) B. Kaboudin, H.
Zahedi, Chem. Lett. 2008, 37, 540; c) G. Kumaraswamy, M. N. V.
Sastry, N. Jena, K. R. Kumar, M. Vairamani, Tetrahedron: Asymme-
try 2003, 14, 3797.
[10] a) J. Gerhard, A. Kirschning, Chem. Eur. J. 2003, 9, 5708; b) A.
Kirschning, W. Solodenko, K. Mennecke, Chem. Eur. J. 2006, 12,
5972; c) M. Baumann, I. R. Baxendale, S. V. Ley, Mol. Diversity
2011, 15, 613; d) X. Y. Mak, P. Laurino, P. H. Seeberger, Beilstein J.
Org. Chem. 2009, 5, No. 19, doi:10.3762/bjoc.5.19; e) R. Yuryev, S.
Strompen, A. Liese, Beilstein J. Org. Chem. 2011, 7, 1449.
[1] a) J. M. Brown, S. G. Davies, Nature 1989, 342, 631; b) S. Kobayashi,
H. Ishitani, Chem. Rev. 1999, 99, 1069; c) V. Farina, J. T. Reeves,
C. H. Senanayake, J. J. Song, Chem. Rev. 2006, 106, 2734; d) C.
Nꢂjera, J. M. Sansano, Chem. Rev. 2007, 107, 4584; e) S. Kobayashi,
Y. Mori, J. S. Fossey, M. M. Salter, Chem. Rev. 2011, 111, 2626.
[2] a) Comprehensive Asymmetric Catalysis, (Eds.: E. N. Jacobsen, A.
Pfaltz, H. Yamamoto), Springer, Heidelberg, Germany, 1999; b) Cat-
alytic Asymmetric Synthesis 3rd Ed. (Ed.: I. Ojima), Wiley, Hobo-
ken, 2010.
[3] Examples of asymmetric reactions with high TONs: a) W. S.
Knowles, R. Noyori, Acc. Chem. Res. 2007, 40, 1238; b) N. Arai, T.
Ohkuma, Chem. Rec. 2012, 12, 284; c) H. Doucet, T. Ohkuma, K.
Murata, T. Yokozawa, M. Kozawa, E. Katayama, A. F. England, T.
Ikariya, R. Noyori, Angew. Chem. 1998, 110, 1792; Angew. Chem.
Int. Ed. 1998, 37, 1703; d) J.-H. Xie, X.-Y. Liu, J.-B. Xie, L.-X.
Wang, Q.-L. Zhou, Angew. Chem. 2011, 123, 7467; Angew. Chem.
Int. Ed. 2011, 50, 7329.
À
[11] As for asymmetric C C bond forming reactions using continuous
flow systems with chiral heterogeneous catalysts, although several
examples have appeared in the literature, most reports have shown
a substrate scope of only one or two for the respective systems. To
the best of our knowledge, only two papers have shown some sub-
strate scope for chiral metal complex-catalyzed continuous flow sys-
tems (except for “primitive” flows using gravity). Namely, for the al-
kylation and arylation of aldehydes with Et2Zn and ArZnEt, for
which the lifetime of the flow systems was 4–6 h (after washing with
solvents they can be reused in some cases); a) M. A. Pericꢃs, C. I.
Herrerꢄas, L. Solꢃ, Adv. Synth. Catal. 2008, 350, 927; b) J. Rolland,
X. C. Cambeiro, C. Rodrꢄguez-Escrich, M. A. Pericꢃs, Beil. J. Org.
Chem. 2009, 5, No. 56. Very recently, three reports on asymmetric
À
[4] Examples attaining high TONs in asymmetric C C bond forming re-
actions: a) P. Pelphrey, J. Hansen, H. M. L. Davies, Chem. Sci. 2010,
1, 254; b) A. T. Axtell, C. J. Cobley, J. Klosin, G. T. Whitaker, A. Za-
notti-Gerosa, K. A. Abboud, Angew. Chem. 2005, 117, 5984; Angew.
Chem. Int. Ed. 2005, 44, 5834; c) K. Mikami, Y. Kawakami, K.
Akiyama, K. Aikawa, J. Am. Chem. Soc. 2007, 129, 12950; d) M. P.
Doyle, I. M. Phillips, W. Hu, J. Am. Chem. Soc. 2001, 123, 5366.
[5] Selected examples of catalytic asymmetric 1,4-addition reactions of
malonates with nitroalkenes: a) J. Ji, D. M. Barnes, J. Zhang, S. A.
King, S. J. Wittenberger, H. E. Morton, J. Am. Chem. Soc. 1999, 121,
10215; b) T. Okino, Y. Hoashi, Y. Takemoto, J. Am. Chem. Soc.
2003, 125, 12672; c) H. Li, Y. Wang, L. Tang, L. Deng, J. Am. Chem.
Soc. 2004, 126, 9906; d) M. Watanabe, A. Ikagawa, H. Wang, K.
Murata, T. Ikariya, J. Am. Chem. Soc. 2004, 126, 11148; e) D. A.
Evans, D. Seidel, J. Am. Chem. Soc. 2005, 127, 9958; f) S. H.
McCooey, S. J. Connon, Angew. Chem. 2005, 117, 6525; Angew.
À
C C bond forming reactions using continuous flow systems with
chiral heterogeneous organocatalysts have appeared; however, sub-
strate scope and lifetime of these systems are still limited; c) S. B.
ꢅtvçs, I. M. Mꢂndity, F. Fꢆlçp, ChemSusChem 2012, 5, 266; d) C.
Ayats, A. H. Henseler, M. A. Pericꢃs, ChemSusChem 2012, 5, 320;
e) O. Bortolini, L. Caciolli, A. Cavazzini, V. Costa, R. Greco, A.
Massi, L. Pasti, Green Chem. 2012, 14, 992.
[12] a) R. Akiyama, S. Kobayashi, Chem. Rev. 2009, 109, 594; b) S. Ko-
bayashi, H. Miyamura, Chem. Rec. 2010, 10, 271.
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Asymmetric Carbon–Carbon Bond Formation
COMMUNICATION
[13] a) S. Harder, Chem. Rev. 2010, 110, 3852; b) S. Kobayashi, Y. Yama-
shita, Acc. Chem. Res. 2011, 44, 58; c) Y. Yamashita, T. Tsubogo, S.
Kobayashi, Chem. Sci. 2012, 3, 967.
stein J. Org. Chem. 2011, 7, 735; c) K. Kaizuka, K.-Y. Lee, H. Miya-
mura, S. Kobayashi, J. Flow Chem. 2012, 2, 1; d) J. Kobayashi, Y.
Mori, K. Okamoto, R. Akiyama, M. Ueno, T. Kitamori, S. Kobaya-
shi, Science 2004, 304, 1305.
[14] Details are given in the Supporting Information. See also: a) A. F.
Trindade, P. M. P. Gois, C. A. M. Afonso, Chem. Rev. 2009, 109, 418;
b) J. M. Fraile, J. I. Garcꢄa, J. A. Mayoral, Coord. Chem. Rev. 2008,
252, 624; c) A. Cornejo, J. M. Fraile, J. I. Garcꢄa, M. J. Gil, S. V. Luis,
V. Martꢄnez-Merino, J. A. Mayoral, J. Org. Chem. 2005, 70, 5536;
d) A. Cornejo, J. M. Fraile, J. I. Garcꢄa, E. Garcꢄa-Verdugo, M. J.
Gil, G. Legarreta, S. V. Luis, V. Martꢄnez-Merino, J. A. Mayoral,
Org. Lett. 2002, 4, 3927.
[16] As a standard, we used glass columns with the following dimensions:
f 1.0 cm ꢁ 10 cm. The number of the columns connected is depend-
ent on the reactions and substrates. In this case, one column (f
1.0 cm ꢁ 20 cm) is required.
[17] To avoid the loss CaCl2, we passed the mixture through a precolumn
(MS 4 A), although we could obtain the products without using a
precolumn.
[15] a) S. Kobayashi, H. Miyamura, R. Akiyama, T. Ishida, J. Am. Chem.
Soc. 2005, 127, 9251; b) H. Oyamada, T. Naito, S. Kobayashi, Beil-
Received: July 3, 2012
Published online: && &&, 0000
Chem. Eur. J. 2012, 00, 0 – 0
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
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S. Kobayashi et al.
Asymmetric Catalysis
T. Tsubogo, Y. Yamashita,
S. Kobayashi* ................. &&&& — &&&&
Toward Efficient Asymmetric Carbon–
Carbon Bond Formation: Continuous
Flow with Chiral Heterogeneous Cata-
lysts
A chiral Ca catalyst based on CaCl2
with a chiral ligand was developed and
applied to the asymmetric 1,4-addition
of 1,3-dicarbonyl compounds to nitro-
alkenes as a model system. To address
product inhibition issues, the Ca cata-
lyst was applied to continuous flow
with a chiral heterogeneous catalyst.
The continuous flow system using a
newly synthesized, polymer-supported
Pybox was successfully employed, and
the TON was improved 25-fold com-
pared with those of the previous
Ca(OR)2 catalysts.
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www.chemeurj.org
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 0000, 00, 0 – 0
ÝÝ
These are not the final page numbers!