Tether-free immobilized bifunctional squaramide organocatalysts for batch and flow reactions

Article abstract of DOI:10.1002/ejoc.201300626

This paper describes the preparation of highly efficient, easily accessible, and robust immobilized bifunctional organocatalysts. There was no need to employ any tether to secure high enantio- and diastereoselectivities in various Michael addition reactions. The synthetically useful Michael adducts were obtained within reasonable reaction times with the advantage of easy product isolation and the possibility of automation by using a flow chemistry apparatus. Easily accessible, robust, and cheap immobilized organocatalysts are developed and used to prepare Michael adducts in excellent yields with excellent enantioselectivities, even on the gram scale. Copyright

Full text of DOI:10.1002/ejoc.201300626

Job/Unit: O30626
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Date: 13-06-13 16:30:58
Pages: 6
SHORT COMMUNICATION
Bifunctional Organocatalysts
G. Kardos, T. Soós* .......................... 1–6
Tether-Free Immobilized Bifunctional
Squaramide Organocatalysts for Batch and
Flow Reactions
Keywords: Organocatalysis
zation / Supported catalysts / Michael ad-
dition / Flow chemistry
/ Immobili-
Easily accessible, robust, and cheap immo-
bilized organocatalysts are developed and
used to prepare Michael adducts in excel-
lent yields with excellent enantioselectivi-
ties, even on the gram scale.
0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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G. Kardos, T. Soós
SHORT COMMUNICATION
DOI: 10.1002/ejoc.201300626
Tether-Free Immobilized Bifunctional Squaramide Organocatalysts for Batch
and Flow Reactions
György Kardos[a] and Tibor Soós*[a]
Keywords: Organocatalysis / Immobilization / Supported catalysts / Michael addition / Flow chemistry
This paper describes the preparation of highly efficient, eas-
ily accessible, and robust immobilized bifunctional organo-
catalysts. There was no need to employ any tether to secure
high enantio- and diastereoselectivities in various Michael
addition reactions. The synthetically useful Michael adducts
were obtained within reasonable reaction times with the ad-
vantage of easy product isolation and the possibility of auto-
mation by using a flow chemistry apparatus.
The cinchona alkaloids and their derivatives feature com-
manding performance in organocatalysis.[2] Among these,
bifunctional cinchonas, especially thiourea[2d–2g] and squar-
amide derivatives,[3] have proven particularly efficient, as
they have provided highly enantio-rich and often diastereo-
rich products in a broad range of reactions. Squaramide-
cinchona catalyst 1a, introduced by Rawal (Figure 1),[4] ex-
cels in Michael additions with the use of relatively acidic
nucleophiles. Interestingly, a unique physicochemical fea-
ture of this type of catalyst is its high thermostability, which
is reflected by its catalytic usage over 110 °C.[3m] Although a
low catalyst loading is generally required (Ͻ2 mol-%), these
catalysts are still expensive, have a high molecular weight,
and their utility is often limited by their poor solubility.
Introduction
Asymmetric organocatalysis is a rapidly advancing re-
search field that not only tackles scientific challenges but
also delivers a broad range of chiral molecules with struc-
tural and functional diversity. Due to their capacity, sim-
plicity and robustness, organocatalytic methodologies have
become an appealing synthetic tool in asymmetric catalysis.
However, these synthetic advantages often come with disad-
vantages including lower turnover frequency, which necessi-
tates the application of higher catalyst loadings and longer
reaction times.
Given that the evolution of this field is inseparable from
practical aspects, the separation and recovery of organocat-
alysts would be a balanced compromise between utility and
production cost. Immobilization of organocatalysts can be
also advantageous in production and waste management,
because organocatalysts are inherently less prone to decom-
position. Thus, the classical catalyst-leaching problem
would be circumvented. Besides green chemical aspects, cat-
alyst immobilization, especially a heterogeneous approach,
should streamline the synthetic work in the laboratory and
might facilitate the permeation of organocatalysis into in-
dustry. Several immobilized organocatalysts[1] have been re-
ported over the last decade; however, their utility is often
hampered by catalyst deactivation, diminished enantio-
selectivities, or the high cost of the resin. In this paper, we
report the development of readily available, cheap, and ef-
ficient quinine-squaramide immobilized organocatalysts
and their utilization in Michael addition reactions in batch
and flow-type manners.
Figure 1. Bifunctional cinchonas squaramide catalysts.
Results and Discussion
[a] Institute of Organic Chemistry, Research Centre for Natural
Sciences of the Hungarian Academy of Sciences
1025 Budapest, Pusztaszeri út 59-67
These challenges prompted us to immobilize this valu-
able catalyst onto a solid support.[5] To develop operation-
ally simple and cost-efficient methodology for bifunctional
squaramide immobilization, we selected aminomethyl-func-
tionalized macroporous and microporous polystyrene solid
supports because of their commercial availability and low
Fax: +36-14381145
E-mail: soos.tibor@ttk.mta.hu
Homepage: www.ttk.mta.hu/organo
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201300626.
2
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Tether-Free Immobilized Bifunctional Squaramide Organocatalysts
cost. The selected resins have a lower loading (0.65– Product 6a was obtained in high purity after an operation-
1 mmolg–1) to minimize the interference between the an- ally simple workup,[7] as judged by NMR spectroscopy;
chored catalysts.[6] Whereas immobilization of a chiral cata- thus, no further chromatography was required. Next, the
lyst often necessitates the usage and careful selection of a influence of the solvent was investigated by using solvents
tether, we aimed to graft the chiral catalyst directly onto that were able to swell the resin. Gratifyingly, variation of
the solid support; thus, the benzylamino group would be an the solvent had a negligible impact on both the enantio-
integral part of the catalytic center. As that type of modifi- selectivity and the yield (Table 1, entries 4–6). The only
cation in the catalytic structure was unknown, we synthe- limitation found during the solvent screening was the poor
sized homogeneous benzylquinine-squaramide analogue 1b solubility of product 6a. Thus, with the use of toluene,
from diethyl squarate (2) and investigated its catalytic prop- product 6a precipitated out and covered the catalyst resin,
erties in the asymmetric Michael addition of acetylacetone which resulted in poor conversion. Finally, the recyclability
(4a) and β-nitrostyrene (5a). Benzyl-derived catalyst 1b per- of our catalyst was studied. Heterogenized organocatalyst
formed similarly (Table 1, entry 1), and even slightly better, 1d proved to be chemically robust enough to withstand 10
than previously reported catalyst 1a.[4] Consequently, modi- cycles without any appreciable decrease in yield or enantio-
fication around that position in the cinchona-squaramide meric excess (Table 1, entry 7). Even after repeated use over
seemed to have little impact on the overall catalyst perform- two years there was still no detectable loss in activity, and
ance in the investigated Michael addition. This observation only the deposition of the nitroolefin polymer onto the
was promising for heterogenization, as fluctuation of the resin required catalyst maintenance by ultrasonic cleaning.
polymeric microenvironment surrounding the organocata- These results demonstrate that immobilized cinchona-squa-
lyst was expected to have little impact on the efficacy of this ramide catalysts 1d and 1e are robust, durable, cheap, and
type of catalyst.
highly efficient catalysts to promote Michael addition be-
tween acetylacetone (4a) and nitrostyrene (5a).
Table 1. Cinchona-squaramide-promoted conjugate additions be-
tween acetylacetone (4a) and nitrostyrene (5a).[a]
Entry Catalyst
(mol-%)
Time
[h]
Solvent
Yield[b]
[%]
ee
[%]
1
2
3
4
5
6
1b (5)
1d (5)
1e (5)
1d (5)
1d (5)
1d (5)
1d (5)
1f (5)
1f (11)
1f (1)
2
8
8
8
8
8
8
8
2
CH2Cl2
CH2Cl2
CH2Cl2
toluene
THF
98
92
92
n.d.
91
87
92
89
91
90
99
99
–99
99
98
97
99
97
96
97
DMF
7[c]
8[d]
9[e]
10[f]
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
16
[a] Reactions were performed with 5a (1 mmol), 4a (2 mmol) in sol-
vent (0.5 mL). [b] Isolated yield. n.d. = not determined. [c] 10th
cycle of the reproducibility experiments. [d] 1 mmol scale in batch
reaction. [e] Flow usage, 1 mmol scale. [f] 20 mmol scale up, flow
synthesis.
Scheme 1. Synthesis of solid-supported cinchona-squaramide cata-
lysts.
Experiments that probed the scope of the substrate are
highlighted in Table 2. Under the previously developed re-
Solid-supported pseudoenantiomeric catalysts 1d and 1e action conditions, immobilized organocatalysts 1d and 1e
were easily prepared by a two-step protocol (Scheme 1).[7] afforded the Michael adducts in remarkably high yields
First, diethyl squarate (2) was anchored to the microporous, with high enantiomeric excess values (Table 2, entries 1–8).
swellable resin followed by reaction of 9-amino-(9-deoxy)- Notably, by using prochiral nucleophiles (Table 3, entries 1–
epiquinine (eQNH2, 3a)[2d] or 9-amino-(9-deoxy)epiquinid- 4) high to excellent diastereoselectivities were obtained.
ine (3b).[2d] Resulting immobilized organocatalysts 1d and
Having developed efficient immobilized squaramide
1e were then evaluated in the Michael reaction between 4a organocatalysts 1d and 1e, we decided to extend our
and 5a. These experiments exceeded our expectations and organocatalyst heterogenization method towards con-
showed that the heterogenization did not reduce the tinuous-flow[8] applications. Therefore, the same quinine-
enantioselectivity at all in the investigated model reaction. based organocatalyst was grafted onto nonswelling, macro-
However, longer but still acceptable reaction times were porous aminomethyl polystyrene to afford squaramide or-
needed to complete the reaction (Table 1, entries 2 and 3). ganocatalyst 1f (Scheme 1). The reaction of acetylacetone
Eur. J. Org. Chem. 0000, 0–0
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G. Kardos, T. Soós
SHORT COMMUNICATION
Table 2. Substrate scope of solid-supported squaramide organocat-
alysts.[a]
Table 3. Examination of the diastereoselectivity of the solid-sup-
ported squaramide organocatalysts by using prochiral nucleo-
philes.[a]
[a] Reactions were performed with the electrophile (1 mmol) and
the nucleophile (2 mmol) in the presence of catalyst (5 mol-%) in
CH2Cl2 (0.5 mL). [b] Isolated yield. [c] Determined by chiral-phase
HPLC.
[a] Reactions were performed with the electrophile (1 mmol) and
the nucleophile (2 mmol) in the presence of catalyst (5 mol-%) in
CH2Cl2 (0.5 mL). [b] Isolated yield. [c] Determined by chiral-phase
HPLC.
Conclusions
In summary, we have developed a protocol to immobilize
quinine- and quinidine-squaramide organocatalysts for
batch and continuous-flow applications. These organocata-
lysts have several practical advantages: Their syntheses are
simple, efficient, and cheap and the heterogenization did
not reduce the enantio- and diastereoselectivity in the inves-
tigated Michael reactions. Moreover, these readily access-
ible catalysts also proved to be durable and robust to sur-
vive several cycles without appreciable loss of activity.
(4a) with nitrostyrene (5a) was used again as a test reaction
to evaluate the catalytic performance of 1f. Gratifyingly, the
macroporous system performed similarly to the micro-
porous catalyst, and high yields and high enantioselectivity
were obtained both in batch and flow operations (Table 1,
entries 8 and 9).[7] Flow reactions were carried out with a
Syrris Asia setup, which contained a syringe pump, reagent
containers, injectors, a column holder, and a backpressure
regulator (9 bar), and we filled the catalyst resin into a
stainless steel tube with polytetrafluoroethylene sealings
and polystyrene frits.[7] Interestingly, in the flow apparatus,
catalyst 1f provided a faster reaction, presumably as a result
of lower product inhibition. The key advantage associated
with the flow set up is the continuous operation that allows
easy scale up and automation. Thus, enantioenriched 6a
was easily produced with high enantioselectivity on gram
scale by using a low overall catalyst loading of 1 mol-%
(Table 1, entry 10). Additionally, 6l was produced in a flow
manner not only with high enantioselectivity but also with
high diastereoselectivity (Table 3, entry 4). The synthesis of
6l occurred directly after the synthesis of 6a; thus, the pro-
duction of different Michael adducts can be automated.
Experimental Section
General Synthesis of Catalysts 1b and 1c: Benzylamine (11 mmol,
1.179 g) was added dropwise over a period of 5 min to a solution of
diethyl squarate (2; 10 mmol, 1.702 g) in Et2O (10 mL) at ambient
temperature, and the mixture was stirred overnight. A small
amount of white powder precipitated, which was removed by fil-
tration. To the filtrate was added the corresponding alkaloid amine
derivative (11 mmol), and the mixture was stirred overnight at
room temperature. The catalyst precipitated out as a white solid,
which was separated by filtration and washed with Et2O (2ϫ
10 mL).
General Synthesis of Catalysts 1d–f: The appropriate aminomethyl
polystyrene (10 mmol aminomethyl substituent) was added to a
solution of diethyl squarate (2; 20 mmol, 3.404 g) in DMF (35 mL),
and the mixture was shaken (or stirred with mechanical stirrer)
overnight at room temperature. The resin was separated by fil-
4
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Tether-Free Immobilized Bifunctional Squaramide Organocatalysts
tration and washed twice with DMF (35 mL). DMF (35 mL) and
the corresponding amine (20 mmol) were then added, and the mix-
ture was shaken (or stirred with mechanical stirrer) overnight at
room temperature. The resin was separated again by filtration,
washed twice with DMF (35 mL), twice with CH2Cl2 (35 mL), and
twice with hexane (35 mL), and dried in air. The substitution rate
was determined by elemental analysis.
cipitated out with Et2O (yield: 91%). The enantiomeric excess val-
ues and the diastereoselectivity were determined directly from the
reaction mixtures: 6l: 99+%ee, 98:2dr; 6a: 96%ee.
Supporting Information (see footnote on the first page of this arti-
cle): Experimental procedures, copies of the 1H NMR and 13C
NMR spectra for all key intermediates and final products, and
HPLC chromatograms of chiral products.
General Method for the Michael Addition Reactions by Using Solu-
ble Catalysts 1b and 1c: The catalyst (5 mol-%, 0.05 mmol) was
added to a mixture of the electrophile (1 mmol) and the nucleophile
(2 mmol) in CH2Cl2 (2 mL), and the resulting solution was stirred
for 2 to 5 h at room temperature until the reaction was complete
(followed by TLC). The product was separated by column
chromatography (hexane/EtOAc, 5:1 to 1:1).
Acknowledgments
We are grateful for the financial support of the Hungarian Scien-
tific Research Fund (OTKA) (grant number K-69086) and the
Lendület Program E-13/11/2010.
General Method for the Michael Addition Reactions by Using Immo-
bilized Catalysts 1d and 1e in a Batch Device: The catalyst resin
(5 mol-%, which contained 0.05 mmol catalytically active substitu-
ent) was added to a mixture of the electrophile (1 mmol) and the
nucleophile (2 mmol) in CH2Cl2 (2 mL), and the resulting mixture
was shaken for 8 h at room temperature. The catalyst was separated
by filtration. The solvent was evaporated, and the product was pre-
cipitated by adding Et2O (0.5 mL), filtered and washed with Et2O
(0.3 mL) (except 6k, for which the isolation process was the same
as that for 6l; for further information see the Supporting Infor-
mation). The enantiomeric excess was determined directly from the
reaction mixture, before the workup procedure. The catalyst resin
was washed with CH2Cl2/DMF (1:1) in an ultrasonic bath for
5 min and then with CH2Cl2 before reuse.
[1] For organocatalyst immobilization, see: a) P. Kasaplar, P. Ri-
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Example Michael Addition Reaction by Using Immobilized Catalyst
1f in a Flow Reactor: A column (C1, internal size: l = 95 mm, r =
6 mm) was filled with catalyst resin 1f (2.36 g, 0.236 mmol catalyst
load). The dead volume was measured by filling with CH2Cl2
(7.3 mL). The column was then attached to the flow system and
equilibrated with CH2Cl2 at a flow rate of 730 μLmin–1 for 10 min.
After that, the vessel containing the solution of pentane-2,4-dione
(4a; 4.80 g, 48 mmol) and β-nitrostyrene (5a; 3.60 g, 24 mmol) in
CH2Cl2 (73 mL) was attached to the inlet of the pump and a flow
rate of 73 μLmin–1 was maintained for 1000 min followed by
10 min of CH2Cl2 at a flow rate of 730 μLmin–1. After evaporation
of the solvent, 3-(2-nitro-1-phenylethyl)pentane-2,4-dione (6a) pre-
cipitated out after the addition of Et2O, yield 5.34 g (89%). The
enantiomeric excess was determined from the reaction mixture:
97%.
Sequential Mode of Operation for Michael Addition Reactions by
Using Immobilized Catalyst 1f in a Flow Reactor: The 1f-filled col-
umn (C1) was used as in the previous example. The column was
attached to the flow system and equilibrated with CH2Cl2 at a flow
rate of 730 μLmin–1 for 10 min. After that, a solution of ethyl 2-
oxocyclopentanecarboxylate (0.312 g, 2 mmol) and β-nitrostyrene
(5a; 0.149 g, 1 mmol) in CH2Cl2 (7.3 mL) was injected with a flow
rate of 73 μLmin–1. This flow rate was maintained for 120 min fol-
lowed by 10 min of CH2Cl2 wash at a flow rate of 730 μLmin–1.
After the collection vessel was changed, a solution of pentane-2,4-
dione (4a; 0.200 g, 2 mmol) and β-nitrostyrene (5a; 0.149 g,
1 mmol) in CH2Cl2 (7.3 mL) was injected with a flow rate of
73 μLmin–1. This flow rate was maintained for 120 min followed
by 10 min of CH2Cl2 at a flow rate of 730 μLmin–1. The first prod-
uct, ethyl 1-(2-nitro-1-phenylethyl)-2-oxocyclopentanecarboxylate
(6l), was isolated by evaporation of the solvent in vacuo followed
by further high-vacuum evaporation of the excess amount of the
nucleophile (yield: 96%). The second product, 3-(2-nitro-1-phenyl-
ethyl)pentane-2,4-dione (6a), was concentrated in vacuo and pre-
[2] For reviews on bifunctional cinchona alkaloid based catalysts,
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[3] For a recent review on squaramide derivatives, see: a) J.
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ˇ
2011, 17, 6890; synthetic applications: b) S. Zari, T. Kailas,
Eur. J. Org. Chem. 0000, 0–0
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[5] In parallel to our work, a supported chiral trans 1,2-diaminocy-
clohexane squaramide was developed for the same Michael ad-
dition reaction by using click-tethered grafting methodology
onto polystyrene resin: P. Kasaplar, P. Riente, C. Hartmann,
M. A. Pericás, Adv. Synth. Catal. 2012, 354, 2905.
[6] Bifunctional organocatalysts are know to have the potential to
undergo self-aggregation, which can result, in: lower catalytic
efficiency: a) G. Tárkányi, P. Király, Sz. Varga, B. Vakulya, T.
Soós, Chem. Eur. J. 2008, 14, 6078; b) P. Király, T. Soós, Sz.
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H. Y. Baea, C. E. Song, Org. Biomol. Chem. 2010, 8, 3918.
[7] For details, see the Supporting Information.
[8] For immobilized organocatalysts used in a flow setup, see: a)
Y. Arakawa, H. Wennemers, ChemSusChem 2013, 6, 211; b)
S. B. Ötvös, I. M. Mándity, F. Fülöp, ChemSusChem 2012, 5,
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Received: April 30, 2013
Published Online: ᭿
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