A polystyrene-supported, highly recyclable squaramide organocatalyst for the enantioselective Michael addition of 1,3-dicarbonyl compounds to β-nitrostyrenes

Article abstract of DOI:10.1002/adsc.201200526

A chiral squaramide has been supported onto a polystyrene (PS) resin through a copper-catalyzed azide-alkyne cycloaddition (CuAAC) reaction and used as a very active, easily recoverable and highly reusable organocatalyst for the asymmetric Michael additio

Full text of DOI:10.1002/adsc.201200526

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DOI: 10.1002/adsc.201200526
A Polystyrene-Supported, Highly Recyclable Squaramide
Organocatalyst for the Enantioselective Michael Addition of
1,3-Dicarbonyl Compounds to b-Nitrostyrenes
Pinar Kasaplar,a Paola Riente,a Caroline Hartmann,a and Miquel A. Pericꢀsa,b,*
a
Institute of Chemical Research of Catalonia (ICIQ), Av. Paꢁsos Catalans 16, 43007 Tarragona, Spain
Fax : (+34)-97-792-0222; e-mail: mapericas@iciq.es
Departament de Quꢂmica Orgꢀnica, Universitat de Barcelona (UB), 08028 Barcelona, Spain
b
Received: June 15, 2012; Published online: October 5, 2012
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201200526.
Abstract: A chiral squaramide has been supported
onto a polystyrene (PS) resin through a copper-cat-
alyzed azide–alkyne cycloaddition (CuAAC) reac-
tion and used as a very active, easily recoverable
and highly reusable organocatalyst for the asym-
metric Michael addition of 1,3-dicarbonyl com-
pounds to b-nitrostyrenes. The PS-supported squar-
amide could be recycled up to 10 times.
Keywords: asymmetric catalysis; catalyst recycling;
heterogeneous catalysis; Michael addition; squara-
mide organocatalysis
Figure 1. General structures of chiral squaramide-based hy-
drogen bonding organocatalysts.
The squaramides feature in their structures a rigid
four-membered ring with very important electron de-
The asymmetric Michael addition is a powerful tool
À
localization. For this reason, they behave as very effi- for the C C bond formation. Starting with the Hajos–
cient, directional hydrogen-bond donors.[1] Together Parrish reaction in the early 1970s,[5] the organocata-
with ureas and thioureas, squaramides are privileged lytic approach to enantiocontrol in the reaction re-
members of an important group of molecules widely mained opened.[6] Within this group of processes, the
used for molecular recognition,[2] especially for the addition of 1,3-dicarbonyl compounds to nitrostyr-
recognition of anions. When compared with ureas and enes[7] depicts particular interest for the rich reactivity
thioureas, squaramides differ in some important as- of the resulting enantiopure nitro carbonyl products.
pects such as acidity, rigidity, hydrogen bond spacing, Enantiocontrol in these reactions has been achieved
and hydrogen bond angle. Probably for these reasons, with organocatalysts based on diamines,[8] amine-thio-
chiral squaramides have emerged as a promising class ureas[9] and Cinchona derivatives.[10] In fact, the initial
of organocatalysts based on non-covalent interactions application of the squaramide scaffold in organocatal-
(Figure 1).[3] From a practical perspective, squar- ysis, due to Rawal, was in the Michael addition of 1,3-
ACHTUNGTRENNUNGamides present an additional advantage over ureas dicarbonyl compounds to nitroolefins, the correspond-
and thioureas. Thus, while these species normally in- ing adducts being obtained with excellent enantiose-
volve the use of a reactive intermediate (an isocya- lectivities.[3a]
nate or an isothiocyanate), squaramides are readily
While catalytic chemistry is nowadays recognized
available by sequential substitution on stable and as a key element in sustainable production, the pro-
commercially available dimethyl squarate. In this gressive focus on recycling and reuse has provoked
manner, highly modular chiral squaramides can be a shift in the interest from homogeneous catalytic spe-
prepared and fine-tuned for specific catalytic applica- cies to immobilized ones.[11] When covalent immobili-
tions.[4]
zation is considered, ligands and catalysts have to be
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properly redesigned to include additional functions al- squarACTHUNRTGNEaGNU mide design. The carboxy group, ultimately
lowing bonding to a support without perturbation of planned for immobilization purposes, was placed in
the catalytic site. When this condition is met, the in- a para position with respect to the amino group to
herent advantages of catalytic synthesis are greatly ensure a maximal spatial separation between the
enhanced by the possibility of repeated recovery and polymer backbone and the squaramide bifunctional
reuse.
catalyst, thus minimizing transition state perturbation
In spite of its interest and potential, the immobili- in the catalytic event.[15] The selected immobilization
zation of squaramides has not been reported so far.[12] strategy was the CuAAC reaction,[16] and two homo-
As a continuation of our efforts toward the develop- geneous analogues (9a, b), depicting different spacers
ment of basic toolkits of organocatalysts covalently between the electron-poor aryl group and the 1,2,3-
immobilized either onto polymers[13] or magnetic tri
ACTHNUTRGNEaNUG zole linker were initially prepared. The catalytic
nanoparticles[14] for batch and continuous flow appli- behaviour exhibited by these models helped in the
cations, we report in this communication the first ex- final design of the immobilized squaramide 9c
ample a chiral squaramide supported onto polystyr- (Figure 2).
ene, and its use as a highly efficient and recyclable
catalyst for the Michael addition of 1,3-dicarbonyls pared in four steps from amino acid 1. The methodol-
compounds to b-nitrostyrenes. ogy followed for the preparation of PS-supported
The target compounds 9a–c could be readily pre-
For the present study (Figure 1), the chiral scaffold squaramide 9c has been summarized in Scheme 1.
in the squaramide design was specified as (1R,2R)-2- Model squaramides 9a and 9b, in turn, were prepared
(piperidin-1-yl)cyclohexanamine (8), as this readily by analogous sequences in 37% and 51% overall
available enantiopure material has been previously yields, respectively (see the Supporting Information
used with success for squaramide organocatalysis.[3] for details). For the preparation of the PS-supported
On the other hand, commercially available 2- squaramide (9c), esterification of 1 with acetylenic al-
trifluoroACHTUNGTRENNUNGmethyl-4-aminobenzoic acid (1) was specified cohol 2 led to ester 3, suitable for CuAAC immobili-
as the source of the electron-poor aryl group in the zation. The squaric acid system was introduced in
high yield at this point by reaction with dimethyl
squarate 4, and the so-formed ester-amide 5 was re-
acted with azidomethyl-polystyrene 6 in the presence
of a catalytic amount of TTM-CuCl[17] to afford 7.
The synthesis of the polymer supported squaramide
9c was completed with the introduction of the chiral
scaffold 8. This particular order of events is the most
appropriate one for the preparation of polymer-sup-
ported squaramides, since the chiral scaffold is intro-
duced in the last step, and this allows the use of an
Figure 2. Homogeneous and heterogeneous chiral squara-
mide organocatalysts in this study.
excess of the chiral moiety (8, that can be easily re-
Scheme 1. Synthesis of PS-supported chiral squaramide organocatalyst 9c.
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A Polystyrene-Supported, Highly Recyclable Squaramide Organocatalyst
Table 1. Screening of the catalyst and the catalyst loading
for the Michael addition of 10a to 11a.[a]
Table 2. Michael addition of 10a to b-nitrostyrenes 11a–h
catalyzed by 9c.[a]
Entry Catalyst (mol%) Time [h] Yield [%][b] ee [%][c]
Entry Nitroolefin
Product Time Yield ee
[h]
[%][b] [%][c]
1
2
3
4
5
6
7
8
9a (2.0)
9a (0.5)
9b (2.0)
9b (0.5)
9c (2.0)
6
24
6
24
8
40
264
288
94
89
93
92
88
62
83
41
91
92
91
94
95
90
97
83
1
2
12a
12b
8
88
87
95
94
13
24
13
13
9c (0.5)
9c (0.25)[d]
9c (0.01)[d]
3
4
5
12c
12d
12e
81
91
87
92
93
92
[a]
11a (1.0 equiv,), 10a (2.0 equiv.) and 9a–c in CH2Cl2 at
room temperature.
Isolated yield.
By HPLC.
[b]
[c]
[d]
At 58C.
covered) to ensure the achievement of the highest
possible functionalization in the catalytic resin. Start-
ing from a slightly cross-linked (1% DVB) Merrifield
resin with f0 =0.52 mmolgÀ1, resin 9c with f=
0.35 mmolgÀ1 was obtained.
With the catalysts 9a–c in hand, their activity was
tested on the Michael addition of 1,3-diketones (10)
to nitrostyrenes (11). Initially, the reaction between
2,4-pentanedione 10a with trans-b-nitrostyrene 11a
was chosen as a model for the optimization of the cat-
alyst loading and to compare the PS-supported chiral
squaramide with its homogeneous analogues
(Table 1).
6
7
12f
24
85
87
12g
12h
13
15
91
91
93
94
8
[a]
10a (0.4 mmol), 11a–h (0.2 mmol), 9c (2 mol%) in
CH2Cl2 (0.6 mL) at room temperature.
Isolated yield.
[b]
[c]
By HPLC.
The model catalysts 9a and 9b were studied first in
order to determine the nature of the optimal spacer.
Both catalysts performed equally well at 2 mol% loading 12a is obtained in high (83%) enantiomeric
loading at room temperature in dichloromethane (en- purity, albeit at an impractical rate.
tries 1 and 3), but 9b led to higher ee (94 vs. 92%; en-
The use of catalyst 9c was next tested in the Mi-
tries 4 and 2) at 0.5 mol%. For this reason, the longer chael reaction of a series of b-nitrostyrenes (11a–h)
spacer was selected for the polymer-supported ver- with 2,4-pentanedione (10a) under the optimal reac-
sion. Interestingly, the activation provided by the 4- tion conditions (2 mol%, dichloromethane, room tem-
alkACHTUNGTRENNUNGoxycarbonyl-3-trifluoromethylphenyl moiety is perature). The results of this study are summarized in
only slightly lower than that provided by the standard Table 2. In general, substrates bearing either ortho,
3,5-bis(trifluoromethyl)phenyl one,[3a] and this vali- meta or para electron-donating or electron-withdraw-
dates the design used in the present study. The results ing substituents afforded the corresponding Michael
obtained with the polymer-supported catalyst 9c adducts with excellent yields and enantioselectivities.
under similar reaction conditions (entry 5 vs. entries 1 Over the full range of studied substrates, the reactivi-
and 3) were even better, leading to higher ee without ty profile observed for 9c is very similar to that de-
significant decrease in reaction rate. Interestingly, cat- picted by the reference system I (n=1).[3a]
alyst loading could be importantly reduced (entries 6–
The catalytic activity of 9c in the enantioselective
8). When the reaction was carried out with 0.25 mol% Michael reaction of b-nitrostyrene 11a with a variety
9c at 58C, 12a was obtained in excellent enantiomeric of 1,3-dicarbonyl compounds (10b–h) was also studied
purity (97% ee, entry 7), and even at 0.01 mol% 9c (Table 3). The corresponding conjugate addition ad-
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Table 3. Michael addition of 1,3-dicarbonyl compounds 10b–
h to b-nitrostyrene 11a catalyzed by 9c.[a]
Entry NuH
Product Time Yield[%][b]/ ee
[h]
dr[c]
[%][d]
1
2
3
4
5
12i
20
56
86
Figure 3. Recycling of 9c in the asymmetric addition of 10a
to 11a.
92
(90)
12j
12k
12l
9
88/1:1.1
89
(89)
10a with 11a as model substrates. Ten consecutive re-
action cycles were performed in dichloromethane at
room temperature with a single catalyst sample, ini-
tially representing 4 mol% of the limiting 11a reac-
tant. Reaction time was arbitrarily fixed to 6 h, and
reaction product (12a) in every individual cycle was
isolated and purified for yield calculation. After each
cycle, the catalyst was separated by filtration, washed,
dried and reused. The results of this study have been
represented in Figure 3, where data for every individ-
ual cycle represent the average value of two inde-
pendent experiments.
Very gratifyingly, enantioselectivity is preserved
along the ten-cycle experiment. Conversion, in turn,
suffers some deterioration, but remains high (>70%)
over the whole series. The joint behaviour of enantio-
selectivity and conversion is typical for situations
where the catalyst is chemically stable, but stirring
provokes some etching in the beads of the immobi-
lized catalyst leading to a decrease in the effective
catalyst loading as the series of experiments progress-
es.[18] With sufficiently active immobilized catalysts,
this phenomenon can be suppressed by performing
the reactions in continuous flow mode.[13a,19]
16
24
60
98/
85/
ACHTUNGTNER(NUNG 1:1)
93
(92)
AHCTUNGTERG(NNUN 1:1)
89
(91)
12m
60/2.2:1
89/29:1
96
(87)
6
12n
12o
24
24
83
(88)
7
62/5:1
[a]
10b–h (0.4 mmol), 11a (0.2 mmol) 9c (2 mol%) in
CH2Cl2 (0.6 mL) at room temperature.
Isolated yield.
[b]
[c]
[d]
1
By H NMR.
By HPLC; ees of the minor diastereomers in parenthesis.
ducts were obtained with good to excellent yields. For
In conclusion, we have reported the first example
acyclic 1,3-dicarbonyls, diastereoselectivity was low to of a chiral squaramide organocatalyst covalently im-
moderate (entries 2–5) in agreement with previous re- mobilized onto a polystyrene (Merrifield type) resin.
ports.[3a] For cyclic substrates (entries 6–7) higher dia- A CuAAC immobilization strategy has been imple-
stereoselectivities were recorded. Enantioselectivity mented involving short, simple and high yielding
in these reactions followed the same trend observed steps from readily available precursors. The functional
in Table 2. Thus, values around 90% ee were uniform- resin prepared in this way has been applied to the
ly observed, 4.0% below (mean value) those observed asymmetric Michael addition of 1,3-dicarbonyl com-
with the reference, homogeneous system.[3a]
pounds to b-nitrostyrenes with good to excellent
As mentioned above, the ultimate reason for the yields and enantioselectivities. The 1,2,3-triazole
immobilization of homogeneous catalysts is to open linker provides the immobilized squaramide with ex-
a simple way for recovery (by simple filtration) and cellent catalytic stability, thus allowing its successful
reuse, thus upgrading the sustainability characteristics recovery and reuse in 10 consecutive reaction cycles.
of the processes where the considered catalysts act.
The recyclability of 9c was studied in the reaction of
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A Polystyrene-Supported, Highly Recyclable Squaramide Organocatalyst
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Experimental Procedure for Michael Reactions
To a suspension of squaramide organocatalyst 9c (2 mol%)
in CH2Cl2 (0.6 mL), the nitroolefin 11 (0.2 mmol) and the
1,3-dicarbonyl compound 10 (0.4 mmol) were added at
room temperature. The reaction mixture was magnetically
stirred at room temperature and monitored by TLC until
complete conversion of the starting material. The resultant
suspension was filtered, the resin was washed twice with
CH2Cl2 on the same filter, and the filtrate was concentrated
under reduced pressure and purified by column chromatog-
raphy (silica gel, hexane/EtOAc) to give the pure Michael
adduct.
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Recycling of 9c
trans-b-Nitrostyrene (11a) (45 mg, 0.3 mmol) and catalyst 9c
(34.2 mg, f=0.35 mmolgÀ1, 4 mol%) were mixed with 2.4-
pentanedione (10a) (60 mL, 0.6 mmol) in CH2Cl2 (0.9 mL).
The suspension was stirred at room temperature for 6 h and
then directly filtered. The solid resin was washed twice with
CH2Cl2 and the organic filtrate was concentrated under re-
duced pressure. The addition product, 12a, was purified by
column chromatography and the functional resin 9c was
dried overnight under vacuum and directly used in the next
reaction cycle.
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Acknowledgements
This work was funded by MINECO (Grants CTQ2008-
00947/BQU and CTQ2012-38594-C02-01), DEC Generalitat
de Catalunya Grant (Grant 2009SGR623) and ICIQ Founda-
tion. P.K. thanks MICINN for an FPI fellowship and P.R.
thanks MICINN for a Torres Quevedo postdoctoral grant.
The authors gratefully acknowledge ICIQ NMR and MS
Units for their help.
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ꢃ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2012, 354, 2905 – 2910