Combined bead polymerization and Cinchona organocatalyst immobilization by thiol-ene addition

Article abstract of DOI:10.3762/bjoc.8.125

In this work, we report an unusually concise immobilization of Cinchona organocatalysts using thiol-ene chemistry, in which catalyst immobilization and bead polymerization is combined in a single step. A solution of azo initiator, polyfunctional thiol, polyfunctional alkene and an unmodified Cinchona-derived organocatalyst in a solvent is suspended in water and copolymerized on heating by thiol-ene additions. The resultant spherical and gel-type polymer beads have been evaluated as organocatalysts in catalytic asymmetric transformations.

Full text of DOI:10.3762/bjoc.8.125

Combined bead polymerization and Cinchona
organocatalyst immobilization by thiol–ene addition
Kim A. Fredriksen1, Tor E. Kristensen*2 and Tore Hansen*1
Letter
Open Access
Address:
Beilstein J. Org. Chem. 2012, 8, 1126–1133.
1Department of Chemistry, University of Oslo, P.O. Box 1033
Blindern, NO-0315 Oslo, Norway and 2Norwegian Defence Research
Establishment (FFI), P.O. Box 25, NO-2027 Kjeller, Norway
doi:10.3762/bjoc.8.125
Received: 08 May 2012
Accepted: 25 June 2012
Published: 20 July 2012
Email:
Tor E. Kristensen* - tor-erik.kristensen@ffi.no; Tore Hansen* -
tore.hansen@kjemi.uio.no
This article is part of the Thematic Series "Organocatalysis".
Guest Editor: B. List
* Corresponding author
Keywords:
© 2012 Fredriksen et al; licensee Beilstein-Institut.
License and terms: see end of document.
asymmetric catalysis; Cinchona derivatives; organocatalysis;
polymerization; thiol–ene reaction
Abstract
In this work, we report an unusually concise immobilization of Cinchona organocatalysts using thiol–ene chemistry, in which cata-
lyst immobilization and bead polymerization is combined in a single step. A solution of azo initiator, polyfunctional thiol, polyfunc-
tional alkene and an unmodified Cinchona-derived organocatalyst in a solvent is suspended in water and copolymerized on heating
by thiol–ene additions. The resultant spherical and gel-type polymer beads have been evaluated as organocatalysts in catalytic
asymmetric transformations.
Introduction
Polymer-supported chiral organocatalysts have emerged as a utilization of polymer-supported reagents or catalysts as part of
rapidly expanding field of research in recent years [1], in part conventional chemical synthesis.
due to the traditionally emphasized advantages of polymeric
immobilization (facilitated separation and recovery procedures, Consequently, we have been engaged in the development of
recycling etc.), but perhaps even more due to the enhanced scalable and expedient syntheses of polymer-supported
activity and selectivity sometimes exhibited by such organocat- organocatalysts for some time now [6,7]. In our bottom-up ap-
alysts, especially under aqueous conditions [2]. Recently, the proach for the preparation of polymer-supported organocata-
use of polymer-supported organocatalysts in continuous-flow lysts, the catalyst immobilization and the preparation of the
systems has also surfaced in the literature, and their develop- polymer scaffold are closely connected, to facilitate the syn-
ment is quickly gaining momentum [3-5]. Regrettably, cost thesis of larger quantities of supported catalyst [6,7]. Acrylic
issues linger over the field as a whole, due to the lengthy and derivatives of established organocatalysts are prepared on a
laborious syntheses involved in the preparation of these gram scale by using nonchromatographic procedures and
polymer-supported entities, hampering the more widespread copolymerized with suitable comonomers to give cross-linked
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Beilstein J. Org. Chem. 2012, 8, 1126–1133.
and microporous beads. Such polymer beads have provided The thiol–ene addition was described by Theodor Posner
good to excellent results as organocatalysts in various asym- already in 1905 [10], and it has been in more or less continuous
metric transformations [6,7].
use since then. The thiol–ene addition can readily be adapted
for polymerization, by using polyfunctional alkenes in combina-
Cinchona derivatives are used in several types of organocata- tion with polyfunctional thiols [11-13]. We envisaged that poly-
lysts, and they are all equipped with a pendant vinylic function- merization into a cross-linked and beaded resin could be
ality susceptible to activation by chemical transformations combined with immobilization of a Cinchona derivative in a
based on radical intermediates [1]. As a result, polymeric single step under suitable conditions. Such a procedure would
immobilization of Cinchona derivatives by using thiol–ene ad- enable us to prepare polymer-supported Cinchona organocata-
dition has a substantial history, founded on procedures devel- lysts directly in a single step and on a large scale, using unmod-
oped already in the early 1970s [1]. Cinchona derivatives are ified Cinchona organocatalyst precursors.
either copolymerized with certain comonomers, such as acry-
Results and Discussion
lonitrile, directly in a bottom-up fashion to give linear copoly-
Building blocks for the preparation of cross-
linked thiol–ene resins
mers [1,8], or anchored to prefabricated cross-linked and thiol-
funtionalized resins in a traditional post-modification approach
[1,9]. However, for the preparation of the preferred beaded and
cross-linked polymer resins, so easily handled and separated
from reaction mixtures by filtration, this necessitates several
steps, as the cross-linked resin must be prepared first by copoly-
merization, then equipped with thiol functionalities, and
finally joined with the Cinchona derivative through thiol–ene
coupling.
Research oriented towards thiol–ene chemistry has experienced
near explosive growth in the past few years, perhaps due to its
efficiency and functional tolerance, but possibly even more due
to its recent conceptualization as a “click” reaction [13]. In
order to prepare different polymer beads with varying degrees
of swelling characteristics, we assembled a small collection of
useful thiol and alkene building blocks (Figure 1).
Figure 1: Thiol, alkene and organocatalyst building blocks for combined bead polymerization and Cinchona organocatalyst immobilization.
1127

Beilstein J. Org. Chem. 2012, 8, 1126–1133.
Trithiol 4 is a readily available commercial product, whereas organocatalyst 2 was prepared from quinine, via the azide, in a
dithiol 5 was easily obtained from esterification of 3-mercapto- two-step sequence by using the Bose–Mitsunobu reaction fol-
propionic acid and propane-1,3-diol [14]. Trivinyl ether 6, poly- lowed by Staudinger reduction, as described by others [15].
ethylene glycol (PEG) dimethacrylate 7, diacrylate 8 and diallyl Thiourea Cinchona organocatalyst 3 was easily obtained from
ether 9 are all commercially available compounds. For catalyst 2 by reaction with the appropriate aromatic isothio-
thiol–ene additions via the radical pathway, the order of reactiv- cyanate [15].
ity of unsaturated compounds 6–9 towards the thiols is general-
Single step thiol–ene polymerization and
ly so: vinyl ether 6 > allyl ether 9 > acrylate 8 > methacrylate 7
[11]. Thiol–ene additions according to the anionic (Michael- Cinchona organocatalyst immobilization
type) mechanism have not been investigated in this work. As a With the assortment of building blocks depicted in Figure 1
minimum for obtaining cross-linked polymeric networks, either available, we could now obtain immobilized versions (10–12)
trithiol 4 has to be copolymerized with dialkenes 7–9, or dithiol of unmodified Cinchona catalysts 1–3 directly by oil-in-water
5 has to be copolymerized with trivinyl ether 6. These two main type thiol–ene suspension copolymerization. A solution of poly-
approaches can then be modified or finely tuned to match suit- functional thiol, polyfunctional alkene and Cinchona organocat-
able swelling characteristics by incorporation of smaller alyst in a water immiscible solvent, such as chlorobenzene or
amounts of any of the other constituents 4–9, thereby adjusting toluene, containing a small amount of azo radical initiator
the degree of cross-linking.
(AIBN), was suspended in dilute aqueous polyvinyl alcohol
(PVA) and heated under vigorous agitation. The suspended
As for the Cinchona organocatalysts, we wanted to incorporate and stabilized droplets then converted to spherical and gel-
either unmodified quinine (1), the primary amine organocata- type polymer beads. An overview of the immobilized
lyst 2, or thiourea organocatalyst 3 into the thiol–ene network Cinchona organocatalysts, and their constituents, is provided in
(Figure 1). While quinine is available directly, primary amine Scheme 1.
Scheme 1: Combined bead polymerization and Cinchona organocatalyst immobilization by thiol–ene addition.
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Beilstein J. Org. Chem. 2012, 8, 1126–1133.
After polymerization, the polymer beads were filtered and puri-
fied by Soxhlet extraction, and their organocatalyst loadings
were determined on the basis of CHN analysis, as only the
organocatalytic moiety contains nitrogen. Generally, the yield
of polymer beads, calculated on the basis of recovered material
versus the combined mass of starting materials, varied between
ca. 60–80%. Only an azo initiator, such as AIBN, could be
utilized, because peroxide initiators, such as dibenzoyl
peroxide, oxidise thiols.
Table 1: Polymer-supported quinines in asymmetric Michael addition.
Catalyst
Yield [%]a
ee [%]b
1
>95
>95
>95
92
23
14
11
14
12
10a
10b
10c
10d
The thiol-ene polymer beads 10–12 had a distinctively soft and
gel-like appearance, but were easily handled like conventional
microporous beads. They had favourable swelling characteris-
tics in several organic solvents, particularly in THF and
CH2Cl2, despite their significant degree of cross-linking. As
such, they have much in common with the CLEAR (cross-
>95
aIsolated yield. bDetermined by HPLC analysis.
linked ethoxylate acrylate resin) resins, a type of polymer transformation that we have investigated in our group as part of
support with all the characteristics of a microporous polymer developmental work in primary amine organocatalysis on a
that also has an unusually high degree of cross-linking [16]. previous occasion (Table 2) [18]. Compared to the free catalyst
Unlike vinyl ether 6 and allyl ether 9, acrylic building blocks 2, the yields obtained by using supported catalysts 11a,b are
such as 7 and 8 may undergo some degree of acrylic homopoly- inferior, but this is most probably due to the lack of solubility of
merization during network formation, although the thiol–ene the hydroxycoumarin, a very insoluble compound, in the reac-
addition is usually more rapid than the polymerization.
tion medium (CH2Cl2) and probably not so much a lack of
inherent activity. Interestingly, catalyst 11b, made by using
The ratio of thiol and alkene functionalities was adjusted to be dithiol 5 and trivinyl ether 6 (in addition to a few mol % of
close to unity, and the thiol–ene reaction usually has a high trithiol 4 to increase cross-linking slightly, giving beads of
degree of conversion; however, the presence of free thiol groups better quality), exhibited markedly improved selectivity
is probably unavoidable. We were, nevertheless, curious to compared to catalyst 11a, even matching that of the free cata-
investigate how these supported organocatalysts would func- lyst 2. This may be connected to the fact that the Cinchona
tion in asymmetric transformations when compared to the moiety becomes bound to the polymer network through the
unsupported catalysts.
Table 2: Polymer-supported primary amine Cinchona organocatalysts
in asymmetric preparation of warfarin.
Asymmetric organocatalytic transformations
using immobilized Cinchona organocatalysts
With supported Cinchona organocatalysts 10–12 available,
numerous organocatalytic transformations were potentially
available for benchmarking. As a rough indication of activity,
we started out by investigating quinine (1) and supported cata-
lyst 10a–d in the Michael addition of 3-methoxythiophenol and
cyclohex-2-enone (Table 1) [17]. Although the performance of
quinine in this reaction is poor with regards to selectivity
(providing only 23% ee), and probably not very useful for
Catalyst
Yield [%]a
ee [%]b
benchmarking, the supported catalysts 10a–d were obviously
catalytically active, albeit modestly selective compared to the
free catalyst, giving quantitative yields and a selectivity of
11–14% ee.
2
75
15
25
15
—
92
77
94
84
—
11a
11bc
11bd
11be
Of greater interest was the performance of the primary amine
organocatalysts 11. Polymer-supported catalysts 11a,b were
tried out in the asymmetric preparation of the anticoagulant
warfarin from benzylideneacetone and 4-hydroxycoumarin, a
aIsolated yield. bDetermined by HPLC analysis. cFirst cycle. dSecond
cycle. eThird cycle.
1129

Beilstein J. Org. Chem. 2012, 8, 1126–1133.
thiol, and use of a difunctional thiol then improves the mobility resin may explain this, and indeed, CHN analysis of polymer
of this catalytic unit as it is now positioned at the end of a linker resins after recycling verified that a loss of nitrogen content,
of greater length. This effect does not seem to have played out meaning leaching of the active species, had occurred.
for catalyst 10d though. Catalysts 10a–d all seemed to behave
much the same. Catalyst 11b could be recycled, but both yield
Table 4: Polymer-supported thiourea Cinchona organocatalyst in the
and selectivity quickly eroded (Table 2).
asymmetric Michael addition.
Having confidence in the overall validity of our approach to
polymer-supported Cinchona organocatalysts, we tested the
supported thiourea catalyst 12 in the Michael addition of thio-
phenol and cyclohex-2-enone [17], a transformation known to
be very efficiently catalysed by the free thiourea catalyst 3
(Table 3) [19,20]. The immobilized catalyst 12 proved highly
active (the uncatalysed reaction is very slow), rapidly giving
quantitative yield, but somewhat reduced selectivity of the addi-
tion product compared to the free thiourea catalyst 3. To
investigate the extent to which free thiol groups could influence
the reaction by catalyzing a racemic pathway, we also tested
polymer beads without any Cinchona moiety present in this
transformation. Undeniably, polymer beads prepared without
any Cinchona organocatalyst present did also catalyze the reac-
tion. However, we found that several other polymer resins, such
as unmodified Merrifield resin (chloromethylated and cross-
Catalyst
Conversion [%]a
ee [%]b
12c
12d
12e
12f
>95
>95
34
92
92
92
—
trace
aDetermined by 1H NMR analysis of crude reaction mixture.
bDetermined by HPLC analysis. cFirst cycle, 3 d reaction time.
dSecond cycle, 4 d reaction time. eThird cycle, 4 d reaction time.
fFourth cycle, 4 d reaction time.
linked polystyrene), influence the reaction in the same manner. Conclusion
Consequently, we do not believe this to be an intrinsic property We have developed an unusually concise immobilization of
of our thiol–ene polymer beads, connected to the effect of free Cinchona organocatalysts by thiol–ene suspension copolymer-
thiol groups. In addition, capping free thiol groups on before- ization of polyfunctional thiols and alkenes together with
hand by treatment with excess methyl acrylate did not affect the unmodified Cinchona organocatalyst precursors. As such, bead
performance in this transformation.
polymerization and catalyst immobilization is combined in a
single step. Vinyl ethers, allyl ethers, acrylates and methacry-
lates can all be effectively incorporated as part of such thiol–ene
networks. The supported organocatalysts have been tried out
successfully in several asymmetric transformations, but catalyst
recycling so far is relatively poor. Hopefully, this expedient
method for immobilization of Cinchona derivatives can be
further developed in the future to improve activity and selec-
tivity, and also be widened to include other useful Cinchona-
derived species.
Table 3: Polymer-supported thiourea Cinchona organocatalyst in the
asymmetric Michael addition.
Catalyst
Yield [%]a
ee [%]b
Experimental
3
>95
>95
83
69
12
General: 1H NMR and 13C NMR spectra were recorded on a
Bruker AV 600 (600/150 MHz), Bruker Advance DRX 500
(500/125 MHz), Bruker DPX 300 (300/75 MHz) or Bruker
DPX 200 (200/50 MHz) spectrometer. Dry THF was obtained
aIsolated yield. bDetermined by HPLC analysis.
Catalyst 12 was also tested in the Michael addition of methyl from a solvent purification system (MB SPS-800 from
malonate to trans-β-nitrostyrene (Table 4) [21]. The catalyst MBraun). All other reagents and solvents were used as
gave quantitative yield and excellent enantioselectivity after 3–4 received. CHN analyses were carried out in the School of
days reaction time. However, the catalyst exhibited poor recy- Chemistry, at the University of Birmingham, UK. For flash
cling properties as yields fell sharply after the second reaction chromatography, silica gel from SdS (60 A, 40–63 μm,
cycle; but selectivity remained largely untouched. At this point, 550 m2/g, pH 7) and Merck (silica gel 60, 0.40–0.63 mm,
we suspected that loss of the catalytic entities from the polymer 480–540 m2/g, pH 6.5–7.5) were used, either manually or with
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Beilstein J. Org. Chem. 2012, 8, 1126–1133.
an automated system (Isco Inc. CombiFlash Companion with an oil-in-water type emulsion. The system was flushed with
PeakTrak software), with EtOAc/hexanes of technical quality. argon for 5 min. The suspension was heated to 70 °C and kept
Enantiomeric excess was determined by HPLC analysis using at this temperature for 3 h under stirring, allowed to cool to
analytical columns (Chiralpak AS-H or AD-H from Daicel room temperature, and then poured into a beaker containing
Chemical Industries).
MeOH (250 mL). The suspension was stirred for 15 min, and
the polymer beads were allowed to settle by gravity for 10 min.
The Cinchona organocatalysts 2 and 3 were prepared from The supernatant was removed by decantation, and the process
quinine (1) as described in the literature [15]. Dithiol 5 was was repeated until the supernatant was transparent (1–2 repeti-
prepared as described in the literature [14], and this compound tions). CH2Cl2 (50 mL) was added, the suspension was filtered
was kept refrigerated and protected from light in order to avoid by vacuum, and the polymer beads washed with water
deterioration on storage.
(1000 mL), THF–H2O (200 mL, 1:1), MeOH (200 mL) and
CH2Cl2 (50 mL). The polymer beads were then transferred to a
Preparation of polymer-supported quinines 10a–d: Quinine cellulose paper thimble and purified by Soxhlet extraction with
(1, 2.10 mmol for 10a or 2.00 mmol for 10b/10c or 1.50 mmol CH2Cl2 (70 mL) for 12 h, and then the purified beads were left
for 10d), trithiol 4 (6.20 mmol for 10a/10c or 6.00 mmol for to dry at room temperature for 24 h (75% yield for 11a, 85%
10b or 0.18 mmol for 10d), dithiol 5 (4.00 mmol for 10d), yield for 11b). Catalyst loadings were determined by CHN
dimethacrylate 7 (8.90 mmol for 10a), diacrylate 8 (8.10 mmol analysis.
for 10b), diallyl ether 9 (8.10 mmol for 10c), trivinyl ether 6
(2.43 mmol for 10d) and AIBN (5 wt % relative to monomers) Preparation of polymer-supported thiourea Cinchona
were dissolved in a monomer diluent (13 mL PhCl for 10a or organocatalyst 12: Cinchona derivative 3 (0.538 mmol),
15 mL PhCl for 10b/10c or 5 mL PhCl for 10d). Aqueous PVA trithiol 4 (0.17 mmol), dithiol 5 (3.48 mmol), trivinyl ether 6
(100 mL for 10a or 70 mL for 10b/10c or 39 mL for 10d, 0.5% (2.32 mmol) and AIBN (15 wt % relative to monomers) were
Mowiol 40-88) was added under stirring to give an oil-in-water dissolved in PhMe (7 mL). Aqueous PVA (50 mL, 0.5%
type emulsion. The system was flushed with argon for 5 min. Mowiol 40-88) and potassium iodide (to inhibit polymerization
The suspension was heated to 70 °C and kept at this tempera- in the aqueous phase, 20 mg) was added under stirring to give
ture for 3 h under stirring, allowed to cool to room temperature, an oil-in-water type emulsion. The system was flushed with
and poured into a beaker containing MeOH (250 mL). The argon for 5 min. The suspension was heated to 70 °C and kept
suspension was stirred for 15 min, and the polymer beads were at this temperature for 1 h under stirring, allowed to cool to
allowed to settle by gravity for 10 min. The supernatant was room temperature, and poured into a beaker containing MeOH
removed by decantation and the process was repeated until the (250 mL). The suspension was stirred for 15 min, and the
supernatant was transparent (1–2 repetitions). CH2Cl2 (50 mL) polymer beads were allowed to settle by gravity for 10 min. The
was added, the suspension was filtered by vacuum, and the supernatant was removed by decantation, and the process was
polymer beads were washed with water (1000 mL), THF–H2O repeated until the supernatant was transparent (1–2 repetitions).
(200 mL, 1:1), MeOH (200 mL) and CH2Cl2 (50 mL). The CH2Cl2 (50 mL) was added, the suspension was filtered by
polymer beads were then transferred to a cellulose paper vacuum, and the polymer beads washed with water (1000 mL),
thimble and purified by Soxhlet extraction with CH2Cl2 THF–H2O (200 mL, 1:1), MeOH (200 mL) and CH2Cl2
(70 mL) for 12 h, and then the purified beads were left to dry at (50 mL). The polymer beads were then transferred to a cellu-
room temperature for 24 h (67% yield for 10a, 67% yield for lose paper thimble and purified by Soxhlet extraction with
10b, 63% yield for 10c, 64% yield for 10d). Catalyst loadings CH2Cl2 (70 mL) for 12 h, and the purified beads were left to
were determined by CHN analysis.
dry at room temperature for 24 h (62% yield). Catalyst loadings
were determined by CHN analysis.
Preparation of polymer-supported primary amine Cinchona
organocatalysts 11a,b: Cinchona derivative 2 (2.00 mmol for General procedure for asymmetric Michael addition of
11a or 1.20 mmol for 11b), trithiol 4 (5.00 mmol for 11a or 3-methoxythiophenol to cyclohex-2-enone: 3-Methoxythio-
0.16 mmol for 11b), dithiol 5 (4.20 mmol for 11b), dimethacry- phenol (0.30 mL, 3.10 mmol), and catalyst (1 mol %) were
late 7 (6.24 mmol for 11a), trivinyl ether 6 (2.51 mmol for 11b) dissolved in CH2Cl2 (6 mL). Cyclohex-2-enone (0.50 mL,
and AIBN (5 wt % relative to monomers) were dissolved in a 4.03 mmol) was then added in one portion, and the resulting
monomer diluent (12 mL PhCl for 11a or 6 mL PhMe for 11b). mixture was stirred at room temperature for 2 h. The crude reac-
Aqueous PVA (70 mL for 11a or 40 mL for 11b, 0.5% Mowiol tion mixture was filtered, and the polymer beads were washed
40-88) and potassium iodide (to inhibit polymerization in the with CH2Cl2 (50 mL). The combined organic phase was evapo-
aqueous phase, 23 mg for 11b) was added under stirring to give rated in vacuo, and the crude product was purified by flash
1131

Beilstein J. Org. Chem. 2012, 8, 1126–1133.
References
chromatography on silica gel (10% EtOAc in hexanes) to give
the product as a colorless oil. This is a known compound [17].
Enantiomeric excess was determined by HPLC analysis
(Chiralpak AS-H, 50% iPrOH in isohexane, 0.3 mL/min):
tR = 25.2 min and 38.2 min.
1. Kristensen, T. E.; Hansen, T. Synthesis of Chiral Catalysts Supported
on Organic Polymers. In Catalytic Methods in Asymmetric Synthesis:
Advanced Materials, Techniques and Applications; Gruttadauria, M.;
Giacalone, F., Eds.; John Wiley & Sons, Inc.: Hoboken, NJ, USA,
2011; pp 209–256. doi:10.1002/9781118087992.ch4
2. Gruttadauria, M.; Giacalone, F.; Noto, R. Adv. Synth. Catal. 2009, 351,
33–57. doi:10.1002/adsc.200800731
General procedure for asymmetric Michael addition of
4-hydroxycoumarin to benzylideneacetone: To a vial
containing 4-hydroxycumarin (0.35 g, 2.17 mmol), benzyl-
ideneacetone (0.56 g, 3.82 mmol) and catalyst (20 mol %), was
added CH2Cl2 (18 mL) and CF3CO2H (60 μL, 40 mol %). The
reaction mixture was stirred at room temperature for 72 h,
diluted with CH2Cl2 and filtered. The polymer beads were
washed with CH2Cl2 (70 mL). The combined organic phase
was evaporated in vacuo, and the crude product was purified by
flash chromatography on silica gel (10% EtOAc in hexanes and
then 25% EtOAc in hexanes) to give the product as a colorless
solid. This is a known compound [18]. Enantiomeric excess was
determined by HPLC analysis (Chiralpak AD-H, 20% iPrOH in
isohexane, 1.0 mL/min): tR = 7.3 min and 14.7 min.
3. Alza, E.; Rodríguez-Escrich, C.; Sayalero, S.; Bastero, A.;
Pericàs, M. A. Chem.–Eur. J. 2009, 15, 10167–10172.
doi:10.1002/chem.200901310
4. Cambeiro, X. C.; Martín-Rapún, R.; Miranda, P. O.; Sayalero, S.;
Alza, E.; Llanes, P.; Pericàs, M. A. Beilstein J. Org. Chem. 2011, 7,
1486–1493. doi:10.3762/bjoc.7.172
5. Alza, E.; Sayalero, S.; Cambeiro, X. C.; Martín-Rapún, R.;
Miranda, P. O.; Pericàs, M. A. Synlett 2011, 464–468.
doi:10.1055/s-0030-1259528
6. Kristensen, T. E.; Vestli, K.; Fredriksen, K. A.; Hansen, F. K.;
Hansen, T. Org. Lett. 2009, 11, 2968–2971. doi:10.1021/ol901134v
7. Kristensen, T. E.; Vestli, K.; Jakobsen, M. G.; Hansen, F. K.;
Hansen, T. J. Org. Chem. 2010, 75, 1620–1629. doi:10.1021/jo902585j
8. Kobayashi, N.; Iwai, K. J. Am. Chem. Soc. 1978, 100, 7071–7072.
doi:10.1021/ja00490a053
9. Hedge, P.; Khoshdel, E.; Waterhouse, J.; Fréchet, J. M. J.
J. Chem. Soc., Perkin Trans. 1 1985, 2327–2331.
doi:10.1039/P19850002327
General procedure for asymmetric Michael addition of thio-
phenol to cyclohex-2-enone: Thiophenol (0.20 mL,
1.95 mmol) and catalyst (1 mol %) were dissolved in CH2Cl2
(1.7 mL). Cyclohex-2-enone (0.15 g, 1.52 mmol) was added in
one portion, and the resulting reaction mixture was stirred at
room temperature for 2.5 h. The crude reaction mixture was
diluted with CH2Cl2 and filtered, and the polymer beads were
washed with CH2Cl2 (70 mL). The combined organic phase
was evaporated in vacuo, and the crude product was purified by
flash chromatography on silica gel (5% EtOAc in hexanes) to
give the product as a colorless oil. This is a known compound
[17]. Enantiomeric excess was determined by HPLC analysis
(Chiralpak AD-H, 2% iPrOH in isohexane, 1.0 mL/min):
tR = 19.2 min and 26.2 min.
10.Posner, T. Ber. Dtsch. Chem. Ges. 1905, 38, 646–657.
doi:10.1002/cber.190503801106
11.Hoyle, C. E.; Lee, T. Y.; Roper, T. J. Polym. Sci., Part A: Polym. Chem.
2004, 42, 5301–5338. doi:10.1002/pola.20366
12.Kade, M. J.; Burke, D. J.; Hawker, C. J.
J. Polym. Sci., Part A: Polym. Chem. 2010, 48, 743–750.
doi:10.1002/pola.23824
13.Hoyle, C. E.; Bowman, C. N. Angew. Chem., Int. Ed. 2010, 49,
1540–1573. doi:10.1002/anie.200903924
14.Song, J.; Chen, L.; Wang, Y.; Chen, W.; Wang, R.
Front. Chem. Eng. China 2008, 2, 390–395.
doi:10.1007/s11705-008-0080-6
15.Vakulya, B.; Varga, S.; Csámpai, A.; Soós, T. Org. Lett. 2005, 7,
1967–1969. doi:10.1021/ol050431s
16.Kempe, M.; Barany, G. J. Am. Chem. Soc. 1996, 118, 7083–7093.
doi:10.1021/ja954196s
17.Hiemstra, H.; Wynberg, H. J. Am. Chem. Soc. 1981, 103, 417–430.
doi:10.1021/ja00392a029
General procedure for asymmetric Michael addition of
methyl malonate to trans-β-nitrostyrene: trans-β-Nitrostyrene
(83.4 mg, 0.56 mmol) and methyl malonate (0.23 g, 1.78 mmol)
were dissolved in toluene (1 mL). Catalyst 12 (10 mol %) was
added, and the reaction mixture was left at −30 °C for 72 h. The
crude reaction mixture was diluted with CH2Cl2 and filtered,
and the polymer beads were washed with CH2Cl2 (50 mL). The
combined organic phase was evaporated in vacuo, and the crude
product was purified by flash chromatography on silica gel
(Gradient: 5–40% EtOAc in hexanes). This is a known com-
pound [21]. The conversion of starting material was determined
by 1H NMR analysis of the crude product. Enantiomeric excess
was determined by HPLC analysis (Chiralpak AD-H,
30% iPrOH in isohexane, 1.0 mL/min): tR = 7.3 min and
9.3 min.
18.Kristensen, T. E.; Vestli, K.; Hansen, F. K.; Hansen, T.
Eur. J. Org. Chem. 2009, 5185–5191. doi:10.1002/ejoc.200900664
19.Jang, H. B.; Rho, H. S.; Oh, J. S.; Nam, E. H.; Park, S. E.; Bae, H. Y.;
Song, C. E. Org. Biomol. Chem. 2010, 8, 3918–3922.
doi:10.1039/c0ob00047g
20.Li, B.-J.; Jiang, L.; Liu, M.; Chen, Y.-C.; Ding, L.-S.; Wu, Y. Synlett
2005, 603–606. doi:10.1055/s-2005-863710
21.McCooey, S. H.; Connon, S. J. Angew. Chem. 2005, 117, 6525–6528.
doi:10.1002/ange.200501721
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