Polystyrene-supported organocatalysts for α-selenenylation and Michael reactions: A common post-modification approach for catalytic differentiation

Article abstract of DOI:10.1016/j.catcom.2011.08.040

Three different resin-supported catalysts have been prepared by using the well established post-modification approach by means of thiol-ene coupling reaction. Two catalysts were tested for the first time in the asymmetric α-selenenylation of propanal, whi

Full text of DOI:10.1016/j.catcom.2011.08.040

Catalysis Communications 16 (2011) 75–80
Contents lists available at SciVerse ScienceDirect
Catalysis Communications
journal homepage: www.elsevier.com/locate/catcom
Short Communication
Polystyrene-supported organocatalysts for α-selenenylation and Michael reactions
A common post-modification approach for catalytic differentiation
⁎
Francesco Giacalone, Michelangelo Gruttadauria , Paola Agrigento, Vincenzo Campisciano, Renato Noto
Dipartimento di Scienze e Tecnologie Molecolari e Biomolecolari (STEMBIO), Sez. Chimica Organica “E. Paternò”, Università di Palermo, Viale delle Scienze, Ed. 17, 90128, Palermo, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 30 April 2011
Received in revised form 2 August 2011
Accepted 5 August 2011
Available online 16 September 2011
Three different resin-supported catalysts have been prepared by using the well established post-modification
approach by means of thiol-ene coupling reaction. Two catalysts were tested for the first time in the asym-
metric α-selenenylation of propanal, while the third catalyst was used in the Michael addition reaction.
While the preliminary results are not encouraging in the case of supported Jørgensen’ catalyst, interesting
data have been collected with both for the supported MacMillan and prolyl-prolinol catalysts. In fact, these
catalysts displayed good activity and selectivity. A reversed enantioselectivity in the α-selenenylation was
observed by changing the polarity of the solvent. Finally, these materials were easily recovered, and used
four and five times, respectively.
Keywords:
Organocatalysis
Supported catalysts
Michael reaction
α-selenenylation
© 2011 Elsevier B.V. All rights reserved.
1. Introduction
Hillman reactions [11]. In order to show the general applicability of
our approach (Fig. 1) we have decided to synthesize other polystyrene-
The supporting of homogeneous chiral organocatalysts is of great
interest since it allows to obtain heterogeneous catalytic materials
which can be easily manipulated. Particularly, polymers, in insoluble
bead form, offer a great advantage in recovery of the supported chiral
catalyst by filtration [1–4]. In fact, the main reason that prompted
chemists to immobilize chiral organocatalysts lies in the synthetic
advantages for larger scale production of cheap, easily available and
recoverable materials, able to be reused for several cycles. The organic
catalyst, or its precursor, can be introduced after the macromolecular
synthesis (polymerization), or before it. The first case is described as
post-modification strategy whereas the second approach is referred
as a bottom-up strategy. Recently, a discussion on such approaches
has been reported [5]. In the last years, our research group has devoted
efforts to the development of recyclable polystyrene-supported orga-
nocatalysts employing the post-modification strategy. In this way,
several proline and prolinamide-supported catalysts were synthe-
sized starting from commercially available mercaptomethylpolystyr-
ene (1% cross-linked with DVB). The proper organic catalysts were
immobilized using a styrene functionality as anchorage moiety
through the thiol-ene coupling protocol. Starting from this common
immobilization strategy, we got a set of diversified catalysts, which
were successfully employed in the enantioselective aldol reaction
[6–9] and non-enantioselective α-selenenylation [10] and Baylis–
supported organocatalysts employing the same strategy. In this com-
munication, we report preliminary results on the synthesis and use
of three different resin-supported catalysts. Two catalysts were test-
ed in the asymmetric α-selenenylation of propanal, being this the
first example in which the title reaction is performed using a sup-
ported catalyst. The third catalyst was employed in the Michael addi-
tion between nitrostyrene and aldehydes. These reactions furnish
useful intermediates that could be converted into valuable chiral
building blocks [12, 13].
2. Experimental
2.1. General
2-(Phenylselenyl)propanal [14] and Michael products [15,16] are
known compounds and showed spectroscopic and analytical data in
agreement with their structures. The configurations of the products
were assigned by comparison with literature data. Derivatives 9, 10
[17] and 12[9] are known compounds and have been prepared as
reported in the literature. Chiral HPLC analyses for ee determinations
were performed by using a Shimadzu LC-10 AD apparatus equipped
with an SPD-M10 A UV detector and Daicel columns (OD-H, AD-H,
AS-H) by using hexane/2-propanol as the eluent. Semi-solid NMR
spectra were recorded with a Bruker Avance 2 400 MHz spectrometer
at 300 K by using the CPMG pulse sequence with a proton pulse of
8.77 μs and MAS rate 5 KHz. Samples (ca. 5 mg) were swollen in
CDCl350 μL.
⁎
Corresponding author. Tel.: +39 091 596919; fax: +39 091 596825.
E-mail address: michelangelo.gruttadauria@unipa.it (M. Gruttadauria).
1566-7367/$ – see front matter © 2011 Elsevier B.V. All rights reserved.
doi:10.1016/j.catcom.2011.08.040

76
F. Giacalone et al. / Catalysis Communications 16 (2011) 75–80
amount of available catalyst (7: 0.47 mmol/g; 11: 0.91 mmol/g; 15:
1.0 mmol/g).
2.3. Typical procedure for α-selenenylation of propanal
To a mixture of the propanal (0.4 mmol) and N-(phenylseleno)
phthalimide (80%, 0.44 mmol) in the solvent of choice (0.8 mL), cat-
alyst 7 or 11 and the co-catalyst were added (0.04 mmol of each)
and the reaction mixture was stirred at rt for 2 h. The mixture
is filtered off in order to recover the catalyst and washed with
CH2Cl2, methanol and diethyl ether. The solvent was concentrated
under reduced pressure and the residue was quickly purified by a
short column chromatography (SiO2, petroleum ether/ethyl acetate)
gave 2-(phenylselanyl)propanal. Enantiomeric ratio has been deter-
mined by means of HPLC analysis by using a chiral AD-H column
(80/20 hexanes/i-PrOH; 0.75 mL/min; λ=214 nm).
Fig. 1. Catalytic differentiation by post-modification strategy based on thiol-ene
coupling.
2.2. General procedure for immobilization of catalysts
Mercaptomethylpolystyrene (1% cross-linked with DVB, spherical
beads, particle size 100–200 mesh, 2.5 mmol/g of -SH; 400 mg,
1 mmol) was added to precursors 6, 10 or 14 (2–3 mmol) and AIBN
(2–5 mol%) in toluene (25 mL) and the solution was degassed bub-
bling argon. The mixture was stirred at 110 °C overnight under
argon. After cooling to room temperature, the resin was filtered and
washed with dichloromethane, methanol and diethyl ether. The
weight increase serves as an estimation on catalyst precursor cova-
lently attached to the resin [18]. When Boc deprotection was needed,
the resin was suspended in HCOOH (1.4 mL, for 7) or in CH2Cl2/TFA
5:1 v/v and stirred for 20 h. After this time, water was added and
the mixture was filtered off. The resin was washed with a saturated
solution of NaHCO3, water, methanol and diethyl ether. Hence, the
resin was dried in oven at 60 °C for 2 h. The weight difference corre-
sponds to the amount of Boc removed, which is identical to the
2.4. Typical procedure for Michael reaction
A mixture of nitrostyrene (75 mg, 0.5 mmol), benzoic acid (3.4 mg,
0.025 mmol) and catalyst 15 (24 mg, 0.025 mmol) in the proper solvent,
was stirred for 20 minutes. After this period the aldehyde (1.5 mmol)
was added and the mixture was further stirred. Then the solution was
filtered off and the catalyst was washed with ethyl acetate and diethyl
ether. The organic phase was concentrated under reduced pressure and
the residue was purified by a column chromatography (SiO2, petroleum
ether/ethyl acetate) to give the corresponding known Michael adduct.
Scheme 1. Synthesis of supported Jørgensen catalyst 7.

F. Giacalone et al. / Catalysis Communications 16 (2011) 75–80
77
good yield. The carbamate deprotection followed by silylation leads
to key intermediate 6, which was in turn immobilized onto a cross-
linked mercaptomethylpolystyrene through a thiol-ene coupling pro-
tocol to give resin 7 with a loading of 0.47 mmol/g.
Analogously, the same protocol has been used to covalently an-
chor MacMillan catalyst's precursor 10[17], which led to the final cat-
alyst with a loading of 0.91 mmol/g (Scheme 2). The lowest loading
showed by resin 7 may be due to the major steric hindrance of the
precursor 6 with respect to 10, which make more difficult the right
orientation during the coupling. However, we think that the remain-
ing unreacted SH groups on the resin surface are not able to affect the
catalytic process.
Catalysts 7 and 11 were characterized by semi-solid 1H NMR. In
Figs. 2 and 3 are reported 1H NMR spectra.
Next, we tested the so-obtained catalytic materials in the asymmet-
ric α-selenenylation reaction of propanal, employing N-(phenylseleno)
phthalimide (NPSP) as selenenylating agent. Unfortunately, applying
the best reaction conditions reported for this reaction [14], catalyst 7
revealed to work worst and slowest even compared with the precursor
6 itself (Table 1, entry 5). Probably, both the presence of the support and
that of the styrenic linker negatively affects the catalytic activity.
Better results were obtained with catalyst 11 (Table 2) [19]. In
fact, this time it was possible carry out reactions in only 2 h. A screen-
ing of solvent revealed dichloromethane as the best one (entry 6), but
it is noteworthy to note that in acetonitrile a decrease in enantios-
electivity was observed (entry 3) while in DMSO or DMF (entries 4–
5), a change in enantioselectivity was observed. This finding has
been already noticed, but only just explained in terms of influence
of solvent dielectric constant [20,21]. We think this behavior deserves
for a more in depth investigation due to its mechanistic implications
and further experiments are currently underway.
Scheme 2. Synthesis of supported MacMillan catalyst 11.
3. Results and discussion
3.1. Synthesis and test of supported catalysts for asymmetric
α-selenenylation
Supported Jørgensen catalyst has been prepared by following the
synthetic strategy depicted in Scheme 1. Starting from commercially
available trans-N-Boc-4-hydroxy-L-proline methyl ester, the corre-
sponding derivative endowed with a styrene moiety 3 has been easily
prepared. This can react with freshly prepared 3,5-bis(trifluoro-
methyl)phenylmagnesium bromide 4 to afford diaryl prolinol 5 with
The temperature has a minor influence in the stereochemical out-
come (entries 6–8). In fact, cooling down the reaction mixture results
in a slightly increase in enantioselectivity, although longer reaction
times are needed. In dichloromethane, the presence of TFA as co-
catalyst has been proved to be necessary, in order to achieve better
Fig. 2. Semi-solid 1H CPMG NMR spectra of resin 7.

78
F. Giacalone et al. / Catalysis Communications 16 (2011) 75–80
Fig. 3. Semi-solid 1H CPMG NMR spectra of resin 11.
yield and enantiomeric ratio (entry 9). Finally, we carried out recy-
cling studies (entries 10–12). After reactions took place, the catalyst
has been recovered by filtration, washed with CH2Cl2, methanol and
diethyl ether, dried and reused. Interestingly its selectivity remains
almost unaffected after 4 cycles with only a slight decrease in activity.
It is also interesting to note that, the levels of activity and selectivity
displayed in homogeneous conditions by using monomer 10 have
been matched with resin 11 (compare entries 13 and 6–8) indicating
that in this case the post-modification approach is a good choice. Fi-
nally, resin used in DMF in the first cycle (entry 5) was used in a sec-
ond cycle employing CH2Cl2. Er value (entry 14) indicated the
reproducibility of the catalyst.
3.2. Synthesis and test of supported catalysts for asymmetric Michael
reaction
The post-modification strategy has been also followed in order to
prepare resin-supported prolyl-prolinol (Scheme 3). In this case, con-
densation between proline-derivative 12 and L-prolinol afforded the
Table 2
Asymmetric α-selenenylation reaction between propanal and N-(phenylseleno)phtha-
limide employing 11 as catalyst.a
Table 1
Asymmetric α-selenenylation reaction between propanal and N-(phenylseleno)phtha-
limide (NPSP) employing 7 as catalyst.a
Entry
Cycle
Solvent
T (°C)
t (h)
Yieldb (%)
Erc (%)
1
2
3
4
5
6
7
8
1
1
1
1
1
1
1
1
1
2
3
4
1
2
THF
25
25
25
25
25
25
0
−20
25
25
25
25
25
25
2
2
2
2
2
2
24
24
2
2
2
2
2
29
58
67
35
41
86
75
72
67
66
70
64
82
75
70/30
73/27
62/28
39/61
30/70
85/15
86/14
88/12
73/27
85/15
83/17
83/17
88/12
85/15
Toluene
MeCN
DMSO
DMF
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
9d
10
11
12
13e
14f
Entry
Cycle
Solvent
T (°C)
t (h)
Yield(b) (%)
Er(c) (%)
1
2
3
1
1
2
2
–
Toluene
Toluene
CH2Cl2
CH2Cl2
CH2Cl2
0
25
0
25
25
22
22
24
22
22
–
–
76
20
30
82
51/49
87/13
75/25
80/20
2
4
a
Reaction conditions: propanal (0.4 mmol), NPSP (0.44 mmol), 11 (0.04 mmol), tri-
fluoroacetic acid (0.04 mmol), solvent (0.8 ml).
5(c)
aReaction conditions: propanal (0.4 mmol), NPSP (0.44 mmol),
nitrobenzoic acid (0.04 mmol), solvent (0.8 mL).
bIsolated yields.
7
(0.04 mmol), 4-
Isolated yields.
Enantiomeric ratio determined by HPLC.
Reaction carried out without TFA.
Reaction carried out using 0.04 mmol of 10 as catalyst.
b
c
d
cEnantiomeric ratio determined by HPLC.
dReaction carried out using 0.04 mmol of 6 as catalyst.
e
f
This cycle was carried out with resin used in DMF (entry 5).

F. Giacalone et al. / Catalysis Communications 16 (2011) 75–80
79
Table 4
Asymmetric Michael reaction between nitrostyrene and aldehydes catalyzed by 15:
substrate scope.
Entry
1
Aldehyde
t (h)
24
Cycle
1
Yield(B)
96
Syn/Anti(c)
92/8
Ee(d) (%)
92/8
2
24
24
2
3
78
97
93/7
92/8
92/8
92/8
Scheme 3. Synthesis of supported prolyl-prolinol catalyst 15.
3e
expected prolinamide 14 in not good yield, although such procedure
has not been optimized. Once again, thiol-ene coupling reaction
with mercaptomethyl resin followed by Boc deprotection successfully
led to the new catalytic material 15 with a loading of 1.0 mmol/g (see
supporting information for semi-solid 1H NMR spectrum).
4
72
3
–
–
–
5
24
72
1
3
33
97/3
92/8
Once prepared, catalyst 15 has been used in the Michael reaction be-
tween propanal and nitrostyrene (Table 3). As a starting point we ap-
plied the best reaction condition found for the homogeneous catalyst
[22], namely 0.2 M of nitrostyrene in CH2Cl2 with 5 mol% of 15 and
5 mol% of benzoic acid (entry 1). Although selectivity was good, after
45 h only a 33% yield was obtained. Then we employed more concen-
trated solutions (2 M) in which the low surface area catalyst performed
better with or without the presence of water (entries 2–3). In order to
see the real effect of water [23–24], reaction time was shortened from
45 to 24 h, and this helped to discriminate the beneficial presence of
water both on the yield and in the selectivity (entries 4–5). A third
cycle with the same catalyst resulted in a decrease of activity, which
was completely restored in the forth cycle after an easy regeneration
step (entries 6–7) [7–9].
6e
–
–
–
7e
8e
24
24
4
4
72
54
77/23
92/8
100/0
80/20
9f
48
5
64
97/3
80/20
Next, we extended the scope of the reaction employing a set of dif-
ferent aliphatic aldehydes (Table 4). Excellent results have been also
obtained with butyraldehyde although between the first and the
third cycles a regeneration step has been needed in order to restore
aReaction conditions: aldehyde (1.5 mmol), nitrostyrene (0.5 mmol), 15 (0.025 mmol),
benzoic acid (0.025 mmol), CH2Cl2 (250 μL), water (100 μL), room temperature.
bIsolated yields.
cDetermined by 1H NMR spectroscopic analysis of the crude product.
dEnantiomeric ratio determined by HPLC.
eReaction carried out with catalyst regenerated with 200 μL of formic acid during 2.5 h.
fReaction carried out with catalyst regenerated two times.
Table 3
Asymmetric Michael reaction between propanal and nitrostyrene catalyzed by 15.
catalyst activity (entries 1–3). No products, even with longer reaction
time, were achieved from branched aldehydes such as isobutyralde-
hyde and cyclohexanecarboxaldehyde (entries 4 and 6, respectively),
whilst isovaleraldehyde reacted slowly (entry 5). Excellent enantios-
electivity has been showed by hexanal, while hydrocinnamic alde-
hyde needed an extended reaction time for improving the yield
(entries 7–9). It is worth mentioning that resin 15 worked nicely for
5 cycles, being the regeneration protocol able to restore the catalytic
activity several times. Moreover, in some case, better performances
than in homogeneous conditions have been achieved with the sup-
ported catalyst [22].
Entry Solvent
t (h) Cycle Yield(b) Syn/Anti(c) Er(d) (%)
1
2
CH2Cl2 (2.5 mL)
CH2Cl2 (250 μL)
45
45
1
1
1
2
2
3
4
33
95
98
64
82
48
99
91/9
95/5
96/4
96/4
95/5
96/4
96/4
96/4
88/12
87/13
87/13
92/8
3
4
CH2Cl2/H2O (250/100 μL) 45
CH2Cl2 (250 μL) 24
5
CH2Cl2/H2O (250/100 μL) 24
CH2Cl2/H2O (250/100 μL) 24
CH2Cl2/H2O (250/100 μL) 24
6
92/8
91/9
4. Conclusions
7(e)
aReaction conditions: propanal (1.5 mmol), nitrostyrene (0.5 mmol), 15 (0.025 mmol),
benzoic acid (0.025 mmol), solvent, room temperature.
bIsolated yields.
In summary, three different supported organocatalysts have been
prepared employing the useful post-grafting strategy. In doing so,
catalyst precursors were covalently linked by means of thiol-ene cou-
pling protocol. Whilst the supported Jørgensen catalyst does not
reach similar levels of activity and selectivity than their unsupported
cDetermined by 1H NMR spectroscopic analysis of the crude product.
dEnantiomeric ratio determined by HPLC.
eReaction carried out with catalyst regenerated with 200 μL of formic acid during 2.5 h.

80
F. Giacalone et al. / Catalysis Communications 16 (2011) 75–80
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and recyclable at least for four cycles. This is the first example of
asymmetric α-selenenylation reaction carried out in the presence of
a supported organocatalyst. Moreover, it appears to be interesting
the reversal in enantioselectivity observed by changing the solvent.
Analogously, the supported version of prolyl-prolinol efficiently
promoted the asymmetric Michael reaction between nitrostyrene
and aliphatic aldehydes just in 5 mol%. Moreover, in some case the
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Acknowledgements
Financial support from the University of Palermo (Funds for selected
topics), the Italian MIUR within the national project “Catalizzatori, meto-
dologie e processi innovativi per il regio e stereocontrollo delle sintesi
organiche” and the “Centro Grandi Apparecchiature—UniNetLab—
Università di Palermo funded by P. O. R. Sicilia 2000–2006, Misura
3.15 Quota Regionale” (1H CPMG NMR spectra) are gratefully
acknowledged.
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Appendix A. Supplementary data
Supplementary data to this article can be found online at doi:10.
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