Solid acids as heterogeneous support for primary amino acid-derived diamines in direct asymmetric aldol reactions

Article abstract of DOI:10.1002/adsc.201000871

We have achieved the non-covalent immobilization of chiral primary amino acid-derived diamines on organic and inorganic sulfonated solid acids through acid-base interaction. With the commercial sulfonated fluoropolymer nafion NR50 as support an optimal ba

Full text of DOI:10.1002/adsc.201000871

FULL PAPERS
DOI: 10.1002/adsc.201000871
Solid Acids as Heterogeneous Support for Primary Amino Acid-
Derived Diamines in Direct Asymmetric Aldol Reactions
Anneleen L. W. Demuynck,a Li Peng,a Filip de Clippel,a Jozef Vanderleyden,b
Pierre A. Jacobs,a and Bert F. Selsa,*
a
Centre for Surface Chemistry and Catalysis, Katholieke Universiteit Leuven, Kasteelpark Arenberg 23, B-3001 Leuven,
Belgium
Fax : (+32)-016-321-998; e-mail: bert.sels@biw.kuleuven.be
Centre of Microbial and Plant Genetics, Katholieke Universiteit Leuven, Kasteelpark Arenberg 20, B-3001 Leuven,
b
Belgium
Received: November 19, 2010; Revised: December 30, 2010; Published online: March 10, 2011
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.201000871.
Abstract: We have achieved the non-covalent immo- to 98% ee). Furthermore, catalysis with the support-
bilization of chiral primary amino acid-derived di- ed diamine was demonstrated to occur truly hetero-
ACHTUNGTRENNUNGamines on organic and inorganic sulfonated solid geneously and the loaded nafionꢀ NR50 beads
acids through acid-base interaction. With the com- could be reused several times. Ultimately, the immo-
mercial sulfonated fluoropolymer nafionꢀ NR50 as bilized catalyst/nafionꢀ NR50 system was successful-
support an optimal balance was found between activ- ly implemented in a fixed-bed reactor set-up under
ity and stereoselectivity of the supported catalyst in continuous flow conditions.
direct asymmetric aldol reactions of linear ketones
and aromatic aldehydes. Under optimized conditions Keywords: aldol reaction; chiral primary amines;
aldol products were obtained in high yields and with continuous flow conditions; heterogeneous catalysis;
excellent enantioselectivities for the syn-product (up nafionꢀ; non-covalent immobilization
Introduction
overcome these disadvantages.[4] Towards the discov-
ery of more advanced catalysts and their implementa-
After a decade of intensive research, organocatalysis tion in larger scale asymmetric synthesis, immobiliza-
has been established into a powerful method for tion will be justified by the requisite for high efficien-
enantioselective transformations, filling the gap be- cy of the catalytic system.
tween enzyme and metal-based catalysis.[1] The devel-
As for other homogeneous chiral catalysts, the im-
opment of secondary amine catalysts for various mobilization of aminocatalysts can be achieved by co-
asymmetric reactions has been breathtaking,[2] and valent linkage to a suitable support.[5] Various exam-
more recently primary amines have been recognized ples of polymer-supported enamine or iminium cata-
as valuable enamine and iminium catalysts.[3] Among lysts have been described over the past decade and
other driving factors, this explosive growth can be as- this topic has been reviewed recently.[6] The attach-
cribed to the fundamental advantages that the appli- ment to a dendritic support could, aside from facilitat-
cation of organocatalysts offers to chemists, including ing the recovery of the catalyst, also promote emul-
their stability in water and air, their non-toxic nature sion formation in aqueous conditions, thereby permit-
and the ready accessibility of the chiral starting mate- ting the use of water as a solvent or co-solvent.[7] Fur-
rial, for example, from biological sources. Major thermore, the use of inorganic materials as heteroge-
drawbacks, however, are associated with high catalyst neous supports can provide some additional benefits
loadings and difficulties with catalyst separation and due to their thermal and mechanical stability, lack of
recycling, thereby limiting the efficiency of the cata- swelling tendency and insolubility in organic solvents.
lytic system. Ever since the introduction of organoca- Hence, silica-based materials, among which are zeo-
talysis in asymmetric synthesis, heterogenization of lites and other mesoporous materials, have been em-
successful organic catalysts has been considered to ployed repeatedly for the covalent immobilization of
Adv. Synth. Catal. 2011, 353, 725 – 732
ꢁ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
725

Anneleen L. W. Demuynck et al.
FULL PAPERS
amino catalysts.[8] Another interesting application is Results and Discussion
the use of magnetic nanoparticles (MNPs) for the co-
valent functionalization with cyclohexanediamines.[9] Clearly, the non-covalent immobilization of amino-
These chiral MNP-supported primary amines have
ACHTUNGTRENcNGNU atalysts is highly desirable and in spite of the re-
demonstrated high activity and stereoselectivity as en- markable advances mentioned above, it remains a
amine-based catalysts and could be easily recycled via challenging goal. Besides, except for Chengꢂs notable
magnetic forces.
efforts,[9,16] heterogeneous systems with primary
A different heterogenization strategy involves the amine-based catalysts are quite rare to date. Here, we
immobilization of a homogeneous catalyst by non-co- describe the successful non-covalent immobilization
valent linkage. This approach limits synthetic modifi- of primary amino acid-derived catalysts on different
cations of the parent catalyst and its modularity ena- solid supports, following Chengꢂs strategy. We extend-
bles the fine-tuning of both catalyst and support. Re- ed the research to both organic and inorganic solid
cently, the non-covalent immobilization of enantiose- acids. After identifying the most optimal heterogene-
lective catalysts has been reviewed by Fraile et al., ous catalyst/solid acid system for direct asymmetric
classifying the immobilization methods into four cate- aldol reactions of linear ketones, we developed a re-
gories depending on the nature of catalyst-support in- actor set-up for continuous flow reactions over a fixed
teraction.[10] Although this review focuses on metal- bed.
based catalysts, similar principles have been applied
Very recently, we reported in this journal the use of
for the immobilization of amino catalysts. For in- primary amino acid-derived diamines with long alkyl
stance, Li and co-workers have immobilized proline tails as syn-selective aldol catalysts.[18] With these cat-
and primary amino acids on g-alumina by simple ad- alysts, in the presence of TFA as Brønsted acid and
sorption.[11] Interestingly, with these hybrid catalysts a DNP as co-catalyst, syn-aldol products have been ob-
remarkable inversion in enantioselectivity with re- tained with excellent enantioselectivities. Hence, we
spect to the free amino acids has been observed. selected diamines 1a and 1b (Scheme 2) for the non-
Using a coordinative method, a homochiral metal-or- covalent immobilization on organic and inorganic
ganic porous material (MOPM) has been synthesized solid acids.
very recently by post-modification of MIL-101 with a
proline-derived chiral ligand and employed as catalyst
in asymmetric aldol reactions.[12] Most non-covalent
immobilization techniques, however, make use of
electrostatic interactions through ion pairs. Examples
include the intercalation of l-proline in Mg-Al
layered double hydroxides[13] and the use of a l-pro-
line-polyelectrolyte catalyst.[14] Very recently, the im-
mobilization of a prolinamide catalyst on Montmoril-
Scheme 2. Chiral primary amino acid-derived diamines used
lonite using a cation-exchange method has been pub-
in this study.
lished in this journal.[15] Another interesting applica-
tion of the electrostatic method was reported by
Cheng et al. and Arakawa et al.[16,17] Here, chiral
The aldol reaction of 2-butanone and 4-(trifluoro-
amines have been immobilized on polystyrene/sulfon- methyl)benzaldehyde was chosen as a benchmark to
ic acid supports through acid-base interaction. In this evaluate the catalytic performance of the supported
approach, the solid acid not only acts as anchor for diamines. The heterogeneous catalysts were easily
the amine, but also plays a crucial role in modulating prepared in situ by mixing the solid acid and the dia-
the activity and stereoselectivity of the supported mine in a 1/1 molar ratio. The screening results are
catalyst
G
summarized in Table 1.
First, we considered the use of inorganic solids con-
taining Brønsted acid sites as suitable supports.
Among others, zeolites are crystalline inorganic solids
with well-defined structures consisting of channels
and cavities with molecular dimensions. Proton-ex-
changed zeolites have been frequently used as acid
catalysts in the synthesis of fine chemicals.[19] Recent
examples are, for instance, the alcoholysis of gly-
AHCTUNGTRENNUNG
cals,[19a] the retro-Diels–Alder reaction of masked cy-
clopentadienones,[19b] the dehydration and rearrange-
ment of trioses into alkyl lactates[19c] and the hydroly-
sis of cellulose.[21b] Here, we selected ultrastable H-
Scheme 1. Non-covalent immobilization of an organic cata-
lyst through acid-base interactions, as introduced by Cheng
et al.[16]
726
asc.wiley-vch.de
ꢁ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2011, 353, 725 – 732

Solid Acids as Heterogeneous Support for Primary Amino Acid-Derived Diamines
Table 1. Screening of solid acids.[a]
Entry
Cat.
Acid additive
Yield[b][%]
rr[b] b/l
dr[b] syn/anti
ee[c] [%]
1[d]
2[d]
3[e]
4
1a
1b
1a
1a
1a
1a
1a
1b
1a
1a
1b
1a
1b
1a
1b
1b
1b
1b
TFA
TFA
USY CBV 720
USY CBV 760
H-BEA 25
59
82
16
13
17
<5
42
38
40
77
86
12
10
25
14
33
39
30
7/1
8/1
5/1
4/1
4/1
n.d.
2/1
4/1
4/1
4/1
4/1
4/1
12/1
4/1
6/1
5/1
6/1
8/1
3/1
3/1
3/1
3/1
3/1
n.d.
2/1
5/2
2/1
3/1
2/1
3/1
3/1
3/1
5/2
7/2
3/1
7/2
97
96
92
88
92
n.d.
93
98
70
90
91
92
96
90
87
96
97
96
5[e]
6[f]
7
Amberlystꢀ 15
Nafionꢀ SAC-13
Nafionꢀ SAC-13
Nafionꢀ NR50
Nafionꢀ NR50
Nafionꢀ NR50
FA-500-75-SO3H
Si33C66-400-SO3H
Si66C33-400-SO3H
Si33C66-550-SO3H
Si50C50-550-SO3H-HF
Si50C50-550-SO3H-HF
CMK-3-600-SO3H
8
9
10[g]
11
12[h]
13
14
15
16
17[i]
18
[a]
All reactions were carried out under neat conditions in 2-butanone with aldehyde (0.125M), 15 mol% of catalyst and
15 mol% of acid additive at room temperature, and analyzed after 20–22 h, unless indicated otherwise.
Determined with chiral GC and verified with H NMR (rr=regioisomer ratio, b/l=ratio of branched and linear prod-
[b]
1
ucts).
[c]
[d]
[e]
[f]
The ee of the major syn-isomer, determined by chiral GC.
See ref.[18]
After 44–68 h of reaction.
Not determined.
With 15 mol% of DNP (2,4-dinitrophenol) as co-catalyst.
With catalyst/solid acid ratio of 3/2.
With catalyst/solid acid ratio of 2/1.
[g]
[h]
[i]
USY zeolites with varying proton density, viz. CBV with TFA. Thus, it appears that the Brønsted acidity
720 and 760, and H-beta zeolite, viz. H-BEA 25, for stemming from the zeolitic framework is not sufficient
screening in the model reaction (Table 1, entries 3–5). for good catalysis of 1a. Next, we investigated the in-
H-USY zeolites of the CBV series are ultrastable zeo- fluence of commercial sulfonated polymers on the
lites Y containing different SiO2/Al2O3 ratios as a performance of 1a and 1b in the model reaction. In
result of the different protocols used for the hydro- the presence of amberlystꢀ 15, a macroreticular sty-
thermal treatment of the parent zeolites Y. In general, rene-divinylbenzene resin with sulfonic acid function-
the higher the SiO2/Al2O3 ratio, the less Brønsted acid alities, almost no reaction occurs with diamine 1a
sites are associated with the zeolite framework. Thus, (entry 6). On the other hand, with sulfonated fluoro-
USY CBV 720 contains more acidic sites (of similar polymers nafionꢀ SAC-13 and NR50, good yields and
acid strength) compared to CBV 760. Furthermore, good to excellent enantioselectivities are obtained for
both types of proton-exchanged zeolites are charac- the model reaction catalyzed by 1a and 1b (entries 7–
terized by an excellent accessibility to their Brønsted 11). From both materials, nafionꢀ NR50 consisting of
acid sites due to the existence of mesopores (in the pure polymer beads, gives the highest activity, where-
case of USY CBV 720 and 760) and to the large ex- as in the presence of nafionꢀ SAC-13, a silica-poly-
ternal surface area of small crystallites (in the case of mer nanocomposite, diamine 1b shows better enantio-
H-BEA 25). Among the examined zeolites USY CBV selectivity but lower activity. Previously, we reported
720 and H-BEA 25 give the best results (entries 3 and the synthesis of different types of sulfonated ordered
5). Nevertheless, with these materials, the activity of micro- and mesoporous carbon and silica/carbon
1a is limited compared to the homogeneous reaction nanocomposites.[20,21] A selection of these materials
Adv. Synth. Catal. 2011, 353, 725 – 732
ꢁ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
727

Anneleen L. W. Demuynck et al.
FULL PAPERS
was examined as acid support for diamines 1a and 1b diamines 1a and 1b and therefore were selected for
in the model reaction (entries 12–18). A detailed de- further investigation.
scription of the synthesis procedure and physicochem-
In order to gain more insight in the kinetics of the
ical properties of these materials is provided in the 1b/nafionꢀ catalytic system, the model reaction was
Supporting Information. Interestingly, with these ma- monitored in time for both nafionꢀ types. Figure 1
terials, a similar trend as with the commercial poly- (panels a and b) shows that for nafionꢀ NR50, to-
mers is observed, namely that with the silica-free ma- gether with the yield, the enantiomeric excess of the
terials (entries 16–18) catalysts 1a and 1b show a syn-aldol product is increasing as a function of time.
better overall performance in the model reaction. As With this nafionꢀ type support, in the absence of 1b,
mentioned in our previous report on homogeneous the branched aldol product is obtained in 47% yield
catalysis with diamines 1a and 1b, the strength of the as a racemic mixture after 20 h of reaction by general
acid additive is crucial for efficient catalysis.[18] Hence, acid catalysis. Thus, the initial enantioselectivity of 1b
we presume that the acidity of the silica-containing in the model reaction is low due to competing catalyt-
supports is not sufficient for efficient catalysis with di- ic activity of free Brønsted acid sites.
amines 1a and 1b. Plausibly, the acidic strength of the
Increasing the catalyst loading to a 1.2/1 molar
sulfonic acid groups in these materials is leveled upon ratio 1b/nafionꢀ NR50 instead of 1/1, has a favoura-
H-bond interaction with the surrounding free silanol ble influence on the initial enantioselectivity, although
groups in comparison to the silica-free supports. as could be expected, with a small decline in initial
Based on the screening results, the commercial sulfo- activity (Figure 1, panel b). Nafionꢀ SAC-13 acts as a
nated polymers nafionꢀ NR50 and SAC-13 emerge weaker acid catalyst and yields only 8% of the
as most promising supports for the immobilization of branched aldol product after 20 h in the absence of
1b. Consequently, the reaction with 1b/nafionꢀ SAC-
13 proceeds with very high (initial) enantioselectivity
but at the expense of its activity (Figure 1, panel a).
With regard to the efficiency of the catalytic system,
further optimization of the reaction conditions was
conducted for 1b/nafionꢀ NR50 (Table 2). In consis-
tency with our previous findings for the homogeneous
reaction with TFA,[18] the addition of 2,4-dinitrophe-
nol (DNP) as a co-catalyst is beneficial to both the ac-
Table 2. Optimization of catalytic system 1b/nafionꢀ NR50
in the model reaction.[a]
Entry Conditions (conc. Yield[b][%] rr[b] dr[b]
ee[c]
aldehyde, T)
b/l syn/
anti
[%]
1[d]
2
0.125M, r.t.
0.125M, r.t.
0.125M, r.t.
0.125M, r.t.
0.25M, r.t.
0.125M, 408C
0.125M, 458C
0.25M, 458C
86
87
7
90
93
82
91
95
4/1 2/1
5/1 5/2
8/1 2/1
5/1 3/1
3/1 2/1
2/1 2/1
2/1 2/1
2/1 3/2
91
94
88
95
92
86
86
80
3[e]
4[f]
5[g]
6
7
8
[a]
All reactions were carried out under neat conditions in
2-butanone with 18 mol% of 1b and 15 mol% of nafionꢀ
NR50 and analyzed after 20–22 h, unless indicated other-
wise.
Determined with chiral GC and verified with H NMR
(rr=regioisomer ratio, b/l=ratio of branched and linear
products).
The ee of the major syn-isomer, determined by chiral
GC.
With 1b/nafionꢀ NR50 ratio of 1/1.
Reaction in DCM/2-butanone 3/1
With 15 mol% of DNP (2,4-dinitrophenol) as co-catalyst.
After 44 h of reaction.
[b]
[c]
1
[d]
[e]
[f]
Figure 1. a) Comparison of yield (%) and ee (%) versus
time in the model reaction catalyzed by 1b/nafionꢀ NR50
and 1b/nafionꢀ SAC-13. b) Influence of catalyst loading on
initial activity and enantioselectivity of 1b/nafionꢀ NR50.
[g]
728
asc.wiley-vch.de
ꢁ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2011, 353, 725 – 732

Solid Acids as Heterogeneous Support for Primary Amino Acid-Derived Diamines
tivity and selectivity of 1b in the model reaction
In order to affirm the heterogeneous nature of the
(entry 4). Further, with a more concentrated solution 1b/nafionꢀ NR50 catalytic system, a dual split test
higher yields but lower regio- and stereoselectivities was accomplished (see Supporting Information for de-
are obtained (entries 5 and 8). Elevating the tempera- tails). The model reaction was catalyzed by 1b/
ture up to 458C has a similar effect on the catalytic nafionꢀ NR50 under optimized conditions for 6 h,
performance of 1b/nafionꢀ NR50 (entries 6–8).
yielding 36% of aldol product. Then, after removal of
To further explore the scope of the optimized cata- the 1b/nafionꢀ beads, the supernatant was equally
lytic system, 1b/nafionꢀ was applied in the aldol reac- transferred into two different reaction vessels for fur-
tion of various ketones and aromatic aldehydes under ther stirring. Since diamine 1b requires an acidic addi-
optimized conditions (Table 3). As for the model re- tive to act as a catalyst,[18] in fact no further reaction
action, nafionꢀ-supported 1b shows great catalytic could be expected in the supernatant solution, even in
performance in 2-butanone (entries 3–6). With the the presence of free diamine 1b. Hence, in order to
symmetrical 3-pentanone as ketone donor (entries 7– properly probe leaching of 1b fresh, unloaded
12), high activity and enantioselectivity could be ob- nafionꢀ NR50 beads were added to one vessel. After
tained by increasing both the temperature and alde- 20 h of stirring, analysis of both solutions demonstrat-
hyde concentration (entry 10). Furthermore, good ed that for the nafionꢀ-free mixture the yield of aldol
yields and good to excellent enantioselectivities of up product was quasi unchanged whereas with freshly
to 98% ee are achieved with hydroxyacetone as added nafionꢀ NR50 the yield was only marginally
ketone donor (entries 15–20). With acetone and 2- increased with 4% (Figure 2). These results indicate
pentanone (entries 13 and 14), the catalytic perfor- that dissociation of diamine 1b from the nafionꢀ
mance of 1b/nafionꢀ NR50 is limited, as also was ob- NR50 beads was negligible and catalysis with
served for the homogeneous reactions with TFA.[18]
1b/nafionꢀ NR50 occurs mainly heterogeneously.
Furthermore, the absence of characteristic signals
Table 3. Application of the optimized system in the aldol reaction of different linear ketones and aromatic aldehydes.
Entry
nafionꢀ
R1, R2, R
time [h]
Yield[b][%]
dr[b] syn/anti
ee[c] [%]
1
NR50
SAC-13
NR50
NR50
NR50
NR50
NR50
NR50
NR50
NR50
SAC-13
SAC-13
NR50
NR50
NR50
NR50
SAC-13
NR50
NR50
NR50
H, Me, 4-CF3
22
30
44
20
20
20
48
94
20
44
44
44
24
48
24
20
20
24
20
24
87
78
99
99
98
96
24
80
76
91
8
19
81
37
49
79
80
49
84
86
5/2
5/2
1/1
1/1
2/1
7/2
2/1
3/1
3/1
2/1
4/1
3/1
–
2/1
8/1
4/1
7/1
4/1
2/1
7/2
94
96
93
90
98
98
69
87
91
93
96
96
65
56
92
87
86
94
98
89
2[d]
3
H, Me, 2-NO2
H, Me, 2-Cl
4[e]
5
6[e]
7
Me, Me, 4-CF3
8[e]
9[e,f]
10[e,f]
11[d]
12[d,e,f]
13
H, H, 4-CF3
H, Et, 4-CF3
H, OH, 2-NO2
14
15
16[e]
17[d,e,f]
18
H, OH, 4-NO2
H, OH, 4-CF3
19[e]
20
[a]
All reactions were carried out under neat conditions with aldehyde (0.125M), 18 mol% of catalyst and 15 mol% of acid
additive at room temperature, unless indicated otherwise.
Determined with chiral GC or H NMR.
The ee of the major syn-isomer, determined by chiral GC or HPLC.
With a 1b/nafionꢀ SAC-13 ratio of 1/1.
Reaction at 458C.
[b]
[c]
[d]
[e]
[f]
1
With 0.25M aldehyde.
Adv. Synth. Catal. 2011, 353, 725 – 732
ꢁ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
729

Anneleen L. W. Demuynck et al.
FULL PAPERS
Figure 2. Dual split test.
1
from 1b in the H NMR spectrum of the nafionꢀ-free
supernatant confirms these findings (Figure S1, Sup-
porting Information).
Next, the recycling capacity of 1b/nafionꢀ NR50
was investigated in the optimized model reaction at
458C. After each run, the reaction mixture was re-
moved by simple decantation and fresh reagents were
added to the recovered polymer beads. As shown in
Table 4, the activity remains unchanged in the first
two runs. In the subsequent third cycle, the activity of
the recycled catalyst starts declining but the enantio-
selectivity is maintained. Furthermore, by prolonging
the reaction time, good yields are still achieved after
the fifth run.
Finally, the implementation of the immobilized
chiral catalyst in a continuous system, rather than
working under batch conditions, is the ultimate goal
when considering large-scale synthesis. Recently,
Figure 3. Continuous flow reaction.
Odedra and Seeberger reported the first example of bed which was then continuously fed with a preheated
an organocatalytic asymmetric aldol reaction conduct- aldehyde containing ketone solution (for details on
ed in a microreactor under homogeneous condi- the set-up and operating conditions, see Experimental
tions.[22] Almost simultaneously, a continuous flow Section and Supporting Information). The out-coming
system has been developed for the Mannich reaction flow was monitored for 11 h and samples were taken
of aldehydes and ketones with a covalently supported at several time intervals. As shown in Figure 3 (panel
proline/polystyrene catalyst.[23] Hence, we integrated a) the 1b/nafionꢀ NR50 fixed bed shows good cumu-
the loaded 1b/nafionꢀ NR50 beads in a fixed catalyst lative activity in the model reaction under continuous
conditions. To our delight, the (initial) diastereo- and
enantioselectivity of the catalyst were significantly im-
Table 4. Recycling and reuse of 1b/nafionꢀ NR50 in the proved with respect to the batch reactions (with syn/
model reaction at 458C under optimized conditions.
anti=3/1 and ee values of up to 97%, Figure 3, panel
b). To the best of our knowledge, this is the first ap-
plication of a chiral non-covalently immobilized
amino catalyst in a continuous flow system.
Entry
Cycle
Time (h)
Yield[a] [%]
ee[b] [%]
1
2
3
1st
24
24
24
24
68
91
92
82
74
82
86
87
87
87
81
2nd
3rd
4th
5th
4
Conclusions
5[c]
[a]
We have achieved the non-covalent immobilization of
chiral primary amino acid-derived diamines on both
organic and inorganic sulfonated solid supports
Determined with GC.
The ee of the syn-isomer, determined by chiral GC.
Yield after 44 h of reaction=73%.
[b]
[c]
730
asc.wiley-vch.de
ꢁ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2011, 353, 725 – 732

Solid Acids as Heterogeneous Support for Primary Amino Acid-Derived Diamines
through acid-base interactions. In this approach, the Acknowledgements
solid acid has a dual function acting as anchor for im-
We are grateful to the IWT (ALWD) (instituut voor Innovatie
mobilization and governing the activity and selectivity
of the chiral catalyst. Screening a series of home-
made micro- and mesoporous carbon and silica/
carbon materials and commercial polymers revealed a
similar trend with regard to the catalytic performance
of the immobilized diamines. With silica-containing
supports lower activities are attained compared to the
silica-free materials, which we presume is attributed
to the reduced acidity strength of the Brønsted acid
sites. With the sulfonated fluoropolymer nafionꢀ
NR50 as support an optimal balance between activity
and stereoselectivity was established for diamine 1b
in the model reaction and hence, this support was
chosen for further investigation. With 1b/nafionꢀ
NR50 under optimized conditions aldol products of
various challenging linear ketones and aromatic alde-
hydes were obtained in high yields and with excellent
enantioselectivities for the syn-product (up to 98%
ee). Catalysis with 1b/nafionꢀ NR50 was shown to
occur truly heterogeneously and the robustness of the
non-covalently immobilized catalyst was illustrated by
the possibility of extending its use by simple recovery
and recycling. Ultimately, the success of the 1b/
nafionꢀ NR50 catalytic system was demonstrated in a
reactor set-up under continuous flow conditions. We
believe this work represents a valuable contribution
to the current search for more efficient, heterogene-
ous systems in asymmetric organocatalytic transfor-
mations.
door Wetenschap en Technologie), IAP (Interuniversity At-
traction Poles) and Methusalem long-term structural funding
of the Flemish government (CASAS) for the financial sup-
port.
References
[1] E. Marquꢃs-Lꢄpez, R. P. Herrera, M. Christmann, Nat.
Prod. Rep. 2010, 27, 1138–1167.
[2] For selected reviews, commentaries and special issues,
see: a) P. I. Dalko, L. Moisan, Angew. Chem. 2004, 116,
5248–5286; Angew. Chem. Int. Ed. 2004, 43, 5138–
5175; b) B. List, J. W. Yang, Science 2006, 313, 1584–
1586; c) B. List, Chem. Commun. 2006, 819–824; d) H.
Pellissier, Tetrahedron 2007, 63, 9267–9331; e) M. J.
Gaunt, C. C. C. Johansson, A. McNally, N. T. Vo, Drug
Discovery Today 2007, 12, 8–27; f) S. Jaroch, H. Wein-
mann, K. Zeitler, ChemMedChem 2007, 2, 1261–1264;
g) A. Dondoni, A. Massi, Angew. Chem. 2008, 120,
4716–4739; Angew. Chem. Int. Ed. 2008, 47, 4638–
4660; h) D. W. C. MacMillan, Nature 2008, 455, 304–
308; i) P. Melchiorre, M. Marigo, A. Carlone, G. Barto-
li, G. Angew. Chem. 2008, 120, 6232–6265; Angew.
Chem. Int. Ed. 2008, 47, 6138–6171; j) C. F. Barbas III,
Angew. Chem. 2008, 120, 44–50; Angew. Chem. Int.
Ed. 2008, 47, 42–47; k) S. Bertelsen, K. A. Jørgensen,
Chem. Soc. Rev. 2009, 38, 2178–2189; l) special issues:
Adv. Synth. Catal. 2004, 346, 1007–1249; Acc. Chem.
Res. 2004, 37, 487–631; Tetrahedron 2006, 62, 243–502;
Chem. Rev. 2007, 107, 5413–5883.
[3] For reviews, see: a) F. Peng, Z. Shao, J. Mol. Catal. A
2008, 285, 1–13; b) L.-W. Xu, Y. Lu, Org. Biomol.
Chem. 2008, 6, 2047–2053; c) L.-W. Xu, J. Luo, Y. Lu,
Chem. Commun. 2009, 1807–1821.
Experimental Section
Representative Procedure for Aldol Reaction
[4] For reviews, see: a) M. Benaglia, A. Puglisi, F. Cozzi,
Chem. Rev. 2003, 103, 3401–3429; b) F. Cozzi, Adv.
Synth. Catal. 2006, 348, 1367–1390.
[5] a) Chiral Catalyst Immobilization and Recycling, (Eds.:
D. E. De Vos, I. F. Vankelecom, P. A. Jacobs), Wiley-
VCH, Weinheim, 2000; b) D. E. De Vos, M. Dams, B. F.
Sels, P. A. Jacobs, Chem. Rev. 2002, 102, 3615–3640;
c) M. Heitbaum, F. Glorius, I. Escher, Angew. Chem.
2006, 118, 4850-4881; Angew. Chem. Int. Ed. 2006, 45,
4732–4762.
Batch reactions: Organocatalyst 1b (18 mol%) and the acid
additive (15 mol%) were mixed together with the ketone at
room temperature, followed by the addition of the aldehyde
(0.125M). The reaction mixture was stirred at room temper-
ature or 458C for the given time and extracted with ethyl
acetate and water. The organic phase was analyzed with
1H NMR and chiral GC to calculate yields and regio- and
diastereomeric ratios. The enantiomeric excess (ee) was de-
termined with chiral GC or chiral HPLC.
Continuous reactions: A preheated solution of 2-buta-
none and 4-(trifluoromethyl)benzaldehyde (0.125M) was
fed continuously with a syringe pump (flow rate 1 mLhÀ1)
over a catalyst bed consisting of 375 mg nafionꢀ NR50 pel-
lets (0.3 mmol) preloaded with 134 mg 1b (0.36 mmol). The
outlet of the reactor was sampled at different time intervals.
The crude mixtures were directly analyzed by chiral GC. A
more detailed picture of the reactor set-up is provided in
the Supporting Information.
[6] T. E. Kristensen, T. Hansen, Eur. J. Org. Chem. 2010,
3179–3204.
[7] a) Y. Wu, Y. Zhang, M. Yu, G. Zhao, S. Wang, Org.
Lett. 2006, 8, 4417–4420; b) G. Lv, R. Jin, W. Mai, L.
Gao, Tetrahedron: Asymmetry 2008, 19, 2568–2572;
c) C.-M. Lo, H.-F. Chow, J. Org. Chem. 2009, 74, 5181–
5191; d) K. Goren, T. Kehat, M. Portnoya, Adv. Synth.
Catal. 2009, 351, 59–65.
[8] a) A. Corma, H. Garcia, Adv. Synth. Catal. 2006, 348,
1391–1412; b) Y.-B. Zhao, L.-W. Zhang, L.-Y. Wu, X.
Zhong, R. Li, J.-T. Ma, Tetrahedron: Asymmetry 2008,
19, 1352–1355; c) A. Zamboulis, N. J. Rahier, M. Geh-
ringer, X. Cattoꢅn, G. Niel, C. Bied, J. J. E. Moreau,
Adv. Synth. Catal. 2011, 353, 725 – 732
ꢁ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
731

Anneleen L. W. Demuynck et al.
FULL PAPERS
M. W. C. Man, Tetrahedron: Asymmetry 2009, 20,
2880–2885.
[9] S. Luo, X. Zheng, J.-P. Cheng, Chem. Commun. 2008,
5719–5721.
[10] J. M. Fraile, J. I. Garcꢆa, J. A. Mayoral Chem. Rev.
2009, 109, 360–417.
[11] L. Zhong, J. Xiao, C. Li, J. Catal. 2006, 243, 442–445.
[12] M. Banerjee, S. Das, M. Yoon, H. J. Choi, M. H. Hyun,
S. M. Park, G. Seo, K. Kim, J. Am. Chem. Soc. 2009,
131, 7524–7525.
Demuynck, P. Levecque, A. Kidane, D. W. Gammon,
E. Sickle P. Jacobs, D. De Vos, B. F. Sels, Adv. Synth.
Catal. 2010, 352, 3419–3430; c) P. P. Pescarmona,
K. P. F. Janssen, C. Delaet, C. Stroobants, K. Hou-
thoofd, A. Philippaerts, C. De Jonghe, J. S. Paul, P. A.
Jacobs, B. F. Sels, Green Chem. 2010, 12, 1083–1089;
d) C. Tsangarakis, M. Stratakis Adv. Synth. Catal. 2005,
347, 1280–1284; e) C. Tsangarakis, C. Raptis, E. Ar-
koudis, M. Stratakis, Adv. Synth. Catal. 2008, 350,
1587–1600.
[13] a) Z. An, W. Zhang, H. Shi, J. He, J. Catal. 2006, 241,
319–327; b) S. Vijaikumar, A. Dhakshinamoorthy, K.
Pitchumani, Appl. Catal. A: General 2008, 340, 25–32.
[14] A. S. Kucherenko, M. I. Struchkova, S. G. Zlotin, Eur.
J. Org. Chem. 2006, 2000–2004.
[20] F. de Clippel, A. Harkiolakis, X. Ke, T. Vosch, G. Van
Tendeloo, G. V. Baron, P. A. Jacobs, J. F. M. Denayer,
B. F. Sels, Chem. Commun. 2010, 46, 928–930.
[21] a) L. Peng, A. Philippaerts, X. Ke, J. Van Noyen, F. De
Clippel, G. Van Tendeloo, P. A. Jacobs, B. F. Sels,6841
Catal. Today 2010, 150, 140–146; b) S. Van de Vyver,
L. Peng, J. Geboers, H. Schepers, F. de Clippel, C. J.
Gommes, B. Goderis, P. A. Jacobs, B. F. Sels, Green
Chem. 2010, 12, 1560–1563.
[22] A. Odedra, P. H. Seeberger, Angew. Chem. 2009, 121,
2737–2740; Angew. Chem. Int. Ed. 2009, 48, 2699–
2702.
[23] E. Alza, C. Rodrꢆguez-Escrich, S. Sayalero, A. Bastero,
M. A. Pericꢇs, Chem. Eur. J. 2009, 15, 10167–10172.
[15] N. Hara, S. Nakamura, N. Shibata, T. Torua, Adv.
Synth. Catal. 2010, 352, 1621–1624.
[16] S. Luo, J. Li, L. Zhang, H. Xu, J.-P. Cheng, Chem. Eur.
J. 2008, 14, 1273–1281.
[17] Y. Arakawa, N. Haraguchi, S. Itsuno, Angew. Chem.
2008, 120, 8356–8359; Angew. Chem. Int. Ed. 2008, 47,
8232–8235.
[18] A. L. W. Demuynck, J. Vanderleyden, B. F. Sels, Adv.
Synth. Catal. 2010, 352, 2421–2426.
[19] a) P. Levecque, D. W. Gammon, P. Jacobs, D. De Vos,
B. F. Sels, Green Chem. 2010, 12, 828–835; b) A. L. W.
732
asc.wiley-vch.de
ꢁ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2011, 353, 725 – 732