An improved protocol for the direct asymmetric aldol reaction in ionic liquids, catalysed by onium ion-tagged prolines

Article abstract of DOI:10.1002/adsc.200700136

Two onium ion-tagged prolines, imidazolium bis(trifluoromethylsulfonyl) imide-substituted proline 6 and butyldimethylammonium bis(trifluoromethylsulfonyl)imide-substituted proline 7, were synthesised and their catalytic activity in the direct asymmetric a

Full text of DOI:10.1002/adsc.200700136

UPDATES
DOI: 10.1002/adsc.200700136
An Improved Protocol for the Direct Asymmetric Aldol Reaction
in Ionic Liquids, Catalysed by Onium Ion-Tagged Prolines
Marco Lombardo,a,b,* Filippo Pasi,a Srinivasan Easwar,a and Claudio Trombinia,b,*
a
Dipartimento di Chimica “G.Ciamician”, Università degli Studi di Bologna, via Selmi 2, 40126 Bologna, Italy
Fax : (+39)-051-2099-456; e-mail: marco.lombardo@unibo.it or claudio.trombini@unibo.it
Consorzio Interuniversitario Nazionale “La Chimica per l’Ambiente”, via delle Industrie 21/8, 30175 Marghera (VE),
b
Italy
Received: March 15, 2007
Supporting information for this article is available on the WWW under http://asc.wiley-vch.de/home/.
Abstract: Two onium ion-tagged prolines, imidazoli-
um bis(trifluoromethylsulfonyl)imide-substituted
Despite the parallel exponential profile of the
growth of organocatalysis on one hand and of the
ionic liquid investigations on the other in the chemical
literature, only rarely do the two fields cross each
other.Focusing attention on the proline-catalysed
direct aldol addition of acetone to aromatic aldehydes
(Scheme 1), to the best of our knowledge, very few
examples are known where the classical solvents,
namely acetone itself and dimethyl sulfoxide
(DMSO), have been replaced by ILs.In 2002, Toma
and co-workers[6] and Loh and co-workers,[7] inde-
proline 6 and butyldimethylammonium bis(trifluoro-
methylsulfonyl)imide-substituted proline 7, were
synthesised and their catalytic activity in the direct
asymmetric aldol condensation was studied in ionic
liquids.For the reaction of acetone with various al-
dehydes, using 5% of the catalyst, the yields of the
aldols varied between 50–85% while the ee values
were in the 80–85% range.Other ketones were
studied too, the yields obtained in those cases being
in the 35–78% range while the enantioselectivities
varied between 75–94%.
pendently studied the use of [bmim]ACHTRE[UNG PF6] as solvent
in the proline-catalysed reaction of acetone with aro-
matic aldehydes.Their results, reported side-by-side
in Scheme 1, were based on the use of 30% of cata-
lyst along with 7–30 equivalents of acetone and reac-
tion times of 24 h (Scheme 1).Interestingly, when
only 5% of proline was used, it was observed that the
chemical yield of the aldol dropped to 43% over
48 h.[7] A direct comparison with the results of the
original protocol developed by List et al.,[2] also pre-
sented in Scheme 1, revealed that chemical yields,
Keywords: aldol reaction; ionic liquids; organoca-
talysis; proline-derived catalysis
Introduction
In 2000, three decades after the discovery of the pro- enantioselectivities and turnover numbers (TONs) in
line-catalysed asymmetric intramolecular aldol reac- [bmim]ACHTRE[UNG PF6] ranged in the same levels as recorded in
tion,[1] it was found that proline[2] as well as proline DMSO.Two advantages are associated to the use of
derivatives and other a-amino acids[3] are also able to the IL: (i) the catalytic process takes place under ho-
catalyse the intermolecular version of the direct asym- mogeneous conditions, and (ii) thanks to the tuneble
metric aldol reaction.[4] These studies gave impetus to miscibility of an IL with molecular solvents, heteroge-
the extraordinary development of organocatalysis.An
neous conditions can be found allowing the products
analogous dramatic growth has been witnessed over to be extracted from the catalyst-containing IL, which
the last 7 years in the use of ionic liquids as new reac-
tion media.[5] However, the exceptional research ef-
forts in the synthesis of room temperature ionic liq-
uids (ILs) and in their use as reaction media were not
accompanied by a parallel growth in the understand-
ing of their structure and properties, a fact that im-
pairs the rational design of the ideal solvent for the
desired reaction on the basis of a consistent structure-
reactivity framework.
Scheme 1.
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Marco Lombardo et al.
UPDATES
can be reused for a few runs.In related, proline-cata-
lysed direct asymmetric Mannich reactions of N-PMP
protected a-iminoethyl glyoxylate with various car-
bonyl compounds in ILs, beside a facile product isola-
tion and catalyst recycling, significantly improved re-
action rates compared to molecular solvents were also
enjoyed.[8]
The recently developed strategy based on the use
of solid-supported ionic liquid phases (SILP)[9] was
applied to the proline-catalysed reaction shown in
Scheme 1 by Gruttadauria and co-workers; a mono-
layer of an ionic liquid covalently attached to the
silica gel surface hosted proline acting as the reaction
medium for the aldol reaction of acetone with the al-
dehyde.[10] Yields and ees were comparable with those
obtained in DMSO, the best improvement of SILP
being its regeneration and recyclability up to 10 times.
An alternative approach to the use of ILs as sol-
vents or of SILP as catalyst is offered by the use of
catalysts containing a quaternary ammonium ion on a
side chain.Such a strategy was applied by Miao and
Chan to an asymmetric aldol reaction catalysed by
Figure 2.
trans 4-hydroxy-l-proline derivative 3 (Figure 1) using Scheme 2.
either DMSO or acetone as the solvent.The onium
ion-tagged catalyst dissolves in the polar molecular
solvent where the aldol reaction takes place under ho- promoted by organocatalysts 6 and 7 (Figure 2), in
mogeneous conditions, then the catalyst can be recov- different ILs.Both 6 and 7 are derived from trans 4-
ered by extracting the product in a less polar solvent, hydroxy-l-proline 4 via the common intermediate 5,
where the catalyst is not soluble.[11] In the reported re- as shown in Scheme 2.
action conditions (30% catalyst, 25 h), the TON was
Chloroacetate 5 is interesting, for it offers the op-
close to 2, with ees in the 48–72% range for 1a and in portunity to generate diversity upon reaction with a
the 71–85% range for 1b.[12]
library of tertiary amines.The choice of the bis(tri-
fluoromethylsulfonyl)imide (Tf2NÀ) anion was dictat-
ed by the very low hydrophilicity conferred to the
quaternary salt by this counterion.
We studied the aldol reaction of acetone with the
p-nitrobenzaldehyde (1b) under various conditions so
as to determine the optimum reaction parameters.
Table 1 collects a selection of experiments.Reactions
are run at room temperature in various ILs, keeping
Figure 1.
Attracted by the structure of 3, we anticipated that a the aldehyde concentration at ~1M.We chose
quaternary ammonium-tagged proline like 3 should in- [bmim][TfO] and [bmim][Tf2N] as imidazolium-based
A
ACHTREUNG
teract much better with an ionic liquid used as solvent, ILs, and butylmethylpyrrolidinium (bmpy) as saturat-
thus combining the advantages of a homogeneous ed cyclic quaternary ammonium ion in the form of
phase with the opportunity of exploiting solubility dif- [bmpy]
A
ACHTRE[UNG Tf2N] (runs 11 and 12).
ferences in the work-up step.More importantly, the en-
amine route to the asymmetric cross-aldol reaction
AHCTRE[UNG Tf2N] using the molar ratios adopted for proline/
could enjoy rate acceleration in ILs, since charged DMSO[2a] resulted in near quantitave yield of the
transition states leading from uncharged reactants to aldol in 24 h (Table 1, run 1) with improved enantio-
iminium ion intermediates could be stabilised by the selectivity (see Scheme 1).In another experiment
coulombic environment of the reaction medium.[5]
(Table 1, run 2) using the same catalyst loading
(30%), in just 3 h we recovered 83% of the aldol
with an almost 30% increase in ee with respect to the
Results and Discussion
use of proline in [bmim]
results clearly indicate that the cross-aldol condensa-
[PF6][7] (see Scheme 1).These
ACHTREUNG
Herein, we report our results on the asymmetric tion enjoys a significant rate acceleration and an en-
cross-aldol addition of acetone to aromatic aldehydes, hanced stereoselectivity using the onium-tagged pro-
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Adv. Synth. Catal. 2007, 349, 2061 – 2065

An Improved Protocol for the Direct Asymmetric Aldol Reaction in Ionic Liquids
UPDATES
Table 1. Asymmetric catalytic cross-aldol reactions of ace-
tone (10 equivs.) and p-nitrobenzaldehyde 1b.
Table 2. Recycling experiments using acetone (10 equivs),
catalyst 7 (5%) and p-nitrobenzaldehyde 1b in [bmim]
[Tf2N] for 24 h at room temperature.
Run Solvent
Catalyst, t
[%]
2b, Yield 2b, ee TON
[h] [%][a]
[%][b]
Run
2b, Yield [%][a]
2b, ee [%][b]
TON
1[c]
2
3
5
6
7
8
9
C
U
82
83
80
85
85
83
84
84
82
82
80
3.1
2. 7
5.2
1
2
3
75
65
30
85
82
80
15.0
13.0
6.
3
0
13 62
24 75
48 25
24 79
15 68
24 85
24 72
24 70
12.4
15.0
25.0
15.8
13.6
17.0
14.4
14.0
[a]
Isolated yields after purification by flash chromatography
on silica.
Determined by chiral HPLC on crude reaction mixture.
[b]
10
11
12
1a, 1c and p-chlorobenzaldehyde (1d) under what we
had chosen as routine reaction conditions; the results
are presented in Table 3.
With these results in hand, we performed a few
other experiments that provided us a definite indica-
tion of the advantages in using onium-tagged prolines
as catalysts in ILs.Thus, upon performing a reaction
under solventless conditions using the same parame-
ters of run 6 in Table 1, the chemical yield of the
ACHTREUNG
ACHTREUNG
[a]
[b]
[c]
line/IL system.The neat kinetic benefit arising from
the use of the IL with 6 or 7 is confirmed by runs 3–8, aldol diminished by 50% and the ee by 10% with re-
where catalyst loading was progressively decreased. spect to our optimised conditions.We then decided to
Finally, we selected the acetone/1b/catalyst molar check the performance of 5% proline in [bmim]-
ratio=10:1:0.05 as the most promising for further
ACHTREUNG
studies.
The 5-fold or even higher improvement in terms of 7, under identical experimental conditions.These re-
catalytic efficiency can be appreciated by comparing sults are presented in Table 4.Experiments carried
TON values of the results discussed in Scheme 1,
which ranged from 2 to 8, with the ones reported in
Table 1 (TONs up to 17).
Table 3. Asymmetric catalytic cross aldol reactions of ace-
Noteworthy is the increase in the enantioselectivity
tone (10 equivs.) and aromatic aldehydes in [bmim]
for 24 h at room temperature.
ACHTREUNG[Tf2N]
recorded, corresponding to a 10–20% improvement
with respect to the use of proline in DMSO[2a,b] and
[bmim]ACHTREUNG
[PF6][6,7] (Scheme 1).We are not in a position
Run ArCHO Catalyst,
[%]
2, Yield
2, ee
TON
[%][a]
[%][b]
to correlate the stereochemical results with a different
structural organisation of proline and of the onium-
ion tagged catalysts 6 and 7 in the ionic liquid, nor we
have evidence about the different environment tested
by 3 in acetone and by its analogous 6 in ILs.Never-
theless, a high affinity of ion pairs 6 and 7 for ILs
could be hypothesised, resulting in a more organised
association of the catalyst to the IL within the struc-
tured domains of the solvent.[13] If the consequence
was a tighter transition state in the rate-determining
step of the catalytic cycle, a higher enantioselectivity
could follow.
1
2
3
1a
1c
1d
6, 5%
7, 5%
7, 5%
50
57
80
80
84
84
10.0
11.4
16.0
[a]
Isolated yields after purification by flash chromatography
on silica.
Determined by chiral HPLC on crude reaction mixture.
[b]
Table 4. Results of the cross-aldol reaction using 5% proline
in [bmim][Tf2N].
AHCTREUNG
The only drawback of this procedure was represent-
ed by the difficult recovery and reuse of the catalyst
at the concentration level used.Indeed, a recycling
experiment showed that the catalyst could be effi-
ciently recovered once (entry 2, Table 2), but at the
third cycle, a significant drop in catalytic activity was
observed (entry 3, Table 2).
Run ArCHO t [h] 2, Yield [%][a] 2, ee [%][b] TON
1
1b
1d
1d
24
24
24
50
45
20
72
70
68
10.0
9.0
4.0
2
3[c]
[a]
Isolated yields after purification by flash chromatography
on silica.
[b]
[c]
Having carried out the above studies with 1b, we
then performed the aldol reaction using the aldehydes
Determined by chiral HPLC on crude reaction mixture.
2nd cycle.
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Marco Lombardo et al.
UPDATES
Table 5. Asymmetric cross-aldol reactions explored for other ketones catalysed by 7 (5 mol%) in [bmim]ACHTREU[GN Tf2N] for 24 h at
room temperature.
Run
1
ArCHO
Major product
8, Yield [%]
8, anti:syn[a]
anti-8 (syn-8), ee [%][b]
1b
78[c]
70:30
94 (80)
2
3
4
5
1c
1d
1b
1d
36[c]
38[c]
75[d]
35[d]
80:20
85:15
67:33
70:30
90 (70)
80 (63)
91 (48)
86 (34)
6[e]
1b
72[d]
70:30
75 (56)
[a]
1
Determined by H NMR on crude reaction mixture.
Determined by chiral HPLC on crude reaction mixture.
[b]
[c]
[d]
[e]
Isolated yields after purification by flash chromatography on silica.
Estimated yields by H NMR.
Reaction time was increased to 72 h.
1
out with aldehydes 1b and 1d resulted in a decrease 1) are comparable with respect to the use of proline[14]
of 30% in yield and 15% in ee as compared to our but the ee was considerably higher with the onium
conditions.In attempting to recycle the catalyst, we
tagged catalysts.A 50% increase in ee for the anti
were not able to obtain an acceptable chemical yield aldol (94% vs. 63%) and more than 100% increase
in the 2nd cycle (run 3); in particular this last result for the syn aldol (80% vs. 36%) was obtained.High
was clearly poorer than that obtained in the first recy- ees were obtained in the reaction of 8a with other al-
cle with the onium-tagged analogue (Table 2, run 2).
dehydes too, although low chemical yields after 24 h
To confirm the excellent performance of onium are obtained with 1c and 1d (runs 2 and 3).A similar
ion-tagged catalysts in ILs, we selected 7 in [bmim]- behaviour was displayed by hydroxyacetone (runs 4
ACHTREUNG[Tf2N] as model system for the reaction of three dif- and 5).With the less reactive ketone derived from di-
ferent ketones with 1b–d.These new experiments are
shown in Table 5.
hydroxyacetone (run 6),[15] the reaction had to be car-
ried out over 72 h at room temperature under our cat-
The chemical yield and diastereoselectivity ob- alytic protocol to furnish the corresponding aldol with
tained for the reaction of cyclohexanone with 1b (run a good chemical yield.
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An Improved Protocol for the Direct Asymmetric Aldol Reaction in Ionic Liquids
UPDATES
perature.Acetone was removed under reduced pressure and
the reaction mixture was extracted with ether (2 mL”4).
The reaction mixture was then vacuum-dried before the
second loading of the reacting components.The ether ex-
tract was concentrated under vacuum and the residue was
purified by silica gel column chromatography (cyclohexane/
ethyl acetate, 7:3) to obtain the pure aldol.
Conclusions
In summary, the onium ion-tagged proline catalysts in
ILs proved to be an excellent catalytic system for the
direct asymmetric aldol reaction.The catalytic proto-
col we developed makes use of a 6-fold lower amount
of catalyst with respect to the preceding reports[2,6,7,12]
and affords greater chemical yields and higher enan-
tioselectivity.
In the recycling studies reported in literature,[7,12]
four cycles were carried out without appreciable loss
of activity of catalyst using 30 mol% loading.It must
be considered that four cycles require four extensive
work-up procedures with the corresponding waste
generation, and requires more than 100 h to complete
the series (reaction time plus time required to recover
the catalyst between two cycles).
Acknowledgements
This work was supported by MIUR (Rome) PRIN project
grant: “Sintesi e Stereocontrollo di Molecole Organiche per
lo Sviluppo di Metodologie Innovative di Interesse Applicati-
vo”.
A direct comparison of the efficiency of our proto-
col with respect to the previously reported procedures
is possible when p-nitrobenzaldehyde (1b) and ben-
zaldehyde (1a) are used.The former aldehyde
(Table 1, run 6) using the same molar amount of cata-
lyst as in ref.[11] generates up to 70% more of the
aldol product in overall 26 h with respect to four
cycles in acetone as solvent and using 30% of 3.[12]
Similarly, an analogous comparison of run 1 of
Table 3 shows that our protocol applied to 1a affords
up to 37% more of the aldol with respect to four
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(0.014 g, 0.025 mmol) in [bmim]ACHTRE[UNG Tf2N] (0.5 mL) and the mix-
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