Direct asymmetric aldol reaction catalyzed by an imidazolium-tagged trans-4-hydroxy-l-proline under aqueous biphasic conditions

Article abstract of DOI:10.1055/s-2008-1078055

Imidazolium-tagged trans-4-hydroxy-L-proline, recently reported by us as an efficient catalyst for the asymmetric cross-aldol reaction in [bmim][Tf ₂N], gives much better results in terms of catalytic activity and stereochemical performance und

Full text of DOI:10.1055/s-2008-1078055

LETTER
2471
Direct Asymmetric Aldol Reaction Catalyzed by an Imidazolium-Tagged
trans-4-Hydroxy-L-proline under Aqueous Biphasic Conditions
Asymmetric
A
ldol Rea
a
ction Catal
r
yzed by
c
Imidazolium
o
-
Tagged trans-4-
H
ydroxy-
L
-prol
o
ine mbardo,*a,b Filippo Pasi,a Srinivasan Easwar,a Claudio Trombini*a,b
a
Dipartimento di Chimica ‘G. Ciamician’, Università degli Studi di Bologna, via Selmi 2, 40126 Bologna, Italy
Consorzio Interuniversitario Nazionale ‘La Chimica per l’Ambiente’, via delle Industrie 21/8, 30175 Marghera (VE), Italy
Fax +39(051)2099456; E-mail: marco.lombardo@unibo.it; E-mail: claudio.trombini@unibo.it
b
Received 26 June 2008
used to abate acetone miscibility with water by salting
out.5a
Abstract: Imidazolium-tagged trans-4-hydroxy-L-proline, recently
reported by us as an efficient catalyst for the asymmetric cross-aldol
reaction in [bmim][Tf2N], gives much better results in terms of cat-
alytic activity and stereochemical performance under aqueous bi-
phasic conditions, providing aldols with anti/syn ratios up to 98:2
and ee (anti) up to 99%. The peculiar solubility properties of imida-
zolium-tagged trans-4-hydroxy-L-proline ensure an efficient sepa-
ration of the product from the catalyst and the recycling of trans-4-
hydroxy-L-proline for five times without appreciable loss of catalyt-
ic activity and stereochemical performance.
Water plays two roles: (i) it reduces side reactions such as
the formation of undesired iminium ions from the accep-
tor aldehyde and the catalyst,7 and (ii) it speeds up reac-
tions occurring in the boundary layer of the emulsion
through the development of hydrogen bonds between the
reactants and/or transition states and water molecules re-
siding in the interfacial layer. The last effect has been re-
cently rationalized by Jung and Marcus.8 The concept is
that when reactions take place in the organic–water
boundary layer, ‘dangling OH groups’ (those OH bonds
belonging to at least the 25% of surface water molecules
that are not H-bonded and protrude into the hydrophobic
phase) speed up reactions whenever the transition state is
more H-bonded to the surface of water than the reactants
are.
Key words: asymmetric organocatalysis, aldol reactions, biphasic
aqueous catalysis, ionic-tagged proline, catalyst recycling
The direct asymmetric intermolecular aldol reaction cata-
lyzed by proline, originally developed by List et al. in
2000,1 has been deeply explored over the last seven years
with the aim of improving catalyst performance and reac-
tion conditions. A comprehensive review by List et al.2
covers the main contributions up to 2006. Among the best
most recent achievements, reactions in water occupy a
prominent position. In particular we refer to reactions car-
ried out under aqueous biphasic conditions, where the or-
ganic phase is represented by the donor (the enolizable
ketone) used in molar excess and the acceptor aldehyde.3
Two main families of catalysts afford the best results, the
first one includes chiral amines4 or amides5 deriving from
L-proline, the second is represented by 4-O-modified
trans-4-hydroxy-L-proline derivatives.6 The catalysts be-
longing to these two groups invariably incorporate hydro-
phobic substituents on the proline structure that abate the
original hydrophilicity of the reference proline. The key to
success in all these examples is that all the reaction part-
ners, namely the catalyst, the donor and acceptor carbonyl
compounds, do not dissolve appreciably in water, thus
forming a water-saturated, concentrated hydrophobic
phase where the reaction takes place. A confirmation that
formation of a biphasic system is a necessary condition to
get good results is that water-miscible ketones afford
moderate yield and stereoselectivity in water.6b A single
example from Maya et al. reports excellent stereochemi-
cal results using acetone as donor, but in this case brine is
An alternative strategy for the design of hydrophobic cat-
alytic entities to be exploited under aqueous heteroge-
neous conditions entails the installation of an ionic group
on the catalyst structure, according to what Miao and
Chan defined as an ionic liquid supported catalyst.9 Two
roles are played by the supplementary ionic functionality.
On one hand, it allows to employ water10 or ionic liquids11
as the reaction media, where the strong coulombic inter-
action between the catalyst and the solvent can result in a
substantially modified activity or stereoselectivity. Sec-
ondly, thanks to the opportunity to tune the solubility of
the charged species by a suitable choice of the cation/an-
ion structure, conditions to separate the catalyst from the
reaction products, a necessary condition to develop an ef-
ficient catalyst recovery and reuse, can be easily found.
Imidazolium ion tagged catalysts of general structure 1
(Figure 1), where the tag is connected to the 4-OH group
of trans-4-hydroxy-L-proline, have been reported in the
recent literature to ensure good catalytic and stereochem-
ical performances in the direct aldol reaction.
Miao and Chan first reported the use of 1a as an efficient
aldolization catalyst in an experimental protocol which
used DMSO or acetone as the solvent.12 Considering that
the strong interactions occurring between ionic liquids
(ILs) used as solvent and the ion-tagged catalysts could
result in noticeable effects on the catalyst performance,
we checked 1b in cross-aldol reactions in ILs. The result
was an improved aldolization procedure, particularly
when the counterion of both the catalyst and the solvent
SYNLETT 2008, No. 16, pp 2471–2474
x
x
.x
x
.2
0
0
8
Advanced online publication: 12.09.2008
DOI: 10.1055/s-2008-1078055; Art ID: G22708ST
© Georg Thieme Verlag Stuttgart · New York

2472
M. Lombardo et al.
LETTER
H
O
O
OH
Y
O
N
O
Z
N
∗
+
∗
1b (5 mol%)
R
–X
+
O
H2O (0.8 mL)
24 h, 25 °C
NO2
N
H
OH
Z
NO2
(0.5 mmol)
97% yield
anti/syn = 96:4
99% ee
(5 equiv)
R
X
Y
Me
BF4
CH2
CH2
1a
C=O
C=O
Scheme 1
Me
Me
NTf2
1b
1c
BF4
CH2
CH2
poor solubility in water and different aromatic aldehydes
by applying the same simple and efficient protocol report-
ed for 4-nitrobenzaldehyde (Table 1, entry 1).16
n-C12H25 PF6 (CH2)4
1d
C=O
Figure 1
Cyclohexanone invariably afforded good yields and very
good to excellent diastereo- and enantioselectivities
(Table 1, entries 1–9). On the other hand, cycloheptanone
gave rise to a very slow reaction with very good stereo-
chemical results (Table 1, entry 10), while cyclopen-
tanone resulted as active as cyclohexanone but with a
quite disappointing diastereo- and enantioselectivity
(Table 1, entry 11).
was the lipophilic bis(trifluoromethyl sulfonyl)imide ion
(Tf2N–).13 Catalyst 1c was used in an analogous way in
ionic liquids by Zhou and Wang.14 Finally, catalyst 1d
was recently described by Zlotin et al. to work under
aqueous biphasic conditions, which also allow an easy re-
cycle of the catalyst.15 Even though two long lipophilic
–
chains were installed on 1d, the use of BF4 as counterion
–
instead of lipophilic PF6 abated the catalytic activity. The
In Table 2, results obtained in heterogeneous aqueous
conditions are directly compared to those previously re-
ported by us in ionic liquids.13
same authors found that under the identical aqueous bi-
–
phasic conditions, 1a, containing the hydrophilic BF4
ion, was completely inactive.15
In terms of stereochemical outcome, diastereoselectivity
showed an outstanding improvement passing from the use
of 1b under homogeneous conditions in [bmim][Tf2N] to
heterogeneous aqueous conditions. Enantioselectivity in-
creased, too, with a neat gain of 5–6% (Table 2, entries 1
The concept we wish to propose here is that, once the
structure of the imidazolium ion tagged catalyst has been
defined, it is possible to carry out an efficient and stereo-
selective cross-aldol reaction under aqueous heteroge-
neous conditions by a proper choice of the counterion, in
order to confer to the catalyst the proper hydrophobicity/
hydrophilicity profile. Indeed, the catalyst has to be ex-
tracted from water into the organic phase formed by the
donor and acceptor carbonyl compounds and in this phase
the whole catalytic cycle has to take place, enjoying the
benefits due to the presence of an organic phase–water
boundary layer. Moreover, in view of the today strong
commitment toward recoverable and reusable catalysts,
the product should be recovered selectively from the orga-
nocatalyst during the workup process.6a,f Again, a correct
choice of the counterion can be exploited to make the ion-
tagged catalyst insoluble in a range of organic solvents,
such as hydrocarbons or ethers.
Thus we reasoned that 1b containing the lipophilic Tf2N–
ion could be an excellent candidate to be checked. To our
delight, in the benchmark reaction of cyclohexanone and
4-nitrobenzaldehyde we obtained the corresponding prod-
uct in 97% yield with an anti/syn ratio of 96:4 and a 99%
ee of the major aldol using 5 mol% of 1b after stirring 24
hours at 25 °C (Scheme 1). Replacement of Tf2N– in 1b
with highly hydrophilic chloride ion resulted in a com-
plete lack of catalytic activity under the same conditions
as a consequence of a much poorer ability of the catalyst
to dissolve into the organic phase.
Table 1 Asymmetric Cross-Aldol Reactions Catalyzed by 1b under
Aqueous Biphasic Conditions
O
O
OH
O
1b (5 mol%)
Ar
+
H
Ar
H2O (0.8 mL), 25 °C
n
n
(0.5 mmol)
(5 equiv)
Entry
Ar
n
Time Yield
anti/synb ee (%)b
(h)
24
24
48
48
48
48
60
60
24
24
(%)a
97
95
94
98
72
64
50
41
25
91
1
2
4-O2NC6H4
4-NCC6H4
2-O2NC6H4
C6F5
1
1
1
1
1
1
1
1
2
0
96:4
96:4
98:2
91:9
95:5
95:5
95:5
91:9
91:9
58:42
99
99
99
99
99
99
97
96
98
80
3
4
5
4-ClC6H4
4-BrC6H4
Ph
6
8
9
b-Naph
10
11
4-O2NC6H4
4-O2NC6H4
Table 1 collects a selection of results obtained in the direct
aldol reaction of cycloalkanones, ideal donors to be
checked under aqueous biphasic conditions owing to their
a Isolated yields after purification by flash chromatography on silica.
b Determined by chiral HPLC on crude reaction mixture.
Synlett 2008, No. 16, 2471–2474 © Thieme Stuttgart · New York

LETTER
Asymmetric Aldol Reaction Catalyzed by Imidazolium-Tagged trans-4-Hydroxy-L-proline
2473
Table 2 Comparison of 1b Performances in an Aqueous Biphasic
Table 3 Asymmetric Cross-Aldol Reactions Catalyzed by 1b Using
Environment and in [bmim][NTf2] Ionic Liquid
Aliphatic Acceptor Aldehydes
O
O
OH
O
O
OH
O
O
1b
1b (5 mol%)
R
Ar
+
+
H
R
H
Ar
solvent (0.8 mL), 25 °C
H2O, 25 °C, 72 h
(5 equiv)
(0.5 mmol)
(0.5 mmol)
(5 equiv)
1b (mol%) Yield anti/synb ee (%)b
Entry Ar
Solvent Time Yield anti/synb ee (%)b
Entry
R
H2O
(mL)
(h) (%)a
(%)a
1
2
3
4
5
6
4-O2NC6H4 H2O
4-O2NC6H4 ILc
24
24
48
24
60
24
97
78
72
38
41
36
96:4
99
94
99
80
96
90
1
2
3
4
5
6
i-Pr
Cy
0.8
0.8
0.8
0.8
5
–
–
–
70:30
95:5
5
–
–
–
4-ClC6H4
4-ClC6H4
b-Naph
H2O
i-Pr
Cy
10
10
9
>99:1
>99:1
>99:1
>99:1
99
99
99
99
ILc
85:15
91:9
7
H2O
ILc
i-Pr
Cy
0.012 10
0.012 10
60
52
b-Naph
80:20
a Isolated yields after purification by flash chromatography on silica.
b Determined by chiral HPLC on crude reaction mixture; absolute
configuration was assigned by comparison with the retention times of
the known products.
a Isolated yields after purification by flash chromatography on silica.
b Determined by chiral HPLC on crude reaction mixture; absolute
configuration was assigned by comparison with the retention times of
the known products.
c IL = 1-Butyl-3-methylimidazolium bis(trifluoromethylsulfonyl)im-
ide.
and 2, 5 and 6) up to 19% in the case of 4-chlorobenzalde- In conclusion, an alternative approach in organocatalyst
hyde (Table 2, entries 3 and 4).
design is presented that finds here an interesting applica-
tion. The successful results in the asymmetric cross-aldol
reaction are due to the combination of the hydrophilic cat-
ionic frame of 1b (it contains two hydrophilic portions,
the proline moiety and the imidazolium ion) and the high-
ly hydrophobic Tf2N– ion. The solubility profile proper of
the cation–anion combination in 1b is shaped in such a
way that 1b is present into the organic phase of the bipha-
sic ketone–water system where the aldol reaction takes
place in high yields and excellent stereocontrol. In partic-
ular using cyclohexanone as donor, anti/syn ratios were
up to 98:2 and anti ee up to 99%. At the workup level, on
the other hand, aldol products and 1b can be efficiently
separated, after evaporation of the excess ketone and wa-
Finally, to widen the scope of the cross-aldol reaction here
reported, we tested a few aliphatic aldehydes (i.e., isobu-
tyraldehyde and cyclohexanecarboxaldehyde) as the part-
ner acceptors. Results are summarized in Table 3.17
Using 5 mol% of 1b only trace amounts of aldol products
were observed after stirring 72 hours at 25 °C (Table 3,
entries 1 and 2). Raising the catalyst amount to 10 mol%
afforded the desired products in very low yields (Table 3,
entries 3 and 4), although with very good levels of both
diastereo- and enantioselectivity. The failure of the aque-
ous biphasic protocol with aliphatic aldehydes prompted
us to explore homogeneous conditions in the presence of
trace amounts of water. Thus, we tried the cross-aldol re-
action using 10 mol% of 1b, five equivalents of the donor
and the aliphatic aldehyde under neat conditions, adding
only a small amount of water (ca. 4%, v/v). Fairly good
yields of the desired adducts were obtained, again with ex-
cellent values of diastereo- and enantioselectivity.
Table 4 Recycling Experiments Using Cyclohexanone, Catalyst
1b, and 4-Nitrobenzaldehyde in Water
Cycle
Yield (%)b
anti/sync
96:4
ee (%)c
99
1
2
3
4
5
90
89
90
88
80
The last observations we wish to discuss refer to recycling
experiments of the organocatalyst. To this purpose we de-
veloped an efficient workup procedure, which involved
the preliminary removal of the ketone and water under re-
duced pressure, followed by extraction of the products
with diethyl ether.
96:4
99
95:5
99
96:4
99
95:5
98
Results obtained using the same amount of catalyst 1b for
five cycles, each being conducted under the same experi-
mental procedure outlined in Scheme 1, are reported in
Table 4.18 Only in the fifth cycle a 10% decrease in the
isolated yield was observed, while a substantially identi-
cal diastereo- and enantioselectivity was maintained.
a Reagents and conditions: cyclohexanone (5 equiv), catalyst 1b (5
mol%), and 4-nitrobenzaldehyde (1 mmol) in H2O (1.6 mL) for 24 h
at 25 °C.
b Isolated yields after purification by flash chromatography on silica.
c Determined by chiral HPLC on crude reaction mixture.
Synlett 2008, No. 16, 2471–2474 © Thieme Stuttgart · New York

2474
M. Lombardo et al.
LETTER
(7) Zotova, N.; Franzke, A.; Armstrong, A.; Blackmond, D.
ter, 1b being insoluble in diethyl ether. This last separa-
tion offers the opportunity to recycle 1b, which was used
for five runs without any loss of catalytic activity and ste-
reochemical performances.
J. Am. Chem. Soc. 2007, 129, 15100.
(8) Jung, Y.; Marcus, R. A. J. Am. Chem. Soc. 2007, 129, 5492.
(9) Miao, W.; Chan, T. H. Acc. Chem. Res. 2006, 39, 897.
(10) (a) Li, C.-J. Chem. Rev. 2005, 105, 3095. (b) Lindström,
U. M. Chem. Rev. 2002, 102, 2751.
(11) (a) Weingärtner, H. Angew. Chem. Int. Ed. 2008, 47, 654.
(b) Parvulescu, V. I.; Hardacre, C. Chem. Rev. 2007, 107,
2615. (c) Chowdhury, S.; Mohan, R. S.; Scott, J. L.
Tetrahedron 2007, 63, 2363. (d) Welton, T. Chem. Rev.
1999, 99, 2071.
Acknowledgment
This work was supported by MIUR (Rome) PRIN project grant:
‘Sintesi e Stereocontrollo di Molecole Organiche per lo Sviluppo di
Metodologie Innovative di Interesse Applicativo’.
(12) Miao, W.; Chan, T. H. Adv. Synth. Catal. 2006, 348, 1711.
(13) Lombardo, M.; Pasi, F.; Easwar, S.; Trombini, C. Adv.
Synth. Catal. 2007, 349, 2061.
References and Notes
(14) Zhou, L.; Wang, L. Chem. Lett. 2007, 36, 628.
(15) Siyutkin, D. E.; Kucherenko, A. S.; Struchkova, M. I.;
Zlotin, S. G. Tetrahedron Lett. 2008, 49, 1212.
(1) (a) List, B. Tetrahedron 2002, 58, 5573. (b) List, B.;
Pojarliev, P.; Castello, C. Org. Lett. 2001, 3, 573. (c) List,
B. Synlett 2001, 1675. (d) Notz, W.; List, B. J. Am. Chem.
Soc. 2000, 122, 7386. (e) List, B.; Lerner, R. A.; Barbas,
C. F. III J. Am. Chem. Soc. 2000, 122, 2395.
(16) General Procedure for Cross-Aldol Condensation of
Aromatic Aldehydes (Table 1, entry 1)
Catalyst 1b (13.4 mg, 0.025 mmol) was stirred in H2O
(0.8 mL) until a clear solution was obtained. Cyclohexanone
(0.259 mL, 2.5 mmol) was added and the mixture was stirred
for 20 min whereupon the reaction mixture became an
emulsion. 4-Nitrobenzaldehyde (75.5 mg, 0.5 mmol) was
then added, and the reaction mixture was allowed to stir for
a further 24 h at 25 °C. Cyclohexanone and water were
removed under reduced pressure and the residue was
extracted with Et2O (4 × 3 mL). The combined organic
extracts were dried over Na2SO4, concentrated in vacuo, and
purified by silica gel column chromatography
(2) Mukherjee, S.; Yang, J. W.; Hoffmann, S.; List, B. Chem.
Rev. 2007, 107, 5471.
(3) For a recent debate on the role of water in organocatalytic
reactions, see: (a) Blackmond, D. G.; Armstrong, A.;
Coombe, V.; Wells, A. Angew. Chem. Int. Ed. 2007, 46,
3798. (b) Hayashi, H. Angew. Chem. Int. Ed. 2006, 45,
8103. (c) Brogan, A. P.; Dickerson, T. J.; Janda, K. D.
Angew. Chem. Int. Ed. 2006, 45, 8100.
(4) (a) Aratake, S.; Itoh, T.; Okano, T.; Usui, T.; Shoji, M.;
Hayashi, Y. Chem. Commun. 2007, 2524. (b) Mase, N.;
Nakai, Y.; Ohara, N.; Yoda, H.; Takabe, K.; Tanaka, F.;
Barbas, C. F. III J. Am. Chem. Soc. 2006, 128, 734.
(5) (a) Maya, V.; Raj, M.; Singh, V. K. Org. Lett. 2007, 9, 2593.
(b) Guizzetti, S.; Benaglia, M.; Raimondi, L.; Celentano, G.
Org. Lett. 2007, 9, 1247. (c) Wang, C.; Jiang, Y.; Zhang,
X.-X.; Huang, Y.; Li, B.-G.; Zhang, G.-L. Tetrahedron Lett.
2007, 48, 4281. (d) Wu, Y.; Zhang, Y.; Yu, M.; Zhao, G.;
Wang, S. Org. Lett. 2006, 8, 4417. (e) Fu, Y.-Q.; Li, Z.-C.;
Ding, L.-N.; Tao, J.-C.; Zhang, S.-H.; Tang, M.-S.
Tetrahedron: Asymmetry 2006, 17, 3351.
(6) (a) Font, D.; Sayalero, S.; Bastero, A.; Jimeno, C.; Pericàs,
M. A. Org. Lett. 2008, 10, 337. (b) Aratake, S.; Itoh, T.;
Okano, T.; Nagae, N.; Sumiya, T.; Shoji, M.; Hayashi, Y.
Chem. Eur. J. 2007, 13, 10246. (c) Huang, J.; Zhang, X.;
Armstrong, D. W. Angew. Chem. Int. Ed. 2007, 46, 9073.
(d) Hayashi, Y.; Sumiya, T.; Takahashi, J.; Gotoh, H.;
Urushima, T.; Shoji, M. Angew. Chem. Int. Ed. 2006, 45,
958. (e) Hayashi, Y.; Aratake, S.; Okano, T.; Takahashi, J.;
Sumiya, T.; Shoji, M. Angew. Chem. Int. Ed. 2006, 45,
5527. (f) Font, D.; Jimeno, C.; Pericàs, M. A. Org. Lett.
2006, 8, 4653.
(cyclohexane–EtOAc, 7:3) to obtain the pure anti-aldol
adduct in 93% yield and the syn-adduct in 4%.
(17) General Procedure for Cross-Aldol Condensation of
Aliphatic Aldehydes (Table 3, entry 5)
Catalyst 1b (26.8 mg, 0.05 mmol) was dissolved in
cyclohexanone (0.259 mL, 2.5 mmol), H2O was added
(0.012 mL), and the solution was stirred for 10 min before
the addition of isobutyraldehyde (0.046 mL, 0.5 mmol). The
reaction mixture was allowed to stir for a further 72 h at
25 °C. Cyclohexanone and water were removed under
reduced pressure and the residue was purified by silica gel
column chromatography (cyclohexane–EtOAc, 9:1) to
afford the pure anti-aldol adduct in 60% yield.
(18) General Procedure for the Recycling Experiment
(Table 4)
The recycling studies were performed using the same
procedure reported above on a 1 mmol scale of 4-nitro-
benzaldehyde. After completion of the workup, the reaction
flask was dried under vacuum for 1 h and recharged with
H2O and the starting substrates.
Synlett 2008, No. 16, 2471–2474 © Thieme Stuttgart · New York