Proline-catalysed asymmetric aldol reaction in the room temperature ionic liquid [bmim]PF6

Article abstract of DOI:10.1039/b206911c

Proline-catalysed asymmetric direct aldol reaction of different aromatic aldehydes with acetone and several other ketones in the room temperature ionic liquid 1-n-butyl-3-methylimidazolium hexafluorophosphate achieved good yields of aldolisation products

Full text of DOI:10.1039/b206911c

Proline-catalysed asymmetric aldol reaction in the room temperature
ionic liquid [bmim]PF6†
ˆ
Peter Kotrusz, Iveta Kmentová, Battsengel Gotov, Stefan Toma* and Eva Sol cˆ ániová
Department of Organic Chemistry, Faculty of Natural Sciences, Comenius University, 842 15 Bratislava,
Slovakia. E-mail: toma@fns.uniba.sk; Fax: +421 2 602 96 690; Tel: +421 602 96 208
Received (in Cambridge, UK) 16th July 2002, Accepted 9th September 2002
First published as an Advance Article on the web 26th September 2002
Proline-catalysed asymmetric direct aldol reaction of differ-
ent aromatic aldehydes with acetone and several other
ketones in the room temperature ionic liquid 1-n-butyl-
mixture.† The ionic liquid phase was dried in vacuo at 40 °C for
2 h and was used directly for subsequent reaction. The achieved
results are summarised in Table 1.
3
-methylimidazolium hexafluorophosphate achieved good
The benzaldehyde (entry 1) aldol reaction product with
acetone was obtained in 55% yield and 76% ee (R) in our case
yields of aldolisation products with reasonable enantiose-
lectivities, even when just 1–5% of proline was used as the
catalyst; immobilisation of the catalyst in an ionic liquid
phase offers simple product isolation and reuse of the
catalytical system in subsequent reactions.
5
c
compared to 62% yield and 60% ee (R) from the literature.
The regenerated catalyst gave product in 42% yield and 72% ee
(entry 2). The next known case was p-nitrobenzaldehyde (entry
10), but we received much lower yield and enantioselectivity
compared to results obtained in DMSO5 (21% yield, 48% ee
vs. 68% yield, 76% ee). Nevertheless, by modification of the
experimental procedure we were able to improve yield and
enantioselectivity (68%, 65%ee, entry 12). The low yield of the
product under the standard conditions could be caused by
reaction of 4-nitrobenzaldehyde with the ionic liquid, as was
suggested by one of the referees, and described in ref. 8. An
experiment was therefore performed in which acetone was
missing from the reaction medium. No reaction was observed,
practically all 4-nitrobenzaldehyde was recovered and there
were no aromatic chemical shifts in the ionic liquid used in this
c,d
The aldol reaction is one of the basic organic transformations
1
for the formation of new C–C bonds. The synthetic value of the
aldol reactions has been proven by their application in the total
synthesis of natural products.2
There is a broad range of effective approaches leading to
3
stereoselective aldol reactions. The most promising of them,
especially from an industrial point of view, deals with usage of
4
the small organic molecules as enzyme mimics.
In recent years, the proline-catalysed asymmetric direct aldol
5
reaction in intermolecular fashion was investigated. A strong
solvent influence on the resulting enantiopurity of products was
observed and anhydrous DMSO has been found to be the most
suitable solvent.5 Indeed, the aldol-product of benzaldehyde
with acetone, which was used as co-solvent, was obtained in
c
6
2% yield and 60% ee (R) in the presence of (S)-proline (30
5c,d
mol%).
Two routes to catalyst recovery have been studied.5d The first
method was based on the fact that proline is not soluble in
chloroform. The reaction was performed in a heterogeneous
manner and the catalyst was recovered by simple filtration.
However, the product was obtained with lower enantioselectiv-
ity (in the case of p-nitrobenzaldehyde 61 vs. 76% ee). The
second method was immobilisation of the catalyst on a silica
surface and the resulting heterogeneous catalyst was applied to
run reactions in DMSO–acetone (4+1) mixture. However, a
significant reduction of enantioselectivity was also observed.
The advantages of proline based aldolisation are that the
methodology is metal free and that both enantiomers of the
catalyst are cheap and easily available. A possible limitation
factor might be the utilisation of DMSO as the reaction
solvent.
Scheme 1
Table 1 Proline-catalysed aldol reaction in [bmim]PF
6
ionic liquid
according to Scheme 1
Entry
X
Yield (%)a
ee (%)b
1
2
3
4
5
6
7
8
9
(H)
(2. run)
4-CF
(2. run)
(3. run)
4-F
(2. run)
4-OMe
(2. run)
55
43
91
75
74
90
87
69
52
21
20
68
74
71
61
54
69
60
93
86
94
76
71
73
67
63
68
61
50
48
48
47
65
70
46
63
62
68
62
82
54
70
3
Room temperature ionic liquids have been applied as
alternative solvents in many catalytical organic transforma-
1
1
1
1
1
15
16
17
1
1
2
2
0
1
2
3
4
4-NO
(2. run)
4-NO
4-CN
(2. run)
2-Br
(2. run)
2-OMe
(2. run)
2
6
tions. The RTIL were also used recently for aldol reaction of
7
propanal with 2-methylpentanal under NaOH catalysis. There-
c
2
fore, it was interesting to investigate the proline-catalysed direct
asymmetric aldol reaction in ionic liquid and to compare the
results with published data for more common organic solvents.
The next important aspect was examination of the catalyst
recovery and the possibility for catalyst reuse in subsequent
reactions.
At first, several substituted benzaldehyde derivatives (1)
were investigated and aldol reaction products (2) (Scheme 1)
have been isolated after simple extraction of the reaction
8
9
0
1
2-NO
(2. run)
3-NO
2
2
a
Isolated yields after chromatography. b Determined by 1H-NMR with
3
chiral shift reagent Eu(hfc) and/or by HPLC analysis (AD-H or AS
†
Electronic supplementary information (ESI) available: experimental
Chiralpak® column). Modified procedure: aldehyde was added after 30
c
1
details and H-NMR spectra of the prepared compounds. See http://
www.rsc.org/suppdata/cc/b2/b206911c/
min stirring of proline in acetone-ionic liquid mixture.
2
510
CHEM. COMMUN., 2002, 2510–2511
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reaction. A variety of 2- and 4-substituted benzaldehydes (1)
have been employed and aldol products 2 were obtained in good
yields (61–94%) and reasonable enantioselectivities (61–93%
ee).
The recovered catalyst was reused and only a slight decrease
of the chemical yields as well as enantioselectivities was
observed, except for p-cyano (from 70 to 46% ee) and o-nitro
Table 3 Proline-catalysed (30 mol%) aldolisation of p-CF
with cyclopentanone (entry 1), cyclohexanone (entry 2) and cyclobutanone
entry 3)
3
-benzaldehyde
(
b
Entry
Yield (%)a
de (%) (anti+syn)
ee (%)
1
2
3
a
94
91
53
1+1
20+1
6+1
32 (anti)
8
6 (syn)
(
from 82% to 54% ee), where a significant drop of enantiose-
93 (anti)
n.d. (syn)
10 (anti)
lectivity was observed (entries 14 and 20). We do not have any
reasonable explanation for this drop in selectivity. The reaction
of 1-naphthalene-carbaldehyde with acetone gave, under the
same conditions, aldolisation product in 55% yield and 68% ee
compared to the 54% yield and 77% ee described for
DMSO.5
8
(syn)
Isolated yields after chromatography. b According to NMR spectra of
crude reaction mixtures.
c,d
We next examined the influence of catalyst amount in the
case of p-trifluoromethylbenzaldehyde (Table 2). No reaction
took place in the absence of proline (entry 1). The same result
was obtained with 10 mol% of proline compared to the reaction
catalysed by 30 mol% of proline (entry 2). With 5 mol% of
catalyst, the product yield remained at a comparable level, but
with 1 mol% of catalyst the drop in reactivity was more
significant (entries 3 and 4). In all cases the enantioselectivity
was not affected (72–75% ee). Experiments with 1 mol% of (S)-
proline were repeated several times and a serious drop in yield
was observed after the third repetition (first reuse 75%, second
reuse 75%, third reuse 30%). Nevertheless, the enantioselectiv-
ity of the reaction was preserved (75% ee) even after the eighth
repetition. The addition of 0.5 mol% of catalyst to the reaction
medium returned the yield to the original value (74%).
Proline-catalysed reaction of p-trifluoromethylbenzaldehyde
with butan-2-one was also investigated (Scheme 2). The desired
aldolisation product was isolated in 59% yield and 76% ee. The
reused catalytical system gave product in 52% yield and 71%
ee.
with cyclohexanone, after the product was extracted from the
ionic liquid, but the yield dropped to 67%. The diaster-
eoselectivity of the reaction with cyclobutanone (entry 3) was
reasonable, but enantioselectivity was, in this case, very low.
1
The ee of the products were determined solely by H-NMR
spectra using a chiral shift reagent because the product
decomposed upon transport for HPLC measurements in Koeln.
No reaction was observed with cycloheptanone.
Unfortunately, we were not able to detect aldol reaction
products with acetophenone, pentan-3-one, 3,3-dimethylbuta-
nal, dimedone and Meldrum’s acid. Only condensation products
and subsequent Michael addition by-products were detected
after the reactions under standard conditions.
In conclusion, we have demonstrated that the room tem-
6
perature ionic liquid [bmim]PF is a suitable solvent for proline-
catalysed asymmetric aldol reactions.
The catalyst immobilised in an ionic liquid phase is
recyclable and in many cases the product yield and enantiopur-
ity remained at a comparable level as in the case of the fresh
catalyst. Further investigations in this laboratory involve the
study of different proline-catalysed reactions in ionic liquids.
This work was supported by Comenius University grant
The reactions of p-trifluoromethylbenzaldehyde with cyclo-
pentanone, cyclohexanone and cyclobutanone were also per-
formed. Surprisingly, very different results were obtained
9
8/2002/UK and VEGA grant 1/0072/03.
(
Table 3). The aldolisation of cyclopentanone resulted in ~ 1+1
mixture of anti- and syn-diastereomers, 32% ee for the anti-
diastereomer and 86% ee for the syn-diastereomer (entry 1).
However, cyclohexanone gave virtually pure anti-diastereomer
Notes and references
1
(a) Comprehesive Organic Synthesis, Vol. 2, ed. B.M. Trost, I. Fleming
and C.H. Heathcock, Pergamon, Oxford, 1991; (b) For a recent review
about asymmetric aldol reactions, see C. Palomo, M. Oiarbide and . J. M.
Garcia, Chem. Eur. J., 2002, 8, 36.
(
de > 20+1) with high enantiopurity (93% ee) (entry 2). An
attempt to reuse the catalytic system was made for the reaction
Table 2 Influence of catalyst amount on the reaction yield and enantiose-
2
3
(a) T. Mukaiyama, Tetrahedron, 1999, 55, 8609; (b) K. C. Nicolau, D.
Vourloumis, N. Winssinger and P. S. Baran, Angew. Chem., Int. Ed.
Engl., 2000, 39, 44.
3
lectivity in the aldolisation of p-CF -benzaldehyde with acetone
(
S)-proline
(a) H. Gröger, E. M. Vogl and M. Shibasaki, Chem. Eur. J., 1988, 4,
Entry
(mol%)
Yield (%)a
ee (%)b
1
137; (b) T. D. Machajewski and C. H. Wong, Angew. Chem., Int. Ed.
Engl., 2000, 39, 1352.
H. Gröger and J. Wilken, Angew. Chem., Int. Ed. Engl., 2001, 40, 529.
(a) B. List, Synlett, 2001, 1675; (b) B. List, Tetrahedron, 2002, 58, 5573;
1
2
3
4
0
10
5
0
92
89
74
4
5
72
74
75
(c) B. List, R. A. Lerner and C. F. Barbas III, J. Am. Chem. Soc., 2000,
1
1
22, 2395; (d) K. Sakthivel, W. Notz, T. Bui and C. F. Barbas III, J. Am.
a
Isolated yields after chromatography. b Determined by HPLC analysis
AD-H Chiralpak® column).
Chem. Soc., 2001, 123, 5260; (e) W. Notz and B. List, J. Am. Chem. Soc.,
2000, 122, 7386; (f) B. List, P. Pojarliev and C. Castello, Org. Lett., 2001,
(
3
, 573.
(a) J. D. Holbrey and K. R. Seddon, Clean Prod. Process., 1999, 1, 233;
b) K. R. Seddon, J. Chem. Technol. Biotechnol., 1997, 68, 351; (c) T.
6
(
Welton, Chem. Rev., 1999, 99, 2071; (d) P. Wasserscheid and W. Keim,
Angew. Chem., Int. Ed Engl., 2000, 39, 3772; (e) R. Sheldon, Chem.
Commun., 2001, 2399; (f) C. M. Gordon, Appl. Catal., A, 2001, 222,
1
01.
C. P. Mehnert, N. C. Dispenziere and R. A. Cook, Chem. Commun, 2002,
610.
7
1
Scheme 2 Proline-catalysed aldol reaction of p-CF
butan-2-one in [bmim]PF
3
-benzaldehyde with
8 V. K. Aggarwal, I. Emme and A. Mereu, Chem. Commun., 2002,
1612.
6
CHEM. COMMUN., 2002, 2510–2511
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