Asymmetric aldol reactions in poly(ethylene glycol) catalyzed by L-proline

Article abstract of DOI:10.1016/j.tetlet.2004.03.116

A rapid L-proline catalyzed direct aldol reaction between various aldehydes and acetone was achieved using PEG as the solvent with comparable enantioselectivities and yields to those obtained in other solvents. Recycling the catalyst and solvent (PEG) was possible 10 times without loss of activity.

Full text of DOI:10.1016/j.tetlet.2004.03.116

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 4581–4582
Asymmetric aldol reactions in poly(ethylene glycol)
catalyzed by
-prolineq
L
S. Chandrasekhar,* Ch. Narsihmulu, N. Ramakrishna Reddy and S. Shameem Sultana
Indian Institute of Chemical Technology, Hyderabad 500 007, India
Received 5 November 2003; revised 8 March 2004; accepted 19 March 2004
Abstract—A rapid L-proline catalyzed direct aldol reaction between various aldehydes and acetone was achieved using PEG as the
solvent with comparable enantioselectivities and yields to those obtained in other solvents. Recycling the catalyst and solvent (PEG)
was possible 10 times without loss of activity.
Ó 2004 Elsevier Ltd. All rights reserved.
The asymmetric aldol reaction of an aldehyde and a
modified/unmodified ketone is one of the most powerful
C–C bond forming reactions.1 This reaction yields
b-hydroxy carbonyl compounds, which in turn have
great potential in organic synthesis.2 Even though several
catalysts have been reported for this transformation,
more emphasis recently has been given to nonmetallic
small molecule chiral catalysts as they are more efficient
earlier cases studied), PEG (2 g, 400 Da) and nitro-
benzaldehyde (1 mmol) (Table 1, entry 1). To our satis-
faction the reaction was complete in 30 min and yielded
94% of the product with 67% ee (Scheme 1). The reac-
tion medium was diluted with anhydrous ether (5 mL),
stirred for 5 min, allowed to separate out and the ether
layer was decanted. This process was repeated twice to
obtain the product in ether whereas the mother liquor
(PEG + proline) was kept aside for further runs.
and environment friendly.3
L-Proline is one such small
molecule, which has given rich dividends in ee’s and
yields. However some of the protocols reported to date
involve high boiling DMSO as the solvent and also
require long reaction times.4 Recent work has attempted
to overcome this by using a recyclable ionic liquid as the
solvent,5 or buffered aqueous media,6 or a Zn–proline
complex in aqueous media7 or aqueous micelles.8
Encouraged by this result, we studied the reusability of
the catalyst as well as the solvent. A second run was
performed without any modification. The simple addi-
tion of nitrobenzaldehyde (1 mmol) and acetone
(4 equiv) to the mother liquor with stirring for 30 min
resulted in the aldol product in a 93% yield with similar
enantioselectivity (68% ee) to first run. The efficient
recycling of the reaction medium (catalyst and solvent)
was then proved by additional experiments until a tenth
run. Except for the third run, which showed a slight
increase in enantioselectivity (71%), all the runs were
similar in product yields and enantioselectivities.
We were particularly interested in developing an eco-
friendly approach9 for the direct aldol reaction using
PEG as the solvent for the following reasons. (a) PEG is
biologically compatible.10 (b) The polymer is available
at a vey affordable price.11 (c) The requirement for only
a low concentration of catalyst. (d) A highly practical
and simple workup procedure. Our results are presented
herein.
The efficiency of the transformation was examined by
subjecting various aldehydes to an aldol reaction in
PEG. All the examples studied gave similar results to
those reported using conventional solvents and other
methods. The 2- and 3-nitrobenzaldehydes (entries 11
and 12) underwent the aldol reaction smoothly giving
the products in 90% and 88% yields with 64% and 70%
ee’s, respectively. Benzaldehyde (entry 13) gave the aldol
product, which was comparable in yield and enantio-
meric excess to that obtained with DMSO as the solvent.
In the case of 4-bromobenzaldehyde (entry 14) there was
First we examined the reaction of acetone (4 mmol),
L
-proline (10 mol % compared to 30 mol % in all the
Keywords: Asymmetric aldol reaction; L-Proline; PEG; Reusability.
q ICT Communication no 031101.
* Corresponding author. Tel.: +91-40-27193434; fax: +91-40-271605-
12; e-mail: srivaric@iict.res.in
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.03.116

4582
S. Chandrasekhar et al. / Tetrahedron Letters 45 (2004) 4581–4582
Table 1. L-Proline catalyzed asymmetric aldol reactions in PEG
In conclusion poly(ethylene glycol) (PEG) has been
shown to be a rapid and reusable reaction medium
for -proline catalyzed asymmetric aldol reactions. The
Entry
Substrate
Time
(min)
Yielda (%) Ee (%)
L
reusability of this solvent was studied over 10
runs without loss of activity of either the catalyst or
solvent.
CHO
1
30
94
67b
O2N
2
2nd run
3rd run
4th run
5th run
6th run
7th run
8th run
9th run
10th run
30
30
30
30
30
30
30
30
30
93
90
89
90
88
87
88
86
84
68b
71b
67b
66b
64b
67b
65b
67b
66b
3
4
5
6
Acknowledgements
7
8
We C.N., N.R.K. and S.S.S. thank CSIR New Delhi for
financial support.
9
10
CHO
11
12
30
90
64b
NO2
CHO
References and notes
30
88
70b
1. (a) Comprehensive Organic Synthesis; Trost, B. M., Flem-
ing, I., Heathcock, C. H, Eds.; Pergamon: Oxford, 1991;
Vol. 2; For a review, see: (b) Palomo, C.; Oiarbide, M.;
Garcia, J. M. Chem. Eur. J. 2002, 8, 36.
2. (a) Mukaiyama, T. Tetrahedron 1999, 55, 8609; (b)
Nicolaou, K. C.; Vourloumis, D.; Winssinger, N.; Baran,
P. S. Angew. Chem., Int. Ed. 2000, 39, 44.
3. (a) Groger, H.; Wilken, J. Angew. Chem., Int. Ed. 2001, 40,
529; (b) Dalko, P. I.; Moisan, L. Angew. Chem., Int. Ed.
2001, 40, 3726; (c) List, B. Synlett 2001, 1675; (d) Alcaide,
B.; Almendros, P. Eur. J. Org. Chem. 2002, 1595; (e)
Jarvo, E. R.; Miller, S. J. Tetrahedron 2002, 58, 2481;
(f) List, B. Tetrahedron 2002, 58, 5573; (g) Alcaide,
B.; Almendros, P. Angew. Chem., Int. Ed. 2003, 42,
858; (h) Duthaler, R. O. Angew. Chem., Int. Ed. 2003, 42,
975.
4. (a) List, B.; Lerner, R. A.; Barbas, C. F., III. J. Am. Chem.
Soc. 2000, 122, 2395; (b) Loh, T.-P.; Feng, L.-C.; Yang,
H.-Y.; Yang, J. Y. Tetrahedron Lett. 2002, 43, 8741; (c)
Kotrusz, P.; Kmentova, I.; Gotov, B.; Toma, S.; Solkani-
ova, E. Chem. Commun. 2002, 2510.
NO2
CHO
13
14
30
30
58
85
58b
65b
CHO
Br
O2N
CHO
Cl
15
16
30
30
90
88
61b
60
CHO
Cl
CHO
CHO
17
18
120
180
90
65
84c
71c
a Isolated yields after chromatography; the products were character-
ized by spectral data.
b Ee% by chiral HPLC.
c Ee% by optical rotation.
5. Chowdari, N. S.; Ramachary, D. B.; Barbas, C. F., III.
Synlett 2003, 1906.
6. Cordova, A.; Notz, W.; Barbas, C. F., III. Chem.
Commun. 2002, 3024.
7. Darbre, T.; Machuqueiro, M. Chem. Commun. 2003,
1090.
O
OH
O
8. Peng, Y.-Y.; Ding, Q. P.; Li, Z.; Wang, P. G.; Cheng, J.-P.
Tetrahedron Lett. 2003, 44, 3871.
9. (a) Chandrasekhar, S.; Narsihmulu, Ch.; Sultana, S. S.;
Reddy, N. R. Org. Lett. 2002, 4, 4399; (b) Chandrasekhar,
S.; Narsihmulu, Ch.; Sultana, S. S.; Reddy, N. R. Chem.
Commun. 2003, 171.
L-Proline (10 mol%)
H
Acetone (4 eq)
PEG, r.t 30 min
O2N
O2N
Yields up to 94% (10 runs)
ee's up to 71% (10 runs)
Scheme 1.
10. Harris, J. M.; Zalipsky, S. Poly(ethylene glycol): Chem-
istry and Biological Applications; ACS Books: Washing-
ton, DC, 1997.
11. Ionic liquids cost 60–400 USD/50 g, as against PEG (400),
which cost 23 USD/500 g.
an increase in the yield (85%) of the product. Aliphatic
aldehydes (entries 17 and 18) were also good substrates
for the aldol reaction.