L-Prolinamide derivatives as efficient organocatalysts for aldol reactions on water

Article abstract of DOI:10.1016/j.tetlet.2011.10.009

A series of l-prolinamide derivatives have been evaluated as potential organocatalysts for aldol reactions. To synthesize these catalysts, a novel and simple route has been developed using proline N-carboxyanhydride (proline-NCA). A new catalyst with a tr

Full text of DOI:10.1016/j.tetlet.2011.10.009

Tetrahedron Letters 52 (2011) 7034–7037
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L-Prolinamide derivatives as efficient organocatalysts for aldol
reactions on water
Gongkun Tang a, Xianming Hu b, Hans Josef Altenbach a,
⇑
a Department of Organic Chemistry, University of Wuppertal, Gaußstr. 20, 42097 Wuppertal, Germany
b College of Pharmacy, Wuhan University, 430072 Wuhan, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of L-prolinamide derivatives have been evaluated as potential organocatalysts for aldol reactions.
Received 2 August 2011
Revised 28 September 2011
Accepted 3 October 2011
Available online 25 October 2011
To synthesize these catalysts, a novel and simple route has been developed using proline N-carboxyan-
hydride (proline-NCA). A new catalyst with a trifluoromethyl-sulfonamide group has been found exhib-
iting excellent diastereoselectivity (anti/syn: 97/3) and enantioselectivity (99% ee) with 10 mol % loading
and being easily recyclable in water.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Aldol reaction
Enantioselecitvity
Organocatalysis
Proline amide derivative
Proline-NCA
In recent years organocatalysis with proline, its derivatives and
with proline analogs has experienced an impressive develop-
ment.1,2 Furthermore, the use of water as solvent for organocatal-
ysis,3 especially in enantioselective aldol reactions,4 has found a lot
of interest. Despite promising results, however, the design of new
effective catalysts for aldol reaction in or on water is still a
challenge.3
Two factors seem to be crucial for an efficient organocatalyst in
an aqueous environment: its hydrophobic/hydrophilic properties
and its acidity. Imid structures derived from proline like N-sulfo-
derivatives with long hydrophobic chains as efficient catalysts for
aldol reactions with high enantio- and diastereoselectivities.
Most of the reported sulfonamide derivatives contain hydro-
phobic groups in order to have good liposolubility.6,9,11 But this
leads inevitably to increasing difficulties in the separation of prod-
uct and organocatalyst. Perfluorinated residues have a specific
hydrophobic character and a strong electron withdrawing ability.
Recently the trifluoromethyl group has been noted as an interest-
ing functional group for organocatalysts12 and N-(trifluoroacetyl)
pyrrolidine-2-carboxamide (2a) has been tested as an organocata-
lyst in the aldol reaction (Fig. 1).13
nyl-L-prolin-amide (1) and N-carboxyl-L-prolinamide (2) provide
potential in both directions. A recent paper features the relation-
ship between amide acidity and catalytic activity of proline deriv-
atives in aldol reactions in DMSO on theoretical calculations, which
in most cases correlate well with experimental results.5 Amazingly
All the known L-proline amide derivatives have been prepared
by acylation of N-protected proline. But when we tried to synthe-
size a series of imide products from N-Boc-prolinamide with differ-
ent acylating reagents by this procedure, we got no satisfying
results. Therefore we developed a novel route starting with
the most acidic compound, N-(trifluoromethyl)sulfonyl-L-proline
amide (1c), which was predicted to give the highest selectivity,
has not been prepared so far.
Strongly acidic amide derivatives of proline have been found to
be good catalysts for direct aldol and Mannich reactions. In 2005,
first Berkessel6 reported a sulfonamide derivative of proline as a
9
catalyst for aldol reactions. Later on, Kokotos,7 Ley,8 Wang, and
Liu10 published similar derivatives for aldol reactions and Mannich
reactions affording good results. Later, Carter11 used sulfonamide
⇑
Corresponding author.
E-mail address: altenbach@uni-wuppertal.de (H.J. Altenbach).
Figure 1. Structures of organocatalysts.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.10.009

G. Tang et al. / Tetrahedron Letters 52 (2011) 7034–7037
7035
Table 2
Screening of conditions for the aldol reactiona
Entry Catalyst [mol %] Time [h] Yield [%]b anti/
sync
ee [%] (major)d
Scheme 1. R1 = C6H5CH3, CH3, CF3, R2 = CF3, CCl3, C(CH3)3, C6H5.
proline-N-carboxyanhydride (proline-NCA) (3), which can be easily
prepared in solution according to a published procedure from pro-
line.14 Reaction with the corresponding deprotonated amides leads
to the imide series of compounds in an easy and general way
(Scheme 1).15 In comparison to the old three step procedure by
which the yields of 1a and 1b are 25% and 44%,9 our route of react-
ing proline-NCA with the corresponding deprotonated amides has
only two steps starting from proline and gives better yields (46%
and 42%). Following this route we could even synthesize trif-
luorosulfonyl derivative (1c) for the first time.
1
2
3
30
20
10
5
10
10
10
24
48
72
72
72
72
72
64
63
60
48
77
67
64
96/4
91/9
96/4
90/10
95/5
97/3
97/3
93
94
99
96
97
98
99
4
5e
6f
7g
a
The reaction was performed with 1c, 4a (0.51 mL, 5.0 mmol) and 5a (76 mg,
0.5 mmol), water (1 mL), and at room temperature.
Combined yields of isolated diastereomers.
b
c
d
e
f
Determined by 1H NMR of the crude product.
Determined by chiral-phase HPLC analysis of the major product.
Reaction in 0.5 mL water.
Reaction in 0.5 mL water with 2.5 mmol cyclohexanone.
Reaction in 0.5 mL water with 1 mmol cyclohexanone.
For testing L-proline imide derivatives 1and 2, we used the stan-
dard model aldol reaction with 4-nitrobenzaldehyde and cyclohex-
anone in DMSO (Table 1). As in the known examples the main
product is the anti isomer with 2R, 10S-configuration.6 The results
obviously show that the catalysts with sulfonamide structure gave
much better yield and selectivity than the catalysts with carboxyl
imide structure (Table 1). With 2a, we also observed the aldol con-
densation product as Wang13 reported, but as the main product we
isolated the unsaturated condensation product. In the other cases
water elimination did not occur under the described conditions
at room temperature. In accordance with our expectation the most
acidic prolinamide 1c proved to be the best catalyst in the model
reaction in DMSO, but unexpectedly gave even better results in
dichloromethane (DCM) and water (entries 10 and 11, Table 1).
Whereas in DCM the reaction phase is still homogeneous, in pure
water a two phase system is observed, but this has no significant
g
effect on the reactivity and selectivity. With 1c the anti/syn ratio
of 96/4 in both solvents was the highest of all tested catalysts
and with 92% ee in DCM and 93% ee on water the best enantiose-
lectivity was detected (entries 10 and 11, Table 1). With these
promising results for trifluoromethylsulfonamide derivative 1c of
proline as an effective catalyst for the aldol reaction on water,
the influence of catalyst loading, the water volume, the amount
of ketone, and the reaction time were studied. We tested 30, 20,
10, and 5 mol % catalyst loading in water under the standard con-
ditions in the model reaction. As expected the reaction rate is obvi-
ously affected by the loading amount (Table 2), the medial rate was
Table 1
Screening of organocatalysts for the aldol reactiona
Entry
Catalyst
Solvent
Catalyst [mol %]
Time [h]
Yield [%]b
anti/sync
ee [%] (major)d
1
2
3
4
5
1a
1b
1c
2a
2b
2c
2d
2c
2d
1c
1c
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DCM
30
30
30
30
30
30
30
30
30
30
30
24
24
24
24
24
24
24
24
24
24
24
58
54
64
33
88/12
73/37
94/6
58/42
56/44
ND
82
61
85
20
13
ND
ND
4
22
6
7
Trace
Trace
14
12
58
ND
8e
9e
10f
11g
55/45
56/44
96/4
96/4
5
92
93
H2O
64
a
b
c
d
e
f
The reaction was performed with 1 or 2 (0.15 mmol), 4a (0.51 mL, 5.0 mmol) and 5a (76 mg, 0.5 mmol), DMSO (1 mL), and at room temperature.
Combined yields of isolated diastereomers.
Determined by 1H NMR of the crude product.
Determined by chiral-phase HPLC analysis of the major product.
With 10 mol % TFA.
The reaction was performed with 1 mL DCM as solvent.
The reaction was performed with 1 mL H2O as solvent
g

7036
G. Tang et al. / Tetrahedron Letters 52 (2011) 7034–7037
Table 3
Direct aldol reaction of substituted benzaldehydes with ketones catalyzed by catalyst 1ca
Entry
R3
R4
H
R5
Product
Yield [%]b
anti/sync
ee [%] (major)d
1
2
3
–(CH2)3–
–(CH2)2–
H
–(CH2)3–
–(CH2)3–
–(CH2)3–
–(CH2)3–
NO2
NO2
NO2
Cl
OCH3
NO2
NO2
4a
4b
4c
4d
4e
4a
4a
64
54
55
43
42
58
61
97/3
97/3
99
94
86
97
91
98
98
4
99/1
97//3
98/2
97/3
5
6e
7f
a
b
c
d
e
f
The reaction was performed with 1c (10 mol %), 4 (0.1 mL, 1.0 mmol) and 5 (0.5 mmol), water (0.5 mL), and at room temperature for 72 h.
Combined yields of isolated diastereomers.
Determined by 1H NMR of the crude product.
Determined by chiral-phase HPLC analysis of the major product.
The reaction was performed with 1c (10 mol %) recycled after use in entry 1, 4, 5, and water with the same moleratio with entry 1.
The reaction was performed with 1c (10 mol %) recycled after use in entry 7, 4, 5, and water with the same moleratio with entry 1.
observed with 30 mol % of catalyst leading after 24 h to a high yield
of 64% (entry 1, Table 2), whereas the reaction with 10 mol % load-
ing gave a 77% yield compared to 48% with 5 mol % loading after
72 h (entries 2 and 3, Table 2), showing that higher catalyst loading
or longer reaction time will raise the yield. The reaction with
5 mol % catalyst resulted only in a little lower enantioselectivity
(96%) than with 10 mol % (entry 4, Table 2). After this, we tested
the dependence of the reaction from water volume, and found that
the result is similar between 110 and 55 equiv water. Decreasing
the excess of ketone had only little influence on selectivity. With
10 mol % catalyst, the highest enantiomeric excess (99%) was
reached with 10 equiv as well as with 2 equiv of ketone (entries
3 and 7, Table 2). Therefore it should be pointed out that a decrease
in the catalyst loading had no significant impact on the enantiose-
lectivity and large excess of ketone is not necessary for high yield
and selectivity.
Getting the highest enantioselectivity in the reaction on water
with 10 mol % loading, we further studied the aldol reaction with
different ketones and aldehydes under these conditions. We found
out that the enantioselectivities for cyclopentanone and acetone
are also high but lower than those for cyclohexanone (Table 3).
For different aromatic aldehydes, the p-chloro and -methoxy sub-
stitution reduced the aldehyde activity—as expected—giving lower
yield, the selectivity, however, was not affected.
Finally, we elaborated a procedure for catalyst recycling utiliz-
ing another advantage of the trifluoromethyl group. After reaction,
diethyl ether (10 mL) and water (5 mL) were added to the reaction
mixture. The organic layer was separated and the aqueous layer
was extracted with ether (2 ꢀ 10 mL). Then, the aqueous layers
were collected, and water was removed by lyophilization. The
remaining is the pure catalyst as revealed by NMR analysis. The
recycling rate can easily reach over 90%, higher than other cata-
lysts.16 The activity of recycled 1c exhibited almost no change in
the test (entries 6 and 7, Table 3).
catalyst could be established with a recovering rate higher than
90%. As has been found for other prolinamide-based catalysts this
catalyst can be expected to be well suited for other organocatalytic
reactions like Mannich reactions, Michael reactions, etc.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.10.009.
References and notes
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In conclusion, a simple way has been developed to synthesize
proline imide and sulfonamide derivatives from L-proline-NCA.
By this route we have prepared a novel proline trifluoromethylsulf-
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prolinamide-based catalysts, better yields (77%) and higher enanti-
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the synthesis of 1 and 2.Proline N-carboxyanhydride was synthesized starting
from
-proline according to the published method.14 The solution was used
L
immediately. A solution of the corresponding amide (6.8 mmol) in THF (50 mL)
was cooled to –78 °C, BuLi (8.5 mL, 13.6 mmol) was added, and the mixture
was stirred for 10 min. A solution of proline N-carboxyanhydride (6.8 mmol) in
THF (10 mL) was added, and the reaction was completed by stirring at –78 °C
for 1 h. The mixture was warmed to room temperature, and the solvent
removed by evaporation. To the mixture 50 mL ethyl acetate and a saturated
solution of NH4Cl (8 mL) were added. The layers were separated, and the
aqueous layer was extracted with EtOAc (2 ꢀ 50 mL). The combined organic
layers were dried with Na2SO4 and concentrated in vacuo. The product was
purified by flash silica gel chromatography (hexane/EtOAc)..
15. Berges, D. A.; DeWolf, W. E., Jr.; Dunn, G. L.; Grappel, S. F.; Newman, D. J.;
Taggart, J. J.; Gilvarg, C. J. Med. Chem. 1986, 29, 89–95. General procedure for
16. Yang, H.; Mahapatra, S.; Cheong, H.-Y. P.; Carter, R. G. J. Org. Chem. 2010, 75,
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