Solvent-free asymmetric direct aldol reactions organocatalysed by recoverable (Sa)-binam-l-prolinamide

Article abstract of DOI:10.1016/j.tetasy.2007.09.020

The combination of (S_a)-binam-l-Pro (5 mol %) and benzoic acid (10 mol %) was used as catalysts in the direct aldol reaction between different aliphatic ketones and 4-nitrobenzaldehyde under solvent-free reaction conditions. Three different pro

Full text of DOI:10.1016/j.tetasy.2007.09.020

Available online at www.sciencedirect.com
Tetrahedron: Asymmetry 18 (2007) 2300–2304
Solvent-free asymmetric direct aldol reactions organocatalysed
by recoverable (Sa)-binam-L-prolinamide
*
´
´
´
Gabriela Guillena, Marıa del Carmen Hita, Carmen Najera and Santiago F. Viozquez
Dpto. Quı´mica Orga´nica and Instituto de Sı´ntesis Orga´nica, Universidad de Alicante, Apdo. 99, E-03080 Alicante, Spain
Received 21 August 2007; accepted 14 September 2007
Available online 10 October 2007
Dedicated to Professor Koichiro Oshima on the occasion of his 60th birthday
Abstract—The combination of (Sa)-binam-L-Pro (5 mol %) and benzoic acid (10 mol %) was used as catalysts in the direct aldol reaction
between different aliphatic ketones and 4-nitrobenzaldehyde under solvent-free reaction conditions. Three different procedures are
assayed: magnetic stirring (method A), magnetic stirring after previous dissolution in THF and evaporation (method B), and ball mill
technique (method C), methods A and B being the simplest. These reaction conditions allowed us to reduce the amount of required
ketone to 2 equiv to give the aldol product in similar reaction times and regio-, diastero-, and enantioselectivities than in organic or aque-
ous solvents.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
erate the aldol products in good yields. Besides this draw-
back, some other aspects, such as the long reaction times
or the high catalyst loadings need to be improved in the
asymmetric organocatalysed direct aldol reaction. Several
reaction conditions have been developed in order to
achieve higher efficiencies, and only recently the use of sol-
vent-free conditions has been reported.5b,d,e Thus, (S)-pro-
line (10 mol %) has been used as an organocatalyst for the
aldol condensation of symmetrical alkyl ketones and alde-
hydes using a ball-milling technique, affording the expected
aldol in high yields (53–99%) mainly as anti-isomers (dr up
to 93:7) and with good enantioselectivities (ee’s from 56%
to 99%) in relatively short reaction times (5–36 h) using
only 2 equiv of ketone.5b,e The use of conventional mag-
netic stirring in the same solvent-free reactions gave similar
results but longer reaction times were required (1–4 d).
These conditions have also been applied to the aldehyde–
aldehyde aldol reaction, giving mainly the anti-aldol prod-
ucts after 1–4 d with good yields, diastereo- and enantio-
selectivities (up to 96% ee).5d,e
The development of sustainable methods for the synthesis
of complex molecules is nowadays a main goal in synthetic
chemistry1 and the application of solvent-free reaction con-
ditions2 meets the established principles for Green Chemis-
try.3 On the other hand, the use of small organic molecules
as chiral organocatalysts4 has several advantages concern-
ing handling, cost, and safety issues. Pursuing the sustain-
ability of chemical processes for the synthesis of chiral
molecules, the marriage between asymmetric organocata-
lytic methods and the use of solvent-free environmentally
friendly reaction conditions is highly desirable.5
The aldol reaction6 is one of the more inexpensive ways to
construct a C–C bond and is extensively applied in industry
either in bulk or in fine chemical manufacture and pharma-
ceutical target production; therefore, the application of
‘green conditions’ is of great interest.7 Concomitant with
the construction of a C–C bond, a molecule bearing one
or more stereogenic centers is created.8 The use of simple
L-proline and other chiral organocatalysts allows the direct
aldol reaction using a highly atom-economic process.9 This
is an equilibrium process, which generally requires a large
excess of one of the reactants, normally the ketone, to gen-
2. Results and discussion
Recently, we and others have studied the use of several
binam-prolinamides as catalysts in the aldol reaction under
different reaction conditions using alkyl10 and a-functional-
ized11 ketones as a source of nucleophiles, with catalyst
*
Corresponding author. Tel.: +34 965 90 3728; fax: +34 965 90 3549;
e-mail: cnajera@ua.es
0957-4166/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2007.09.020

G. Guillena et al. / Tetrahedron: Asymmetry 18 (2007) 2300–2304
2301
(Sa)-binam-L-Pro 1a (Fig. 1) providing the best results.10a
We found that the addition of benzoic acid as a cocatalyst
led to a great acceleration of the reaction, thus allowing the
use of less reactive ketones, such as butanone10c and a-
functionalized ketones even ‘on’ water,10f,11 to give the cor-
responding aldol products with a high level of selectivity.
In addition, catalyst 1a can also be recovered by simple
extractive work-up after reaction completion.11a,c Herein,
we report the highly regio-, diastereo-, and enantioselective
direct intermolecular aldol reaction under solvent-free con-
ditions, cocatalyzed by binam-L-prolinamides 1a and 1b
and benzoic acid in short reaction times and using only
2 equiv of several cyclic and acyclic aliphatic ketones.
of benzoic acid as a catalytic combination was carried out
using three different methods: conventional magnetic stir-
ring (method A); conventional magnetic stirring with a
pre-formed solution in THF and immediate evaporation
of the solvent, which should induce an enhancement of
molecule-to-molecule contacts between the reactants and
therefore an acceleration of the reaction rate (method
B),12 and ball-milling conditions (method C). The aldol
products 3a were obtained after only 1–1.5 h with quantita-
tive conversions and similar results concerning diastereo-
and enantioselectivities using the three methods (Table 1,
entries 1–3). In all cases, the anti-isomer was obtained with
moderate diastereoselectivity. The study of other reaction
parameters was done by using conventional magnetic stir-
ring due to simplicity reasons.
NH
O
NH
When the temperature was lowered to 0 °C, using 10 mol %
of 1a and 20 mol % of benzoic acid and using methods A
and B, an increase in the reaction time but also in the dia-
stereo- and enantioselectivity, up to 93% ee for anti-3a, was
observed, with slightly better results being obtained using
method B (Table 1, entries 4 and 5). Reducing the amount
of catalyst 1a and benzoic acid to 5 mol % and 10 mol %,
respectively, led to an increase in the reaction time, with
a slight increase on the diasteroselectivities achieved (Table
1, entries 6 and 7). The use of catalyst 1b (5 mol %) was less
efficient than catalyst 1a affording product 3a in 8 h (Table
1, compare entries 6 and 8).
NH
NH
NH
O
O
NH2
NH
1a
Figure 1. Binam-L-proline derived catalysts.
1b
Catalysts 1a and 1b were synthesized in 97% and 58% yield,
respectively, by coupling commercially available (S)-1,10-
binaphthyl-2,20-diamine [(Sa)-binam] with in situ generated
Fmoc-L-Pro chloride (2.1 and 1 equiv, respectively), fol-
lowed by deprotection with piperidine.
When L-proline (10 mol %) was used as a catalyst under
method B conditions, low conversion was observed even
after 24 h reaction time, although product 3a was formed
with excellent diastereo- and enantioselectivity (Table 1,
entry 9). In order to increase the conversion, benzoic acid
(10 mol %) was added to the reaction mixture, forming
The model reaction of 4-nitrobenzaldehyde and 2 equiv of
cyclohexanone at 25 °C using 10 mol % of 1a and 20 mol %
Table 1. Optimization of conditions for the reaction of 4-nitrobenzaldehyde with cyclohexanone under solvent-free conditionsa
O
O
OH
O
OH
CHO
1a, PhCO2H
+
+
solvent free, T (ºC),
O2N
NO2
NO2
Method
2a
anti-3a
syn-3a
Entry
Methodb
Catalyst (mol %)
Benzoic acid (mol %)
T (°C)
t (h)
Conversionc (%)
anti/synd
eee (%)
1
2
3
4
5
6
7
8
9
A
B
C
A
B
A
B
A
B
B
1a (10)
1a (10)
1a (10)
1a (10)
1a (10)
1a (5)
1a (5)
1b (5)
L-Pro (10)
L-Pro (10)
20
20
20
20
20
10
10
10
—
10
25
25
25
0
0
0
0
0
0
0
1.0
1.5
1.5
1.5
2.0
2.0
4.0
8.0
24
99
99
100
80
94
99
94
85
34
60
67:33
72:28
69:31
83:17
89:11
90:10
93:7
87:13
96:4
94:6
88
89
88
90
93
86
90
83
96
94
10
24
a The reaction was carried out using 4-nitrobenzaldehyde (0.25 mmol) and cyclohexanone (2 equiv).
b Method A: conventional magnetic stirring. Method B: 4-nitrobenzaldehyde, catalyst and benzoic acid were dissolved in dry THF (0.5 mL) and the
solvent was evaporated prior to the addition of cyclohexanone. Method C: the grinding bowl containing the reaction mixture was rotated in a ball mill at
rotation speed of 300 rpm.
c Conversion based on the unreacted aldehyde.
d Determined by 1H NMR of the crude product.
e Determined by chiral-phase HPLC analysis for the anti-3a isomer.

2302
G. Guillena et al. / Tetrahedron: Asymmetry 18 (2007) 2300–2304
aldol 3a with higher conversion (60%) after the same reac-
tion time (Table 1, entry 10). It can be concluded that the
best compromise between reaction rate, diastereo- and
enantioselectivity was achieved by using 5 mol % of 1a in
the presence of 10 mol % of benzoic acid at 0 °C either un-
der method A or B conditions, with longer reaction times
required when using method B, but with slightly higher
diastereo- and enantioselectivity (Table 1, entries 6 and 7).
gave the anti-3a product in high enantioselectivity using
methods A or B (Table 2, entries 1 and 2), the use of cyclo-
pentanone afforded a nearly 1:2 mixture of anti/syn-3b iso-
mers with higher ee for the anti-isomer (Table 2, entries 3
and 4). Generally, the results achieved using method A
are comparable to those obtained using method B but with
longer reaction times needed when using the last method.
Several alkyl ketones such as acetone and butanone and a-
functionalized ketones as nucleophiles were then employed
in the reaction with 4-nitrobenzaldehyde. When acetone 2c
was used as a donor, the aldol product 3c was obtained in
Once the best reaction conditions were found, these were
applied to study the scope of the solvent-free process
(Scheme 1 and Table 2). Thus, cyclohexanone exclusively
O
OH
O
OH
( )n
n = 0, 1
O
+
( )n
( )n
1a (5 mol %)
CHO
anti-
3
syn-
3
PhCO2H (10 mol%)
O2N
0 ºC
O
OH
O
O
OH
O
OH
R1
+
+
R1
R1
anti-
R1
syn-
NO2
NO2
NO2
iso-4
3
3
Scheme 1. Reaction of 4-nitrobenzaldehyde with different ketones under solvent-free conditions.
Table 2. Reaction of 4-nitrobenzaldehyde with different ketones under solvent-free conditionsa
Entry
Method
Major product
t (h)
Yieldb (%)
Isomer ratioc
eed (%)
Regioselectivity (3/4)
dr (anti/syn)
O
OH
1
2
A
B
2
4
99 (80)
94 (85)
—
—
90:10
97:3
86e
90e
NO2
anti-3a
O
OH
H
3
4
A
B
3
7
92 (64)
97 (86)
—
—
30:70
28:72
80:63
80:46
NO2
anti/syn-3b
O
OH
5
6
A
B
3
8
86
88
—
—
—
—
74
74
NO2
NO2
3c
O
OH
7
8
A
B
24
40
96 (90)f
97
63:37
55:45
>99:1
>99:1
97 (91)g
90 (99)g
anti-3d
O
OH
9
10
A
B
4
21
76
92
>99:1
49:1
75:25
64:36
16e
20e
OH
anti-3e
NO2

G. Guillena et al. / Tetrahedron: Asymmetry 18 (2007) 2300–2304
2303
Table 2 (continued)
Entry
Method
Major product
t (h)
Yieldb (%)
Isomer ratioc
Regioselectivity (3/4)
eed (%)
dr (anti/syn)
O
OH
11
12
A
B
4
21
90 (78)
91 (84)
94:6
91:9
83:17
83:17
60e
80e
OMe
anti-3f
NO2
O
OH
13h
14h
A
B
78
89
92 (78)
96
97:3
88:12
86:14
83:17
84e
86e
OBn
NO2
anti-3g
O
OH
MeS
15
16
A
B
48
168
83 (74)
70
16:84
27:73
50:50
59:41
86i
90i
iso-4h
NO2
a General reaction conditions: 4-nitrobenzaldehyde (0.25 mmol), ketone (2 equiv) (Sa)-binam-L-Pro 1a (5 mol %) and benzoic acid (10 mol %) at 0 °C,
otherwise stated. After completion of the reaction performed under method A or B (see Table 1), 1 M HCl (10 mL) and ethyl acetate (20 mL) were
added. The organic phase was separated, dried and evaporated to afford the crude products, which were purified by flash chromatography.
b Yield of the isolated crude product. In parenthesis, yield of the pure product after column chromatography.
c Determined by 1H NMR of the crude product.
d Determined by chiral-phase HPLC analysis.
e For the anti-isomer.
f Overall yield for both isolated isomers by column chromatography.
g In parenthesis, enantiomeric excess for the iso-4d isomer.
h The reaction was carried out at ꢀ20 °C.
i For the iso-isomer.
only 3 h using method A, with 86% yield and 74% ee (Table
2, entry 5), better results than those reported by using the
ball-milling technique and L-Pro (19 h reaction time, 73%
yield, 56% ee).5b,e Similar results were obtained under
method B conditions but in a longer reaction time (Table
2, entry 6).
acted faster than a-benzyloxyacetone, although the latter
gave better ee.
Finally, a-(methylsulfanyl)acetone 2h was used as a nucle-
ophile, affording mainly the iso-4h product with a regiose-
lectivity of 1:5 and 86% ee (Table 2, entry 15). The use of
method B to carry out the reaction led to a long reaction
time (7 d) without improving the obtained results.
In the case of 2-butanone, a mixture of anti-3d and iso-4d
regioisomers with excellent enantioselectivities (97% and
91% ee, respectively) were obtained in only 1 d reaction
time using method A (Table 2, entry 7). Although, the reac-
tion under method B conditions led to a nearly 1:1 mixture
of the anti-3d and iso-4d with a longer reaction time, the
last compound was obtained as only one enantiomer (Ta-
ble 2, entry 8).
These results are rather similar to those previously de-
scribed in aqueous media.11b L-Pro (10 mol %) was also
employed as a catalyst under method B reaction conditions
for ketones 2f and 2g, only reaction being observed in the
case of a-methoxyacetone 2f, affording the aldol product 3f
with 3% conversion after 2 d, with 80:20 de and 94% ee for
the anti-3f diastereomer.
When a-functionalized ketones were used as donors, the re-
sults were dependant on the functionality. When a-oxygen-
ated ketones were used as donors, good yields and
regioselectivities were achieved in all cases. However,
whereas a-hydroxyacetone 2e gave very poor enantioselec-
tivities (Table 2, entries 9 and 10), a-methoxyacetone 2f
and a-benzyloxyacetone 2g both gave mainly the anti-ald-
ols 3f and 3g, respectively, with higher enantioselectivities
(Table 2, entries 11–14). In the case of a-methoxyacetone
2f, better enantioselectivities were achieved by carrying
the reaction under method B conditions (Table 2, entry
12), whereas a-benzyloxyacetone 2g gave the best regio-
and diastereoselectivity under method A conditions (Table
1, entry 13). It can be concluded that a-methoxyacetone re-
3. Conclusion
It can be concluded that catalyst (Sa)-binam-L-Pro 1a com-
bined with benzoic acid is a better catalyst system than L-
Pro to be used in the direct aldol reaction of a wide scope
with ketones under solvent-free conditions using simple
conventional magnetic stirring. This procedure allowed
us to reduce the amount of required ketone to 2 equiv,
forming the aldol product in similar reaction times com-
paring to using solvents.10,11 The same observation was
found with respect to the regio- diastero-, and enantio-
selectivity. Generally, anti-isomers were obtained with

2304
G. Guillena et al. / Tetrahedron: Asymmetry 18 (2007) 2300–2304
´
Neudo¨rfl, J. M. Org. Lett. 2006, 8, 4195–4198; (b) Rodrıguez,
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the ketone. These results are better than those previously
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catalyst,5b,e with the additional advantage that a simpler
conventional magnetic stirring is used.
´
Shoji, M. Chem. Commun. 2007, 957–959; (e) Rodrıguez, B.;
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Acknowledgments
6. Modern Aldol Reactions; Marhrwald, R., Ed.; Wiley-VCH:
Weinheim, 2004; Vols. 1–2,.
´
This work was financially supported by the Direccion Gen-
´
´
eral de Investigacion of the Ministerio de Educacion y
Ciencia of Spain (Grant CTQ2004-00808/BQU and Con-
solider Ingenio 2010 CSD2007-00006), the Generalitat Val-
enciana (Grant CTIOIB/2002/320, GRUPOS03/134 and
GV05/157) and the University of Alicante (GRJ06-05).
7. Green, M. M.; Wittcoff, H. A. Organic Chemistry Principles
and Industrial Practice; Wiley-VCH: Weinheim, 2003.
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