BINAM-prolinamides as recoverable catalysts in the direct aldol condensation

Article abstract of DOI:10.1016/j.tetasy.2006.02.004

New BINAM-prolinamides were developed and tested as organocatalysts in the direct aldol condensation between aldehydes and several aliphatic ketones. C₂-symmetrical (Sa)-BINAM-l-prolinamide gives the best enantioselectivities for this transform

Full text of DOI:10.1016/j.tetasy.2006.02.004

Tetrahedron: Asymmetry 17 (2006) 729–733
BINAM-prolinamides as recoverable catalysts
in the direct aldol condensation
Gabriela Guillena, Mar ´ı a del Carmen Hita and Carmen N a´ jera*
Dpto. Qu ı´ mica Org a´ nica and Instituto de S ı´ ntesis Org a´ nica, Universidad de Alicante, Apdo. 99, E-03080 Alicante, Spain
Received 27 January 2006; accepted 6 February 2006
Available online 24 March 2006
Abstract—New BINAM-prolinamides were developed and tested as organocatalysts in the direct aldol condensation between alde-
hydes and several aliphatic ketones. C
mation, being recovered and reused after the reaction by simple extractive techniques. The reaction was performed in DMF/H
2
-symmetrical (Sa)-BINAM-L-prolinamide gives the best enantioselectivities for this transfor-
O at
2
0
ꢀC to give the aldol products in up to 95% ee for acetone. For 2-butanone, the corresponding iso-regioisomers were regioselectively
obtained in up to 96% ee working in DMF at rt. In the case of cyclohexanone, dr up to 10:1 in favour of the anti products, which
were obtained in 90–93% ee, was achieved.
ꢁ
2006 Elsevier Ltd. All rights reserved.
1. Introduction
sity of the catalysts and therefore the ability to fine tune
their reactivity.
The direct generation of carbanion equivalents via an
asymmetric enamine intermediate and reaction with
electrophiles is one of the most elegant and straightfor-
ward methods to build a C–C bond in an enantioselec-
Some of these proline derivatives were designed to
resemble the peptides involved in the active pocket of
an enzyme. In that case, the achieved stereoselectivity
is reasoned due to the presence of several amide bonds
with restricted rotation, which creates a non-covalent
bonding environment similar to that of an enzyme.
The goal of our approach was to find a new system with
the broad substrate scope of proline and the specificity
1
tive and catalytic way. In this sense, small organic
2
molecules, known as organocatalysts, have shown their
3
synthetic efficiency in the direct aldol reaction. Using
this strategy, pre-generation of enolates is not needed
and a wide substrate scope can be achieved. In this field,
proline is a cornerstone in the direct intramolecular
9
of aldolase enzymes for the direct aldol reaction. Here-
4
,5
aldol reaction, its reactivity and stereoselectivity as
an organocatalyst being attributed to the formation of
cyclic transition states in which the presence of an acidic
in, we report the synthesis of new prolinamides derived
0
0
from 2,2 -diamino-1,1 -binaphthalene (BINAM) and
1
0
their application as catalysts. The design of these cata-
lysts is based on the following facts: the binaphthyl
moiety would provide restricted rotation around the
biaryl axis due to steric hindrance of the aryl groups.
This structural motif would look like the b-turn pocket
associated with the presence of proline residues in the
active sites of several enzymes, and it could work as spe-
cifically as the proper enzyme. Moreover, the modifica-
tion of this binaphthyl moiety would allow further
modulation of catalytic activity. Furthermore, the pres-
ence of the aryl counterpart might increase the solubility
of the catalyst in common organic solvents and would
make feasible the recovery of the catalyst by acid/base
extractive techniques. Finally, the presence of a binaph-
thyl derivative would allow us to study the influence of
6
proton seems to be crucial. However, the development
of new organocatalysts, in which the highly acidic pro-
ton of proline is replaced by another less acidic one
has shown that it is the ability to form hydrogen bonds
and not the proton acidity, that is a necessary condition
for successful enantioselection. For instance, prolin-
7
8
amides and small peptides are efficient and selective
catalysts in this transformation. Moreover, these new
systems permit the enhancement of the structural diver-
*
0
Corresponding author. Tel.: +34 965 90 3728; fax: +34 965 90
549; e-mail: cnajera@ua.es
3
957-4166/$ - see front matter ꢁ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2006.02.004

730
G. Guillena et al. / Tetrahedron: Asymmetry 17 (2006) 729–733
the axial stereoelement in the stereochemical outcome of
the reaction products.
Table 1. Direct aldol reaction of 4-nitrobenzaldehyde with acetone
catalyzed by 1
a
O
OH
O
O
1
(10 mol%)
H
2
. Results and discussion
Solvent, Tª
O N
O N
2
2
The synthesis of the BINAM-prolinamides 111 was per-
formed by coupling the commercially available (S)- or
2a
Entry Cat.
Solvent
T (ꢀC) t (d) Yield ee
(
R)-BINAM with the acyl chloride derived from
b
c
(
%)
(%)
Fmoc-L-Pro or Fmoc-D-Pro followed by final deprotec-
tion with piperidine in the yields indicated in Figure 1.
Once the catalysts were prepared, they were tested in
the classical model aldol reaction between acetone and
p-nitrobenzaldehyde, to examine the efficiency of cata-
1
2
3
4
5
6
7
8
9
1a
1b
THF
THF
DMSO
DMF
DMF/H
DMF/H
DMF/H
DMF/H
DMF/H
DMF/H
25
25
25
25
25
0
0
0
0
0
3
7
8
3
1
3
5
5
6
3
3
6
6
96
28
76
71
85
99
83
60
67
97
87
80
81
11
36
52
35
15
79
54
1
1a
1a
d
d
e
1a
1a
2
2
2
2
2
2
2
2
O
O
O
O
O
O
O
O
1
2
lysts 1 (Table 1).
1a
d
d,f
d
d
d
d
L-Pro
1a
1c
51
45
60
80
79
NH
NH
O
10
g
1
1
1
2
ent-1a DMF/H
0
0
0
h
HN
HN
O
O
1a
1a
DMF/H
DMF/H O
NH
i
13
2
NH2
a
The reaction was carried out using 27.6 equiv of acetone per equiv-
alent of aldehyde in the presence of 10 mol % of catalyst in 1 mL of
solvent.
Isolated products after column chromatography.
Determined by HPLC (Chiracel AS, hexane/isopropanol: 85:15), the
absolute configuration of the major enantiomer being R.
1:1.
NH
b
c
1a, Sa-BINAM-
L
-Pro (97%)
NH
1b, (58%)
d
e
f
NH
1
5
:4.
mol % of catalyst 1a was used.
The opposite enantiomer was obtained.
Second cycle with the recovered catalyst.
O
O
O
O
HN
HN
HN
HN
g
h
i
Third cycle with the recovered catalyst.
NH
NH
6
1
7% yield and 51% ee (Table 1, entry 9). Thus,
0 mol % of catalyst 1a seems to be the appropriate
1c, Ra-BINAM-
L
-Pro (80%)
ent-1a, Ra-BINAM-D-Pro (75%)
Figure 1. BINAM-derived prolinamides.
loading to carry out the reaction. Other prolinamide cat-
alysts such as those derived from chiral b-amino alco-
7
f
7i
Concerning the reaction time and chemical yield, cata-
hols (I) or C -symmetric bisprolinamide (II) (Fig. 2)
2
lyst 1a (96% yield, 11% ee) was more efficient than 1b
led to 2a, with up to 99% ee in both cases but decreasing
the reaction temperature to ꢀ25 ꢀC or ꢀ35 ꢀC,
respectively.
(
28% yield, 36% ee, Table 1, compare entries 1 and 2)
in THF at rt. Changing the solvent to DMSO and using
catalyst 1a, the aldol product was obtained in 52% ee
(
(
Table 1, entry 3), with the reaction time being very long
Ph
Ph
8 d). Under these conditions and using proline as cata-
O
4
CO
2
Et
O
O
lyst, a 76% ee was achieved. In DMF, the reaction time
was shorter (3 d) but the enantioselectivity decreased to
3
NH HN
N
CO Et
N
2
H
H
5% (Table 1, entry 4). Recently, it has been reported
NH
HN
HO
that the addition of an amount of water to the solvent
accelerated the reaction rate. When the reaction was
1
3
I
II
carried out in a 1/1 mixture DMF/H O at 25 ꢀC, the
2
Figure 2. Prolinamides used as catalysts in the direct aldol reaction.
reaction took place in only 1 d although with a poor
1
5% ee (Table 1, entry 5). Decreasing the temperature
to 0 ꢀC, increased the ee up to 79%, with the reaction
time being 3 d (Table 1, entry 6). The addition of a higher
amount of water had a negative effect on the enantio-
selectivity and reaction time (Table 1, entry 7). As
comparison and, once the best reaction conditions were
found, we tested the catalytic efficiency of L-Pro under
the same conditions, achieving a 60% yield and a nearly
racemic product 2a, after 5 d (Table 1, entry 8). Decreas-
ing the catalyst loading to 5 mol %, 2a was obtained in
The recovery of the catalyst after the reaction had fin-
ished was carried out by quenching with 6 M HCl and
the aldol product was extracted into the organic layer.
The acidic aqueous extract was treated with NaOH until
pH ꢁ 11 and then extracted with AcOEt to recover the
catalyst, which was recrystallized from CHCl /Et O.
3
2
This recovered prolinamide 1a was re-used in two subse-
quent cycles as catalyst in the reaction of p-nitrobenz-
aldehyde and acetone in DMF/H O 1:1 giving the same
2

G. Guillena et al. / Tetrahedron: Asymmetry 17 (2006) 729–733
731
a
Table 2. Direct aldol reaction of catalyzed by BINAM-prolinamide 1a
O
R2
OH
O
R2
R1
2
(
R = H, Me)
2
2
3
(R = H)
(R = Me)
O
1a (10 mol%)
O
2
R1
o
OH
O
H
DMF/H O, 0 C
2
or DMF, rt
R1
4
1
b
c
d
Entry
1
R
Ketone
No.
t (d)
Yield %
dr
ee %
O
4-NO
2
2
C
C
6
H
H
4
4
2a
3
99
—
—
79
O
O
O
O
O
2
3
4
5
2-NO
6
2b
2c
2d
2e
3a
3f
3
99
98
75
52
85
95
65
78
96
86
2-ClC
6
H
4
1.5
4.5
2.5
—
—
—
—
—
Ph
6 11
C H
e
f
6
4-NO
2
C
6
H
4
11
8
96
e
O
O
7
(CH
3
)
2
CH
53
98
8
9
4-NO
2
C
6
H
4
4a
3
10:1
93 (44)
O
O
2-ClC
6
H
4
4b
4c
2.5
98
99
8:1
92 (7)
10
Ph
4.5
4.3:1
90 (72)
a
b
c
d
e
f
The reaction was carried out using 27.6 equiv of ketone per equivalent of aldehyde in the presence of 10 mol % of catalyst in 1 mL of solvent.
Isolated products after column chromatography.
Determined by H NMR.
Determined by HPLC. In parenthesis the ee for the syn-isomer.
The reaction was carried out in DMF at rt.
1
4% of anti-5a in 31% ee was also obtained.
results as the freshly prepared catalyst, although with
longer reaction times (Table 1, compare entries 6, 12
and 13). Once the best catalyst 1a (10 mol %) and reac-
a non-symmetrical ketone, such as 2-butanone, was used
as a substrate and the reaction carried out in DMF at rt.
Using p-nitrobenzaldehyde as nucleophile, the major
product was the expected iso-isomer 3a, and 4% of the
anti-isomer 5a. Compound 3a had a 96% ee, while the
anti-isomer was obtained with a 3% ee. (Table 2, entry
6). When L-proline was used as catalyst under these
reaction conditions, 67% of product 3a (96% ee) and
33% of the anti-isomer 5a (13% ee) were obtained.
tion conditions (DMF/H O: 1:1, 0 ꢀC) were found, we
2
extended its application to the reaction of acetone with
different aldehydes, the obtained results being summar-
ized in Table 2.
With acetone, the best enantioselectivities (up to 95%)
were achieved when ortho-susbstituted aromatic alde-
hydes were used as nucleophiles (Table 2, entries 2 and
OH
O
3
). The use of less activated aldehydes, such as benzalde-
hyde or cyclohexanecarboxaldehyde led to a decrease in
the reaction yields, the enantioselectivities being 65%
and 78%, respectively (Table 2, entries 4 and 5). Then,
O N
2
5a

732
G. Guillena et al. / Tetrahedron: Asymmetry 17 (2006) 729–733
The aldol reaction of 2-butanone also took place with
less reactive and hindered aldehydes, such as isobutyr-
aldehyde, to afford iso-isomer 3f as the only product with
an 86% ee (Table 2, entry 7). As a comparison and using
L-proline or prolinamide II as catalysts in DMSO the
only detected products with p-nitrobenzaldehyde and
isobutyraldehyde were the iso-isomers but with lower
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(
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3
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found were also very high, 93% and 92%, respectively
(
1
Asymmetry 1998, 9, 357–389; (c) Carreira, E. M. In
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(
Table 2, entries 8 and 9). Barbas et al. used L-proline
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diasteroselectivities (dr. 2:1) and enantioselectivities
4
(
89% ee for anti-4a). On the other hand, b-amino alco-
hol derived prolinamides I gave product 4a with excel-
lent diastereoselectivity (95:5) but lower ee for anti-4a
1
601; (g) Modern Aldol Reactions; Marhrwald, R., Ed.;
7
f
Wiley-VCH: Weinheim, 2004; Vols. 1–2; (h) Palomo, C.;
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79% ee). Meanwhile, with C -symmetric bisprolina-
2
mides II, a 97:3 anti:syn ratio was obtained for 4a, the
7
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4
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Soc. 2000, 122, 2395–2396.
7
i
ble to our results (93% ee). For catalyst 1a, the reaction
between benzaldehyde and cyclohexanone was less dia-
stereoselective, affording the anti:syn mixture of diastero-
isomers with a 4.3:1 ratio. In this case, both isomers
were obtained with high enantioselectivity (90% ee for
the anti-isomer and 72% ee for the syn, Table 2, entry
5. For latest uses of proline in the direct aldol reaction, see:
(a) Ikishima, H.; Sekiguchi, Y.; Ichikawa, Y.; Kotsuki, H.
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1537.
1
0).
3. Conclusion
6
In conclusion, C -symmetrical (Sa)-BINAM-L-prolin-
2
amide 1a has shown to be an efficient catalyst for the
direct aldol reaction between several ketones and alde-
hydes, its recovery being possible by extractive tech-
niques. The reaction conditions were mild, involving
aqueous DMF at 0 ꢀC in reasonable reaction rates.
The aldol products were obtained with high enantio-
selectivities, comparable or even better to those obtained
with L-proline and related prolinamide systems. For 2-
butanone, the iso-isomers were obtained regioselectively
and for cyclohexanone the corresponding anti-isomers
were formed diastereoselectively. The scope of this reac-
tion and the application of this catalyst to other related
transformations are currently being studied.
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323; (j) He L.; Tang, Z.; Cun, L.-F.; Mi, A. Q.; Jiang,
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This work was financially supported by the Direcci o´ n
General de Investigaci o´ n of the Ministerio de Educaci o´ n
y Ciencia of Spain (Grant BQU2001-0724-CO2-01 and
CTQ2004-00808/BQU), the Generalitat Valenciana
8
(
Grant CTIOIB/2002/320, GRUPOS03/134 and GV05/
57) and the University of Alicante.
1

G. Guillena et al. / Tetrahedron: Asymmetry 17 (2006) 729–733
733
2
287; (e) Zou, W.; Ibrahem, I.; Dziedzic, P.; Sund e´ n, H.;
CDCl ): d = 25.2, 30.7, 46.2, 60.7, 111.4, 118.1, 119.9,
3
C o´ rdova, A. Chem. Commun. 2005, 4946–4948; (f) Aka-
gawa, K.; Sakamoto, S.; Kudo, K. P. Tetrahedron Lett.
120.2, 122.5, 123.6, 124.8, 125.1, 126.8,126.9, 128.0, 128.3,
129.2, 129.9, 131.0, 132.3, 133.6, 135.2, 142.6, 173.9;
2
005, 46, 8185–8187; (g) Luppi, G.; Cozzi, P. G.; Monari,
3
HRMS (m/z): Calcd for C25H23ON : 381.1841; found:
M.; Kaptein, B.; Broxterman, Q. B.; Tomasini, C. J. Org.
Chem. 2005, 70, 7418–7421; (h) Krattiger, P.; Kovasy, R.;
Revell, J. D.; Ivan, S.; Wennemers, H. Org. Lett. 2005, 7,
381.1818.
2
D
5
Compound 1c: ½aꢂ ¼ þ6:7 (c 1, MeOH); Mp 120 ꢀC
(CHCl , Et O); R = 0.21 (AcOEt/MeOH 1:1); m = 3349,
3
2
f
ꢀ
1 1
1
101–1103; (i) Andreae, M. R. M.; Davis, A. P. Tetra-
3203, 3059, 2968, 1685, 1594 cm ; H NMR (300 MHz,
CDCl ): d = 1.29, 1.49, 1.73, 1.93, 2.22, 2.57, 3.52, 7.14,
7.25, 7.40, 7.93, 8.04, 8.79, 9.68; C NMR (75 MHz,
CDCl ): d = 25.7, 30.7, 46.6, 60.6, 119.1, 119.7, 124.8,
125.0, 126.9, 128.2, 129.6, 130.9, 132.4, 135.1, 173.6;
hedron: Asymmetry 2005, 16, 2487–2492; (j) Dziedzid, P.;
Zou, W.; H a´ nfren, J.; C o´ rdova, A. Org. Biomol. Chem.
3
1
3
2
006, 4, 38–40.
3
9
. (a) Wong, C.-H.; Whitesides, G. Enzymes in Synthetic
Organic Chemistry; Pergamon Press: Oxford, 1994; (b)
Gijsen, H. J. M.; Qiao, L.; Fitz, W.; Wong, C.-H. Chem.
Rev. 1996, 96, 443–474.
32 2 4
HRMS (m/z): Calcd for C30H O N : 480.2525; found:
480.2521.
12. Typical procedure: To a solution of aldehyde (37.8 mg,
0.25 mmol), in dry solvent (1 mL) under argon was added
the corresponding ketone (5.5 mmol). The catalyst was
added (10 mol%) to the resulting solution in one portion,
and the resulting mixture stirred at the corresponding
1
1
0. Recently, the synthesis and structural properties of several
BINAM prolinamides derived from acyclic amino acids
have been described: Kowalczyk, B.; Tarnowska, A.;
Weseli n´ ski, L.; Jurczak, J. Synlett 2005, 2372–2375.
2
6
1
1. Compound 1a: ½aꢂ ¼ þ108:6 (c 1, MeOH); Mp 230 ꢀC
temperature. The reaction was monitored by H NMR
D
(
3
CHCl , Et O); R = 0.70 (AcOEt/MeOH 1:1); m = 3335,
192, 2964, 2869, 1676, 1592 cm ; H NMR (300 MHz,
spectroscopy and quenched with a 6 M aqueous solution
of hydrochloric acid (5 mL) and ethyl acetate (5 mL). The
mixture was stirred vigorously for 10 min. The emulsion
was separated (3 · 5 mL satd NaCl) and the aqueous
phase treated with a satd NaOH solution until pH >9 and
then ethyl acetate was added (3 · 15 mL). The organic
layer was separated, dried over MgSO and evaporated
4
recovering pure catalyst (85%). The organic phase from
the acidic workup was dried over MgSO and evaporated
to dryness. The residue was purified by flash chromatog-
raphy yielding pure aldol products.
3
2
f
ꢀ1 1
CDCl
.24, 7.41, 7.93, 8.04, 8.79, 9.69; C NMR (75 MHz,
CDCl ): d = 25.3, 30.6, 46.1, 60.6, 119.3, 119.7, 124.9,
3
): d = 0.89, 1.26, 1.48, 1.71, 1.87, 2.34, 3.55, 7.15,
1
3
7
3
1
25.0, 126.9, 128.2, 129.6, 130.9, 132.4, 135.1, 173.9;
HRMS (m/z): Calcd for C30 : 480.2525; found:
80.2501.
H
32
O
2
N
4
4
2
9
Compound 1b: ½aꢂ ¼ ꢀ87:4 (c 1, MeOH); Mp 265 ꢀC
D
4
(
CHCl
3
, Et
2
O); R
f
= 0.40 (AcOEt/MeOH 1:1); m = 3466,
ꢀ1
1
3
345, 3203, 3055, 2970, 1668, 1591 cm
;
H NMR
(
7
300 MHz, CDCl ): d = 1.45, 1.75, 2.36, 3.55, 3.68, 6.90,
.29, 7.71, 7.83, 7.92, 7.99, 8.82, 9.73; C NMR (75 MHz,
13. Nyberg, A. I.; Usano, A.; Pinko, P. M. Synlett 2004,
1891–1896.
3
1
3