1(R),2(R)-Bis[(S)-prolinamido]cyclohexane/[bmim][BF4] ionic liquid as an efficient catalytic system for direct asymmetric aldol reactions

Article abstract of DOI:10.1016/j.mencom.2007.09.009

A direct asymmetric aldol reaction between unmodified ketones and aldehydes was achieved for the first time using the 1(R),2(R)-bis[(S)-prolinamido]cyclohexane/[bmim][BF₄] ionic liquid catalytic system.

Full text of DOI:10.1016/j.mencom.2007.09.009

Mendeleev
Communications
Mendeleev Commun., 2007, 17, 277–278
1
(R),2(R)-Bis[(S)-prolinamido]cyclohexane/
[
bmim][BF ] ionic liquid as an efficient catalytic
4
system for direct asymmetric aldol reactions
Alexander S. Kucherenko,* Dmitriy E. Siyutkin, Vladislav O. Muraviev,
Marina I. Struchkova and Sergei G. Zlotin
N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 119991 Moscow, Russian
Federation. Fax: +7 495 135 5328; e-mail: zlotin@ioc.ac.ru
DOI: 10.1016/j.mencom.2007.09.009
A direct asymmetric aldol reaction between unmodified ketones and aldehydes was achieved for the first time using the 1(R),2(R)-
bis[(S)-prolinamido]cyclohexane/[bmim][BF ] ionic liquid catalytic system.
4
A direct asymmetric aldol reaction between unmodified aldehydes
and ketones is used for the synthesis of chiral β-hydroxy car-
8
0
1
2
bonyl compounds, which are valuable intermediates in organic
70
60
synthesis.1
(a)–(c)
Native amino acids, in particular, (S)-proline,
2(a)
(b)
2(c)
(
S)-tryptophan2 etc.,
are generally employed as catalysts.
5
4
3
2
0
0
0
0
As a rule, a 20- to 30-fold excess of a ketone is required to
complete the process, which limits the scope of reaction appli-
cations (acetone and simple cycloalkanones) and hampers the
product isolation.
S)-Proline containing amides3(a)–(g) and peptides are more
4
10
0
(
active catalysts of the asymmetric aldol reaction. They enhance
enantioselectivity by running the reaction at lower temperatures
0
20
40
60
t/min
(
to –40 °C). The reaction rate grew further when an ionic liquid
5
Figure 1 Activities of organocatalysts 1 (curve 1) and 2 (curve 2) in the
asymmetric aldol reaction between p-nitrobenzaldehyde 3a and acetone 4a
in [bmim][BF ]. Reagents and conditions: 1 and 2 (0.013 mmol each), 3a
was used as a solvent.
Here, we report the first application of the proline amide/
ionic liquid catalytic system in the direct asymmetric aldol
reaction between unmodified ketones and aldehydes taken in a
ratio of 3:1 (Scheme 1).
4
(
0.13 mmol), 4a (0.40 mmol), ionic liquid (0.1 ml), 20 °C.
Apart from [bmim][BF ], we studied [bmim][PF ], [bmim][NTf ]
4
6
2
1
(R),2(R)-Bis[(S)-prolinamido]cyclohexane 1 obtained from
and 1-butyl-2,3-dimethylimidazolium tetrafluoroborate ([bdmim]-
available and inexpensive reagents [1(R),2(R)-diaminocyclo-
hexane and N-benzyloxycarbonyl-(S)-proline] by a known scheme6
was used as an organocatalyst. First, we compared the activities
of amide 1 and (S)-proline 2 (10 mol% each) in a model
reaction between p-nitrobenzaldehyde 3a (1 equiv.) and acetone
[BF ]) ionic liquids (Table 1). The reactions were run at 0 °C,
4
the catalyst amount was 5 mol% and the 3a/ionic liquid molar
ratio was 1:4. The highest yield of aldol 5a (83%) with moderate
ee (50%) was achieved in [bmim][BF4].
Table 1 Asymmetric aldol reaction between 3a and 4a catalysed by amide
4
a (3 equiv.) in the 1-butyl-3-methylimidazolium tetrafluoro-
a
1
in ionic liquids.
borate ([bmim][BF ]) (4 equiv.) media. Noticeably higher con-
4
versions of 3a at different reaction stages were achieved in the
reaction catalysed by amide 1 than in the respective reaction
catalysed by amino acid 2. These are indicative of a higher
efficiency of the chosen catalyst (Figure 1). Reduction of the
Isolated yield
of 5a (%)
ee (%)b
Entry
Iolic liquid
Cycle
t/h
1
2
3
4
5
6
[bmim][PF6]
[bmim][NTf2]
[bdmim][BF4]
[bmim][BF4]
1
1
1
1
2
3
15
15
15
15
15
25
76
70
79
83
84
70
47
36
48
50
50
51
4
a:3a molar ratio down to 2:1 resulted in a decrease of the con-
version of 3a by ~10% in 60 min, even though active catalyst 1
was used.
a
Reagents and conditions: 1 (0.006 mmol), 3a (0.13 mmol), 4a (0.40 mmol),
b
ionic liquid (0.54 mmol), 0 °C. HPLC, chiral phase Chirapak OJ-H,
t(R) 20.73 min, t(S) 24.93 min.
O
O
NH HN
O
N
O
OH
O
H
OH
NH
HN
O
1 (5 mol%)
2
R3
R1
1
R3
1
2
+
[
bmim][BF4], 0 °C
R1
H
R2
4a–f
R2
Next, we investigated the influence of ionic liquid nature on
the reaction of asymmetric aldol between p-nitrobenzaldehyde
a (1 equiv.) and acetone 4a (3 equiv.) catalysed by amide 1.
3
a–c
5a–h
Scheme 1
3
–
277 –

Mendeleev Commun., 2007, 17, 277–278
Table 2 Synthesis of β-hydroxycarbonyl compounds 5 catalysed by the 1/[bmim][BF ] system.a
4
dr (%)
ee (%)b
Entry
Reagents
Product
R1
R2
R3
t/h
Isolated yield (%)
syn anti syn anti
1
2
3
4
5
6
7
8
3a, 4a
3a, 4b
3a, 4c
3a, 4d
3a, 4e
3a, 4f
3b, 4a
3c, 4a
5a
5b
5c
5d
5e
5f
4-NO C H
H
H
H
H
Me
Et
15
35
50
60
30
30
15
40
83
56
54
38
43
63
80
62
—
—
—
60
42
45
2
6
4
4
4
4
4
4
4
4-NO C H
2
6
4-NO C H
cyclopropyl
(CH ) CH=CMe
2
6
4-NO C H
—
52
2
6
2 2
2
4-NO C H
(CH )
2 3
72 28
30 70
—
54 70
2
6
4-NO C H
OH
H
H
Me
Me
Me
6
42
2
6
5g
5h
3-NO C H
52
40
2
6
h-CpMn(CO)3
—
a
b
Reagents and conditions: 1 (0.013 mmol), 3 (0.26 mmol), 4 (0.80 mmol), [bmim][BF ] (1.08 mmol), 0 °C. Determined by HPLC.
4
The 1/[bmim][BF ] system was further examined in asym-
tions even in the presence of 30 mol% of 2). Furthermore,
4
metric aldol reactions between aromatic aldehydes 3 and ketones
given a high catalytic activity of the 1/[bmim][BF ] system
4
†
4
. The reactions were carried out under the same conditions.
we managed to synthesise for the first time chiral aldol 5h,
bearing an organometal moiety, from cymantrene aldehyde 3c
and acetone 4a (Table 2, entry 8).
In all the instants aldols 5 were synthesised in moderate to high
yields and with reasonable ee (Scheme 1, Table 2). Asymmetric
ketones 4b–d reacted regioselectively at the methyl group adjacent
to the carbonyl group affording respective aldols 5b–d (Table 2,
The catalytic system 1/[bmim][BF ] can be used repeatedly.
4
After each reaction cycle, aldol 5 was extracted with an organic
solvent (EtOAc) and fresh portions of reagents 3 and 4 were
added to the remaining catalyst. At least triple catalyst recycling
was possible without a significant activity and enantioselec-
tivity loss (Table 1, entries 4–6).
As a result, a new highly active recoverable catalytic system
of 1(R),2(R)-bis[(S)-prolinamido]cyclohexane 1/[bmim][BF4]
was developed to perform an asymmetric aldol reaction between
unmodified ketones and aldehydes in a ratio of 3:1, which is much
lower than that required in respective (S)-proline-catalysed
reactions.
2
entries 2–4). Aldols 5e,f with substituents at C (Scheme 1)
were produced in reactions of aldehydes 3a,b with cyclopentanone
4
e and hydroxyacetone 4f (Table 2, entries 5, 6). A diastereo-
meric ratio in products 5e,f depended on the ketone structure.
1
1
According to H NMR (coupling constants between H and
2
H ), a syn-diastereomer prevailed in aldol 5e (J
whereas an anti-diastereomer dominated in aldol 5f (J
1
2
2 Hz),
5 Hz).
H –H
H –H
1
2
Note that aldol 5b was only reported as a product of the native
aldolase-catalysed asymmetric aldol reaction between 3a and 4b.7
Compounds 5c,d,h have not been synthesised so far, assumingly,
because of low activity of the employed organocatalysts (ketones
4
b–d do not react with aldehydes 3 under the studied condi-
References
1
(a) C. E. Song and S. Lee, Chem. Rev., 2002, 102, 3495; (b) Q. H. Fan,
Y. M. Li and A. S. C. Chan, Chem. Rev., 2002, 102, 3385; (c) B. List,
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†
1
NMR spectra were recorded on Bruker AM 300 (300.13 MHz { H})
1
13
and Bruker DRX 500 instruments (500.13 { H}, 125.76 { C} in CDCl ).
1
3
13
H and C chemical shifts were recorded relative to Me Si and CDCl ,
4
3
2
(a) B. List, R. A. Lerner and C. F. Barbas III, J. Am. Chem. Soc., 2000,
respectively. Optical yields of aldols 5 were determined using HPLC
122, 2395; (b) M. Amedjkouh, Tetrahedron Asymmetry, 2007, 18, 390;
8
(Daicel Chirapak OJ-H and OD-H columns). Ionic liquids [bmim][PF ],
6
(c) K. Sakthivel, W. Notz, T. Bui and C. F. Barbas III, J. Am. Chem.
Soc., 2001, 123, 5260.
9
10
11
[
bmim][NTf2], [bdmim][BF4] and [bmim][BF4] were synthesised
by reported methods and dried at 70 °C (2 Torr) for 4 h. Ionic liquid
purity was controlled by H, C and F NMR spectra. Residual water
content was not determined, in [bmim][NTf ] according to reported
data it is 0.03%.
General procedure. Aldehyde 3 (0.26 mmol) and ketone 4 (0.80 mmol)
were added to a stirred suspension of catalyst 1 (4.0 mg, 0.013 mmol) in
ionic liquid (1.08 mmol). The reaction mixture was stirred for 15–60 h at
3
(a) Z. Tang, F. Jiang, L. T. Yu, X. Cui, L. Z. Gong, A. Q. Mi, Y. Z. Jiang
and Y. D. Wu, J. Am. Chem. Soc., 2003, 125, 5262; (b) S. Samanta,
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1
13
19
2
9
0
°C and extracted with EtOAc (3×5 ml). Combined extracts were
(
g) L. He, J. Jiang, Z. Tang, X. Cui, A. Q. Mi, Y. Z. Jiang and L.-Z. Gong,
evaporated at a reduced pressure (30 °C, 15 Torr), aldols 5 were isolated
by column chromatography on silica gel (0.060–0.200 nm, Acros); eluent,
n-hexane–EtOAc (3:1). Compounds 5a,b,e,f,g were identified by their
Tetrahedron Asymmetry, 2007, 18, 265.
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4
5
6
7
1
3(a)–(e),7 1
13
H NMR spectra compared with the reported data.
H, C NMR
and HPLC [t(R) (major enantiomer), t(S)] data for newly synthesised
compounds 5c,d,h are given below. Yields, ee and dr of compounds 5
are summarised in Tables 1 and 2.
1
1
-Cyclopropyl-3-hydroxy-3-(4-nitrophenyl)propan-1-one 5c: H NMR, d:
.01 (m, 2H), 1.13 (m, 2H), 1.93 (m, 2H), 3.74 (s, 1H), 5.20 (m, 1H),
.56 (d, 2H, J 8.3 Hz), 8.23 (d, 2H, J 8.3 Hz). C NMR, d: 11.5, 21.8,
1.0, 68.9, 123.8, 126.5, 147.3, 150.2, 210.9. HPLC: Chirapak OJ-H,
1
7
5
1
3
8
9
i
3
–1
n-hexane/Pr OH, 85:15 (0.5 cm min ), t(R) 20.51 min, t(S) 27.19 min.
10 K.-P. Ho, K.-Y. Wong and T. H. Chan, Tetrahedron, 2006, 62, 6650.
1
1
-Hydroxy-7-methyl-1-(4-nitrophenyl)oct-6-en-3-one 5d: H NMR, d:
11 P. A. Z. Suarez, J. E. L. Dullius, S. Einloft, R. F. De Souza and J. Dupont,
1
3
8
1
.63 (s, 3H), 1.69 (s, 3H), 2.30 (m, 2H), 2.46 (m, 2H), 2.81 (m, 2H),
Polyhedron, 1996, 15, 1217.
.60 (br. s, 1H), 5.05 (m, 1H), 5.27 (t, 1H, J 5.4 Hz), 7.53 (d, 2H, J 8.8 Hz),
1
3
.20 (d, 2H, J 8.8 Hz). C NMR, d: 17.2, 23.6, 25.6, 44.1, 52.0, 71.1,
21.0, 123.5, 128.3, 136.2, 147.9, 148.4, 210.1. HPLC: Chirapak OJ-H,
i
3
–1
n-hexane/Pr OH 85:15 (1 cm min ), t(R) 13.73 min, t(S) 14.94 min.
1
4
-Hydroxy-4-(h-cyclopentadienylmanganese)butan-2-one 5h: H NMR,
d: 2.22 (s, 3H), 2.81 (m, 2H), 3.20 (br. s, 1H), 4.68 (m, 2H), 4.78–4.92
(
2
m, 3H). 13C NMR, d: 30.6, 51.3, 63.9, 80.9, 81.1, 82.0, 82.1, 107.5,
07.8. HPLC: Chirapak OD-H, n-hexane/Pr OH 90:10 (1 cm min ),
i
3
–1
t(S) 20.92 min, t(R) 19.91 min.
Received: 12th April 2007; Com. 07/2909
–
278 –