Highly efficient asymmetric aldol reaction in brine using a fluorous sulfonamide organocatalyst

Article abstract of DOI:10.1039/c2ob06955e

A fluorous organocatalyst promotes direct asymmetric aldol reactions of aromatic aldehydes with ketones in brine to afford the corresponding anti-aldol products in high yield with up to 96% ee. Fluorous organocatalyst can be readily recovered by solid phase extraction using fluorous silica gel and reused without purification. The Royal Society of Chemistry 2012.

Full text of DOI:10.1039/c2ob06955e

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COMMUNICATION
Highly efficient asymmetric aldol reaction in brine using a fluorous
sulfonamide organocatalyst†‡
Tsuyoshi Miura,*a Hikaru Kasuga,a Kie Imai,a Mariko Ina,a Norihiro Tada,a Nobuyuki Imaib and
Akichika Itoha
Received 22nd November 2011, Accepted 6th January 2012
DOI: 10.1039/c2ob06955e
reported a method for the synthesis of both enantiomeric aldol
products in brine using organocatalysts 1a12 and 2,13 which are
easily prepared from L-phenylalanine, a commercially available,
inexpensive natural amino acid (Scheme 1). The asymmetric
synthesis of both enantiomeric products using two different orga-
nocatalysts, which are prepared from a common chiral source,
has not been extensively reported, although Maruoka and co-
worker elaborated the concept for the first time.14 Furthermore,
we successively developed the recyclable fluorous organocatalyst
1b,7 which can provide the anti-aldol product 6a, by appending
a fluorous tag to β-aminosulfonamide 1a. However, direct aldol
reactions using organocatalyst 2,13 which afford the opposite
absolute configuration product 7a, require high catalyst loading
(0.2 equiv). In addition, a protocol for recovery and reuse of 2
has not yet been developed. Therefore, to improve the catalytic
activity of 2 and enable catalyst recovery, we attempted to
develop a novel organocatalyst 4 bearing a fluorous tag that
can effectively promote asymmetric aldol reactions in water.
Herein, we report highly efficient direct asymmetric aldol
reactions using 4.
A fluorous organocatalyst promotes direct asymmetric aldol
reactions of aromatic aldehydes with ketones in brine to
afford the corresponding anti-aldol products in high yield
with up to 96% ee. Fluorous organocatalyst can be readily
recovered by solid phase extraction using fluorous silica gel
and reused without purification.
Formation of new carbon–carbon bonds is one of the most
important transformations in organic chemistry. In particular,
direct asymmetric aldol reactions using organocatalysts have
attracted considerable attention in recent years. Proline and its
derivatives with cyclic secondary amino groups are good organo-
catalysts for direct aldol reactions.1 Moreover, many chiral
primary amines have been reported as excellent organocata-
lysts.2,3 In addition, the use of water as a reaction solvent plays
an important role in the field of green chemistry.4 Organocata-
lysts that can promote aldol reactions in water have recently been
reported by several research groups.2,5 Most of the organocata-
lysts used in water bear hydrophobic units such as alkyl chain
groups or aromatic groups that function as a reaction field in
water. In addition, fluorous chain groups such as perfluoroalkyl
groups can be utilized as hydrophobic reaction fields; however,
asymmetric reactions in water using organocatalysts bearing a
fluorous tag have rarely been reported.5m,6,7 Fluorous compounds
with high fluorine content can be easily separated from non-
fluorous compounds by fluorous solid phase extraction (FSPE)
using fluorous silica gel or fluorous organic solvent extraction.8
There are many reports of asymmetric reactions in which
fluorous organocatalysts are recyclable.9
We have recently reported a direct aldol reaction in water
using the fluorous sulfonamide organocatalyst 1b,7 the Michael
addition reaction using a fluorous thiourea organocatalyst,10 and
the oxidation reaction using fluorous IBX.11 In addition, we have
The preparation of 4 bearing a fluorous tag is shown in
Scheme 2. Treatment of 8, which is an intermediate in the syn-
thesis of chiral ligand 3,15 with methanesulfonyl chloride
(MsCl) in the presence of triethylamine in THF afforded 9 in
98% yield. Azide 10 was then obtained in 85% yield via the
reaction of 9 with sodium azide in DMF. Next, the Boc group of
10 was removed by treatment with hydrogen chloride in ethyl
acetate, followed by reaction with trifluoromethanesulfonic anhy-
dride (Tf2O) in the presence of triethylamine in CH2Cl2 to give
aGifu Pharmaceutical University 1-25-4, Daigaku-nishi, Gifu 501-1196,
Japan. E-mail: miura@gifu-pu.ac.jp
bFaculty of Pharmacy, Chiba Institute of Science, 15-8 Shiomi-cho,
Choshi, Chiba 288-0025, Japan
†Electronic supplementary information (ESI) available: Experimental
procedure and spectral data for compound 4, 7a–7n and 9–12. See DOI:
10.1039/c2ob06955e
‡This article is part of the joint ChemComm–Organic & Biomolecular
Chemistry ‘Organocatalysis’ web themed issue.
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 2209–2213 | 2209

Scheme 1 Our previous work.
Scheme 2 Preparation of organocatalyst.
Table 1 Optimization of reaction conditions
Entry
4 (equiv)
TFA (equiv)
Cyclohexanone (equiv)
Time (h)
Yield (%)a
anti : synb
%eec
1
2
3
4
5
6
7
0.1
0.1
0.1
0.1
0.05
0.05
0.05
0.1
0.05
0.025
0.025
0.0125
0.0125
—
10
10
10
5
5
3
72
72
72
48
48
48
48
58
93
79
98
90
98
98
87 : 13
92 : 8
89 : 11
88 : 12
94 : 6
92 : 8
85 : 15
88
92
94
86
94
86
87
5
a 1H NMR yield. b Determined by 1H NMR. c Determined by HPLC analysis using Chiralcel AS-H.
the corresponding sulfonamide 12 in excellent yield. Finally, the
azide group of 12 was reduced by triphenylphosphine in THF–
H2O to afford 4.
Optimized conditions for enantioselective direct aldol reac-
tions using 4 are shown in Table 1. Aldol reactions were carried
out with p-nitrobenzaldehyde (5a) and cyclohexanone as test
reactants in the presence of a catalytic amount of 4 and trifluoro-
acetic acid (TFA) in brine. Finally, the most suitable conditions
were found when the reaction was performed in the presence of
TFA (0.0125 equiv) and 4 (0.05 equiv) at room temperature
(entry 5). When no TFA was added, a slight reduction in enan-
tioselectivity was observed (entry 7). Fluorous organocatalyst 4
is an excellent catalyst and provides high yield and excellent
stereoselectivity even at low catalyst loading (0.05 equiv) and
with reasonable amount of cyclohexanone (5 equiv) as compared
to 2, which requires high catalyst loading (0.2 equiv) and large
amount of cyclohexanone (10 equiv).
Considering the optimized reaction conditions, the scope and
limitation of the direct asymmetric aldol reactions between
various aldehydes and ketones were examined (Table 2). We
2210 | Org. Biomol. Chem., 2012, 10, 2209–2213
This journal is © The Royal Society of Chemistry 2012

Table 2 Direct asymmetric aldol reactions using organocatalyst 4
Table 2 (Contd.)
Time
(h)
Yield
(%)a
%
Time
(h)
Yield
(%)a
%
Entry Product
14e,f
anti : synb eec
Entry Product
1
anti : synb eec
120
40
—
70
48
90
96
54
93
94 : 6
94
94
95
91
a 1H NMR yields. b Determined by 1H NMR. c Determined by HPLC
analysis. d Catalyst 4 (0.1 equiv) and TFA (0.025 equiv) were used.
e The reaction was carried at 0 °C. f The reaction was carried out with
30 equiv of acetone in brine.
2
3
4
72
91 : 9
120
120
88 : 12
78 : 22
Table 3 Recycling and reuse of the fluorous catalyst by FSPE
5
120
11
92 : 8
91
6
7
120
120
34
69
93 : 7
95 : 5
94
96
Time
(h)
Yield
(%)a
Cat. recovery
(%)
Entry
anti : synb
%eec
Initial
1st reuse
2nd reuse
48
72
168
82
82
70
89 : 11
90 : 10
87 : 13
88
77
91
100
77
83
8d
120
120
79
21
79 : 21
93 : 7
91
94
a Isolated yield. b Determined by 1H NMR. c Determined by HPLC
analysis using Chiralcel AS-H.
9
selected methoxy substituents as the representative electron-
donating group and nitro, trifluoromethyl, and halogen substitu-
ents as the electron-withdrawing groups on the benzene ring of
benzaldehyde. The reactions between aromatic aldehydes with
electron-withdrawing groups and cyclohexanone smoothly
resulted in the corresponding anti-aldol products in good to
excellent yield with 84–96% ee (entries 1–4, 7, 8, and 10 and
11). On the other hand, the reactions between aldehydes with
electron-donating groups and cyclohexanone provided the anti-
aldol products in low yield; however, high enantioselectivity was
obtained (entries 5 and 9). Moreover, we examined the reactions
between other types of ketones and p-nitrobenzaldehyde (5a).
The aldol reactions of cycloheptanone and cyclopentanone with
4a resulted in the expected aldol products 7l and 7m in high
yield with 73 and 88% ee, respectively (entries 12 and 13). The
reaction of acetone as an acyclic ketone with 5a afforded 7n in
moderate yield with 70% ee (entry 14). The stereochemistry of
the anti-aldol products obtained using 4 was determined by com-
parison with reported chiral-phase HPLC retention times, optical
rotation data, and NMR spectroscopy.
10
11
120
120
86
81
94 : 6
94
84
88 : 12
12
13
120
96
79
70
68 : 32
70 : 30
73
88
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 2209–2213 | 2211

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in the aldol reaction between cyclohexanone and 5a under the
similar conditions, 4 was readily recovered by FSPE using
fluorous silica gel.8 Moreover, the recovered 4 can be reused,
and it retained its catalytic activity and enantioselectivity without
further purification although longer reaction times were necess-
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Conclusions
In conclusion, the novel fluorous organocatalyst 4 can be easily
prepared from L-tyrosine, an inexpensive and commercially
available amino acid. Fluorous organocatalyst 4, which is a
simple β-aminosulfonamide with only one chiral center,
efficiently catalyzes the direct aldol reactions of various aromatic
aldehydes with ketones in brine to afford the corresponding anti-
aldol products with high enantioselectivity. Fluorous organocata-
lyst 4 is a better catalyst than the original organocatalyst 213 and
can efficiently catalyze aldol reactions even under mild reaction
conditions, at only low catalyst loading (0.05 equiv) and with
reasonable amount of cyclohexanone (5 equiv). The excellent
performance is probably due to the ability of the fluorous tag
(–C8F17) on 4 to function as a preferable hydrophobic reaction
field in brine. Fluorous organocatalyst 4 was readily recovered
by simple solid phase extraction using fluorous silica gel and
was immediately reusable without purification. Further appli-
cation of this catalyst in the synthesis of bioactive compounds is
currently under progress in our laboratory.
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This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 2209–2213 | 2213