Asymmetric Michael reactions catalyzed by a highly efficient and recyclable quaternary ammonium ionic liquid-supported organocatalyst in aqueous media

Article abstract of DOI:10.1039/c3ob27398a

A novel ionic liquid-support organocatalyst, which contains the quaternary ammonium ion moiety, was recently developed and successfully applied to the asymmetric Michael reaction in the presence of a newly developed ionic liquid-supported (ILS) benzoic ac

Full text of DOI:10.1039/c3ob27398a

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Asymmetric Michael reactions catalyzed by a highly
efficient and recyclable quaternary ammonium ionic
liquid-supported organocatalyst in aqueous media†
Cite this: Org. Biomol. Chem., 2013, 11,
1801
Received 10th December 2012,
Accepted 18th January 2013
Subrata K. Ghosh, Yupu Qiao, Bukuo Ni* and Allan D. Headley*
DOI: 10.1039/c3ob27398a
www.rsc.org/obc
A novel ionic liquid-support organocatalyst, which contains the for a direct intermolecular aldol reaction,6 different types of
quaternary ammonium ion moiety, was recently developed and proline-derived catalysts have been developed. In this research,
successfully applied to the asymmetric Michael reaction in the we have developed a new type of ionic-liquid supported organo-
presence of
a newly developed ionic liquid-supported (ILS) catalyst, which contains an ammonium ion moiety (catalyst 1).
benzoic acid as co-catalyst. For the reactions studied, in which Ionic liquids have a unique combination of physical proper-
various aldehydes and nitroolefins were examined, excellent dia- ties, such as extremely high polarity, they lack measurable
stereo- and enantioselectivities were obtained with low catalyst vapor pressure and they are thermally and chemically stable,7
loading. Also, the catalyst could be recycled for ten times without which makes them ideal to be used as reusable homogenous
significant loss of enantioselectivity.
supports for catalysts and co-catalysts. In addition, they are
very polar molecules, which have been shown to synergistically
enhance reaction rates of various reactions.8 For this quater-
nary ammonium ILS organocatalyst, the bulky benzyl group
introduces steric bulk in addition to the other bulky groups on
the catalyst; they will serve to increase the stereoselectivity.
Even though quaternary ammonium ILS catalysts have been
introduced before and successfully used to catalyze asym-
metric reactions,9 they lack the added bulkiness found in this
catalysis.
We have recently reported the development and use of a
new type of diarylprolinol silyl ether as a water-soluble organo-
catalyst for the highly asymmetric Michael addition of alde-
hydes to nitroolefins in water with high enantioselectivity;
these catalysts are easily recycled from the organic products by
separation of the aqueous phase.10 A major challenge that was
discovered in the use of this catalytic system however, is the
separation of the co-catalyst, typically benzoic acid, from the
reaction products. Since benzoic acid and the organic products
are both typically soluble in the organic phase, separation of
the products from the catalytic system is extremely difficult.11
In order to address this problem, we have developed recently a
new type of co-catalyst that contains an ionic liquid moiety,
shown in Table 1. We have demonstrated that this ionic liquid-
supported (ILS) benzoic acid is an effective, water-soluble, and
recyclable co-catalyst in aqueous media.12
The ability to carry out asymmetric organocatalyzed reactions
in aqueous media has many advantages, and this area of
research has attracted the attention of many researchers in
recent years.1 Water has unique physical properties, which
make it a very desirable medium for various reactions and it is
an environmental safe liquid and also relatively cheap.2 Over
the years, many water-compatible organocatalysts have been
developed and applied to a wide range of organic transform-
ations, in which the asymmetric products are obtained with
high stereoselectivities.3,4 Such organocatalysts typically
contain large hydrophobic groups, which serve to concentrate
the organic phase and assemble the hydrophobic reactants in
water. A problem encountered with the use of such catalysts
however, is that difficulty is typically encountered in the separ-
ation of the product phase from the catalyst, which is typically
soluble in the organic phase. Another problem encountered is
that large amounts of the catalysts that are usually used, typi-
cally 10–30 mol%, present an environmental challenge for
disposal.
Water-compatible recyclable and environmentally benign
organocatalysts recently developed in our lab are specifically
designed to address some of the problems described earlier in
the use of other catalysts.5 Ever since List, Lerner and Barbas
reported that L-proline is an efficient enantioselective catalyst
In this research, the effectiveness of this new catalytic
system shown in Table 1 was examined by studying the
Michael reaction of n-pentanal and β-nitrostyrene by using
benzoic acid and our recently developed ionic liquid-sup-
ported (ILS) benzoic acid as an additive. For the broad
Department of Chemistry, Texas A&M University-Commerce, Commerce,
TX 75429-3001, USA. E-mail: allan.headley@tamuc.edu, bukuo.ni@tamuc.edu
†Electronic supplementary information (ESI) available. See DOI: 10.1039/
c3ob27398a
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Table 1 Optimization of the Michael addition reaction conditionsa
Table 2 Organocatalytic asymmetric Michael reaction using aldehydes and
nitroalkenesa
Time
(h)
Yieldb
(%)
syn/
eed
(%)
Entry
R1
R2
antic
1
2
3
4
5
6
7
8
9
Ph
Ph
Ph
Ph
n-Pr
i-Pr
n-Bu
n-C5H11
n-C7H15
n-Pr
n-Pr
n-Pr
n-Pr
Bn
18
70
16
21
60
60
30
20
42
20
99/2a
73/2b
99/2c
98/2d
94/2e
87/2f
96/2g
99/2h
94/2i
75/2j
96 : 4
98 : 2
98 : 2
98 : 2
98 : 2
94 : 6
95 : 5
99 : 1
92 : 8
96 : 4
>99
>99
>99
99
>99
99
>99
>99
>99
99
Ph
Acid
(eq.)
Time
(h)
Yieldb
(%)
syn/
eed
(%)
4-MeO–C6H4
3-MeO–C6H4
2-Furan
4-Br–C6H4
n-Bu
Entry
Acid
antic
1
2
3
4
5
Benzoic acid
Benzoic acid
ILS benzoic acid
ILS benzoic acid
ILS benzoic acid
6
10
6
10
3
36
24
18
18
19
99
99
99
99
99
94 : 6
94 : 6
96 : 4
97 : 3
93 : 7
99
99
>99
>99
>99
10
a Reactions performed on 0.4 mmol scale using catalyst 1, acid,
n-pentanal (2 equiv.), and water (0.5 mL). b Yields of isolated product.
c Determined by 1H NMR. d Determined by chiral HPLC.
a Reactions performed on 0.4 mmol scale using catalyst 1, acid,
n-pentanal (2 equiv.), and water (0.5 mL). b Yields of isolated product.
c Determined by 1H NMR. d Determined by chiral HPLC.
acid at room temperature to give the Michael adducts 2a–j in
moderate to high yields (73–99%) with excellent enantio- (up
spectrum of reactions that are essential for organic synthesis, to >99% ee) and diastereoselectivities (syn/anti ratio up to 99/
the catalyzed asymmetric Michael reaction of aldehyde with 1). Also, nitroolefins bearing electron-withdrawing and elec-
nitroolefins is especially important.13 This type reaction is tron-donating aromatic substituents, as well as a heterocyclic
especially important because it is one of the most powerful aromatic group were excellent Michael acceptors for n-penta-
reactions for carbon–carbon bond formation and also affords nal (Table 2, entries 1, 6–9). Furthermore, this catalytic system
synthetically useful γ-nitro carbonyl compounds with excellent is also highly effective for Michael addition of aldehyde to ali-
diastereoselectivities both in nature and in modern organic phatic nitroolefin at room temperature for providing product
synthesis.14 Screening of the type acid and their ratios was 2j in good yield and excellent stereoselectivities (Table 2, entry
investigated to optimize the reaction conditions; the results 10).
are summarized in Table 1.
The recyclability of this catalytic system was examined for
Initially, the reaction was performed in water with 5 mol% the reaction of trans-β-nitrostyrene and n-pentanal. After the
of the catalyst and 6 eq. of benzoic acid as additive. The reac- reaction was completed, the reaction mixture was extracted by
tion afforded the product with 99% yield with excellent selec- a solvent mixture of Et2O–hexane (1 : 8). The product was
tivity after 36 hours (Table 1, entry 1). However, the reaction obtained after evaporation of the organic solvent and purified
time was shorter when 10 eq. of benzoic acid was used by silica gel column chromatography. The recovered aqueous
(Table 1, entry 2); further increase of the amount of acid did phase, which contains the catalyst and co-catalyst, was reused
not improve in the reaction time. When 6 eq. of the ILS for the next cycle directly by addition of fresh portions of
benzoic acid was used as additive, the reaction was completed n-pentanal and trans-β-nitrostyrene. As shown in Table 3, the
within 18 hours with excellent yield and excellent stereoselec- recovered catalytic system retained good activity and high
tivity (Table 1, entry 3). However, an increase in amount of ILS levels of enantioselectivity for at least ten cycles despite some
benzoic did not improve the results (Table 1, entry 4), and by progressive loss of activity observed in cycles 2–10. However,
decreasing the amount of ILS benzoic acid, a decrease in the the enantioselectivity was not affected and remains above 99%
diastereoselectivity of the reaction was observed (Table 1, entry up to 8 catalytic cycles. These results demonstrate that this cata-
5). Thus, the conditions for entry 3 were taken as optimized lytic system is recyclable and effective for the asymmetric con-
conditions to be used to test the reaction scope.
jugate addition reactions between aldehydes and nitroolefins
The scope of the Michael addition reactions between a in water with excellent stereoselectivities.
series of aldehydes and nitroolefins by using the catalytic
In summary, a newly developed organocatalyst when used
system was studied in water and the results are summarized in in combination with ILS-benzoic acid results in a highly
Table 2. From these results, it is obvious that all aldehydes can efficient catalytic system for the Michael additions of alde-
efficiently undergo Michael reactions with different aryl-substi- hydes to nitroolefins in water. This new catalytic system dis-
tuted nitrostyrenes as well as aliphatic nitroolefins in presence plays remarkable features. Not only does it give excellent
of 5 mol% of the catalyst and 6 eq. of the additive ILS benzoic enantioselectivities and high diastereoselectivities for a wide
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pentanal to trans-β-nitrostyrenesa
Cycle
Time (h)
Yieldb (%)
syn/antic
eed (%)
1
2
3
4
5
6
7
8
9
10
9
20
24
27
28
38
44
45
48
60
96
95
96
94
90
85
70
66
45
46
97 : 3
97 : 3
96 : 4
97 : 3
99 : 1
94 : 6
92 : 8
90 : 10
90 : 10
86 : 14
>99
>99
>99
>99
>99
>99
99
99
98
98
a Reactions performed on 0.4 mmol scale using catalyst 1, acid,
n-pentanal (2 equiv.), and water (0.5 mL). b Yields of isolated product.
c Determined by 1H NMR. d Determined by chiral HPLC.
range of nitroolefins, including aromatic and aliphatic nitro-
olefins, but it can be easily reused for at least 10 times without
significant loss of stereoselectivities. In addition, only 5 mol%
of catalyst and a slight excess of donor aldehydes (2 equiv.) are
required. Moreover, no organic solvent is required except
during the final purification step. These remarkable advan-
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