A novel recyclable organocatalytic system for the highly asymmetric michael addition of aldehydes to nitroolefins in water

Article abstract of DOI:10.1055/s-0030-1260465

A novel strategy for the asymmetric Michael addition of aldehydes to nitroolefins with a catalytic system of organocatalyst 1 in combination with ionic-liquid-supported (ILS) benzoic acid in water has been developed. The Michael adducts of this system giv

Full text of DOI:10.1055/s-0030-1260465

PAPER
1993
A Novel Recyclable Organocatalytic System for the Highly Asymmetric
Michael Addition of Aldehydes to Nitroolefins in Water
A
symmetric Micha
h
el
A
ddition
r
of
A
ldeh
u
yde
s
to
N
itro
b
olefins a Sarkar, Ramesh Bhattarai, Allan D. Headley,* Bukuo Ni*
Department of Chemistry, Texas A & M University-Commerce, Commerce, Texas 75429-3011, USA
Fax +1(903)4686020; E-mail: allan_headley@tamu-commerce.edu; E-mail: bukuo_ni@tamu-commerce.edu
Received 9 March 2011
To overcome these problems, the development of water-
soluble recyclable organocatalysts is highly desirable to
expand the various applications of organocatalysis and
also to address important issues, such as the development
Abstract: A novel strategy for the asymmetric Michael addition of
aldehydes to nitroolefins with a catalytic system of organocatalyst
1 in combination with ionic-liquid-supported (ILS) benzoic acid in
water has been developed. The Michael adducts of this system give
excellent diastereo- and enantioselectivities. A notable feature of of environmentally benign catalysts that have practical
this organocatalytic system is that the catalyst can be recycled more
and industrial applications. One aspect of our research in-
than 12 times without significant loss of enantioselectivity. In addi-
volves the development of environmentally unique orga-
tion, the synthetic methodology presented is simple, practical, and
nocatalysts for asymmetric organic reactions in water.4
environmentally benign.
We have recently reported for the first time the develop-
ment and use of diarylprolinol silyl ether 1 as a water-sol-
uble organocatalyst for the highly asymmetric Michael
Key words: aldehydes, asymmetric catalysis, green chemistry, ion-
ic liquids, Michael addition
addition of aldehydes to nitroolefins in water with high
enantioselectivity; the catalytic system is easily recycled
from the product by separation of the aqueous phase.4b
However, such a system has the disadvantage that it re-
quires the addition of the co-catalyst benzoic acid (10
equiv of catalyst) in each cycle and since benzoic acid and
the organic products are both soluble, separation of the
products from the catalytic system is extremely diffi-
cult.2o,5 To further optimize the catalytic system, we now
report on the use of diarylprolinol silyl ether 1 in combi-
nation with the easily prepared ionic-liquid-supported
(ILS) benzoic acid as an effective, water-soluble, and re-
cyclable organocatalyst in water (Scheme 1). The new
catalyst system can be used for the asymmetric Michael
addition of aldehydes to nitroolefins to afford the Michael
adducts with high diastereo- and enantioselectivities.
Most important is that the new catalyst can be recovered
and reused for at least 10 times without a significant loss
of its ability to affect the outcome of the asymmetric in-
duction.
Asymmetric organocatalysis that can be performed in wa-
ter has received growing attention and has become a very
active field of research in recent years. Owing to the
unique physical properties of water, it is a desirable medi-
um, in which various reactions can be carried out since it
is an environmentally safe liquid and also relatively
cheap.1 Many water-compatible asymmetric organocata-
lysts have been developed and applied to a wide range of
organic transformations, in which the asymmetric prod-
ucts are obtained with high stereoselectivities.2 These or-
ganocatalysts typically have a common feature in that
they were specifically designed as water-insoluble and
contain large hydrophobic groups, which accurately serve
as ‘concentrated organic phase’ and assemble with hydro-
phobic reactants in water and sequester the formation of
transition state from water.3 The basic problem associated
with these organocatalytic systems, however, is the sepa-
ration of the product phase from the catalyst, which is sol-
uble. In addition, large catalytic amounts, typically 10–30
mol% are normally used, and the catalysts are typically
very difficult to separate and recycle for further use.
The ILS benzoic acids 3 and 4a,b with an imidazolium
cation and bromide, PF6, or NTf2 anions were synthesized
Me
Me
N
NH+
Me
Me
CO2H
X–
X–
Me
NH+
Me
Me
X–
N
N+
Me
n-Bu
N
X = Br, PF6, or NTf2
N
N
OTMS
OTMS
catalytic system
H
H
1
Scheme 1 New design of water-soluble recyclable organocatalysts
SYNTHESIS 2011, No. 12, pp 1993–1997
x
x.
x
x
.
2
0
1
1
Advanced online publication: 13.05.2011
DOI: 10.1055/s-0030-1260465; Art ID: C26011SS
© Georg Thieme Verlag Stuttgart · New York

1994
D. Sarkar et al.
PAPER
CO2Me
EtOAc
CO2Me
+
N
N
r.t., 2 h, 92%
N
N+
n-Bu
Br
n-Bu
Br–
2
CO2H
CO2H
KPF6 or LiNTf2
H2O
HCl
reflux, 4 h, 94%
N+
X–
N
N+
N
n-Bu
n-Bu
Br–
3
4a: X = PF6, 92%
4b: X = NTf2, 90%
Scheme 2 Synthesis of ionic liquid-supported benzoic acid
Table 1 Optimization of the Michael Reaction Conditionsa
by a sequence of reactions, which includes the alkylation
of 1-butylimidazole with methyl 4-(bromomethyl)ben-
zoate, hydrolysis of ester 2 in concentrated HCl, followed
by the transformation of bromide 3 into PF6 4a or NTf2 4b
by anion exchange in water (Scheme 2). Total yields of
compounds 3 and 4a,b were 78–86%.
Ph
O
Ph
NO2
NO2
catalyst 1 (3 mol%)
H
+
acid, H2O, r.t.
n-Pr
7a
O
n-Pr
H
6a
With ILS benzoic acids 3 and 4a,b in hand, we started
testing their efficiency as additives in combination with
organocatalyst 1 for the Michael addition of n-pentanal to
trans-b-nitrostyrene in water, using 3 mol% catalyst load-
ing in the presence of 2 equivalents of aldehyde. Repre-
sentative results are summarized in Table 1. Initially, the
Michael addition reaction was conducted in water with 30
mol% of ILS benzoic acid 4a as additive. The reaction
displayed an outstanding activity and selectivity, and the
Michael product 7a was obtained in 98% yield with dia-
stereoselectivity of 94:6 (syn/anti) and enantioselectivity
of 98% ee after five hours at room temperature (Table 1,
entry 1). When the amount of 4a was decreased from 30
mol% to 21 mol%, the reaction gave comparable yield and
diastereo- and enantioselectivities (Table 1, entry 2). In a
comparison using the same amount of non-supported ben-
zoic acid versus ILS benzoic acid as additive, the ILS ben-
zoic acid gave superior results with respect to the reaction
time and selectivities (5 h vs 24 h; dr: 96:4, ee: 99% vs dr:
94:6, ee: 97).4b These results indicate an important role of
the ionic liquid moiety, which can increase the catalytic
activity and selectivity. By further decreasing the amount
of additive 4a from 21 mol% to 15 mol%, 9 mol%, and 6
mol%, respectively, comparable yields and enantioselec-
tivities were obtained. However, the diastereoselectivies
dropped gradually and prolonged reaction time was need-
ed, especially in the use of 3 mol% ILS 4a (Table 1, en-
tries 3–6). It was found that in the presence of ILS 3 and
4b where the anions are bromide and NTf2, respectively,
the reaction either gave very poor reactivity or relative
lower stereoselectivity, compared to those obtained when
ILS 4a with PF6 as anion was used (Table 1, entries 7, 8).
The absolute stereochemistry of major syn product 7a was
determined to be 2R,3S by comparing its optical rotation
with literature values.6 The absolute stereochemical re-
sults can be explained by the transition-state models pre-
viously discussed for (S)-diphenylprolinol silyl ether
catalyzed Michael reactions.5
Entry
Acid
Amount of Time
acid (%) (h)
Yield
(%)b
syn/antic ee
(%)d
1
2
3
4
5
6
7
8
4a
4a
4a
4a
4a
4a
3
30
21
15
9
5
5
98
97:3
96:4
93:7
88:12
82:18
79:21
–
98
97
99
99
97
98
99
–
5
98
5
97
6
5
98
3
7
97
21
21
48
7
trace
88
4b
95:5
96
a Reactions performed on 0.5 mmol scale using catalyst 1, acid, n-pen-
tanal (2 equiv), and H2O (0.5 mL).
b Isolated yields of pure product.
c Determined by 1H NMR spectroscopy.
d Determined by chiral HPLC of the syn product.
Next, the recyclability of catalytic system (5 mol% of cat-
alyst 1 and 35 mol% of additive ILS benzoic acid 4a were
used) was studied in a reaction of n-pentanal with trans-
b-nitrostyrene. Upon completion of the reaction, the reac-
tion mixture was extracted two times with diethyl ether.
The product was obtained by simple evaporation of the di-
ethyl ether phase and further purification by flash silica
gel chromatography. The recovered aqueous phase was
used again for the next cycle directly by addition of the
new reactants n-pentanal and trans-b-nitrostyrene. As
shown in Table 2, the catalyst 1 catalytic system could be
recovered and reused for at least 11 times without any loss
of enantioselectivity (99% ee) despite slightly prolonged
reaction times were needed after cycle 5. The observation
of the gradual drop in activity and diastereoselectivity of
catalyst could be explained by catalyst’s leaching into the
organic solvent (Et2O) or by its transformation into cata-
lytically less-active desilylated compound.7 However,
Synthesis 2011, No. 12, 1993–1997 © Thieme Stuttgart · New York

PAPER
Asymmetric Michael Addition of Aldehydes to Nitroolefins
1995
these results demonstrate that catalyst 1 in combination hydes, such as n-hexanal, n-hepanal, and n-nonanal, can
with additive 4a is the best recyclable organocatalytic sys- be all employed successfully as the Michael donors to af-
tem developed so far for the asymmetric Michael reac- ford the products 7a–d in excellent yields (95–98%) and
tions between aldehydes and nitroolefins in water with stereoselectivities (syn/anti: up to 97:3, 99% ee) except
excellent stereoselectivities as well as a very simple, prac- that a longer reaction time is required for the long-chain
tical, and green procedure for catalytic system recovery. n-nonanal (Table 3, entries 1–3 vs entry 4). An aldehyde
In contrast, other recyclable chiral organocatalysts, such bearing a substituent on the b-position also provided prod-
as polymer-supported pyrrolidine and fluorous pyrroli- uct 7e in high yield with near optical purity (Table 3, entry
dine sulfonamide, which have been used to catalyze this 5). Nitroolefins bearing both electron-deficient and elec-
reaction in aqueous medium, all have the disadvantage of tron-rich aromatic substituents were excellent Michael ac-
requiring high catalyst loading (10–20 mol%) and the use ceptors for n-pentanal (Table 3, entries 6–8). The
of large excess of aldehydes (5–20 equivalents).8 In addi- heteroaromatic nitroolefin was also a suitable substrate as
tion, low catalytic activity and enantioselectivities (48– Michael donor affording the product 7i in excellent stereo-
62% ee) were observed for these systems since heteroge- selectivity and yield (Table 3, entry 9). Furthermore, cat-
neous reaction conditions6a or expensive fluorous solvents alyst 1 is also highly effective for Michael addition of
were required for phase separation.6b
aldehyde to aliphatic nitroolefin at room temperature for
five hours providing product 7j in good yield and excel-
lent stereoselectivities (syn/anti: 95:5, 99% ee) (Table 3,
entry 10).
Table 2 Recycling Studies of Water-Soluble 1 Catalyzed Michael
Addition of n-Pentanal to trans-b-Nitrostyrenea
Ph
O
Ph
NO2
Table 3 Organocatalytic Asymmetric Michael Reaction Using Al-
NO2
catalyst 1 (3 mol%)
dehydes and Nitroolefinsa
H
+
acid, H2O, r.t.
n-Pr
7a
O
R1
NO2
n-Pr
O
R1
H
5
6a
catalyst 1 (3 mol%)
NO2
H
+
4a (21 mol%), H2O, r.t.
R2
7
Cycle
Time (h)
Yield (%)
syn/anti
96:4
ee (%)
99
O
R2
1
2
5
5
5
5
5
6
8
97
96
95
95
94
94
92
89
88
78
64
55
H
6
96:4
99
Entry R1
R2
Product Time Yield syn/ ee
3
96:4
99
(h)
(%)b antic (%)d
4
95:5
99
1
2
Ph
Ph
Ph
Ph
Ph
n-Pr
7a
7b
5
98
96
95
98
85
85
93
81
91
74
96:4
96:4
96:4
97:3
99
99
99
99
5
95:5
99
n-Bu
5
6
95:5
99
3
n-C5H11 7c
n-C7H15 7d
8
7
95:5
99
4
20
20
24
10
24
5
8
11
16
24
24
30
95:5
99
5
i-Pr
7e
7f
7g
7h
7i
95:5 >99
9
94:6
99
6
4-BrC6H4
n-Pr
95:5
94:6
96:4
99:1
95:5
99
99
99
99
99
10
11
12
93:7
99
7
3-MeOC6H4 n-Pr
4-MeOC6H4 n-Pr
90:10
88:12
99
8
98
9
2-furyl
n-Pr
a Reactions performed on 0.5 mmol scale using catalyst 1, acid 4a, n-
pentanal (2 equiv), and H2O (0.5 mL).
10
n-Bu
Bn
7j
5
a Reactions performed on 0.5 mmol scale of nitroolefin using catalyst
1, acid 4a, aldehyde 6 (2 equiv), and H2O (0.5 mL).
b Isolated yields of pure product.
Based on the excellent results obtained with the model re-
action and the catalytic system in Table 1, the reaction
conditions of entry 2 (Table 1) were chosen to investigate
the scope of the Michael reactions using a range of alde-
hydes and nitrostyrenes in the presence of 3 mol% of cat-
alyst 1. Good to excellent yields and excellent
stereoselectivities were obtained for a variety of alde-
hydes and nitroolefins reacting at room temperature, and
the results are summarized in Table 3. As demonstrated in
Table 3, not only n-pentanal, but also other linear alde-
c Determined by 1H NMR spectroscopy.
d Determined by chiral HPLC of the syn product.
The large-scale (10 mmol) preparation of the Michael
product of n-pentanal to trans-b-nitrostyrene under stan-
dard reaction conditions was also investigated. After the
reaction was completed, the reaction mixture was separat-
ed into two phases. The aqueous layer was removed by the
Synthesis 2011, No. 12, 1993–1997 © Thieme Stuttgart · New York

1996
D. Sarkar et al.
PAPER
13C NMR (100 MHz, CD3OD): d = 168.9, 140.1, 137.6, 132.7,
simple two-phase separation. The organic phase was puri-
fied by flash chromatography on silica gel to give the
131.6, 129.6, 124.2, 124.0, 53.9, 50.8, 48.4, 33.0, 20.4, 13.7.
Michael product in 96% yield with excellent diastereose- HRMS (ESI+): m/z (%) calcd for [C15H19N2O2]+: 259.1446; found:
259.1443.
lectivity (syn/anti: 96:4) and enantioselectivity (99% ee).
Notably, the procedure is green and practical, and no or-
Compound 4a
ganic solvent is required for the workup step.
To a solution of compound 3 (3.0 g, 8.8 mmol) in H2O (5 mL) was
In summary, a highly efficient organocatalyst in combina-
tion with ILS-benzoic acid as a catalytic system for
Michael additions of aldehydes to nitroolefins in water
has been developed. This new catalytic system displays
remarkable features. Not only does it give excellent enan-
tioselectivities and high diastereoselectivities for a wide
range of nitroolefins, including aromatic and aliphatic in-
troolefins, but it can be easily recovered and reused for at
least 12 times without significant loss of stereoselectivi-
ties. In addition, only 3 mol% of catalyst and a slight ex-
cess of donor aldehydes (2 equiv) are required. Moreover,
no organic solvent is required except during the final pu-
rification step and the reaction can be easily scaled up in
which similar results are obtained. These remarkable ad-
vantages make this approach more suitable for practical
use in the fine chemical synthesis. Further studies focus-
ing on the scope of this unique organocatalyst-catalyzed
asymmetric transformations are currently under investiga-
tion and will be reported in due course.
added KPF6 (1.6 g, 8.8 mmol), and the reaction mixture was stirred
for 4 h. White precipitate was formed, which was filtered and dried
under reduced pressure to give the compound 4a; yield: 3.6 g
(92%).
1H NMR (400 MHz, CD3OD): d = 9.02 (s, 1 H), 8.05–8.03 (d,
J = 8.0 Hz, 2 H), 7.64–7.60 (d, J = 15.6 Hz, 2 H), 7.49–7.47 (d,
J = 8.4 Hz, 2 H), 5.47 (s, 1 H), 4.22–3.19 (t, J = 7.6 Hz, 2 H), 1.90–
1.82 (m, 2 H), 1.40–1.30 (m, 2 H), 0.97–0.94 (t, J = 7.6 Hz, 1 H).
13C NMR (100 MHz, CD3OD): d = 169.0, 140.1, 137.5, 132.8,
131.6, 129.5, 124.2, 124.0, 53.6, 50.8, 33.0, 20.4, 13.7.
HRMS (ESI+): m/z (%) calcd for [C15H19N2O2]+: 259.1446; found:
259.1449.
HRMS (ESI–): m/z (%) calcd for [PF6]–: 144.9642; found:
144.9642.
Compound 4b
To a solution of compound 3 (3.0 g, 8.8 mmol) in H2O (5 mL) was
added LiNTf2 (2.5 g, 8.8 mmol), and the mixture was stirred for 5 h
at r.t. A colorless oil was formed, which was extracted with CH2Cl2
(3 × 20 mL). The combined extracts were dried (Na2SO4) and evap-
orated under reduced pressure to give the product 4b; yield: 4.2 g
(89%).
1H NMR (400 MHz, CD3OD): d = 9.04 (s, 1 H), 8.06–8.04 (d,
J = 8.4 Hz, 2 H), 7.65–7.61 (d, J = 14.8 Hz, 2 H), 7.48–7.46 (d,
J = 87.2 Hz, 2 H), 5.47 (s, 1 H), 4.23–4.19 (t, J = 7.2 Hz, 2 H),
1.90–1.82 (m, 2 H), 1.40–1.30 (m, 2 H), 0.97–0.94 (t, J = 7.2 Hz, 1
H).
Commercial reagents were used as received, unless otherwise stat-
ed. Merck 60 silica gel was used for chromatography, and Whatman
silica gel plates with fluorescence UV254 were used for thin-layer
1
chromatography (TLC) analysis. H NMR and 13C NMR spectra
were recorded on a Bruker 400 spectrometer. All the compounds
synthesized Table 3 are known compounds. The relative and abso-
lute configurations of the products were determined by comparison
13C NMR (100 MHz, CD3OD): d = 166.3, 137.3, 134.7, 130.0,
128.9, 126.8, 119.6 (q, J = 319.4 Hz, 1C), 50.9, 48.9, 30.2, 17.7,
10.9.
1
with the known H NMR and 13C NMR spectra and chiral HPLC
analysis.
HRMS (ESI+): m/z (%) calcd for [C15H19N2O2]+: 259.1446; found:
259.1455.
HRMS (ESI–): m/z (%) calcd for [N(SO2CF3)2]–: 279.9173; found:
279.9156.
Compound 2
To a solution of methyl 4-bromomethylbenzoate (3.0 g, 13.1 mmol)
in EtOAc (5 mL) was added n-butylimidazole (1.7 mL, 13.1 mmol).
The reaction mixture was stirred at r.t. for 2 h under exclusion of
moisture. The white solid precipitated formed was filtered and dried
to give 2; yield: 4.0 g (86%).
1H NMR (400 MHz, CD3OD): d = 9.23 (s, 1 H), 8.04–8.02 (m, 2 H),
7.71–7.68 (m, 2 H), 7.54–7.52 (d, J = 4 Hz, 2 H), 5.54 (s, 1 H),
4.27–3.23 (t, J = 8.0 Hz, 2 H), 3.88 (s, 3 H), 1.91–1.84 (m, 2 H),
1.41–1.31 (m, 2 H), 0.98–0.94 (m, 1 H).
Michael Reaction of Aldehydes and Nitroolefins; General Pro-
cedure
Aldehyde 6 (1 mmol), catalyst 1 (7 mg, 0.015 mmol), nitroolefin 5
(0.5 mmol), and ILS benzoic acid 4a (0.105 mmol, 7 times of cata-
lyst 1), and H2O (0.5 mL) were added in a vial at r.t. The reaction
mixture was stirred until complete conversion of the starting mate-
rials (monitored by TLC) and then extracted with Et2O (2 × 4 mL).
The combined organic phases were concentrated under vacuum to
give the crude product, which was purified by flash column chroma-
tography (silica gel, hexane–EtOAc) to afford the Michael adduct.
The syn/anti-ratio was determined by 1H NMR spectroscopy of the
crude mixture and the enantiomeric excess (ee) was determined by
HPLC on a chiral phase (Table 3).
13C NMR (100 MHz, CD3OD): d = 168.9, 140.1, 137.6, 132.7,
131.6, 129.6, 124.2, 124.0, 53.9, 50.8, 48.4, 33.0, 20.4, 13.7.
Compound 3
A solution of compound 2 (4.0 g, 11.2 mmol) in concd HCl (11 mL)
was heated under reflux for 4 h. Then the reaction mixture was
cooled to r.t. and subsequently extracted with Et2O (3 × 5 mL). The
aqueous phase was concentrated under reduced pressure and the
residue was dried in a desiccator to give the product 3; yield: 3.2 g
(94%).
Acknowledgment
1H NMR (400 MHz, CD3OD): d = 9.23 (s, 1 H), 8.04–8.02 (m, 2 H),
7.71–7.68 (m, 2 H), 7.54–7.52 (d, J = 4.0 Hz, 2 H), 5.54 (s, 1 H),
4.27–3.23 (t, J = 8.0 Hz, 2 H), 1.91–1.83 (m, 2 H), 1.41–1.31 (m, 2
H), 0.98–0.94 (t, J = 8.0 Hz, 1 H).
We are grateful to the Robert A. Welch Foundation (T-1460) and
NSF-REU (grant No. 0851966) for financial support of this re-
search.
Synthesis 2011, No. 12, 1993–1997 © Thieme Stuttgart · New York

PAPER
Asymmetric Michael Addition of Aldehydes to Nitroolefins
1997
Y.; Ma, D. W. Angew. Chem. Int. Ed. 2008, 47, 545.
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