A Recyclable Organocatalyst for Asymmetric Michael Addition

Article abstract of DOI:10.1007/s10562-016-1693-x

In this study, a new organocatalyst derived from proline was developed and shown to be an efficient catalyst for asymmetric Michael addition reactions of ketones and aldehydes to nitroolefins with high diastereo- and enantioselectivities. (syn;anti up to

Full text of DOI:10.1007/s10562-016-1693-x

Catal Lett
DOI 10.1007/s10562-016-1693-x
A Recyclable Organocatalyst for Asymmetric Michael Addition
1
1
1
1
2
•
Mei Yang
Xiaohui Cao
•
Yuecheng Zhang
1
•
Jiquan Zhao
•
Qiusheng Yang
•
Yi Ma
Received: 5 January 2016 / Accepted: 8 January 2016
Ó Springer Science+Business Media New York 2016
Abstract In this study, a new organocatalyst derived
from proline was developed and shown to be an efficient
catalyst for asymmetric Michael addition reactions of
ketones and aldehydes to nitroolefins with high diastereo-
and enantioselectivities. (syn;anti up to 99:1, ee. up to
9
8 %.). Furthermore, the catalyst is easily recovered and
could be reused six times without significant loss of its
ability to affect the outcome of the asymmetric reactions.
In addition, computational studies at the B3LYP/6-
3
11G(d,p)//6-311 ? G(2dp,f) level was conducted on a
model reaction, and confirmed the following hypotheses:
first, the hydrogen bonding between carboxyl group and
nitro group plays an important role in catalysis, and second,
the energy barrier for re-face attack in reactions of ketones
to form 2S, 3R products is lower than that for the si-face
attack leading to 2S, 3R products.
Keywords Proline Á Asymmetric Michael addition Á
Recyclable Á Computational studies
Graphical Abstract Structural modification of a previ-
ously reported organocatalyst (lead compound in figure)
was used to design an efficient and recyclable organocat-
alyst for asymmetric Michael addition. The introduced
carboxyl group not only enhances the enantioselectivity but
also brings convenience to the recovery of the catalyst.
1
Introduction
Recently, organocatalyzed asymmetric carbon–carbon
bond-forming reactions have received much attention [1–
1
0]. Particularly, the organocatalytic asymmetric Michael
1
reaction of aldehydes and ketones to nitroolefins is a key
reaction in organic synthesis [11–22]. After the pioneering
work of List and Barbas [23–25], many organo-catalysts
derived from proline have been reported to exhibit high
activities and excellent enantioselectivities for this reaction
Electronic supplementary material The online version of this
article (doi:10.1007/s10562-016-1693-x) contains supplementary
material, which is available to authorized users.
[
15, 19, 26–47]. However, there are some major problems
associated with these catalysts, including that a high cata-
lyst loading (10–30 mol%) is generally required, and they
are hard to recover. These problems limit the widespread
application of the catalysts. The design and synthesis of
highly active, easily recoverable and reusable catalysts
&
Xiaohui Cao
nkallwar@126.com
1
2
School of Chemical Engineering and Technology, Hebei
University of Technology, Tianjin, China
National Key Laboratory of Elemento-Organic Chemistry,
Nankai University, Tianjin, China
1
Special issue on different aspects of organocatalysis in Ref List [4].
123

M. Yang et al.
have been proved to be a significant challenge. Recently,
only limited success has been achieved [17, 41, 48–56].
Although initial strategies toward organocatalyst recycling
using ionic liquid support, fluorous technologies and water-
soluble salts have been developed, some of these catalysts
still have some drawbacks. For example, the expensive
fluorous solvents are required for phase separation [17, 53]
or the addition of new protonic acid is necessary for
reusing [54]. A catalyst overcoming these limitations
would be advantageous. It is well known that structural
modification is a valuable tool in the development of new
catalysts. Recently, we have developed a series of proline-
based reduced dipeptides, which produced by modifica-
tions of dipeptides, as efficient organocatalysts for asym-
metric Michael addition [57]. In this paper, structural
modification of a previously reported organocatalyst 1 [27,
and silica gel (200–300 mesh) was used for flash chro-
matography both purchased from Qingdao Haiyang Chem.
Company, Ltd.
1
13
H and C NMR were recorded on Varian-500 instru-
ments. Chemical shifts were reported in ppm down field
from internal Me Si. All the multiplet patterns assigned the
4
first-order splitting patterns. Mass spectra were recorded
using electrospray ionization (ESI) on LCQ Advanced
MAX Mass instruments. Optical rotations were tested on a
WZZ-3 polarimeter using 10 mL cell with a 1 dm path
length and Autopol II polarimeter using 1 mL cell with a
1 dm path length. HPLC analysis was measured using
Chiralpak AS-H column.
2.2 Preparation of Catalyst
2
8, 36] (Fig. 1, lead compound) was used to design and
2.2.1 (S)-1-(Pyrrolidin-2-ylmethyl) Pyrrolidine-2, 5-dione (3)
prepare an efficient and recyclable organocatlayst for
asymmetric Michael addition.
Succinimide (2.97 g, 30 mmol) and K CO (4.97 g,
3
2
3
1
5
6 mmol) was added to a solution of tosylate 5 (3.89 g,
0 mmol) in 20 ml DMF. The reaction mixture was stirred at
0 °C for 24 h. The mixture was diluted with 60 mL of
2
Experimental Section
water, and the resulted mixture was extracted with CH Cl
2
.1 General Details
2
2
(20 mL 9 3). The combined organic layer was washed with
brine (20 mL 9 2), dried over anhydrous Na SO , and
2
Commercial reagents were used without purification except
for otherwise explanation. Analytical thin layer chro-
matography was performed on 0.20 mm silica gel plates
4
concentrated in vacuo. The residue was chromatographed to
give the intermediate 6. The crude product was dissolved in
EtOH (20 mL), and the 0.1 g Pd/C (10 %) was added. The
reaction mixture was stirred at r.t under 1 atm H overnight.
2
The Pd/C was filtrated and the solution was concentrated in
vacuo. The residue was purified by flash chromatograph on
silica gel to give the desired product 3 as yellowy solid.
D
rt
1
(
0.94 g, 51.6 % yield). ½aŠ = -35.1° (1.01, MeOH), H
NMR (500 MHz, CDCl ) d: 1.32–1.38 (1H, m), 1.66–1.85
3
(3OH, m), 2.17 (1H, br), 2.69 (4H, s), 2.77–2.81(1H, m),
2
.94–2.99 (1H, m), 3.32–3.35 (1H, m), 3.44–3.55 (2H, m).
1
3
C NMR (125 MHz, CDCl ) d: 25.70, 28.39, 30.08, 43.54,
3
?
6.75, 57.32, 177.85. MS (ESI, m/z) 183.1 (M?H ). HRMS
4
?
ESI) calcd for C H N O (M?H ): 183.1128, found:
(
9
15 2 2
183.1131.
2.2.2 (S)-5-Oxo-1-((S)-pyrrolidin-2-ylmethyl) Pyrrolidine-
2-carb-oxylic Acid (4a)
To a stirred solution of N-Boc-L-prolinol 7 (20.1 g,
.1 mol) in dry CH Cl (300 mL) were added pyridinium
0
2
2
˚
chlorochromate (30.0 g, 0.14 mol) and 4 A molecular
sieves (30.0 g). The mixture was stirred at room tempera-
ture over night, then diluted with 300 mL Et O (300 mL).
2
The mixture was filtered through a silica gel G pad and
concentrated in vacuo. The residue was chromatographed
to afford pure 8 as a light yellow oil (15.2 g, 76 %).
Fig. 1 New design of catalyst
1
23

A Recyclable Organocatalyst for Asymmetric Michael Addition
D
rt
1
2
.32–2.49 (3H, m), 3.24 (1H, dd, J = 9.0 Hz, J = 6.5 Hz),
1 2
½
aŠ = -101° (0.66, CHCl ) H NMR(500 MHz, CDCl )
3
3
3
.27–3.33 (2H, m), 3.57 (1H, dd, J1 = 14.5 Hz,
d: 1.37 (5H, s),1.42 (4H, s),1.76–2.15 (4H, m), 3.44 (2H,
m), 4.00–4.15 (1H, m),9.41 (0.6H, d), 9.50 (0.4H, br).
1
3
J = 4.0 Hz), 4.12 (1H, t, J = 8.0 Hz), 4.35–4.40 (1H, m).
2
C
1
3
C NMR (125 MHz, CD OD) d: 24.22, 24.39, 28.24, 30.20,
NMR (125 MHz, CDCl ) d: 23.89, 24.58, 27.91, 28.21,
8.33, 46.47, 46.80, 64.82, 64.98, 76.80, 77.12, 77.43,
0.11, 80.51, 154.86, 200.29, 200.55.
3
3
4
4.99, 46.34, 48.84, 56.46, 64.50, 178.19, 178.97. MS (ESI
2
8
?
m/z): 213.2 (M?H ). HRMS (ESI) calcd for: C H N O
10 17
2
3
?
M?H ), m/z 213.1328, found 213.1325.
(
To a solution of 8 (2.0 g, 10 mmol) in 20 mL MeOH was
˚
added L-aspartic acid dimethyl ester(2.1 g, 12 mmol), 4 A
molecular sieves (2.0 g) and Pd/C (wet, 5 %, 0.2 g). The
reaction mixture was stirred at room temperature under 1 atm
2.3 General Experimental Procedure
for the Michael Addition
H until the TLC (EtOAc: Petroleum ether = 1:1) showed that
2
2
.3.1 General Experimental Procedure for the Michael
8
had disappeared and intermediate 9 had generated. The
mixture was filtered to remove the catalyst, then TsOH
0.34 g, 2 mmol) was added into the filtrate. The mixture
Addition of Cyclohexanone to Nitroalkene by Chiral
Catalyst 2 and 3
(
refluxed for 24 h, then concentrated in vacuo. The residue
To a solution of the amide catalyst (0.1 mmol), TFA
(0.1 mmol) and the nitroalkene (0.5 mmol) in solvent
was purified by chromatograph to afford product 10 as a light
D
1
yellow oil. ½aŠ = 36.51° (0.1, MeOH) H NMR(500 MHz,
rt
(1 mL) was added cyclohexanone (5 mmol), and the solution
CDCl ) d: 1.44(9H, s), 1.80–1.97 (4H, m), 2.12 (1H, m),
3
was stirred at ambient temperature until TLC showed the
nitroalkene disappeared. Ethyl acetate (10 volumes) was
added. The solution was washed with water and 1 N HCl,
dried (Na SO ) and concentrated to give the crude product
2
3
4
2
7
.36–2.50 (3H, m) 2.95–3.02 (1H, m), 3.30–3.37 (2H, m),
.68–3.73 (1H, m), 3.77 (3H, s), 3.83–3.95 (1H, m),
1
3
.26–4.35 (1H, m). C NMR (125 MHz, CDCl ) d: 22.53,
3
2
4
3.36, 28.44, 29.20, 29.67, 45.58, 46.20, 52.42, 55.12, 59.42,
which was purified by flash chromatography on silica gel.
Relative and absolute configurations of the products were
1
determined by comparison with the known H NMR, chiral
6.71, 77.02, 77.34, 79.58, 154.71, 172.24, 175.62.
10 (2.3 g, 6 mmol) was dissolved in MeOH 20 mL.
NaOH aqueous solution (1 M, 12 mL) was added into the
solution. After stirring for 2 h, the mixture was acidified with
HPLC analysis, and optical rotation values.
1
M HCl (pH = 4–5) and the solvent was removed in vacuo.
2
.3.2 General Experimental Procedure for the Michael
Addition of Cyclohexanone to Nitroalkene by Chiral
Catalyst 4a and 4b
The residue was added into 20 mL CH Cl and the slurry
2
2
chilled to 5 °C, then was added 10 mL TFA. The mixture
stirred until TLC showed the starting material disappeared.
After removed the solvent in vacuo, the residue was dis-
To a solution of the catalyst (0.075 mmol) in MeOH
0.5 mL) was added cyclohexanone (2.5 mmol) and the
solved in 30 mL H O. The aqueous solution was neutralized
2
(
with NaHCO , and then poured into a column with cation
3
nitroalkene (0.5 mmol). The solution was stirred at ambient
temperature until TLC showed the nitroalkene disappeared.
The mixture was concentrated and the residue diluted by
exchange resin (30 g). The target compound 4a was washed
off by 2 N aqueous ammonia then purified by chromato-
D
1
graph. (0.95 g, 74 %). ½aŠ = -40.1° (1.0, MeOH) H NMR
rt
1
mL mixture solvent (ethyl acetate: petroleum ether = 1:1)
(
500 MHz,CD OD) d: 1.71–1.79(1H, m), 1.98–2.18 (4H, m),
3
to precipitate the catalyst. The catalyst was recovered by
filter and washed with petroleum ether. The filtrate was
concentrated to give crude product which was purified by
chromatography on silica gel. Compounds 13a–i reported in
Table 2 (entries 1–9) are known in literature and our
spectroscopic data are in agreement with published data.
2
3
.31–2.42 (2H, m), 2.44–2.51 (1H, m), 3.23–3.28 (1H, m),
.33–3.38 (1H, m), 3.48 (1H, dd, J1 = 14.5 Hz,
J = 3.5 Hz), 3.72–3.77 (1H, m), 3.82 (1H, m), 4.07–4.09
2
1
3
(
1H, m). C NMR (125 MHz, CD OD) d: 24.13, 25.59,
3
2
8.67, 30.84, 45.42, 45.98, 61.00, 65.98, 178.16, 179.10. MS
?
ESI m/z): 213.2 (M?H ). HRMS (ESI) calcd for:
(
?
C H N O (M?H ), m/z 213.1328, found 213.1323.
1
0 17 2 3
2.4 Computational Details
2
.2.3 (R)-5-Oxo-1-((S)-pyrrolidin-2-ylmethyl) Pyrrolidine-
-carb-oxylic Acid (4b)
DFT calculations were carried out with the Gaussian 09
package [58]. The transition structure are fully optimized
by B3LYP [59–61] method using 6-311G(d,p) basis set.
Frequency calculations were performed at the same level
on all optimized geometries to ensure only positive
eigenvalues for minima and one negative imaginary fre-
quency for transition states. The transition state was further
2
The catalyst 4b was synthesized from D-aspartic acid
dimethyl ester utilizing the similar procedure of 4a.
D
1
½
aŠ = ?91.4° (1.0, MeOH) H NMR(500 MHz, CD OD)
rt
3
d: 1.68–1.75(1H, m), 1.97–2.09 (3H, m), 2.15–2.22 (1H, m),
123

M. Yang et al.
Scheme 1 Preparation of the
catalysts
verified by the connectivity between the reactant and
transition sate confirmed by intrinsic reaction coordinate
ortho-carbonyl may hinder the N atom from moving to the
appropriate position for forming the hydrogen bond.
In order to understand the effect of the carbonyl, amide
3 (Fig. 1) was prepared and employed to catalyze the
model reaction. Interestingly, catalyst 3 afforded better
enantio-selectivity (93 % ee, Table 1, entry 6) than the lead
compound 1. This encouraging result implies that the
strategy of introducing more potential hydrogen bond
acceptors works. A comparison of 2 and 3 indicates that it
is the steric effect of the ortho-carbonyl that is responsible
for hindering the enantioselectivity.
(
IRC) [62] calculation. The single point energy is recal-
culated by B3LYP method using 6-311 ? G(2dp,f) basis
set on the optimized geometries. All the energies discussed
in the paper are Gibbs free energies unless otherwise
specified.
3
Result and Discussion
In previous studies, the hydrogen bond was used as a
general strategy for designing the new catalyst [17, 63–66].
The common transition state TS1 (Fig. 1) shows that
hydrogen bonding is an important factor in forming a
favorable transition state. Inspired by this, derivatives of
the lead compound 2–4b, which contain more hydrogen
Although amide 3 afforded good yield and a high level of
diastereo- and enantioselection, it is very difficult to recover
this catalyst because the added acid makes the reaction system
much more complicated. When amide 2 or 3 was used to
catalyze the reaction without a protonic acid, the Michael
productwasnotobtained(Table 1, entries1,3,5,7), becausea
large amount of polymerized 12 was quickly formed under
these conditions. Other studies have indicated that amines
behave as polymerization initiators [68], and Barbas’s group
has reported that the addition of Brønsted acids can promote
the formation of enamines and thus inhibit polymerization
[69]. Therefore the use of catalysts containing carboxyl group
might be a way to simplify the reaction system [57]. The
introduced carboxyl groups could take the place of the added
Brønsted acid as a hydrogen donor. In addition, the carboxyl
group and the secondary amine can form an inner salt, which
should enhance the aqueous solubility of the catalyst and thus
provide easy recovery of the catalysts. To test this hypothesis,
derivatives 4a–b were prepared and their catalytic perfor-
mance in the model reaction was examined. The model
reaction proceeded effectively in methanol in the presence of
2
acceptor or donor groups were prepared [67] as shown in
Scheme 1, and evaluated for the model Michael addition
reaction of cyclohexanone 11 to nitrostyrene 12. The rep-
resentative results are summarized in Table 1 text
(
although the first paragraph and paragraphs that follow
headings should not be indented).
Derivative 2 was designed because the oxygen atom of
the carbonyl group adjacent to the chiral center might
provide an extra hydrogen bond acceptor. Unfortunately, it
yielded poorer enantioselectivity (36 % ee, Table 1, entry
2
) than that of the lead compound (84 % ee) [36]. Thus, the
carbonyl group has a negative impact on the enantiose-
lectivity. Two possible reasons are: the carbonyl group
decreases the electron density on the N atom and thus
weakens the hydrogen bond, or the steric effect of the
2
0 mol% 4a without any additives, with a high yield (93 %),
an excellent diastereoselectivity of 99:1 (syn:anti) and an
2
The Catalyst 2 was prepared according to the Ref Asami [67].
1
23

A Recyclable Organocatalyst for Asymmetric Michael Addition
Table 1 Results of the model reaction
a
b
c
d
Entry
Cat.
Mol (%)
Solvent
Additive
Time (h)
Yield
Syn/anti
ee(syn)
1
2
3
4
5
6
7
8
9
2
20
20
20
20
20
20
20
20
20
15
5
DMSO
DMSO
MeOH
MeOH
DMSO
DMSO
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
–
–
–
–
–
2
TFA
48
–
86 %
–
93:7
–
36 %
–
2
–
2
TFA
48
–
73 %
–
95:5
–
31 %
–
3
–
3
TFA
48
–
90 %
–
96:4
–
93 %
–
3
–
3
TFA
48
48
72
144
72
168
78 %
93 %
91 %
90 %
97:3
99:1
99:1
99:1
–
86 %
97 %
97 %
97 %
–
4a
4a
4a
4a
4b
–
–
–
–
–
10
11
12
13
a
1
Trace
67 %
20
98:2
93 %
5
eq ketone used
b
Yields of isolated product after column chromatography
1
Determined by H NMR analysis of the crude product
c
d
Enantioselectivities were determined for syn-product by chiral-phase HPLC analysis (Daicel Chiralpak AS-H)
enantio-selectivity of 97 % ee (Table 1, entry 9). The catalyst
loading could be reduced to 15 or 5 mol% to get similar
results, butalongerreactiontimewasneeded(Table 1, entries
As demonstrated in Table 3, catalyst 4a can be applied to
several Michael reactions for a variety of carbonyl com-
pounds and nitroolefins in MeOH. Cyclohexanone effi-
ciently underwent Michael reactions with different aryl-
substituted nitroolefins to give Michael adducts 13a–h in
high yields with excellent enantio-(91–98 % ee) and
diastereoselectivities (syn/anti ratio up to[20:1). The results
in Table 3 also show that the nature of the substituents on
aryl groups slightly influences the yields and enantio-se-
lectivities. For nitroolefins with electron-rich groups (methyl
and methoxyl), the reaction proceeded smoothly to afford
Michael adduct 13b–c in excellent enantio- (91–98 % ee)
and diastereoselectivities (syn/anti[ 20:1) (Table 3, entries
2–3). For nitroolefins with electron-deficient groups, the
Michael adducts 13d–g were also obtained in high yields
(87–93 %) with excellent enantio- (95–98 % ee) and
diastereoselectivities (syn/anti ratio up to [20:1) (Table 3,
entries 4–7). In addition, 3-pentanone and n-butyraldehyde
are also suitable Michael donor with high diastereoselec-
tivity as well as enantios (Table 3, entries 8 and 9). We also
tested the aliphatic nitroolefin as Michael reaction substrate
but only give the moderate enantioselectivity (76 % ee,
Table 3, entry 10).These results indicate that catalyst 4a
should be broadly plicable to the synthesis of c-nitro car-
bonyl compounds.
1
0 and 11). When the loading was further reduced to 1 mol%,
the reaction was too slow to be detected (Table 1, entry 12).
Interestingly, the diastereo-isomer 4b led to lower yield
(
67 %) and slightly decreased enantioselectivity (93 % ee),
even with a prolonged reaction time of 168 h. (Table 1, entry
3).
The addition of cyclohexanone to trans-b-nitrostyene was
used as a model to examine the recyclability of the catalyst
a (at 20 mol%). After the reaction was completed, the
1
4
reaction mixture was concentrated and the residue was
diluted with a mixture solvent (ethyl acetate: petroleum
ether = 1:1) to precipitate the catalyst, which was easily
recovered by filtration. The first time recovered catalyst was
1
characterized by H NMR to confirm that the structure did
not change after the reaction. The recovered catalyst was
used for the next run of the reaction. As shown in Table 2,
catalyst 4a can be recycled and reused for at least six times
without a significant loss of stereoselectivity (ee[ 95 %)
although the catalytic activity decreased gradually.
The scope of the Michael reactions using catalyst 4a in
MeOH was examined with a variety of carbonyl com-
pounds and nitroolefins (Table 3).
123

M. Yang et al.
Table 2 Recycling studies of 4a catalyzed Michael addition of
cyclohexanone to trans-nitrostyrene
4 Computation Studies
To gain a more detailed understanding of the origin of the
high enantio- and diastereoselectivity of the processes
catalyzed by 4a, we have computationally studied the
transition states by density functional theory (DFT) at the
B3LYP/6-311G(d,p) level. The geometric and energetic
parameters of possible transition states are listed in Table 3
and structures are displayed in Fig. 2.
a
b
c
d
Cycle
T (h)
Yield (%)
ee (%)
Syn:anti
1
2
3
4
5
6
48
48
48
60
72
90
93
91
88
84
80
75
97
96
96
97
97
95
99:1
99:1
99:1
98:2
99:1
97:3
As show in Scheme 2, the enamine intermediates can
adopt anti and syn conformations, For each of them, two
different transition states exist for the approach of the
nitropropene to the diastereotopical Re and Si faces of the
enamine, resulting in the formation of four different tran-
sition states, two for each enantiomer (Fig. 2). The two
transition states arising from the anti enamine (TSA and
The reaction was conducted with 20 mmol of 12 and 100 mmol of 11
in 2 mL of solvent at room temperature
1
The first recovered catalyst was characterized by HNMR
TS ) can benefit from hydrogen-bonding activation
B
a
b
c
d
between the carboxyl group and the nitro group, and our
initial hypothesis was that this interaction might contribute
to a lowering in the energy barriers, resulting in faster
reaction rates. Meanwhile, reaction through syn-enamine
conformations would occur without the help of hydrogen-
bonding activation (TS and TS ). As shown in Table 4,
Yields of isolated products
Determined by Chiral HPLC
1
Determined by H NMR
The stereochemical results may be explained by the
C
D
transition state (Favorable TS) shown in Scheme 2. Similar
to the protonated nitrogen atom in TS1, the carboxyl group
hydrogen bonds with the nitroalkene to keep it in a
favorable position for the approach of the nitroalkene from
the re face of the anti-enamine.
we found that the lowest in energy (9.8 kcal/mol) corre-
sponds to TS , the one that leads to the experimentally
A
observed 2S, 3R enantiomer. According to our initial
hypothesis, this result shows the COOH delivers the
nitroalkene by hydrogen bonding thus favours the approach
Table 3 Michael reactions of ketones to nitroolefins
b
c
d
Entry
R1
R2
R3
Product
Yield (%)
Syn:anti
ee (%)
1
2
3
–(CH
–(CH
–(CH
2
)
2
)
2
)
4
–
4
–
4
–
Ph
13a
13b
13c
91
90
80
[20:1
[20:1
20:1
97
98
91
4-Me-Ph
4-OMe-
Ph
4
5
6
7
8
9
–(CH
–(CH
–(CH
–(CH
2
2
2
2
)
)
)
)
4
4
4
4
–
–
–
–
4-Cl-Ph
2-Cl-Ph
2,4-Cl-Ph
13d
13e
13f
13g
13h
13i
91
87
92
93
78
90
85
[20:1
[20:1
[20:1
[20:1
[20:1
[20:1
[20:1
95
97
98
97
90
82
76
2-NO
Ph
2
-Ph
Et Me
H n–Pr
–(CH
Ph
1
0
2
)
4
–
n-Bu
13j
Unless otherwise noted, the reaction was conducted with 5 mmol of 12 and 25 mmol of 11 in 1 mL of solvent at room temperature
b
Yields of isolated products
c
1
Determined by H NMR
d
Determined by Chiral HPLC
1
23

A Recyclable Organocatalyst for Asymmetric Michael Addition
Scheme 2 The proposed
mechanism and transition state
C3
C2
TS
A
(anti-Re)
TS
B
(anti- Si)
TS
C
(syn-Re)
TS
D
(syn- Si)
Product (2S, 3R)
Product (2R, 3S)
Product (2S, 3R)
Product (2R, 3S)
Fig. 2 Transition-state geometries for the reaction between 11 and 12 catalyzed by 4a, calculated at B3LYP/6-311G(d,p) level
Table 4 The geometric and energetic parameters of transition states
a
˚
Istances (A) COOH—O=N=O
Enamine conformation
Attack
Product
Ea (DDG) (Kcal/mol)
DC2–C3
TS
TS
TS
TS
a
A
B
C
D
anti
anti
syn
syn
Re
Si
2S, 3R
2R, 3S
2S, 3R
2R, 3S
9.8
2.14
2.17
1.99
2.04
1.59
1.67
–
12.7
14.1
21.1
Re
Si
–
Ea(DDG) = DG(TS) - DG(Reactant). Activation energy, the geometries are optimized at B3LYP/6-311G(d,p) level and the frequencies
calculations are performed at the same level, single point energies are recalculated at B3LYP/6-311 ? G(2df,p) level
123

M. Yang et al.
9. Diez D, Gil MJ, Moro RF, Marcos IS, Garcı
Garrido NM, Broughton HB, Urones JG (2007) Tetrahedron
3:740
´
a P, Basabe P,
of nitroalkene from the re face of the anti-enamine. The
minor enantiomer 2R, 3S is formed through a Si approach
6
of the nitro alkene to the anti enamine (TS ), whose acti-
B
1
0. Lu A, Wu R, Wang Y, Zhou Z, Wu G, Fang J, Tang C (2011) Eur
J Org Chem 122:3507
vation energy is 12.7 kcal/mol. The different activated
barriers between TSA and TS should be considered that
B
11. Berner OM, Tedeschi L, Enders D (2002) Eur J Org Chem
12:1877
˚
TS has the stronger hydrogen bond than TS (1.59 A vs
A
B
1
1
2. Krause N, Hoffmann-R o¨ der A (2001) Synthesis 1:171
3. Tsogoeva SB (2007) Eur J Org Chem 11:1701
˚
.67 A, Table 3). Meanwhile, reaction through syn-
1
enamine conformations (TSC and TS ) cannot benefit
D
14. Almasi D, Alonso DA, N a´ jera C (2007) Tetrahedron Asymmetry
18:299
from hydrogen bonding (Fig. 1). Therefore, their activa-
tion energies are much higher than those of their acti-
1
1
5. Cao CL, Ye MC, Sun XL, Tang Y (2006) Org Lett 8:2901
6. Freund M, Schenker S, Tsogoeva SB (2009) Org Biomol Chem
vated counterparts (activation energy: TS [ TSA and
C
7
:4279
17. Zu L, Wang J, Li H, Wang W (2006) Org Lett 8:3077
TS [ TS , Table 4).
D
B
1
1
2
8. Lu AD, Gao P, Wu Y, Wang YM, Zhou ZH, Tang CC (2009) Org
Biomol Chem 7:3141
9. Wang J, Li H, Lou B, Zu L, Guo H, Wang W (2006) Chem Eur J
5
Conclusion
1
2:4321
0. Lu A, Wu R, Wang Y, Zhou Z, Wu G, Fang J, Tang C (2010) Eur
J Org Chem 2010:2057
1. Chen JR, Lai YY, Lu HH, Wang XF (2009) Tetrahedron 65:9238
2. Cao YJ, Lu HH, Lai YY, Lu LQ, Xiao WJ (2006) Synthesis
In summary, a novel organocatalyst 4a which can be used to
promote highly efficient asymmetric Michael addition
reactions of ketones and aldehydes to nitroolefins has been
developed. The main advantages of this catalyst are ease of
synthesis and low loading (5 mol%) for high steroselectiv-
ities (ee up to 98 %, syn/anti up to 99/1) at room tempera-
ture. Moreover, the catalyst is easily recovered and reused.
These advantages make 4a a potential catalyst for industrial
applications. Computational studies at the B3LYP/6-
2
2
2
2:3795
23. List B, Pojarliev P, Martin HJ (2001) Org Lett 3:2423
24. Betancort JM, Barbas CF III (2001) Org Lett 3:3737
2
2
5. Enders D, Seki A (2002) Synlett 1:26
6. Ishii T, Fujioka S, Sekiguchi Y, Kotsuki H (2004) J Am Chem
Soc 126:9558
27. Mase N, Thayumanavan R, Tanaka F, Barbas CFIII (2004) Org
Lett 6:2527
2
8. Betancort JM, Sakthivel K, Thayumanavan R, Tanaka F, Barbas
CFIII (2004) Synthesis 9:1509
9. Alexakis A, Andrey O (2002) Org Lett 4:3611
3
11G(d,p) level have been conducted on a model reaction,
confirming the initial hypothesis that the hydrogen bonding
between carboxyl group and nitro group plays an important
role in the activation of the nitro alkene and helps to dis-
criminate between the two diastereofacial approaches. The
computational results, which are in good agreement with the
experimental observations, are discussed in the context of
the stereochemical course of these Michael addition reac-
tions. These results provide valuable insight into the mech-
anisms of asymmetric organocatalysis and might help the
design of new and more efficient organocatalysts.
2
30. Andrey O, Alexakis A, Tomassini A, Bernardinelli G (2004) Adv
Synth Catal 346:1147
3
1. Cobb AJA, Longbottom DA, Shaw DM, Ley SV (2004) Chem
Commun 16:1808
2. Cobb AJA, Shaw DM, Longbottom DA, Gold JB, Ley SV (2005)
Org Biomol Chem 3:84
3
33. Reyes E, Vicario JL, Badia D, Carrillo L (2006) Org Lett 8:
135
3
3
36. Mase N, Watanabe K, Yoda H, Takabe K, Tanaka F, Barbas
CFIII (2006) J Am Chem Soc 128:4966
6
4. Wang W, Wang J, Li H (2005) Angew Chem Int Ed 44:1369
5. Pansare SV, Pandya K (2006) J Am Chem Soc 128:9624
Acknowledgments This work was supported by Supported by
National Natural Science Foundation of China (No. 21306038) and
Natural Science Foundation of Hebei Province (No. B2013202216).
37. Vishnumaya, Singh VK (2007) Org Lett 9:1117
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