Highly enantioselective Michael addition of ketones to nitroolefins with a pyrrolidine-based phthalimide as an enamine-type organocatalyst

Article abstract of DOI:10.1002/ejoc.201101093

A new type of pyrrolidine-based phthalimide and otheranalogous imide catalysts 5a-c were found to be efficient organocatalysts for the asymmetric Michael reaction of ketones to nitroalkenes. After fine optimization of solvents, temperature, and the additi

Full text of DOI:10.1002/ejoc.201101093

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201101093
Highly Enantioselective Michael Addition of Ketones to Nitroolefins with a
Pyrrolidine-Based Phthalimide as an Enamine-Type Organocatalyst
Shu-rong Ban,*[a][‡] Hong-yu Xie,[a][‡] Xi-xia Zhu,[a] and Qing-shan Li*[a]
Keywords: Organocatalysis / Diastereoslectivity / Enantioselectivity / Michael addition / Nitroalkenes / Chirality
A new type of pyrrolidine-based phthalimide and other
analogous imide catalysts 5a–c were found to be efficient or-
ganocatalysts for the asymmetric Michael reaction of ketones
to nitroalkenes. After fine optimization of solvents, tempera-
ture, and the additive, good to excellent enantioselectivities
and diastereoselectivities (up to 99% ee, up to Ͼ99:1 dr) can
be achieved.
the asymmetric Michael reaction of ketones to nitro-
alkenes.[16] Further, the chirality of binaphthyl did not affect
the configuration of the addition product, and it has no
obvious impact on enantioselectivity. In addition, the back-
bone of binaphthyl sulfonimide 1 is somewhat complicated,
which makes it “high-carbon economic” and not easily ob-
tained. On the basis of the above facts, we presented the
optimized strategy to replace the sulfonimide with the sim-
pler cyclic imide unit, and the possible transition state is
shown in Scheme 1: the imide carbonyl oxygen atom and
the co-additive proton anchor the nitroalkenes together. To
the best of our knowledge, such cyclic imide organocata-
lysts are not reported in an asymmetric reaction. In this
communication, we describe the study of a pyrrolidine-
based phthalimide and other analogous imide catalysts 5a–
c that catalyze highly enantioselective Michael addition re-
actions of ketones with nitroolefins.
Introduction
In recent years, organocatalysis has been the subject of
intensive development, and many organocatalysts have been
applied in a variety of asymmetric reactions.[1,2] The com-
parable advantages, including the mild reaction conditions,
environmentally benign reaction, and facile recovery of cat-
alysts, render the organocatalytic reaction to possess some
features of green chemistry.[3] Enamine catalysis,[4] imine ca-
talysis,[5] hydrogen-bond activation,[6] carbene catalysis,[7]
and phase-transfer catalysis[8] are often mentioned in the
literature and are deeply researched in the asymmetric or-
ganocatalytic reaction. Among the organocatalysts used
currently, a great number of pyrrolidine-type organocata-
lysts have been reported in an asymmetric reaction such as
the Aldol reaction,[9] Mannich reaction,[10] Michael ad-
dition,[11] and Diels–Alder reaction.[12]
The asymmetric Michael addition of ketones to trans-
β-nitrostyrene, which provides optically active nitroalkane
derivatives of synthetic and biological importance, was pi-
oneered by List[13] and Barbas[14] independently, and since
then great effort has been devoted to the development of
more selective and efficient catalytic systems for this syn-
thetically useful transformation.[15] Despite the excellent re-
sults that have been achieved by these systems, the design
and development of novel backbones and efficient chiral
organocatalysts remain major challenges in synthetic or-
ganic chemistry.
Scheme 1. Strategy to simplify the binaphthyl sulfonimide catalyst
1 and the possible transition state of 5.
In our previous work, the pyrrolidine-based binaphthyl
sulfonimide 1 was synthesized and found to be efficient in
[a] School of Pharmaceutical Science, Shanxi Medical University,
Taiyuan 030001, People’s Republic of China
Fax: +86-351-4690322
Results and Discussion
Cyclic imide catalysts 5a–c were readily prepared by a
straightforward route from the corresponding cyclic anhy-
dride 2 and (S)-tert-butyl-2-(aminomethyl)pyrrolidine-1-
carboxylate (3) in two steps with 25.6–68.9% overall yields
(Scheme 2).
E-mail: qingshanl@yahoo.com
shurongban@163.com
[‡] These two authors contributed equally to this work
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201101093 or from
the author.
Eur. J. Org. Chem. 2011, 6413–6417
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
6413

S.-r. Ban, H.-y. Xie, X.-x. Zhu, Q.-s. Li
SHORT COMMUNICATION
4-bromobenzoic acid (Table 1, Entry 6, 96% ee), 4-meth-
ylbenzoic acid (Table 1, Entry 7, 96% ee), and 2,4-dichlo-
robenzoic acid (Table 1, Entry 8, 97% ee). 2,4-Dichloroben-
zoic acid is the best choice because of the higher diastereo-
selectivity and reaction rate.
Other chiral catalysts 5b–c were screened by employing
these optimized conditions (Table 1, Entry 8), and the re-
sults are summarized in Table 2. Compounds 5a–c facili-
tated the asymmetric Michael addition of cyclohexanone to
nitrostyrene with good to excellent stereoselectivities and
yields. Moreover, 5a is the best catalyst (Table 2, Entry 1,
Ͼ99:1 dr, 97% ee). We also found that for catalyst 5a, the
stereoselectivity increases as the reaction temperature de-
creases from 20 to 0 °C (Table 2, Entry 4, Ͼ99:1 dr, 98%
ee). To our delight, the above results show that imide cata-
lyst 5a has a higher catalytic performance than binaphthyl
sulfonimide 1 for this model reaction.[16]
Scheme 2. Synthesis of imide catalysts 5a–c.
With the desired catalysts in hand, we immediately began
to optimize the reaction conditions. Using 5a as the cata-
lyst, a number of parameters were screened in the model
asymmetric Michael addition of cyclohexanone to β-nitro-
styrene. The results are summarized in Table 1. Initially, the
conjugate addition was examined in a few solvents at room
temperature with benzoic acid as the additive. Among the
various organic solvents tested, dichloromethane, toluene,
and no solvent were better in terms of both the diastereo-
selectivity and enantioselectivity, with 93% ee, 96% ee and
95% ee in enantioselectivity, respectively (Table 1, Entries
1, 2, and 5). When the reaction proceeded in polar solvents
(THF and EtOH), the yields of 8a were very poor (Table 1,
Entries 3 and 4). Toluene was then selected as the solvent
in the study of the influence of the additive, catalyst, and
temperature. The additive carboxylic acid was found to be
an essential factor for this reaction. In the absence of any
carboxylic acid or in the presence of CF3COOH, no prod-
uct was obtained (Table 1, Entries 9 and 10). Almost the
Table 2. Screening of the catalysts.[a]
Entry
Catalyst
T
[°C]
Time
[h]
Yield dr
ee
[%][b] [syn/anti][c] [%][c]
1
2
3
4
5a
5b
5c
5a
20
20
20
0
12
12
12
24
98
91
75
98
Ͼ99:1
98:2
97:3
97
97
90
98
Ͼ99:1
[a] All reactions were carried out with cyclohexanone (6; 100 mg,
1.0 mmol) and nitrostyrene (7a; 18.7 mg, 0.13 mmol) in the pres-
ence of catalyst 5 (10 mol-%). [b] Yield of the isolated product after
chromatography on silica gel. [c] Determined by chiral HPLC on a
Chiralpak AS-H column with n-hexane and 2-propanol as eluents.
With the optimized reaction conditions in hand, a variety
same level of enantioselectivity was observed for substituted of nitrostyrenes bearing different substitutions were investi-
benzoic acid as for benzoic acid (Table 1, Entry 2, 96% ee): gated, and the results are summarized in Table 3. Various
Table 1. Screening of reaction conditions for the conjugate addition of cyclohexanone to β-nitrostyrene.[a]
Entry Additive
Solvent
T [°C]
Time [h]
Yield [%][b]
dr [syn/anti][c]
ee[%][c]
1
2
3
4
5
6
7
8
9
10
benzoic acid
benzoic acid
benzoic acid
benzoic acid
benzoic acid
4-bromobenzoic acid
4-methylbenzoic acid
2,4-dichlorobenzoic acid toluene
trifluoroacetic acid
No additive
DCM
toluene
THF
EtOH
neat
toluene
toluene
20
20
20
20
20
20
20
20
20
20
12
12
12
12
12
12
12
12
12
12
82
93
23
trace
84
98
93
98
0
98:2
Ͼ99:1
99:1
–
98:2
99:1
99:1
Ͼ99:1
–
93
96
92
–
95
96
96
97
–
toluene
toluene
0
–
–
[a] All reactions were carried out with cyclohexanone (6; 100 mg, 1.0 mmol) and nitrostyrene (7a; 18.7 mg, 0.13 mmol) in the presence
of catalyst 5a (10 mol-%). [b] Yield of the isolated product after chromatography on silica gel. [c] Determined by chiral HPLC on a
Chiralpak AS-H column with n-hexane and 2-propanol as eluents.
6414
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© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 6413–6417

Highly Enantioselective Michael Addition of Ketones to Nitroolefins
styrene-type nitroalkenes reacted smoothly with cyclohexa- rived nitroalkenes also appear to be good candidates for
none to provide the corresponding adducts in moderate to this asymmetric Michael addition reaction (Table 3, Entry
excellent yields with excellent diastereoselectivities and 12 and 13).
enantioselectivities (Table 3, Entries 1–11). Excellent di-
Acetophenone, acetone, and isobutyraldehyde were sub-
asteroselectivities (up to Ͼ99:1 dr) and enantioselectivities sequently examined in the 5a-catalyzed Michael addition
(93–99% ee) were observed regardless of the electronic na- with nitrostyrene (7a). Unfortunately, as depicted in
ture of the aromatic substituent R. The nature of the sub- Scheme 3, the results are not satisfactory. Acetone gave a
stituent on the benzene ring slightly influences the reaction moderate yield (85%) and enantioselectivity (41% ee), and
rate and yield. When an electron-donating substituent was no product was obtained for acetophenone or isobutyral-
introduced to the benzene ring, low to moderate yields were dehyde as a nucleophile.
obtained (Table 3, Entries 9). In addition, thiophenyl- or
furyl-containing nitroalkenes as Michael acceptors gave low
yields (Table 3, Entries 10 and 11). Aliphatic aldehyde de-
Conclusions
We have successfully prepared new pyrrolidine-based
Table 3. Catalytic asymmetric Michael addition of ketones to nitro-
phthalimide and other analogous imide catalysts 5 as highly
efficient and stereoselective organocatalysts for the asym-
metric Michael addition of ketones to nitroalkenes. Moder-
ate to excellent diastereoselectivities and enantioselectivities
were obtained for the addition of ketones to a variety of
nitroalkenes under the catalysis of 5a. The presence of a
Brønsted acid with proper acidity, such as 2,4-dichloroben-
zoic acid, proved to be critical for the excellent performance
of this catalyst system. The application of this new type of
organocatalyst in other asymmetric reactions is underway
in our laboratory.
alkenes.[a]
Entry
R
Time
[h]
Yield dr
ee
[%][b]
[syn/anti][c] [%][c]
1
2
3
4
5
6
7
8
Ph
24
36
48
48
48
48
48
72
120
108
72
72
72
98
99
92
95
99
99
99
99
52
50
86
50
80
Ͼ99:1
98:2
Ͼ99:1
99:1
97:3
Ͼ99:1
98:2
98:2
93:7
97:3
98:2
98
96
99
98
97
95
96
97
93
94
93
98
92
4-MeC6H4
2,4-Cl2C6H4
4-BrC6H4
3-NO2C6H4
2-ClC6H4
4-ClC6H4
4-FC6H4
Experimental Section
N-{[(S)-Pyrrolidin-2-yl]methyl}phthalimide (5a): The mixture of o-
phthalic anhydride (148 mg, 1.0 mmol) and (S)-tert-butyl 2-(ami-
nomethyl) pyrrolidine-1-carboxylate (210 mg, 1.04 mmol) was
heated to 150 °C for 10 min and then separated directly by silica
gel column chromatography to give the white solid, which was then
dissolved in a mixture of concentrated HCl (2 mL) and EtOAc
(10 mL) and stirred for 4 h at room temperature. The pH of the
mixture was adjusted to about 8 with saturated NaHCO3, after
which extraction with dichloromethane was carried out
(3ϫ20 mL). The solution was dried with anhydrous Na2SO4. After
removal of the solvent, the product was obtained as white solid
(115.5 mg, 50.2% yield). M.p. 96.8–97.5 °C. [α]2D0 = –18.0 (c = 0.2,
CH2Cl2). 1H NMR (400 MHz, CDCl3): δ = 7.85 (dd, J = 3.03 and
5.44 Hz, 2 H), 7.72 (dd, J = 3.07 and 5.46 Hz, 2 H), 3.72–3.66 (m,
2 H), 3.51–3.48 (m, 1 H), 3.23 (br. s, 1 H), 3.05–3.00 (m, 1 H),
2.90–2.84 (m, 1 H), 1.92–1.69 (m, 3 H), 1.49–1.43 (m, 1 H) ppm.
13C NMR (100 MHz, CDCl3): δ = 168.63, 133.88, 132.00, 123.23,
9
3,4-(MeO)2C6H3
2-thiophenyl
2-furyl
10
11
12
13
[d]
PhCH2CH2
98:2
75:25
iPr[d]
[a] All reactions were carried out with cyclohexanone (6; 100 mg,
1.0 mmol) and nitrostyrene (7; 0.13 mmol) in the presence of cata-
lyst 5a (10 mol-%). [b] Yield of the isolated product after
chromatography on silica gel. [c] Determined by chiral HPLC on a
Chiralpak AS-H column with n-hexane and 2-propanol as eluents.
[d] These reactions were carried out at room temperature.
57.50, 46.43, 43.60, 29.61, 25.37 ppm. IR (KBr): ν = 3456, 3213,
˜
2962, 2817, 1717, 1694, 1645, 1614, 1431, 1398, 1132, 1051,
721 cm–1. HRMS: m/z
= 231.11204 [M +
H]+ (calcd. for
C13H15N2O2 231.11280).
N-{[(S)-Pyrrolidin-2-yl]methyl}-1,8-naphthalimide (5b): Compound
5b was prepared according to the method used for 5a with 1,8-
naphthalic anhydride (198 mg, 1.0 mmol) and (S)-tert-butyl 2-(ami-
nomethyl) pyrrolidine-1-carboxylate (210 mg, 1.04 mmol). A white
solid was obtained (192.9 mg, 68.9% yield). M.p. 157.7–158.9 °C.
[α]2D0 = –0.3 (c = 0.5, CH2Cl2). H NMR (400 MHz, CDCl3): δ =
1
8.56 (d, J = 6.65 Hz, 2 H), 8.18 (d, J = 8.31 Hz, 2 H), 7.72 (t, J =
7.77 Hz, 2 H), 4.27–4.25 (m, 2 H), 3.63–3.59 (m, 1 H), 3.12–3.06
(m, 1 H), 2.89–2.83 (m, 1 H), 2.68 (br. s, 1 H), 1.99–1.69 (m, 3 H),
1.58–1.50 (m, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 164.68,
Scheme 3. Michael addition of ketones and aldehyde to 7a.
Eur. J. Org. Chem. 2011, 6413–6417
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6415

S.-r. Ban, H.-y. Xie, X.-x. Zhu, Q.-s. Li
SHORT COMMUNICATION
Gong, Prog. Chem. 2010, 22, 1362; f) A. Studer, D. P. Curran,
Angew. Chem. Int. Ed. 2011, 50, 5018–5022.
133.98, 131.52, 131.17, 128.23, 126.90, 122.58, 57.94, 46.51, 44.23,
30.00, 25.38 ppm. IR (KBr): ν = 3442, 3207, 2949, 2858, 1724,
˜
[3]
[4]
a) C. H. Luo, D. M. Du, Synthesis-Stuttgart 2011, 1968–1973;
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For selected hydrogen-bond activated reactions, seea) Y.
Zhang, Y. K. Liu, T. R. Kang, Z. K. Hu, Y. C. Chen, J. Am.
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1666, 1645, 1624, 1589, 1436, 1379, 1357, 1323, 1236, 1165, 1097,
781 cm–1. HRMS: calcd. for C17H17N2O2 281.12845 [M + H]+;
found 281.12832.
N-{[(S)-Pyrrolidin-2-yl]methyl}-3,4,5,6-tetrachlorophthalimide (5c):
The reaction mixture of tetrachlorophthalic anhydride (286 mg,
1.0 mmol), dicyclohexylcarbodiimide (DCC, 200 mg, 1 mmol), and
(S)-tert-butyl 2-(aminomethyl) pyrrolidine-1-carboxylate (210 mg,
1.04 mmol) in dried THF (10 mL) was heated at reflux for 12 h,
and the mixture was separated directly by silica gel column
chromatography to give a white solid, which was then dissolved in
a mixture of concentrated HCl (2 mL) and EtOAc (10 mL) and
stirred for 4 h at room temperature. The pH of the mixture was
adjusted to about 8 with saturated NaHCO3, after which extraction
with dichloromethane was carried out (3ϫ20 mL). The solution
was dried with anhydrous Na2SO4. After removal of the solvent,
the product was obtained as a white solid (94.2 mg, 25.6% yield).
M.p. decomposed at 280 °C. [α]2D0 = +8.7 (c = 0.5, CH2Cl2). 1H
NMR (400 MHz, CDCl3): δ = 4.68–2.86 (m, 6 H), 2.23–1.44 (m, 4
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 163.70, 133.97, 129.67,
[5]
127.80, 53.45, 48.95, 40.90, 30.96, 23.49 ppm. IR (KBr): ν = 3465,
˜
3227, 2941, 2858, 1774, 1717, 1681, 1651, 1633, 1435, 1398, 1371,
1298, 1200, 1060, 737 cm–1. HRMS: calcd. for C13H11Cl4N2O2
366.95691 [M + H]+; found 366.95843.
General Procedure for the Asymmetric Michael Addition of Ketones
to Nitroalkenes Catalyzed by 5: A solution of the catalyst 5
(0.013 mmol) and cyclohexanone (0.1 mL, 0.1 mmol) in toluene
(0.2 mL) was stirred at room temperature for 30 min. 2,4-Dichlo-
ridebenzoic acid (2.5 mg, 0.013 mmol) was then added, and the re-
action mixture was stirred for 15 min. To the resulting mixture was
added nitroalkene (0.13 mmol) at the required temperature. After
the reaction was completed (monitored by TLC), the mixture was
purified by column chromatography on silica gel (200–300 mesh,
petroleum ether/ethyl acetate = 10:1) to afford the product.
[6]
Supporting Information (see footnote on the first page of this arti-
cle): Experimental details for the products of the catalytic asym-
metric Michael addition reactions are presented. 1H and 13C NMR
spectra, IR spectra and mass spectra are also given for all the com-
pounds.
[7]
For selected carbene-catalyzed reactions, seea) I. Piel, M. Stein-
metz, K. Hirano, R. Frohlich, S. Grimme, F. Glorius, Angew.
Chem. Int. Ed. 2011, 50, 4983–4987; b) Y. R. Zhang, H. Lv, D.
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A. Md, T. Tanoi, N. Nomura, M. Sato, Tetrahedron 2011, 67,
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Acknowledgments
The authors would like to acknowledge financial support from the
Shanxi Province Science Foundation for Youths of China (No.
2009021041–1) and from the Main Cultivate Object of Progam for
the Top Science and Technology Innovation Teams of Higher
Learning Institutions of Shanxi.
[8]
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6416
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Received: July 27, 2011
Published Online: October 10, 2011
Eur. J. Org. Chem. 2011, 6413–6417
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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