Ion-supported chiral pyrrolidines as enantioselective catalysts for direct Michael addition of nitroalkenes in [BMIm]PF6

Article abstract of DOI:10.1055/s-2006-950443

Imidazolium-supported-pyrrolidine-catalyzed asymmetric Michael addition reactions of unmodified ketones and aldehydes to nitroalkenes were performed in [BMIm]PF₆ to give products in up to 98% yield and 99% enantioselectivity. The catalytic system presented a synergistic effect in the improvement of reaction performance and could be recycled. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-950443

LETTER
2569
Ion-Supported Chiral Pyrrolidines as Enantioselective Catalysts for Direct
Michael Addition of Nitroalkenes in [BMIm]PF6
I
on-SupportedChi
a
ra
l
Pyrrolid
n
ines as Catal
q
ysts for
D
ir
e
i
ct Mich
a
ael
A
dditio
n
n
Xu, Shuping Luo, Huadong Yue, Liping Wang, Yunkui Liu, Zhenyuan Xu*
State Key Laboratory Breeding Base of Green Chemistry-Synthesis Technology, Zhejiang University of Technology,
Hangzhou, 310014, P. R. of China
Fax +86(571)88320066; E-mail: greenchem@zjut.edu.cn
Received 31 May 2006
imparted with a particularly reactive fragment.7 These
functionalized and so-called ‘task-specific’ ionic liquids
promote the capacity for interactions with specific sub-
strates. Herein we describe a new strategy for designing
Abstract: Imidazolium-supported-pyrrolidine-catalyzed asymmet-
ric Michael addition reactions of unmodified ketones and aldehydes
to nitroalkenes were performed in [BMIm]PF6 to give products in
up to 98% yield and 99% enantioselectivity. The catalytic system
presented a synergistic effect in the improvement of reaction per- chiral pyrrolidines as efficient organocatalysts, which
formance and could be recycled.
features the introduction of an ionic-liquid fragment.
Therefore, the new ion-supported pyrrolidines combined
with ionic liquids as the reaction media presented a syner-
gistic effect in the improvement of reaction performance
and the catalytic system could be recycled.
Key words: imidazolium-supported pyrrolidine, asymmetric
Michael reaction, nitroalkenes, ketones, aldehydes, ionic liquids
Asymmetric organocatalysis has recently emerged as a
powerful methodology owing to the growing need for
environmentally benign transformations of nonmetal-
catalyzed asymmetric synthesis. In particular, the natural
amino acid L-proline, pioneered by List and Barbas III and
their co-workers, has been fully appreciated as an attrac-
tively enantioselective catalyst for direct asymmetric
carbon–carbon and carbon–heteroatom bond-forming
reactions, such as aldol, Mannich, Michael, a-amination
and a-aminoxylation reactions of carbonyl compounds.1
Although impressive, the catalytic scope of L-proline was
not very efficient to address all the above reactions; only
low to moderate enantioselectivities were typically ob-
served in Michael addition of carbonyl compounds to ni-
troalkenes,2 and this reaction led to nitroalkanes which
were useful chiral precursors of diverse functionalized or-
ganic compounds.3 Efforts to improve enantioselectivity
of the process have been explored recently by using new
chiral pyrrolidine-type amines.4,5 It was noted that the de-
sign of the organocatalyst was of vital importance to attain
high enantioselectivity. However, few reports have de-
scribed the reusability of these novel amine catalysts,
which is an extremely important concept in homogeneous
catalysis. Therefore development of more effective
organocatalysts in terms of both enantioselectivity and
recyclability is quite necessary.
The ion-supported chiral pyrrolidines 4 were readily syn-
thesized by treating 1-alkylimidazole with (S)-(+)-2-bro-
momethylpyrrolidine hydrobromide (3), which was
obtained from commercially available L-proline (1) by
reduction with NaBH4–I2, a neutralization step and bromi-
nation with PBr3 successively. Anion exchange of 4 with
either AgBF4 or KPF6 afforded 5 in high yield
(Scheme 1).8,9 These new organocatalysts were then
tested in the direct asymmetric Michael addition of cyclo-
hexanone (6) to b-nitrostyrene (7) to afford the Michael
adduct 8 (Equation 1).10
As can be seen from the results summarized in Table 1,
dramatically superior catalytic performance was observed
with 4a,b to that achieved with the parent L-proline (1) in
1. HBr, H2O
O
2. PBr3, ∆
NaBH4, I2, THF
88% yield
Br
N
Br
86% yield
N
H
OH
OH
N
H2
H
3
2
1
N
N
R
AgBF4 or KPF6
MeCN–H2O, r.t.
1. MeCN, reflux
2. NaOH
Br
N
N
≥95% yield
≥92% yield
H
N
Ionic liquids have currently become an exciting area of
research as reaction media due to their unique characteris-
tics. In addition, ionic liquids have shown to be superior
to traditional solvents in some organocatalysis reactions
in terms of activity, selectivity and stability of the
catalysts.6 More recently, ionic liquids have been further
applied as soluble supports for organic synthesis by being
R
4
4a: R = Me
4b: R = Et
Y
N
N
H
N
R
5
5a: R = Me, Y = BF4
5c: R = Me, Y = PF6
5b: R = Et, Y = BF4
5d: R = Et, Y = PF6
SYNLETT 2006, No. 16, pp 2569–2572
Advanced online publication: 22.09.2006
0
4
.1
0
.2
0
0
6
DOI: 10.1055/s-2006-950443; Art ID: W11006ST
© Georg Thieme Verlag Stuttgart · New York
Scheme 1 Preparation of ion-supported chiral pyrrolidines

2570
D. Xu et al.
LETTER
ionic liquid 1-n-butyl-3-methyl imidazolium hexafluoro- addition, the ionic medium of [BMIm]PF6 might play an
phosphate ([BMIm]PF6) (entries 1–3), and catalysts 5a,d important role in stabilizing the formed iminium-ion
also gave moderate to good enantioselectivities (entries transition state, owned greater charge density than the
4–7). Significantly, 4b-catalyzed Michael addition pro- initial reaction molecules, by operating the favorable elec-
ceeded more smoothly in [BMIm]PF6 to give adduct 8 in trostatic interactions, which led to the enhancement of the
much higher yield (98%) and much better enantioselec- overall reaction efficiency.12 A model to explain the reac-
tivity (97% ee) than those resulting from the use of con- tion mode is depicted in Scheme 2.
ventional organic solvents (entry 3 vs. entries 8–10). On
the contrary, the L-proline-catalyzed reaction exhibited
worse results in [BMIm]PF6 than in isopropanol (entry 1
vs. entry 11). The lower efficiency of 4b in molecular
organic solvents indicated the importance of synergistic
effect in the catalytic system of ion-supported pyrrolidine-
[BMIm]PF6.
Br
Br
NO2
N
catalyst
N
N
H
N
H
N
N
O2N
R
H
R
Ph
O
O
Scheme 2 Proposed reaction model for ion-supported pyrrolidine-
catalyzed Michael addition
20 mol% catalyst
solvent, r.t.
NO2
NO2
+
Ph
The general utility of this asymmetric transformation was
examined with the results summarized in Table 2. Various
aromatic-substituted nitroalkenes reacted smoothly and
the yields were generally good, though the type of sub-
strate appeared to influence the enantioselectivity of the
reaction. b-Nitrostyrenes substituted with an electron-do-
nating group and aromatic nitroalkenes without substitu-
ents were found to be excellent Michael acceptors to give
products with high enantioselectivities (up to 99%), while
b-nitrostyrenes with an electron-attracting group, linear
ketones and aldehydes provided the desired adducts in
moderate enantioselectivities.
7
6
8
Equation 1
Table 1 Solvent Screen for the Michael Addition of Cyclohexanone
(6) to b-Nitrostyrene (7)a
Entry Catalyst Solvent
Time Yield dr
ee
(h)
96
24
24
96
96
96
96
96
96
96
50
(%)b (syn/anti)c (%)d
1
2
1
[BMIm]PF6
[BMIm]PF6
[BMIm]PF6
[BMIm]PF6
[BMIm]PF6
[BMIm]PF6
[BMIm]PF6
DMSO
30
97
98
52
55
71
78
53
49
45
93
86:14
93:7
24
95
97
77
80
76
88
79
81
98
43
4a
4b
5a
5b
5c
5d
4b
4b
4b
1
3
92:8
Table 2 Catalytic Asymmetric Michael Addition of
Nitroalkenes
4
91:9
5
92:8
Catalyst Adducta
Yield (%) dr (syn/anti) ee (%)b
6
88:12
90:10
91:9
C6H4-m-NO2
O
7
NO2
4a
4b
80
86
74:26
83:17
86
78
8
9
9
DMF
90:10
93:7
C6H4-p-OMe
10
11
i-PrOH
O
NO2
i-PrOH
89:11
4a
4b
90
90
95:5
95:5
99
96
a Unless otherwise noted, all reactions were conducted in solvent (3
mL) using 6 (3 mmol) and 7 (1.5 mmol) in the presence of the catalyst
10
(20 mol%).
b Isolated yields.
C6H4-p-Me
O
c Determined by GC–MS.
NO2
d Enantioselectivity of syn adduct was determined by chiral HPLC
analysis with CD detector (Daicel Chiralpak AS-H, hexane–i-PrOH =
95:5).
4a
4b
88
90
81:19
91:9
96
99
11
C6H4-p-Cl
The Michael adduct 8 was determined to have a syn con-
figuration by X-ray crystallographic analysis. Therefore,
based on Seebach’s model,11 imidazolium-supported pyr-
rolidine must catalyze a Re-face attack on 7 via an enam-
ine intermediate, in which the Si face was shielded
effectively by the imidazolium moiety on the catalyst. In
O
NO2
4a
4b
83
83
83:17
85:15
97
99
12
Synlett 2006, No. 16, 2569–2572 © Thieme Stuttgart · New York

LETTER
Ion-Supported Chiral Pyrrolidines as Catalysts for Direct Michael Addition
2571
Table 2 Catalytic Asymmetric Michael Addition of
Nitroalkenes (continued)
Table 3 Study of the Recyclability of the Catalytic System
Recycle Time
(h)
Conversion Yield
dr
ee
Catalyst Adducta
Yield (%) dr (syn/anti) ee (%)b
(%)
100
100
99
(%)
98
97
97
90
(syn/anti) (% syn)
C6H4-p-CF3
O
24
92:8
97
97
97
96
NO2
4a
4b
78
77
88:12
91:9
70
79
1
2
3
32
40
90:10
91:9
13
100
95
90:10
O
O
In conclusion, we have developed a new imidazolium-
supported-pyrrolidine-type catalysts, readily prepared
from L-proline, for the direct asymmetric Michael addi-
tion reactions of ketones and aldehydes to nitroalkenes.
Remarkably better catalytic performance was provided by
the reactions in [BMIm]PF6 in terms of productivity (up to
98%), enantioselectivity (up to 99%) and recyclability.
Even so, improvements in this system would be welcome,
such as developing the new ion-supported pyrrolidines as
heterogeneous catalysts. Efforts toward this end are in
progress.
4a
4b
83
80
71:29
72:28
84
99
NO2
14
O
4a
4b
86
85
89:11
95:5
98
98
NO2
15
References and Notes
Ph
O
4a
87
92
–
–
58
66
(1) For selected reviews of organocatalysis, see: (a) Dalko, P.
I.; Moisan, L. Angew. Chem. Int. Ed. 2004, 43, 5138.
(b) List, B. Acc. Chem. Res. 2004, 37, 548. (c) Notz, W.;
Tanaka, F.; Barbas, C. F. III Acc. Chem. Res. 2004, 37, 580.
(d) Berkessel, A.; Gröger, H. Asymmetric Organocatalysis:
From Biomimetic Concepts to Applications in Asymmetric
Synthesis; Wiley-VCH Verlag GmbH & Co. KGaA:
Weinheim, 2005. (e) List, B. Chem. Commun. 2006, 819.
(2) (a) List, B.; Pojarliev, P.; Martin, H. J. Org. Lett. 2001, 3,
2423. (b) Enders, D.; Seki, A. Synlett 2002, 26. (c)Kotrusz,
P.; Toma, S.; Schmalz, H.-G.; Adler, A. Eur. J. Org. Chem.
2004, 1577. (d) Rasalkar, M. S.; Potdar, M. K.; Mohile, S.
S.; Salunkhe, M. M. J. Mol. Catal. A: Chem. 2005, 235, 267.
(3) For recent reviews dealing with enantioselective Michael
addition reactions, see: (a) Yamaguchi, M. In
NO2
4b
16
Ph
O
NO2
4a
4b
90
90
–
–
62
69
17
Ph
O
NO2
4a
4b
87
88
68:32
70:30
77
81
H
Comprehensive Asymmetric Catalysis, Vol. I–III; Jacobsen,
E. N.; Pfaltz, A.; Yamamoto, H., Eds.; Springer: Berlin,
1999. (b) Sibi, M. P.; Manyem, S. Tetrahedron 2000, 56,
8033. (c) Berner, O. M.; Tedeschi, L.; Enders, D. Eur. J.
Org. Chem. 2002, 1877.
18
Ph
O
4a
4b
81
85
–
–
61
65
NO2
H
(4) (a) Betancort, J. M.; Barbas, C. F. III Org. Lett. 2001, 3,
3737. (b) Alexakis, A.; Andrey, O. Org. Lett. 2002, 4, 3611.
(c) Andrey, O.; Vidonne, A.; Alexakis, A. Tetrahedron Lett.
2003, 44, 7901. (d) Cobb, A. J. A.; Longbottom, D. A.;
Shaw, D. M.; Ley, S. V. Chem. Commun. 2004, 1808.
(e) Andrey, O.; Alexakis, A.; Tomassini, A.; Bernardinelli,
G. Adv. Synth. Catal. 2004, 346, 1147. (f) Betancort, J. M.;
Sakthivel, K.; Thayumanavan, R.; Tanaka, F.; Barbas, C. F.
III Synthesis 2004, 1509. (g) Mase, N.; Thayumanavan, R.;
Tanaka, F.; Barbas, C. F. III Org. Lett. 2004, 6, 2527.
(h) Ishii, T.; Fujioka, S.; Sekiguchi, Y.; Kotsuki, H. J. Am.
Chem. Soc. 2004, 126, 9558. (i) Mitchell, C. E. T.; Cobb, A.
J. A.; Ley, S. V. Synlett 2005, 611. (j) Wang, W.; Wang, J.;
Li, H. Angew. Chem. Int. Ed. 2005, 44, 1369. (k) Hayashi,
Y.; Gotoh, H.; Hayashi, T.; Shoji, M. Angew. Chem. Int. Ed.
2005, 44, 4212.
19
a All adducts were characterized by 1H NMR, MS and IR.
b Enantioselectivities of syn adducts were determined by chiral HPLC
analysis with CD detector (Daicel Chiralpak AS-H, hexane–i-PrOH).
One noteworthy feature of the present study was the re-
cyclability of the organocatalyst as well as the reaction
media. The 4b–[BMIm]PF6 system was used for three
consecutive runs for the addition of 6 to 7 (Table 3).
Though the reaction time was prolonged gradually, the
desired adduct 8 was obtained in high yield and excellent
enantioselectivity. The slight solubility of enamine inter-
mediate in extracting agents was the possible reason of the
catalyst loss, which led to the gradual decrease of the
reactivity.13
Synlett 2006, No. 16, 2569–2572 © Thieme Stuttgart · New York

2572
D. Xu et al.
LETTER
(5) For other types of organocatalytic Michael addition
reactions, see: (a) Halland, N.; Hazell, R. G.; Jørgensen, K.
A. J. Org. Chem. 2002, 67, 8331. (b) Halland, N.; Aburel,
P. S.; Jørgensen, K. A. Angew. Chem. Int. Ed. 2003, 42, 661.
(c) Andrey, O.; Alexakis, A.; Bernardinelli, G. Org. Lett.
2003, 5, 2559. (d) Halland, N.; Hansen, T.; Jørgensen, K. A.
Angew. Chem. Int. Ed. 2003, 42, 4955. (e) Halland, N.;
Aburel, P. S.; Jørgensen, K. A. Angew. Chem. Int. Ed. 2004,
43, 1272. (f) Peelen, T.; Chi, Y.; Gellman, S. H. J. Am.
Chem. Soc. 2005, 127, 11598. (g) Hayashi, Y.; Gotoh, H.;
Tamura, T.; Yamaguhi, H.; Masui, R.; Shiji, M. J. Am.
Chem. Soc. 2005, 127, 16028.
(6) For recent reviews, see: (a) Wasserscheid, P.; Welton, T.
Ionic Liquids in Synthesis; Wiley-VCH: Weinheim, 2003.
(b) Wilkes, J. S. J. Mol. Catal. A: Chem. 2004, 214, 11.
(c) Song, C. E. Chem. Commun. 2004, 1033. (d) Welton, T.
Coord. Chem. Rev. 2004, 248, 2459.
(9) Data of 4a: Solid; mp 141–143 °C; [a]D20 6.5 (c = 2, EtOH).
1H NMR (400 MHz, DMSO-d6): d = 1.69–1.74 (m, 1 H),
1.90–1.94 (m, 1 H), 2.00–2.01 (m, 1 H), 2.10–2.14 (m, 1 H),
3.16–3.21 (m, 1 H), 3.26–3.31 (m, 1 H), 3.90 (s, 3 H), 3.99–
4.03 (m, 1 H), 4.62–4.67 (m, 2 H), 7.80 (s, 1 H), 7.91 (s, 1
H), 9.29 (s, 1 H). 13C NMR (100 MHz, DMSO-d6): d =
23.133, 27.779, 36.390, 45.139, 49.012, 59.257, 122.854,
124.197, 137.572. IR (film): 3403, 3133, 2944, 2873, 1566,
1412 cm–1. MS (ESI+): m/z (%) = 166 [M – Br]+. MS
(ESI–): m/z (%) = 80 [Br]–. HRMS (ESI+): m/z calcd for
[C9H16N3]+: 166.1339; found: 166.1338. Data of 4b: Solid;
mp 128–131 °C; [a]D20 5.5 (c = 2, EtOH). 1H NMR (400
MHz, DMSO-d6): d = 1.40 (t, J = 7.4 Hz, 3 H), 1.78–1.81
(m, 1 H), 1.83–2.20 (m, 3 H), 3.15–3.18 (m, 1 H), 3.25–3.36
(m, 1 H), 4.07 (m, 1 H), 4.23 (t, J = 7.4 Hz, 2 H), 4.71–4.73
(m, 2 H), 7.94 (d, 2 H), 9.41 (s, dr, 1 H, NH), 9.44 (s, 1 H).
13C NMR (100 MHz, DMSO-d6): d = 15.165, 22.928,
27.654, 44.667, 44.942, 48.738, 59.088, 122.624, 122.878,
136.665. IR (film): 3425, 3133, 2941, 2717, 1563, 1450
cm–1. MS (ESI+): m/z (%) = 180 [M – Br]+. MS (ESI–):
m/z (%) = 80 [Br]–. HRMS (ESI+): m/z calcd for
(7) (a) Audic, N.; Clavier, H.; Mauduit, M.; Guillemin, J.-C. J.
Am. Chem. Soc. 2003, 125, 9248. (b) Miao, W.; Chan, T. H.
Org. Lett. 2003, 5, 5003. (c) Song, G.; Cai, Y.; Peng, Y. J.
Comb. Chem. 2005, 7, 561. (d) Qian, W.; Jin, E.; Bao, W.;
Zhang, Y. Angew. Chem. Int. Ed. 2005, 44, 952.
[C10H18N3]+: 180.1495; found: 180.1494.
(8) Experimental Procedure for the Synthesis of Ion-
Supported Chiral Pyrrolidines: A mixture of N-alkyl-
imidazole (11 mmol) and (S)-(+)-2-bromomethylpyrrol-
idine hydrobromide (3; 2.50 g, 10 mmol) in MeCN (30 mL)
was heated with stirring at 80 °C for 8 h. After completion,
the solvent was removed by distillation, and the residue was
neutralized by NaOH and recrystallized in EtOH to afford
the imidazolium-supported pyrrolidine 4a or 4b as a
colorless solid. The mixture of 4a or 4b (7 mmol), AgBF4 or
KPF6 (7 mmol), and MeCN–H2O (20 mL) was stirred at r.t.
Solvents of the mixtures were distilled and evaporated under
vacuum. The residue was then dissolved in MeOH–acetone
to let the inorganic salts precipitate, which were then filtered
off. After evaporating the solvents, the desired imidazolium-
supported pyrrolidines 5a–d were obtained.
(10) In the process of this manuscript preparation, Luo and co-
workers reported the asymmetric Michael addition catalyzed
by similar organocatalysts based on imidazolium pyrrolidine
derivatives: Luo, S.; Mi, X.; Zhang, L.; Liu, S.; Xu, H.;
Cheng, J.-P. Angew. Chem. Int. Ed. 2006, 45, 3093.
(11) Seebach, D.; Golinski, J. Helv. Chim. Acta 1981, 64, 1413.
(12) Chiappe, C.; Pieraccini, D. J. Phys. Org. Chem. 2005, 18,
275.
(13) Typical Procedure for the Michael Reaction:
Cyclohexanone (3 mmol) was added to a solution of b-nitro-
styrene (1.5 mmol) and imidazolium-supported pyrrolidine
catalyst (0.3 mmol) in [BMIm]PF6 (4 mL). The mixture was
stirred at r.t. until completion of the reaction was established
by GC. The reaction mixture was then extracted with Et2O–
EtOAc (1:1, 3 ×), the combined extract phases were dried
(Na2SO4), concentrated and purified by preparative TLC
(PE–CH2Cl2, 1:1) to afford the Michael adduct. The ee of the
product was determined by chiral HPLC analysis. On the
other hand, the left ion-supported pyrrolidine-[BMIm]PF6
system could be reused directly in subsequent reactions
without further disposal.
Synlett 2006, No. 16, 2569–2572 © Thieme Stuttgart · New York