Pyrrolidine-based chiral pyridinium ionic liquids (ILs) as recyclable and highly efficient organocatalysts for the asymmetric Michael addition reactions

Article abstract of DOI:10.1016/j.tetlet.2007.12.024

A novel series of pyrrolidine-based chiral pyridinium ionic liquids (ILs) have been developed by using commercially available (S)-(2-aminomethyl)-1-N-Boc-pyrrolidine. These chiral ILs have been found to be recyclable and efficient organocatalysts for the

Full text of DOI:10.1016/j.tetlet.2007.12.024

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 1249–1252
Pyrrolidine-based chiral pyridinium ionic liquids (ILs) as
recyclable and highly efficient organocatalysts for the
asymmetric Michael addition reactions
Bukuo Ni, Qianying Zhang, Allan D. Headley *
Department of Chemistry, Texas A&M University-Commerce Commerce, TX 75429-3011, USA
Received 29 October 2007; revised 3 December 2007; accepted 5 December 2007
Available online 8 December 2007
Abstract
A novel series of pyrrolidine-based chiral pyridinium ionic liquids (ILs) have been developed by using commercially available (S)-(2-
aminomethyl)-1-N-Boc-pyrrolidine. These chiral ILs have been found to be recyclable and efficient organocatalysts for the asymmetric
catalytic Michael addition reactions of ketones to nitroolefins with high yields, high enantioselectivies, and diastereoselectivies.
Ó 2007 Elsevier Ltd. All rights reserved.
Owing to the intriguing properties of ionic liquids (ILs),
they have been intensively investigated as solvents for syn-
thetic organic reactions, and most recently for their ability
reveals only one example in which chiral pyridinium ILs
have been used as solvents for an asymmetric reaction
5
c
and no enantioselective induction was observed. Herein,
we report the design and synthesis of a novel class of pyrrol-
idine-based chiral pyridinium ILs, which are very effective
organocatalysts for highly enantioselective Michael addi-
tion of cyclic ketones to nitroalkenes; in addition, they are
easily recoverable for reuse.
1
to also act as catalysts for specific reactions. Even though
much progress has been achieved in the design and synthesis
2
of new chiral ILs, there has been limited success in them
3
being able to affect the outcomes of asymmetric reactions.
There have been cases where imidazolium ionic liquids have
been used successfully for asymmetric reactions, for exam-
It is known that asymmetric Michael addition reaction is
among the most powerful and convergent strategies for the
enantioselective formation of C–C bonds in organic syn-
3
e,f
ple, Luo et al.
reported the reactions of cyclohexanone
with nitroolefins catalyzed by pyrrolidine-type chiral imi-
dazolium ILs, in which high diastereo- and enantioselectiv-
ity were observed, but there are major problems associated
with the use of chiral ILs derived from imidazolium ILs
when used as catalysts or solvents for asymmetric reactions.
For example, side products often result due to the relatively
6
thesis. Recently, several efficient small-molecular chiral
7
organocatalysts, such as pyrrolidine-based amine, pyrrol-
8
9
0
idine–pyridine, aminomethylpyrrolidine, 2,2 -bipyrrol-
1
0
11
12
idine, pyrrolidinyltetrazole, pyrrolidine sulfonamide,
1
3
and pyrrolidine–thiourea, have been developed for the
asymmetric Michael reaction of ketones to nitroolefins
with high enantioselectivity and diastereoselecivity. These
approaches provide a unique methodology in asymmetric
Michael addition, but a major disadvantage is that they
are not easily recovered and recycled. As a result, the devel-
opment of environment-friendly and metal-free chiral
organocatalysts for asymmetric Michael reaction with high
enantioselectivity, as well as efficient catalyst recovery and
reuse, remains a challenging task.
4
acidic nature of the C2 hydrogen of the imidazolium ring.
Pyridinium derived ionic liquids offer a better alternative
since most of the problems encountered in the use of imi-
dazolium ionic liquids can be avoided or minimized in these
ionic liquids. Amazingly, chiral pyridinium ILs have been
5
exploited far less. A thorough review of the literature
*
Corresponding author. Tel.: +1 903 886 5159; fax: +1 903 886 5165.
E-mail address: allan_headley@tamu-commerce.edu (A. D. Headley).
0
040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.12.024

1250
B. Ni et al. / Tetrahedron Letters 49 (2008) 1249–1252
temperature (entry 1). Interestingly, addition of TFA
increased the reaction rate without losing enantioselectivity
N
Cl
NO2
1. n-BuOH, reflux
2. HCl/dioxane
ꢀ
ꢀ
N+
(entry 2). The anion exchange of Cl to BF (1b) provided
NH2
+
N
H
4
N
Cl
comparable selectivity with enhanced reaction activity
when TFA was added (entry 4). When the reaction was
performed at lower temperature (4 °C), the adduct was
obtained in high yield (92%) with nearly optically purity
(99% ee) and excellent diastereoselectivity (syn/anti ratio
Boc
3. NaHCO
3
1
a
overall yield: 85%
NO
2
1b: X=BF
1c: X=PF6 94%
1d
: X=NTf2 98%
92%
AgBF , KPF , or LiNTf
2
4
4
6
N+
N
H
X
>
99%) (entry 5). The slightly low selectivities were
ꢀ
ꢀ
Scheme 1.
observed with PF6 (1c) and NTf2 (1d) as anions (entries
–9). In addition, catalyst 1b could be recycled two times
6
with only slightly decreased yield (82%) and selectivities
in the third cycle (entries 10 and 11). Overall, chiral
ILs 1a–b with Cl and BF4 as anions gave the best
The synthesis of pyrrolidine-based chiral pyridinium ILs
a–d is outlined in Scheme 1. Starting from commercially
1
ꢀ
ꢀ
available (S)-(2-aminomethyl)-1-N-Boc-pyrrolidine, using
Marazano’s reaction with Zincke’s salt, and followed by
Boc deprotection afforded 1a, which was subjected to anion
exchange to give 1b–d (Scheme 1). All the chiral ILs synthe-
sized were soluble in polar solvent, such as MeOH,
performances with high yields, high diastereo- and
1
5
enantioselectivity.
Encouraged by these results, we next probed the conju-
gate addition of a few cyclic ketones to a variety of nitro-
olefins with catalysts 1a/TFA at ambient temperature
and 1b/TFA at 4 °C, respectively (Table 2). The results
showed that the reactions proceeded efficiently with cyclo-
hexanone and nitroolefins to give the Michael adducts with
high yields (73–100%), excellent levels of diastereoselecti-
vities (syn/anti ratio up to >99/1) and enantioselectivities
CH CN, DMF, and DMSO, but were immiscible in
3
Et O, EtOAc, and hexane. Chiral ILs 1a–c were soluble
2
in H O, while the anion NTf 1d was immiscible in H O.
2
2
2
The different solubility allows them to be easily extracted
for reuse.
1
4
As shown in Table 1, all chiral pyridinium ILs 1a–d
catalyzed the asymmetric Michael reaction of cyclohexa-
none with nitrostyrene. The catalytic and enantioselective
activities varied significantly with different anion moieties
of chiral ILs and the additive acid. Compound 1a with
(ee up to 99%). More significantly, nitroolefins possessing
either electron-rich or electron-deficient substituents
reacted smoothly with Michael donors (entries 1–14),
including tetrahydro-4H-pyran-4-one (entries 15 and 16).
Cyclopentanone and acetone also provided the desired
adducts 2j and 2k, respectively, but in low selectivities; in
these two cases, catalyst 1d showed a higher catalytic
activity, compared to 1b (entries 17–20). Isovaleraldehyde
was also a suitable Michael donor and afforded the desired
product 2l with moderate enantioselectivity and good dia-
stereoselectivity (entry 21).
ꢀ
Cl as anion was used as a catalyst to show the high dia-
stereo- and enantioselectivity with moderate yield at room
Table 1
The effect of catalyst in the Michael reaction of cyclohexanone and
nitrostyrene
The high diastereo- and enantioselectivities may be
explained by an acyclic synclinal transition state A, in
which the pyridinium ring plays an important role in
O
O
Ph
Ph
NO2
1
5 mol % catalyst
+
NO2
neat
16
shielding the si-face of enamine double bond. The
2
a
possible ionic attraction between pyridinium cation
and nitro group of the substrate (transition state B in
Fig. 1) should also contribute to the enantioselectivity
observed.
a
b
c
d
Entry Catalyst TFA
T
Time Yield
ee (%) dr
(
mol %)
(h)
(%)
(syn)
(syn/
anti)
1
2
3
4
5
6
7
8
1a
1a
1b
1b
1b
1c
1c
1d
1d
1b
1b
—
5
rt
rt
rt
rt
36
36
36
16
74
91
75
95
92
90
92
81
95
90
82
99
99
94
98
99
93
86
95
93
99
94
98/2
In conclusion, we have designed and synthesized a new
class of chiral ILs that serve as efficient catalysts for the
asymmetric Michael reaction of cyclic, six-membered
ketones to nitroolefines. These pyrrolidine-based chiral
pyridinium ILs catalysts are easily prepared from commer-
cially available (S)-(2-aminomethyl)-1-N-Boc-pyrrolidine
in two or three steps. Our chiral ILs are environment-
friendly, easy recovery and can be reused as catalysts for
a broad range of Michael acceptors and donors with high
yields (up to 100%), high diastereoselectivities (syn/anti
up to >99:1) and enantioselectivies (ee up to 99%). The
applications of these new ILs to other asymmetric reac-
tions, such as diamination and aminohalogenation, are
presently being carried out in our lab.
97/3
>99/1
99/1
>99/1
99/1
95/5
96/4
96/4
99/1
—
5
5
4 °C 30
—
5
—
5
5
5
rt
rt
rt
rt
72
48
43
16
9
e
1
1
0
4 °C 30
4 °C 30
f
1
a
b
c
96/4
TFA (trifluoroacetic acid).
Isolated yield.
Determined by Chiral HPLC.
d
e
1
Determined by H NMR.
Second cycle of 1b.
Third cycle of 1b.
f

B. Ni et al. / Tetrahedron Letters 49 (2008) 1249–1252
1251
Table 2
Asymmetric Michael reaction of ketones to nitroolefins catalyzed by 1a/TFA or 1b/TFA
a
b
c
Entry
Product
Cat. (T)
Time (h)
Yield (%)
ee (%) (syn)
dr (syn/anti)
O
C H -4-OMe
6
4
1
2
1a (rt)
1b (4 °C)
48
48
73
91
98
98
93/7
>99/1
NO2
2b
O
O
O
O
O
O
C H -3-OMe
6
4
NO2
3
4
1a (rt)
1b (4 °C)
48
48
75
98
96
95
>99/1
99/1
2c
C H -4-Me
6
4
NO2
5
6
1a (rt)
1b (4 °C)
48
36
77
91
99
98
96/4
97/3
2d
C H -2-Cl
6
4
NO2
7
8
1a (rt)
1b (4 °C)
36
21
85
98
96
96
99/1
99/1
2e
C H -2-CF
6
4
3
NO2
9
1a (rt)
1b (4 °C)
48
36
83
92
96
97
97/3
99/1
10
2f
C H -2-NO
6
4
2
NO2
1
1
1
2
1a (rt)
1b (4 °C)
41
24
94
100
96
94
99/1
99/1
2g
C H -2,4-Cl
6
3
2
NO2
1
1
3
4
1a (rt)
1b (4 °C)
36
24
87
95
97
97
>99/1
>99/1
2h
O
Ph
NO2
1
1
5
6
1a (rt)
1b (4 °C)
36
36
76
90
89
92
94/6
94/6
2i
O
O
Ph
d
d
1
1
7
8
1b (rt)
1d (rt)
36
36
<10
69
nd
nd
NO2
62/82
53/47
2j
O
Ph
1
2
9
0
1b (rt)
1d (rt)
72
36
82
90
35
40
—
—
NO
2
2k
O
Ph
NO2
21
1b (rt)
144
46
42
93/7
H
2
l
a
b
c
Isolated yield.
Determined by Chiral HPLC.
Determined by H NMR spectroscopy (400 MHz).
Not determined.
1
d

1
252
B. Ni et al. / Tetrahedron Letters 49 (2008) 1249–1252
F.; Pizzo, F.; Tortoioli, S.; Vaccaro, L. J. Org. Chem. 2004, 69, 7745;
X
X
N
(c) Drahonovasky, D.; Labat, G. C.; Sevick, J.; von Zelewsky, A.
Heterocycles 2005, 65, 2169; (d) Baudoux, J.; Judeinstein, P.; Cahard,
D.; Plaquevent, J. C. Tetrahedron Lett. 2005, 46, 1137; (e) Ni, B.;
Zhang, Q.; Headley, A. D. J. Org. Chem. 2006, 71, 9857.
H
NNO2
N
O
N
N
R
O
H
R
6
. Selected reviews: (a) List, B. Acc. Chem. Res. 2004, 37, 548; (b) Dalko,
P. I.; Moisan, L. Angew. Chem., Int. Ed. 2004, 43, 5138; (c) Notz, W.;
Tanaka, F.; Barbas, C. F., III. Acc. Chem. Res. 2004, 37, 580. For
selected studies with aiming at the recovery and reuse of organocat-
alysts, see: (d) Chowdari, N. S.; Ramachary, D. B.; Barbas, C. F., III.
Synlett 2003, 1906; (e) Bensa, D.; Constantieux, T.; Rodriguez, J.
Synthesis 2004, 923; (f) Zu, L.; Li, H.; Wang, J.; Yu, X.; Wang, W.
Tetrahedron Lett. 2006, 47, 5131; (g) Zu, L.; Wang, J.; Li, H.; Wang,
W. Org. Lett. 2006, 8, 3077.
A
B
Fig. 1. Transition state for Michael additions.
Acknowledgment
We are grateful to acknowledge the support of this
research by the Robert A. Welch Foundation (T-1460).
7
. (a) Mase, N.; Watanabe, K.; Yoda, H.; Takabe, K.; Tanaka, F.;
Barbas, C. F., III. J. Am. Chem. Soc. 2006, 128, 4966; (b) Pansare, S.
V.; Pandya, K. J. Am. Chem. Soc. 2006, 128, 9624.
Supplementary data
8
. Ishii, T.; Fujioka, S.; Sekiguchi, Y.; Kotsuki, H. J. Am. Chem. Soc.
2
004, 126, 9558.
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.
9. (a) Mase, N.; Thayumanavan, R.; Tanaka, F.; Barbas, C. F., III. Org.
Lett. 2004, 6, 2527; (b) Betancort, J. M.; Sakthivel, K.; Thayuman-
avan, R.; Tanaka, F.; Barbas, C. F., III. Synthesis 2004, 1509.
0. (a) Alexakis, A.; Andrey, O. Org. Lett. 2002, 4, 3611; (b) Andrey, O.;
Alexakis, A.; Tomassini, A.; Bernardinelli, G. Adv. Synth. Catal.
2
007.12.024.
1
1
References and notes
2
004, 346, 1147.
1. (a) Cobb, A. J. A.; Longbottom, D. A.; Shaw, D. M.; Ley, S. V.
Chem. Commun. 2004, 1808; (b) Cobb, A. J. A.; Shaw, D. M.;
Longbottom, D. A.; Gold, J. B.; Ley, S. V. Org. Biomol. Chem. 2005,
3, 84.
12. Wang, J.; Li, H.; Lou, B.; Zu, L.; Guo, H.; Wang, W. Chem. Eur. J.
2006, 12, 4321.
13. Cao, C.-L.; Ye, M.-C.; Sun, X.-L.; Tang, Y. Org. Lett. 2006, 8, 2901.
14. For the solvent and additive effect of catalyst 1b for Michael addition
see Supplementary data.
1
. Selected reviews: (a) Dupont, J.; de Souza, R. F.; Suarez, P. A. Z.
Chem. Rev. 2002, 102, 3667; (b) Wasserscheid, P.; Welton, T. Ionic
Liquids in Synthesis; Wiley-VCH: Weinheim, Germany, 2003; (c)
Rogers, R. D.; Seddon, K. R.; Volkov, S. Green Industrial Applica-
tions of Ionic Liquids; Kluwer Academic: Dordrecht, 2002; (d)
Baudequin, C.; Baudoux, J.; Levillain, J.; Cahard, D.; Gaumontb,
A. C.; Plaqueventa, J. C. Tetrahedron: Asymmetry 2003, 14, 3081; (e)
Handy, S. T. Curr. Org. Chem. 2005, 9, 959.
2
. Selected reviews: (a) Ding, J.; Armstrong, D. W. Chirality 2005, 17,
15. Typical procedure: Catalyst 1b (8 mg, 15 mol %) was dissolved in
MeOH (20 lL). Then cyclohexanone (0.4 mL) and trifluoroacetic acid
solution of MeOH (16 lL, 14 lL/mg, 5 mol %). After stirring for
30 min at room temperature, b-nitrostyrene was added and the
reaction mixture was stirred at 4 °C for 30 h. Ethyl ether was added to
precipitate the catalyst and the organic layer was separated. Removal
of the solvent and purification by silica gel column (eluent: hexane–
2
81; (b) Baudequin, C.; B e´ rgeon, D.; Levillain, J.; Guillen, F.;
Plauevent, J.-C.; Gaumont, A.-C. Tetrahedron: Asymmetry 2005, 16,
3921; (c) Imperato, G.; K o¨ nig, B.; Chiappe, C. Eur. J. Org. Chem.
2007, 1049; (d) Headley, A. D.; Ni, B. Aldrichim. Acta 2007, 40, 107.
3
. (a) P e´ got, B.; Vo-Thanh, G.; Gori, D.; Loupy, A. Tetrahedron Lett.
004, 45, 6425; (b) Ding, J.; Desikan, V.; Han, X.; Xiao, T. L.; Ding,
2
R.; Jenks, W. S.; Armstrong, D. W. Org. Lett. 2005, 7, 335; (c) Wang,
Z.; Wang, Q.; Zhang, Y.; Bao, W. Tetrahedron Lett. 2005, 46, 4657;
ethyl acetate = 4:1) gave the Michael adduct (45 mg, 92%) as a white
1
solid; H NMR (400 MHz, CDCl
3
) d 7.35–7.23 (m, 3H), 7.20–7.14 (m,
(
d) Miao, W.; Chan, T. H. H. Adv. Synth. Catal. 2006, 348, 1711; (e)
2H), 4.94 (dd, J = 12.4 and 4.4 Hz, 1H), 6.43 (dd, J = 12.4 and
10.0 Hz, 1H), 3.76 (dt, J = 9.6 and 4.4 Hz, 1H), 2.74–2.64 (m, 1H),
2.52–2.34 (m, 2H), 2.13–2.03 (m, 1H), 1.83–1.50 (m, 4H), 1.30–1.18
Luo, S.; Mi, X.; Zhang, L.; Liu, S.; Xu, H.; Cheng, J.-P. Angew.
Chem., Int. Ed. 2006, 45, 3093; (f) Luo, S.; Mi, X.; Liu, S.; Xu, H.;
Cheng, J. P. Chem. Commun. 2006, 3687; (g) Qu, W.-H.; Huang, Z.-Z.
Green Chem. 2006, 8, 731; (h) Guo, H. M.; Cun, L. F.; Gong, L. Z.;
Mi, A. Q.; Jiang, Y. Z. Chem. Commun. 2005, 1450; (i) Guo, H. M.;
Niu, H. Y.; Xue, X.; Guo, Q. X.; Cun, L. F.; Mi, A. Q.; Jiang, Y. Z.;
Wang, J. J. Green Chem. 2006, 8, 682; (j) Ni, B.; Zhang, Q.; Headley,
A. D. Green Chem. 2007, 9, 737.
1
3
3
(m, 1H); C NMR (100 MHz, CDCl ) d 211.9, 137.7, 128.9, 128.2,
2
0
127.8, 78.9, 52.5, 43.9, 42.7, 33.2, 28.5, 25.0; ½aꢁ ꢀ37.0 (c = 0.48
D
3
in CHCl ); syn/anti > 99/1; ee = 99%; HPLC (Chiralpak AS-H,
i-propanol/hexane = 10/90, flow rate 0.7 mL/min, k = 238 nm):
minor = 24.7 min, tmajor = 37.5 min. The catalyst was dissolved in
MeOH and neutralized with NaHCO solid. Removal of the solvent
left a residue, which was diluted with a mixture solvent (CH Cl
t
3
4
. (a) Handy, S. T.; Okello, M. J. Org. Chem. 2005, 70, 1915; (b)
Aggarwal, V. K.; Emme, I.; Mereu, A. Chem. Commun. 2002, 1612;
2
2
–
MeOH = 10:1), and the insoluble was removed by filtration. The
filtrate was concentrated and dried to give the catalyst, which was
used for the next run reaction.
(c) Ni, B.; Satish, G.; Headley, A. D. Tetrahedron Lett. 2007, 48, 1999.
5
. (a) Patrascu, C.; Sugisaki, C.; Mintogaud, C.; Marty, J.-D.; G e´ nisson,
Y.; Lauth de Viguerie, N. Heterocycles 2004, 63, 2033; (b) Fringuelli,
16. Seebach, D.; Golinski, J. Helv. Chim. Acta 1981, 64, 1413.