Organocatalysts wrapped around by poly(ethylene glycol)s (PEGs): A unique host-guest system for asymmetric Michael addition reactions

Article abstract of DOI:10.1039/b708525g

Asymmetric Michael addition reactions of unmodified ketones to nitroalkenes were performed in PEGs catalyzed by novel pyrrolidinyl-thioimidazolium salts to give products in up to 97% yield and 99% enantioselectivity; ESI mass spectrometric detection for t

Full text of DOI:10.1039/b708525g

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Organocatalysts wrapped around by poly(ethylene glycol)s (PEGs): a
unique host–guest system for asymmetric Michael addition reactions{
Dan Qian Xu, Shu Ping Luo, Yi Feng Wang, Ai Bao Xia, Hua Dong Yue, Li Ping Wang and Zhen Yuan Xu*
Received (in Cambridge, UK) 6th June 2007, Accepted 6th August 2007
First published as an Advance Article on the web 17th August 2007
DOI: 10.1039/b708525g
Asymmetric Michael addition reactions of unmodified ketones
to nitroalkenes were performed in PEGs catalyzed by novel
pyrrolidinyl-thioimidazolium salts to give products in up to
97% yield and 99% enantioselectivity; ESI mass spectrometric
detection for the first time gave evidence of the presence of the
PEG–organocatalyst host–guest complex.
Recently, a significant advantage of organocatalysis in mimicking
enzyme function in organic synthesis has been exhibited.1 In
particular, proline-based compounds have become attractively
powerful catalysts for asymmetric Michael addition of carbonyl
compounds to nitroalkenes, which have been studied extensively
due to their broad application.2 In this process the configuration of
the final Michael adducts is generally controlled by steric
hindrance or by hydrogen-bond donors of the substituent a to
the pyrrolidine nitrogen.3 On the other hand, it is also important to
recognize the functions and potential advantages associated with
the stereoelectronic effect of the solvent, which can provide a
reaction circumstance in favor of desired enamine configurations
and transition state stabilities. Therefore, development of a
strategy to improve organocatalytic performance in a favorable
solvent system is desirable. In this communication, we wish to
present a unique catalytic system for the Michael addition reaction
using chiral ionic organocatalysts in poly(ethylene glycol) (PEG)
media.
Scheme 1 Proposed catalytic system.
precursor (S)-(+)-2-bromomethylpyrrolidine hydrobromide was
synthesized from commercially available L-proline according to
our previous work.6 NMR, IR, HRMS and X-ray diffraction
analysis results confirmed their molecular structures (ESI{).
The Michael addition of cyclohexanone 4 to b-nitrostyrene 5
was selected as a model reaction (Table 1). As expected, to
our delight, apparent higher enantioselectivities were achieved
using 1–3 in PEGs than in DMSO and other conventional organic
solvents (entries 2–14). Moreover, PEG-800 led to a considerable
rate acceleration with yields reaching 58–84% after 2–3 days
(entries 12–14), while it took 6 days to reach 78–97% yields in
DMSO, 77% in DMF, 91% in MeOH, 66% in THF and even less
Liquid PEGs, as novel green solvents, have been attracting
increasing interest. Moreover, PEGs have especially been used as
phase-transfer catalysts for catalytic reactions since the ‘‘crown-
like’’ poly(ethylene oxide) chains can form complexes with metal
cations.4,5 Based on the metal cation coordination ability of PEGs,
we anticipated that an appropriate combination of PEGs and
organocatalysts, whose catalytic reactive unit have a positively-
charged group, might make it possible to form a unique host–guest
complex of PEG–organocatalyst and thus to develop an
alternative catalytic system for asymmetric organocatalysis
(Scheme 1).
The organocatalysts investigated herein were novel pyrrolidinyl-
thioimidazolium salts 1–3, which were designed and readily
synthesized by treating 2-mercapto-1-methylimidazole or analogs
with (S)-(+)-2-bromomethylpyrrolidine hydrobromide. Anion
metathesis of 1a with KY afforded 1b–1i (Scheme 2). The key
State Key Laboratory Breeding Base of Green Chemistry-Synthesis
Technology, Zhejiang University of Technology, Hangzhou, China.
E-mail: greenchem@zjut.edu.cn; Fax: +86 571 8832 0066;
Tel: +86 571 8832 0066
{ Electronic supplementary information (ESI) available: Experimental
procedures, spectra and crystallographic information. See DOI: 10.1039/
b708525g
Scheme 2 Synthesis of organocatalysts 1–3.
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Table 1 Catalytic asymmetric Michael addition of cyclohexanone 4
to b-nitrostyrene 5 in conventional organic solvents and PEGsa
Yieldb drc
Time/h (%)
eed (%)
32
Entry Catalyst Solvent
(syn/anti) (syn)
1
DMSO
10
93
91/9
L-Proline
1
2
3
1
2
3
4
5
DMSO
DMSO
DMSO
DMF
144
144
144
144
144
144
144
97
84
78
77
91
66
,10
59
63
54
84
79
58
95
94/6
92/8
93/7
93/7
90/10
95/5
78
75
78
76
73
81
N. D.
91
90
88
87
80
89
6
7
8
1
1
1
MeOH
THF
CH2Cl2
N. D.f
90/10
89/11
92/8
92/8
96/4
96/4
90/10
9
1
PEG-200 144
PEG-400 144
PEG-600 144
PEG-800 48
PEG-800 72
PEG-800 72
PEG-800 24
10
11
12
13
14
15
1
1
1
2
Fig. 1 ESI mass spectra: (a) PEG-800; (b) 1h–PEG-800.
Therefore, signals in the high mass region of Fig. 1(b) could be
assigned to ions of [PEG + 1h 2 PhCO22]+, which demonstrated
that the pyrrolidinyl-thioimidazolium cation could be completely
wrapped by PEG-800. In addition, it formed a 1 : 1 (molar ratio)
inclusion of PEG–catalyst-cation, as no other signals were
observed in a higher mass region than m/z 1400 of Fig. (1b).
The obtained facts also implied that PEGs with molecular weight
lower than 720 should be difficult to form stable complexes with
these ionic-organocatalysts due to their shorter poly(ethylene
oxide) chains, which coincided with the investigation result that
such apparent peak shifting was not found for lower molecular
weight PEGs such as PEG-200, PEG-400 and PEG-600.
The general utility of the novel PEG–organocatalyst system for
the asymmetric transformation was examined. The results are
summarized in Table 2. Various aryl nitroalkenes reacted smoothly
with 4 to afford high enantioselectivities (88–99%) in the catalytic
system 1h–PEG-800 (entries 1–10). Tetrahydropyran-4-one and
tetrahydrothiopyran-4-one were also suitable substrates as Michael
donors (entries 11–12).
3
36
L-Proline
16
17
18
19
20
21
22
23
24
a
1b
1c
1d
1e
1f
PEG-800 48
PEG-800 48
PEG-800 24
PEG-800 24
PEG-800 36
PEG-800 36
PEG-800 12
65
68
90
92
81
80
95
89
78
97/3
95/5
95/5
97/3
96/4
93/7
97/3
92/8
91/9
96
98
87
93
91
92
97
88
92
1ge
1h
1h
1i
DMSO 36
PEG-800 36
All reactions were conducted in solvent (2 mL) using 4 (1 mmol)
and 5 (0.5 mmol) in the presence of 20 mol% of the catalyst at room
b
c
temperature (25 uC). Isolated yield. Determined by GC-MS.
Determined by chiral HPLC analysis with CD detector (Daicel
d
e
Chiralpak AS-H).
N. D. = not determined.
Anion of 1g was b-naphthalenesulfonate.
f
than 10% in CH2Cl2 respectively (entries 2–8). In the case of the
non-ionic-organocatalyst L-proline, the reaction was almost not
improved in PEG-800 (entries 1 and 15). The influence effect of the
anion of the catalyst on the catalytic performance in PEG-800 was
also investigated. In contrast to Br2 anion, most anions screened
displayed positive effects on the activity and enantioselectivity
One of the noteworthy features of the present catalytic system is
its reusability. As shown in Table 3, the stable unsupported 1h–
PEG-800 system could be directly reused after adduct 6 had been
extracted with hexane–ether (6 : 1). Though the reaction time was
prolonged gradually, the desired 6 was obtained with steady good
yield, excellent enantioselectivity (94–97%) and diastereoselectivity
(¢93/7) even after seven recycles.
except anions BF4 and PF62, which showed negative effects on
2
the activity (entries 16–17). The greatest enhancement was
2
recorded from the choice of PhCO2 anion (1h), which afforded
95% yield and 97% ee after 12 h (entry 22). The present
improvement of ionic organocatalyst in PEG-800 unambiguously
indicated the synergistic effect of an appropriate PEG, which could
provide a favorable microenvironment for the catalysis.
In conclusion, we have developed novel pyrrolidinyl-thioimida-
zolium salts as chiral organocatalysts and described the unique
host–guest complex of PEG–ionic-pyrrolidine as a highly efficient
and reusable system for the direct enantioselective Michael
addition of ketones to nitroalkenes. Mass spectrometry analysis
results showed apparent evidence for PEGs’ coordination ability to
the ionic organocatalyst. The obtained facts may open new
opportunities and alternatives of the PEG-mediated construction
of chiral suprastructures and their intriguing prospects for
asymmetric organocatalysis.
Electrospray ionization (ESI) mass spectrometric detection gave
direct evidence supporting the presence of the presumed PEG–
organocatalyst complex, from which the synergistic action of
PEGs resulted.7 As shown in Fig. 1, signals in Fig. 1(a) could be
assigned to [PEG + Na]+ inclusions, whereas signals in the high
mass region of Fig. 1(b) (m/z 900–1400) were observed to be the
result of y175 Da shift from signals in Fig. 1(a) (m/z 720–1200)
respectively. For example, y175 Da shift from the signal at m/z
878.2 in Fig. 1(a) gave rise to the signal at m/z 1052.9 in Fig. 1(b).
The authors acknowledge the Ministry of Science and
Technology of China for the financial support of National Basic
Research Program of China (2003CB114400).
4394 | Chem. Commun., 2007, 4393–4395
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Table 2 Catalytic asymmetric Michael addition of ketones to nitroalkenes in 1h–PEG-800 systema
Entry
Adduct
X
Ar
Time/h
Yieldb (%)
drc (syn/anti)
eed (%) (syn)
1
2
3
4
5
6
7
8
7
8
9
C
C
C
C
C
C
C
C
C
C
O
S
o-MeO–C6H4
m-MeO–C6H4
p-MeO–C6H4
p-Me–C6H4
p-Cl–C6H4
p-CF3–C6H4
o-NO2–C6H4
2-Furanyl
2-Thioanyl
2-Naphthyl
Ph
12
12
12
24
12
48
48
12
12
12
12
12
97
90
79
87
94
90
78
96
75
88
87
70
93/7
96/4
97/3
93/7
93/7
94/6
96/4
90/10
94/6
90/10
95/5
96/4
94
93
99
99
98
99
88
94
92
96
99
90
10
11
12
13
14
15
16
17
18
9
10
11
12
a
Ph
All reactions were conducted in PEG-800 (2 mL) using ketone (1 mmol) and nitroalkene (0.5 mmol) in the presence of 20 mol% 1h.
Isolated yield. Determined by GC-MS. Determined by chiral HPLC analysis with CD detector (Daicel Chiralpak AS-H).
b
c
d
Table 3 Reusability of the catalytic system 1h–PEG-800
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4 For recent reviews dealing with poly(ethylene glycol), see: (a)
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Conversion
(%)
Yield
(%)
dr
(syn/anti)
ee (%)
(syn)
Recycle
Time/h
12
12
12
18
18
24
24
24
100
100
99
95
90
89
85
82
95
95
93
90
88
83
76
75
97/3
96/4
96/4
93/7
94/6
96/4
98/2
96/4
97
97
97
96
97
94
96
96
1
2
3
4
5
6
7
Notes and references
{ Crystal structure of 1f’s hydrobromide salt: CCDC 639780. For
crystallographic data in CIF format see DOI: 10.1039/b708525g
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KGaA, Weinheim, 2005; (c) B. List, Chem. Commun., 2006, 819; (d)
M. Marigo and K. A. Jørgensen, Chem. Commun., 2006, 2001.
2 For recent reviews dealing with enantioselective Michael addition
reactions, see: (a) M. Yamaguchi, Comprehensive Asymmetric Catalysis
I–III, ed. E. N. Jacobsen, A. Pfaltz and H. Yamamoto, Springer, New
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J. M. Betancort and C. F. Barbas, III, Org. Lett., 2001, 3, 3737; (c)
6 (a) D.-Q. Xu, S.-P. Luo, H.-D. Yue, L.-P. Wang, Y.-K. Liu and
Z.-Y. Xu, Synlett, 2006, 2569; (b) S.-P. Luo, D.-Q. Xu, H.-D. Yue,
L.-P. Wang, W.-L. Yang and Z.-Y. Xu, Tetrahedron: Asymmetry, 2006,
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7 The detected samples were mixtures of 1h (0.025 mmol) and/or PEG-800
(20 mg) in 1 mL ethyl acetate–methanol (3 : 1).
This journal is ß The Royal Society of Chemistry 2007
Chem. Commun., 2007, 4393–4395 | 4395