2-[(Imidazolylthio)methyl]pyrrolidine as a trifunctional organocatalyst for the highly asymmetric Michael addition of ketones to nitroolefins

Article abstract of DOI:10.1002/ejoc.200700856

The direct asymmetric Michael addition of ketones to nitroolefins catalyzed by 2-[(imidazol-2-ylthio)methyl]pyrrolidine, constructed from natural L-proline and imidazolylthio platforms, with salicylic acid as a co-catalyst has been developed to give the products in high yields (up to 95%) and with excellent enantioselectivities (up to 99% ee). The highly efficient catalytic performance may be attributed to the dual activation of the Michael substrates by the trifunctional organocatalysts and the co-catalyst salicylic acid, leading to the formation of a stable transition state complex through the synergic effect of hydrogen-bonding and electrostatic interactions. Wiley-VCH Verlag GmbH & Co. KGaA, 2008.

Full text of DOI:10.1002/ejoc.200700856

FULL PAPER
DOI: 10.1002/ejoc.200700856
2-[(Imidazolylthio)methyl]pyrrolidine as a Trifunctional Organocatalyst for the
Highly Asymmetric Michael Addition of Ketones to Nitroolefins
Dan-Qian Xu,[a] Li-Ping Wang,[a] Shu-Ping Luo,[a] Yi-Feng Wang,[a] Shuai Zhang,[a] and
Zhen-Yuan Xu*[a]
Keywords: Michael addition / Catalysis / Ketones / Nitroolefins / Organocatalysis
The direct asymmetric Michael addition of ketones to nitro-
olefins catalyzed by 2-[(imidazol-2-ylthio)methyl]pyrrolidine,
constructed from natural L-proline and imidazolylthio plat-
forms, with salicylic acid as a co-catalyst has been developed
to give the products in high yields (up to 95%) and with ex-
cellent enantioselectivities (up to 99% ee). The highly ef-
ficient catalytic performance may be attributed to the dual
activation of the Michael substrates by the trifunctional or-
ganocatalysts and the co-catalyst salicylic acid, leading to the
formation of a stable transition state complex through the
synergic effect of hydrogen-bonding and electrostatic inter-
actions.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2008)
Introduction
Organocatalysis has emerged as an important area of re-
search over the last decade. Compared with biocatalysts
and metal catalysts, organocatalysts are usually more stable,
more environmentally friendly, more readily available, less
expensive and can be applied in less demanding reaction
conditions, such as rigorously anhydrous or anaerobic con-
ditions. Therefore much attention has recently been paid
to the design and application of organocatalysts[1] with a
particular focus on the development of efficient small chiral
amine molecules for use in the asymmetric Michael ad-
dition of aldehydes or ketones to nitroolefins[2] due to the
versatility of the nitro functionality which can be easily
transformed into, for example, amine, nitrile oxide, ketone,
carboxylic acid, hydrogen.[3] -Proline[4] and chiral pyrrol-
idines in which a tertiary amino,[5] pyridyl,[6] pyrrolidinyl,[7]
tetrazolyl,[8] diphenyl(silyloxy)methyl,[9] sulfonamido,[10]
thiourea functionality[11] and others[12] replace the carboxy
group of -proline have been extensively investigated as or-
ganocatalysts for the Michael addition reaction (Figure 1).
In this process the pyrrolidine portion is regarded as a
unique backbone for the asymmetric catalysis which facili-
tates enamine- and imine-based transformations of alde-
hyde or ketone precursors and the configuration of the final
Michael adducts is generally controlled by steric hindrance
or by hydrogen-bond donors of the substituent groups α to
the pyrrolidine nitrogen atom.
Figure 1. Examples of pyrrolidine-based chiral organocatalysts.
Therefore, as part of a program aimed at developing new
organocatalysts, we herein report the behaviour of our
novel designed chiral 2-[(imidazol-2-ylthio)methyl]pyrrol-
idines (Scheme 1) in catalyzing the asymmetric Michael ad-
dition of ketones to nitroolefins. We envisioned that the
pyrrolidine portion serves as the catalytic site and the imid-
azole functionality in the pyrrolidine-based diamine motif
has the potential to enhance the enantioselectivity, while
the thioether moiety, which is found to be a very useful
[a] State Key Laboratory, Breeding Base of Green Chemistry, Syn-
thesis Technology, Zhejiang University of Technology,
Hangzhou 310014, China
Scheme 1. Synthesis of (imidazolylthio)methyl-pyrrolidine catalysts
1a–c.
Fax: +86-0571-88320066
E-mail: greenchem@zjut.edu.cn
Eur. J. Org. Chem. 2008, 1049–1053
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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D.-Q. Xu, L.-P. Wang, S.-P. Luo, Y.-F. Wang, S. Zhang, Z.-Y. Xu
FULL PAPER
functionality in coordination compounds, supramolecular Table 1. Performance of catalysts 1 and acid co-catalysts in the
asymmetric Michael addition of cyclohexanone (5) to β-nitrosty-
chemistry and nanomaterials, should benefit the formation
of a stable enamine- or imine-based transition state during
rene (6) in iPrOH at room temperature.[a]
the catalytic cycle through electrostatic interactions.
Results and Discussion
The novel designed trifunctional catalysts 1a–c were
Entry Catalyst Co-catalyst
Time
%
dr[c]
ee[d]
readily synthesized by etherification of 1-substituted 2-mer-
captoimidazole with (S)-(+)-2-(bromomethyl)pyrrolidine
hydrobromide (4) in refluxing MeCN, followed by neutral-
ization with NaOH (Scheme 1). The key precursor 4 was
prepared according to our previous work from commer-
cially available -proline by reduction with NaBH4/I2, a
neutralization step and bromination with PBr3.[13] NMR,
IR and HRMS analysis results were in full accordance with
their molecular structures, and the X-ray crystallographic
analysis result of N-(p-tolylsulfonyl)-1a, which was obtained
by treatment of 1a with p-toluenesulfonyl chloride, further
confirmed their relative configurations as described above
(Figure 2).[14]
[h] Yield[b] (syn/anti) (%)
1
2
3
4
5
6
7
8
1a
1b
1c
1a
1b
1c
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
–
–
–
HBr
HBr
HBr
HBF4
HPF6
CH3SO3H
CH3COOH
ClCH2COOH
CF3COOH
CH3(CH2)5COOH
HOOCCH2COOH
p-CH3C6H4SO3H
PhCOOH
o-OH-C6H4COOH
156
156
156
72
72
72
72
72
72
72
72
28
96
96
72
40
20
28
4
88:12
n.d.[e]
n.d.[e]
98:2
92:8
93:7
n.d.[e]
95:5
93:7
96:4
92:8
99:1
92:8
97:3
95:5
97:3
97:3
96:4
84
n.d.[e]
n.d.[e]
91
10
78
70
72
4
13
44
56
67
72
58
81
80
90
95
37
85
83
n.d.[e]
91
9
93
92
91
92
87
91
85
74
10
11
12
13
14
15
16
17
18
99
90
m-OH-C6H4COOH 96
[a] All reactions were conducted in iPrOH (2 mL) using 5 (1 mmol)
and 6 (0.5 mmol) in the presence of 20 mol-% of the catalysts. [b]
Isolated yield. [c] Determined by GC-MS. [d] Determined by chiral
HPLC analysis with a CD detector (Daicel Chiralpak AS-H, hex-
ane/iPrOH = 95:5). [e] n.d. = not determined.
The Michael addition reaction catalyzed by 1a with the
co-catalyst salicylic acid in various solvents at room tem-
Figure 2. X-ray crystal structure of N-(p-tolylsulfonyl)-1a.
To investigate the catalytic performance of 1, the Michael perature was next probed. As shown in Table 2, in weak
addition reaction of β-nitrostyrene (6) and 2 equiv. of cyclo- and non-polar solvents such as hexane, Et2O and CH2Cl2,
hexanone (5) was initially carried out in iPrOH at room the reactions were sluggish with 62–70% yields after 156 h,
temperature in the presence of 20 mol-% of the catalysts. although good enantioselectivities (85–89% ee) were ob-
As can be seen from the results summarized in Table 1, the served (entries 1–3). However, in THF and DMSO the
reaction was slow when treated with 1 alone without co- Michael reaction proceeded relatively smoothly to give 80–
catalysts, affording the Michael adduct 7 in low yields of 91% yields with a high enantioselectivity of 91% after 60–
less than 28% after 156 h (entries 1–3), because a powdery 72 h (entries 4 and 5). Among the conventional organic sol-
and insoluble solid side-product was formed which might vents investigated, the greatest enhancement was recorded
be the polymerization product of 6.[5b] To our delight, the with iPrOH, affording 95% yield and 99% ee within 20 h
addition of hydrobromic acid as co-catalyst increased dra- (entry 6). The reaction in H2O was very slow due to the
matically the catalytic activity to provide 70–78% yields and poor solubility of β-nitrostyrene (entry 7). At the same
a high level of diastereo- and enantioselectivity after 72 h time, the use of ionic liquids such as [BMIm]BF4 and
(entries 4–6). After screening various co-catalysts of various [BMIm]PF6 gave enantioselectivities of 86 and 72% and 70
acids, including HBF4, HPF6, TFA, TsOH (entries 7–18), and 65% yields after 156 h, respectively (entries 8 and 9).
salicylic acid was found to be the co-catalyst of choice for In addition, the reaction proceeded readily under solvent-
1a, which afforded 7 within 20 h in a high yield of 95% free conditions and 95% yield with 91% ee could be ob-
with excellent diastereo- and enantioselectivity of 97:3 and tained within 12 h (entry 10). Therefore, iPrOH was chosen
99% ee, respectively (entry 17). This observation highlights for further reactions.
the importance of the use of an acid co-catalyst with the
After optimization of the reaction conditions, the asym-
pyrrolidine-based diamine motif.[5–7] In addition, one fea- metric Michael additions of diverse unmodified ketones to
ture that seems to be favourable for the carboxylic acid co- a variety of nitroolefins promoted by 1a/salicylic acid were
catalysts is an adjacent hydrogen-bond donor (entries 16– conducted in iPrOH at room temperature. As shown in
18).
Table 3, cyclohexanone reacted readily with various sty-
1050
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© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 1049–1053

New Trifunctional Organocatalyst
Table 2. Solvent effects on the asymmetric Michael addition of cy- and enantioselectivities of 88–99% (entries 13 and 14). Lin-
clohexanone (5) to β-nitrostyrene (6) catalyzed by 1a/salicylic ac-
ear ketones and isovaleraldehyde also provided the desired
adducts in moderate enantioselectivities (entries 15–17).
id.[a]
Entry Solvent
Time
[h]
%
dr[c]
(syn/anti)
ee
On the basis of the experimental results described above
and Seebach and Pieraccini’s enamine-based reaction
mechanism,[15] a stereochemical model was developed to ac-
count for the high enantioselectivity of this Michael ad-
dition reaction. As shown in Scheme 2, multiple interac-
tions between nitrostyrene (6), salicylic acid and the en-
amine A, formed from the catalyst 1a and cyclohexanone
(5), occur to afford the complex B through two synergic
effects: 1) the electrostatic attractions of the electrophilic
nitro nitrogen of 6 and the thioether functional group[16]
and 2) hydrogen-bonding between the nitro oxygen of 6,
the hydroxy group of the salicylic acid and the protonated
imidazole moiety of the enamine A. Moreover, the solvent
of iPrOH may participate in an additional hydrogen-bond-
ing interaction with the carboxy group of salicylic acid
which results in the stabilization of carboxy anion of sali-
cylic acid. Consequently, this complex B may impose a
strong directing effect with the enamine A attacking the ac-
tivated nitrostyrene (6) from the Re face to predominately
give the Michael adduct 7, which is consistent with experi-
mental results.
Yield[b]
(%)[d]
1
2
3
4
5
6
7
8
9
hexane
Et2O
CH2Cl2
THF
DMSO
iPrOH
H2O
[BMIm]BF4
[BMIm]PF6
neat[e]
156
156
156
60
72
20
156
156
156
12
70
65
62
91
80
95
20
70
65
95
92:8
92:8
93:7
92:8
94:6
97:3
90:10
92:8
85:15
94:6
88
85
89
91
91
99
85
86
72
91
10
[a] Unless otherwise noted, all reactions were conducted in solvent
(2 mL) using 5 (1 mmol) and 6 (0.5 mmol) with 20 mol-% of 1a/
salicylic acid at room temperature. [b] Isolated yield. [c] Deter-
mined by GC–MS. [d] Determined by chiral HPLC analysis with
a CD detector (Daicel Chiralpak AS-H, hexane/iPrOH = 95:5). [e]
Cyclohexanone (2 mL) was used.
rene-type nitroolefins with high enantioselectivity (87–99%
ee, entries 1–9). The O- and S-heteroaromatic nitroolefins
could also be used as acceptors, giving the corresponding
Michael adducts in 85 and 90% yields with 78 and 92%
ee, respectively (entries 10 and 11). Cyclopentanone worked
well to give the desired adduct with an excellent enantio-
selectivity of 95% (entry 12). Tetrahydropyran-4-one and
tetrahydrothiopyran-4-one were suitable substrates as do-
nors as well, providing the products in yields of 90–91%
Table 3. Asymmetric Michael addition of ketones to nitroolefins in
iPrOH catalyzed by 1a/salicylic acid.[a]
Entry
Adduct
%
dr[c]
Yield[b] (syn/anti)
ee[d]
(%)
R1–R2
R3
1
2
3
4
5
6
7
8
–(CH2)4–
–(CH2)4–
–(CH2)4–
–(CH2)4–
–(CH2)4–
–(CH2)4–
–(CH2)4–
–(CH2)4–
–(CH2)4–
o-MeOC6H4
p-MeOC6H4
p-MeC6H4
p-ClC6H4
o-BrC6H4
m-BrC6H4
p-CF3C6H4
o-NO2C6H4
2-naphthyl
2-furanyl
2-thienyl
Ph
94
89
92
92
95
83
86
85
91
85
90
88
90
91
50
82
85
91:9
94:6
97:3
92:8
92:8
87:13
93:7
80:20
98:2
85:15
86:14
83:17
98:2
87:13
–
94
99
99
87
95
96
95
89
96
78
92
95
99
88
63
56
63
Scheme 2. Plausible reaction mechanism for the Michael addition
of cyclohexanone (5) to nitrostyrene (6) with 1a/salicylic acid.
Conclusions
9
10
11
12
13
14
15
16
17[e]
–(CH2)4–
–(CH2)4–
–(CH2)3–
In summary, trifunctional organocatalysts based on 2-
[(imidazol-2-ylthio)methyl]pyrrolidines 1 have been de-
signed and readily synthesized from commercially available
-proline. The catalytic system of compound 1a and sali-
cylic acid in iPrOH demonstrated high yields (83–95%) and
good enantioselectivities (78–99% ee) in the Michael ad-
dition of unmodified cyclohexanones to various aromatic
nitroolefins. The key to the highly efficient catalytic per-
formance might be the dual activation of the Michael sub-
strates by the organocatalyst 1a and the co-catalyst salicylic
acid which leads to the formation of complex B through
the synergic effect of hydrogen-bonding and electrostatic in-
–CH2CH2OCH2–
–CH2CH2SCH2–
Ph
Ph
Ph
Ph
CH3
CH3
H
iPr
H
iPr
–
Ph
80:20
[a] All reactions were conducted in iPrOH (2 mL) using ketones
(1 mmol) and nitroolefins (0.5 mmol) with 20 mol-% of 1a/salicylic
acid. [b] Isolated yield. [c] Determined by GC-MS. [d] Determined
by chiral HPLC analysis with a CD detector. [e] The product with
the 2R,3S configuration was observed which resulted from a Si-
face attack on the aldehyde-derived enamine.[10b]
Eur. J. Org. Chem. 2008, 1049–1053
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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1051

D.-Q. Xu, L.-P. Wang, S.-P. Luo, Y.-F. Wang, S. Zhang, Z.-Y. Xu
FULL PAPER
127.3, 127.9, 128.8, 128.9, 136.9, 140.2 ppm. IR (KBr): ν = 3388,
˜
teractions in the enamine-based mechanism. Further in-
vestigations on the application of these trifunctional cata-
lysts in asymmetric organocatalysis are currently in progress
and results will be reported in due course.
3029, 2928, 2708, 1604, 1496, 1454, 1358, 715, 693 cm–1. MS (ESI):
m/z = 274 [M – Br]+. HRMS (ESI+): calcd. for [C15H20N3S]+
274.1372; found 274.1380.
Typical Experimental Procedure for the Asymmetric Michael Ad-
dition of Ketones to Nitroolefins: Cyclohexanone (5) (98 mg,
1 mmol) was added to a solution of nitrostyrene (6) (74.5 mg,
0.5 mmol), catalyst 1a (19.7 mg, 0.1 mmol) and salicylic acid
(13.8 mg, 0.1 mmol) in iPrOH (2 mL). The mixture was stirred at
room temperature until completion of the reaction (by GC moni-
toring) H2O was added to the reaction mixture to give an infusible
substance. After filtration the residue was dissolved in ethyl acetate
and purified by preparative TLC (hexane/CHCl3 = 4:1) to afford
the Michael adduct 7 (117.3 mg, 95%). The ee of the product was
determined by chiral HPLC analysis with a CD detector [(Daicel
Chiralpak AS-H, hexane/iPrOH = 95:5, flow rate 1.0 mL/min, λ =
254 nm): tR = 14.28 (minor), 20.84 min (major)]. 1H NMR
(400 MHz, CDCl3, 25 °C): δ = 1.19–2.72 (m, 9 H, cycl), 3.75 (ddd,
J = 10, 10, 4.8 Hz, 1 H), 4.63 (dd, J = 12.4, 10 Hz, 1 H), 4.95 (dd,
J = 12.4, 4.8 Hz, 1 H), 7.16–7.34 (m, 5 H) ppm. MS (EI): m/z (%)
= 55 (30), 77 (12), 91 (63), 104 (34), 115 (25), 141 (15), 157 (13),
171 (100), 183 (21), 200 (60), 247 (1).
Experimental Section
General: All the starting chemicals were commercial products (Ald-
rich or J&K Chemica) of analytical grade. Organic solvents were
dried and purified before use by the usual methods. 1H and 13C
NMR spectra were recorded with a Varian NMR spectrometer.
Chemical shifts are given in δ relative to tetramethylsilane (TMS).
Coupling constants J are given in Hz. IR spectra were obtained
with a Bruker EQUINOX 55 spectrometer. Electrospray ionization
(ESI) mass spectrometry was performed with a Finnigan LCQ Ad-
vantage spectrometer. ESI-HRMS spectra were obtained with a
Bruker APEX III FTICR mass spectrometer. GC-MS experiments
were performed with an Agilent 6890N GC system equipped with
a 5973N mass-selective detector. HPLC experiments were carried
out using a JASCO LC-2000 Plus system consisting of MD and
CD detectors.
Synthesis and Characterization of 2-[(Imidazol-2-ylthio)methyl]pyr-
rolidine Catalysts 1: (S)-(+)-2-(Bromomethyl)pyrrolidine hydrobro-
mide (4) was prepared, in accord with our previous work, from
commercially available -proline by reduction with NaBH4/I2, a
neutralization step and bromination with PBr3.[13] Then a mixture
of the 1-substituted 2-mercaptoimidazole (10 mmol) and (S)-(+)-2-
(bromomethyl)pyrrolidine hydrobromide (4) (2.45 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 recrystallized from EtOH and then neutralized by NaOH to
pH 12. After extraction with CH2Cl2 (3ϫ10 mL), the solvent was
removed to afford 1.
Acknowledgments
This work was supported by the National Natural Science Founda-
tion of China (No. 20772110).
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3-Methyl-2-[(2S)-(pyrrolidin-2-yl)methylthio]-3H-imidazol-1-ium
Bromide (Hydrobromide Salt of 1a): 1H NMR (400 MHz, [D6]-
DMSO, 25 °C): δ = 1.68–1.77 (m, 1 H), 1.83–1.98 (m, 2 H), 2.07–
2.16 (m, 1 H), 3.19–3.22 (m, 2 H), 3.35–3.42 (m, 2 H), 3.61 (s, 3
H), 3.81–3.84 (m, 1 H), 7.01 (d, J = 1.6 Hz, 1 H), 7.33 (d, J =
1.6 Hz, 1 H), 9.36 (br. s, 2 H) ppm. 13C NMR (100 MHz, [D6]-
DMSO, 25 °C): δ = 23.4, 29.2, 33.2, 34.4, 44.6, 59.1, 123.6, 127.9,
139.7 ppm. IR (KBr): ν = 3418, 3107, 2953, 2748, 1631, 1461,
˜
687 cm–1. ESI-MS: m/z = 198 [M – Br]+, 79 and 81 [Br]–. HRMS
(ESI+): calcd. for [C9H16N3S]+ 198.1059; found 198.1056.
3-Phenyl-2-[(2S)-(pyrrolidin-2-yl)methylthio]-3H-imidazol-1-ium
Bromide (Hydrobromide Salt of 1b): 1H NMR (400 MHz, [D6]-
DMSO, 25 °C): δ = 1.69–1.76 (m, 1 H), 1.84–1.98 (m, 2 H), 2.06–
2.14 (m, 1 H), 3.16–3.26 (m, 2 H), 3.39–3.51 (m, 2 H), 3.86–3.92
(m, 1 H), 7.17 (d, J = 1.6 Hz, 1 H), 7.47–7.53 (m, 3 H), 7.55–7.60
(m, 3 H), 9.27 (br. s, 2 H) ppm. 13C NMR (100 MHz, [D6]DMSO,
25 °C): δ = 23.5, 29.4, 34.5, 44.9, 58.8, 123.3, 125.2, 128.5, 129.1,
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129.5, 136.5, 140.5 ppm. IR (KBr): ν = 3427, 3086, 2961, 2722,
˜
1593, 1498, 1478, 1344, 767, 695 cm–1. MS (ESI): m/z = 260 [M –
Br]+. HRMS (ESI+): calcd. for [C14H18N3S]+ 260.1216; found
260.1221.
3-Benzyl-2-[(2S)-(pyrrolidin-2-yl)methylthio]-3H-imidazol-1-ium
Bromide (Hydrobromide Salt of 1c): 1H NMR (400 MHz, [D6]-
DMSO, 25 °C): δ = 1.68–1.76 (m, 1 H), 1.83–1.98 (m, 2 H), 2.06–
2.12 (m, 1 H), 3.18–3.24 (m, 2 H), 3.34 (s, 2 H), 3.35–3.49 (m, 2
H), 3.87–3.91 (m, 1 H), 7.17 (d, J = 1.6 Hz, 1 H), 7.46–7.53 (m, 3
H), 7.56–7.60 (m, 1 H), 9.20 (br. s, 2 H) ppm. 13C NMR (100 MHz,
[D6]DMSO, 25 °C): δ = 23.6, 29.4, 35.2, 45.0, 49.6, 59.3, 123.2,
1052
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Received: September 12, 2007
Published Online: December 14, 2007
Eur. J. Org. Chem. 2008, 1049–1053
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