2-pyrrolidinecarboxylic acid ionic liquid as a highly efficient organocatalyst for the asymmetric one-pot Mannich reaction

Article abstract of DOI:10.1002/ejoc.200901088

A. novel one-pot: three-component asymmetric Mannich reaction using [EMIm][PrO] (1) as a catalyst has been developed. By employing this new reaction system, a variety of optically active ss-amino carbonyl compounds were synthesized in up to 99% yield with up to >99 dr and >99% ee. The reaction conditions have been optimized and the mechanism for the asymmetric induction is discussed.

Full text of DOI:10.1002/ejoc.200901088

FULL PAPER
DOI: 10.1002/ejoc.200901088
2-Pyrrolidinecarboxylic Acid Ionic Liquid as a Highly Efficient Organocatalyst
for the Asymmetric One-Pot Mannich Reaction
Xin Zheng,[a] Yun-Bo Qian,[a] and Yongmei Wang*[a]
Keywords: Asymmetric synthesis / Ionic liquids / Organocatalysis / Enantioselectivity
A novel one-pot three-component asymmetric Mannich reac-
tion using [EMIm][Pro] (1) as a catalyst has been developed.
By employing this new reaction system, a variety of optically
active β-amino carbonyl compounds were synthesized in up
to 99% yield with up to Ͼ99 dr and Ͼ99% ee. The reaction
conditions have been optimized and the mechanism for the
asymmetric induction is discussed.
tions[13] and an increasing number of Mannich-type reac-
tions catalyzed by ionic liquids, we proposed that the com-
bination of proline as an effective module with ionic liquids
could catalyze enantioselective Mannich reactions. Pre-
viously we reported that a CIL with (S)-proline as the anion
[1-ethyl-3-methylimidazolium (S)-2-pyrrolidinecarboxylic
acid salt [EMIm][Pro] (1)] could facilitate the asymmetric
Michael addition reaction by the enamine mechanism.[14]
This CIL is readily available from simple and inexpensive
starting materials (proline and 1-methyl-1H-imidazole) and
we routinely prepare it on a large scale. Herein, we disclose
an efficient protocol for the direct enantioselective one-pot
three-component Mannich reaction catalyzed by [EMIm]-
[Pro] (1), which affords the corresponding adducts with
high diastereo- (up to Ͼ99) and enantioselectivities (up to
Ͼ99%). To the best of our knowledge, this is the first asym-
metric Mannich reaction induced by a CIL and it may sig-
nificantly extend the design and application of CILs in or-
ganic synthesis.
Introduction
The Mannich reaction occupies an important position in
the field of organic synthesis for the construction of enan-
tiomerically enriched β-amino carbonyl motifs such as
amino acids, amino alcohols, and their derivatives.[1] It has
emerged as a crucial synthetic methodology for accessing
key intermediates in the synthesis of natural products as
well as pharmaceutically valuable compounds.[1f,1g–1l] Over
the past decade, Lewis acids,[2] Lewis bases,[3] Brønsted ac-
ids,[4] and rare metal salts[5] have been investigated as cata-
lysts in Mannich-type reactions. Recently, the development
of asymmetric Mannich reactions has attracted consider-
able attention. Since List and co-workers[6] first reported
a direct organocatalytic one-pot three-component Mannich
reaction catalyzed by proline, proline-derived tetrazole,[7]
acylic amino acids and their derivatives,[8] and chiral phos-
phoric acids[9] have also been successfully utilized as enan-
tioselective organocatalysts in this type of transformation.
In recent years, a growing number of chiral ionic liquids
(CILs) have been considered as extremely promising green
reaction media,[10] not only because of their favorable prop-
erties, including reusability, nonvolatile nature and high
thermal stability, but also because of their unique selectivity
and reactivity, avoiding the use of expensive and/or toxic
metals. Furthermore, ionic liquids have currently been em-
ployed either as catalysts or as solvents in a large number
of reactions,[11] especially in direct and indirect Mannich
reactions.[12] However, no CIL has been reported as a cata-
lyst in direct or indirect asymmetric Mannich reactions.
In view of a myriad of examples employing proline as a
successful organocatalyst in asymmetric Mannich reac-
The amino acid ionic liquid [EMIm][Pro] (1) was easily
synthesized in 70% overall yield by the published pro-
cedure[15] (Scheme 1).
[a] Department of Chemistry, The Key Laboratory of Elemento-
Organic Chemistry, Nankai University,
Tianjin 300071, China
Scheme 1. Synthesis of the chiral amino acid ionic liquid 1-ethyl-
3-methylimidazolium (S)-2-pyrrolidinecarboxylic acid salt [EMIm]-
[Pro] (1). Reagents and conditions: a) CH3CH2Br, CH3CO2C2H5,
∆, 80%; b) 201ϫ7 styrene-DVB; c) proline, 70%.
Fax: +86-22-2350-2654
E-mail: ymw@nankai.edu.cn
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Table 1. Examples of solvents screened for the direct asymmetric
Results and Discussion
Mannich reaction of 2a, 3a and 4a.[a]
We initially examined the three-component Mannich re-
action of cyclohexanone (2a), p-anisidine (3a), and p-ni-
trobenzaldehyde (4a) in CH2Cl2 at room temperature in the
presence of 30 mol-% [EMIm][Pro] (1). [EMIm][Pro] (1)
proved to be a viable catalyst for this direct Mannich reac-
tion, affording the syn isomer 5a with 78% ee, although the
yield and dr were not satisfactory (Table 1, entry 1). In light
of these results, we screened a variety of solvents. When
the reaction was performed in DMF or DMSO, the desired
product 5a was isolated in good yield (66–78%) with excel-
lent enantioselectivity (80–86%) within 24 h (Table 1, en-
tries 9 and 12). Other solvents, such as THF, hexane, and
[BMIm][PF6], were found to be less satisfactory in terms
of the yield and enantioselectivity (Table 1, entries 2–8). To
accelerate the reaction and improve the diastereo- and
enantioselectivity, we added 2 equiv. of water to the reac-
tion mixture. As expected, the addition of excess water to
the reaction mixture had a significant effect on both the
diastereo- and enantioselectivity of the Mannich product.
The enantioselectivity increased to 90% ee and the yield
was 80%, albeit in roughly equal amounts of both the syn
and anti isomers (Table 1, entry 13). Reducing the amount
of water to 1 equiv. led to improved stereoselectivity, fur-
nishing the corresponding product in 82% yield with an
approximately 3:1 dr and 90% ee (Table 1, entry 14). Fur-
ther decreasing the amount of water to 0.5 equiv. did not
lead to an improvement in the ratio of diastereoisomers or
the enantioselectivity. Thus, the inclusion of water in these
reactions proved to be favorable for obtaining high dia-
stereo- and enantioselectivities and enhancing the reaction
rate.[16] Importantly, lowering the catalyst loading to
10 mol-% did not compromise the ee of the reaction (77:23
dr, 90% ee) (Table 1, entry 18).
Entry Catalyst
[mol-%]
Solvent Temp. Yield dr (syn/anti)[c,d] ee (syn)
[°C] [%][b]
[%][d]
1
2
3
4
5
6
7
8
30
30
30
30
30
30
30
30
30
30
30
30
30
30
30
30
20
10
CH2Cl2
CH3CN
EtOH
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
45
51
65
35
33
37
24
32
66
68
62
78
80
82
85
73
70
67
56:44
51:49
73:27
55:45
61:39
71:29
66:34
56:43
52:48
71:29
82:18
67:33
56:44
72:28
68:32
81:19
68:32
77:23
78
78
58
82
78
84
82
82
80
90
97
86
90
90
88
93
88
90
THF
hexane
dioxane
EtOAc
[BMIm][PF6] r.t.
9
DMF
DMF
r.t.
0
10[e]
11[e]
12
DMF
–20
r.t.
r.t.
r.t.
r.t.
0
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
13[f]
14[g]
15[h]
16[g,e]
17[g,e]
18[g,e]
r.t.
r.t.
[a] The reaction was performed using cyclohexanone (2a; 2 mmol,
10 equiv.), 4-nitrobenzaldehyde (4a; 0.22 mmol, 1.1 equiv.), p-anisi-
dine (3a; 0.2 mmol, 1 equiv.) and 1 (0.06 mmol, 0.3 equiv.) in a sol-
vent (0.5 mL) for 24 h. [b] Isolated yields of the product 5a after
column chromatography. [c] Determined by 1H NMR spectroscopy.
[d] Determined by chiral-phase HPLC using a Daicel Chiralpak
AD-H column. [e] After 48 h. [f] 2 equiv. of H2O was added. [g]
1 equiv. of H2O was added. [h] 0.5 equiv. of H2O was added.
In addition, the [EMIm][Pro]-catalyzed Mannich reac- line resulted in the formation of product 5j with 77:23 dr
tion was extremely sensitive to the reaction temperature. and 91% ee (Table 2, entry 10).
The expected product 5a was generated in DMF at 0 °C
Acyclic ketones were also examined as asymmetric Man-
with approximately 3:1 dr and 90% ee (Table 1, entry 10). nich donors. Excellent diastereo- (up to Ͼ99) and enantio-
Reduction of the temperature to –20 °C gave the highest selectivities (up to Ͼ99%) were achieved under the same
diastereo- and enantioselectivity (about 5:1 dr, 97% ee) reaction conditions (Table 2, entries 11 and 12). The reac-
(Table 1, entry 11). This is an improvement compared with tion with 2-butanone (Table 2, entry 11) is highly regioselec-
the proline-catalyzed direct three-component Mannich re- tive as shown by the facts that carbon–carbon formation
action performed at room temperature[6a,6b] (50% yield, 2:1 occurred predominantly at the more substituted α-carbon
dr and 84% ee).
atom and no aldol product was observed in contrast to the
Given the remarkable performance of [EMIm][Pro] (1) in reaction catalyzed by proline (furnished a 2.5:1 regioisom-
DMF at –20 °C, we next investigated the scope of the reac- eric mixture).[6b]
tion using cyclohexanone (2a) as the ketone donor, a set
To broaden the scope of this transformation, hydroxyace-
of different benzaldehyde derivatives as acceptors, and two tone was used as a nucleophile to generate 1,2-amino
aniline derivatives. The results are illustrated in Table 2 (en- alcohol derivatives. Initially, the reaction was complete
tries 1–10) and show that the reaction proceeded smoothly within 3 h in DMSO at room temperature, typically afford-
in moderate yields (48–65%) with up to 94:6 dr and excel- ing only one product in higher yields and ee values than in
lent levels of enantioselectivity (90–99%). Only trace DMF at –20 °C (Table 2, entries 13 and 14, 21 and 22). Un-
amounts of aldol addition side-products were observed. der the optimized conditions, a series of aromatic aldehydes
Note that the reaction proceeded smoothly with different were treated with hydroxyacetone, giving rise to the corre-
kinds of aromatic aldehydes bearing either electron-with- sponding amino alcohol derivatives (5m–5t) in yields of up
drawing or -donating groups. For example, the reaction be- to 99% with up to Ͼ99 dr and Ͼ99% ee (Table 2, en-
tween cyclohexanone (2a), p-methylbenzaldehyde, and ani- tries 13–22). In particular, carbon–carbon bond formation
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2-Pyrrolidinecarboxylic Acid Ionic Liquid as an Organocatalyst
Table 2. Direct asymmetric Mannich reactions catalyzed by [EMIm][Pro] (1).[a]
Entry
Ketone
R3
R4
Product
Temp. [°C] Time [h] Yield [%][b] dr (syn/anti)[c,d] ee (syn)[%][d]
1
2
3
4
5
6
7
8
2a
OMe
OMe
H
H
H
H
H
H
H
NO2
CN
NO2
Cl
CN
F
5a
5b
5c
5d
5e
5f
5g
5h
5i
–20
–20
–20
–20
–20
–20
–20
–20
–20
–20
–20
–20
r.t.
–20
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
–20
48
48
36
36
18
36
36
36
18
36
72
48
3
12
3
3
3
3
3
3
3
12
62
65
56
49
53
48
59
57
58
48
60
49
97
90
78
88
98
92
98
96
99
91
82:18
54:46
74:26
92:8
86:14
89:11
94:6
87:13
80:20
77:23
98:2
Ͼ99
95:5
97:3
94:6
91:9
95:5
94:6
91:9
93:7
Ͼ99
Ͼ99
97
90
95
98
98
96
99
97
99
91
97
Ͼ99
99
97
95
96
98
97
93
93
98
97
2a
2a
2a
2a
2a
2a
H
Br
2a
9
2a
CF3
CH3
NO2
NO2
CN
CN
NO2
NO2
Cl
F
H
CH3
Br
Br
10
11
12
13
14
15
16
17
18
19
20
21
22
2a
H
OMe
H
5j
5k
5l
R1 = H, R2 = CH3
R1 = CH3, R2 = CH3
R1 = H, R2 = OH
R1 = H, R2 = OH
R1 = H, R2 = OH
R1 = H, R2 = OH
R1 = H, R2 = OH
R1 = H, R2 = OH
R1 = H, R2 = OH
R1 = H, R2 = OH
R1 = H, R2 = OH
R1 = H, R2 = OH
OMe
OMe
OMe
H
OMe
OMe
OMe
OMe
OMe
OMe
5m
5m
5n
5o
5p
5q
5r
5s
5t
5t
[a] Reaction conditions: see the Exp. Sect. [b] Isolated yields after column chromatography. [c] Determined by 1H NMR spectroscopy
chiral-phase HPLC. [d] Determined by chiral-phase HPLC using a Daicel Chiralpak AD-H column.
with hydroxyacetone selectively occurred at the carbon nitrogen atom of the imidazolium moiety of the catalyst. A
bearing the hydroxy group. Furthermore, most compounds switch of the facial selectivity is disfavored because of steric
exhibited higher stereoselectivities and yields than proline repulsion between the Ar group of the imine and the imid-
under mild conditions.[6b]
azolium moiety of the catalyst.
The absolute configurations of the Mannich products
were determined by 1H NMR analysis, from the chiral-
phase HPLC retention times as well as by comparison with
the literature.[6a,6b]
On the basis of the previous mechanism for proline-cata-
lyzed Mannich reactions, we reasoned that this asymmetric
Mannich reaction could also proceed by an enamine path-
way because nucleophilic addition of the in situ generated
enamine would be faster to an imine than to an alde-
hyde.[6a,6b] As shown in Scheme 2, the reaction starts with
enamine I activation of the cyclohexanone by the proline
anion and an electrostatic interaction with the imidazolium
moiety of the catalyst. In a second pre-equilibrium, the al-
dehyde and the aniline form an imine. Then enamine-acti-
vated I reacts with the imine to form II via transition state
A. The last step is a dehydration reaction to afford the cor-
recponding product 5 (Figure 1). The catalyst 1 is regener-
ated in the subsequent step. The stereochemical results can
be explained by the plausible transition state A. Because
additional water is added and the reaction is conducted in
wet solvents, the transition state is stabilized by hydrogen-
Scheme 2. Proposed mechanism for the 1-catalyzed asymmetric
bonding between the nitrogen atom of the imine and the one-pot Mannich reaction.
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an anion-exchange resin (201ϫ7 Styrene-DVB). An aqueous solu-
tion of [EMIm]OH was added dropwise to a slight excess of an
aqueous proline (6.9 g, 0.06 mol) solution. After stirring for 24 h
at room temp., water was evaporated at 50 °C under vacuum. Ace-
tonitrile (90 mL) and methanol (10 mL) were added to the residue
and the mixture was stirred vigorously. The excess proline was then
filtered. The filtrate was evaporated to remove the solvents and the
product [EMIm][Pro] was dried in vacuo for 24 h at 80 °C; yield
Figure 1. Proposed structure of transition state A.
1
9.84 g (87.5%). H NMR (300 MHz, [D6]DMSO, 25 °C): δ = 9.67
(s, 1 H, imidazole), 7.87 (s, 1 H, imidazole), 7.79 (s, 1 H, imidazole),
4.25 (q, J = 10.17 Hz, 2 H, N-CH2), 3.90 (s, 3 H, N-CH3), 3.32
(br., 1 H, CH pyrrolidine), 2.97–3.05 (m, 1 H, CH pyrrolidine),
2.72 (br., 1 H, CH pyrrolidine), 1.83–1.90 (m, 1 H, CH pyrrolidine),
1.69–1.74 (m, 1 H, CH pyrrolidine), 1.53–1.59 (m, 2 H, CH2 pyr-
rolidine), 1.42 (t, J = 7.30, 7.30 Hz, 3 H, CH3-CH2) ppm. 13C
NMR (75 MHz, [D6]DMSO): δ = 176.0, 136.9, 123.5, 121.9, 61.8,
Conclusions
We have reported herein the first employment of CIL
[EMIm][Pro] (1) as a catalyst for the one-pot three-compo-
nent asymmetric Mannich reaction with excellent chemo-,
regio-, and enantioselectivities either under mild conditions
or at a low temperature. The desired products were isolated
in up to 99% yield and with up to Ͼ99 dr and Ͼ99% ee.
Additionally, this catalyst is readily prepared from rather
inexpensive starting materials and the reactions could be
conducted in wet solvent without an inert atmosphere. The
proposed mechanism and transition state have been dis-
cussed on the basis of the stereochemistry of the corre-
sponding Mannich products. Hence, the study demonstrates
that [EMIm][Pro] is a promising organocatalyst for the syn-
thesis of enantioenriched β-amino carbonyl molecules. Fur-
ther investigations of this novel transformation and the syn-
thetic applications of [EMIm][Pro] are underway.
+
46.4, 44.0, 35.5, 30.6, 25.3, 15.1 ppm. ESI-MS: calcd. for C6H11N2
111.09 [M]+; found 111.21; calcd. C5H8NO2 114.06 [M]–; found
–
114.21.
General Procedure for One-Pot Three-Component Asymmetric Man-
nich Reaction for Solvent Screening: See Table 1. A 25 mL round-
bottomed flask was charged with p-anisidine (25 mg, 0.2 mmol), 4-
nitrobenzaldehyde (33 mg, 0.22 mol), [EMIm][Pro] (1; 13 mg,
0.06 mol), and solvent (0.5 mL). After being stirred vigorously for
1 h at room temperature until the imine had formed, as monitored
by TLC, cyclohexanone (0.2 mL, 2 mmol) was added to the mix-
ture. When the reaction was finished, the reaction mixture was
worked up by adding saturated ammonium chloride and then ex-
tracted with AcOEt. The organic layers were washed with water,
dried with Na2SO4, filtered, concentrated under vacuum, and puri-
fied by flash column chromatography (ethyl acetate/hexane, 1:2) to
afford the adducts as a syn/anti mixture. The anti and syn dia-
stereomers could not be discriminated by TLC.
General Procedure for the Catalytic Asymmetric Mannich Reaction
at Room Temperature: See Table 2. A 25 mL round-bottomed flask
was charged with p-anisidine or aniline (0.2 mmol, 1 equiv.), alde-
hyde (0.22 mol, 1.1 equiv.), [EMIm][Pro] (1) (0.06 mol, 0.3 equiv.),
H2O (0.2 mmol, 1 equiv.), and DMSO (0.5 mL). After being stirred
vigorously for 1 h at room temperature until the imine had formed,
as monitored by TLC, ketone (2 mmol, 10 equiv.) was added to the
mixture. When the reaction was finished, the reaction mixture was
worked up by adding saturated ammonium chloride and then ex-
tracted with AcOEt. The organic layers were washed with water,
dried with Na2SO4, filtered, concentrated under vacuum, and puri-
fied by flash column chromatography (ethyl acetate/hexane, 1:2) to
afford the adducts as a syn/anti mixture. The anti and syn dia-
stereomers could not be discriminated by TLC.
Experimental Section
General: Commercial reagents were used as received unless other-
1
wise stated. H and 13C NMR spectra were recorded with either a
Bruker-DPX 400 or AV-400 spectrometer. Chemical shifts (δ) are
reported in ppm relative to tetramethylsilane with the solvent reso-
nance as the internal standard. Coupling constants (J) are given
in Hz. HRMS data were recorded with an IonSpec FT-ICR mass
spectrometer with an ESI source. HPLC analysis was performed
with a Shimadzu CTO-10AS instrument using a Chiralpak AD-H
column purchased from Daicel Chemical Industries. All Mannich
products are known compounds (see Table 3 and footnotes) and
exhibited spectroscopic and analytical data in agreement with their
structures. The configurations of the products were assigned by
comparison with literature data (Table 3).
General Procedure for the Catalytic Asymmetric Mannich Reaction
at –20 °C: See Table 2. A 25 mL round-bottomed flask was charged
with p-anisidine or aniline (0.2 mmol, 1 equiv.), aldehyde (0.22 mol,
1.1 equiv.), [EMIm][Pro] (1; 0.06 mol, 0.3 equiv.), and DMF
(0.5 mL). After being stirred vigorously for 1 h at room tempera-
ture until the imine had been consumed, as monitored by TLC,
the reaction mixture was cooled to –20 °C and ketone (2 mmol,
10 equiv.) was added to the mixture. When the reaction was fin-
ished, the reaction mixture was worked up by adding saturated am-
monium chloride and then extracted with AcOEt. The organic lay-
ers were washed with water, dried with Na2SO4, filtered, concen-
trated under vacuum, and purified by flash column chromatog-
raphy (ethyl acetate/hexane, 1:2) to afford the adducts as a syn/anti
mixture. The anti and syn diastereomers could not be discriminated
by TLC.
Synthesis of Amino Acid Ionic Liquid [EMIm][Pro] (1):[15] Under
vigorous stirring, freshly distilled bromoethane (58.2 g, 0.53 mol)
was added dropwise over 1 h to a solution of 1-methylimidazole
(20.6 g, 0.25 mol) in ethyl acetate (60 mL). The mixture, already
turbid, was heated at reflux for 6 h. When the reaction was cooled
to room temp., it was filtered and the white solid filtrate ([EMIm]-
Br) was washed twice with ethyl acetate (20 mL, each). After
recrystallization from a mixture of acetonitrile and ether acetate,
[EMIm]Br was dried on a Rotavapor for 1 h at 70 °C under
0.1 mbar of pressure: Yield: 38.4 g of white solid (80%). Then an
aqueous solution of 1-ethyl-3-methylimidazolium hydroxide
([EMIm]OH) was prepared from[EMIm]Br (9.55 g, 0.05 mol) using
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2-Pyrrolidinecarboxylic Acid Ionic Liquid as an Organocatalyst
1
Table 3. Selected H NMR spectroscopic data for diastereoisomers and HPLC data for enantiomers of Mannich adducts.
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Table 3. (Continued).
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2-Pyrrolidinecarboxylic Acid Ionic Liquid as an Organocatalyst
[7]
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This work was supported financially by the National Natural Sci-
ence Foundation of China (Grant No. 20672061). We also thank
the Nankai University State Key Laboratory of Elemento-organic
Chemistry for their support.
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