Highly efficient AILs/L-proline synergistic catalyzed three-component asymmetric Mannich reaction

Article abstract of DOI:10.1080/00397910601163976

A three-component asymmetric Mannich reaction of isovaleraldehyde, methyl ketones, and aromatic amines was efficiently synergistic catalyzed by amide-task-specific ionic liquids (AILs)/L-proline under mild conditions. The corresponding asymmetric Mannich reaction adducts were obtained in moderate to high yields and stereo selectivity in all the cases tested. The product was easily isolated, and the remaining catalysis system can be readily recovered and reused at least three times without significant loss of catalytic activity and selectivity. Copyright Taylor & Francis Group, LLC.

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Highly Efficient AILs/L‐Proline Synergistic
Catalyzed Three‐Component Asymmetric
Mannich Reaction
Baoyou Liu a , Danqian Xu b , Jianfang Dong a , Huilong Yang a , Dishun Zhao c
, Shuping Luo b & Zhenyuan Xu b
a College of Environmental Science and Engineering, Hebei University of
Science and Technology, Shijiazhuang, China
b Catalytic Hydrogenation Research Center, Zhejiang University of
Technology, Hangzhou, China
c College of Chemical and Pharmaceutical Engineering, Hebei University of
Science and Technology, Shijiazhuang, China
Version of record first published: 30 Aug 2007.
To cite this article: Baoyou Liu , Danqian Xu , Jianfang Dong , Huilong Yang , Dishun Zhao , Shuping Luo &
Zhenyuan Xu (2007): Highly Efficient AILs/L‐Proline Synergistic Catalyzed Three‐Component Asymmetric
Mannich Reaction, Synthetic Communications: An International Journal for Rapid Communication of Synthetic
Organic Chemistry, 37:17, 3003-3010
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Synthetic Communicationsw, 37: 3003–3010, 2007
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910601163976
Highly Efficient AILs/L-Proline Synergistic
Catalyzed Three-Component Asymmetric
Mannich Reaction
Baoyou Liu
College of Environmental Science and Engineering, Hebei University
of Science and Technology, Shijiazhuang, China
Danqian Xu
Catalytic Hydrogenation Research Center, Zhejiang University
of Technology, Hangzhou, China
Jianfang Dong and Huilong Yang
College of Environmental Science and Engineering, Hebei University
of Science and Technology, Shijiazhuang, China
Dishun Zhao
College of Chemical and Pharmaceutical Engineering, Hebei University
of Science and Technology, Shijiazhuang, China
Shuping Luo and Zhenyuan Xu
Catalytic Hydrogenation Research Center, Zhejiang University
of Technology, Hangzhou, China
Abstract: A three-component asymmetric Mannich reaction of isovaleraldehyde,
methyl ketones, and aromatic amines was efficiently synergistic catalyzed by amide-
task-specific ionic liquids (AILs)/L-proline under mild conditions. The corresponding
asymmetric Mannich reaction adducts were obtained in moderate to high yields and
stereo selectivity in all the cases tested. The product was easily isolated, and the
Received in Japan June 13, 2006
Address correspondence to Baoyou Liu, College of Environmental Science and
Engineering, Hebei University of Science and Technology, Shijiazhuang 050018,
China. E-mail: lby7150@sina.com
3003

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B. Liu et al.
remaining catalysis system can be readily recovered and reused at least three times
without significant loss of catalytic activity and selectivity.
Keywords: amide-task-specific ionic liquids (AILs), L-proline, Mannich reaction,
synergistic catalysis
INTRODUCTION
The Mannich reaction is a very important carbon–carbon bond-forming
reaction in synthetic organic chemistry and a classic method for the preparation
of b-amino carbonyl compounds. The three-component asymmetric Mannich
reaction of aldehydes, ketones, and amines, however, generally requires compli-
cated, expensive, and highly toxic metal catalysts and harmful organic solvents
such as dimethyl sulfone (DMSO),[1,2] N,N-dimethyl formamide (DMF),[3] and
H2O/tetrahydrofuran (THF).[4] Commercially available, efficient, economic,
and environmentally friendly catalysts and solvents are still urgent. Fortu-
nately, L-proline, an inexpensive and readily available biomimetic, has
become a mostly promising catalyst in many asymmetric reactions,[5,6] and
high yields and ees have always been reported for the Mannich reaction in
normal solvents.[7] At the same time, task-specific ionic liquids (TSILs),
because of their useful properties such as high thermal stability, excellent
solubility, efficient catalytic activity, and ease of product isolation,[8] are
becoming promising alternative solvents to traditional organic solvents. So,
establishing a novel catalytic system of TSILs/proline in an asymmetric
Mannich reaction seems an ideal solution to the traditional method.
Noticing that DMF had been used as an effective solvent and showed
excellent dual catalytic effects in the Mannich reaction, we intended to link
the similar structure to ionic liquids, prepare a series of the amide-task-
specific ionic liquids (AILs), and explore the asymmetric Mannich reaction
of a series of isovaleraldehyde, methyl ketones, and aromatic amines to
form b-amino ketones catalyzed by AILs/L-proline (Scheme 1). To the best
of our knowledge, this is the first report on the AILs/L-proline synergistic
catalyzed organic reaction.
EXPERIMENTAL
Typical Reaction Procedure for 4-p-Tolylamino-6-methyl-2-
heptanone (4a)
All ILs were synthesized according to the literatures.[9–11] Isovaleraldehyde
(0.43 g, 5 mmol), acetone (0.29 g, 5 mmol), p-tolylamine (0.54 g, 5 mmol),
DEMImBF4 (2 mL), L-proline (5% mmol) were added successively to a
20-mL round-bottomed flask under stirring. The reaction proceeded for 2 h at
208C. Then reaction mixture extracted with isopropyl ether (5 mL ꢀ 3); the

Three-Component Asymmetric Mannich Reaction
3005
Scheme 1. AILs/L-proline synergistic catalyzed asymmetric Mannich reaction of
isovaleraldehyde, methyl ketones, and aromatic amines.
organic phases were combined, washed with water (5 mL), dried with
anhydrous magnesium sulfate, and distilled to remove the solvent. The
product was obtained as a light yellowish oil (1.091 g, yield 96%), and the
pure product was obtained by column chromatography (eluent, ethyl acetate–
hexane, 3 : 1). Satisfactory spectrometric data characterized the structure.
RESULTS AND DISCUSSION
To select a suitable AIL, the solubility of synthesized AILs with common
solvents was first tested. The results showed that they are easily soluble in
high-polarity solvents and partly soluble or immiscible in moderates or
weak-polarity solvents. The solubility in water is greatly affected by the sub-
stitution structure of amide; DEMImBF4, DEEImBF4, and BEImBF4 are
miscible in water whereas MEImBF4 and PEImBF4 are partly miscible. Con-
sidering ease of product isolation, we thought the water-miscible AILs might
Table 1. AILs/L-proline synergistic catalyzed asymmetric Mannich reaction of iso-
valeraldehyde, acetone, and p-tolylamine in different solventsa
Entry
Solvents
Time (h)
Conversion (%)b
Selectivity (%)
Ee (%)
1
2
3
4
5
6
DEMImBF4
BEImBF4
DEEImBF4
BMImBF4
DMF
2
2
98.8
98.7
98.1
94.8
76.0
95.0
.99.0
97.4
97.6
94.6
—
.99.0
.99.0
.99.0
91.2
2
6
6
24
—
.99.0
DMF
92.7
aReaction conditions: substrate (5 mmol), 5% mol L-proline, solvent 3 mL, rt. Con-
version and selectivity were detected by GC/MS. Ee were based on GC or HPLC
(chiral column, comparison was made to racemic standards); the absolute configuration
of the major product was R type.
bBased on p-tolylamine.

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B. Liu et al.
be the choice for the Mannich reaction. We explored the reaction of the iso-
valeraldehyde, acetone, and p-tolylamine catalyzed by L-proline in three
water-miscible AILs to compare their efficiency. The results listed in
Table 1 show that AILs/L-proline have good catalytic activity and selectivity
as compared with the nonfunctional counterpart (BMImBF4). DEMImBF4 is
found to be the best medium for the reaction; almost quantitative conversion
and selectivity within 2 h were found. The aldol condensation side product in
DMF/L-proline, which is the main side product characterized by GC-MS, was
effectively suppressed under the AILs/L-proline catalytic system. The results
indicated that the new catalytic system significantly shortened the reaction
time in ionic liquids as compared to the reactions run in DMF (entries 1–3
and 6), improved regioselectivity over the BMImBF4/L-proline system, and
showed an apparently synergistic catalysis effect.
With these results in hand, various substrates were employed in the
DEMImBF4/L-proline system, and the results are listed in Table 2. Acetone,
various aromatic amines, and isovaleraldehyde were almost smoothly
converted to the corresponding b-amino ketones with high ee value (entries
1, 4–11). However, when the asymmetric methyl ketones were selected as
starting materials, the objective Mannich products were hardly obtained
(entries 2, 3). Using acetone as a starting material, the space obstacle effect
of aromatic amines has also a great effect on the reaction, so reactions
involving p, m-aromatic amines showed better conversion and selectivity
than those involving o-aromatic amines (entries 1, 4, 6–8). The new catalytic
system could be recycled after simple product isolation and reused three
times without significant loss of catalytic activity (Table 3). Although the
further exploration of substrate scope and synergistic catalytic mechanism is
still needed, the primary research results had suggested that the new catalytic
system would be a more suitable one for the asymmetric Mannich reaction.
SELECTED CHARACTERIZATION DATA
4-p-Tolylamino-6-methyl-2-heptanone (4a)
IR (film): 3310 (NH), 1720 (C55O), 1600, 1500 (Ar), 1376, 1285, 1120 cm21
.
1H NMR (400 MHz, CDCl3), d, ppm: 7.03 (d, J ¼ 8.0 Hz, 2H), 6.44
(d, J ¼ 8.0 Hz, 2H), 3.76 (s, 1H, CH-N), 3.44 (s, broad, 1H, NH), 2.62–
2.45 (m, 2H, CH2CO), 2.15 (s, 3H, Me-Ar), 2.04 (s, 3H, MeCO), 1.67
(m, 1H), 1.41 (m, 1H), 1.27 (m, 1H), 0.84 (m, 6H, Me2C); MS: m/z, 233
(Mþ), 176 (100), 160, 134, 118, 106, 91; ES calculated for C15H23NO: C,
77.20; H, 9.94; N, 6.00; found: C, 77.20; H, 9.97; N, 6.01.
4-p-Tolylamino-3,6-dimethyl-2-heptanone (4b)
MS: m/z, 247(Mþ), 190 (100), 176, 160, 133, 118, 106, 91, 85, 77, 69, 55.

Table 2. DEMImBF4/L-proline synergistic catalyzed Mannich reaction of isovaleraldehyde, methyl ketones, and aromatic aminesa
Entry
Product
Ketone
Amine
Time(h)
Yield (%)
Ee/dr
1
2
4a
4b
4c
4d
4e
4f
CH3COCH3
CH3COEt
p-Tolylamine
2
2
96
79
.99
3.1/1b
—
p-Tolylamine
p-Tolylamine
o-Tolylamine
p-Anisidine
3
CH3COC3H5
CH3COCH3
CH3COCH3
CH3COCH3
CH3COCH3
CH3COCH3
CH3COCH3
CH3COCH3
CH3COCH3
24
6
Trace
82
95
4
28
99
96
82
33
97
93
78
5
2
6
p-Chloroaniline
m-Chloroaniline
o-Chloroaniline
p-Fluoroaniline
Aniline
2
83
93
7
4g
4h
4i
4
8
2
72
94
9
2
10
11
4j
4k
2
90
78
m-Trifluoromethylaniline
4
aReaction conditions: substrate (5 mmol), DEMImBF4/L-proline, 3 mL, 5% mol, rt. The conversion (based on amine) and yields were calculated
by GC/MS; ee detection was based on GC or HPLC (chiral column, comparison was made to racemic standards).
1
bDiastereomeric ratio (syn:anti) was based on H NMR analysis of crude products and GC/MS.
cDetected by GC/MS, not further isolated or characterized.

3008
B. Liu et al.
Table 3. Recycle of the catalysis system
Yield
(%)
Ee
(%)
Entry
Test
Fresh
Isovaleraldehyde Acetone
p-Tolylamine
1
2
3
4
5 mmol
5 mmol
5 mmol
5 mmol
5 mmol
5 mmol
5 mmol
5 mmol
5 mmol
5 mmol
5 mmol
5 mmol
96
92
89
85
.99
.99
.99
.99
Recycle 1
Recycle 2
Recycle 3
4-o-Tolylamino-6-methyl-2-heptanone (4d)
IR (film): 3370 (NH), 1710 (C55O), 1600, 1500 (Ar), 1480, 1435, 1400, 1018
cm21. 1H NMR (400 MHz, CDCl3), d, ppm 7.12 (m, 1H), 7.04 (m, 1H), 6.65
(d, J ¼ 8 Hz, 2H) 3.95 (m, 1H), 3.58 (s, 1H), 2.74–2.71 (m, broad, 1H) 2.64
(m, 1H), 2.12 (m, 6H), 1.75–1.74 (m, broad, 1H) 1.53 (m, 1H), 1.39 (m, 1H),
0.98 (m, 6H); MS: m/z, 233 (Mþ), 176 (100), 168, 160, 144, 134, 127, 118,
107, 100, 91, 84, 77, 69, 55; ES calculated for C15H23NO: C, 77.20; H,
9.94; N, 6.00; found: C, 77.17; H, 9.96; N, 6.03.
4-[(p-Methoxyphenyl)amino]-6-methyl-2-heptanone (4e)
CAS:306776-15-8
IR (film): 3348 (NH), 1712 (C55O), 1600, 1502 (Ar), 1220 (Ar-O-C),
1
1020 cm21. H NMR (400 MHz, CDCl3), d, ppm 6.69 (d, J ¼ 8 Hz, 2H),
6.52 (d, J ¼ 8 Hz, 2H), 3.74 (m, 3H), 3.66 (m, 3H), 2.61 (m, 2H), 2.04
(m, 3H), 1.64 (m, 1H), 1.39 (m, 1H), 1.23 (m, 1H), 0.87 (m, 6H); MS: m/z,
249 (Mþ), 192 (100), 176, 160, 150, 134, 123, 117, 108, 102, 92, 80, 69, 63, 55.
4-[(p-Chlorophenyl)amino]-6-methyl-2-heptanone (4f)
IR (film): 3340 (NH), 1710 (C55O), 1600, 1500 (Ar), 1290, 810 (Ar-Cl) cm21
.
1H NMR (400 MHz, CDCl3), d, ppm 7.10 (d, J ¼ 8 Hz, 2H), 6.53 (d, J ¼ 8 Hz,
2H), 4.31 (s, 1H, CH-N), 3.84 (m, 1H, NH), 2.67 (m, 2H, CH2CO), 2.12 (s, 2H),
1.72 (m, 1H), 1.50 (m, 3H), 0.90 (m, 6H), MS: m/z, 253 (Mþ), 196 (100), 180,
154, 140, 127, 118, 111, 99, 91, 84, 75, 65, 55; ES calculated for C14H20NOCl:
C, 66.26; H, 7.94; N, 5.52; found: C, 66.20; H, 7.91; N, 5.50.
4-[(m-Chlorophenyl)amino]-6-methyl-2-heptanone (4g)
IR (film): 3350 (NH), 1710 (C55O), 1600, 1500 (Ar), 1370, 1080, 790 (Ar-Cl)
cm21. 1H NMR (400 MHz, CDCl3), d, ppm 7.08 (m, 1H), 6.65 (m, 3H), 3.85
(m, 2H), 2.66 (m, 2H), 2.14 (m, 2H), 1.72 (m, 1H), 1.39 (m, 3H), 0.91 (m, 6H),

Three-Component Asymmetric Mannich Reaction
3009
MS: m/z, 253 (Mþ), 196 (100), 180, 154, 140, 127, 119, 111, 100, 91, 77, 69,
55; ES calculated for C14H20NOCl: C, 66.26; H, 7.94; N, 5.52; found: C,
66.21; H, 7.92; N, 5.48.
4-[(o-Chlorophenyl)amino]-6-methyl-2-heptanone (4h)
IR (film): 3346 (NH), 1715 (C55O), 1598, 1500 (Ar), 1404, 1180, 1020, 740
1
(Ar-Cl) cm21. H NMR (400 MHz, CDCl3), d, ppm 7.25 (m, 1H), 7.14
(m, 1H), 6.73 (m, 1H), 6.60 (m, 1H), 4.12 (s, broad, 1H), 4.03 (m, 1H),
2.74 (d, 1H), 2.62 (d, 1H), 2.17 (s, 3H); 1.78 (m, 1H), 1.54 (m, 1H), 1.43
(m, 1H), 0.97 (m, 6H), MS: m/z, 253 (Mþ), 200 (100), 184, 172, 158, 144,
132, 124, 117, 107, 99, 91, 77, 65, 55; ES calculated for C14H20NOCl: C,
66.26; H, 7.94; N, 5.52; found: C, 66.20; H, 7.96; N, 5.55.
4-[(p-Fluorophenyl)amino]-6-methyl-2-heptanone (4i)
IR (film): 3350 (NH), 1710 (C55O), 1600, 1500 (Ar), 1450, 1364, 1210 (Ar-F)
1
cm21. H NMR (400 MHz, CDCl3), d, ppm 6.79 (m, J ¼ 8 Hz, 2H), 6.47
(m, J ¼ 8 Hz, 2H), 3.73 (m, 1H), 3.25 (s, broad 1H, NH), 2.56–2.46
(m, 2H), 2.05 (s, 3H), 1.63 (m, 1H), 1.41 (m, 1H), 1.24 (m, 1H),
0.84 (m, 6H), MS: m/z, 237 (25, Mþ), 180 (100), 164, 138, 124, 111, 95,
83, 75, 55; ES calculated for C14H20NOF: C, 70.86; H, 8.49; N, 5.90;
found: C, 70.90; H, 8.46; N, 5.91.
4-Phenylamino-6-methyl-2-heptanone (4j)
IR (film): 3350 (NH), 1710 (C55O), 1600, 1500 (Ar), 1370, 1308, 1250, 1140
cm21. 1H NMR (400 MHz, CDCl3), d, ppm 7.10 (m, 2H), 6.62 (m, 1H), 6.56
(m, 2H), 3.82 (m, 1H), 3.45 (m, 1H), 2.63 (m, 2H), 2.04 (s, 3H), 1.67 (m, 1H),
1.43 (m, 2H), 0.84 (m, 6H); MS: m/z, 219 (Mþ), 162 (100), 146, 120, 106, 93,
77, 65; ES calculated for C14H21NO: C, 76.67; H, 9.65; N, 6.39; found: 76.69;
H, 9.60; N, 6.41.
4-[(m-Trifluorophenyl)amino]-6-methyl-2-heptanone (4k)
IR (film): 3352 (NH), 1709 (C55O), 1600, 1500 (Ar), 1320, 1158, 1120(C-F)
cm21. 1H NMR (400 MHz, CDCl3), d, ppm 7.25 (m, 1H), 6.91 (m, 1H), 6.76
(d, J ¼ 8 Hz, 2H) 3.90 (s, 1H, CH-N), 3.88 (s, 1H, NH), 2.63–2.61 (m, 2H,
CH2CO), 2.15 (s, 3H), 1.72 (m, 1H), 1.49 (m, 1H), 1.36 (m, 1H), 0.97
(m, 6H, MeC); MS: m/z, 303 (Mþ), 220 (100), 206, 192, 178, 164, 140,
127, 111, 97, 83, 69, 55; ES calculated for C15H20NO2F3: C, 59.40; H,
6.65; N, 4.62; found: C, 59.32; H, 6.61 N, 4.63.

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B. Liu et al.
CONCLUSION
In summary, DEMImBF4/L-proline has been demonstrated to be an excellent
catalytic system for the Mannich reaction of a series of isovaleraldehyde,
methyl ketones, and aromatic amines. The adducts, b-amino ketones, were
obtained by simple manipulation in moderate to high yields (up to 96%) and
enantioselectivities (up to .99% ee) under mild conditions. The catalysis
system is easily to be recycled at least three times with a slightly activity loss.
ACKNOWLEDGMENT
This work was financially supported by the National Science Foundation of
China (Project No. 20576026), State Key Laboratory Breeding Base of
Green Chemistry–Synthesis Technology (Project No. 200402), and Science
and Technology Office of HeBei Province (Project No. 04213036).
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