One-pot, three-component Mannich-type reaction catalyzed by functionalized ionic liquid

Article abstract of DOI:10.1007/s00706-009-0182-y

A three-component Mannich-type reaction of aromatic aldehydes, aromatic amines, and ketones was catalyzed by a novel functionalized ionic liquid, 3-(N,N-dimethyldodecylammonium)propanesulfonic acid hydrogen sulfate ([DDPA][HSO₄]) at room temperature to give various β-amino carbonyl compounds in good yields. The catalyst could be reused at least six times without noticeably reducing catalytic activity.

Full text of DOI:10.1007/s00706-009-0182-y

Monatsh Chem (2009) 140:1325–1329
DOI 10.1007/s00706-009-0182-y
ORIGINAL PAPER
One-pot, three-component Mannich-type reaction catalyzed
by functionalized ionic liquid
Dong Fang Æ Kai Gong Æ Dai-zhen Zhang Æ
Zu-liang Liu
Received: 1 November 2008 / Accepted: 31 August 2009 / Published online: 7 October 2009
Ó Springer-Verlag 2009
Abstract A three-component Mannich-type reaction of
aromatic aldehydes, aromatic amines, and ketones was
catalyzed by a novel functionalized ionic liquid, 3-(N,N-
dimethyldodecylammonium)propanesulfonic acid hydro-
gen sulfate ([DDPA][HSO4]) at room temperature to give
various b-amino carbonyl compounds in good yields. The
catalyst could be reused at least six times without notice-
ably reducing catalytic activity.
include assistance of microwave [4, 5] or ultrasound irra-
diation [6], and use of Lewis acids [7–9], Lewis base [10],
Brønsted acids [11–13], rare metal salts [14, 15], or organo
catalysts [16–18], etc., as promoters to catalyze Mannich-
type reactions. However, most of these methods suffer
from severe drawbacks including the use of large amounts
of catalysts, expensive reagents or catalysts, long reaction
times, harsh reaction conditions, toxicity, difficulty in
product separation, and low yield, etc. Hence, the search
for new, readily available, and green catalysts is still being
actively pursued.
Keywords Mannich-type reaction Á Ionic liquid Á
Catalyst Á One-pot reaction
Nowadays ionic liquids attract much interest in the
context of green synthesis, and functionalized ionic liquids
(FILs) have been one of the most exciting topics. Use of
FILs as catalysts and solvents for Mannich-type reaction
has been reported in recent years [19–22]. However, FILs
with imidazole or triphenylphosphine as the cation are
relatively expensive, which hinders their industrial appli-
cations. Furthermore, the biodegradability of commonly
used dialkylimidazolium ionic liquids, e.g. [BMIM]X, in
the closed bottle test (OECD 301 D) was negligible, and
typical ionic liquids consist of halogen-containing anions
(for example [PF6]-, [BF4]-, [CF3COO]-, [CF3SO3]-, or
[(CF3SO2)2N]-) which in some regard limits their
‘‘greenness’’ [23–26]. Thus, it is necessary to synthesize
less expensive and halogen-free ionic liquids which can be
used straightforwardly in simple procedures.
Introduction
The Mannich-type reaction is one of the most important
fundamental carbon–carbon bond-forming reactions in
organic synthesis for preparation of b-amino carbonyl
compounds and 1,2-amino alcohol derivatives, which are
valuable synthetic intermediates for the synthesis of drugs
and biologically active compounds [1–3]. The Mannich-
type reaction has gained popularity in synthetic chemistry
over recent decades, and many synthetic methods for
preparing these b-amino carbonyl compounds have
been reported to improve and modify this reaction. These
D. Fang (&) Á D. Zhang Á Z. Liu (&)
Jiangsu Provincial Key Laboratory of Coast Wetland
Bioresource & Environment Protection,
224002 Yancheng, People’s Republic of China
e-mail: fang-njust@hotmail.com
As a part of our research to develop green chemistry by
one-pot syntheses of target molecules in solvent-free or
water alone as the reaction medium [27–30], we report here
a novel SO3H-functional Brønsted-acidic halogen-free
ionic liquid [DDPA][HSO4] that bears a propanesulfonic
acid group in an acyclic dimethyldodecylammonium cation
(Scheme 1), and which has been used as the catalyst in a one-
pot, three-component Mannich-type reaction (Scheme 2). To
D. Fang Á K. Gong Á Z. Liu
School of Chemical Engineering,
Nanjing University of Science & Technology,
210094 Nanjing, People’s Republic of China
123

1326
D. Fang et al.
Scheme 1
C
N
12H25
CH3
O
O
O
S
+
N
C12H25
SO3
CH3
CH3
CH3
CH3
H2SO4
N
C12H25
SO3H HSO4
CH3
[DDPA][HSO4]
R1
Scheme 2
O
O
R2
CH3
Ar
Ar
N
H
CHO
NH2
[DDPA][HSO4]
EtOH/r.t
R1
R2
or
or
O
+
+
R1
O
R2
N
H
1
2
3
4
the best of our knowledge of the open literature, Mannich-
type reactions catalyzed by the functionalized ionic liquid
[DDPA][HSO4] have not yet been reported.
water. [M - H]- (432.21) was observed by full scan MS in
the range 170–600 amu, which was consistent with the
proposed structure in Scheme 1. A full MS–MS scan of the
fragment 432.08 in the range 30–440 amu gave the base
peak [HSO4]- (96.88), which suggested cleavage of the
fragment [HSO4]- from the molecular ion. Additionally,
ionic association by forming hydrogen bonds could be
observed, for example 194.90 ([H2SO4 ? HSO4]-), etc.
In the initial experiments, different solvents were
screened for three-component Mannich-type reactions.
Herein the reaction of benzaldehyde, cyclohexanone, and
aniline was selected as model. The results are summarized
in Table 1. It was shown that Mannich-type reactions could
proceed effectively in polar organic solvents, for example
ethanol, methanol, and acetonitrile (entries 2, 3, 4), and
[DDPA][HSO4]/C2H5OH was found to be the most effec-
tive catalyst/solvent system and gave the highest yield of
87% (entry 2) among the solvents selected.
Results and discussion
The procedure for synthesis of [DDPA][HSO4] was made
up of a two-step atom-economic reaction. The zwitterionic-
type precursor 3-(N,N-dimethyldodecylammonio)propane-
sulfonate was prepared by one-step direct sulfonation
of N,N-dimethyldodecylamine and 1,3-propanesulfone.
Acidification of the zwitterions was accomplished by
mixing with sulfuric acid (98%, aq.) to convert the pendant
sulfonate group into [DDPA][HSO4]. The chemical yields
for both zwitterion formation and acidification steps were
essentially quantitative, because neither reaction produced
byproducts; the [DDPA][HSO4] synthesis was 100% atom-
efficient. The catalyst was characterized by negative ion
chemical ionization mass spectrometric (MS) analysis in
To optimize the reaction conditions, the same reaction of
benzaldehyde, cyclohexanone, and aniline was employed as
123

One-pot, three-component Mannich-type reaction
1327
aldehydes bearing an electron-withdrawing group were
favorable for the Mannich-type reaction compared with
those carrying electron-donating substituents, and anilines
with electron-donating groups are beneficial for the
reaction.
Table 1 Effect of the [DDPA][HSO4]/solvent system on the Mannich-
type reaction
Entry
Catalyst/solvent
Isolated yield (%)
1
2
3
4
5
6
7
8
[DDPA][HSO4]/H2O
78
87
81
82
65
64
60
62
[DDPA][HSO4]/C2H5OH
[DDPA][HSO4]/CH3OH
[DDPA][HSO4]/CH3CN
[DDPA][HSO4]/CH2Cl2
[DDPA][HSO4]/CHCl3
[DDPA][HSO4]/C6H5CH3
[DDPA][HSO4]/None
The recycling performance of [DDPA][HSO4] in the
same model Mannich-type reaction was also investigated.
After the reaction, the products were isolated from the
catalytic system by filtration. The filtrate (ethanol media
containing the catalyst) was reused in the next run without
further purification. As shown in Fig. 1, the catalyst could
be reused at least six times without appreciable decrease in
yield and reaction rate.
Reaction conditions: 10 mmol benzaldehyde, 10 mmol aniline,
10 mmol cyclohexanone, 1 mmol [DDPA][HSO4], r.t., 6 h
In summary, it was demonstrated that the readily
available, functionalized ionic liquid behaved as a recy-
clable catalyst for the three-component Mannich-type
reaction at room temperature, offering a procedure with
generality and which is environmentally benign, and has
the practical convenience of easy product separation from
the reaction system.
Table 2 Effect of amount of [DDPA][HSO4] on Mannich-type
reaction
Entry
Catalyst (mol%)
Reaction time (h)
Isolated yield (%)
1
2
3
4
5
6
7
8
None
2
36
6
0
59
62
74
87
87
68
87
5
6
8
6
Experimental
10
20
10
10
6
6
Melting points were determined by use of an X6-Data
microscope apparatus. 1H NMR spectra were recorded on a
Bruker DRX300 (300 MHz). Mass spectra were obtained
with an automated Finnigan TSQ Quantum Ultra AM
(Thermal) LC–MS spectrometer. All chemicals (AR grade)
were commercially available and used without further
purification.
3
10
Reaction conditions: 10 mmol benzaldehyde, 10 mmol aniline,
10 mmol cyclohexanone, and 6 cm3 C2H5OH, r.t.
the model reaction to screen the effect of the amounts of
[DDPA][HSO4] on the Mannich-type reaction (Table 2). The
results showed thatnoMannich base could be detected when a
mixture of benzaldehyde, cyclohexanone, and aniline was
stirred for 36 h without any catalyst (entry 1), which indicated
that the catalyst was absolutely necessary for the Mannich-
type reaction. When the amount of [DDPA][HSO4] was
increased, a ramp in the yield of Mannich base was clearly
observed. The optimum amount of [DDPA][HSO4] was
1.0 mmol (10 mol% based on cyclohexanone) (entry 5), and
increasing the amount of catalyst beyond this led to no sub-
stantial improvement in the yield (entry 6).
The SO3H-functionalized ionic liquid [DDPA][HSO4]
was synthesized according to our previous method [29]
with some changes.
3-(N,N-Dimethyldodecylammonio)propanesulfonate
(C17H37NO3S)
To
a solution of 21.3 g N,N-dimethyldodecylamine
(0.10 mol) in 50 cm3 1,2-dichloroethane was added
12.2 g 1,3-propanesulfone (0.10 mol), in portions, within
15 min. The mixture was then stirred under nitrogen for
2 h at 55–60 °C. The white precipitate thus formed was
cooled to room temperature, and then isolated by filtration
and washed with petroleum ether. The product was
recrystallized from a mixture of water, ethanol, and diethyl
ether to give 98% yield of white solid product, mp 300–
302 °C (dec) with darkening at 300 °C.
Subsequently, the scope of the Mannich-type reaction of
other aromatic aldehydes 1, aromatic amines 2, and ketones
3 in the presence of [DDPA][HSO4] was investigated under
the optimized reaction conditions (Table 3). In general, the
three-component Mannich-type reaction proceeded
smoothly to give the corresponding products in reasonable
to good yields ranging from 77 to 96%. For aromatic
ketones, aromatic aldehydes carrying either electron-with-
drawing or electron-donating substituents could facilitate
Mannich-type reaction, and gave almost the same yields
(entries 15–19). For cyclohexanone, however, aromatic
3-(N,N-Dimethyldodecylammonio)propanesulfonic acid
hydrogen sulfate (C17H39NO7S2)
To a solution of 33.6 g 3-(N,N-dimethyldodecylammo-
nio)propanesulfonate (0.10 mol) in 10 cm3 water was
added 10.0 g sulfuric acid solution (98%) (0.10 mol).
The mixture was then stirred for 2 h at 80 °C. The
123

1328
D. Fang et al.
Table 3 Three-component
Mannich-type reaction of
aromatic aldehydes, aromatic
amines, and ketones catalyzed
by [DDPA][HSO4]
Entry
R1
R2
3
Yielda (%)
m.p. (°C) (Ref.b)
1
H
H
(CH2)5CO
87
92
86
82
80
77
90
92
90
96
93
91
93
87
90
91
91
90
90
114–115 (115–116) [9]
116–117 (116–118) [15]
135–136 (137–138) [15]
97–98 (98–99) [9]
2
H
4-CH3
4-Cl
4-Br
4-Cl
4-Br
H
(CH2)5CO
3
H
(CH2)5CO
4
H
(CH2)5CO
5
4-CH3O
4-CH3O
4-Cl
(CH2)5CO
123–124 (122–123) [9]
130–131 (131–132) [9]
134–135 (135–136) [9]
95–96 (96–97) [9]
6
(CH2)5CO
7
(CH2)5CO
8
4-Cl
4-Cl
4-Br
4-Cl
4-CH3
H
(CH2)5CO
9
4-Cl
(CH2)5CO
135–136 (134–135) [9]
125–126 (125–126) [9]
136–137 (137–138) [9]
168–169 (169–171) [11]
169–170 (170–171) [11]
171–172 (170–171) [11]
151–152 (151–152) [15]
160–161 (160–162) [11]
117–118 (116–118) [11]
130–131 (130–131) [12]
135–136 (135–137) [12]
10
11
12
13
14
15
16
17
18
19
3-NO2
4-NO2
H
(CH2)5CO
(CH2)5CO
C6H5COCH3
C6H5COCH3
C6H5COCH3
C6H5COCH3
C6H5COCH3
C6H5COCH3
4-CH3OC6H4 COCH3
4-CH3OC6H4COCH3
Reaction conditions: 10 mmol
benzaldehyde, 10 mmol aniline,
10 mmol cyclohexanone,
1 mmol [DDPA][HSO4], and
6 cm3 C2H5OH, r.t., 6 h
H
4-CH3
4-Cl
H
H
4-CH3O
4-CH3O
4-CH3O
4-NO2
4-NO2
a
4-CH3
3-Cl
H
Isolated yield based on
carbonyl compounds
b
The spectroscopic data used
for proof of identity have been
described
4-CH3
General procedure for the three-component
Mannich-type reaction catalyzed by [DDPA][HSO4]
To a mixture of 10 mmol aromatic benzaldehyde, 10 mmol
aniline derivative, and 10 mmol ketone in 6 cm3 ethanol
was added 1.0 mmol [DDPA][HSO4]. The mixture was
stirred at room temperature until TLC indicated that the
starting materials had disappeared. The resulting mixture
was filtered and then the crude product was purified by
recrystallization or chromatography (silica gel, petroleum
ether:ethyl acetate = 5:1). The filtrate containing the
[DDPA][HSO4] could be reused directly in the next run
without further purification. The products were identified
by comparison of 1H NMR and m.p. with those reported in
the literature [9, 11, 12, 15].
Number of run
Fig. 1 Recycling performance of [DDPA][HSO4]
2-(Phenyl(phenylamino)methyl)cyclohexanone (4a)
White crystals; m.p. 114–115 °C. 1H NMR data were used
to identify the compound by comparison with literature
data [9].
combined solution was then dried under vacuum at 100 °C
to remove the water. The [DDPA][HSO4] produced was
washed repeatedly with diethyl ether to remove unreacted
material and again dried under vacuum. [DDPA][HSO4]
was obtained quantitatively and in high purity as a
colorless oil. 1H NMR (300 MHz): d = 0.53 (t, 3H,
J = 6.62 Hz, –CH3), 0.95–1.02 (m, 18H, –(CH2)9–), 1.42
(m, 2H, –C–CH2–C–N), 1.83–1.87 (m, 2H, –C–CH2–C
–SO3), 2.60 (t, 2H, J = 6.91 Hz, –CH2–SO3), 2.77 (s, 6H,
N–CH3), 2.98 (t, J = 7.95 Hz, 2H, –C–CH2–N), 3.14 (t,
J = 8.25 Hz, 2H, –CH2–C–C–SO3) ppm; MS: m/z =
432.21 [M – H]-, 356.97 (100), 194.90 [H2SO4 ?
HSO4]-.
Acknowledgments We are grateful to the Education Commission
of Jiangsu Province (07KJD530238) and Jiangsu Provincial Key
Laboratory of Coast Wetland Bioresource and Environment Protec-
tion (JLCBE09023) for financial support.
References
1. Arend M, Westermann B, Risch N (1998) Angew Chem Int Ed
37:1044
2. Kobayashi S, Ishitani H (1999) Chem Rev 99:1069
123

One-pot, three-component Mannich-type reaction
1329
3. Cordova A (2004) Acc Chem Res 37:102
4. Leadbeater NE, Torenius HM, Tye H (2003) Mol Divers 7:135
5. Aberg V, Almstedt H, Westermark A, Almqvist F (2004) J Org
Chem 69:7830
19. Zhao G, Jiang T, Gao H, Han B, Huang J, Sun D (2004) Green
Chem 6:75
20. Li J, Peng Y, Song G (2005) Catal Lett 102:159
21. Sahoo S, Joseph T, Halligudi SB (2006) J Mol Catal A: Chem
6. Hu DY, Song BA, Zhang GP, Yang S, He W, Wu YL, Hong YP,
Jin LH, Liu G (2005) Chin J Org Chem 25:845
7. Loh TP, Liung S, Wei LL (2000) Tetrahedron Lett 39:323
8. Komoto I, Kobayashi S (2001) Chem Commun 1842
9. Yang YY, Shou WG, Wang YG (2006) Tetrahedron 62:10079
10. Takahashi E, Fujisawa H, Mukaiyama T (2004) Chem Lett
33:936
244:179
22. Gong K, Fang D, Wang HL, Liu ZL (2007) Monatsh Chem
138:1195
23. Garcia MT, Gathergood N, Scammells PJ (2005) Green Chem 5:9
24. Gathergood N, Garcia MT, Scammells PJ (2004) Green Chem
6:166
¨
25. Wasserscheid P, Hal R, Bosmann A (2002) Green Chem 4:400
11. Yi L, Lei HS, Zou JH, Xu XJ (1991) Synthesis 717
12. Chen HL, Zou JH (1999) Chin J Southwest Norm Univ 24:644
13. Iimura S, Nobutou D, Manable K, Kobayashi S (2003) Chem
Commun 1644
14. Wang L, Han J, Sheng J, Tian H, Fan Z (2005) Catal Commun
6:201
15. Yi WB, Cai C (2006) J Fluorine Chem 127:1515
16. Rodriguez B, Bolm C (2006) J Org Chem 71:2888
17. List B, Pojarliev P, Biller WT, Martin HJ (2002) J Am Chem Soc
124:827
26. Fraga-Dubreuil J, Bourahla K, Rahmouni M, Bazureau JP,
Hamelin J (2002) Catal Commun 3:185
27. Fang D, Luo J, Zhou XL, Liu ZL (2007) Catal Lett 116:76
28. Fang D, Luo J, Zhou XL, Ye ZW, Liu ZL (2007) J Mol Catal
A: Chem 274:208
29. Fang D, Zhou XL, Ye ZW, Liu ZL (2006) Ind Eng Chem Res
45:7982
30. Fang D, Shi QR, Cheng J, Gong K, Liu ZL (2008) Appl Catal A:
Gen 345:158
´
18. Ibrahem I, Casas J, Cordova A (2004) Angew Chem Int Ed
43:6528
123