Mannich reactions catalyzed by perchloric acid in Triton X10 aqueous micelles

Article abstract of DOI:10.1016/j.catcom.2010.02.007

Perchloric acid can efficiently catalyze the one-pot, three-component Mannich reactions of ketones with aromatic aldehydes and aromatic amines in Triton X10 aqueous micelles at room temperature. This protocol has several advantages such as excellent yields, mild conditions, clear reaction profile and simple work-up procedure.

Full text of DOI:10.1016/j.catcom.2010.02.007

Catalysis Communications 11 (2010) 745–748
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Catalysis Communications
journal homepage: www.elsevier.com/locate/catcom
Mannich reactions catalyzed by perchloric acid in Triton X10 aqueous micelles
*
Guo-ping Lu, Chun Cai
School of Chemical Engineering, Nanjing University of Science and Technology, 200 Xiaoling Wei, Nanjing 210094, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Perchloric acid can efficiently catalyze the one-pot, three-component Mannich reactions of ketones with
aromatic aldehydes and aromatic amines in Triton X10 aqueous micelles at room temperature. This pro-
tocol has several advantages such as excellent yields, mild conditions, clear reaction profile and simple
work-up procedure.
Received 29 November 2009
Received in revised form 25 January 2010
Accepted 9 February 2010
Available online 12 February 2010
Ó 2010 Elsevier B.V. All rights reserved.
Keywords:
Perchloric acid
Mannich reactions
Triton X10
Aqueous micelles
1. Introduction
tions being carried out in water have attracted much attention
[22–29]. However, most of reactions required long reaction time
Recently, water as a sole medium for organic reactions has re-
ceived considerable attention in synthetic organic chemistry for
several reasons. First, water as a cheap, abundant, non-toxic,
non-flammable solvent is more suitable for industrial production
than toxic and expensive organic solvents [1–4]. Second, in aque-
ous reactions, it is unnecessary to dry solvents, substrates and re-
agents before use. Third, water with its chemical and physical
properties imposes unique selectivity and reactivity in reactions
conducted in aqueous media which cannot be gained using organic
solvents [5–9].
in the presence of different catalysts (Table 1). To develop new pro-
tocols to pronounced catalyze Mannich reactions in water, we have
found perchloric acid to be an efficient catalyst in Triton X10
(TX10) aqueous micelles at room temperature for the synthesis
of b-amino carbonyl compounds (Scheme 1).
2. Experimental
2.1. Materials and characterization
Nevertheless, in many cases, the poor solubility of reactants and
the deleterious effect on many organic transformations are the
main obstacles to use water as reaction medium. An intriguing
means of achieving aqueous solubility is by using surfactants in
water to form micelles which appear to be homogeneous since
these aggregates are of colloidal size, however, in reality the ab-
sorbed reactants are in a microheterogeneous system [10]. It can
cause an acceleration of many organic reactions relative to the
equivalent reaction in aqueous medium which refers to as ‘‘micel-
lar catalysis” [11–14].
Melting points were determined uncorrected. 1H NMR spectra
were recorded on Bruker DRX500 (500 MHz) or Bruker DRX500
(300 MHz) and 13C NMR spectra on Bruker DRX500 (125 MHz)
spectrometer. Triton X10 (Polyoxyethylene(10) octylphenyl ether,
TX10) was purchased from the petrochemical plant of Jiangsu
Haian. All other chemicals (AR grade) were commercially available
and used without further purification. All products are known
compounds and identified by physical data (m.p.) or 1H NMR with
those reported in the literature.
Mannich reaction as one of the most important carbon–carbon
bond forming reactions provides b-amino carbonyl compounds,
which are important synthetic intermediates for various pharma-
ceuticals and natural products [15–21]. To replace expensive, toxic,
flammable organic solvents with water, Mannich and related reac-
2.2. Mannich reactions catalyzed by perchloric acid in TX10 aqueous
micelles
To a solution of 5 wt.% TX10 aqueous micelles (4.0 ml) were
added amine (2.5 mmol), aldehyde (2.5 mmol), and ketone
(2.5 mmol) successively at room temperature. Perchloric acid
(0.25 mmol, as a 70 wt.% aqueous solution) was added, and the
mixture was stirred at the same temperature for the period of time
listed in Table 3. After the reaction completed, water (10.0 ml) was
* Corresponding author. Tel.: +86 25 84315514; fax: +86 25 84315030.
E-mail address: c.cai@mail.njust.edu.cn (C. Cai).
1566-7367/$ - see front matter Ó 2010 Elsevier B.V. All rights reserved.
doi:10.1016/j.catcom.2010.02.007

746
G.-p. Lu, C. Cai / Catalysis Communications 11 (2010) 745–748
Table 1
Different catalytic systems for the Manncih reaction of benzaldehyde, aniline, and acetophenone.
Entry
Catalyst
Reaction medium
Time (h)
Yield (%)
Reference
1
2
3
4
5
6
7
8
HCl
NaBArF4
SDS/H2O
H2O
H2O
H2O
H2O
H2O
[bmim]BF4/H2O
TX10/H2O
24
48
18
12
24
36
12
6
98
81
76
70
63
30
90
92
[20]
[22]
[25]
[26]
[27]
[28]
[29]
–
H3PW12O40
FQAS/TsOH
DBSA
C6H11N(C6H4)2Bi(OSO2C8F17
[cmmim][BF4]
HClO4
)
R2
O
HN
O
10mol% HClO4
5wt.% TX 10/H2O r.t.
R2 NH2
R1 CHO
R4
R1
+
R3
+
R3
R4
O
NH2
CHO
O
HN
O
HN
+
+
+
syn
anti
H
C
(OCH CH )
2 2 10
OH
Triton X10(TX10)
17
8
Scheme 1. Mannich reactions in TX10 aqueous micelles.
added to the mixture, and the solid precipitated was separated
with a simple filtration, washed with water and dried to afford
the desired product.
3. Results and discussion
In order to optimize the reaction conditions, the reaction of
benzaldehyde, aniline, and acetophenone was selected as a model
reaction. When feasible, the use of Brønsted acids to catalyze
organic reactions in water is one of the most convenient and envi-
ronmentally benign methods, and TX10 as a cheap, non-toxic sur-
factant is widely applied in industry for emulsifier, detergent and
so on, so we first studied the reaction in TX10 aqueous micelles
with different Brønsted acids as catalysts (Table 2, entries 1–3,
5). The yield was highest, when perchloric acid was used as cata-
lyst. After screening different reaction medium (Table 2, entries
4–9), 5 wt.% TX10 aqueous micelles proved to be the best choice.
In order to verify the merit of the TX10 aqueous micelles, the reac-
tion was run in the absence of TX10 under similar conditions, as a
2.2.1. 2-[10-(N-phenylamino)-10-(p-dimethylaminophenyl)]
methylcyclohexanone (Table 3, entry 17)
A light yellow solid; m.p. 160–162 °C; 1H NMR (500 MHz,
CDCl3) d: 1.56–1.72 (m, 4H), 1.84–1.94 (m, 4H), 2.45–2.53 (m,
1H), 2.94 (s, 6H), 3.04 (s, 1H), 4.57 (d, 0.65H, anti, J = 7.5 Hz),
4.72 (d, 0.35H, syn, J = 4 Hz), 6.57–6.60 (m, 2H), 6.63–6.66 (m,
1H), 6.69–6.78 (m, 2H), 7.06–7.11 (m, 2H), 7.17–7.28 (m, 2H);
13C NMR (125 MHz, CDCl3) d: 23.28, 27.87, 30.87, 40.62, 41.46,
42.41, 56.71, 57.71, 112.55, 112.62, 113.81, 114.08, 117.41,
128.00, 128.29, 128.99, 129.26, 129.27, 147.33, 149.48, 213.26.
Table 2
Optimization of the reaction conditions.a
Entry
Catalyst (10 mol%)
Reaction medium (4 ml)
Yield (%)b
1
2
3
4
5
6
7
8
HCl
5 wt.% TX10/H2O
5 wt.% TX10/H2O
5 wt.% TX10/H2O
2 wt.% TX10/H2O
5 wt.% TX10/H2O
10 wt.% TX10/H2O
CH3COCH3
CH2Cl2
C2H5OH
H2O
Trace
48
16
73
92
89
Trace
62
81
19
TsOHc
CF3COOH
HClO4
HClO4
HClO4
HClO4
HClO4
HClO4
HClO4
None
9
10
11
5 wt.% TX10/H2O
Trace
a
b
c
Reaction condition: benzaldehyde 2.5 mmol, aniline 2.5 mmol, acetophenone 2.5 mmol, room temperature, 6 h.
Isolated yields.
TsOH is 4-toluenesulfonic acid.

G.-p. Lu, C. Cai / Catalysis Communications 11 (2010) 745–748
747
Table 3
Perchloric acid-catalyzed direct Mannich reactions of various aromatic aldehydes and aromatic amines with different ketones.a
Entry
Time (h)
Ketone
R3
Aldehyde
R1
Amine
R2
Yield (%)b
M.p. (°C)/(lit.)
R4
1
2
3
4
5
6
7
8
6
4
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Ph
Ph
Ph
Ph
Ph
Ph
Ph
92
93
91
167–169(168–170)[30]
200–202(202–203)[21]
148–150(147–149)[30]
–
4-(CH3)2NC6H4
4-CH3OC6H4
4-O2NC6H4
4-ClC6H4
4-BrC6H4
Ph
Ph
Ph
Ph
Ph
Ph
Ph
2-ClC6H4
Ph
Ph
10
10
12
12
6
12
18
18
6
6
8
24
24
1
Iminec
91
130–132(131–132)[30]
128–130(130–131)[30]
164–166(166–167)[18]
142–144(140–142)[18]
168–170(168–170)[18]
177–179(177–178)[30]
144–146(144–146)[18]
119–121(119–120)[18]
136–138(138–139)[18]
–
89
97
98
83
80
95
94
88
Trace
Trace
97(99:1)d
84(65:35)
90(61:39)
98(76:24)
89(100:0)
4-ClC6H4
3-O2NC6H4
4-CH3C6H4
4-O2NC6H4
Ph
Ph
Ph
Ph
2-CH3C6H4
Ph
Ph
Ph
4-ClC6H4
Ph
9
Ph
Ph
10
11
12
13
14
15
16
17
18
19
20
4-O2NC6H4
4-ClC6H4
4-CH3C6H4
Ph
Ph
–
Cyclohexanone
Cyclohexanone
Cyclohexanone
Cyclohexanone
CH3CH2
137–139(135–137)[26]
160–162
154–156
135–137(137–138)[18]
128–130
1
2
1
10
4-(CH3)2NC6H4
2-O2NC6H4
Ph
Ph
CH3
a
b
c
Reaction condition: aldehyde 2.5 mmol, amine 2.5 mmol, ketone 2.5 mmol, HClO4 0.25 mmol, 5 wt.% TX10/H2O 4 ml, room temperature.
Isolated yields.
The final product was imine formed from the reaction of 4-nitrobenzaldehyde and aniline.
d
Anti/syn ratio, determined by 1H NMR.
Ph
Ph
O
HN
10mol% HClO4
PhCOCH3
6h
Ph
PhNH2
PhCHO
+
N
Ph
5wt.% TX 10/H2O
r.t. 6h
Ph
the same conditions
the same conditions
PhCOCH3
PhCOCH3
PhCHO
PhNH2
No reaction
+
+
No reaction
Scheme 2. Chemoselectivity of acetophenone to aldimine.
result, the reaction was sluggish and only 19% of desired product
was gained (Table 2, entry 10). On the other hand, a very low yield
of product was obtained in the 5 wt.% TX10 aqueous micelles in the
absence of perchloric acid (Table 2, entry 11).
syn ratios (Table 3, entries 16–20) indicated it was feasible to get
high stereoselectivity product by the protocol in some cases.
To explore the mechanism of Mannich reactions in aqueous mi-
celles, we performed experiments as shown in Scheme 2. Only the
reaction of benzaldehyde with aniline could take place to obtain
corresponding imine, which then could react with acetophenone
to form the b-amino carbonyl compound under the same condi-
tions. It could be concluded that when the reaction of aldehyde,
amine and ketone occurred, the aldehyde could coordinate with
amine to form an iminium ion in the presence of perchloric acid
at first, and then it was followed by insertion of the C@N bond into
ketone to produce the b-amino carbonyl compound. If the electro-
philicity of the iminium ion is not enough to react with the ketone,
only the corresponding imine is obtained as final product (such as
Table 3, entry 4). The catalytic effect of TX10 micelles in Mannich
reactions could be explained as shown in Fig. 1. In TX10 aqueous
micelles, according to substrates polarity, they were buried in
hydrophobic cores. On one hand, due to the huge interfacial area
in micelles, the catalyst could contact with substrates sufficiently.
On the other hand, micelle droplets formed by TX10 with sub-
strates were hydrophobic enough to exclude water molecules [7],
making it easy to form the iminium ion. Thus, the reaction oc-
curred more easily in a micelle special with respect to its function-
ing as a micro- or nanoreactor [10].
With the optimized conditions in hand, the reactions of vari-
ous aromatic ketones, aromatic aldehydes and aromatic amines
were examined to ascertain the generality and scope of the pro-
tocol (Table 3, entries 1–15). There are several noteworthy fea-
tures in these reactions as follow. (1) It was found that both
electron-rich and electron-deficient benzaldehydes resulted in
good yields, but only imine could be obtained as the final product
for the benzaldehyde with strong electron-withdrawing group
such as nitro group (Table 3, entry 4). (2) The reaction was not
affected obviously by the characteristics of the substituent group
on aniline or acetophenone. (3) Generally, the ortho-substituted
aromatic amines and aromatic aldehydes gave trace of the de-
sired products because of large steric hindrance effect (Table 3,
entries 14 and 15).
The remarkable results obtained with this protocol promoted us
to use cyclohexanone under these conditions (Table 3, entries 16–
19). The results indicated that cyclohexanone was more active than
acetophenone, because its enol formation was much faster than
acetophenone. Instead of cyclohexanone, 3-pentanone also gave a
good yield of product (Table 3, entry 20). The results of the anti/

748
G.-p. Lu, C. Cai / Catalysis Communications 11 (2010) 745–748
O
R1 CHO
R2 NH2
R4
O-
+
H+
+
R3
H+
R2
R1
N+
H
H
HO
R2
H
N
H+
R1
H
H
O
H
R2
N
R1
+
R3
H
O
H
H2O
R4
R2
R2
-H+
+H+
N+
N
R1
R1
H
H+
R3
R2
R1
R4
NH
O
O-
R3
R4
R2
R1
soild product
immediate precipitate
NH
O
hydrophobic core
R3
hydrophilic environment
R4
Fig. 1. Tentative mechanism of Mannich reactions in aqueous micelles.
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4. Conclusions
In conclusion, Mannich reactions catalyzed by perchloric acid
can be performed in TX10 aqueous micelles effectively. The proce-
dure provides several advantages, such as shorter reaction time,
mild conditions, high yields, good stereoselectivities and clear
reaction profile. In addition, all products are solid and insoluble
in water, so they can be obtained directly by filtration.
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