Three-component mannich reaction of aromatic ketones, aldehydes and amines catalyzed by reusable aluminium methanesulfonate

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Three-Component Mannich Reaction
of Aromatic Ketones, Aldehydes
and Amines Catalyzed by Reusable
Aluminium Methanesulfonate
Min Wang a , Zhi-Guo Song b & Heng Jiang c
a College of Chemistry and Chemical Engineering, Bohai University,
Jinzhou, P. R. China
b Center for Science & Technology Experiment, Bohai University,
Jinzhou, P. R. China
c Liaoning Shihua University, Fushun, P. R. China
Version of record first published: 10 Jul 2009.
To cite this article: Min Wang , Zhi-Guo Song & Heng Jiang (2009): Three-Component Mannich
Reaction of Aromatic Ketones, Aldehydes and Amines Catalyzed by Reusable Aluminium
Methanesulfonate, Organic Preparations and Procedures International: The New Journal for Organic
Synthesis, 41:4, 315-321
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Organic Preparations and Procedures International, 41:315–321, 2009
Copyright © Taylor & Francis Group, LLC
ISSN: 0030-4948 print
DOI: 10.1080/00304940903078111
Three-Component Mannich Reaction of Aromatic
Ketones, Aldehydes and Amines Catalyzed
by Reusable Aluminium Methanesulfonate
Min Wang,1 Zhi-Guo Song,2 and Heng Jiang3
1College of Chemistry and Chemical Engineering, Bohai University Jinzhou,
P. R. China
2Center for Science & Technology Experiment, Bohai University Jinzhou,
P. R. China
3Liaoning Shihua University, Fushun, P. R. China
Mannich type reactions are very important carbon-carbon bond forming reactions in or-
ganic synthesis and one of the most useful methods for the preparation of β-aminocarbonyl
compounds, which are valuable synthetic intermediates for pharmaceuticals and natural
products.1 Among the three-component reactions, the Mannich processes have elicited enor-
mous interest and several procedures for the synthesis of β-aminocarbonyl compounds have
been widely described in the literature.2 Earlier literature reported that β-aminocarbonyl
compounds derived from aromatic ketones, aldehydes and amines can only be realized in-
directly by “amine exchange reaction” or “the addition of ketones to Schiff bases”.3,4 Yi and
co-workers described the three-component Mannich reaction of aromatic ketones, aldehy-
des and amines could be catalyzed by HCl/EtOH in 1991.5 Since then, the Mannich reaction
has been expanded to include various ketones, aldehydes and amines using HCl/EtOH.6
However, the hydrochloride salts of the Mannich bases using HCl/EtOH are unstable
on standing.5 Furthermore, hydrochloric acid is environmentally unfriendly. Therefore,
more practical synthetic methods for these multiply-substituted Mannich bases have been
reported, using dodecylbenzenesulfonic acid,7 polystyrene-SO3H,8 NbCl5,9 Re(PFO)3,10
Re(OPf)3,11 an acidic ionic liquid,12 H3PW12O40,13 NaBAr4F,14 SiO2-OAlCl2,15 QAS gem-
ini fluorosurfactant,16 etc. However, several drawbacks such as large excesses of catalyst,
expensive reagents, long reaction time, and low yields still exist. Moreover, the Mannich
reaction of ortho-substituted aromatic amine gave none of desired product due to steric
effects. In addition, conventional Lewis acid cannot be used because of the presence of
free amines and water produced in the imine formation. Thus, from atom-economy and
environmental standpoints, it is desirable to develop a new efficient system for the direct
one-pot Mannich reaction.
Received March 20, 2009; in final form May 15, 2009.
Address correspondence to Min Wang, College of Chemistry and Chemical Engineering, Bohai
University, Jinzhou 121000, P. R. China. E-mail: minwangszg@yahoo.com.cn
315

316
Wang, Song, and Jiang
Recently, the use of methanesulfonates as Lewis acid catalysts has been well
documented.17–20 Properties such as low toxicity, moisture and air stability, and their re-
cyclability make them attractive alternatives to conventional Lewis acids. As a part of our
studies to explore the utility of methanesulfonates, we found that aluminium methanesul-
fonate (Al(CH3SO3)3·4H2O) can catalyze the one-pot three-component Mannich reaction
of aromatic ketones, aldehydes and amines efficiently at ambient temperature (Scheme 1).
O
CHO
NH2
Al(CH3SO3)3 4H2O (5 mol %)
EtOH, r.t.
CH3
R2
R1
R3
1
3
2
R3
HN
O
R2
R1
4 (a z)
Scheme 1
First, we compared the catalytic activity of Al(CH3SO3)3·4H2O with other protic acids
and Lewis acids in the model condensation of acetophenone, benzaldehyde and aniline
(Table 1). Screening of different catalysts revealed that Al(CH3SO3)3·4H2O was the most
effective catalyst for this transformation since it resulted in the highest conversion to the
desired product. Some traditional Lewis acids such as Ce(SO4)2·4H2O, Fe2(SO4)3·6H2O,
Zn(OAc)2·2H2O and Al2(SO4)3·18H2O did not furnish the product 4a at all. The recycla-
bility of Al(CH3SO3)3·4H2O was also investigated, and it could be recycled four times
without any loss of activity (Table 1, Entry 10). Encouraged by above results, the ef-
fect of solvents on the yield of acetophenone, benzaldehyde and aniline was investigated
(Table 2). EtOH provided excellent yield and proved to be the choice, whereas CH3CN af-
forded lower yield. The reactions carried out in THF, toluene, CH2Cl2, Et2O, cyclohexane,
and H2O all failed to yield any product.
Next, we determined for the optimized reaction conditions using the same model
reaction. The effect of different molar ratio of reactants, amount of catalyst, and solvent on
the yields was studied. The best result (86% yield) was obtained by carrying out the reaction
with 1.1:1:1 molar ratio of acetophenone, benzaldehyde, aniline at ambient temperature in
the presence of 5 mol% (based on benzaldehyde) of Al(CH3SO3)3·4H2O in 5 mL EtOH for
8 h. The amount of catalyst affected the reaction significantly. We observed that 5 mol%
Al(CH3SO3)3·4H2O could catalyze the reaction efficiently and increasing the amount of
catalyst did not lead to better yields.

Mannich Reaction of Aromatic Ketones, Aldehydes and Amines
317
Table 1
Mannich Reaction of Acetophenone, Benzaldehyde and Aniline Catalyzed
by Different Catalystsa
Entry
Catalyst
Time (h)
Isolated yield (%)
1
2
3
4
5
6
7
8
9
None
HOAc
ClCH2COOH
30
16
16
16
16
16
16
16
8
0
0
0
0
0
0
56
71
Ce(SO4)2·4H2O
Fe2(SO4)3·6H2O
Zn(OAc)2·2H2O
CeCl3·7H2O
SnCl2·2H2O
Al2(SO4)3·18H2O
Al(CH3SO3)3·4H2O
0
10
8
86, 82, 76, 70b
aReaction conditions: acetophenone (11 mmol), benzaldehyde (10 mmol), aniline
(10 mmol), catalyst (0.5 mmol), EtOH (5 mL), room temperature.
bCatalyst was reused four times.
Using these optimized reaction conditions, the one-pot three-component Mannich
reactions of various aromatic ketones, aldehydes and amines were investigated and the
results are shown in Table 3. In all cases except entry 4b, the reactions proceeded smoothly
within 0.5–20 h and good yields (82–99%) of β-aminocarbonyl compounds were obtained.
Aromatic aldehydes and aromatic amines carrying either electron-withdrawing or electron-
donating groups were all suitable to the reactions. The position of meta-substituent or
Table 2
Al(CH3SO3)3·4H2O-catalyzed Mannich Reaction of Acetophenone,
Benzaldehyde and Aniline in Different Solventsa
Entry
Solvent
Isolated Yield (%)
1
2
3
4
5
6
7
8
9
EtOH
CH3CN
THF
Toluene
CH2Cl2
Et2O
Cyclohexane
H2O
86
25
0
0
0
0
0
0
0
None
aReaction conditions: acetophenone (11 mmol), benzaldehyde (10 mmol),
aniline (10 mmol), Al(CH3SO3)3·4H2O (0.5 mmol), solvent (5 mL), room
temperature, 8 h.

318
Wang, Song, and Jiang
Table 3
Al(CH3SO3)3·4H2O-catalyzed One-pot Three-component Mannich Reaction of Aromatic
Ketones, Aldehydes and Aminesa
Entry
R1
R2
R3
Time (h) Yield (%)b mp. (◦C) lit. mp. (◦C)
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
4q
4r
4s
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
4-Cl
4-Cl
4-Cl
4-Cl
H
2-Cl
3-Cl
3-NO2
4-CH3
3-COOH
4-COOH
4-OCH3
H
3-Cl
4-Cl
4-CH3
4-COOH
H
3-Cl
4-COOH
4-Cl
8
24
7
10
7
20
13
12
7
3
10
8
12
8
20
86
50
90
93
86
87
92
87
97
92
98
90
94
95
91
87
90
90
99
86
87
87
82
87
95
92
169–170 169–17015
115–116
–
130–131 135–13710
140–142 140–14211
163–166 167–1689
159–161 162–16310
193–195 190–19221
127–129 124–12516
109–111 114–11515
119–122 128–13021
121–123 118–11915
112–114 118–11921
162–165 159–16015
4-Cl
4-NO2
4-NO2
4-NO2
3-NO2
4-OCH3
4-OCH3 3-Cl
4-OCH3 4-CH3
H
H
H
H
3-NO2
H
80–82
99–102
190–192
89–9116
—
—
0.5
8
10
2
15
14
14
13
13
10
12
155–156 153–15522
137–139 142–14315
117–119 116–1186
153–155 160–16112
115–116 119–1206
109–110 108–1106
128–130 130–1326
135–137 141–1426
136–138 141–14322
H
4t
4u
4v
4w
4x
4y
4z
4-Cl
4-Cl
4-Cl
4-Cl
4-Cl
4-NO2
H
3-Cl
4-Cl
4-CH3
4-Cl
4-Cl
146–148
—
1
aThe structures of all the products were characterized by mp., H NMR, IR, MS and elemental
analysis. The physical and spectroscopic data of our known samples were identical with those reported
in the literatures.
bIsolated yields.
para-substituent on the aromatic ring shows little effects on this conversion. One of the out-
standing advantages of this method is its efficiency for the conversion of ortho-substituted
aromatic amine to the corresponding Mannich base in moderate yield (Entry 4b), a reaction
that generally fails to yield any product in the presence of the previously reported catalysts
because of steric hindrance. In addition, 4-chloroacetophenone and 4-nitroacetophenone
were also used and provided good yields.
In summary, a novel procedure for one-pot three-component Mannich reactions of
aromatic ketones, aldehydes and amines have been developed. It is notable that the catalyst

Mannich Reaction of Aromatic Ketones, Aldehydes and Amines
319
is easy to prepare, stable and storable, easily recycled and reused without substantial loss
of catalytic activity, which make them attractive and environmental friendly. This approach
could make a valuable contribution to the existing processes in the field of β-aminocarbonyl
compounds synthesis.
Experimental Section
Melting points were determined using RY-1 micromelting point apparatus and are uncor-
rected. Infrared spectra were recorded on Scimitar 2000 series Fourier Transform instru-
ment of VARIAN. 1H NMR spectra were determined on Bruker ARX-600 spectrometer in
DMSO-d6 using TMS as an internal standard. Mass spectra were obtained with an Agi-
lent 1100 series LC/MSD VL ESI instrument. Elemental analyses were carried out on EA
2400II elemental analyzer (Perkin-Elmer).
Representative Procedure for the Synthesis of 4
A mixture of aromatic ketone 1 (11 mmol), aromatic aldehyde 2 (10 mmol), aromatic amine
3 (10 mmol) and 0.192 g Al(CH3SO3)3·4H2O (5 mol%) was stirred in EtOH (5 mL) at room
temperature. When the reaction was completed as indicated by TLC, the reaction mixture
was allowed to evaporate at ambient temperature, then 60 mL hot CH2Cl2 was added to
dissolve the solid product. The catalyst was removed by hot gravity filtration and dried
for its next use. The organic filtrate was washed twice with saturated NaHCO3 solution
(10 mL), dried (Na2SO4), and evaporated to yield the crude product. The crude product
was purified by recrystalization from ethanol or ethanol/acetone (v/v = 3:2) to give the
1
corresponding pure compound 4. The pure products were identified by their mp., IR, H
NMR, MS, and elemental analysis.
3-(2-Chlorophenylamino)-3-phenyl-1-phenylpropan-1-one (4b), white solid. IR
1
(KBr): 3392, 1681, 1594, 1512, 1216 cm−1; H NMR (600 MHz, DMSO-d6): δ 3.44
(dd, J = 4.2, 4.2 Hz, 1H, COCH2), 3.98 (dd, J = 8.4, 8.4 Hz, 1H, COCH2), 5.12 (s, 1H,
NH), 5.83 (d, J = 7.8 Hz, 1H, NCH), 6.55 (t, J = 7.8 Hz, 1H, ArH), 6.61 (d, J = 8.4 Hz,
1H, ArH), 7.01 (t, J = 8.4 Hz, 1H, ArH), 7.22 (dd, J = 7.8, 7.2 Hz, 2H, ArH), 7.31 (t, J =
12.0 Hz, 2H, ArH), 7.53–7.48 (m, 4H, ArH), 7.65 (t, J = 7.2 Hz, 1H, ArH), 7.98 (d, J =
7.8 Hz, 2H, ArH); MS (ESI): m/z 336 (M+H)+.
Anal. Calcd for C21H18ClNO: C, 75.11; H, 5.40; N, 4.17. Found: C, 75.08; H, 5.40; N,
4.18.
3-(3-Chlorophenylamino)-3-(4-nitrophenyl)-1-phenylpropan-1-one (4o), yellow
1
solid. IR (KBr): 3408, 1679, 1598, 1515, 1414 cm−1; H NMR (600 MHz, DMSO-d6)
δ 3.41 (dd, J = 4.2, 4.2 Hz, 1H, COCH2), 3.72 (dd, J = 9.0, 9.0 Hz, 1H, COCH2), 5.16 (s,
1H, NH), 6.46 (d, J = 7.2 Hz, 1H, NCH), 6.52 (d, J = 7.8 Hz, 2H, ArH), 6.71 (d, J = 7.2
Hz, 1H, ArH), 7.17 (t, J = 8.4 Hz, 1H, ArH), 7.54 (t, J = 8.4 Hz, 2H, ArH), 7.66 (t, J =
7.2 Hz, 1H, ArH), 7.77 (d, J = 9.0 Hz, 2H, ArH), 7.98 (d, J = 7.2 Hz, 2H, ArH), 8.19 (d,
J = 9.0 Hz, 2H, ArH); MS (ESI): m/z 381 (M+H)+.
Anal. Calcd for C21H17ClN2O3: C, 66.23; H, 4.50; N, 7.35. Found: C, 66.21; H, 4.49;
N, 7.36.

320
Wang, Song, and Jiang
3-(4-Carboxylphenylamino)-3-(4-nitrophenyl)-1-phenylpropan-1-one (4p), pale
yellow solid. IR (KBr): 3389, 1661, 1600, 1519, 1124 cm−1; 1H NMR (600 MHz, DMSO-
d6): δ 3.45 (dd, J = 4.8, 4.8 Hz, 1H, COCH2), 3.78 (dd, J = 9.0, 9.0 Hz, 1H, COCH2),
5.24 (s, 1H, NH), 6.55 (d, J = 9.0 Hz, 2H, ArH), 7.13 (d, J = 7.2 Hz, 1H, NCH), 7.55 (t,
J = 7.8 Hz, 2H, ArH), 7.61 (d, J = 9.0 Hz, 2H, ArH), 7.66 (t, J = 7.2 Hz, 1H, ArH), 7.76
(d, J = 9.0 Hz, 2H, ArH), 7.99 (d, J = 7.2 Hz, 2H, ArH), 8.21 (d, J = 9.0 Hz, 2H, ArH),
8.43 (s, 1H, COOH); MS (ESI): m/z 389 (M-H)+.
Anal. Calcd for C22H18N2O5: C, 67.68; H, 4.65; N, 7.17; Found C, 67.66; H, 4.66; N,
7.17.
3-(4-Chlorophenylamino)-3-phenyl-1-(4-nitrophenylpropan)-1-one (4z), yellow
solid. IR (KBr): 3412, 1689, 1598, 1515, 1270 cm−1; 1H NMR (600 MHz, DMSO-d6): δ
3.42 (dd, J = 4.2, 4.2 Hz, 1H, COCH2), 3.71 (dd, J = 9.0, 9.0 Hz, 1H, COCH2), 4.95 (s,
1H, NH), 6.46 (d, J = 7.2 Hz, 1H, NCH), 6.50 (d, J = 8.4 Hz, 2H, ArH), 7.01 (t, J = 7.2
Hz, 2H, ArH), 7.22 (t, J = 7.2 Hz, 1H, ArH), 7.32 (t, J = 7.2 Hz, 2H, ArH), 7.45 (d, J
= 7.2 Hz, 2H, ArH), 8.20 (d, J = 7.2 Hz, 2H, ArH), 8.34 (d, J = 7.2 Hz, 2H, ArH); MS
(ESI): m/z 379 (M-H)+.
Anal. Calcd for C21H17ClN2O3: C, 66.23; H, 4.50; N, 7.35; Found C, 66.25; H, 4.50;
N, 7.34.
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