SnCl45H2O-catalyzed synthesis of β-amino carbonyl compounds via a direct Mannich-type reaction

Article abstract of DOI:10.1080/10826068.2010.489008

An efficient three-component, one-pot synthesis of β-amino carbonyl compounds from aromatic ketones, aromatic aldehydes, and aromatic amines using tin tetrachloride at room temperature in ethanol is described. The advantages of the new method are good yields (62-96%), simple workup, and inexpensive catalyst. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/10826068.2010.489008

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SnCl4·5H2O-CATALYZED SYNTHESIS OF
β-AMINO CARBONYL COMPOUNDS VIA A
DIRECT MANNICH-TYPE REACTION
Min Wang a , Zhiguo Song b & Yan Liang a
a College of Chemistry and Chemical Engineering, Bohai University,
Jinzhou, Liaoning, P.R. China
b Center for Science & Technology Experiment, Bohai University,
Jinzhou, Liaoning, P.R. China
Version of record first published: 10 Jan 2011.
To cite this article: Min Wang , Zhiguo Song & Yan Liang (2010): SnCl4·5H2O-CATALYZED SYNTHESIS OF
β-AMINO CARBONYL COMPOUNDS VIA A DIRECT MANNICH-TYPE REACTION, Preparative Biochemistry
and Biotechnology, 41:1, 1-6
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Preparative Biochemistry & Biotechnology, 41:1–6, 2011
Copyright # Taylor & Francis Group, LLC
ISSN: 1082-6068 print/1532-2297 online
DOI: 10.1080/10826068.2010.489008
SnCl4 ꢀ 5H2O-CATALYZED SYNTHESIS OF b-AMINO CARBONYL
COMPOUNDS VIA A DIRECT MANNICH-TYPE REACTION
Min Wang,1 Zhiguo Song,2 and Yan Liang1
1College of Chemistry and Chemical Engineering, Bohai University, Jinzhou,
Liaoning, P.R. China
2Center for Science & Technology Experiment, Bohai University, Jinzhou,
Liaoning, P.R. China
& An efficient three-component, one-pot synthesis of b-amino carbonyl compounds from aromatic
ketones, aromatic aldehydes, and aromatic amines using tin tetrachloride at room temperature in
ethanol is described. The advantages of the new method are good yields (62–96%), simple workup,
and inexpensive catalyst.
Keywords b-amino carbonyl compounds, Mannich reaction, one-pot synthesis, tin
tetrachloride
INTRODUCTION
As is well known, b-amino carbonyl compounds are important
synthetic intermediates for various pharmaceuticals, natural products,
and biologically attractive compounds.[1,2] Generally, b-amino carbonyl
compounds are synthesized from aromatic ketones, aromatic aldehydes,
and aromatic amines through the Mannich reaction catalyzed by
HCl=EtOH,[3] dodecylbenzenesulfonic acid,[4] Ps-SO3H,[5] NbCl5,[6]
Re(PFO)3,[7] Re(OPf)3,[8] ionic liquid,[9] H3PW12O40,[10] NaBAr4F ,[11]
SiO2-OAlCl2,[12] QAS gemini fluorosurfactant,[13] etc. However, most of
these methods suffer from drawbacks such as the use of a corrosive
reagent, expensive and large amount of catalyst, harmful reaction media
(fluorous solvent), and low yields. Furthermore, ortho-substituted aromatic
amines generally gave trace or no products because of large steric hin-
drance effects. Hence, it was of interest to develop a more universal
method for the synthesis of these products.
Address correspondence to Min Wang, College of Chemistry and Chemical Engineering, Bohai
University, Jinzhou, Liaoning 121000, P.R. China. E-mail: minwangszg@yahoo.com.cn

2
M. Wang et al.
FIGURE 1 SnCl4 ꢀ 5H2O-catalyzed Mannich reaction.
Recently, SnCl4 has emerged as an efficient Lewis acid in promoting
various organic transformations, such as aromatization,[14] heterocyclo
additions,[15] coupling reactions,[16] rearrangement of epoxides,[17]
oxidation,[18] and ring opening reactions.[19] The versatility of this reagent
encouraged us to study its utility for the three-component Mannich-type
reaction. To our knowledge, direct Mannich-type reactions catalyzed
by SnCl4 ꢀ 5H2O have not been reported. Herein, we report an SnCl4 ꢀ
5H2O-catalyzed three-component, one-pot Mannich-type reaction of
aromatic ketones 1, aromatic aldehydes 2, and aromatic amines 3, which
led to the efficient synthesis of b-amino ketones 4 under mild conditions
(Figure 1).
EXPERIMENTAL
Melting points were determined using RY-1 micro-melting-point appar-
atus. Infrared spectra were recorded on a Perkin-Elmer Spectrum GX series
Fourier transform instrument. 1H-Nuclear magnetic resonance (NMR)
spectra were recorded on a Bruker ARX-600 spectrometer in dimethyl sulf-
oxide (DMSO)-d6 using tetramethylsilane (TMS) as an internal standard.
Mass spectra were obtained with an Agilent 1100 series LC=MSD VL ESI
instrument. Elemental analyses were carried out on an EA 2400II elemental
analyzer (Perkin-Elmer) and agreed well with calculated values.
General Procedures for the Preparation of Products (4)
A mixture of aromatic ketone 1 (11 mmol), aromatic aldehyde 2
(10 mmol), aromatic amine 3 (10 mmol), and SnCl4 ꢀ 5H2O (0.5 mmol)
was stirred in EtOH (5 mL) at room temperature for an appropriate time
(Table 3). After completion of the reaction (monitored by TLC), saturated
NaHCO3 solution (10 mL) was added, and the precipitated solid was
collected by filtration and washed with ethanol. The crude product was
purified via recrystallization from ethanol or ethanol=acetone (v=v ¼ 3:2)

Mannich Reaction Catalyzed by Tin Tetrachloride
3
to give the corresponding pure compound. Then the pure products 4 were
identified by comparing their melting point (mp), infrared (IR), 1H-NMR,
mass spectroscopy (MS), and elemental analysis with those reported for the
authentic samples.
RESULTS AND DISCUSSION
In the initial experiments, we screened different solvents for their
effects on the yields in the three-component reaction of acetophenone,
benzaldehyde, and aniline at room temperature, and the results are
summarized in Table 1. Ethanol provided an excellent yield and proved
to be the best, whereas acetonitrile afforded a lower yield. The reactions
in tetrahydrofuran (THF), toluene, CH2Cl2, Et2O, cyclohexane, H2O,
and under solvent-free conditions all failed to yield any product.
Next, we groped for the optimal reaction conditions using the same
model reaction. The amounts of acetophenone, SnCl4 ꢀ 5H2O, and EtOH
are studied in Table 2. It was found that the use of 3 mol% (based on
benzaldehyde) catalyst gave a low yield even after a long reaction time
(Entry 3). In comparison, 5 mol% catalyst led to a 92% yield of product
in 2 hr (Entry 2). Increasing the amount of catalyst could not bring better
results. Hence, the best result was obtained after several trials by carrying
out the reaction with 1.1:1:1 molar ratio of acetophenone, benzaldehyde,
and aniline at ambient temperature in the presence of 5 mol% of
SnCl4 ꢀ 5H2O in 5 mL EtOH for 2 hr (Entry 2).
To generalize our protocol, a serial of b-amino ketones were prepared
from different aromatic ketones, aromatic aldehydes, and aromatic amines
under optimal reaction conditions described earlier. As shown in Table 3,
the reactions proceeded smoothly at room temperature in the presence
TABLE 1 SnCl4 ꢀ 5H2O-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
92
69
0
0
0
0
0
0
0
Cyclohexane
H2O
None
aReaction conditions: acetophenone (11 mmol), benzaldehyde (10 mmol), aniline
(10 mmol), SnCl4 ꢀ 5H2O (0.5 mmol), solvent (5 mL), room temperature, 2 hr.

4
M. Wang et al.
TABLE 2 Screening of Different Reaction Conditions for the Mannich Reactions of Acetophenone,
Benzaldehyde, and Anilinea
Entry Acetophenone (mmol) SnCl4 ꢀ 5H2O (mol%) EtOH (mL) Time (h) Isolated Yield (%)
1
2
3
4
5
10
11
11
11
11
5
5
3
5
5
5
5
5
3
8
2
2
6
2
2
83
92
72
81
67
aReaction conditions: benzaldehyde (10 mmol), aniline (10 mmol), room temperature.
of SnCl4 ꢀ 5H2O to afford the desired products in good yields. The sub-
stituents of aromatic aldehydes affect the yields of b-amino ketones to an
extent. Electron-donating substituents of aromatic aldehydes are disadvan-
tageous to the Mannich reaction, and the yield of 4-methoxybenzaldehyde
(4o) was lower than those of other aromatic aldehydes. Moreover, no
b-amino ketone was obtained when using 4-dimethylaminobenzaldehyde
TABLE
3
SnCl4 ꢀ 5H2O-Catalyzed One-Pot, Three-Component Mannich Reaction of Aromatic
Ketones, Aromatic Aldehydes, and Aromatic Aminesa
mp (ꢁC)
Found Reported
Product
R1
R2
R3
Time (h) Isolated Yield (%)
4a
4b
4c
4d
4e
4f
4g
4h
4i
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
2-Cl
3-Cl
2
48
2
48
35
35
32
5.5
26.5
18
12
17.5
48
0.5
34
48
92
68
87
80
68
82
85
64
62
87
90
93
96
74
78
0
168–170 169–170[20]
114–116 115–116[20]
130–133 130–131[20]
170–172 171–173[21]
156–158 159–161[20]
193–195 193–195[20]
143–145 140–142[20]
162–164 163–166[20]
123–126 127–129[20]
108–110 109–111[20]
4-Cl
3-COOH
4-COOH
3-NO2
4-CH3
4-OCH3
H
H
3-Cl
4-Cl
4-COOH
H
H
H
3-Cl
4-Cl
4-Cl
4-Cl
4j
4k
4l
4-Cl
4-NO2
4-NO2
4-NO2
4-NO2
4-OCH3
4-(CH3)2N
H
H
H
3-NO2
H
80–82
100–102
127–130 129–131[21]
190–192 190–192[20]
135–137 137–139[20]
80–82[20]
99–102[20]
4m
4n
4o
4p
4q
4r
4s
4t
—
—
4-Cl
4-Cl
4-Cl
4-Cl
4-NO2
7.5
2.5
1.4
18
81
75
64
82
75
114–117 115–116[20]
105–108 109–110[20]
126–128 128–130[20]
133–135 136–138[20]
145–147 146–148[20]
4u
3
aThe structures of all the products were characterized by mp, 1H NMR, IR, MS, and elemental
analysis. The physical and spectroscopic data of our samples were identical with those reported in
the literature.

Mannich Reaction Catalyzed by Tin Tetrachloride
5
as an aldehyde component (4p). As to aromatic amines, either electron-
withdrawing or electron-donating groups were all suitable to the reactions.
The position of a meta-substituent or para-substituent on the aromatic ring
shows little effect on this conversion. One of the outstanding advantages of
this method is its efficiency for the conversion in moderate yield of ortho-
substituted aromatic amine to the corresponding Mannich base (4b), a
reaction that generally fails to yield any product in the presence of the
previously reported catalysts because of steric hindrance. As to aromatic
ketones, 4-chloroacetophenone and 4-nitroacetophenone were also investi-
gated and provided good yields.
CONCLUSIONS
In summary, SnCl4 ꢀ 5H2O was found to be an efficient catalyst for the
three-component, one-pot Mannich-type reaction of aromatic ketones,
aromatic aldehydes, and aromatic amines. The catalyst is cheap and stable.
The protocol could make a valuable contribution to the existing processes
in the field of b-amino carbonyl compounds synthesis.
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