SnCl2-catalyzed three-component one-pot Mannich-type reaction: Efficient synthesis of β-aminocarbonyl compounds

Article abstract of DOI:10.1007/s00706-009-0163-1

SnCl₂-catalyzed three-component one-pot Mannich reaction of acetophenone or p-chloroacetophenone with different aromatic aldehydes and aromatic amines in ethanol at ambient temperature gave the corresponding β-aminocarbonyl compounds in good to excellent yields. Four new compounds are reported for the first time.

Full text of DOI:10.1007/s00706-009-0163-1

Monatsh Chem (2009) 140:1205–1208
DOI 10.1007/s00706-009-0163-1
ORIGINAL PAPER
SnCl2-catalyzed three-component one-pot Mannich-type reaction:
efficient synthesis of b-aminocarbonyl compounds
Min Wang Æ Zhi-Guo Song Æ Xin Wan Æ
Suang Zhao
Received: 10 October 2008 / Accepted: 6 June 2009 / Published online: 23 June 2009
Ó Springer-Verlag 2009
Abstract SnCl2-catalyzed three-component one-pot
Mannich reaction of acetophenone or p-chloroacetophe-
none with different aromatic aldehydes and aromatic
amines in ethanol at ambient temperature gave the corre-
sponding b-aminocarbonyl compounds in good to excellent
yields. Four new compounds are reported for the first time.
a large number of derivatives it is preferable to use a three-
component one-pot strategy, involving the in-situ formation
of imine intermediates from aldehydes and amines, which
are readily available with a wide range of structural varia-
tions. Unfortunately, only a few three-component one-pot
procedures using aromatic ketones, aldehydes, and amines
have been reported in the literature, and few catalysts,
including conc. HCl [7], NbCl5 [8], Yb(OPf)3 [9], PS–SO3H
[10], dodecylbenzenesulfonic acid [11], H3PW12O40 [12],
HClO4–SiO2 [13], SiO2–OAlCl2 [14], quaternary ammo-
nium salt gemini fluorosurfactants [15], and ionic liquids
[16, 17], etc., have been developed. Moreover, most of these
methods suffer from disadvantages such as strong acids or
expensive catalysts, elevated reaction temperature, toxic
reagents, low yields, and requiring special effort for catalyst
preparation; also, ortho-substituted aromatic amines give no
products. Hence, there is an increasing interest in developing
environmentally benign reactions and atom-economic
catalytic processes for synthesis of b-aminocarbonyl
compounds. Herein, we report a SnCl2-catalyzed three-
component Mannich-type reaction of acetophenone or
p-chloroacetophenone with a variety of aromatic aldehydes
and aromatic amines at room temperature, which led to the
efficient synthesis of b-aminocarbonyl compounds under
mild conditions (Scheme 1). To the best of our knowledge,
direct Mannich-type reactions catalyzed by SnCl2 have not
been reported previously.
Keywords Mannich reaction Á b-Aminocarbonyl
compound Á One-pot synthesis Á SnCl2
Introduction
Mannich-type reactions are very important carbon–carbon
bond-forming reactions in organic synthesis. It is a crucial
method for preparation of b-aminocarbonyl compounds, and
it is a key step in the synthesis of numerous pharmaceuticals,
natural products, and versatile synthetic intermediates [1].
Classical Mannich reactions were plagued by a number of
serious disadvantages and their application has been limited.
Numerous modern procedures have been developed to
overcome the drawbacks of conventional methods.
In general, the improved methodology relies on a two-
component system using preformed electrophiles, for
example imines, and stable nucleophiles, for example eno-
lates, enol ethers, and enamines [2–6]. However, the two-
component system is not always ideal. In order to synthesize
M. Wang (&) Á X. Wan Á S. Zhao
Results and discussion
College of Chemistry and Chemical Engineering,
Bohai University, Jinzhou, China
e-mail: minwangszg@yahoo.com.cn
Initially, the effect of solvent, for example H2O, THF,
CH2Cl2, and EtOH, on the three-component Mannich reac-
tion of acetophenone (11 mmol), benzaldehyde (10 mmol),
and aniline (10 mmol) was examined. No product was
Z.-G. Song
Center for Science and Technology Experiment,
Bohai University, Jinzhou, China
123

1206
M. Wang et al.
R3
O
CHO
NH2
SnCl2 (10 mol%)
O
HN
CH3
EtOH, r.t.
R1
R2
R3
R2
R1
2
1
3
4a-4y
Scheme 1
obtained in H2O, THF, and CH2Cl2. EtOH proved to be the
best in terms of yields. Therefore, EtOH was selected as the
reaction solvent in the following investigations.
or even no product [8, 9, 14, 18], because of the large steric
hindrance, also yielded the corresponding Mannich base 4b
in moderate yield when our method was used. Therefore,
the position of the substituents on the aromatic ring of
amines has no obvious effects on this conversion. In the
case of aromatic ketones, besides acetophenone substituted
p-chloroacetophenone could also be employed to give good
yields (4u–4y).
In order to optimize the reaction conditions, the amounts
of acetophenone, SnCl2, and EtOH were screened in a
model reaction of acetophenone, benzaldehyde (10 mmol),
and aniline (10 mmol); the results are shown in Table 1.
After several trials, the best result with 93% yield was
obtained by carrying out the reaction with 1.1:1:1:0.1
molar ratio of acetophenone, benzaldehyde, aniline, and
SnCl2 at room temperature in 3 cm3 EtOH for 10 h.
In order to explore the generality and scope of the new
procedure, three-component one-pot Mannich reactions of
acetophenone or p-chloroacetophenone with different aro-
matic aldehydes and aromatic amines were tested under the
optimal conditions. The results are summarized in Table 2.
All the reactions proceeded smoothly in the presence of
10 mol% SnCl2 (based on aldehyde) at room temperature
to give the corresponding b-aminoketones in moderate to
high yields (65–99%). Aldehydes carrying either electron-
withdrawing groups (–Cl and –NO2) or an electron-
donating group (–OCH3) were all suitable for use with this
new procedure. However, aromatic aldehydes with strongly
electron-donating substituents, for example –N(CH3)2,
failed to give the desired product (4t). Aromatic amines
bearing different substituents, for example ortho-Cl, meta-
Cl, para-Cl, meta-COOH, para-COOH, meta-NO2, para-
OCH3, and para-NO2, were all suitable for use in this
reaction. It is worth mentioning that the ortho-substituted
aromatic amines, which generally gave only trace amounts
In conclusion, we have described a simple and efficient
strategy for three-component one-pot Mannich-type reac-
tion using SnCl2 as catalyst. The method has several
advantages including mild reaction conditions, high yields
of products, simple workup procedure, inexpensive, non-
toxic, and commercially available catalysts, which makes it
a valuable contribution for the synthesis of b-aminocar-
bonyl compounds.
Experimental
Melting points were determined using an RY-1 micro-
melting point apparatus. Infrared spectra were recorded on
a Perkin–Elmer Spectrum GX series Fourier-transform
1
instrument. H NMR spectra were recorded on a Bruker
ARX-600 spectrometer in DMSO-d6 using TMS as 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 procedure for the synthesis
of b-aminocarbonyl compounds 4
Table 1 Screening of different reaction conditions for the Mannich
reaction of acetophenone, benzaldehyde, and aniline
Entry
Acetophenone
(mmol)
SnCl2
(mol%)
EtOH
(cm3)
Isolated
yield (%)
A mixture of aromatic ketone 1 (11 mmol), aromatic
aldehyde 2 (10 mmol), aromatic amine 3 (10 mmol), and
0.190 g SnCl2 (10 mol%) was stirred in 3 cm3 EtOH at
room temperature for 3–48 h. After completion of the
reaction (monitored by TLC), 10 cm3 saturated NaHCO3
solution was added, and the precipitated solid was collected
by filtration and washed with ethanol. The crude product
was purified by recrystallization from ethanol or ethanol–
acetone 3:2 (v/v) to give the corresponding pure compound.
1
2
3
4
5
6
11
10
11
11
11
11
10
10
5
3
3
93
86
55
88
84
75
3
10
10
10
5
8
10
All reactions were carried out at room temperature for 10 h
123

SnCl2-catalyzed three-component one-pot Mannich-type reaction
1207
Table 2 SnCl2-catalyzed Mannich reactions of acetophenone or p-chloroacetophenone with aromatic aldehydes and aromatic amines
Entry
R1
R2
R3
Time (h)
Yield (%)a
M.p. (°C)
Found
Reported
4a
4b
4c
4d
4e
4f
H
H
H
10
48
3.5
48
20
24
20
20
6
93
66
92
88
82
99
92
74
91
91
85
80
74
89
82
89
63
89
93
0
170–171
113–115
132–134
171–173
149–150
194–196
139–141
136–138
114–115
119–121
123–124
164–166
133–135
86–88
169–170 [14]
–
H
H
2-Cl
H
H
3-Cl
135–137 [18]
170–171 [14]
162–163 [18]
190–192 [16]
140–142 [9]
124–125 [15]
114–115 [14]
128–130 [16]
118–119 [14]
159–160 [14]
132–133 [14]
89–91 [15]
–
H
H
4-Cl
H
H
3-COOH
4-COOH
3-NO2
4-OCH3
H
H
H
4g
4h
4i
H
H
H
H
H
4-Cl
4-Cl
4-Cl
4-Cl
4-Cl
4-NO2
4-NO2
4-NO2
4-NO2
4-OCH3
4-OCH3
4-(CH3)2N
H
4j
H
3-Cl
5.5
10
10.5
30
5.5
9.5
48
9.5
24
12
24
12
9.5
12
48
48
4k
4l
H
4-Cl
H
4-COOH
3-NO2
H
4m
4n
4o
4p
4q
4r
4s
4t
H
H
H
3-Cl
99–101
H
4-Cl
129–131
190–193
137–139
112–114
–
–
H
4-COOH
H
–
H
142–143 [14]
116–118 [7]
202–203 [14]
119–120 [7]
108–110 [7]
130–132 [7]
150–151 [7]
170–172 [7]
H
3-Cl
H
H
4u
4v
4w
4x
4y
a
4-Cl
4-Cl
4-Cl
4-Cl
4-Cl
H
88
92
76
86
71
117–119
104–106
128–130
147–149
162–165
H
3-Cl
H
4-Cl
H
3-NO2
4-NO2
H
Isolated yield, the purity and the identity of the products was determined by m.p., IR, 1H NMR, and mass spectroscopy, and elemental analysis
2H, ArH), 7.17 (t, J = 8.4 Hz, 1H, ArH), 6.71 (d,
J = 7.2 Hz, 1H, ArH), 6.52 (d, J = 7.8 Hz, 2H, ArH),
6.46 (d, J = 7.2 Hz, 1H, NCH), 5.16 (s, 1H, NH), 3.72 (dd,
J = 9.0, 9.0 Hz, 1H, COCH2), 3.41 (dd, J = 4.2, 4.2 Hz,
1H, COCH2) ppm; MS (ESI): m/z = 381 (M ? H)?.
The pure products were identified by comparing their m.p.,
IR, 1H NMR, MS, and elemental analysis with those
reported for authentic samples [7, 9, 14–16, 18].
3-(2-Chlorophenylamino)-3-phenyl-1-phenylpropan-1-one
(4b, C21H18ClNO)
1
White solid; IR (KBr): v = 3,392, 1,681 cm-1; H NMR
3-(4-Chlorophenylamino)-3-(4-nitrophenyl)-1-
phenylpropan-1-one (4p, C21H17ClN2O3)
(600 MHz, DMSO-d6): d = 7.98 (d, J = 7.8 Hz, 2H,
ArH), 7.65 (t, J = 7.2 Hz, 1H, ArH), 7.53–7.48 (m, 4H,
ArH), 7.31 (t, J = 12.0 Hz, 2H, ArH), 7.22 (dd, J = 7.8,
7.2 Hz, 2H, ArH), 7.01 (t, J = 8.4 Hz, 1H, ArH), 6.61 (d,
J = 8.4 Hz, 1H, ArH), 6.55 (t, J = 7.8 Hz, 1H, ArH), 5.83
(d, J = 7.8 Hz, 1H, NCH), 5.12 (s, 1H, NH), 3.98 (dd,
J = 8.4, 8.4 Hz, 1H, COCH2), 3.44 (dd, J = 4.2, 4.2 Hz,
1H, COCH2) ppm; MS (ESI): m/z = 336 (M ? H)?.
1
Yellow solid; IR (KBr): v = 3,395, 1,673 cm-1; H NMR
(600 MHz, DMSO-d6): d = 8.20 (d, J = 8.4 Hz, 2H,
ArH), 7.98 (d, J = 7.2 Hz, 2H, ArH), 7.75 (d,
J = 8.4 Hz, 2H, ArH), 7.66 (t, J = 7.2 Hz, 1H, ArH),
7.54 (t, J = 7.8 Hz, 2H, ArH), 7.03 (d, J = 9.0 Hz, 2H,
ArH), 6.58 (d, J = 7.2 Hz, 1H, NCH), 6.51 (d, J = 9.0 Hz,
2H, ArH), 5.12 (s, 1H, NH), 3.72 (dd, J = 9.0, 9.0 Hz, 1H,
COCH2), 3.40 (dd, J = 4.8, 4.8 Hz, 1H, COCH2) ppm; MS
(ESI): m/z = 380 (M?).
3-(3-Chlorophenylamino)-3-(4-nitrophenyl)-1-
phenylpropan-1-one (4o, C21H17ClN2O3)
1
Yellow solid; IR (KBr): v = 3,408, 1,678 cm-1. H NMR
3-(4-Carboxylphenylamino)-3-(4-nitrophenyl)-1-
phenylpropan-1-one (4q, C22H18N2O5)
(600 MHz, DMSO-d6): d = 8.19 (d, J = 9.0 Hz, 2H, ArH),
7.98 (d, J = 7.2 Hz, 2H, ArH), 7.77 (d, J = 9.0 Hz, 2H,
ArH), 7.66 (t, J = 7.2 Hz, 1H, ArH), 7.54 (t, J = 8.4 Hz,
1
Pale yellow solid; IR (KBr): v = 3388, 1661 cm-1; H
NMR (600 MHz, DMSO-d6): d = 8.43 (s, 1H, COOH),
123

1208
M. Wang et al.
6. Cobb AJA, Shaw DM, Longbottom DA, Gold JB, Ley SV (2005)
Org Biomol Chem 3:84
7. Yi L, Lei HS, Zou JH, Xu XJ (1991) Synthesis, p 717
8. Wang R, Li BG, Huang TK, Shi L, Lu XX (2007) Tetrahedron
Lett 48:2071
9. Yi WB, Cai C (2006) J Fluor Chem 127:1515
10. Iimura S, Nobutou D, Manabe K, Kobayashi S (2003) Chem
Commun, p 1644
11. Manabe K, Kobayashi S (1999) Org Lett 1:1965
12. Azizi N, Torkiyan L, Saidi MR (2006) Org Lett 8:2079
13. Bigdeli MA, Nemati F, Mahdavinia GH (2007) Tetrahedron Lett
48:6801
8.21 (d, J = 9.0 Hz, 2H, ArH), 7.99 (d, J = 7.2 Hz, 2H,
ArH), 7.76 (d, J = 9.0 Hz, 2H, ArH), 7.66 (t, J = 7.2 Hz,
1H, ArH), 7.61 (d, J = 9.0 Hz, 2H, ArH), 7.55 (t,
J = 7.8 Hz, 2H, ArH), 7.13 (d, J = 7.2 Hz, 1H, NCH),
6.55 (d, J = 9.0 Hz, 2H, ArH), 5.24 (s, 1H, NH), 3.78 (dd,
J = 9.0, 9.0 Hz, 1H, COCH2), 3.45 (dd, J = 4.8, 4.8 Hz,
1H, COCH2) ppm; MS (ESI): m/z = 389 (M - H)?.
References
14. Li Z, Ma XL, Liu J, Feng X, Tian GQ, Zhu AG (2007) J Mol
Catal A Chem 272:132
1. Arend M, Westermann B, Risch N (1998) Angew Chem Int Ed
37:1044
2. Matsunaga S, Kumagai N, Harada S, Shibasaki M (2003) J Am
Chem Soc 125:4712
3. Trost BM, Terrell LR (2003) J Am Chem Soc 125:338
4. Akiyama T, Takaya J, Kagoshima H (2002) Adv Synth Catal
344:338
15. Shen W, Wang LM, Tian H (2008) J Fluor Chem 129:267
16. Li JZ, Peng YQ, Song GH (2005) Catal Lett 102:159
17. Fang D, Luo J, Zhou XL, Liu ZL (2007) Catal Lett 116:76
18. Wang LM, Han JW, Sheng J, Tian H, Fan ZY (2005) Catal
Commun 6:201
5. Kobayashi S, Hamada T, Manabe K (2002) J Am Chem Soc
124:5640
123