One-pot three-component Mannich-type reactions using Sulfamic ...

One-pot three-component Mannich-type reactions using Sulfamic acid catalyst
under ultrasound irradiation
Hongyao Zeng, Hua Li, Huawu Shao *
Natural Products Research Center, Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610041, PR China
Graduate School of Chinese Academy of Sciences, PR China
article info
Article history:
Received 3 February 2009
Received in revised form 3 March 2009
Accepted 18 March 2009
Available online 27 March 2009
Keywords:
Mannich reaction
Ultrasound
b-Aminocarbonyl compound
One-pot reaction
Sulfamic acid
1. Introduction
abstract
The Mannich reaction is one of the most important carbon–carbon
bond forming reactions in organic synthesis [1] because it affords
synthetically and biologically important b-aminocarbonyl
compounds, which are important intermediates for the construction
of various nitrogen-containing natural products and pharmaceuticals
[2]. However, rather harsh conditions, moderate yields
and complex workup and purification procedures still have limited
a wider application [3]. To overcome the drawbacks of the classic
method, in the last few years the Lewis acid-catalyzed condensation
of silyl enol ethers or silyl ketene acetals to pre-formed imines
has been made with the versions of Mannich-type reactions leading
to various N-substituted b-aminocarbonyl compounds [4],
but due to the instability of many imines in water, this Lewis
acid-catalyzed three component reaction of aldehydes, amines
and silyl enolates in the same vessel has to be carried out under
strict anhydrous conditions. In addition, when water was produced
in the imine formation, most Lewis acids cannot be used in this
one-pot reaction. Therefore, from atom economical and environmental
points of view, the preferred route is to use a one-pot
three-component strategy that gives a wide range of structural
variations. Recently, some one-pot Mannich reactions on the use
of unmodified ketones, aldehydes and amines have been catalyzed
by organic or mineral acids like proline [5], p-dodecyl benzene sul-
* Corresponding author. Fax: +86 28 85222753.
E-mail address: shaohw@cib.ac.cn (H. Shao).
1350-4177/$ - see front matter Ó 2009 Elsevier B.V. All rights reserved.
doi:10.1016/j.ultsonch.2009.03.008
Ultrasonics Sonochemistry 16 (2009) 758–762
Contents lists available at ScienceDirect
Ultrasonics Sonochemistry
journal homepage: www.elsevier.com/locate/ultsonch
Sulfamic acid (NH2SO3H, SA) was used as an efficient, inexpensive, non-toxic and recyclable green catalyst
for the ultrasound-assisted one-pot Mannich reaction of aldehydes with ketones and amines. This
ultrasound protocol has advantages of high yield, mild condition, no environmental pollution, and simple
work-up procedures. Most importantly, b-aminocarbonyl compounds with ortho-substituted aromatic
amines are obtained in acceptable to good yields by this methodology for the first time.
Ó 2009 Elsevier B.V. All rights reserved.
phonic acid (DBSA) [6], Lewis acids [7], Bronsted acid catalysts [8]
as well as heterogeneous catalysts [9]. However, many of Lewis
acids are corrosive, moisture-sensitive and non-recoverable reagents.
The synthesis of heterogeneous catalysts often involves
long and tedious procedures. Moreover, most of one-pot Mannich
reactions are slow (10–20 h) especially for ortho-substituted aromatic
amines. Therefore, it has attracted continuous interest to develop
methods for the synthesis of b-aminocarbonyl compounds.
In recent years, Sulfamic acid (NH2SO3H, SA) has emerged as a
promising substitute for conventional Bronsted- and Lewis acid
catalysts. It is a relatively dry, non-volatile, non-hygroscopic, noncorrosive,
and odorless crystalline solid with outstanding physical
stability. It possesses distinctive catalytic features related to its zwitterionic
nature and displays an excellent activity over a vast array of
acid-catalyzed organic transformations, as witnessed by numerous
reports published in the past three years [10]. These properties
prompted us to investigate the use of Sulfamic acid for the onepot,
three-component synthesis of b-amino ketones. Very recently,
Xia and co-workers reported that fluorinated b-aminobutanones
could be obtained through one-pot three-component Mannich reaction
of unmodified acetone with aldehydes and fluorinated anilines
in good to excellent yields catalyzed by SA but in conventional
conditions [10a].
Likewise, ultrasonic-assisted organic synthesis (UAOS) as a
green powerful synthetic approach is now well known to enhance
the reaction rates and yields/selectivity of reactions and in several
cases facilitates organic transformation at ambient conditions
which otherwise require drastic conditions of temperature and
pressure [11,12]. More recently, ultrasound (US), for the first time,

has been employed to promote two-component and three-component
asymmetric Mannich reactions and a self-Mannich reaction
efficiently and rapidly [5a]. Here, we report ultrasound assisted
one-pot approach to direct Mannich Reactions of aldehydes,
ketones and amines in absolute EtOH catalyzed by SA, which led
to a rapid and efficient synthesis of b-amino ketones under mild
conditions (Scheme 1).
2. Method
2.1. Apparatus and analysis
All reagents were purchased from commercial sources and all
were further purified by recrystallization or distillation using standard
procedures. Ultrasonication was performed in a KQ-600GKDV
ultrasound cleaner with a frequency of 40 kHz and an output
power of 600 W. The temperature of the water bath can be controlled
by a controlled automatic constant temperature cooling circulatory
system. High speed stirring was carried out with the
Yuhua DF-101S series aggregating heat constant temperature blender
with magnetic force. TLC was carried out on silica gel 60F 254
precoated plates (0.20–0.25 mm thickness) and visualized with UV
light (254 nm). Column chromatography was performed on silica
gel 90, 200–300 mesh. Melting points were determined with X-6
(Beijing Fukai Co. Ltd.) melting point apparatus and are uncorrected.
1 H NMR and 13 C NMR (600 and 150 MHz, respectively)
spectra were recorded on a Bruker Avance 600 spectrometer using
TMS as an internal standard. All spectroscopic data of the products
were identical to data from authentic samples.
2.2. General procedure
To the mixture of acetophenone (1) (2.2 mmol), aldehyde (2)
(2 mmol) and aniline (3) (2 mmol) in 3 mL of absolute ethanol,
SA (0.02 g, 0.2 mmol) was added. The mixture was sonicated at
room temperature in an US bath having a frequency of 40 kHz
and an input power of 600 W. The flask was suspended at the center
of the bath. The progress of the reaction was monitored by TLC
and then filtrated. The filtrated solid, which was washed with ether
(3 5 mL) and activated at 70 °C for 2 h, could be reused in next
cycle without considerable activity loss at least twice for the same
reaction. The filtrate was concentrated under reduced pressure and
then isolated by silica gel column chromatography with EtOAc/
petroleum ether (5:1) as the eluent or recrystallization from
acetone/ethanol (2:3) to offer the pure product (4) as solid in good
to excellent yields. Compounds 4a–4d, 4f–4p were compared with
the corresponding compounds prepared by the reported procedure
[7–9]. Compounds 4e, 4q–4x were new and were characterized by
spectral analysis.
2.2.1. 3-[(4-Fluorophenyl)amino]-1,3-diphenylpropan-1-one (4e)
m.p. 162–163 °C. 1 H NMR (CDCl3): d 3.42 (dd, J=7.6 Hz,
J=16.3 Hz, 1 H), 3.49 (dd, J=4.9 Hz, J=16.3 Hz, 1 H), 4.91 (dd,
J=7.6 Hz, J=4.9 Hz, 1 H), 6.49–6.52 (m, 2 H), 6.78 (t, J=8.7 Hz, 2
O
CH 3
H. Zeng et al. / Ultrasonics Sonochemistry 16 (2009) 758–762 759
CHO
+ +
R 1
NH 2
R 2
H), 7.24 (t, J=7.4 Hz, 2 H), 7.32 (t, J=7.6 Hz, 2 H), 7.41 (m,
J=8.0 Hz, 4 H), 7.56 (t, J=7.4 Hz, 1 H), 7.91 (d, J=7.4 Hz, 2 H).
13 C NMR (CDCl3): d 46.3, 55.7, 115.2, 115.5, 115.6, 126.4, 127.5,
128.2, 128.7, 128.9, 133.5, 136.7, 142.6, 143.1, 198.2. IR (KBr,
cm 1 ): v 3386, 1671, 1595, 1511, 1449, 1289, 1220, 815, 701,
684. ESI HRMS Anal. calcd. for C 21H 18FNONa [M+Na] 342.1265;
found: 342.1268.
2.2.2. 3-[(2-Fluorophenyl)amino]-1,3-diphenylpropan-1-one (4q)
m.p. 163–164 °C. 1 H NMR (CDCl 3): d 3.51–3.59 (m, 2 H), 5.07 (dd,
J=6.4 Hz, J=5.9 Hz, 1 H), 6.57–6.63 (m, 2 H), 6.84 (t, J = 7.6 Hz, 1
H), 6.93 (dd, J = 8.3 Hz, J = 11.5 Hz, 1 H), 7.24 (t, J = 7.1 Hz, 1 H),
7.31 (t, J = 7.5 Hz, 2 H), 7.41–7.52 (m, 5 H), 7.56 (t, J = 7.4 Hz, 1
H), 7.91 (d, J = 7.3 Hz, 2 H). 13 C NMR (CDCl 3): d 46.2, 54.9, 114.3,
114.4, 114.5, 117.9, 124.4, 126.5, 127.6, 128.2, 128.4, 128.6,
128.7, 128.9, 133.4, 136.7, 142.1, 197.8. IR (KBr, cm 1 ): v 3392,
1680, 1618, 1595, 1525, 1449, 1289, 735, 683. ESI HRMS Anal.
calcd. for C21H18FNONa [M+Na] 342.1270; found: 342.1267.
2.2.3. 3-[(2-Fluorophenyl)amino]-3-(4-methylphenyl)-1phenylpropan-1-one
(4r)
m.p. 130–131 °C. 1 H NMR (CDCl3): d 2.29 (s, 3 H), 3.48 (d,
J = 6.5 Hz, 2 H), 4.74 (brs, 1 H), 5.03 (dd, J=6.6 Hz, J=6.3 Hz, 1
H), 6.54–6.59 (m, 2 H), 6.83 (t, J = 7.7 Hz, 1 H), 6.91–6.94 (m, 1
H), 7.12 (d, J = 7.7 Hz, 2 H), 7.31 (d, J = 8.0 Hz, 2 H), 7.43 (t,
J = 7.8 Hz, 2 H), 7.55 (t, J = 7.3 Hz, 1 H), 7.89 (d, J = 7.3 Hz, 2 H).
13 C NMR (CDCl3): d 21.1, 46.5, 54.2, 113.6, 114.3, 114.4, 117.1,
117.2, 124.4, 126.3, 128.2, 128.7, 129.6, 133.4, 135.4, 135.5,
136.8, 137.1, 139.5, 150.9, 152.6, 197.8. IR (KBr, cm 1 ): v 3388,
1679, 1618, 1513, 1449, 1288, 1249, 742, 683. ESI HRMS Anal.
calcd. For C 22H 20FNONa [M+Na] 356.1421; found: 356.1430.
2.2.4. 3-[(2-Fluorophenyl)amino]-3-(4-methoxyphenyl)-1phenylpropan-1-one
(4s)
m.p. 123–124 °C. 1 H NMR (CDCl 3): d 3.48 (d, J=6.4 Hz, 2 H),
3.76 (s, 3 H), 4.77 (brs, 1 H), 5.02 (dd, J=6.4 Hz, J=6.4 Hz, 1 H),
6.55–6.59 (m, 2 H), 6.84 (t, J=9.4 Hz, 3 H), 6.91–6.95 (m, 1 H),
7.34 (d, J=8.7 Hz, 2 H), 7.43 (t, J=7.8 Hz, 2 H), 7.55 (t, J=7.4 Hz,
1 H), 7.89 (t, J=7.4 Hz, 2 H). 13 C NMR (CDCl 3): d 46.4, 53.9, 55.3,
113.7, 114.2, 114.3, 114.4, 117.2, 117.3, 124.4, 127.5, 128.2,
128.7, 133.4, 134.5, 135.3, 135.4, 136.8, 151.0, 152.6, 158.9,
197.9. IR (KBr, cm 1 ): v 3388, 1679, 1618, 1513, 1288, 1249,
1222, 742, 683. ESI HRMS Anal. calcd. for C 22H 20FNO 2Na [M+Na]
372.1370; found: 372.1387.
2.2.5. 3-[(2-Chlorophenyl)amino]-1,3-diphenylpropan-1-one (4t)
m.p. 116–117 °C. 1 H NMR (CDCl 3): d 3.48–3.55 (m, 2 H), 5.08
(dd, J=6.4 Hz, J=6.3 Hz, 1 H) (t, J=6.4 Hz, 1 H), 5.27 (brs, 1 H),
6.51 (d, J=8.2 Hz, 1 H), 6.57–6.60 (m, 1 H), 6.94–6.98 (m, 1 H),
7.23 (t, J=7.6 Hz, 2 H), 7.32 (t, J=7.4 Hz, 1 H), 7.41–7.45 (m, 4
H), 7.54 (t, J=7.4 Hz, 1 H), 7.90 (d, J=7.2 Hz, 2 H). 13 C NMR
(CDCl3): d 46.4, 54.5, 112.8, 117.7, 119.6, 126.3, 127.5, 127.6,
128.2, 128.7, 128.9, 129.1, 133.4, 136.8, 142.4, 142.8, 197.7. IR
(KBr, cm 1 ): v 3396(NH), 1683, 1595, 1515, 1324, 735, 683. ESI
NH 2SO 3H (10 mol%)
EtOH, U.S. r.t.
1 2 3 4
Scheme 1. One-pot Mannich reaction of ketones, aldehydes and amines catalyzed by SA under US.
O
HN
R 2
R 1

760 H. Zeng et al. / Ultrasonics Sonochemistry 16 (2009) 758–762
HRMS Anal. calcd. for C21H18ClNONa [M+Na] 358.0974; found:
358.0972.
2.2.6. 3-[(2-Bromophenyl)amino]-1,3-diphenylpropan-1-one (4u)
1
m.p. 84–86 °C. H NMR (CDCl3): d 3.48 (dd, J=5.7 Hz,
J=16.3 Hz, 1 H), 3.53 (dd, J=7.0 Hz, J=16.3 Hz, 1 H), 5.08 (dd,
J=7.0 Hz, J=5.7 Hz, 1 H), 5.23 (brs, 1 H), 6.48–6.52 (m, 2 H),
6.97–7.00 (m, 1 H), 7.22 (t, J=7.4 Hz, 1 H), 7.30 (t, J=7.6 Hz, 2
H), 7.37–7.44 (m, 5 H), 7.54 (t, J=7.4 Hz, 1 H), 7.89 (d, J=7.2 Hz,
2 H). 13 C NMR (CDCl3): d 46.4, 54.8, 110.2, 112.9, 118.3, 126.3,
127.5, 128.2, 128.3, 128.5, 128.7, 128.9, 132.4, 133.4, 136.8,
142.3, 143.7, 197.8. IR (KBr, cm 1 ): v 3350, 1661, 1615, 1595,
1567, 1510, 1353, 1266, 1225, 736, 699. ESI HRMS Anal. calcd.
for C21H18BrNONa [M+Na] 402.0416; found: 402.0477.
2.2.7. 3-[(2-Nitrophenyl)amino]-1,3-diphenylpropan-1-one (4v)
m.p. 118–120 °C. 1 H NMR (CDCl3): d 3.51 (dd, J=5.4 Hz,
J=16.7 Hz, 1 H), 3.64 (dd, J=7.4 Hz, J=16.7 Hz, 1 H) 5.36 (dd,
J=6.5 Hz, J=12.6 Hz, 1 H). 6.61–6.64 (m, 1 H), 6.80 (d, J=8.7 Hz,
1 H), 7.24–7.27 (m, 1 H), 7.28–7.31 (m, 1 H), 7.34 (t, J=7.7 Hz, 1
H), 7.47 (m, J=7.1 Hz, 4 H), 7.56 (t, J=7.4 Hz, 1 H), 7.91 (d,
J=7.3 Hz, 2 H), 8.15(dd, J=1.5 Hz, J=8.6 Hz, 1 H), 8.62 (d,
J=5.3 Hz, 1 H). 13 C NMR (CDCl 3): d 46.8, 53.6, 115.0, 115.9,
126.3, 126.8, 127.8, 128.2, 128.8, 129.1, 132.6, 133.6, 136.1,
136.6, 141.6, 144.3, 196.6. IR (KBr, cm 1 ): v 3350, 1661, 1615,
1595, 1567, 1510, 1353, 1266, 1225, 736, 699. ESI HRMS Anal.
calcd. for C 21H 18N 2O 3Na [M+Na] 369.1215; found: 369.1210.
2.2.8. 3-[(2-Methylphenyl)amino]-1,3-diphenylpropan-1-one (4w)
m.p. 102–103 °C. 1 H NMR (CDCl3): d 2.20 (d, J=3.5 Hz, 3 H),
3.41–3.45 (m, 1 H), 3.52–3.55 (m, 1 H), 4.58 (brs, 1 H), 4.99–5.01
(m, 1 H), 6.38–6.40 (m, 1 H), 6.58–6.61 (m, 1 H), 6.91–6.93 (m, 1
H), 7.01–7.03 (m, 1 H), 7.20–7.23 (m, 1 H), 7.29–7.33 (m, 2 H),
7.41–7.44 (m, 4 H), 7.53–7.56 (m, 1 H), 7.89–7.91 (m, 2 H). 13 C
NMR (CDCl 3): d 17.6, 46.4, 55.1, 111.3, 117.4, 122.6, 126.3, 126.9,
127.4, 128.3, 128.7, 128.9, 130.0, 133.4, 136.8, 143.1, 144.9,
198.6. IR (KBr, cm 1 ): v 3402, 1677, 1604, 1515, 1449, 1286,
1219, 741, 683. ESI HRMS Anal. calcd. for C22H21NONa [M+Na]
338.1521; found: 338.1515.
2.2.9. 3-[(2-Methoxyphenyl)amino]-1,3-diphenylpropan-1-one (4x)
m.p. 107–108 °C. 1 H NMR (CDCl3): d 3.45–3.52 (m, 2 H), 3.82 (d,
J=1.1 Hz, 3 H), 5.03–5.05 (m, 2 H), 6.43–6.46 (m, 1 H), 6.59–6.62
(m, 1 H), 6.67–6.70 (m, 1 H), 6.72 (d, J=7.9 Hz, 1 H), 7.18–7.22
(m, 1 H), 7.23–7.30 (m, 2 H), 7.39–7.43 (m, 4 H), 7.50–7.53 (m, 1
H), 7.88 (d, J=8.1 Hz, 2 H). 13 C NMR (CDCl3): d 46.7, 54.5, 55.5,
109.6, 111.5, 117.0, 121.1, 126.5, 127.3, 128.2, 128.6, 128.8,
133.3, 136.8, 136.9, 143.1, 147.1, 197.9. IR (KBr, cm 1 ): v 3412,
1673, 1600, 1519, 1448, 1271, 1232, 736, 688. ESI HRMS Anal.
calcd. for C22H21NO2Na [M+Na] 354.1470; found: 354.1465.
3. Results and discussion
Initially, we screened different common Lewis acids for their
ability to catalyze the three-component Mannich reaction and
acetophenone, benzaldehyde and aniline was selected as model
and the results are summarized in Table 1. No reaction was
observed in the absence of SA with or without US (Table 1, entries
1–2). The common Lewis acids such as ZnCl 2 and CuCl 2 did not furnish
the desired products (Table 1, entries 3–5). InCl3 and p-TsOH
afforded the desired product but only in moderate to good yields
(Table 1, entries 6–7). Due to its shortcoming of difficult recovery,
I 2 could not be considered as economic and green catalysts even if
I2 displayed good catalytic capacity (Table 1, entry 8). In contrast,
SA could efficiently catalyze Mannich reaction to afford the desired
Table 1
The direct Mannich reaction catalyzed by different catalysts. a
Entry Catalyst (mol%) Method Time (h) Yield (%) b
1 No cat.( ) High speed stirring 48 NR
2 No cat.( ) Ultrasound 1.5 NR
3 ZnCl 2(10) High speed stirring 20 NR
4 ZnCl 2(10) Ultrasound 1.5 NR
5 CuCl 2(10) Ultrasound 1.5 NR
6 InCl 3(10) Ultrasound 1.5 83
7 p-TsOH(10) Ultrasound 1.5 87
8 I 2(10) Ultrasound 1.5 90
9 NH2SO3H(10) High speed stirring 18 88
10 NH2SO3H(3) Ultrasound 1.5 79
11 NH 2SO 3H(5) Ultrasound 1.5 88
12 NH 2SO 3H(10) Ultrasound 1.5 95
13 NH 2SO 3H(15) Ultrasound 1.5 94
a
Reaction conditions: acetophenone (2.2 mmol), benzaldehyde (2 mmol), aniline
(2 mmol), absolute ethanol (3 mL).
b
Isolated yield.
products in high yield (Table 1, entries 9–13). Thus, in view of
excellent catalytic capacity, easy availability, inexpensive cost, outstanding
stability and ready recovery, SA was proved the best catalyst
for such direct Mannich reaction.
Next, the amount of SA catalyst was examined: it seemed that
10 mol% SA was sufficient to drive the reaction completely in
88% yield with high speed stirring. It is a well-established fact that
power ultrasound (US) accelerates organic reactions. Gratifyingly,
the conversions were up to 95% yield under US and the reaction
time was shortened within 1.5 h (Table 1, entries 10–13). We
found that using less SA led to lower yield even with reaction time
extended. While using more SA failed to produce an obvious increase
in yield but shortened the reaction time. Hence, the optimal
amount of catalyst was chosen 10 mol% (Table 1, entry 12) in the
following reactions.
The solvents also played an important role in the Mannich reaction
catalyzed by SA. Further studies established that absolute
EtOH was the best choice among the solvents (DMF, THF, CH 3CN,
DCM, H2O and EtOH) screened (Table 2). The reaction failed to
yield any products in DCM or H 2O and very poor yields in CH 3CN
and THF.
Furthermore, Mannich reaction was very sensitive to reaction
temperature. The high temperature could improve the reaction
rate and shorten the reaction time, but favor side reactions and
the oxygenolysis of aldehyde and amine. It was found that the
room temperature was an appropriate condition for Mannich reaction
catalyzed using SA.
To explore the scope and generality of the present method, different
aldehydes and amines were tested for the Mannich reactions
with acetophenone in absolute ethanol under ultrasonic irradiation
at room temperature as shown in Table 3. The three-component
Table 2
The direct Mannich reaction catalyzed by 10 mol% SA in different solvents. a
Entry Solvent Method Yield (%) b
1 EtOH Ultrasound 95
2 EtOH High speed stirring 88
3 DMF Ultrasound 61
4 DMF High speed stirring 56
5 THF Ultrasound 20
6 CH 3CN High speed stirring Trace
7 DCM Ultrasound 0
8 H 2O Ultrasound 0
a
Reaction conditions: acetophenone (2.2 mmol), benzaldehyde (2 mmol), aniline
(2 mmol), solvent (3 mL) at room temperature.
b
Isolated yield.

Table 3
Direct Mannich reaction catalyzed using SA under US. a
Entry R1 R2 Product Time (min) Yield (%) b
1 H H 4a 90 95
2 H 4-CH3 4b 100 92
3 H 3-CH 3 4c 110 91
4 H 4-CH 3O 4d 100 90
5 H 4-F 4e 90 97
6 H 4-Cl 4f 80 94
7 H 3-Cl 4g 90 95
8 H 3-Br 4h 100 92
9 H 3-NO2 4i 90 91
10 H 4-COOH 4j 85 89
11 4-CH 3 H 4k 100 95
12 4-CH 3O H 4l 100 95
13 4-OH 4-CH 3 4m 80 93
14 4-Cl H 4n 110 92
15 4-Cl 3-Br 4o 80 91
16 4-NO2 H 4p 120 88
a Reaction conditions: acetophenone (2.2 mmol), aldehyde (2 mmol), aniline
(2 mmol) and absolute ethanol (3 mL) under ultrasonic irradiation at room
temperature.
b Isolated yield.
Mannich reactions proceeded smoothly in short time (80–120 min)
in the presence of 10 mol% of SA under ultrasound irradiation to
give the corresponding products in high yield (Table 3, entries 1–
16). Various aromatic aldehydes bearing different substitutes, such
as para-OMe, Me, Cl and NO2 were all suitable to the reactions, and
aromatic amines bearing para-OMe, Me, F, Cl, Br, COOH and meta-
NO2, Br were favorable to the reactions.
However, it was reported [7,9] that under conventional high
speed stirring conditions the ortho-substituted aromatic amines
generally gave very low yield, even trace of the products because
of large steric hindered effect (Scheme 2). That is to say, steric factors
played a key role in affecting the rate of reaction and the reac-
O CHO NH 2
CH 3
+ +
R 1
R 2
tion requires a longer time. To the best of our knowledge, there has
not been reported the one-pot approach to direct Mannich reactions
of aldehydes, ketones and ortho-substituted aromatic amines.
Encouraged by the above excellent results, we carried out a comparative
study of direct Mannich reactions of sterically hindered
substrate amines under conventional high speed stirring conditions
and under US (Table 4) for the first time. Clearly, sluggish
reactions were also observed with arylamines both containing
electron-deficient and electron-donating bulky groups like Cl, Br,
NO 2 and Me, OMe (Table 4, entries 4–8) catalyzed by SA under conventional
conditions. It showed that longer reaction time and excess
of catalysts were required to achieve better transformation.
However, to our delight, the combination of Sulfamic acid and US
displayed a synergistic effect that was more striking with sterically
hindered amines. In case of o-fluoroaniline reaction time was reduced
from 18 to 2 h (Table 4, entry 1). Likewise with o-chloroaniline,
o-bromoaniline, o-nitroaniline, o-anisidine, o-methylaniline,
a considerable shortening of reaction time was observed (Table 4,
entries 4–8). Thus the accelerating effect of US can be an important
tool for the one-pot Mannich reaction of sterically hindered arylamines.
It should be mentioned that as minor atomic radius of
fluorine atom, o-fluoroaniline displayed no above-mentioned steric
hindered effect and reacted faster than any other ortho-substituted
aromatic amines. All comparable results were obtained in conventional
as well as US.
4. Conclusion
In summary, we have developed an environmentally friendly,
high yield and mild condition protocol for the three-component
Mannich-type reactions, which is a rapid and convenient procedure
for the synthesis of b-aminocarbonyl compounds via direct
three-component Mannich reaction catalyzed by SA under US. This
method offers several advantages, compared to those reported in
literature, i.e., (1) mild, highly efficient catalyst activity, (2) ease
NH 2SO 3H
EtOH, U.S. r.t.
1 2 3
4
R1= H, CH3, OCH3 R2= OCH3, CH3, F, Cl, Br, NO2 Scheme 2. One-pot Mannich reaction of ortho-substituted aromatic amines catalyzed by SA under US.
Table 4
Comparison of Mannich reactions of ortho-substituted aromatic amines with or without US. a
H. Zeng et al. / Ultrasonics Sonochemistry 16 (2009) 758–762 761
Entry R 1 R 2 Product conventional Ultrasound m.p.(°C)
Time (h) Yield (%) b
O
R 2
HN
R 1
Time (h) Yield (%) b
1 H 2-F 4q 18 90 2 95 163–164
2 4-CH3 2-F 4r 19 88 2 94 130–131
3 4-CH3O 2-F 4s 19 87 2 94 123–124
4 H 2-Cl 4t c
50 65 7 73 116–117
5 H 2-Br 4u c
72 24 9 40 84–86
6 H 2-NO2 4v c
50 58 7 66 118–120
7 H 2-CH3 4w c
55 33 8 53 102–103
8 H 2-CH3O 4x c
55 37 8 55 107–108
a
Reaction conditions: acetophenone (2.2 mmol), aldehyde (2 mmol), ortho-substituted aromatic amine (2 mmol), absolute ethanol (3 mL) at room temperature.
b
Yields refer to the isolated products.
c
20 mol% SA.

762 H. Zeng et al. / Ultrasonics Sonochemistry 16 (2009) 758–762
of handling and cost efficiency of the catalyst, (3) avoidance of the
troublesome preparation of enol derivatives and pre-formed imines,
(4) wide substrate scope and generality especially for orthosubstituted
aromatic amine, (5) effective reusability of catalyst,
making it a useful and attractive strategy for the synthesis of baminocarbonyl
compounds. Further investigations on the appellation
of this commercial complex on other catalytically synthetic
reactions are in progress.
Acknowledgment
We acknowledge the financial support from Chinese Academy
of Sciences (Hundreds of Talents Program). We are also grateful
to the Analytical and Testing Center of Chengdu Institute of Biology
for supports in NMR and MS analyses.
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