Dramatically accelerated synthesis of β-aminoketones via aqueous Mannich reaction under combined microwave and ultrasound irradiation

Article abstract of DOI:10.1055/s-2005-872246

An efficient green chemistry approach to the synthesis of β-aminoketones was developed under combined microwave and ultrasound irradiation. With this technique, the title compounds were rapidly synthesized in aqueous media with good yields. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2005-872246

LETTER
2245
Dramatically Accelerated Synthesis of b-Aminoketones via Aqueous Mannich
Reaction under Combined Microwave and Ultrasound Irradiation
Synthesis of
b
-Am
a
inoketone
s
n
via
A
queous
q
M
annichRe
i
actionng Peng, Ruiling Dou, Gonghua Song,* Jun Jiang
Shanghai Key Laboratory of Chemical Biology, Institute of Pesticides & Pharmaceuticals, East China University of Science and
Technology, Shanghai 200237, P. R. China
Fax +86(21)64252603; E-mail: ghsong@ecust.edu.cn
Received 22 June 2005
R1
Abstract: An efficient green chemistry approach to the synthesis of
b-aminoketones was developed under combined microwave and ul-
trasound irradiation. With this technique, the title compounds were
rapidly synthesized in aqueous media with good yields.
O
O
⋅
HN
HCl
R1
R2
N
Me
R2
(HCHO)3 / H2O
CMUI
⋅
HCl
R
R
Key words: Mannich reaction, b-aminoketones, microwave, ultra-
sound, aqueous media
Scheme 1
of rapid reaction, satisfactory yields, simple operation,
safety, and environmental acceptability compared with
those previously reported.
The Mannich reaction, a classic example of a three-com-
ponent condensation, is one of the most important reac-
tions in organic chemistry.1 As a useful carbon–carbon
bond-forming method, it is widely applied as a key step in
the synthesis of numerous pharmaceuticals2 and natural
products.3 Generally, formaldehyde (or paraformalde-
hyde), an amine, and an ‘active-hydrogen’ component are
allowed to react to afford the corresponding amino-
methylation products. Organic solvents, such as ethanol,
should be used in the preparation of b-aminoketones by
the Mannich reaction. Even in such homogeneous sys-
tems, reaction times between three and ten hours were
needed.4 Recently, microwave irradiation was found to be
an efficient tool for the Mannich reaction in alcohol.5 De-
spite the success and advantages of this procedure, there
is still a limitation on the use of volatile and flammable
solvent.
Initially, we studied the reaction of 4-nitroacetophenone
(20 mmol) with trioxymethylene (8 mmol) and dimethyl-
amine hydrochloride (24 mmol) in water. Several control
experiments were carried out in order to demonstrate the
superiority of CMUI over other methods. As shown in
Table 1, b-aminoketone was obtained in moderate yield
(74%) after four hours under reflux conditions (oil bath
heating). Ultrasound irradiation accelerated the reaction
and microwave irraditation enabled rapid formation of the
desired b-aminoketone as well. To show the usefulness of
CMUI, a control experiment was carried out with the ap-
paratus we described previously (microwave 200 W/2450
MHz and ultrasound 50 W/20 KHz).7 Only 45 seconds
were needed to afford the desired product in a slightly
higher yield. The product was obtained simply by pouring
the resulting solution into acetone and cooling for several
hours. The superiority of CMUI-assisted reactions over
other methods may be attributed to the rapid core heating,
as well as acoustically strengthened interphase mass
transfer, and microemulsification. It is noteworthy that, in
all cases, prolonged reaction times led to a decrease in
yield, which might be due to the formation of by-products
from the decomposition of the Mannich bases formed.
Over recent years, one of the most imperative issues for
chemists is the search for cleaner chemical transforma-
tions. One of the aims of green chemistry is to replace vol-
atile organic solvents with clean solvents as the reaction
media. Due to its characteristics such as non-toxicity, low
cost, and enormous abundance, water is superior to organ-
ic solvents normally used for organic reactions from both
the environmental and economic points of view.6 Recent-
ly, we pointed out that the integrated application of micro-
wave and ultrasound irradiation is highly advantageous
for heterogeneous organic reactions in aqueous media,
such as hydrazinolysis of esters,7 Williamson reaction,8
and Knoevenagel–Doebner reaction.9 Continuing our
studies in this area, we disclose herein the synthesis of b-
aminoketones via Mannich reaction in water promoted by
combining microwave and ultrasound irradiation (CMUI)
(Scheme 1). This protocol provides advantages in terms
The investigation was then extended to a variety of sub-
strates to evaluate the generality of our protocol
Table 1 Synthesis of 3-Dimethylamino-1-(4-nitrophenyl)propan-1-
one Hydrochloride under Different Conditions
Run Method
Time
4 h
Yield (%)
1
2
3
4
Conventional reflux
74
79
73
80
Ultrasound (50 W) + reflux
Microwave (200 W)
20 min
10 min
45 s
SYNLETT 2005, No. 14, pp 2245–2247
0
2
.0
9
.2
0
0
5
Advanced online publication: 03.08.2005
DOI: 10.1055/s-2005-872246; Art ID: U19205ST
© Georg Thieme Verlag Stuttgart · New York
CMUI (MW 200 W + US 50 W)

2246
Y. Peng et al.
LETTER
(Table 2).10 For the sake of comparison, reactions were
performed under both microwave and CMUI conditions.
All transformations showed complete conversion after 50
seconds under CMUI, comparing favorably with reaction
times of 1.5–11 minutes observed under microwave irra-
diation. It is interesting to note that the reaction of 4-ni-
troacetophenones with morpholine hydrochloride using
microwave dielectric heating showed a much faster reac-
tion rate compared to other substrates (Table 2, Entry 8).
All products are known and give 1H NMR and IR spectra
consistent with the assigned structures.11
We were surprised to find that the microwave-assisted re-
actions succeeded here, although they were considered to
be a heterogeneous process, giving comparable (even su-
perior) results in comparison with its homogeneous coun-
terpart reported in the literature.5 Clearly, this interesting
phenomenon merited more detailed examination. We hy-
pothesized that it could be attributed to the hydrotropic ef-
fect of the products. Hydrotropes are a class of highly
water soluble organic molecules that significantly in-
crease the aqueous solubility of certain lipophilic com-
pounds.12 Many different compounds have been used as
hydrotropes, including neutral salts of organic acids and
amines, aromatic sulfonates, urea, guanidinium chloride,
nicotinamide, tetraalkyl ammonium halides, and so on.
Several organic transformations, such as the Hantzsch
1,4-dihydropyridines synthesis,13 have been carried out in
aqueous hydrotrope solutions. As observed in our experi-
ments, the b-aminoketone hydrochloride formed could act
as a hydrotrope to solubilize hydrophobic acetophenones
in aqueous media and gradually give homogeneous solu-
tions.
Figure 1 Time–yield plot for the microwave-promoted Mannich
reaction in heterogeneous (water) and homogeneous (H2O–
HOCH2CH2OMe) systems.
proceeded smoothly under microwave irradiation. In the
case of the heterogeneous reaction without a co-solvent
(Figure 1, plot b), HPLC data revealed that this process
actually followed complicated kinetics. In the initial stage
of the transformation, a slow but steady increase in prod-
uct yields occurred. At about three minutes, the curve ex-
hibits an inflection point, then the trend is similar to the
‘normal’ version that is observed in the homogeneous re-
action.
In conclusion, we have demonstrated an efficient and
clean method for the synthesis of b-aminoketones in aque-
ous media under combined microwave and ultrasound ir-
radiation. The procedure described here leads to the
products in high yields, within very short reaction times,
with simplified and safe work-up. The combination of
CMUI technique with the aqueous media also provides an
excellent methodology for achieving an environmentally
friendly and efficient organic synthesis.
To demonstrate our presumption, microwave-assisted
control experiments were carried out using the same
amount of reactants at a similar temperature in a homoge-
neous solution by using ethylene glycol monomethyl
ether as the co-solvent (azeotropic temperature 99.9 °C).
As shown in Figure 1, the homogeneous reaction (plot a)
Table 2 Aqueous Synthesis of b-Aminoketones via Mannich Reaction under CMUI and Microwave Irradiation
Entry
R
Amines
Microwave
Time (min)
CMUI
Yield (%)
Time (s)
Yield (%)
1
2
H
Me2NH
11
10
8.5
7
72
73
50
69
75
79
75
78
79
80
50
45
45
45
45
45
35
20
45
40
82
80
60
72
80
81
79
81
84
81
NO2
H
Me2NH
3
Et2NH
4
NO2
H
Et2NH
5
Piperidine
Piperidine
Morpholine
Morpholine
Pyrrolidine
Pyrrolidine
8.5
7.5
6.5
1.5
8.5
8
6
NO2
H
7
8
NO2
H
9
10
NO2
Synlett 2005, No. 14, 2245–2247 © Thieme Stuttgart · New York

LETTER
Synthesis of b-Aminoketones via Aqueous Mannich Reaction
2247
24 mmol) in a 25 mL two-necked flask was added water (3
mL). The mixture was then subjected to CMUI (microwave
200 W/2450 MHz; ultrasound: 50 W/20 KHz) for 45 s
(monitored by TLC). The resulting solution was then poured
into acetone (15 mL) and cooled in a refrigerator for several
hours. The crude product thus precipitated was collect by
filtration and recrystallized from 95% aqueous EtOH (95%)
gave pure product (4.14 g, 80% yield) as yellowish crystals.
(11) Characteristic data of selected b-aminoketones:
3-Dimethylamino-1-(4-nitrophenyl)propan-1-one
hydrochloride (2): mp 190–191 °C (lit.4d 187.5–188.5 °C);
FTIR (KBr): 3110, 3066, 2965, 2910, 2680, 2580, 2475,
1700, 1525, 1335, 1214, 964, 855, 740 cm–1; 1H NMR (500
MHz, CD3OD): d = 2.96 (s, 6 H, 2 ꢀ CH3), 3.57 (t, 2 H,
J = 6.4 Hz, NCH2), 3.68 (t, 2 H, J = 6.4 Hz, COCH2), 8.23
(d, 2 H, J = 8.8 Hz, C6H4NO2), 8.39 (d, 2 H, J = 8.8 Hz,
C6H4NO2).
Acknowledgment
Financial support from the NSFC (Grant 20376022), National Basic
Research Program of China (2003 CB 114402), Shanghai Commis-
sion of Science and Technology, and Shanghai Educational Com-
mission are gratefully acknowledged.
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hydrochloride (8): mp 207–209 °C (lit.4d 207–209 °C);
FTIR (KBr): 3100, 3060, 3035, 3000, 2960, 2895, 2640,
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3.63 (t, 2 H, J = 6.4 Hz, NCH2), 3.71 (t, 2 H, J = 6.4 Hz,
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3-Pyrrolidino-1-(4-nitrophenyl)propan-1-one
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(10) Typical experimental procedure under CMUI condition:
The apparatus employed in the experiments has been
described in detail in the literature.7 To a mixture of aromatic
4-nitroacetophenone (3.30 g, 20 mmol), trioxymethylene
(0.72 g, 8 mmol), and dimethylamine hydrochloride (1.96 g,
Synlett 2005, No. 14, 2245–2247 © Thieme Stuttgart · New York