K3PO4-catalyzed one-pot synthesis of β-amino ketones

Article abstract of DOI:10.1007/s00706-012-0729-1

A new strategy which uses cheap K₃PO₄ as a very effective catalyst has been developed for synthesis of β-amino ketones by one-pot reaction of an aryl aldehyde, acetophenone derivative, and amine in EtOH at room temperature. Springer-Verlag 2012.

Full text of DOI:10.1007/s00706-012-0729-1

Monatsh Chem
DOI 10.1007/s00706-012-0729-1
ORIGINAL PAPER
K3PO4-catalyzed one-pot synthesis of b-amino ketones
•
Barahman Movassagh Sakineh Khosousi
Received: 24 August 2011 / Accepted: 22 January 2012
Ó Springer-Verlag 2012
Abstract A new strategy which uses cheap K3PO4 as a
very effective catalyst has been developed for synthesis of
b-amino ketones by one-pot reaction of an aryl aldehyde,
acetophenone derivative, and amine in EtOH at room
temperature.
conjugate addition of amines to a,b-unsaturated carbonyl
compounds (aza-Michael addition).
Owing to its operational simplicity and mildness, aza-
Michael reaction has attracted much attention in recent
years. It also has a prominent advantage over the Mannich
reaction in covering a wide range of nitrogen nucleophiles
including amides, carbamates, and sulfonamides, which
can hardly be utilized using conventional Mannich con-
densation. In recent years a number of Lewis acid catalysts,
solid acids, and Brønsted acids, i.e., LiClO4 [16], Bi(OTf)2
[17], Yb(OTf)3 [18], SmI2 [7], Bi(NO3)2 [19], CeCl3Á7H2O
[20], InCl3 [21], Cu(OTf)2 [22], boric acid [23], silica gel
[24], Amberlyst-15 [25], and others, have been employed.
Some drawbacks such as high cost and toxicity of catalysts
and harsh reaction conditions associated with the above
methods led to development of several other catalysts or
promoters in conjugate addition, including ZrOCl2Á8H2O
on montmorillonite K10 [26], b-cyclodextrin [27], ceric
ammonium nitrate (CAN) [28], iodine [29], sodium dode-
cylsulfate (SDS) [30], [HP(HNCH2CH3)3N]NO3 [31],
Cu(acac)2/ionic liquid [32], silica gel supported TaBr5 [33],
FeCl3/TMSCl [34, 35], KF/Al2O3 [36], alkaline Al2O3
[37], [Bmim]OH [38], and Cu–Al hydrotalcite [39].
Unfortunately, most of these procedures suffered from
some disadvantages such as the requirement for large
excess of reagents or catalysts, long reaction times, use of
expensive heavy-metal salts, and toxic solvents such as
1,2-dichloroethane, dichloromethane, or acetonitrile. Also,
most of the reported procedures were only applicable to
aliphatic amines and failed to work with aromatic amines
[24, 26, 27, 31–33, 36]. Although the recent protocols
made this route attractive, the development of fast, simple,
and environmentally friendly approaches that could be
performed at ambient temperature for aza-Michael addition
is highly desirable.
Keywords Aza-Michael reaction Á One-pot reaction Á
Potassium phosphate Á Chalcones Á Conjugate addition
Introduction
The b-amino carbonyl functionality is not only a segment
of biologically active natural products but also serves
as key intermediate for synthesis of important nitrogen-
containing compounds such as b-amino acids, b-lactams,
and b-amino alcohols [1–6]. Over the past few decades,
synthesis of b-amino carbonyl compounds has become a
field of increasing interest in organic synthesis [7, 8].
Mannich-type reaction is one of the classical and powerful
methods for construction of this functionality [9–15].
However, this type of reaction suffers from harsh reaction
conditions and long reaction times. Another approach
for preparing b-amino carbonyl compounds is based on
Electronic supplementary material The online version of this
article (doi:10.1007/s00706-012-0729-1) contains supplementary
material, which is available to authorized users.
B. Movassagh (&) Á S. Khosousi
Department of Chemistry,
K. N. Toosi University of Technology,
P. O. Box 16315-1618, Tehran, Iran
e-mail: bmovass1178@yahoo.com
123

B. Movassagh, S. Khosousi
Table 1 Optimization of the K3PO4-catalyzed reaction
To find the optimal conditions, a mixture of acetophe-
none (2.0 mmol), p-tolualdehyde (2.0 mmol), and aniline
(2.6 mmol) was stirred under different reaction conditions
catalyzed by K3PO4 at room temperature (Table 1). The
best result was obtained when 15 mol% K3PO4 in absolute
EtOH was used (Scheme 1).
Entry
Solvent
Catalyst/mol%
Time/h
Yielda/%
1
EtOH (abs.)
EtOH (abs.)
EtOH (abs.)
EtOH (abs.)
EtOH (98%)
MeOH
10
15
20
30
15
15
15
15
15
15
15
3
0.83
1.5
1
50
77
68b
65b
68
70
65
24
30
15
10
2
3
4
After optimization, a variety of other aromatic alde-
hydes and acetophenones having electron-donating and
electron-withdrawing substituents as well as different
amines were shown to undergo the reaction smoothly,
giving the desired products in high to excellent yields
(Scheme 2). The results are summarized in Table 2.
All products were fully characterized by spectroscopic
methods and compared with authentic spectra. As seen in
Table 2, aliphatic amines (benzylamine, n-butylamine)
needed longer reaction times and afforded lower yields
(entries 11, 12, and 19) than anilines. Aromatic aldehydes
containing a methoxy substituent took longer reaction
times and had generally lower yields (entries 2, 8, and 15).
The results clearly show that K3PO4 is an efficient catalyst
in aza-Michael addition reaction. This is because (i) tri-
potassium phosphate has a strong electron-withdrawing
counteranion, namely PO34-, to make the K? ion oxophilic
enough to form a strong coordinate bond with the oxygen
atom of the enone and thereby make Cb sufficiently elec-
trophilic, and (ii) K3PO4 is basic enough to deprotonate
amines (specially the aromatic ones) having pKA values in
the range 7–11 [46] to convert them to their conjugate
bases and assist the aza-Michael addition.
5
1
6
3
7
t-BuOH
6
8
CH3CN
10
12
10.5
24
9
DMF
10
11
a
DMSO
–
Isolated yields
b
Several by-products were observed
Results and discussion
Very recently, we reported a simple and very efficient one-
pot three-component procedure for synthesis of b-sulfido
ketones from aldehydes, acetophenones, and thiols via
Claisen–Schmidt/Michael addition reactions catalyzed by
potassium tert-butoxide at room temperature [40]. Tripo-
tassium phosphate, K3PO4, is nontoxic, cheap, and a strong
inorganic base, used as an alternative nonnucleophilic base
in several reactions [41–45]. We have now developed an
easy and highly convenient methodology for synthesis of
b-amino ketones by one-pot reaction of an aryl aldehyde,
acetophenone derivative, and amine in the presence of a
catalytic amount of anhydrous K3PO4 in EtOH at room
temperature. To the best of our knowledge, there is no
report of construction of b-amino ketones by one-pot aza-
Michael-type reaction.
In conclusion, we have developed an easy, efficient, and
fast protocol for preparation of b-amino ketones using
K3PO4 as catalyst. The salient features of this protocol
include operational simplicity, high yields of the products,
short reaction times, ready availability, low toxicity of the
catalyst, and use of a green solvent.
O
O
NHPh
O
H
C
O
K P
O4
Ph
H
C
x m
o
l
%
Ph
PhNH2
3
+
(
)
3
r
H
t
,
Et
O
H
C
H
3C
H
C
3
3
Scheme 1
O
NHR3
O
H
C O
mo
r. .
t
1 K P
15
(
l Et H
%
,
)
O4
O
,
)
3
+
2 R3NH2
3
( )
)
R1
R2
R2
R1
1
2
4
Scheme 2
123

K3PO4-catalyzed one-pot synthesis
Table 2 K3PO4-catalyzed one-pot preparation of b-amino ketones 4
O
NHR3
R2
R1
4a-4s
Entry
Comp
R1
R2
R3
Time/min
Yielda/%
M.p. (lit. m.p.)/°C
1
4a
4b
4c
4d
4e
4f
H
H
C6H5
C6H5
C6H5
C6H5
C6H5
30
70
95
79
90
77
82
94
78
60
85
81
52
50
84
83
76
91
78
86
32
168–170 (168–170 [49])
156–158 (150–152 [47])
129–130 (131–132 [49])
129–130 (128–130 [49])
105–106 (105–106 [50])
164–165 (165–167 [47])
170–171 [51]
2
H
4-CH3O
4-Cl
4-CH3
4-NO2
H
3
H
40
4
H
50
5
H
55
6
H
4-CH3O–C6H4
4-CH3O–C6H4
4-CH3O–C6H4
4-Cl–C6H4
4-NO2–C6H4
C6H5CH2
C6H5CH2
4-Cl–C6H4
C6H5
35
7
4g
4h
4i
H
4-Cl
4-CH3O
H
40
8
H
85
180–182 (182 [52])
9
H
55
169–170 (166–167 [48])
175–177 (177–178 [49])
73–74 (75–76 [53])
10
11
12
13
14
15
16
17
18
19
4j
H
H
80
4k
4l
H
H
300
330
60
H
4-Cl
4-Cl
H
97–98 (98–100 [53])
116–118 (118–119 [54])
139–140 (136–137 [48])
158–160 (159–160 [48])
118–119 (118–119 [48])
143–145 (146–148 [15])
123–125 (123–125 [48])
Oil [47]
4m
4n
4o
4p
4q
4r
4s
H
4-CH3
H
65
4-CH3O
H
4-Cl–C6H4
C6H5
75
4-Cl
4-NO2
4-CH3O
H
45
H
4-Cl–C6H4
C6H5
65
H
75
H
n-C4H9
480
1
All products were characterized by infrared (IR), and H and 13C nuclear magnetic resonance (NMR) spectroscopy as well as melting points
a
Yields of pure isolated products
Experimental
completely. Amine (2.6 mmol) was then added, and the
mixture was stirred for the appropriate time (Table 2). On
completion of the reaction (TLC), ethanol was evaporated,
10 cm3 water was added, followed by extraction with
CH2Cl2 (2 9 10 cm3) and drying over anhydrous Na2SO4.
The solvent was removed under vacuum, and the residue
was recrystallized from acetone:EtOH = 3:2 to afford the
pure product. The spectral data of some representative
b-amino ketones are given in the Supplementary Material.
Chemicals were purchased from Merck chemical company.
1
Yields refer to isolated products. H (300 MHz) and 13C
(75 MHz) nuclear magnetic resonance (NMR) spectra were
recorded using a Bruker AQS-300 Avance spectrometer.
Chemical shifts were determined by reference to residual
CHCl3 in CDCl3. Infrared (IR) spectra were obtained using
an ABB FTLA 2000 instrument.
Acknowledgments We acknowledge the K.N. Toosi University of
Technology Research Council for financial support of this work.
General procedure
A suspension of 0.064 g anhydrous K3PO4 (15 mol%) in
1 cm3 absolute ethanol was placed in a flask. While stirring
magnetically at room temperature, a mixture of aldehyde
(2.0 mmol) and ketone (2.0 mmol) was added to the above
suspension and stirring was continued for 15 min. The
course of the reaction was monitored by thin-layer chro-
matography (TLC) until the starting materials disappeared
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