Download one pot three-component mannich reaction promoted by iron(iii)

One pot three-component Mannich reaction catalyzed by FePO4
Section A-Short Communication
ONE POT THREE-COMPONENT MANNICH REACTION
PROMOTED BY IRON(III) PHOSPHATE
Farahnaz K. Behbahani[a]* and Leili Mohammadi Ziarani[a]
Keywords: -aminocarbonyl compounds, iron (III) phosphate, catalytic synthesis, one pot three component Mannich reaction
β-Aminocarbonyl compounds are selectively synthesized in high yields under extremely mild conditions via the condensation of aromatic
aldehydes, aryl amines and ketones using catalytic amount of iron (III) phosphate under solvent free conditions. The use of readily available
iron (III) phosphate as a reusable and recyclable catalyst makes this process quite simple, convenient, and environment-friendly.
Corresponding Authors
Tel: +98 026 34418145
Fax: +98 026 34418156
E-Mail: [email protected]
[a] Department of chemistry, Karaj Branch, Islamic Azad
University, Karaj, Iran.
chloride, THF, ether or water. Although they accelerate
the rate and shorten the reaction time, higher temperatures
(100°C) also promote side reactions and oxidation of the
amines and of the aldehydes; thus the reaction in ethanol
was performed at room temperature. From a green
chemistry standpoint, solvent-free conditions are best and
were chosen in the present investigation.
Introduction
The Mannich reaction is an important carbon–carbon
bond-forming process for the preparation of βaminocarbonyl compounds and 1,2-amino alcohols.1,2
Several methods to improve and modify this threecomponent reaction3,4 have been reported such as the use
of microwaves,5,6 or ultrasound irradiation,4 Lewis acids,710
Lewis bases,11 Bronsted acids,12,13 rare and transition
metal salts,14-16 or organo catalysts.17-20 However, most
catalysts are difficult to remove, and some of them are
corrosive and volatile and often cause environmental
problems. Hence, there is increased interest in the
development of environmentally benign reactions and
atom-economical catalytic processes for the synthesis of
β-aminocarbonyl compounds. Herein, we report the threecomponent Mannich reaction of acetophenone derivatives
with a variety of aromatic aldehydes and aromatic amines
at room temperature catalyzed by anhydrous FePO 4
(Scheme 1).
O
R3
NH2
CHO
NH
O
FePO4
R1
R2
R3
Solventfree
r.t.
R1= H, 4-NO2, 4-MeO
It is likely that FePO4 activates the aldehyde27-30 toward
attack by the amine and also promotes the enolization of
the acetophenones. Condensation of the amine with the
aldehyde to the aldimine followed by nucleophilic attack
by the enolized ketone on the aldimine would account for
the formation of the observed product(Scheme 2).
R1
R2
4(a-k)
Experimentals
R2= H, 4-NO2, 3-NO2, 4-Cl, 3-Cl, 2,5-diMeO, 2,6-diCl, 2,3-diMeO
R3= H, 4-Br, 4-NO2, 4-MeO, 2,4-diF, (2-Cl)-4-F, 3,4-diMeO
Results and discussion
To the best of our knowledge, the direct one-step
Mannich reaction catalyzed by anhydrous ferric
phosphate (FePO4) has not been reported previously.
Although the reaction may be performed under solventfree conditions on a small scale, it may also be carried out
in ethanol; hardly any reaction occurred in methylene
Eur. Chem. Bull., 2013, 2(10), 782-784
Initially, optimized conditions for the reaction of
acetophenone, benzaldehyde and aniline in the presence
of a catalytic amount of anhydrous iron(III) phosphate (5
mol %) were investigated under solvent-free conditions
and at room temperature (Table 1). Various aromatic
aldehydes, acetophenones and arylamines were used with
catalytic amounts of FePO4 to define the scope of this
new protocol. Aldehydes bearing either electronwithdrawing groups (–Cl and –NO2) or electron-donating
group (–OCH3) at the m- or p-positions were all suitable.
The position of the substituents on the aromatic ring of
amines has no obvious effect on this conversion. Other
aromatic ketones such as propiophenone and
desoxybenzoin, and aliphatic ketones such as
cyclohexanone failed to give any product. The method is
not applicable to aliphatic aldehydes (hexanal) and
amines (cyclohexylamine).
Mps were measured in capillary tubes on an Electro
Thermal 9200 apparatus and are uncorrected. IR spectra
were recorded as on a KBr pellets Perkin Elmer FT-IR
spectrometer. 1H NMR and 13C-NMR spectra were
obtained on Bruker DRX-300MHZ NMR instrument in
CDC13. Chemicals shifts are reported in parts per million
(δ) relative to tetramethylsilane (δ 0.0) as an internal
standard. Elemental analyses were performed by
Elemental analyzer Vario EL. All starting materials were
purchased from Merck Co. and used without further
purification.
DOI: 10.17628/ECB.2013.2.782
782
One pot three-component Mannich reaction catalyzed by FePO4
Section A-Short Communication
Table 1. FePO4-catalyzed Manich Reaction of Acetophenone with Aromatic Aldehydes and Aromatic amines under solvent-free
conditions.
Product
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4la
4ma
4na
4oa
4l
4m
4n
4o
4p
R1
H
H
H
H
H
4-NO2
H
4-MeO
H
H
4-MeO
H
H
H
H
H
H
H
H
H
R2
R3
H
4-NO2
4-NO2
3-NO2
4-Cl
H
3-Cl
4-NO2
H
2,5-(MeO)2
H
2-Cl
H
2-Cl
4-Me2N
2,6-Cl2
H
H
H
2,3-(MeO)2
Time, min
H
H
4-Br
4-Br
H
H
H
4-MeO
4-NO2
H
H
H
2-Cl
2-Cl
H
H
2-Cl,4-F
2,4-F2
3,4-(MeO)2
H
30
15
20
20
30
45
30
25
45
20
300
300
300
300
300
60
60
60
40
45
Yield, %
95
90
90
93
91
87
93
94
85
93
95
75
60
60
68
70
50
92
91
Found
170-171
90-95
180-186
84-88
114-115
169-171
139-141
100-101
184-186
125-127
123-126
135-137
111-113
200-201
125-127
162-163
175-176
144-146
123-125
M.p., °C
Reported
169-7023
89-9124
Table 2
Table 2
114-11523
170-17125
140-14126
Table 2
185-18618
126-12825
123-12526
134-13631
113-11532
202-23021
126-12826
163-16526
174-17626
145-14628
126-12731
a) The reaction was stirred in ethanol.
Table 2. M.p.’s, color, and elemental analysis data of 4c, 4d, 4h
Product
Mol. Formula
M.p., 0C
Color
4c
4d
4h
C21H17BrN2O3
C21H17BrN2O3
C23H22N2O5
180-186
84-88
100-101
yellow
yellow
white
C
59.02 (59.31)
59.02 (59.31)
67.88 (67.97)
Elemental Analysis (Calcd)
H
N
4.01 (4.03)
6.51 (6.59)
4.02 (4.03)
6.50 (6.59)
5.24 (5.46)
6.76 (6.89)
Table 3. FT-IR, 1H NMR and mass spectroscopic data of 4c, d, h
NMR(δ: ppm)
No.
IR(KBr, cm-1)
1H
4c
3458.9(-NH stretching of secondary
amine), 2978(-CH, stretching of
aliphatic), 1690(C=O stretching of
aromatic ketone), 1583, 1409.8(C=Cstretching of aromatic ring);
425(M+)
427(M+2)+
4d
3434.8(-NH stretching of secondary
amine), 2928(-CH, stretching of
aliphatic), 1684(C=O stretching of
aromatic ketone), 1563, 1353(C=Cstretching of aromatic ring)
8.28 (2H, d, J=8.6Hz, ArH), 8.02 (2H, d, J=8.6Hz, ArH), 7.89
(2H, d, J=8.7Hz, ArH), 7.44 (1H, d, J=7.4Hz, ArH), 7.35 (1H,
t, J=7.6Hz, ArH), 7.16 (1H, t, J=7.8Hz, ArH), 7.02 (2H, d,
J=8.6Hz, ArH), 6.78 (1H, t, J=7.1 Hz, ArH), 6.66 (1H, d,
J=7.8Hz, ArH), 5.07(1H, t, J=6.2Hz, NCH), 3.61 (2H, t,
J=5.0Hz, COCH2);
8.00 (2H, d, J=9.1Hz, ArH), 7.88 (2H, d, J=7.2Hz, ArH), 7.60
(1H, t, J=7.2Hz, ArH), 7.51 (1H, s, ArH), 7.44 (2H, t, J=7.6Hz,
ArH), 7.35 (1H, d, J=7.2Hz, ArH), 7.28 (1H, d, J=8.0HZ, ArH),
7.18 (1H, t, J=8.0Hz, ArH), 6.60 (2H, d, J=9.2Hz, ArH), 5.58
(1H, d, J=6.4Hz, NH), 5.02 (1H, q, J=6.0Hz, NCH), 3.48 (2H,
d, J=6.0Hz, COCH2)
4h
3466(-NH stretching of secondary
amine), 3077(-CH, stretching of
aromatic), 1692(C=O stretching of
aromatic ketone), 1587, 1295(C=Cstretching of aromatic ring)
8.00 (2H, d, J=9.1Hz, ArH), 7.88 (2H, d, J=7.2Hz, ArH), 7.60
(1H, t, J=7.2Hz, ArH), 7.51 (1H, s, ArH), 7.44 (2H, t, J=7.6Hz,
ArH), 7.35 (1H, d, J=7.2Hz, ArH), 7.28 (1H, d, J=8.0Hz, ArH),
7.18 (1H, t, J=8.0Hz, ArH), 6.60 (2H, d, J=9.2Hz, ArH), 5.58
(1H, d, J=6.4Hz, NH), 5.02 (1H, q, J=6.0Hz, NCH), 3.48 (2H,
d, J=6.0Hz, COCH2)
406(M+)
Eur. Chem. Bull., 2013, 2(10), 782-784
DOI: 10.17628/ECB.2013.2.782
GC/Mass
425(M+)
427(M+2)+
783
One pot three-component Mannich reaction catalyzed by FePO4
General Procedure for the Synthesis of β-Aminocarbonyl
Compounds
A mixture of an aromatic aldehyde (5 mmol), an aromatic
amine (5 mmol), the acetophenone (5.5 mmol) and FePO 4
(0.0375 g, 5.0 mol%) was ground using a mortar and
pestle at room temperature for the indicated times in
Table 1. After completion of the reaction (monitored by
TLC, eluent: n-hexane/ethyl acetate: 4/1), ethyl acetate
(10 ml) was added to the reaction mixture. After the
catalyst was filtered off, 10 ml of a saturated NaHCO3
solution was added, and the organic layer was separated
using a separatory funnel and dried over MgSO4. The
crude product obtained after evaporation of solvent was
purified by recrystallization from ethanol or ethanol/water
3:2 (v/v) to give the pure compounds. The pure products
were identified by comparison of their mp, IR, 1H NMR
with those of authentic samples5. Tables 2 and 3 provide
the color, melting points, elemental analysis and
spectroscopic data of new compounds 4c, 4d, 4h
respectively.
Section A-Short Communication
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The reaction (entry 1, Table 1) was run in larger-scale
using bezaldehyde (21.2 g, 200 mmol), aniline (18.6 g,
200 mmol) and acetophenone (25.2 g, 210 mmol) and
FePO4 (1.5 g, 200 mol%) in 150 ml of ethanol at room
temperature for 5.0 h. After completion of the reaction,
ethanol was removed and the product was obtained 57.2 g
in 95%.
18Rodriguez,
At the end of the reaction, the catalyst was recovered by
gravity filtration and recycled after washing with ethyl
acetate and could be subjected to five additional runs and
after five runs the yield was reduced only slightly.
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Conclusion
26Wang,
In summary, the present work has reported a general,
efficient, convenient, catalytic and green reaction medium
for the selective synthesis of β-aminocarbonyl
compounds by the Mannich condensation of
acetophenones with aromatic aldehydes and aromatic
amines in the presence of anhydrous FePO4 catalyst. This
general, simple, rapid and clean protocol does not require
the organic solvent and energy and is atom-economical.
R., Li, B. G., Huang, T. K., Shi L. and Lu, X. X.,
Tetrahedron Lett., 2007, 48, 2071.
27Behbahani,
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A., Heterocycl. Commun., 2006, 12, 369.
29Behbahani.
F. K. and Homafar, M., Synth. React. Inorg. M.,
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30Behbahani,
31Wu,
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Eur. Chem. Bull., 2013, 2(10), 782-784
DOI: 10.17628/ECB.2013.2.782
Received: 07.04.2013.
Accepted: 29.05.2013.
784