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Highly Efficient Fe(HSO4)3-Catalyzed One-Pot Mannich-Type Reactions: Three Component Synthesis of β-amino Carbonyl Compounds

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Fe(HSO4)3-catalyzed three-component one-pot Mannich reaction of acetophenone with different aromatic aldehydes and aromatic amines in ethanol at ambient temperature afforded the corresponding -aminocarbonyl compounds in very good to excellent yields. Short reaction time, excellent yield, easy work-up procedure, applicability of using various amines and aldehydes, capability of conversion of ortho-substituted aromatic amines to the corresponding Mannich base in satisfying yields, and eventually high reusability of the catalyst show the merit of this study.
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Highly Efficient Fe(HSO
4
)
3
-Catalyzed One-Pot Mannich-Type Reactions:
Three Component Synthesis of β-amino Carbonyl Compounds
Hossein Eshghi
a
; Afsaneh Alipour
a
; Saman Damavandi
a
a
Department of Chemistry, Faculty of Science, Ferdowsi University of Mashhad, Mashhad, I. R. Iran
Online publication date: 12 April 2011
To cite this Article Eshghi, Hossein , Alipour, Afsaneh and Damavandi, Saman(2011) 'Highly Efficient Fe(HSO
4
)
3
-
Catalyzed One-Pot Mannich-Type Reactions: Three Component Synthesis of β-amino Carbonyl Compounds', Synthesis
and Reactivity in Inorganic, Metal-Organic, and Nano-Metal Chemistry, 41: 3, 266 — 271
To link to this Article: DOI: 10.1080/15533174.2011.555858
URL: http://dx.doi.org/10.1080/15533174.2011.555858
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Synthesis and Reactivity in Inorganic, Metal-Organic, and Nano-Metal Chemistry, 41:266–271, 2011
Copyright © Taylor & Francis Group, LLC
ISSN: 1553-3174 print / 1553-3182 online
DOI: 10.1080/15533174.2011.555858
Highly Efficient Fe(HSO
4
)
3
-Catalyzed One-Pot
Mannich-Type Reactions: Three Component Synthesis
of -amino Carbonyl Compounds
Hossein Eshghi, Afsaneh Alipour, and Saman Damavandi
Department of Chemistry, Faculty of Science, Ferdowsi University of Mashhad, Mashhad, I. R. Iran
Fe(HSO
4
)
3
-catalyzed three-component one-pot Mannich reac-
tion of acetophenone with different aromatic aldehydes and aro-
matic amines in ethanol at ambient temperature afforded the cor-
responding β-aminocarbonyl compounds in very good to excellent
yields. Short reaction time, excellent yield, easy work-up proce-
dure, applicability of using various amines and aldehydes, capa-
bility of conversion of ortho-substituted aromatic amines to the
corresponding Mannich base in satisfying yields, and eventually
high reusability of the catalyst show the merit of this study.
Keywords β-aminocarbonyl, ferric hydrogensulfate, heterogeneous
catalyst, one-pot
INTRODUCTION
Multicomponent reactions (MCRs) are of increasing impor-
tance in organic and medicinal chemistry, as high degrees of
molecular diversity can be introduced in these reactions in a
very fast, efficient, and time saving manner, and without the iso-
lation of any intermediates. As a result, considerable attention
has been paid to the development of new and improved one-pot
multicomponent reactions in recent years.
[1]
Mannich type reactions are very important carbon-carbon
bond forming reactions in organic synthesis and one of the most
useful methods for the preparation of β-aminocarbonyl com-
pounds, which are valuable synthetic intermediates for pharma-
ceuticals and natural products.
[2,3]
The increasing importance
of the Mannich reaction is justified by the ubiquitous nature
of nitrogen containing compounds in drugs and natural prod-
ucts. The products of Mannich reaction are mainly β-amino
carbonyl compounds and its derivatives that are used for the
synthesis of amino alcohols, peptides, lactams and as precur-
sors to optically active amino acids.
[4]
Although earlier litera-
Received 10 May 2010; accepted 19 July 2010.
Address correspondence to Hossein Eshghi, Department of Chem-
istry, Faculty of Science, Ferdowsi University of Mashhad, P.O. Box
91775-1436 Mashhad, I. R. Iran. E-mail: heshghi@ferdowsi.um.ac.ir
tures reported that β-aminocarbonyl compounds derived from
aromatic ketones, aldehydes and amines can only be synthe-
sized indirectly by amine exchange reaction or the addition of
ketones to Schiff bases,
[5]
Yi and Cardova reported the three-
component Mannich reaction of aromatic ketones, aldehydes
and amines catalyzed by HCl/EtOH.
[6]
Following this discov-
ery, many researchers have devoted their efforts to the one pot
three-component Mannich reaction of aromatic ketones, alde-
hydes and amines using different catalysts such as Cu(OTf)
2
,
[7]
NaBAr
F
4
,
[8]
NbCl
5
,
[9]
Re(PFO)
3
,
[10]
ZrOCl
2
·8H
2
O,
[11]
an acidic
ionic liquid,
[12]
H
3
PW
12
O
[13]
40,
SiO
2
-OAlCl
[14]
2,
dodecylbenzene-
sulfonic acid,
[15]
FeCl
3
,
[16]
aluminium methanesulfonate
[17]
and
bromodimethylsulfonium bromide (BDMS).
[18]
However, sev-
eral downsides, such as large excesses of catalyst, expensive
reagents, long reaction time, and low yields, still exist. There-
fore, it is still desirable to develop low-cost and highly efficient
catalysts for this reaction.
Herein, the authors wish to report a convenient and simple
procedure for Fe(HSO
4
)
3
-catalyzed three component one pot
Mannich reaction of acetophenone with a verity of aromatic
aldehydes and amines at mild reaction conditions led to syn-
thesis of β-aminocarbonyl compounds (Scheme 1). To the best
of our knowledge, direct Mannich-type reaction catalyzed by
Fe(HSO
4
)
3
has not been reported previously.
EXPERIMENTAL
Chemicals were either prepared in our laboratories or pur-
chased from Merck, Fluka and Aldrich Chemical Companies.
All yields refer to isolated products. The reactions were moni-
tored by thin-layer chromatography carried out on silica plates.
The products were characterized by comparison of their physical
data with authentic samples or by their spectral data. IR spectra
were recorded on a Shimadzu-IR 470 spectrophotometer.
1
H
NMR spectra was recorded on a Bruker 100-MHz spectrometer
in DMSO as the solvent and TMS as internal standard. Ferric
hydrogensulfate was prepared according to previously reported
procedure.
[19,20]
266
Downloaded By: [Ferdowsi University of Mashhad] At: 09:00 12 April 2011
FE(HSO
4
)
3
-CATALYZED ONE-POT MANNICH-TYPE REACTIONS 267
O HN
O
+
CHO
+
NH
2
R
2
R
1
Fe(HSO
4
)
3
EtOH, r.t.
R
2
R
1
SCH. 1. One-pot multicomponent route to β-aminocarbonyl compounds using ferric hydrogensulfate.
General Procedure to Synthesis of -amino Ketones
Ferric hydrogensulfate (0.2 mmol) was added to a mixture
of benzaldehyde (2 mmol), aniline (2 mmol) and acetophenone
(2.2 mmol) in ethanol, and the reaction mixture was stirred at
room temperature. The progress of the reaction was monitored
by TLC. After completion of the reaction, the catalyst was just
filtered off, washed, and dried for its next use. After remov-
ing solvent, the residue was dissolved in hot ethanol and was
recrystallized to provide the pure product. The pure product
was characterized and identified by the by their melting point,
IR,
1
H NMR, and elemental analysis and compared with those
reported.
Selected Product Characterization Data
3-(4-methylphenyl)-1-phenyl-3-(4-toluidino)-1-propanone
(Entry 4)
1
H NMR (100 MHz, DMSO-d6): δ = 1.65 (s, 3H, CH
3
), 1.80
(s, 3H, CH
3
), 3.05-3.30 (m, 2H, COCH
2
), 5.10 (m, 1H, NCH),
6.80-7.0 (m, 5H, ArH), 7.40-7.70 (m, 9H, ArH); IR (KBr) υ =
3380, 1685, 1572, 1563, 1222 cm
1
. Anal. calcd for C
23
H
23
NO:
C, 83.85; H, 7.04; N, 4.25; O, 4.86. Found: C, 83.76; H,7.13;
N, 4.36.
3-(3,4-dimethylanilino)-1,3-diphenyl-1-propanone (Entry 5)
1
H NMR (100 MHz, DMSO-d6): δ = 1.55 (s, 3H, CH
3
),
1.65 (s, 3H, CH
3
), 3.20 (dd, J = 6.4, 5.9 Hz, 1 H, COCH
2
),
3.35 (dd, J = 8.4, 8.4 Hz, 1H, COCH
2
), 5.10 (m, 1H, NCH),
6.25 (brs, 1H, NH), 6.50–7.20 (m, 5 H, ArH), 7.30–7.45 (m,
5H, ArH), 7.65–7.80 (m, 3H, ArH); IR (KBr) υ = 3373, 1680,
1671, 1525, 1268 cm
1
. Anal. calcd for C
23
H
23
NO: C, 83.85;
H, 7.04; N, 4.25; Found: C, 83.72; H, 6.95; N, 4.11.
3-(2-fluoroanilino)-1,3-diphenyl-1-propanone (Entry 7)
1
H NMR (100 MHz, DMSO-d6): δ = 3.22 (dd, 1 H, COCH
2
),
3.35 (dd, 1H, COCH
2
), 5.33 (m, 1H, NCH), 7.25–7.50 (m, 5H,
ArH), 7.65–7.95 (m, 11 H, ArH); IR (KBr) υ = 3371, 3040,
1660, 1528, 1217 cm
1
. Anal. calcd for C
21
H
18
FNO: C, 18.98;
H, 5.68; N, 4.39; Found: C, 18.85; H, 5.51; N, 4.42.
3-anilino-3-(4-nitrophenyl)-1-phenyl-1-propanone (Entry 10)
1
H NMR (100 MHz, DMSO-d6): δ = 2.85–3.25 (m, 2H,
COCH
2
), 5.15 (m, 1H, NCH), 6.60–6.80 (m, 4H, ArH), 7.05–
7.20 (m, 3H, ArH), 7.40–7.70 (m, 4H, ArH), 7.80–8.10 (m, 4H,
ArH); IR (KBr) = υ 3381, 1671, 1537, 1414, 1185 cm
1
. Anal.
calcd for C
21
H
18
N
2
O
3
: C, 72.82; H, 5.24; N, 8.09. Found: C,
72.71; H, 5.28; N, 8.13.
3-(4-chlorophenyl)-3-(1-naphthylamino)-1-phenyl-1-
propanone (Entry 13)
1
H NMR (100 MHz, DMSO-d6): δ = 3.30 (dd, 1 H, COCH
2
),
3.45 (dd, 1H, COCH
2
), 5.10 (m, 1H, NCH), 6.65–6.75 (m, 3H,
ArH), 6.9–7.10 (m, 3H, ArH), 7.25–7.35 (m, 2H, ArH), 7.50–
7.65 (m, 4H, ArH), 7.80–8.05 (m, 3H, ArH); IR (KBr) = υ
3386, 1659, 1611, 1533, 1240 cm-
1
. Anal. calcd for C
25
H
21
NO:
C, 85.44; H, 6.02; N, 3.99; Found: C, 85.31; H, 6.11; N, 3.90.
3-(cyclohexylamino)-1,3-diphenyl-1-propanone (Entry 14)
1
H NMR (100 MHz, DMSO-d6): δ = 1.0–1.3 (m, 6H, CH
2
),
1.30–1.80 (m, 4H, CH
2
), 2.70–3.30 (m, 3H, COCH
2
,CH),4.45
(brs, 1H, NH), 5.0 (t, 1H, NCH), 7.15–7.70 (m, 10H, ArH); IR
(KBr) = υ 3370, 1664, 1625, 1572, 1241 cm
1
. Anal. calcd
for C
21
H
25
NO: C, 82.04; H, 8.20; N, 4.56; Found: C,81.55 ; H,
7.96; N, 4.49.
3-anilino-3-(2-furyl)-1-phenyl-1-propanone (Entry 15)
1
H NMR (100 MHz, DMSO-d6); δ = 3.20 (dd, 1 H, COCH
2
),
3.35 (dd, 1H, COCH
2
),), 5.0 (m, 1H, NCH), 6.60–6.85 (m, 3H,
ArH), 6.9–7.2 (m, 4H, ArH), 7.30–7.70 (m, 5H, ArH), 8.10 (dd,
2H, ArH); IR (KBr) = υ 3365, 1648, 1611, 1577, 1236 cm
1
.
Anal. calcd for C
19
H
17
NO
2
: C, 78.33; H, 5.88; N, 4.81; Found:
C, 78.40 ; H, 5.91; N, 4.74.
RESULTS AND DISCUSSION
As a preliminary study, several solvents were screened
in the model reaction. Initially, a three-component cou-
pling of acetophenone, benzaldehyde, and aniline using 10
mol% of Fe(HSO
4
)
3
in ethanol was carried out (Scheme
1). Ferric hydrogensulfate could catalyze Mannich reac-
tions in organic solvents such as ethanol, acetonitrile, and
1,2-dichloroethane, and gave the desired products in low
to high yields. Among the screened solvents, ethanol was
found to be the most effective solvent in terms of isolated
yield (92%) (Table 1, entry 1). No reaction was observed in
the absence of Fe(HSO
4
)
3
despite prolonged reaction times
(24 h), indicating that this is indeed a Fe(HSO
4
)
3
-catalyzed
reaction.
Downloaded By: [Ferdowsi University of Mashhad] At: 09:00 12 April 2011
268 H. ESHGHI ET AL.
TABLE 1
Influence of solvent on Fe(HSO
4
)
3
-catalyzed reaction of acetophenone with benzaldehyde and aniline and reusability study
a
Solvent Ethanol Acetonitrile Dichloroethane Toluene Benzene THF
Yield
b
92 41 20 0 0 0
Reusability
c
92
d
91
e
90
f
88
g
87
h
a
All the reactions were carried out at room temperature for 8 h using 10 mol% ferric hydrogenesulfate.
b
Isolated yields.
c
Reusability of the recovered catalyst was investigated in ethanol as the optimum solvent.
dh
Reusability of the recovered catalyst in new runs from run 2[d] to run 6[h].
TABLE 2
Results of β-aminocarbonyl compounds preparation using ferric hydrogensulfate.
Entry
Product
a
Time
(h)
Entry
Product
a
Time
(h)
Yield (%)
b
,
m.p.
o
C
Lit.
Yield (%)
b
,
m.p.
o
C
Lit.
1
O HN
4
92
168
-
169
14
8
O HN
Cl
3
96
116
14
2
O HN
Cl
9
d
76
114
-
115
17
9
O HN
Cl
Me
4
97
113
-
114
14
3
O HN
Cl
7
88
170
-
171
14
10
O HN
NO
2
4.5
95
92
-
93
12
4
O HN
Me
Me
5.5
87
136
-
137
14
11
O
HN
OMe
9
88
142
-
143
14
5
O HN Me
Me
4
90
146
-
147
9
12
ONH
CH
3
7
85
124
-
125
9
6
O HN
OMe
7.5
84
136
-
138
21
13
O HN
Cl
6
d
78
134
-
136
7
O
HN
F
8
d
80
162
-
163
23
14
O HN
10
35
110
-
111
15
O HN
O
8
25
122
-
123
16
ONH
OH
3.5
74
117
-
119
18
a
Reaction conditions: 2.0 equiv. of amine, 2.0 equiv. of aldehyde, 2.2 equiv of acetophenone, 10 mol% ferric
hydrogenesulfate at room temperature.
b
The products were identified by
1
HNMR and IR spectra.
c
Isolated yields.
d
12 mol% catalyst.
Downloaded By: [Ferdowsi University of Mashhad] At: 09:00 12 April 2011
FE(HSO
4
)
3
-CATALYZED ONE-POT MANNICH-TYPE REACTIONS 269
In the present work, reusability of the catalyst was studied
in the reaction of acetophenone, benzaldehyde, and aniline in
the presence of the catalyst in ethanol as an optimum solvent.
After completion of each run, the heterogeneous catalyst was
recovered simply. As it can be seen in Table 1, the catalyst could
be reused without significant loss of its catalytic activity until at
least 4 times.
In order to show the generality and scope of this new pro-
tocol, we used various aldehydes and amines, and the results
illustrated in Table 2 clearly reveal that ferric hydrogen sul-
fate is an efficient catalyst for such Mannich reactions. A vari-
ety of aromatic aldehydes, including electron-withdrawing and
electron-donating groups, were tried out using our new method
in ethanol in the presence of catalytic amount of Fe(HSO
4
)
3
(Table 2).
Subsequently, benzaldehyde was reacted with a variety of
aromatic amines such as 2-chloro-, 4-chloro-,4-methyl-, 3,4-
dimethyl-, 2-fluro- or 4-methoxyaniline in combination with
acetophenone, which provided very good to excellent yields
within 4 to 8 h (Table 1, Entries 1–7). Although the hindrance
obstacle for treating of ortho substituted amines has already been
reported, in this method the desired β-amino ketone obtained
without suffering from steric effects; however, the reactions took
a longer time (Table 2, Entries 2,7). In this case, longer reaction
time and excess amount of catalyst were required to achieve
better transformation.
Then, substituted aldehydes bearing electron-withdrawing
or electron-donating groups, such as 4-bromo- and 4-
methoxybenzaldehyde were treated with aromatic amines in
combination with acetophenone under the same experimental
conditions, and the corresponding desired products were iso-
lated in excellent yields (Table 2, Entries 8–12).
In general, the highest yields of β-amino ketones were
obtained for a variety of aldehydes bearing an electron-
withdrawing group. Using several electron-rich aromatic alde-
hydes resulted in obtaining the desired products in good yields;
however, as it has been reported in the literature, the reaction of
aromatic aldehyde bearing a strong electron-donating groups–
N(CH
3
)
2
was failed to give the desired product.
As it can be seen in Table 2, to extend our study, different
amines were examined. In the case of amines having an electron-
donating group, such as 4-methoxyaniline or 4-mehylaniline,
the corresponding β-amino ketones were obtained in good
yields. Furthermore, amines with electron-withdrawing groups,
such as 2-fluroanilne, 2-chloroaniline and 4-chloroaniline, af-
forded the desired product in good yields. Naphtylamine and
cyclohexylamine were reacted with benzaldehyde derivatives in
combination with acetophenone under the same experimental
conditions, and the corresponding products were obtained in
reasonable yields (Table 2, Entries 13–14). The poor reaction
with heterocyclic aldehydes can be explained by considering
the possible binding of basic heteroatom and the Lewis acidic
surface of the catalyst and thereby decreasing the reactivity with
amine (Table 2, entry 15).
The accepted mechanism involves the imine formation of
the aldehyde and the amine, the protonation of the imine, and
the attack of the enol derived from the ketone to the protonated
imine,
[23]
resulting in the formation of the corresponding β-
amino carbonyl compounds. Ferric hydrogenesulfate catalyzed
both imine formation and its activation with subsequent proto-
nation. Furthermore, this catalyst facilitated the attack of ketone
to the protonated imine by facile enol formation (Scheme 2).
The protonated imine intermediate is susceptible to be affected
by substitutions on the amine or the aldehyde and that’s why
these Mannich-type reactions give various results in terms of
reaction time and yield using different substitutions. As it can
be seen in Table 2 (entry 16), salicylaldehyde reacted with ani-
line in combination with acetophenone under the same experi-
mental conditions and the corresponding product was obtained
in satisfying yield, but the reaction proceeds faster than other
used aldehydes and the isolated β-amino carbonyl compound
afforded in shorter time due to the intramolecular general acid
catalyzed that protonates the imine intermediate leading to facile
attack of the enol.
CHO
NH
2
H
N
+
O
(O
4
SH)
3
Fe
Fe (HSO
4
)
3
CH
3
O
HNO
R
2
R
1
R
1
R
2
R
2
R
1
Fe (HSO
4
)
3
H
SCH. 2. Proposed mechanism to preparation of β-aminocarbonyl compounds using ferric hydrogensulfate.
Downloaded By: [Ferdowsi University of Mashhad] At: 09:00 12 April 2011
270 H. ESHGHI ET AL.
TABLE 3
Mannich reaction of acetophenone, benzaldehyde, and aniline catalyzed by different catalysts
Entry Catalyst Reaction conditions Reaction time Yield (%)
a
1 No catalyst EtOH, r.t. 24 h No reaction
2 FeCl
3
EtOH, r.t. 24 h No reaction
9,16
3AlCl
3
EtOH, r.t. 24 h No reaction
14
4NaBAr
F
4
H
2
O, 30
C48h81
8
5Al(CH
3
SO
3
)
3
·4H
2
O EtOH, r.t. 8 h 86
17
6 SnCl
2
EtOH, r.t. 10 h 93
21
7NbCl
5
EtOH, r.t. 12 h 95
9
8Yb(Opt)
3
C
6
H
5
CH
3
/C
6
F
5
CF
3
, r.t. 12 h 98
22
9ZrCl
4
EtOH, r.t. 8 h 91
24
10 sucrose char sulfonic acid EtOH, 30
C24h76
25
11 NH
2
SO
3
H EtOH, r.t./under US irradiation 90 min 96
23
12 AlCl
3
/SiO
2
EtOH, r.t. 5 h 74
14
13 SiO
2
–OAlCl
2
EtOH, r.t. 5 h 93
14
14 Fe(HSO
4
)
3
EtOH, r.t. 4 h 92
a
Yields refer to the isolated products.
It is worth mentioning that this method is faster and sim-
pler than most of the existing methods. The efficiency, advan-
tages, and generality of the catalyst ferric hydrogensulfate can
be proved by comparison of the results obtained in this study
with those reported previously (Table 3). In order to show the
merit of this study, we compared the obtained results with the
results reported recently. For this comparison, the reaction of
acetophenone, benzaldehyde, and aniline was chosen as a model
reaction, and comparison was carried out on the basis of reaction
conditions, reaction time, and percentage yields obtained.
CONCLUSION
In conclusion, a simple, fast, concise, and efficient one pot re-
action of different aldehydes, ketones, and amines to afford cor-
responding β-amino carbonyl compounds has been described.
Since the Fe(HSO
4
)
3
catalyst is inexpensive, easy to produce and
handle, and readily removable and reusable, our method seems
to be attractive process for the convenient synthesis of substi-
tuted β-amino carbonyl compounds through a three component
reaction. Likewise, it is worth pointing out that this method pro-
vided efficient synthesis of β-amino carbonyl compounds using
ortho-substituted aromatic amines. Finally, this approach could
make a valuable contribution to the existing processes in the
field of β-amino ketones synthesis.
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