Highly efficient Fe(HSO4)3-catalyzed one-pot mannich-type reactions: Three component synthesis of β-amino carbonyl compounds

Article abstract of DOI:10.1080/15533174.2011.555858

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 β-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. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/15533174.2011.555858

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Highly Efficient Fe(HSO4)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
Published online: 12 Apr 2011.
To cite this article: Hossein Eshghi , Afsaneh Alipour & Saman Damavandi (2011) Highly Efficient Fe(HSO4)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: 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(HSO4)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
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]
NaBArF4 ,[8] NbCl5,[9] Re(PFO)3,[10] ZrOCl2·8H2O,[11] an acidic
ionic liquid,[12] H3PW12O[13] SiO2-OAlCl[14] dodecylbenzene-
sulfonic acid,[15] FeCl3,[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(HSO4)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(HSO4)3 has not been reported previously.
Fe(HSO4)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
40,
2,
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-
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
1
were recorded on a Shimadzu-IR 470 spectrophotometer. 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]
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
266

FE(HSO4)3-CATALYZED ONE-POT MANNICH-TYPE REACTIONS
267
O
R2
NH2
CHO
R1
O
HN
Fe(HSO4)3
EtOH, r.t.
+
+
R2
R1
SCH. 1. One-pot multicomponent route to β-aminocarbonyl compounds using ferric hydrogensulfate.
ArH); IR (KBr) = υ 3381, 1671, 1537, 1414, 1185 cm−1. Anal.
General Procedure to Synthesis of ␤-amino Ketones
Ferric hydrogensulfate (0.2 mmol) was added to a mixture calcd for C21H18N2O3: C, 72.82; H, 5.24; N, 8.09. Found: C,
of benzaldehyde (2 mmol), aniline (2 mmol) and acetophenone 72.71; H, 5.28; N, 8.13.
(2.2 mmol) in ethanol, and the reaction mixture was stirred at
3-(4-chlorophenyl)-3-(1-naphthylamino)-1-phenyl-1-
propanone (Entry 13)
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, 1H NMR, and elemental analysis and compared with those
reported.
1H NMR (100 MHz, DMSO-d6): δ = 3.30 (dd, 1 H, COCH2),
3.45 (dd, 1H, COCH2), 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 C25H21NO:
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)
1H NMR (100 MHz, DMSO-d6): δ = 1.0–1.3 (m, 6H, CH2),
1.30–1.80 (m, 4H, CH2), 2.70–3.30 (m, 3H, COCH2, 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 C21H25NO: C, 82.04; H, 8.20; N, 4.56; Found: C,81.55 ; H,
7.96; N, 4.49.
Selected Product Characterization Data
3-(4-methylphenyl)-1-phenyl-3-(4-toluidino)-1-propanone
(Entry 4)
1H NMR (100 MHz, DMSO-d6): δ = 1.65 (s, 3H, CH3), 1.80
(s, 3H, CH3), 3.05-3.30 (m, 2H, COCH2), 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 C23H23NO:
C, 83.85; H, 7.04; N, 4.25; O, 4.86. Found: C, 83.76; H,7.13;
N, 4.36.
3-anilino-3-(2-furyl)-1-phenyl-1-propanone (Entry 15)
1H NMR (100 MHz, DMSO-d6); δ = 3.20 (dd, 1 H, COCH2),
3.35 (dd, 1H, COCH2),), 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,
3-(3,4-dimethylanilino)-1,3-diphenyl-1-propanone (Entry 5)
1H NMR (100 MHz, DMSO-d6): δ = 1.55 (s, 3H, CH3),
1.65 (s, 3H, CH3), 3.20 (dd, J = 6.4, 5.9 Hz, 1 H, COCH2),
3.35 (dd, J = 8.4, 8.4 Hz, 1H, COCH2), 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 C23H23NO: C, 83.85;
H, 7.04; N, 4.25; Found: C, 83.72; H, 6.95; N, 4.11.
2H, ArH); IR (KBr) = υ 3365, 1648, 1611, 1577, 1236 cm−1
.
Anal. calcd for C19H17NO2: 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(HSO4)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
3-(2-fluoroanilino)-1,3-diphenyl-1-propanone (Entry 7)
1H NMR (100 MHz, DMSO-d6): δ = 3.22 (dd, 1 H, COCH2),
3.35 (dd, 1H, COCH2), 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 C21H18FNO: 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)
1H NMR (100 MHz, DMSO-d6): δ = 2.85–3.25 (m, 2H, the absence of Fe(HSO4)3 despite prolonged reaction times
COCH2), 5.15 (m, 1H, NCH), 6.60–6.80 (m, 4H, ArH), 7.05– (24 h), indicating that this is indeed a Fe(HSO4)3-catalyzed
7.20 (m, 3H, ArH), 7.40–7.70 (m, 4H, ArH), 7.80–8.10 (m, 4H, reaction.

268
H. ESHGHI ET AL.
TABLE 1
Influence of solvent on Fe(HSO4)3-catalyzed reaction of acetophenone with benzaldehyde and aniline and reusability studya
Solvent
Ethanol
Acetonitrile
Dichloroethane
Toluene
Benzene
THF
Yieldb
92
41
∼ 20
0
0
0
—
Reusabilityc
92d
91e
90f
88g
87h
aAll the reactions were carried out at room temperature for 8 h using 10 mol% ferric hydrogenesulfate.
bIsolated yields.
cReusability of the recovered catalyst was investigated in ethanol as the optimum solvent.
d−hReusability 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.
Yield (%)b,
Yield (%)b,
Producta
Entry
Producta
Time
(h)
Entry
1
Time
(h)
m.p.oCLit.
m.p.oCLit.
8
92
96
O
HN
O
O
HN
168-
16914
11614
4
3
4
Cl
Me
Cl
2
9
76
11517
97
O
HN
9d
114
-
113
92
-
11414
HN
Cl
Cl
3
4
10
95
-
O
HN
HN
O
HN
12
93
7
4.5
9
88
-171
14
170
NO2
Me
O
O
HN
HN
5.5
11
12
87
13714
88
142-143
14
136
-
OMe
Me
Me
5
6
O
HN
O
Me
4
7
90
146
1479
85
124-
1259
-
CH3
OMe
13
14
O
HN
78
84
13821
O
HN
136-
7.5
8d
6d
134
-
136
Cl
F
35
O
HN
O
HN
7
10
80
162-
16323
110
-111
O
HN
HO
25
122
O
HN
15
8
16
3.518
74
117
O
-
123
-
119
aReaction conditions: 2.0 equiv. of amine, 2.0 equiv. of aldehyde, 2.2 equiv of acetophenone, 10 mol% ferric
hydrogenesulfate at room temperature. bThe products were identified by 1HNMR and IR spectra. cIsolated yields.
d 12 mol% catalyst.

FE(HSO4)3-CATALYZED ONE-POT MANNICH-TYPE REACTIONS
269
In the present work, reusability of the catalyst was studied aromatic aldehyde bearing a strong electron-donating groups–
in the reaction of acetophenone, benzaldehyde, and aniline in N(CH3)2 was failed to give the desired product.
the presence of the catalyst in ethanol as an optimum solvent.
As it can be seen in Table 2, to extend our study, different
After completion of each run, the heterogeneous catalyst was amines were examined. In the case of amines having an electron-
recovered simply. As it can be seen in Table 1, the catalyst could donating group, such as 4-methoxyaniline or 4-mehylaniline,
be reused without significant loss of its catalytic activity until at the corresponding β-amino ketones were obtained in good
least 4 times.
yields. Furthermore, amines with electron-withdrawing groups,
In order to show the generality and scope of this new pro- such as 2-fluroanilne, 2-chloroaniline and 4-chloroaniline, af-
tocol, we used various aldehydes and amines, and the results forded the desired product in good yields. Naphtylamine and
illustrated in Table 2 clearly reveal that ferric hydrogen sul- cyclohexylamine were reacted with benzaldehyde derivatives in
fate is an efficient catalyst for such Mannich reactions. A vari- combination with acetophenone under the same experimental
ety of aromatic aldehydes, including electron-withdrawing and conditions, and the corresponding products were obtained in
electron-donating groups, were tried out using our new method reasonable yields (Table 2, Entries 13–14). The poor reaction
in ethanol in the presence of catalytic amount of Fe(HSO4)3 with heterocyclic aldehydes can be explained by considering
(Table 2).
the possible binding of basic heteroatom and the Lewis acidic
Subsequently, benzaldehyde was reacted with a variety of surface of the catalyst and thereby decreasing the reactivity with
aromatic amines such as 2-chloro-, 4-chloro-,4-methyl-, 3,4- amine (Table 2, entry 15).
dimethyl-, 2-fluro- or 4-methoxyaniline in combination with
The accepted mechanism involves the imine formation of
acetophenone, which provided very good to excellent yields the aldehyde and the amine, the protonation of the imine, and
within 4 to 8 h (Table 1, Entries 1–7). Although the hindrance the attack of the enol derived from the ketone to the protonated
obstacle for treating of ortho substituted amines has already been imine,[23] resulting in the formation of the corresponding β-
reported, in this method the desired β-amino ketone obtained amino carbonyl compounds. Ferric hydrogenesulfate catalyzed
without suffering from steric effects; however, the reactions took both imine formation and its activation with subsequent proto-
a longer time (Table 2, Entries 2,7). In this case, longer reaction nation. Furthermore, this catalyst facilitated the attack of ketone
time and excess amount of catalyst were required to achieve to the protonated imine by facile enol formation (Scheme 2).
better transformation.
The protonated imine intermediate is susceptible to be affected
Then, substituted aldehydes bearing electron-withdrawing by substitutions on the amine or the aldehyde and that’s why
or electron-donating groups, such as 4-bromo- and 4- these Mannich-type reactions give various results in terms of
methoxybenzaldehyde were treated with aromatic amines in reaction time and yield using different substitutions. As it can
combination with acetophenone under the same experimental be seen in Table 2 (entry 16), salicylaldehyde reacted with ani-
conditions, and the corresponding desired products were iso- line in combination with acetophenone under the same experi-
lated in excellent yields (Table 2, Entries 8–12).
mental conditions and the corresponding product was obtained
In general, the highest yields of β-amino ketones were in satisfying yield, but the reaction proceeds faster than other
obtained for a variety of aldehydes bearing an electron- used aldehydes and the isolated β-amino carbonyl compound
withdrawing group. Using several electron-rich aromatic alde- afforded in shorter time due to the intramolecular general acid
hydes resulted in obtaining the desired products in good yields; catalyzed that protonates the imine intermediate leading to facile
however, as it has been reported in the literature, the reaction of attack of the enol.
R2
O
HN
Fe (HSO4)3
H
R2
N+
H
R1
R1
NH2
CHO
Fe (HSO4)3
R2
R1
O
(O4SH)3Fe
O
CH3
SCH. 2. Proposed mechanism to preparation of β-aminocarbonyl compounds using ferric hydrogensulfate.

270
H. ESHGHI ET AL.
TABLE 3
Mannich reaction of acetophenone, benzaldehyde, and aniline catalyzed by different catalysts
Entry
Catalyst
No catalyst
Reaction conditions
EtOH, r.t.
Reaction time
Yield (%)a
1
2
3
4
5
6
7
8
9
10
11
12
13
14
24 h
24 h
24 h
48 h
8 h
10 h
12 h
12 h
8 h
24 h
90 min
5 h
5 h
4 h
No reaction
FeCl3
EtOH, r.t.
No reaction9,16
AlCl3
EtOH, r.t.
No reaction14
818
NaBArF4
H2O, 30◦C
Al(CH3SO3)3·4H2O
EtOH, r.t.
EtOH, r.t.
EtOH, r.t.
8617
SnCl2
9321
NbCl5
Yb(Opt)3
ZrCl4
sucrose char sulfonic acid
NH2SO3H
AlCl3/SiO2
SiO2–OAlCl2
Fe(HSO4)3
959
C6H5CH3/C6F5CF3, r.t.
EtOH, r.t.
9822
9124
EtOH, 30◦C
EtOH, r.t./under US irradiation
EtOH, r.t.
7625
9623
7414
EtOH, r.t.
EtOH, r.t.
9314
92
aYields 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.
3. Schramm, V.L. Synthesis of a transition state analogue inhibitor of purine
nucleoside phosphorylase via the Mannich Reaction. Org. Lett. 2003, 5,
3639–3640.
4. Joshi, N.S.; Whitaker, L.R.; Francis, M.B. A three-component Mannich-
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126, 15942–15943.
5. Blatt, A.H.; Gross, N. The addition of ketones to Schiff bases. J. Org.
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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(HSO4)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.
12. Fang, D.; Luo, J.; Zhou X.L.; Liu, Z.L. One-pot, three-component Mannich-
type reaction catalyzed by functionalized ionic liquid. Monatsh Chem 2009,
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