Efficient one-pot synthesis of β-acetamido carbonyl compounds using Fe3O4 nanoparticles

Article abstract of DOI:10.1002/hlca.201200570

A new, one-pot condensation of aldehydes, enolizable ketones and esters, AcCl, and MeCN, in the presence of Fe₃O₄ nanoparticles (nano-Fe₃O₄) as an efficient catalyst, for the preparation of β-acetamido carbonyl compounds at room temperature is described. Copyright

Full text of DOI:10.1002/hlca.201200570

Helvetica Chimica Acta – Vol. 96 (2013)
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Efficient One-Pot Synthesis of b-Acetamido Carbonyl Compounds Using
Fe3O4 Nanoparticles
by Barahman Movassagh* and Farzaneh Talebsereshki
Department of Chemistry, K. N. Toosi University of Technology, P.O. Box 16315-1618, Tehran, Iran
(e-mail: bmovass1178@yahoo.com)
A new, one-pot condensation of aldehydes, enolizable ketones and esters, AcCl, and MeCN, in the
presence of Fe3O4 nanoparticles (nano-Fe3O4) as an efficient catalyst, for the preparation of b-acetamido
carbonyl compounds at room temperature is described.
Introduction. – The conventional synthesis of b-amino/b-acetamido carbonyl
compounds involves the DakinꢀWest reaction [1], in which an a-amino acid is
condensed with Ac2O in the presence of a base to provide the a-acetamido ketones via
an intermediate aza-lactone [1b]. However, the direct Mannich reaction of aldehydes,
ketones, and aromatic amines for the synthesis of b-amino carbonyl compounds, and of
aldehydes, ketones, and MeCN in the presence of AcCl for the synthesis of b-acetamido
carbonyl compounds by acid catalysis have been reported. Many catalysts such as nano-
ZnO [2], ZrOCl2 · 8 H2O [3], SnCl2 · 2 H2O [4], CeCl3 · 7 H2O [5], silica sulfuric acid
[6], H6P2W18O62 [7], sulfamic acid [8], Sc(OTf)3 [9], P2O5-HMDS [10], FeCl3 [11],
BiOCl [12], I2 [13], montmorillonite K-10 clay [14], Nafion-Hꢀ [15], La(OTf)3 [16],
and Amberlyst-15ꢀ [17] have been used in this one-pot reaction.
Recently, metal nanoparticles have attracted a great attention as heterogeneous
catalysts because of their interesting structure and high catalytic activities in
comparison with the corresponding bulky materials. They can have different melting
points, vapor pressures, heat capacities, and optical, electronic, and magnetic properties
[18]. Of metal nanocatalysts, nano-Fe3O4 is the most promising catalyst because of its
simple handling, ease of recovery with an external magnetic field, high catalytic
activities, and reactivities in various organic transformations [19].
Results and Discussion. – To develop a nontoxic, heterogeneous, reusable, and
potentially eco-friendly catalyst, we considered using Fe3O4 nanoparticles (nano-
Fe3O4) for the one-pot synthesis of b-acetamido carbonyl compounds. Initially, to find
the optimal conditions, we set up a model reaction with benzaldehyde (1 mmol),
acetophenone (1 mmol), AcCl (1 mmol), and MeCN (2.5 ml) under various reaction
conditions at room temperature (Table 1).
As can be seen from Table 1, in the absence of any catalyst, the acetamido product
was obtained in a very low yield after 1.5 h, while better results were obtained in the
presence of catalysts like RuCl3, MgCl2, and nano-CuO (Table 1, Entries 2 – 4). With
nano-Fe3O4 as catalyst, good results were achieved within a short reaction time (1 h) at
ꢁ 2013 Verlag Helvetica Chimica Acta AG, Zꢂrich

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Helvetica Chimica Acta – Vol. 96 (2013)
Table 1. Optimization of the Reaction Conditions for the Formation of N-(3-Oxo-1,3-diphenylpropyl)-
acetamide at Room Temperature
Entry
Catalyst ([mol-%])
Time [h]
Yield [%]a)
1
2
3
4
5
6
7
8
9
–
1.5
5
7
24
1
1
1
1
1
1
17
47
30
81
69
87
86
86
46b)
51
RuCl3 (5)
MgCl2 (5)
nano-CuO (5)
nano-Fe3O4 (3)
nano-Fe3O4 (5)
nano-Fe3O4 (7)
nano-Fe3O4 (10)
nano-Fe3O4 (5)
bulk-Fe3O4 (5)
10
a) Yield of isolated product. b) At 608.
room temperature (Table 1, Entries 5 – 8). The minimum load of nano-Fe3O4 was found
as 5 mol-% (Table 1, Entries 5 – 8). A lower yield (46%) was observed, when the
reaction was carried out at an elevated (608) temperature (Table 1, Entry 9). Also
commercially available bulk Fe3O4 was evaluated. Obviously, under the same reaction
conditions, nano-Fe3O4 gave higher yield than bulk Fe3O4 (87% vs. 51%; Table 1,
Entries 6 and 10). Therefore, the condition of Entry 6 was regarded as optimal. Also, it
was observed that during the course of the reaction the magnetic heterogeneous
catalyst disappeared; this may be due to the formation of homogeneous FeCl3 in
reaction of nano-Fe3O4 with AcCl.
To explore the utility of this multicomponent reaction, a series of b-acetamido
carbonyl compounds was prepared in high yields according to the above protocol
(Table 2). As shown in Table 2, aromatic aldehydes and acetophenone derivatives
containing electron-donating or electron-withdrawing substituents gave the corre-
sponding b-acetamido ketones without the formation of any side-products in high-to-
excellent yields (Table 2, Entries 1 – 13). The present protocol is applicable to other
enolizable ketones such as butanone, propiophenone, and methyl acetoactate (a b-keto
ester) (Table 2, Entries 14 – 18). With butanone, propiophenone, and methyl acetoa-
cetate, mixtures of syn- and anti-diasteroisomers were obtained with the anti-isomer as
the major product (Scheme and Table 2). The vicinal coupling constant 3J
(HꢀC(1),HꢀC(2)) for the anti-isomer is generally 7 – 9 Hz, while it is typically 3 –
5 Hz for the syn-isomer [20].
Conclusions. – In summary, we have presented a highly efficient and convenient
procedure for the synthesis of b-acetamido carbonyl compounds from a variety of
aromatic aldehydes, enolizable ketones, AcCl, and MeCN, using Fe3O4 nanoparticles as
catalyst. The notable feature of the present method lies in the availability, low cost, and
nontoxicity of the catalyst. The method offers also some other advantages such as low

Helvetica Chimica Acta – Vol. 96 (2013)
1945
Table 2. One-Pot Synthesis of b-Acetamido Carbonyl Compounds
Entry
R1
R2
X
Producta)b)
Time [h]
Yield [%]c)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
Ph
Ph
Ph
Ph
Ph
Ph
H
H
H
H
H
H
H
H
H
H
H
H
H
2-Cl
3a [14]
3b [21]
3c [22]
3d [22]
3e [22]
3f [21]
3g [21]
3h [23]
3i [24]
3j [23]
3k [23]
3l [23]
1
0.67
1
1
1
85
90
87
70
72
80
91
90
85
86
87
92
95
82
89
83
89
0
3-NO2
3-Me
4-OH
4-MeO
H
1
1
4-MeOꢀC6H4
4-ClꢀC6H4
4-NO2ꢀC6H4
4-ClꢀC6H4
4-ClꢀC6H4
4-MeOꢀC6H4
4-BrꢀC6H4
Me
Ph
Ph
Ph
Me
H
1.17
1.17
1.17
1.17
0.75
0.67
0.75
0.75
1
4-MeO
2,4-Cl2
4-Me
2-Cl
2-MeO
4-Me
4-Me
4-NO2
4-Cl
H
3m [25]
Me
Me
Me
Me
COOMe
3n (84 : 16) [26]
3o (73 : 27) [26]
3p (64 : 36) [26]
3q (72 : 28) [26]
3r (81 : 19) [26]
1
0.75
H
a) The anti/syn ratio was determined from the 1H-NMR spectrum of the crude product. b) References for
known compounds. c) Yields of isolated products.
Scheme
loading (5 mol-%) of the catalyst, clean reaction, short reaction times, and high yield of
products.
Experimental Part
General Procedure. A soln. of aldehyde (1 mmol), enolizable ketone (1 mmol), AcCl (1 mmol), and
MeCN (2.5 ml), in the presence of Fe3O4 nanoparticles (0.05 mmol, 5 mol%), was stirred at r.t. After
completion of the reaction (monitored by TLC), the mixture was poured into ice-H2O. The solid was
separated, filtered, and recrystallized with either AcOEt/hexane or EtOH/H2O.

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Helvetica Chimica Acta – Vol. 96 (2013)
N-[1-(2-Chlorophenyl)-3-oxo-3-phenylpropyl]acetamide (3b). M.p. 135 – 1368 ([21]: 134 – 1368). IR
(KBr): 3295 (NꢀH), 1689 (C¼O), 1651 (C¼O). 1H-NMR (400 MHz, CDCl3): 2.04 (s, 3 H); 3.48 (dd, J ¼
16.7, 5.6, 1 H); 3.75 (dd, J ¼ 16.7, 6.0, 1 H); 5.85 (dd, J ¼ 13.2, 5.6, 1 H); 7.11 (br. d, J ¼ 6.8, 1 H); 7.17 –
7.23 (m, 2 H); 7.35 (d, J ¼ 7.6, 1 H); 7.44 – 7.48 (m, 3 H); 7.58 (t, J ¼ 7.2, 1 H); 7.92 (d, J ¼ 7.6,
2 H).13C-NMR (100 MHz, CDCl3): 23.4; 41.5; 48.0; 127.0; 128.2; 128.4; 128.7; 128.8; 129.9; 132.5; 133.7;
136.4; 138.2; 169.5; 198.8.
N-[3-(4-Methoxyphenyl)-3-oxo-1-phenylpropyl]acetamide (3g). M.p. 128 – 1298 ([22]: 128 – 1318).
IR (KBr): 3270 (NꢀH), 1676 (C¼O), 1646 (C¼O). 1H-NMR (400 MHz, CDCl3): 2.06 (s, 3 H); 3.39 (dd,
J ¼ 16.6, 5.6, 1 H); 3.73 (dd, J ¼ 16.4, 5.2, 1 H); 3.89 (s, 3 H); 5.57 (dd, J ¼ 13.2, 5.6, 1 H); 6.86 (br. d, J ¼
7.6, 1 H); 6.94 (d, J ¼ 8.8, 2 H); 7.23 – 7.36 (m, 5 H); 7.92 (d, J ¼ 8.8, 2 H).13C-NMR (100 MHz, CDCl3):
23.5; 42.9; 50.1; 55.6; 113.9; 126.5; 127.4; 128.6; 129.7; 130.5; 141.2; 163.8; 169.6; 197.1.
N-[3-(4-Chlorophenyl)-3-oxo-1-phenylpropyl]acetamide (3h). M.p. 106 – 1088 ([23]: 107 – 1098). IR
(KBr): 3302 (NꢀH), 1689 (C¼O), 1646 (C¼O). 1H-NMR (400 MHz, CDCl3): 2.04 (s, 3 H); 3.42 (dd, J ¼
16.6, 6.4, 1 H); 3.76 (dd, J ¼ 16.6, 5.2, 1 H); 5.56 (dd, J ¼ 13.2, 6.0, 1 H); 6.67 (br. d, J ¼ 7.2, 1 H); 7.26 – 7.35
(m, 5 H); 7.44 (d, J ¼ 8.4, 2 H); 7.87 (d, J ¼ 8.4, 2 H).13C-NMR (100 MHz, CDCl3): 23.5; 43.3; 50.0;
126.5; 127.6; 128.8; 129.1; 129.6; 134.9; 140.0; 140.6; 169.6; 197.3.
N-[1-(4-Methoxyphenyl)-3-(4-nitrophenyl)-3-oxopropyl]acetamide (3i). M.p. 89 – 908 ([24]: 87 –
1
898). IR (KBr): 3279 (NꢀH), 1695 (C¼O), 1649 (C¼O). H-NMR (400 MHz, CDCl3): 2.03 (s, 3 H);
3.47 (dd, J ¼ 16.4, 7.2, 1 H); 3.80 (s, 3 H); 3.85 (dd, J ¼ 16.4, 5.2, 1 H); 5.48 (dd, J ¼ 12.4, 7.2, 1 H); 6.35
(br. d, J ¼ 7.2, 1 H); 6.87 (d, J ¼ 8.8, 2 H); 7.27 (d, J ¼ 8.8, 2 H); 8.11 (d, J ¼ 8.8, 2 H); 8.31 (d, J ¼ 8.8,
2 H).13C-NMR (100 MHz, CDCl3): 23.4; 44.4; 49.8; 55.3; 114.2; 123.9; 127.9; 129.3; 132.3; 141.0; 150.4;
159.1; 169.7; 196.8.
N-[1-(2-Chlorophenyl)-3-(4-methoxyphenyl)-3-oxopropyl]acetamide (3l). M.p. 154 – 1558 ([23]:
1
155 – 1568). IR (KBr): 3266 (NꢀH), 1681 (C¼O), 1643 (C¼O). H-NMR (400 MHz, CDCl3): 2.06 (s,
3 H); 3.40 (dd, J ¼ 16.4, 5.2, 1 H); 3.69 (dd, J ¼ 16.2, 6.0, 1 H); 3.88 (s, 3 H); 5.81 (dd, J ¼ 13.4, 6.0, 1 H);
6.92 (d, J ¼ 8.8, 2 H); 7.12 – 7.29 (m, 3 H); 7.35 (d, J ¼ 8.8, 1 H); 7.45 (d, J ¼ 7.6, 1 H); 7.89 (d, J ¼ 8.8,
2 H).13C-NMR (100 MHz, CDCl3): 23.4; 40.9; 48.2; 55.6; 113.9; 127.0; 128.2; 128.6; 129.6; 129.9; 130.6;
132.4; 138.3; 164.0; 169.3; 197.5.
N-[3-(4-Bromophenyl)-1-(2-methoxyphenyl)-3-oxopropyl]acetamide (3m). M.p. 156 – 1578 ([25]:
1
161 – 1628). IR (KBr): 3311 (NꢀH), 1692 (C¼O), 1649 (C¼O). H-NMR (400 MHz, CDCl3): 2.02 (s,
3 H); 3.45 (dd, J ¼ 15.6, 6.4, 1 H); 3.56 (dd, J ¼ 15.2, 5.2, 1 H); 3.90 (s, 3 H); 5.69 – 5.75 (m, 1 H); 6.84 (br.
d, J ¼ 7.2, 1 H); 6.88 – 6.95 (m, 2 H); 7.23 – 7.30 (m, 2 H); 7.58 (d, J ¼ 8.0, 2 H); 7.80 (d, J ¼ 8.0, 2 H).
13C-NMR (100 MHz, CDCl3): 23.6; 43.2; 48.0; 55.4; 110.8; 120.9; 128.0; 128.4; 128.7; 128.9; 129.8; 131.9;
135.4; 156.6; 169.2; 197.6.
N-[2-Methyl-1-(4-methylphenyl)-3-oxobutyl]acetamide (3n). Major isomer. M.p. 114 – 1158 ([26]:
1128). IR (KBr): 3295 (NꢀH), 1711 (C¼O), 1648 (C¼O). 1H-NMR (400 MHz, CDCl3): 1.19 (d, J ¼ 7.2,
3 H); 2.02 (s, 3 H); 2.05 (s, 2 H); 2.33 (s, 3 H); 3.11 (quint., J ¼ 6.4, 1 H); 5.15 (dd, J ¼ 8.6, 6.0, 1 H); 7.01
(d, J ¼ 8.6, 1 H); 7.10 – 7.18 (m, 4 H). 13C-NMR (100 MHz, CDCl3): 15.3; 21.1; 23.4; 28.9; 29.8; 51.3; 55.1;
126.2; 129.3; 137.1; 137.6; 169.9; 213.8.
N-[2-Methyl-1-(4-methylphenyl)-3-oxo-3-phenylpropyl]acetamide (3o). Major isomer. M.p. 147 –
1498 ([26]: 1598). IR (KBr): 3235 (NꢀH), 1682 (C¼O), 1645 (C¼O). 1H-NMR (400 MHz, CDCl3):
1.26 (d, J ¼ 6.8, 3 H); 1.97 (s, 3 H); 2.28 (s, 3 H); 4.09 (quint., J ¼ 7.2, 1 H); 5.49 (t, J ¼ 8.4, 1 H); 6.48 (br. d,
J ¼ 8.4, 1 H); 7.08 (d, J ¼ 7.6, 2 H); 7.22 (d, J ¼ 8.0, 2 H); 7.45 (t, J ¼ 7.6, 2 H); 7.56 (t, J ¼ 7.2, 1 H); 7.90 (d,
J ¼ 7.2, 2 H). 13C-NMR (100 MHz, CDCl3): 14.0; 21.1; 23.4; 45.7; 54.8; 126.9; 128.2; 128.8; 129.3; 133.2;
136.4; 137.1; 137.6; 169.7; 202.1.
N-[1-(4-Chlorophenyl)-2-methyl-3-oxo-3-phenylpropyl]acetamide (3q). Major isomer. M.p. 161 –
1628 ([26]: 1628). IR (KBr): 3268 (NꢀH), 1682 (C¼O), 1651 (C¼O). 1H-NMR (400 MHz, (D6)DMSO):
1.16 (d, J ¼ 6.8, 3 H); 1.89 (s, 3 H); 4.10 (quint., J ¼ 6.8, 1 H); 5.28 (t, J ¼ 8.8, 1 H); 7.29 (d, J ¼ 8.4, 2 H);
7.35 (d, J ¼ 8.4, 2 H); 7.48 (t, J ¼ 8.0, 2 H); 7.59 (t, J ¼ 7.6, 1 H); 7.83 (d, J ¼ 8.0, 2 H); 8.44 (t, J ¼ 9.2, 1 H).
13C-NMR (100 MHz, (D6)DMSO): 15.1; 23.1; 45.6; 54.2; 128.3; 128.6; 129.3; 129.6; 131.9; 133.7; 136.5;
141.5; 169.2; 202.1.
Methyl 2-[(Acetamido)(phenyl)methyl]-3-oxobutanoate (3r). Major isomer. M.p. 158 – 1598 ([26]:
1
129 – 1318). IR (KBr): 3330 (NꢀH), 1746 (C¼O), 1719 (C¼O). H-NMR (400 MHz, CDCl3): 2.01 (s,

Helvetica Chimica Acta – Vol. 96 (2013)
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3 H); 2.17 (s, 3 H); 3.71 (s, 3 H); 4.11 (d, J ¼ 6.0, 1 H); 5.77 (dd, J ¼ 9.0, 6.0, 1 H); 7.08 (br. d, J ¼ 8.8,
1 H); 7.25 – 7.35 (m, 5 H). 13C-NMR (100 MHz, CDCl3): 23.4; 30.8; 52.3; 52.8; 62.5; 126.5; 127.8; 128.8;
139.2; 167.8; 169.6; 203.9.
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Received October 13, 2012