One-pot three-component synthesis of β-acetamido carbonyl compounds catalyzed by heteropoly acids

Article abstract of DOI:10.1007/s00706-011-0669-1

A simple one-pot method for a new Mannich-type reaction is reported. In this method a heteropoly acid is used as a catalyst for the synthesis of β-acetamido carbonyl compounds via a three-component reaction of an aldehyde, acetamide, and dimedone in acetonitrile at room temperature. This method offers several advantages such as good yields, simple procedure, low cost, and ease of workup. Springer-Verlag 2011.

Full text of DOI:10.1007/s00706-011-0669-1

Monatsh Chem (2012) 143:831–834
DOI 10.1007/s00706-011-0669-1
ORIGINAL PAPER
One-pot three-component synthesis of b-acetamido carbonyl
compounds catalyzed by heteropoly acids
•
Ali Javid Majid M. Heravi Fatemeh F. Bamoharram
•
Received: 17 June 2010 / Accepted: 3 October 2011 / Published online: 9 November 2011
Ó Springer-Verlag 2011
Abstract A simple one-pot method for a new Mannich-
type reaction is reported. In this method a heteropoly acid is
used as a catalyst for the synthesis of b-acetamido carbonyl
compounds via a three-component reaction of an aldehyde,
acetamide, and dimedone in acetonitrile at room tempera-
ture. This method offers several advantages such as good
yields, simple procedure, low cost, and ease of workup.
of novel MCRs and modification of them have attracted
much attention in medicinal chemistry and drug discovery.
The development of new MCRs is an ideal target of
research in current organic chemistry [1]. The Biginelli
[2, 3], Ugi [4, 5], Passerini [6], and Mannich [7, 8] reac-
tions are some examples of MCRs. Mannich reaction is an
aminoalkylation reaction of aldehydes and is a very useful
method for the preparation of b-amino compounds. Also, it
is a very important basic reaction in organic synthesis [9].
b-Acetamido carbonyl compounds can be used as pre-
cursors of 1,3-amino alcohols, b-amino acids, and c-lactams
[10–13]. Some of them also have shown biological and
pharmaceutical properties and were used in the preparation
of antibiotic drugs such as nikkomycin or neopolyoxins
[14]. Recently it was reported that b-acetamido ketones can
act as a-glucosidase inhibitors [15]. In 1928, Dakin et al.
[16] first reported the synthesis of these kinds of compounds
via the so-called Dakin–West reaction. This reaction
involves the condensation of an a-amino acid and acetic
anhydride in the presence of a base. In recent years, Iqbal
et al. [17–19] synthesized this class of compounds by one-
pot MCRs that involve an aldehyde, enolizable ketone or
keto ester, acetonitrile, and acetyl chloride in the presence
of CoCl2 and montmorillonite K-10 clay as a catalyst.
Afterwards, a number of catalyst systems were reported for
the synthesis of b-acetamido carbonyl compounds via the
same reaction, including ZrOCl2ꢀ8H2O [20], silica-sup-
ported sulfuric acid [21], Cu(OTf)2 [22], SiCl2–ZnCl2 [23],
Amberlyst 15 [24], I2 [25], heteropoly acids (HPAs) [26, 27],
ZnO [28], and SnCl2ꢀ2H2O [29]. Recently, cellulose
sulfuric acid [30] was also used to accelerate this reaction.
Because b-acetamido carbonyl compounds have become
increasingly useful and important in the field of pharma-
ceuticals, introduction of new and green catalysts is still
much in demand.
Keywords Multicomponent reaction (MCR) ꢀ
Dimedone ꢀ Aldehyde ꢀ b-Acetamido ketones ꢀ
Solid acid catalyst ꢀ Mannich-type reaction
Introduction
Multicomponent reactions (MCRs) are one of the most
important protocols in organic synthesis and medicinal
chemistry. In these reactions, three or more compounds are
used as starting materials. These processes consist of two
or more synthetic steps in a one-pot reaction without
necessity to isolate any intermediates. Thus, they are facile
and simple procedures, very fast, efficient, eco-friendly,
and acceptable for green chemistry. Therefore, the design
A. Javid (&)
Department of Chemistry, Ahvaz Branch,
Islamic Azad University, Ahvaz, Iran
e-mail: alijavids@yahoo.com
M. M. Heravi
Department of Chemistry, Alzahra University,
Vanak, Tehran, Iran
F. F. Bamoharram
Department of Chemistry, Mashhad Branch,
Islamic Azad University, Mashhad, Iran
123

832
A. Javid et al.
Theoretically, because amines are able to produce b-
reaction of the amine component with the protonated none-
nolizable aldehyde (or ketone) to give a hemiaminal. After
proton transfer and elimination of a water molecule, the
electrophilic iminium ion is obtained. The formed iminium
ion then reacts with the enolized carbonyl compound
(nucleophile) at its a-carbon in an aldol-type reaction to give
rise to the Mannich base. HPA might promote the reaction by
accelerating the formation of the C=N bond in the iminium
ionintherate-determining step(Scheme 2). Itisworthnoting
amino ketones and keto esters through Mannich reaction,
acetamide could similarly afford corresponding b-acetamido
ketones and keto esters through this type of reaction. How-
ever, in fact the classical Mannich reaction using amides is
not promising and fruitful, probably due to the low reactivity
and nucleophilicity of amides compared with amines. Pre-
viously, amides were used as nucleophiles in reactions with
aldehyde in order to form N,N0-(methylene)diacetamide
through a Mannich-type reaction in the presence of Lewis
acids such as CF3SO3H [31] and trimethylchlorosilane
(TMSCl) [32], or in the absence of catalyst with long reaction
times under reflux conditions [33]. Recently, Mao and
co-workers reported an efficient Mannich-type MCR to pre-
pare b-acetamido carbonyl compounds from aldehydes,
acetamide, and enolizable ketones (acetylacetone or aceto-
phenone) or b-keto esters in the presence of TMSCl as a
catalyst and 5–10 h reflux conditions [34].
1
that the H NMR spectra of the products show that in the
keto–enol tautomerization, the enol is the dominant form.
However, this is compatible with the fact that 1,3-dicarbonyl
compounds exist predominantly in the enol form in acidic
conditions. This is due to the generation of a conjugated p
systemandtheformationof an intramolecularhydrogenbond
that stabilizes the enol form [47].
The three-component condensation reaction of benzalde-
hyde (1a), acetamide (2), and dimedone (3) in the presence of
a catalytic amount of several acids was chosen as a model
reaction (Table 1). The reaction does not occur in the absence
of the catalyst (Table 1, entry 1). Also, no target product was
formed when HCl was used as a catalyst (Table 1, entry 2).
However, the reaction was completed when HPAs were used
as a catalyst (Table 1, entries 3–5). Our further investigation
showed that Keggin-type 12-tungstophosphoric acid,
H3[PW12O40], has higher catalytic activity than the other
Keggin-type HPAs (H4[SiW12O40] and H4[SiMo12O40]).
Although it is difficult to offer an explanation for the different
activities of these HPAs, there is a complex relationship
between the activity and structure of the polyanion. By
changing the constituent elements of the polyanion (both
hetero and addenda atoms), the acid strength of HPA as well
as its catalytic activity is varied over a wide range [35]. This
behavior is in agreement with the acid strength of Keggin-
type HPAs that decreases in the series H3[PW12O40] [
H4[SiW12O40] [ H4[SiMo12O40] [35]. The best molar ratio
of aldehyde/acetamide/dimedone/HPA was found to be
2:2.2:2.2:0.05.
In the last few decades, HPAs have found numerous
applications as useful and versatile acid catalysts for some
acid-catalyzed reactions. HPAs are more reactive catalysts
than conventional inorganic and organic acids for reactions
in solution. They are solids which are insoluble in nonpolar
solvents but highly soluble in polar ones. HPAs can be used
in bulk or supported forms in both homogeneous and het-
erogeneous systems. HPAs are nontoxic, highly stable
towards humidity, air stable, recyclable, nonexplosive,
easy to handle, compatible with the environment, and
experimentally simple [35].
Results and discussion
In this study and in continuation of our works with HPAs as
a catalyst in organic reactions [36–44], we wish to report
the synthesis of a family of b-acetamido carbonyl com-
pounds (4a–4i) via a Mannich-type three-component
condensation of an aldehyde (1), acetamide (2), and
dimedone (3) in the presence of the Keggin-type HPAs
Hn[XM12O40] (n = 3, 4; X = PV, SiIV; M = WVI, MoVI)
at room temperature (Scheme 1).
Because of the complexity of the behavior of this cat-
alyst in a solvent, we also studied the rate and yield of the
reaction in different solvents such as acetonitrile, ethanol,
dichloromethane, and water (Table 2). We concluded that
acetonitrile is the most suitable solvent for this reaction.
The results of our work are presented in Table 3. It is
clear that aromatic aldehydes with both electron-donating
The mechanism of the Mannich reaction has been exten-
sively investigated [45, 46]. The reaction can proceed under
both acidic and basic conditions, but acidic conditions are
more common. Under acidic conditions the first step is the
Scheme 1
NHAc O
O
O
CHO
HPA
+ CH3CONH2
+
CH3CN/rt
5-6h
O
G
G
1a-1i
2
3
4a-4i
123

One-pot three-component synthesis
833
Scheme 2
OH
OH2
O
O
O
-H2O
N
H2N
HPA
H
Proton
transfer
Hemiaminal
G
G
G
O
O
OH
O
NH
O
NH OH
O
N
H
Iminiumion
O
O
G
G
G
Table 3 Mannich-type three-component synthesis of b-acetamido carbonyl
compounds using a catalytic amount of H3[PW12O40
Table 1 Synthesis of N-[(4,4-dimethyl-2,6-dioxocyclohexyl)(phenyl)
methyl]acetamide in the presence of various acid catalysts
]
Yield/%a
Entry Aldehyde
Product Yield/%a M.p./°C Ref. m.p./°C
Entry
Catalyst
Time/h
1
2
3
4
5
6
7
8
9
a
C6H5CHO
4a
4b
4c
4d
78
74
82
78
85
86
80
74
76
208–210 200 [30]
190–193 105 [30]
198–201 195 [30]
193–195 147 [30]
212–215 188 [30]
196–199 198 [30]
1
2
3
4
5
None
24
24
5
0
0
4-CH3C6H4CHO
4-ClC6H4CHO
3-ClC6H4CHO
HCl
H3[PW12O40
]
78
56
38
H4[SiW12O40
]
6
4-CH3OC6H4CHO 4e
2-CH3OC6H4CHO 4f
H4[SiMo12O40
]
10
Reaction of benzaldehyde (2 mmol), acetamide (2.2 mmol), and
dimedone (2.2 mmol) in 10 cm3 acetonitrile as solvent, in the pres-
ence of different acid catalysts (0.05 mmol) at room temperature
4-HOC6H4CHO
3-HOC6H4CHO
2-HOC6H4CHO
4g
4h
4i
192–194
189–192
195–197
–
–
–
a
Isolated yields
Isolated yields after 5–6 h
Table 2 Effect of various solvents in the synthesis of N-[(4,4-
dimethyl-2,6-dioxocyclohexyl)(phenyl)methyl]acetamide
carbonyl compounds that were prepared via a new Man-
nich-type three-component reaction of aryl aldehydes,
acetamide, and dimedone in acetonitrile at room tempera-
ture in good yields and relatively short reaction time.
Entry
Solvent
Yield/%a
1
2
3
4
H2O
No reaction
EtOH
32
CH2Cl2
CH3CN
Trace
78
Experimental
Reaction of benzaldehyde (2 mmol), acetamide (2.2 mmol), and
dimedone (2.2 mmol) in 10 cm3 solvent, in the presence of
H3[PW12O40] catalyst (0.05 mmol) at room temperature
All chemicals were obtained from Merck and used as
received. Melting points were measured by using the cap-
illary tube method with an electrothermal 9200 apparatus.
1H NMR spectra were recorded on a Bruker AQS
AVANCE-500 MHz spectrometer using TMS as an internal
standard. Thin-layer chromatography (TLC) on commercial
aluminum-backed plates of silica gel, 60 F254, was used to
monitor the progress of reactions.
a
Isolated yields after 5–6 h
and electron-withdrawing groups readily undergo the
reaction giving good yields of corresponding Mannich
reactions, except for an aldehyde containing a nitro group
at the para position. We think that it gives the Knoevenagel
condensation product rather than our desired product [34].
Steric demands of ortho-substituted aromatic aldehydes are
also well tolerated.
Preparation of N-[(4,4-dimethyl-2,6-
dioxocyclohexyl)(aryl)methyl]acetamides
To
a
solution of aldehyde (2 mmol), acetamide
(2.2 mmol), and dimedone (2.2 mmol) in 10 cm3 acetoni-
trile was added HPA (0.05 mmol). The mixture was stirred
for 5–6 h at room temperature. After completion of the
reaction (the progress of the reaction was monitored by
Conclusion
We have used Keggin-type HPAs as efficient and green
catalysts for the synthesis of a family of b-acetamido
123

834
A. Javid et al.
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N-[(4,4-Dimethyl-2,6-dioxocyclohexyl)(4-hydroxy-
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Yield 80%; m.p.: 192–194 °C; 1H NMR (500 MHz,
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2.27 (4H, br s, 2CH2), 6.2 (1H, d, J = 9.2 Hz, PhCH),
6.81–7.25 (4H, m, Ph), 7.9 (1H, d, J = 9.2 Hz, NH), 8.73
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41.12, 46.02, 114.59, 122.71, 125.31, 126.40, 126.73,
130.11, 147.51, 166.04 ppm; MS: m/z = 303 (M?), 260,
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