Green one-pot multicomponent synthesis, biological evaluation and theoretical investigations of some novel β-acetamido ketone derivatives as potent cholinesterase inhibitors

Article abstract of DOI:10.1016/j.tet.2020.131260

A series of novel β-acetamido ketones have been prepared via a four-component condensation between aromatic aldehydes, enolizable ketones, acyl chloride and acetonitrile in the presence of 10 molpercent of phenylboronic acid as a catalyst. The expected pr

Full text of DOI:10.1016/j.tet.2020.131260

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Green one-pot multicomponent synthesis, biological evaluation and theoretical
investigations of some novel β-acetamido ketone derivatives as potent cholinesterase
inhibitors
Adil Ziadi Chibane, Raouf Boulcina, Houssem Boulebd, Chawki Bensouici,
Muhammet Yildirim, Abdelmadjid Debache
PII:
S0040-4020(20)30403-8
https://doi.org/10.1016/j.tet.2020.131260
TET 131260
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 19 March 2020
Revised Date: 20 April 2020
Accepted Date: 5 May 2020
Please cite this article as: Chibane AZ, Boulcina R, Boulebd H, Bensouici C, Yildirim M, Debache A,
Green one-pot multicomponent synthesis, biological evaluation and theoretical investigations of some
novel β-acetamido ketone derivatives as potent cholinesterase inhibitors, Tetrahedron (2020), doi:
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Graphical Abstract
Green one-pot multicomponent synthesis,
Leave this area blank for abstract info.
biological
evaluation
and
theoretical
investigations of some novel
β
-acetamido
ketone derivatives as potent cholinesterase
inhibitors.
Adil Ziadi Chibane, Raouf Boulcina, Houssem Boulebd
Chawki Bensouici, Muhammet Yildirim,
and Abdelmadjid Debache
O
Ar
O
2
O
One-Pot Synthesis
HN
Me
O
R1
R2
R1
R2
Me
+
O
3
Ar
PhB(OH)2
Me
Cl
CH3CN, R.T
4
1
R1= H, B(OH)2
R2= H, Me, NO2, B(OH)2
AChE inhibition (IC50): up to 61.64 µg/mL
BChE inhibition (IC50): up to 4.47 µg/mL
DFT calculations
Ar= C6H5, 4-Br-C6H4, 2,4-(CH3)2-C6H3,
4-CH3-C6H4, 4-B(OH)2-C6H4, 2-Naphtyl, ...

1
Tetrahedron
journal homepage: www.elsevier.com
Green one-pot multicomponent synthesis, biological evaluation and
theoretical investigations of some novel β-acetamido ketone derivatives as
potent cholinesterase inhibitors.
Adil Ziadi Chibanea, Raouf Boulcinaa,*, Houssem Boulebda, Chawki Bensouicib, Muhammet Yildirimc,
and Abdelmadjid Debachea,
a Laboratory of Synthesis of Molecules with Biological Interest, Mentouri-Constantine 1 University, 25000 Constantine, Algeria.
b Biotechnology Research Center,25000 Constantine, Algeria.
c Department of Chemistry, Faculty of Sciences and Arts, Bolu Abant Izzet Baysal University,14030 Bolu, Turkey.
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A series of novel β-acetamido ketones have been prepared via a four-component condensation
between aromatic aldehydes, enolizable ketones, acyl chloride and acetonitrile in the presence of
10 mol% of phenylboronic acid as a catalyst. The expected products have been obtained in good
to excellent yields. In addition, the in vitro cholinesterase inhibitory activity of title compounds
has been studied and the results indicated that some compounds exhibited remarkable BChE
activity. In order to gain insights into the molecular structure and chemical reactivity of the
synthesized β-acetamido ketones, density functional theory (DFT) calculations were also carried
out.
Available online
Keywords:
Multicomponent reaction
Phenylboronic acid
β-acetamido ketones
Cholinesterase inhibitory
DFT calculations
2009 Elsevier Ltd. All rights reserved.
presence of cobalt(II) chloride as catalyst.15 Since then,
this reaction has been extensively studied applying various
homogenous or heterogenous catalysts such as PCl3,16
1. Introduction:
β-Acetamido ketones possess very interesting biological
properties such as antimicrobial,1 antidiabetic,2 anti-
cancer,3 HIV protease inhibitors,4 and antifungal.5 They
have been also used as glycosidase inhibitors.6 In addition,
β-acetamido ketones are usually employed as suitable
intermediates for the synthesis of 1,3-aminoacids,7 1,3-
amino alcohols8 and they also constitute a structural unit of
natural antibiotic peptides.9
ZnO,17 I2,18 BiCl3,19 FeCl3,20 CoCl2,21 CeCl3·7H2O,22
SnCl4/SiO2,23
Cu(OTf)2/Sc(OTf)3,24
ZrOCl2·8H2O,25
NaHSO4·H2O,26 Co(HSO4)3 and Zn(HSO4)3,27 silica
supported perchloric acid,28 heteropoly acid,29 Silver(1)
triflate,30 Trifluoroacetic acid,31 and L-proline.32 Some of
these methods suffer from some disadvantages such as
long reaction times, dangerous catalysts or too high
temperatures.
The best-known classical method for the preparation of β-
acetamido ketones is the Dakin-West reaction10 between
amino acid and ester anhydride in the presence of a base.
Some other synthetic methods providing the β-acetamido
ketones are the photo-isomerization of phthalimides,11
Michael addition to α,β-unsaturated ketones12 and
acylation of β-amino ketones13 which were reported in
recent literature.
In the continuation of our research program directed
toward the development of new synthetic methods for the
preparation of a variety of heterocyclic compounds via
mild and environmentally benign conditions,33 we propose
herein the synthesis of some new acetamido ketones by the
method proposed by Bhatia et al.14 using phenylboronic
acid as a common, available, low toxic, inexpensive,
environmentally friendly and easy-to-handle catalyst
(Scheme 1).
In 1994, Bhatia et al.14 described an important method to
access this important class of compounds via a four-
component reaction between aromatic aldehydes,
enolisable ketone, acyl chloride and acetonitrile in the
———
Corresponding authors. Tel.: +0-213-318-111-77; e-mails: a_debache@yahoo.fr (A. Debache), r.boulcina@univ-batna2.dz (R. Boulcina)

2
Tetrahedron
Scheme 1. Phenylboronic acid-Catalyzed synthesis of β-acetamido ketones
2. Results and discussions:
2.1. Chemistry
(PPTS) and phenylboronic acid to see whether the
reaction promote or not. The results showed that
phenylboronic acid led to the formation of 4a with
a yield of 75% after 3 hours (Table 1, entry 3),
while PPh3 (entry 1) and PPTS (Entry 2) gave 50%
and 70% after 6 hour reactions, respectively. It is
also worth to mention that when multi-component
condensation was carried out without any catalyst
at room temperature it provided trace amounts of
expected product 4a (Entry 4). Consequently, we
have chosen phenylboronic acid as a suitable
In order to carry out the reaction and optimize the
conditions, a model reaction including equimolar
ratios of 4-methylacetophenone 1a, benzaldehyde
2a, acyl chloride 3 in 3 mL of acetonitrile and 10
mol% of catalyst at room temperature was chosen.
This reaction was subjected to different conditions
and the results were summarized in Table 1.
homogenous catalyst for this reaction affording
Acetamido ketones.
β-
We first tried the catalytic activity of
triphenylphosphine, pyridinium p-toluenesulfonate
Table 1. Optimization of the reaction conditions and yieldsa
Entry
Solvent
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
Catalyst
PPh3
PPTS
PhB(OH)2
-
PhB(OH)2
PhB(OH)2
PhB(OH)2
PhB(OH)2
PhB(OH)2
mol (%)
Time (h)
T (°C)
25
25
25
25
25
25
25
25
Yield (%)b
1
2
3
4
5
6
7
8
9
10
10
10
-
6
6
3
72
3
3
3
3
3
50
70
75
Trace
33
29
18
16
37
5
15
20
30
10
50
a The reactions were carried out by the condensation of 4-methyacetophenone (1 equiv), benzaldehyde (1 equiv), acyl chloride (1.5 equiv)
and 3 ml of acetonitrile. b Isolated yields.
In order to find out the optimal amount of the catalyst,
we carried out the model reaction using 5, 15, 20 and 30
mol% of phenylboronic acid and the expected product
4a is obtained in 33, 29, 18 and 16% yields respectively
(Table 1, Entries 5-8). However, the reaction with 10
mol% of PhB(OH)2 at 50°C furnished only the desired
product in 37% yield (Table 1, Entry 9). Therefore, the
optimal conditions for the synthesis of β-acetamido
ketone 4a via a four-component reaction between 4-
methylacetophenone, benzaldehyde, and acetyl chloride
in acetonitrile required 10 mol% of phenylboronic acid
as a homogenous catalyst at room temperature (Table 1,
entry 3).
Thereafter, we applied the optimal conditions to the
reactions of a variety of aromatic aldehydes and some
substituted acetophenone derivatives in the presence of
phenyl boronic acid. The obtained results were also
summarized in Table 2. Thus, three series of new β-
acetamido ketones have been prepared using 4-
methylacetophenone (Table 2, entries 1-8), and 4-
nitroacetophenone (Entries9-14), 4-acetylphenylboronic
acid (Entry 15) and 3-acetylphenylboronic acid (Entries
16-18).
Table 2 shows that whatever the nature of substituent on
the acetophenone or the aldehyde, the expected
products were obtained in good to excellent yields (65-
98%) with only two exceptions (4b and 4i) which are
obtained in 60 and 46% yields. In fact, the use of 4-
methylacetophenone resulted product yields over 60 to
95% due to electron donation effect of methyl group.
However, when the methyl group was replaced with an
electron-withdrawing nitro substituent, the reactions
also led to good yields ranging from 46 to 98% (Table
2, Entries 7-12). β-Acetamido ketones 4p-4r with a
boronic acid group at 3-position were obtained in good
yields (78-73-81%) (Table 2, entries 16-18). While
most of the reactions affording the title compounds (4a-
n) completed within 1.5-3.5 hour, the reactions with
borylated acetophenone derivatives required much
longer reaction times to complete (Table 2, entries 15-
18).

3
Table 2. Synthesis of β-acetamido ketones 4a–o catalyzed by PhB(OH)2 at room temperaturea
Entry
R1
R2
Ar
Product
Time (h)
Yield (%)b
M.p (°C)
Measured
Reported
1
H
Me
Me
Me
Me
Me
Me
Me
Me
NO2
NO2
NO2
NO2
NO2
NO2
B(OH)2
H
C6H5
4a
4b
4c
4d
4e
4f
3
75
60
78
87
95
78
92
75
46
95
80
98
97
98
65
78
73
81
114-116
144-146
104-106
108-110
117-119
162-164
156-158
116-118
102-104
76-78
121-12334a
2
H
4-Br-C6H4
3.5
2
145-14630
3
H
2,4-(CH3)2-C6H3
4-CH3-C6H4
3-CH3-C6H4
4-B(OH)2-C6H4
3-B(OH)2-C6H4
2-Naphtyl
-
4
H
3
117-11934b
5
H
3
113.6-115.331
6
H
2
-
7
H
4g
4h
4i
2
-
8
H
1.5
3
110-11234b
9
H
C6H5
96-9834a
10
11
12
13
14
15
16
17
18
H
4-CH3-C6H4
4-Br-C6H4
4j
2
83-8534c
H
4k
4l
2.5
2
142-144
162-164
157-159
136-138
178-180
156-158
164-166
165-167
141-14328
H
4-B(OH)2-C6H4
3-B(OH)2-C6H4
2-Naphtyl
-
-
-
-
-
-
-
H
4m
4n
4o
4p
4q
4r
2
H
1.5
24
24
24
24
H
4-Br-C6H4
B(OH)2
B(OH)2
B(OH)2
4-Br-C6H4
H
4-Cl-C6H4
H
4-NO2-C6H4
aAll reactions were carried out by the condensation of acetophenones 1 (1 equiv.), aldehydes 2 (1 equiv.), acyl chloride 3 (1.5 equiv.) and 10 mol% of
PhB(OH)2 in acetonitrile (3 ml) at room temperature. bIsolated yields.
A plausible mechanism can be proposed for the formation
of β-acetamido ketones 4 (Scheme 2). This involves first
the formation of intermediate A with the support of
boronic acid catalyst that complexes with acyl chloride 3
and this makes easier the attack on the aldehyde 2.
Condensation of A with acetonitrile leads to the formation
of another key intermediate B which reacts with the enol
form of acetophenone 1 to furnish C. The removal of
hydrogen chloride and acetate molecules by hydrolysis
provides N-(3-oxo-1,3-diphenylpropyl)acedimic acid D
whose tautomerization results in the title compound 4.
2.2.
Biology
Examination of Table 4 shows that compounds tested have
moderate AChE activity with IC50 values varying between
61.64 ± 1.66 μg/mL for 4l and 122.36 ± 1.50 μg/mL for 4m.
On the other hand, all studied compounds exhibited
remarkable BChE activity with IC50 values ranging from
4.47
±
0.08 μg/mL to 101.63
±
0.15 μg/mL.

4
Tetrahedron
Scheme 2. Plausible mechanism for the formation of β-acetamido ketones catalyzed by phenylboronic acid.
Surprisingly, some derivatives such as 4p and 4q with
remarkable IC50 values of 4.47 ± 0.08, and 6.96 ± 0.04
μg/mL have the stronger inhibitory capacities than the
standard reference drug, Glantamine, whose IC50
under the conditions of study is 10.85 ± 0.22 μg/mL.
The other derivatives gave also interesting and lower
values than that of standard drug, galanthamine.
Table 4.The
inhibitory
Compound
AChE
BChE
IC50 (µg/mL)a
Selectivityb
IC50 (µg/mL)a
Selectivityc
4f
4g
4l
4m
4o
4p
> 200
> 200
61.64 ± 1.66
122.36 ± 1.50
>200
>200
>200
6.27±1.15
0.226
0.198
1.649
0.483
0.063
0.022
0.035
1.73
45.28 ± 0.87
39.5 ± 0.58
101.63 ± 0.15
59.08 ± 1.20
12.61 ± 0.32
4.47 ± 0.08
6.96 ± 0.04
10.85 ± 0.22
4.417
5.063
0.607
2.071
15.86
44.743
28.736
0.578
4q
Galantamined
concentration (IC50), calculated Binding energy and selectivity of selected β-acetamido ketones 4 investigated against AChE and BChE.
b
aIC50 values expressed are means ± SD of three parallel measurements (p <0.05). Selectivity for AChE defined as
IC50(BChE)/IC50(AChE). c Selectivity for BChE defined as IC50(AChE)/IC50(BChE).
Firstly, a full geometry optimization has been
performed and all the possible conformers of
compound (S)-4a have been studied. Fig. 1 shows
the obtained most stable conformers. As can be
seen from Fig. 1, compound (S)-4a, in both
2.3. Theoretical investigations
In order to gain insights into the molecular structure
of the synthesized β-acetamido ketones, density
functional theory (DFT) calculations at B3LYP/6-
311++G(d,p) level of theory was carried out for
compound (S)-4a as a representative molecule.
conformations, adopts
a non-planar structure.
Conformer 2 presents an intramolecular hydrogen

5
bond (IHB) between the NH and the acetophenone
carbonyl group (2.17 Å), while non IHB was found
for conformer 1. By comparison, conformer 1 is
slightly stable than conformer 2 by about 0.41
kcal/mol. This small energy suggests that both
conformers could exist in solution. The selected
geometry parameters of conformers 1 and 2 of
compound (S)-4a are listed in Table 5.
Fig. 1. The most stable conformers of compound (S)-4a obtained at B3LYP/6-311G++(d,p) level of theory.
distributions of the FMO of conformers of
The obtained molecular geometries for both
conformers of compound (S)-4a were used to
calculate some structural characteristics such as
frontier molecular orbitals, atomic polar tensor
charges, and molecular electrostatic potential
mapping. Frontier molecular orbitals (FMO) are
important parameters that provide useful
information for the reactivity of molecules as well
as electronic transitions within molecules.43 Highest
occupied molecular orbital (HOMO) is the easiest
orbital to donate electrons, whereas lowest
unoccupied molecular orbital (LUMO) is the easiest
orbital to accept electrons. The energy levels and
compound (S)-4a have been computed at B3LYP/6-
311G++(d,p) level of theory in the gas-phase. 3D
plots of HOMO/LUMO are shown in Fig. 2. The
results showed that the HOMOs of both the
conformers are mainly localized over the amide and
phenyl moieties, while the LUMOs are localized on
the acetophenone unit. These clearly elucidate the
transfer of electron density from the amide and
phenyl moieties to the acetophenone unit. The gap
energies of conformers 1 and 2 are, respectively,
4.77 eV and 4.62 eV, suggesting high kinetic
stability and low chemical reactivity.44-45

6
Tetrahedron
Fig. 2. Frontier molecular orbitals of conformers 1 and 2 of compound (S)-4a obtained in the gas-phase at B3LYP/6-311G++(d,p) level of
theory.
Electric charge distribution in molecules is related
to several physicochemical properties such as
electrostatic potential, chemical reactivity, stability,
oxygen atoms O9 and O19 as well as the N17 atom.
To visualise the charge distributions, molecular
electrostatic potential has been computed at the
same level of theory, and obtained 3D diagrams of
compound (S)-4a are shown in Fig. 3. Considering
the results, the most electron-rich sites for both the
conformers are located around the two carbonyl
oxygen atoms and the nitrogen atom. On the other
hands, the most electron-deficient sites are
distributed on around the carbonyl carbon atoms
and hydrogen atom of the NH bonds. These results
suggest that these sites are the preferred sites for
electrophilic and nucleophilic attacks, respectively.
solubility,
acid-base
properties,
vibrational
spectroscopy and dipole moment.46-47 The electric
charge distribution of the conformers of compound
(S)-4a have been computed at B3LYP/6-
311G++(d,p) level of theory in the gas-phase using
atomic polar tensor (APT) method. The obtained
results are shown in Fig. 3 and Table S1 in
supporting information. It was found that the
highest positive charges for both the conformers are
on the carbonyl carbon atoms C7 and C18, whereas
the highest negative charges are on the carbonyl
Fig. 3. Molecular electrostatic potential (MEP) and atomic polar tensor charges (APT) of conformers 1 and 2 of compound (S)-4a obtained
in the gas-phase at B3LYP/6-311G++(d,p) level of theory.
and low chemical softness have a high reactivity.
The electrophilic index can be interpreted as a
measure of energy lowering associated with a
maximum amount of electron flow between a donor
and an acceptor.50 All these molecular descriptors
were calculated for both conformers of compound
(S)-4a at B3LYP/6-311++G(d,p) level of theory in
the gas-phase, and the obtained results are shown in
Table 5. From the obtained results it is clearly
Electronegativity (χ), chemical hardness (η),
chemical softness (S) and electrophilic index (ω)
are also important parameters that characterize the
48-49
stability and reactivity of organic compounds.
Electronegativity is a physical quantity which
characterizes the capacity of a molecule to attract
electrons. The chemical hardness (η) and chemical
softness (S) are measure of resistance to charge
transfer. Compounds with high chemical hardness

7
observed that both the conformers of compound
(S)-4a have a high chemical hardness (2.31 and
2.39 eV) and low chemical softness (0.21 and 0.22
eV), suggesting low chemical reactivity and high
kinetic stability. The conformers have also
relatively high electronegativity (4.44 and 4.45) and
electrophilic index (4.16 and 4.27, indicating that
(S)-4a prefers to act as electron acceptor rather than
electron donor.38
Table 5. Molecular descriptors of conformers 1 and 2 of compound (S)-4a obtained in the gas-phase at B3LYP/6-311G++(d,p) level of
theory.
Molecular descriptors
(S)-4a conformer 1
(S)-4a conformer 2
(eV)
χ
4.45
2.39
0.21
4.16
4.44
2.31
0.22
4.27
η
S
ω
3. Conclusion
Chromatography System (Agilent 1200/6210) or
MicroTof–Q 98.
In this work, we report a simple procedure for the
preparation of β-acetamidoketones by four-
a
General procedure for the preparation of β-
component reaction between aromatic aldehydes,
enolizable ketones, acyl chloride and acetonitrile
promoted by phenylboronic acid as a homogenous
acetamidoketones:
In a 100-mL roud-bottomed flask, 1 mmol of
aldehyde, 1 mmol of acetophenone derivative, 2 mmol
of acetyl chloride in 3 ml of acetonitrile as solvent and
reagent were introduced in the presence of 10 mol% of
phenylboronic acid as catalyst. The reaction mixture
was left under magnetic stirring at room temperature.
When the reaction was completed (followed by TLC),
ice water was added to the mixture and it was left
under stirring for 20 minutes. The obtained solid was
then filtered and dried. If no solid was formed, the
mixture was extracted with ethyl acetate (2 x 10 mL),
the organic layers were dried over anhydrous
magnesium sulfate, filtered and evaporated to give the
desired product. All products were purified by
recrystallization from ethyl acetate / hexane (1/4).
catalyst,
available,
non-toxic,
inexpensive,
environmentally friendly and easy to handle. Selected
β-acetamidoketones were evaluated for the effect on
AChE and BChE. The results indicated that all
compounds revealed moderate inhibitory activity
against AChE, and some possessed high selectivity for
BuChE over AChE. Among them, compounds 4p and
4q revealed the strongest BChE inhibitory activity
with remarkable IC50 values of 4.47 ± 0.08, and 6.96 ±
0.04 μg/mL respectively and highest selectivity.
Theoretical investigations using DFT/B3LYP method
have been carried out in order to get insight on the
molecular structure and chemical reactivity of
compound (S)-4a as representative molecule.
4. Experimental part
4.1. Chemistry
General
All synthesized β-acetamido ketone derivatives were
fully characterized by 1H NMR, 13C NMR and HRMS
analyses.
N-(3-Oxo-1-phenyl-3-p-tolylpropyl) acetamide (4a):
1
Yield = 75 %. M.p. = 114-116 °C. H NMR (250
All the chemicals were purchased from the Sigma-
Aldrich and used without further purification. All
solvents used for spectroscopic and synthesis studies
were reagent grades and further purified by literature
methods. Thin layer chromatography (TLC) was
performed using mixture of EtOAc and hexane (1:2)
as eluents and silica gel 60 F254 (Merck) plates.
Melting points were determined on an Electrothermal
capillary fine control apparatus. 1H and 13C NMR
spectra were recorded on a Bruker Avance 400/100
MHz or Bruker Avance 250/62.9 MHz, in CDCl3 or
DMSO–d6. Chemical shifts (δ) are given in part per
million downfield from TMS as an internal standard
MHz, CDCl3, ppm) δ: 7.82 (d, 2H, J = 8.1 Hz), 7.36-
7.23 (m, 7H), 6.95 (d, 1H, J = 7.6 Hz, NH), 5.57 (q,
1H, J = 5.6 Hz), 3.73 (dd, 1H, J = 16.8 and J= 5.4 Hz),
3.41 (dd, 1H, J = 16.8 and J= 5.8 Hz), 2.41 (s ; 3H;
CH3), 2.02 (s, 3H, CH3). 13C NMR (62.9 MHz, CDCl3,
ppm) δ: 198.2, 169.7, 144.5, 141.3, 134.1, 129.4,
129.4, 128.6, 128.6, 128.3, 128.3, 127.4, 126.5, 126.5,
50.0, 43.1, 23.4, 21.7.
N-(3-Oxo-1-(4-bromophenyl)-3-p-tolylpropyl)
acetamide (4b): Yield = 60 %. M.p. = 144-146 °C. 1H
NMR (250 MHz, CDCl3, ppm) δ: 7.80 (d, 2H, J = 8.2
Hz), 7.74 (d, 2H, J = 8.2 Hz), 7.44-7.21 (m, 4H), 6.93
(d, 1H, J = 8.0 Hz, NH), 5.52 (q, 1H, J = 5.5 Hz),
3.71 (dd, 1H, J = 17.1 and J = 5.1 Hz), 3.39 (dd, 1H, J
= 17.1 and J = 5.8 Hz), 2.42 (s, 3H, CH3), 2.04 (s, 3H,
CH3). 13C NMR (62.9 MHz, CDCl3, ppm) δ: 198.2,
1
for H and 13C NMR. Coupling constants (J) values
were indicated in Hz. The chemicals were used as
obtained commercially. High Resolution Mass Spectra
(HRMS) were recorded with a High Resolution Time–
of–Flight Mass Spectrometer coupled with Liquid

8
Tetrahedron
169.6, 144.8, 140.3, 134.0, 131.7, 131.7, 129.5, 129.5,
128.3, 128.3, 121.2, 49.4, 42.7, 23.5, 21.8.
ppm) δ: 196.7, 168.3, 143.6, 141.8, 134.1, 132.6,
129.2, 129.2, 129.2, 128.4, 128.1, 128.1, 128.1, 127.3,
49.2, 44.5, 22.7, 21.2. HRMS (ESI-) m/z 324.14059
[M-H]-, calcd for C18H19BNO4: 324.14071.
N-(3-Oxo-1-(2,4-dimethylphenyl)-3-p-tolylpropyl)
acetamide (4c): Yield = 78 %. M.p. = 104-106 °C. 1H
NMR (400 MHz, DMSO-d6, ppm) δ: 8.24 (d, 1H ; J=
12.00 Hz), 8.05 (s, 1H), 7.84 (d, 2H, J= 8.0 Hz), 7.32
(d, 2H, J= 12.0 Hz), 7.23 (d, 1H, J= 8.0 Hz), 6.92 (s,
1H, NH), 5.51 (q, 1H, J= 20.0 Hz), 3.44 (dd, 1H, J =
24.0 and J = 12.0 Hz), 3.30 (dd, 1H, J = 24.0 and J =
8.0 Hz), 2.40 (s, 3H, CH3), 2.29 (s, 3H, CH3), 2.21 (s,
3H, CH3), 1.75 (s, 3H, CH3). 13C NMR (100 MHz,
DMSO-d6, ppm) δ: 197.2, 168.5, 144.0, 138.6, 136.0,
135.2, 134.5, 131.0, 129.6, 129.6, 128.5, 128.5, 126.9,
126.2, 45.5, 44.2, 23.0, 21.6, 20.9, 19.2.
N-(3-oxo-1-(naphth-2-yl)-3-p-tolylpropyl)
acetamide (4h): Yield = 46 %. M.p. = 166-168 °C. 1H
NMR (250 MHz, CDCl3, ppm) δ : 7.85-7.23 (m, 11H),
6.99 (d, 1H, J = 7.9 Hz, NH), 5.74 (q, 1H, J = 5.5 Hz),
3.81 (dd, 1H, J= 16.8 and J = 5.2 Hz), 3.35 (dd, 1H ;
J= 16.8 and J= 5.9 Hz), 2.41 (s, 3H, CH3), 2.06 (s, 3H,
CH3). 13C NMR (62.9 MHz, CDCl3, ppm) δ: 198.3,
169.7, 144.6, 138.5, 134.2, 133.3, 132.7, 129.5, 129.5,
128.5, 128.3, 128.3, 128.0, 127.7, 126.3, 126.0, 125.2,
124.8, 50.1, 43.1, 23.6, 21.8.
N-(3-Oxo-1-p-tolyl-3-p-tolylpropyl) acetamide (4d):
Yield = 78 %. M.p. = 108-110 °C. H NMR (250
N-(3-oxo-1-phenyl-3-p-nitrophenylpropyl)
acetamide (4i): Yield = 75 %. M.p. = 102-104 °C. 1H
NMR (250 MHz, CDCl3, ppm) δ : 8.29 (d, 2H, J= 8.4
Hz), 8.07 (d, 2H, J= 8.4 Hz), 7.40-7.20 (m, 5H), 6.56
(s, 1H, NH), 5.55 (q, 1H, J= 5.9 Hz), 3.84 (dd, 1H, J=
16.7 and J= 5.3 Hz), 3.49 (dd, 1H, J= 16.68 and J= 5.3
Hz), 2.03 (s, 3H, CH3). 13C NMR (62.9 MHz, CDCl3,
ppm) δ: 196.8, 169.8, 150.5, 141.0, 140.3, 129.3,
129.3, 128.9, 128.0, 126.6, 126.6, 124.0, 124.0, 104.9,
50.3, 44.2, 23.4.
1
MHz, CDCl3, ppm) δ: 7.84 (d, 2H, J = 8.4 Hz), 7.27-
7.23 (m, 4H), 7.13 (d, 2H, J= 6.1 Hz), 6.77 (d, 1H, J=
6.3 Hz, NH), 5.60-5.50 (m, 1H), 3.73 (dd, 1H, J = 16.6
and J = 3.0 Hz), 3.41 (dd, 1H, J = 16.6 and J = 3.9
Hz), 2.42 (s, 3H, CH3), 2.32 (s, 3H, CH3), 2.03 (s, 3H,
CH3). 13C NMR (62.9 MHz, CDCl3, ppm) δ: 198.3,
169.5, 144.4, 138.1, 137.1, 134.2, 129.4, 129.4, 129.3,
129.3, 128.3, 128.3, 126.4, 126.4, 49.8, 43.1, 23.5,
21.7, 21.1.
N-(3-oxo-1-p-tolyl-3-p-nitrophenylpropyl)
acetamide (4j): Yield = 92 %. M.p. = 76-78 °C. H
1
N-(3-Oxo-1-m-methylphenyl-3-p-tolylpropyl)
acetamide (4e): Yield = 95 %. M.p. = 117-119 °C. 1H
NMR (250 MHz, CDCl3, ppm) δ: 7.83 (d, 2H, J = 8.2
Hz), 7.26 (d, 2H, J = 8.1 Hz), 7.21-7.04 (m, 4H), 6.78
(d, 1H, J = 7.6 Hz, NH), 5.53 (q, 1H, J= 6.4 Hz), 3.71
(dd, 1H, J = 16.7 and J = 5.4 Hz), 3.41 (dd, 1H, J =
16.7 and J = 5.35 Hz), 2.42 (s, 3H, CH3), 2.33 (s, 3H,
CH3), 2.03 (s, 3H, CH3). 13C NMR (62.9 MHz, CDCl3,
ppm) δ: 198.3, 169.5, 144.5, 141.0, 138.3, 134.2,
129.4, 129.4, 128.6, 128.3, 128.3, 128.2, 127.4, 123.4,
50.0, 43.2, 23.5, 21.7, 21.6.
NMR (250 MHz, CDCl3, ppm) δ: 8.31 (d, 2H, J= 8.6
Hz), 8.09 (d, 2H, J= 8.6 Hz), 7.29-7.10 (m, 4H), 6.39
(d, 1H, J= 7.0 Hz, NH), 5.50 (q, 1H, J= 6.6 Hz), 3.84
(dd, 1H, J= 16.5 and J= 5.1 Hz), 3.48 (dd, 1H, J= 16.5
and J= 6.92 Hz), 2.33 (s, 3H, CH3), 2.03 (s, 3H, CH3).
13C NMR (62.9 MHz, CDCl3, ppm) δ: 196.9, 169.8,
150.5, 141.0, 137.9, 137.2, 129.7, 129.7, 129.3, 129.3,
126.6, 126.6, 124.0, 124.0, 50.2, 44.3, 23.5, 21.1.
N-(3-Oxo-1-p-bromophenyl-3-p-nitrophenylpropyl)
acetamide (4k): Yield = 87 %. M.p. = 142-144 °C.
1H NMR (250 MHz, CDCl3, ppm) δ: 8.32 (d, 2H, J=
8.6 Hz), 8.08 (d, 2H, J= 8.6 Hz), 7.47 (d, 2, J= 8.4
Hz), 7.23 (d, 2H, J= 8.4 Hz), 6.55 (d, 1H, J= 7.5 Hz,
NH), 5.52 (q, 1H, J= 6.1 Hz), 3.83 (dd, 1H, J= 17.1
and J= 5.1 Hz), 3.48 (dd, 1H, J= 17.1 and J= 5.1 Hz),
2.04 (s, 3H, CH3). 13C NMR (62.9 MHz, CDCl3,
ppm) δ: 196.6, 169.7, 150.6, 140.7, 139.4, 132.0,
132.0, 129.2, 129.2, 128.4, 128.4, 124.1, 124.1, 121.8,
104.7, 49.5, 43.8, 23.5.
4-(1-Acetamido-3-oxo-3-p-tolylpropyl)
phenylboronic acid (4f): Yield = 98 %. M.p. = 162-
164 °C. 1H NMR (400 MHz, DMSO-d6, ppm) δ: 8.33
(d ; 1H ; J= 12.00 Hz, NH), 8.01 (s, 2H, B(OH)2), 7.85
(d, 2H, J= 12.0 Hz), 7.73 (d, 2H, J= 12.0 Hz), 7.31
(2d, 4H, J= 12.0 Hz), 5.36 (td, 1H, J= 12.0 Hz), 3.50
(dd, 1H, J= 24.0 and J= 12.0 Hz), 3.34 (dd, 1H, J=
24.0 and J= 8.0 Hz), 2.36 (s, 3H, CH3), 1.79 (s, 3H,
CH3). 13C NMR (100 MHz, DMSO-d6, ppm) δ: 197.0,
168.7, 145.2, 144.0, 134.5, 134.5, 134.5, 134.5, 129.7,
129.7, 128.5, 128.5, 126.1, 126.1, 49.4, 44.8, 23.1,
21.6. HRMS (ESI-) m/z 324.14145 [M-H]-, calcd for
C18H19BNO4: 324.14071.
4-(1-acetamido-3-(4-nitrophenyl)-3-oxopropyl)
phenylboronic acid (4l): Yield = 98 %. M.p. = 162-
1
164 °C. H NMR (400 MHz, DMSO-d6, ppm) δ: 8.37
(s, 1H, NH), 8.33 (d, 2H, J= 8.0 Hz), 8.18 (d, 2H, J =
8.0 Hz), 8.02 (s, 2H, B(OH)2), 7.74 (d, 2H, J = 12.0
Hz), 7.33 (d, 2H, J= 8.0 Hz), 5.37 (td, 1H, J= 12.0
Hz), 3.61 (dd, 1H, J= 24.0 and J= 12.0 Hz), 3.50 (dd,
1H, J = 24.0 and J= 12.0 Hz), 1.80 (s, 3H, CH3). 13C
NMR (100 MHz, DMSO-d6, ppm) δ: 196.5, 168.5,
149.9, 144.5, 141.1, 134.2, 134.2, 134.2, 129.5, 129.5,
125.7, 125.7, 123.8, 123.8, 48.9, 45.1, 22.6. HRMS
(ESI-) m/z 355.10904 [M-H]-, calcd for C17H16BN2O6:
355.11014.
3-(1-Acetamido-3-oxo-3-p-tolylpropyl)
phenylboronic acid (4g): Yield = 80 %. M.p. = 156-
1
158 °C. H NMR (400 MHz, DMSO-d6, ppm) δ: 8.32
(d, 1H, J= 12.00 Hz), 8.05 (s, 2H, B(OH)2), 7.86 (d,
2H ; J= 12.00 Hz), 7.78 (s, 1H), 7.65 (d, 1H, J= 12.0
Hz), 7.38 (d, 1H, J= 12.0 Hz), 7.32 (d, 2H, J= 12.0
Hz), 7.26 (d, 1H, J= 12.0 Hz, NH), 5.38 (q, 1H, J=
12.0 Hz), 3.52 (dd, 1H, J= 24.0 and J= 12.0 Hz), 3.33
(dd, 1H, J= 24.0 et J= 12.0 Hz), 2.36 (s, 3H, CH3),
1.79 (s, 3H, CH3). 13C NMR (100 MHz, DMSO-d6,

9
3-(1-acetamido-3-(4-nitrophenyl)-3-oxopropyl)
HRMS (ESI-) m/z 344.09990 [M-H]-, calcd for
C17H16BClNO4: 344.08609.
phenylboronic acid (4m): Yield = 97 %. M.p. = 157-
1
159 °C. H NMR (400 MHz, DMSO-d6, ppm) δ: 8.33
(d, 2H, J= 12.0 Hz), 8.32 (s, 1H, NH), 8.18 (d, 2H, J=
12.0 Hz), 8.05 (s, 2H, B(OH)2), 7.78 (s, 1H), 7.66 (d,
1H, J= 12.0 Hz), 7.40 (d, 1H, J= 12.0 Hz), 7.29 (t, 1H,
J= 12.0 Hz), 5.36 (td, 1H, J= 12.0 Hz), 3.63 (dd, 1H,
J= 24.0 and J= 12.00 Hz), 3.48 (dd, 1H, J = 20.0 and J
= 12.0 Hz), 1.79 (s, 3H, CH3). 13C NMR (100 MHz,
DMSO-d6, ppm) δ: 196.5, 168.3, 149.9, 141.4, 141.1,
132.7, 132.5, 129.4, 129.4, 129.4, 128.4, 127.3, 123.8,
123.8, 49.0, 45.2, 22.6. HRMS (ESI-) m/z 355.10863
[M-H]-, calcd for C17H16BN2O6: 355.11014.
3-(3-Acetamido-3-(4-
nitrophenyl)propanoyl)phenylboronic acid (4r):
Yield = 81 %. M.p. = 165-167 °C. H NMR (400
1
MHz, DMSO-d6, ppm) δ: 8.48 (d, 1H, J= 8.00 Hz),
8.41 (s, 1H), 8.26 (s, 2H, B(OH)2), 8.19 (d, 2H, J = 8.0
Hz), 8.03 (d, 1H, J = 8.0 Hz, NH), 7.98 (d, 2H, J = 8.0
Hz), 7.64 (d, 2H, J = 8.0 Hz), 5.46 (td, 1H, J= 8.0 Hz),
3.66 (dd, 1H J= 24.0 and J= 8.0 Hz), 3.47 (dd, 1H, J=
20.0 and J= 8.0 Hz), 1.83 (s, 3H, CH3). 13C NMR (100
MHz, DMSO-d6, ppm) δ: 196.6, 168.6, 151.2, 146.3,
138.9, 135.5, 133.8, 129.4, 127.9, 127.9, 127.8, 127.8,
123.4, 123.4, 48.5, 44.0, 22.5. HRMS (ESI-)
m/z 355.10906 [M-H]-, calcd for C17H16BN2O6:
355.11014.
N-(3-oxo-1-(naphthalen-2-yl)-3-(4-
nitrophenyl)propyl) acetamide (4n): Yield = 95 %.
M.p. = 136-138 °C. 1H NMR (250 MHz, CDCl3,
ppm) δ: 8.25 (d, 2H, J= 7.6 Hz), 8.07 (d, 2H, J= 8.6
Hz), 8.02 (s, 1H), 7.75-7.41 (m, 6H), 7.38 (d, 1H, J=
4.7 Hz, NH), 5.62 (q, 1H, J= 6.9 Hz), 3.77 (dd, 1H, J=
16.7 and J= 7.0 Hz), 3.49 (dd, 1H, J= 16.7 and J= 6.5
Hz), 1.91 (s, 3H, CH3). 13C NMR (62.9 MHz, CDCl3,
ppm) δ: 195.6, 169.5, 149.6, 140.6, 138.4, 132.6,
128.8, 128.8, 128.8, 127.8, 127.3, 127.0, 125.7, 125.4,
124.9, 124.7, 123.3, 49.3, 44.4, 22.5.
4.2. In vitro cholinesterase inhibition activity
Acetyl
cholinesterase
(AChE)
and
butyryl
cholinesterase (BChE) inhibitory activity was
measured, by the spectrophotometric method
developed by Ellman, G.L., et al.35 Briefly, 150 µL of
100 mM sodium phosphate buffer (pH 8.0), 10 µL of
sample (4) solution dissolved in methanol at different
concentrations and 20 µL AChE (5.32 x10-3 U) or
BChE (6.85 x10-3U) solution were mixed and
incubated for 15 min at 25 ºC, and 10 µl of 0.5 mM
DTNB [5,5´-dithio-bis(2-nitrobenzoic) acid] were
added. The reaction was then initiated by the addition
of 10 µLof acetylthiocholine iodide (0.71 mM) or
butyrylthiocholine chloride (0.2 mM). The hydrolysis
4-(3-Acetamido-3-(4-bromophenyl)propanoyl)
phenylboronic acid (4o): Yield = 65 %. M.p. = 178-
1
180 °C. H NMR (400 MHz, DMSO-d6, ppm) δ: 8.36
(d ; 1H ; J= 12.00 Hz, NH), 8.30 (s, 2H, B(OH)2), 7.90
(s, 4H ), 7.51 (d, 2H, J = 12.0 Hz), 7.31 (d, 2H, J =
12.0 Hz), 5.32 (td, 1H, J= 12.0 Hz), 3.56 (dd, 1H, J=
24.0 and J= 12.00 Hz). 3.39 (dd, 1H, J= 24.0 and J=
12.0 Hz), 1.79 (s, 3H, CH3). 13C NMR (100 MHz,
DMSO-d6, ppm) δ: 197.1, 168.4, 142.5, 137.5, 134.3,
134.3, 131.1, 131.1, 131.1, 128.9, 128.9, 128.9, 126.8,
119.8, 48.4, 44.3, 22.6. HRMS (ESI-) m/z 388.04833
[M-H]-, calcd for C17H16BBrNO4: 388.03558.
of
these
substrates
were
monitored
spectrophotometrically by the formation of yellow 5-
thio-2-nitrobenzoate anion, as the result of the reaction
of DTNB with thiocholine, released by the enzymatic
hydrolysis
of
acetylthiocholine
iodide
or
a
butyrylthiocholine chloride, respectively, at
wavelength of 412 nm, every 5 min for 15 min,
utilizing a 96-well microplate reader (Perkin Elmer
Multimode Plate Reader EnSpire, USA) in triplicate
experiments. Galanthamine was used as reference
compound. The results were given as 50% inhibition
concentration (IC50) and the percentage of inhibition
of AChE or BChE was determined by comparison of
reaction rates of samples relative to blank sample
(methanol in phosphate buffer, pH 8) using the
formula:
3-(3-Acetamido-3-(4-bromophenyl)propanoyl)
phenylboronic acid (4p): Yield = 78 %. M.p. = 156-
1
158 °C. H NMR (400 MHz, DMSO-d6, ppm) δ: 8.40
(s, 1H), 8.35 (d, 1H, J = 8.0 Hz), 8.26 (s, 2H, B(OH)2),
8.03 (d, 1H, J = 8.0 Hz, NH), 7.97 (d, 1H, J = 8.0 Hz),
7.50 (m 3H), 7.32 (d, 2H, J = 8.0 Hz), 5.34 (td, 1H, J
= 8.0 Hz), 3.57 (dd, 1H, J = 20.0 and J= 8.0 Hz), 3.41
(dd, 1H, J = 20.0 and J = 8.0 Hz), 1.80 (s, 3H, CH3).
13C NMR (100 MHz, DMSO-d6, ppm) δ: 197.0, 168.4,
142.6, 138.9, 135.6, 133.8, 131.7, 131.7, 131.7, 129.4,
128.9, 128.9, 127.8, 119.7, 48.3, 44.2, 22.6. HRMS
(ESI-)
C17H16BBrNO4: 388.03558.
m/z 388.04727
[M-H]-,
calcd
for
E - S
Inhibition of AChE or BChE (%) =
×100
E
3-(3-Acetamido-3-(4-chlorophenyl)propanoyl)
Where E is the activity of enzyme without test sample,
and S is the activity of enzyme with test sample. The
obtained results are given in Table 4.
phenylboronic acid (4q): Yield = 73 %. M.p. = 164-
1
166 °C. H NMR (400 MHz, DMSO-d6, ppm) δ: 8.41
(s, 1H ), 8.37 (d, 1H, J= 12.0 Hz), 8.30 (s, 2H,
B(OH)2), 8.03 (d, 1H, J= 8.00 Hz), 7.97 (d, 1H, J= 8.0
Hz, NH), 7.49 (t, 1H, J= 12.0 Hz), 7.38 (s, 4H), 5.36
(td, 1H, J= 12.0 Hz). 3.58 (dd, 1H, J= 24.0 and J= 8.0
Hz), 3.40 (dd, 1H, J= 24.0 and J= 8.0 Hz), 1.80 (s, 3H,
CH3). 13C NMR (100 MHz, DMSO-d6, ppm) δ: 197.4,
168.8, 142.7, 139.3, 136.1, 134.2, 131.7, 129.8, 128.9,
128.9, 128.6, 128.6, 128.6, 128.3, 48.7, 44.8, 23.0.
4.3. Computational details
All the DFT (density functional theory) calculations
have been carried on the optimized geometries
using Gaussian 09 software.36 The B3LYP

10
Tetrahedron
37-38
18. Das, B.; Ravinder Reddy, K.; Ramu, R.;
Thirupathi, P.; Ravikanth, B. Synlett 2006, 11,
1756-1758.
19. Ghosh, R.; Maity S.; Chakraborty, A. Synlett
2005, 115.
20. Khan. A. T.; Parvin. T.; Choudhury. L. H.
Tetrahedron 2007, 63, 5593-5601.
21. Rao. I. N.; Prabhakaran. E. N.; Das. S. K.; Iqbal.
J. J. Org. Chem. 2003, 68, 4079-4082.
22. Khan. A. T.; Choudhury. L. H.; Parvin. T.; Ali.
M. A. Tetrahedron Lett. 2006, 47, 8137-8141.
23. Mirjalili, B. B. F.; Hashemi, M. M.; Sadeghi, B.;
Emtiazi, H. J. Chin. Chem. Soc., 2009, 56, 386-
391.
24. Pandey. G.; Singh. R. P.; Garg. A.; Singh. V. K.
Tetrahedron Lett. 2005, 46, 2137-2140.
25. Ghosh, R.; Maiti, S.; Chakraborty, A.;
Chakraborty S.; Mukherjee, A.K. Tetrahedron
2006, 62, 4059-4064.
26. Hassnkhani, A.; Maghsodlou, M. T.; Habibi-
Khorassani, S. M.; Housseini-Mahdiabad, H.;
Marandi, G. ARKIVOC, 2008, ii, 134-140.
27. Momeni, A. R.; Sadeghi, M.; Hadizadeh, M. Turk.
J. Chem. 2009, 33, 751-758.
functional
and the 6-311G++(d,p) basis set for
C, H, N and O atoms were employed. The
reliability of this methodology has been confirmed
by previous studies.39-42 All the ground states were
confirmed by vibrational frequency analysis (no
imaginary frequency). Molecular descriptors
(Electronegativity, chemical softness, chemical
hardness and electrophilic index) were calculated
from HOMO/LUMO energies method as reported
in our previous studies.38-39
Acknowledgments
The authors gratefully acknowledge le Ministère de
l’Enseignement Supérieur et de la Recherche
Scientifique (Algeria) for the financial support and
l’Unité de Calcul Intensif of Mentouri-Constantine 1
University for the computational resources used.
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Highlights
•
A series of novel β-acetamido ketones have been prepared via a four-component condensation between
aromatic aldehydes, enolizable ketones, acyl chloride and acetonitrile.
•
•
•
Phenylboronic acid has been used as an efficient catalyst for the present methodology.
The in vitro cholinesterase inhibitory activity of title compounds has been studied.
Theoretical investigations have been carried out in order to understand molecular structure
and chemical reactivity of the synthesized compounds.

Declaration of interests
☒ The authors declare that they have no known competing financial interests or personal relationships
that could have appeared to influence the work reported in this paper.
☐The authors declare the following financial interests/personal relationships which may be considered
as potential competing interests: