Acta Pharmaceutica Sinica B 2011;1(2):100105

Institute of Materia Medica, Chinese Academy of Medical Sciences

Chinese Pharmaceutical Association

Acta Pharmaceutica Sinica B

www.elsevier.com/locate/apsb
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ORIGINAL ARTICLE

Synthesis and antidiabetic activity of b-acetamido ketones

Xing-hua Zhanga, Ju-fang Yanb, Li Fana, Gong-bao Wanga, Da-cheng Yanga,n
a

School of Chemistry and Chemical Engineering, Southwest University, Chongqing 400715, China
Center for Drug Screening, Chengdu Di Ao Pharmaceutical Group Co., Ltd, Chengdu 610041, China

Received 7 March 2011; revised 13 April 2011; accepted 28 April 2011

KEY WORDS
Diabetes mellitus;
DakinWest reaction;
Triuoroacetic acid;
b-Acetamido ketone;
4-Chloroacetophenone

Abstract This paper reports the use of triuoroacetic acid as a catalyst in the DakinWest
reaction for the synthesis of b-acetamido ketones. The method has several advantages such as
requiring only mild conditions and a low concentration of catalyst. Screening of 19 b-acetamido
ketones for antidiabetic activity in vitro showed that their activity as peroxisome proliferatoractivated receptor (PPAR) agonists and as dipeptidyl peptidase 4 (DPP-IV) inhibitors was
fairly weak.
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Corresponding author. Tel.: 13640566978.

E-mail address: hxydc@swu.edu.cn (Da-cheng Yang).

2211-3835 & 2011 Institute of Materia Medica, Chinese Academy of Medical Sciences and Chinese Pharmaceutical Association. Production and
hosting by Elsevier B.V. All rights reserved.
Peer review under responsibility of Institute of Materia Medica, Chinese Academy of Medical Sciences and Chinese Pharmaceutical Association.
doi:10.1016/j.apsb.2011.06.006

Synthesis and antidiabetic activity of b-acetamido ketones

1.

Introduction

Diabetes mellitus (DM) is a chronic disease caused by

inherited or acquired deciency in insulin secretion and/or
insulin resistance. The disease is characterized by increased
blood glucose levels which, in turn, can damage many
physiological systems including blood vessels and nerves1.
Noninsulin-dependent or type 2 diabetes mellitus (T2DM)
accounts for about 95% of all DM and, according to the
World Health Organization (WHO), will likely exceed an
alarming 350 million cases by the year 20302. Owing to this
increasing prevalence, multidisciplinary studies aimed at preventing and treating diabetes is a worldwide research priority.
The generally agreed treatment goal in T2DM is to maintain
near-normal levels of glycemic control in both the fasting and
postprandial states. Although diet and exercise are the rst steps
toward achieving this goal, oral antidiabetic pharmacotherapy
also plays an important role. Successfully marketed T2DM drugs
may be classied into insulin secretagogues (meglitinides and
sulfonylureas), insulin sensitizers, aldose reductase inhibitors,
glucose absorption effectors (such as a-glucosidase inhibitors)
and the newly introduced dipeptidyl peptidase 4 (DPP-IV)
inhibitors3. Although these drugs are useful in the treatment of
T2DM, their long-term use may lead to a variety of adverse effects
including hepatotoxicity, weight gain, edema and indigestion.
Thus there remains an urgent need to develop new antidiabetic
agents with higher efcacy and lower toxicity for the long term
treatment of T2DM.
In the course of our previous work, we observed that
b-amino ketones possess remarkable antidiabetic activity411.
One issue with the synthesis of such molecules containing
multiple aromatic rings is their bulky space volume. In order
to reduce the space volume of this kind of molecule, we have
designed and synthesized a series of b-acetamidoketones in
which the arylamino group of b-amino ketones is replaced
with an acetamido group.
b-Acetamido ketones are versatile intermediates and useful
building blocks in the synthesis of other important organic
molecules like 1.3-amino alcohols12,13 and antibiotic drugs14,15.
This class of compounds was previously prepared via acylation
of b-amino ketones16, Michael addition of a,b-unsaturated
ketones17,18 or photoisomerization of phthalimides19. However,
the most classical and facile method for the synthesis of
b-acetamido ketones is the DakinWest reaction. Over recent
years, several catalysts for the DakinWest reaction have been
developed and now include SnCl2  2H2O20, CeCl3  7H2O21,
ZnO22, SiCl4ZnCl223, heteropoly-acids24, Zr(HSO4)4 and
Mg(HSO4)225, PMA/SiO226, polyaniline supported acid27,
Mn(bpdo)2Cl2/MCM-4128, P2O5-HMDS29, sulfamic acid30
and cellulose sulfuric acid31. Although these catalysts possess
some attractive properties, they also have certain disadvantages
such as requiring a tedious workup, high temperatures, expensive reagents and/or an inert atmosphere as well as producing a
low yield. Therefore, further research and development of new
catalysts is highly desirable.
Triuoroacetic acid (TFA) is not only a useful agent in the
synthesis of uorine-containing organic compounds and uoropolymers, but is also an important reactant in the acylation
of amino acids32 and the deprotection of peptides33. As a
strongly acidic compound, TFA has been extensively used in
alkylation34 and acylation of aromatic compounds as well as
in the polymerization of olens. However, the use of TFA as a

101
catalyst in the DakinWest reaction has not been reported.
Herein, we report the synthesis of a series of b-acetamido
ketones by the TFA-catalyzed DakinWest reaction and an
evaluation of their antidiabetic activity.

2.

Results and discussion

In order to establish the efciency of TFA as a catalyst in the

DakinWest reaction, a model reaction of 4-chloroacetophenone (1 mmol) with 4-methylbenzaldehyde (1 mmol) and
acetyl chloride (0.4 mL) was carried out in the presence of
different amounts of TFA in acetonitrile at room temperature
(Scheme 1).
The results (Table 1) show that TFA is necessary for the
reaction to proceed with around 0.30 mol% being the optimal
amount.
To evaluate the scope of the reaction, other aldehydes and
ketones were used (Scheme 2) with the results shown in
Table 2.
Based on the results in Table 2, it is clear that the nature of
the aromatic aldehyde has a major impact on the yield of the
reaction. Thus aromatic aldehydes with electron-withdrawing
groups react more readily than those with electron-donating
groups although reactions 10, 12, 13 and 16 still produce good
yields. In addition, aromatic aldehydes with ortho- or parasubstituents (reactions 4, 5, 9 and 13) react faster than those
with meta-substituents (reactions 3, 7 and 12) with the
exception of nitrobenzaldehyde (reactions 1 and 2). As for
the liquid aldehydes (reactions 7, 8, 9, 11 and 13), reactions
proceeded with the formation of large quantities of solid
products and gave correspondingly high yields (around 90%).
Unexpectedly, the reaction of 4-methoxybenzaldehyde with
4-chloroacetophenone yielded only the corresponding chalcone despite stirring the chalcone (1 mmol) in acetonitrile
(3 mL) containing TFA (0.30 mol%) and acetyl chloride
(0.4 mL) for 12 h. Interestingly, aromatic aldehydes with
hydroxy groups yielded corresponding b-acetamido ketones

Scheme 1 The model DakinWest reaction using TFA as a

catalyst.

Table 1 The effect of amounts of TFA on the yield of the

model reaction shown in Scheme 1.
Reaction

TFA (mol%)

Time (h)

Yield (%)

1
2
3
4

0.00
0.15
0.30
0.45

24
22
22
22

Trace
88.6
95.2
95.5

Scheme 2 Synthesis of b-acetamido ketones catalyzed by TFA.

102

Xing-hua Zhang et al.

Table 2

Synthesis of b-acetamido ketones according to Scheme 2.

Reaction

R1

R2

Time (h)

m.p. (1C)

Yield (%)a

1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19

4-NO2
3-NO2
3,4-diCl
2,4-diCl
4-Cl
4-Br
3-Cl
3-F
2-Cl
3-CH3O
H
3-CH3
4-CH3
3-CH3O-4-HO
4-HO
3,4,5-triCH3O
H
2-Cl
H

4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
3-NO2C6H4
4-CH3OC6H4
CH3

H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
COCH3

64
47
36
24
16
22
60
28
28
90
22
110
22
36
66
15
65
12
24

139.5140.6
115.4117.4
221.0224.0
150.0151.2
134.5136.2
133.6134.4
113.0116.2
119.0121.4
168.0170.3
107.4109.7
107.5109.0
119.0122.0
130.9133.5
150.0152.4
227.9229.6
177.2178.9
132.1133.2
155.2156.7
132.0133.5

83.0
87.7
89.4
77.5
95.5
83.4
90.1
94.0
89.0
80.0
90.0
86.3
95.2
43.5
53.5
85.0
96.0
81.7
69.0

Isolated yield.

(reactions 14 and 15) without further acetylation of the

hydroxy group albeit giving lower yields. However, the
a-substituted enolisable alkyl ketone, 2,4-pentanedione (reaction 19) produced only a moderate yield of the corresponding
b-acetamido ketone. The structure of all products was established based on their 1H and 13C NMR spectra.
Given that in previous studies, b-acetamido compounds
displayed no a-glucosidase inhibition activity, we designed the
current series of compounds to target the peroxisome proliferator-activated receptor response element (PPRE) and dipeptidyl peptidase 4 (DPP-IV). In evaluating this type of antidiabetic
activity at a concentration of 10.0 mg/mL (Table 3), it was found
that both PPAR agonist activity and DPP-IV inhibition activity
were weak. Nevertheless, the structureactivity relationship
(SAR) for PPAR agonist activity demonstrated that products
with electron-donating groups on the aromatic aldehyde ring
possessed better activity than those with electron-withdrawing
groups in the order: 15 (4-OH)413 (4-CH3)46 (4-Br)41
(4-NO2). Based on these results, we propose that the OH group
in the product of reaction 15 improves water-solubility and
results in stronger binding to the PPAR. The product of reaction
14 is a little less active than that of reaction 15, suggesting that
the additional 3-OCH3 group does not favor the interaction with
PPAR as also seen in the product of reaction 10. Furthermore,
the products of reactions of halogen substituted aromatic
aldehydes (reactions 4, 5, 7, 8 and 9) exhibit some antagonistic
effects.
The presence of different functional groups in the acetophenone ring also appears to produce compounds with different
levels of PPAR agonist activity. For example, the product of
reaction 18 (4-CH3O substituent) shows better PPAR agonist
activity than that of reaction 9 (4-Cl substituent).
The bioactivity of a potential drug is dependent on a
number of factors such as the distribution of electron density,
space volume, hydrogen bond density and molecular exibility. Through examination of the ChemDraw 3D structures
(Fig. 1), we conclude that the product of reaction 15 has

Table 3

Biological activity of b-acetylamino ketones.

Compound Concentration
(nmol/mL)a

1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
Positive
controlb

28.8
28.8
26.9
26.9
29.7
26.3
29.7
31.0
29.7
30.1
33.1
31.7
31.7
28.8
31.5
25.5
32.0
30.1
35.5

PPAR
activation
(%)

DPP-IV
Inhibition
(%)

2.84
1.08
18.45
1.49
0.73
12.21
0.93
0.89
1.53
0.53
3.24
14.17
16.61
19.05
22.86
14.17
11.70
20.75

100

9.53
4.24
8.76
3.79
8.47
0.26
12.71
7.94
11.35
6.30
4.34
1.22
0.48
4.41
3.56
3.61

73.11

a
The concentration of test compounds is 10.0 mg/mL (the
corresponding nmol/mL is shown).
b
Positive controls for PPRE agonist activity and DPP-IV
inhibition activity are pioglitazone (0.78 mg/mL) and KR-62436
(6-{2-[2-(5-cyano-4,5-dihydropyrazol-1-yl)-2-oxoethylamino]ethylamino}nicotinonitrile) (0.78 mg/mL), respectively.

poorer molecular exibility than pioglitazone, making it less

able to t the space structure of PPAR.
Given the limited activity of the target compounds, we
maintain it is essential to synthesize more of these b-acetamido

Synthesis and antidiabetic activity of b-acetamido ketones

103
4.3.

Figure 1 Three-dimensional structures of the product of reaction

15 and pioglitazone.

ketones and assay their biological activity to establish

structureactivity relationships. To date, we have synthesized
more than 200 such compounds and evaluation of their
antidiabetic activity is underway.

3.

Conclusions

We report the use of TFA as an efcient catalyst of the Dakin

West reaction of aromatic aldehydes, enolizable ketones and
acetonitrile in the presence of acetyl chloride to produce bacetamido ketones under mild reaction conditions. We also report
preliminary data on the antidiabetic activity of the b-acetamido
ketones in in vitro assays of PPAR agonist and DPP-IV inhibition
activity. Although the activities were weak, the compounds
represent a valuable starting point in the search for novel
antidiabetic drugs.

4.
4.1.

Experimental procedures
General methods

All solvents and reagents were of chemical or analytical grade.

The progress of reactions was monitored by TLC using
solvent systems of different polarities. Melting points were
measured using an X-6 micro-melting point apparatus and are
uncalibrated. 1H NMR and 13C NMR spectra were recorded
in DMSO-d6 on a Bruker AV-300 spectrometer; chemical
shifts (d) are expressed in ppm downeld from the TMS
internal standard. Coupling constant (J) values are in Hz.
High resolution mass spectra (HRMS) were recorded on a
Bruker Daltonics Data Analysis 3.2, USA.

4.2. General procedure for the synthesis of

b-acetamido ketones
To a solution of an enolizable ketone (1.0 mmol), an aldehyde
(1.0 mmol) and acetyl chloride (0.4 mL) in acetonitrile
(2.0 mL), TFA (0.30 mol%) was added dropwise and the
mixture stirred for 0.5 h at 0 1C, and then allowed to warm
to ambient temperature. On completion of the reaction, the
mixture was poured into iced water (20.0 mL) and the pH
adjusted to 7 with saturated NaHCO3, which resulted in
precipitation of the desired b-acetamido ketone. The precipitate was ltered, washed with diethyl ether (1.0 mL) and
recrystallized from a mixture of ethyl acetate and diethyl
ether. Most of the reaction products are known compounds,
which were easily characterized by comparison of their 1H and
13
C NMR spectra with those of authentic samples.

DPP-IV inhibition activity

A 200 mL reaction system containing DPP-IV (Sigma), a test compound, and 25 mmol/L HEPES buffer (containing 140 mmol/L
NaCl, 1% BSA and 80 mmol/L MgCl2) was preincubated at
room temperature for 10 min. The reaction was initiated by
the addition of dipeptidyl peptidase GlyProGlyGly, and the
reaction mixture incubated at room temperature for 2545 min.
The uorescence intensity (F) at excitation 355 nm and emission
460 nm was then measured. A negative control (no test compound) and a blank control (no enzyme) were run simultaneously.
The test compounds were initially assayed in duplicate at a
concentration of 10 mg/mL. The % inhibition was calculated as
[1(Ftest compoundFblank)/(FnegativeFblank)]  100%. If an inhibition of more than 50% was observed, the compound was
subsequently consequently tested at six concentrations in duplicate
and the IC50 value calculated using the Xlt software.
4.4.

PPAR agonist activity

HepG2 cells were cultured in low glucose DMEM supplemented with 100 U/mL streptomycin and penicillin. One day
prior to transfection, the cells were plated in 96-well plates at
1.5  104 cells per well. After reaching 70% conuence,
plasmid pPPRE-Luc with rey luciferase reporter gene and
the control plasmid phRL-TK with renilla luciferase reporter
gene were transfected into the cells. After 24 h, the medium
was replaced with either fresh medium (negative control) or
fresh medium containing a test compound (10 mg/mL) or
pioglitazone (positive control). Non-transfected cells were
used as blank. After a further 24 h, the expression of
luciferases was measured using the Dual-Luciferase Reporter
Gene Assay Kit (Promega). The percent activation (T%)
were calculated as [(L1SampleL1Blank)/(L1NegativeL1Blank)]/
[(L2SampleL2Blank)/(L2NegativeL2Blank)]  100%, where L1
represents the value for rey luciferase and L2 the value
for Renilla luciferase.
4.5.

Characterization of new products

4.5.1. b-Acetamido-b-(4-bromophenyl)-4chloropropiophenone (6)

1
H NMR (DMSO-d6, 300 MHz); d 1.77 (s, 3H, COCH3), 3.37
(dd, J 6.0 and 17.1 Hz, 1H, CH2), 3.56 (dd, J 8.4 and
17.1 Hz, 1H, CH2), 5.255.32 (m, 1H, CHN)), 7.30 (d, J 8.4
Hz, 2H, ArH), 7.49 (d, J 8.1 Hz, 2H, ArH), 7.58 (d,
J 8.7 Hz, 2H, ArH), 7.95 (d, J 8.7 Hz, 2H, ArH), 8.42 (d,
J 6.0 Hz, 1H, NH). 13C NMR (DMSO-d6, 75 MHz); d 196.4,
168.9, 142.9, 138.6, 135.6, 131.5, 130.4, 129.4, 129.2, 120.3,
48.8, 44.7, 22.9. HRMS calcd. for C17H15BrClNO2Na
401.9865. Found 401.9867.
4.5.2. b-Acetamido-b-(3-uorophenyl)-4chloropropiophenone (8)
1
H NMR (DMSO-d6, 300 MHz); d 1.80 (s, 3H, COCH3), 3.40
(dd, J 6.0 and 17.4 Hz, 1H, CH2), 3.59 (dd, J 8.7 and
17.4 Hz, 1H, CH2), 5.325.39 (m, 1H, CHN), 7.06 (t, J 8.6
Hz, 1H, ArH), 7.20 (d, J 7.2 Hz, 2H, ArH), 7.327.39 (m,
1H, ArH), 7.59 (d, J 8.4 Hz, 2H, ArH), 7.98 (d, J 8.7 Hz,
2H, ArH), 8.47 (d, J7.5 Hz, 1H, NH). 13C NMR (DMSO-d6,
75 MHz); d 196.4, 169.0, 160.9, 146.4, 138.6, 135.6, 130.5,

104
130.4, 129.2, 123.2, 123.1, 113.9, 48.9, 44.8, 22.9. HRMS
calcd. for C17H15ClFNO2Na 342.0669. Found 342.0668.

4.5.3. b-Acetamido-b-(3-methoxyphenyl)-4chloropropiophenone(10)
1
H NMR (DMSO-d6, 300 MHz) d 1.79 (s, 3H, COCH3), 3.36
(dd, J 5.4 and 16.8 Hz, 1H, CH2), 3.52 (dd, J 8.4 and
16.8 Hz, 1H, CH2), 3.74 (s, 3H, OCH3), 5.275.36 (m, 1H,
CHN), 6.79 (d, J 8.1 Hz, 2H, ArH), 6.93 (s, 1H, ArH),
7.22 (t, J 7.8 Hz, 1H, ArH), 7.59 (d, J 8.7 Hz, 2H, ArH),
7.97 (d, J 8.1 Hz, 2H, ArH), 8.41 (d, J 8.1 Hz, 1H, NH).
13
C NMR (DMSO-d6, 75 MHz); d 196.6, 168.9, 159.6, 144.9,
138.5, 135.6, 130.4, 129.7, 129.2, 119.3, 112.9, 112.5, 55.4, 49.4,
45.1, 22.9. HRMS calcd. for C18H18ClNO3Na 354.0869.
Found 354.0867.

4.5.4. b-Acetamido-b-(3-methylphenyl)-4chloropropiophenone (12)

1
H NMR (DMSO-d6, 300 MHz); d 1.79 (s, 3H, COCH3), 2.29
(s, 3H, CH3), 3.343.41 (m, 1H, CH2), 3.483.52 (m, 1H,
CH2), 5.285.33 (m, 1H, CHN), 7.04 (d, J 8.4 Hz, 1H,
ArH), 7.127.23 (m, 3H, ArH), 7.59 (d, J 8.7 Hz, 2H,
ArH), 7.97 (d, J 8.7 Hz, 2H, ArH), 8.30 (d, J 8.4 Hz, 1H,
NH). 13C NMR (DMSO-d6, 75 MHz); d 196.7, 168.7, 143.2,
138.5, 137.7, 135.7, 130.4, 129.2, 128.6, 127.9, 127.7, 124.1,
49.4, 45.3, 23.1, 21.5. HRMS calcd. for C18H18ClNO2 Na
338.0922. Found 338.0918.

4.5.5. b-Acetamido-b-(3-methoxy-4-hydroxyphenyl)-4chloropropiophenone (14)

1
H NMR (DMSO-d6, 300 MHz); d 1.77 (s, 3H, COCH3), 3.40
(dd, J 6.0 and 16.5 Hz, 1H, CH2), 3.48 (dd, J 8.1 and
16.5 Hz, 1H, CH2), 3.75 (s, 3H, OCH3), 5.225.29 (m, 1H,
CHN), 6.68 (d, J 8.1 Hz, 2H, ArH), 6.93 (s, 1H, ArH),
7.59 (d, J 8.4 Hz, 2H, ArH), 7.97 (d, J 8.4 Hz, 2H, ArH),
8.32 (d, J 8.1 Hz, 1H, NH). 13C NMR (DMSO-d6, 75 MHz);
d 197.0, 168.7, 147.8, 145.9, 138.5, 135.8, 134.0, 130.4, 129.2,
119.4, 115.5, 111.6, 56.1, 49.4, 23.0. HRMS calcd. for
C18H18ClNO4 Na 412.0925. Found 412.0917.

4.5.6. b-Acetamido-b-(4-hydroxyphenyl)-4chloropropiophenone (15)

1
H NMR (DMSO-d6, 300 MHz); d 1.75 (s, 3H, COCH3),
3.343.36 (m, 1H, CH2), 3.403.49 (m, 1H, CH2), 5.205.27
(m, 1H, CHN), 6.68 (d, J 8.4 Hz, 2H, ArH), 7.06 (d,
J 8.7 Hz, 2H, ArH), 7.57 (d, J 8.1 Hz, 2H, ArH), 7.94
(d, J 9.0 Hz, 2H, ArH), 8.19 (d, J 8.1 Hz, 1H, NH), 9.28
(s, 1H, OH). 13C NMR (DMSO-d6, 75 MHz); d 196.9, 168.6,
156.7, 138.5, 135.7, 133.3, 130.4, 129.2, 128.2, 48.9, 45.2, 23.0.
HRMS calcd. for C17H16ClNO3 Na 340.0650. Found 340.0646.

Acknowledgments
This project is supported by The Fundamental Research
Funds for the Central Universities (XDJK2010C067). The
authors are grateful to Mr. Qunli Luo and Mr NingWang for
their assistance in measuring 1H and 13C NMR spectra.

Xing-hua Zhang et al.

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