Microwave-assisted rapid and straightforward synthesis of 2-aryl-4-quinolones from acylated 2′-aminoacetophenones

Article abstract of DOI:10.1016/j.tetlet.2006.07.117

The syntheses of a diverse set of 2-aryl-4-quinolone derivatives were achieved by exposing corresponding acylated 2′-aminoacetophenones to microwave irradiation in the presence of NaOH. The microwave accelerated cyclizations were complete within 10-22 min

Full text of DOI:10.1016/j.tetlet.2006.07.117

Tetrahedron Letters 47 (2006) 6997–6999
Microwave-assisted rapid and straightforward synthesis of
2-aryl-4-quinolones from acylated 20-aminoacetophenones
Derong Ding, Xin Li,* Xin Wang, Yongli Du and Jingkang Shen*
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Shanghai Institutes for Biological
Sciences, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, PR China
Received 28 May 2006; revised 22 July 2006; accepted 25 July 2006
Abstract—The syntheses of a diverse set of 2-aryl-4-quinolone derivatives were achieved by exposing corresponding acylated 20-
aminoacetophenones to microwave irradiation in the presence of NaOH. The microwave accelerated cyclizations were complete
within 10–22 min at 120 °C giving 57–95% isolated yields.
Ó 2006 Elsevier Ltd. All rights reserved.
4-Quinolone derivatives are an important class of anti-
bacterial agents. Numerous analogues have been synthe-
sized to evaluate their antibacterial properties and
antibacterial spectrum.1 Recent studies also revealed
that 2-aryl-4-quinolones possessed antitumor activities
owing to their ability of inhibiting tubulin polymeriza-
tion.2 To construct this intriguing 2-aryl-4-quinolone
scaffold, several synthesis methods have been developed
from different starting materials.3 Among them, cycliza-
tion of acylated 20-aminoacetophenones attracts more
attention because diverse starting materials are readily
available and the reaction conditions are relatively mild,
at 70–80 °C in the presence of potassium tert-butoxide
(t-BuOK). However, long reaction time, 10–24 h, is
always needed for reaction completion, and low yields
are sometimes encountered.4
for synthesis of 2-aryl-4-quinolones from acylated 20-
aminoacetophenones with the aid of microwave irradia-
tion. All microwave experiments were performed in a
self-tuning single mode Biotage Initiator Microwave
Synthesizer.7
To optimize the reaction conditions, cyclization of N-(2-
acetyl-phenyl)-benzamide 1a was selected as model reac-
tion (Scheme 1). A mixture of 1a and 5 equiv of t-BuOK
in t-BuOH was initially exposed to microwave irradia-
tion at 80 °C for 10 min. TLC test indicated the reaction
as uncompleted. On increasing the temperature to
120 °C, the process of conversion of 1a was completed
giving 88% of desired product, 2-phenyl-4-quinolone
2a (Table 1, entry 1). Under this condition, other four
commonly used bases were employed to investigate their
influence on the cyclization (Table 1, entries 2–5). Inter-
estingly, 95% yield of product could be afforded under
the effect of NaOH, whereas no product was detectable
with K2CO3 due to its weak basicity. More experiments
were carried out to evaluate the influence of temperature
The introduction of microwave heating has greatly im-
pacted many aspects of chemical synthesis. There are
some excellent reviews and reports on the broad use of
microwave irradiation in organic synthesis.5 It has been
demonstrated that the use of microwave heating can
dramatically cut down reaction time, increase product
purity and yields, and allow precise control of reaction
conditions, all of which make it suited to meet the
increased demands of high throughput chemistry. In this
letter, we report an efficient and good yielding condition
O
O
MW
N
H
N
H
O
Keywords: Microwave-assisted synthesis; 2-Aryl-4-quinolone; Acylated
20-aminoacetophenone.
1a
2a
*
Corresponding authors. Tel.: +86 21 50806896; fax: +86 21 50807088
(J.S.); e-mail: Jkshen@mail.shcnc.ac.cn
Scheme 1.
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.07.117

6998
D. Ding et al. / Tetrahedron Letters 47 (2006) 6997–6999
Table 1. Reaction conditions on the cyclization of 20-aminoacetoph-
O
O
enone benzamide (Scheme 1)
NaOH/
t-BuOH
Entry
Microwave conditions
Conv.a (%)
Yieldsa (%)
R
R
MW /120 ºC
Ar
N
N
H
Ar
1
2
3
4
5
6
7
8
9
t-BuOK, 120 °C, 10 min
NaOEt, 120 °C, 10 min
KOH, 120 °C, 10 min
NaOH, 120 °C, 10 min
K2CO3, 120 °C, 10 min
NaOH, 130 °C, 10 min
NaOH, 110 °C, 10 min
NaOH, 100 °C, 10 min
NaOH, 90 °C, 10 min
NaOH, 80 °C, 10 min
100
100
100
100
0
100
98
75
88
79
82
95
0
84
76
57
44
25
H O
1a-1p
2a-2p
Scheme 2.
of microwave under the condition described above
(Scheme 2). Because t-BuOK and NaOH exhibited sim-
ilar catalytic character (Fig. 1), and NaOH is cheaper
and easily obtainable, reactions listed in Table 2 were
carried out using NaOH as the base. The desired prod-
ucts 2a–p could be precipitated in water at pH 5–6, and
collected by filtration followed by washing with water
and a cold mixture of acetone and dichloromethane.8
Good to excellent isolated yields, 57–95%, were gained,
which are summarized in Table 2. In general, R1 substi-
tuent produced minor influence on the microwave as-
sisted cyclization (Table 2, entries a–c, g–k, and n–p),
but there was still a vague case that 4,5-dimethoxy
substituted substrates afforded relatively lower yields
even exposed to irradiation for a prolonged period (Ta-
ble 2, entries l and m). In contrast, the properties of R
displayed prominent effect on the isolated yields. para-
Chloro substituted benzamides (Table 2, entries b, i,
and o) always afforded lower yields when compared with
benzamides (Table 2, entries a, h, and n) and substituted
benzamides containing electron-donating groups (Table
2, entries c, d, j, and p). However again a vague case was
observed in which a low yield was produced from 3,4,5-
trimethoxy-benzamide cyclization (Table 2, entry e).
Heterocyclic acylated substrates (Table 2, entries f, g,
k, and m) could not afford as much product as benz-
amides (Table 2, entries a, h, and n).
60
40
10
a Determined by HPLC at 215 nm and LC–MS.
on microwave assisted cyclization of benzamide 1a (Ta-
ble 1). With the decrease of the reaction temperature,
both conversions and yields dropped (Table 1, entries
4 and 6–10). Although the starting material disappeared
at 130 °C for 10 min, only 84% yield of expected product
was gained, which possibly suggested that higher tem-
perature might result in more by-products.
It is accepted that both thermal effect and specific micro-
wave effect may induce the acceleration of some reac-
tions somehow on irradiating with microwave. In
order to testify if the microwave speeds up the cycliza-
tion, the model reaction was conducted in a sealed
thick-walled tube under an identical condition but in-
stead heating in an oil bath. The time course results
are plotted in Figure 1. Microwave heated reactions
could produce, through all the way of the reactions’ pro-
cess, higher conversion of the starting material and high-
er yield of the product than when heated in traditional
oil bath (Fig. 1A and B). The differences are especially
significant within 5 min, 90% conversions for microwave
but only 50% for oil-bath heating. And to complete the
cyclization, it takes only 10 min by microwave heating
(Fig. 1A), while normally 10–24 h by previously re-
ported method. These results may elucidate that micro-
wave effect might play a certain role in the cyclization.
In summary, a rapid and straightforward method was
developed for the synthesis of 2-aryl-4-quinolone deriv-
atives from acylated 20-aminoacetophenones under the
irradiation of microwave and in the presence of NaOH.
The reaction time was dramatically reduced from 10 to
24 h by traditional oil bath heating to 10–22 min. A di-
verse range of 2-aryl-4-quinolone derivatives were syn-
thesized to demonstrate that the reported method
To expand the scope of this chemistry to more 2-aryl-4-
quinolone derivatives syntheses, a diverse set of sub-
strates 1a–p were selected and exposed to the irradiation
100
100
A
B
80
60
40
20
0
80
60
40
20
0
0
2
4
6
8
10
0
2
4
6
8
10
Time (min)
Time (min)
NaOH/heating
tBuOK/heating
NaOH/heating
NaOH/microwave
tBuOK/microwave
NaOH/microwave
tBuOK/microwave
tBuOK/heating
Figure 1. Comparison of the effect of microwave and oil-bath heating on the cyclization: (A) kinetic curves of conversion and (B) kinetic curves of
yield.

D. Ding et al. / Tetrahedron Letters 47 (2006) 6997–6999
Table 2. Preparation of 2-aryl-4-quinolones (Scheme 2)
6999
Entry
R
Ar
Time (min)
Yielda (%)
Mp (°C)
Ref.
a
b
c
d
e
H
H
H
H
H
H
H
Phenyl
10
10
10
10
10
10
12
10
10
10
10
22
18
10
10
10
85
67
81
81
63
69
74
87
64
79
73
57
63
84
65
95
251–253
252–254
292–294
234–235
232–234
282–284
>300
>300
>300
>300
>300
271–273
286–289
216–218
257–260
213–216
3b
3b
6
4-Chlorophenyl
4-Methoxyphenyl
2-Methoxyphenyl
3,4,5-Trimethoxyphenyl
4-Chloro-3-pyridyl
2-Thiophene
—
3b
—
—
3c
—
—
—
—
—
4c
—
—
f
g
h
i
j
k
l
m
n
o
p
4-Chloro
4-Chloro
4-Chloro
4-Chloro
4,5-Dimethoxy
4,5-Dimethoxy
3,4,5-Trimethoxy
3,4,5-Trimethoxy
3,4,5-Trimethoxy
Phenyl
4-Chlorophenyl
4-Methoxyphenyl
2-Thiophene
4-Methoxyphenyl
2-Thiophene
Phenyl
4-Chlorophenyl
4-Methoxyphenyl
a Isolated yields.
containing a magnetic stirring bar was charged with
compound 1p (107.4 mg, 0.3 mmol), NaOH (60 mg,
1.5 mmol) and 1.5 mL t-BuOH. The vial was sealed and
the resulting suspension was heated in the Biotage Initiator
Synthesizer under selected microwave conditions. The
conversion was monitored by HPLC and the product
analyzed by LC–MS. The reaction mixture was cooled and
poured onto 8 mL of water and adjusted to pH 5–6. The
solution was concentrated under reduced pressure until
copious solid appeared. The solid was collected and washed
successively with water and a cold mixture of acetone and
dichloromethane to give the pure product.
provided an opportunity to acquire many other
analogues.
Acknowledgements
This work was financially supported by the National
Natural Science Foundation of China (Grant
30230400).
8. All products were characterized by NMR, MS, and IR
spectroscopy. The following spectral data are representa-
tive: Compound 2d: white solid; yield 81%; mp: 234–235 °C.
1H NMR (400 MHz, DMSO-d6): d = 3.90 (s, 3H), 7.23–
7.26 (m, 1H), 7.29 (s, 1H), 7.34–7.36 (m, 1H), 7.67–7.71 (m,
2H), 7.76–7.80 (m, 1H), 8.03–8.07 (m, 1H), 8.14–8.16 (m,
1H), 8.34–8.36 (m, 1H); IR (KBr): 3425, 2941, 1639, 1599,
References and notes
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1496, 1456, 1365, 1248 cmꢀ1 13C NMR (100 MHz, DMSO-
.
d6): d = 56.1, 107.2, 112.4, 119.9, 120.0, 121.0, 121.2, 123.6,
127.2, 131.1, 133.4, 134.4, 139.6, 152.4, 156.8, 170.2. MS
(EI): m/z = 251 (M+), 236, 120. HRMS (EI): m/z calcd for
C16H13NO2 [M+]: 251.0946; found: 251.0947. Compound
2o: white solid; yield 65%; mp: 257–260 °C. 1H NMR
(400 MHz, DMSO-d6): d = 3.81 (s, 3H), 3.85 (s, 3H), 3.94
(s, 3H), 6.75 (s, 1H), 7.34 (s, 1H), 7.70 (d, 2H, J = 8.0 Hz),
7.93 (d, 2H, J = 8.0 Hz). IR (KBr): 3377, 2933, 1630, 1603,
1568, 1527, 1477, 1408, 1265 cmꢀ1 13C NMR (100 MHz,
.
DMSO-d6): d = 55.8, 61.1, 61.9, 95.9, 108.4, 114.2, 128.9
(2C), 129.1 (2C), 132.5, 135.1, 138.7, 139.5, 146.2, 152.1,
156.2, 176.2. MS (EI): m/z = 347, 345 (M+), 330, 315, 302,
287, 272. HRMS (EI): m/z calcd for C18H16NClO4 [M+]:
345.0768; found: 345.0755. Compound 2p: white solid;
1
yield: 95%; mp: 213–216 °C. H NMR (400 MHz, DMSO-
d6): d = 3.81 (s, 3H), 3.85 (s, 3H), 3.86 (s, 3H), 3.94 (s, 3H),
6.73 (s, 1H), 7.17–7.20 (m, 2H), 7.38 (s, 1H), 7.86–7.89 (m,
2H). IR (KBr): 3435, 2941, 2837, 1610, 1517, 1400,
1255 cmꢀ1 13C NMR (100 MHz, DMSO-d6): d = 55.6,
.
56.2, 61.1, 62.1, 96.9, 105.0, 111.4 (2C), 114.7, 124.6, 129.3
(2C), 139.6, 140.3, 150.0, 150.7, 157.4, 161.8, 172.0. MS
(EI): m/z = 341 (M+), 326, 315, 298, 283, 268. HRMS
(EI): m/z calcd for C19H19NO5 [M+]: 341.1263; found:
341.1268.
7. General experimental procedure: The preparation of 2p is
representative for all synthesis. A 10 mL Biotage vial