A simple, Efficient and solvent-Free reaction for the synthesis of quinolones using caesium iodide

Article abstract of DOI:10.3184/174751916X14531246648041

A series of quinoline derivatives has been synthesised from the reactions of 2-aminoacetophenone and 2-aminobenzophenone with different ketones in the presence of caesium iodide under solvent-free and thermal conditions. This method has the advantages of

Full text of DOI:10.3184/174751916X14531246648041

JOURNAL OF CHEMICAL RESEARCH 2016
VOL. 40 FEBRUARY, 97–100
RESEARCH PAPER 97
A simple, efficient and solvent-free reaction for the synthesis of quinolones
using caesium iodide
Nazanin Mokhtarpour, Hossein Eshghi*, Mehdi Bakavoli and Fatemeh Eshkil
Department of Chemistry, Faculty of Sciences, Ferdowsi University of Mashhad, 91775-1436 Mashhad, Iran
A series of quinoline derivatives has been synthesised from the reactions of 2-aminoacetophenone and 2-aminobenzophenone with
different ketones in the presence of caesium iodide under solvent-free and thermal conditions. This method has the advantages of good
yields, a clean reaction, simple methodology, short reaction times, easy work-up and green conditions.
Keywords: quinolones, caesium iodide, solvent-free, simple methodology, easy work-up, Friedländer synthesis
Quinoline and its derivatives display a wide spectrum of
biological activities such as antimalarial, antibacterial,
amines, 2,5-dimethoxytetrahydrofuran and dimethyl/diethyl
acetylenedicarboxylates in high yield at ambient temperature.
17
1,2
antidiabetic, and anti-inflammatory behaviour. Furthermore
Here we report a simple, efficient and solvent-free synthesis
of quinolines by using caesium iodide under thermal conditions.
Thus the treatment of o-amino-substituted aromatic ketones
with dicarbonyl compounds in the presence of caesium iodide
leads to the formation of various 2,3,4-trisubstituted quinolines
(Scheme 1) in excellent yields and in short reaction times.
3
cytotoxic agents like benzo[5,6]pyrrolizino[1,2-b]quinolines
4
and antitumour agents like camptothecin also contain quinoline
nuclei. The benzo[5,6]pyrrolizino[1,2-b]quinoline system,
which displays potent in vitro cytotoxic activity against MCF7
cells, is synthesised using the Friedländer quinoline synthesis
3
as a key step. Recently quinolines have also been shown to be
Results and discussion
potential agents for the treatment of erectile dysfunction as they
5
exhibit potent and selective PDE5 inhibitor activity.
For the reaction between 2-aminoacetophenone and dimedone,
to minimise the formation of byproducts and to achieve good
yields of the desired product 1, the reaction was optimised by
varying the amount of CsI catalyst (Table 1). The yields of the
product with 3, 5, 10 and 15 mol% of catalyst are 73%, 80%,
95% and 78%, respectively (Table 1, entries 2–5). The same
reaction when performed without catalyst for 5 h gave a low
yield of product 1. When the catalyst was increased to 20
mol%, the product yield decreased to 70% (Table 1, entry 6).
Therefore, it was found that the use of 10 mol% of the catalyst
was optimum.
Though numerous methods are available for the synthesis
of quinolines, the synthesis reported by Friedländer is of
great importance because it is simple and leads to a variety
of polysubstituted quinolines. The Friedländer annulation
is catalysed by both acids and bases, but the acids are more
effective. Brønsted acids like hydrochloric acid, sulfuric acid,
p-toluenesulfonic acid, citric acid and phosphoric acid have been
6
–8
widely used to effect the Friedländer condensation. However,
many of these classical methods require high temperature,
prolonged reaction time and drastic reaction conditions and the
yields are unsatisfactory due to the occurrence of side reactions.
To further optimise the reaction conditions, we conducted the
Friedländer condensation of 2-aminobenzophenone with ethyl
acetoacetate to the form desired quinoline 10 in the presence of
catalyst (10 mol%) in different solvents such as CH Cl , EtOH,
9
10
11
Lewis acids such as ZnCl , AuCl .3H O, SnCl .2H O,
2
3
2
2
2
12
13
14
Bi(OTf) , LiOTf and I2 are also found to be effective in the
3
Friedländer condensation, but the use of environmentally toxic
ZnCl and expensive AuCl limits their application.
2
2
MeOH, CH CN and CHCl (Table 2, entries 1–5). Reaction in
2
3
3
3
In order to avoid the toxic and chronic effects of organic
solvents, the solvent-free microwave-assisted synthesis of
CHCl and dichloromethane (DCM) gave low product yields
3
even after 16 h (Table 2, entries 1 and 2) and the yields were
moderate in the case of methanol, acetonitrile and ethanol under
reflux (Table 2, entries 3–5). The best results were obtained
when the reaction was carried out in solvent-free conditions at
100 °C for 30 min in the presence of catalyst (Table 2, entry 6).
Therefore, solvent-free conditions were selected for the reaction.
Our investigations clarified that the best results can be
obtained when the reaction was performed in the absence
of solvent at 100 °C using 10 mol% of CsI as catalyst. The
results of the reaction between 2-aminoacetophenone and
2-aminobenzophenone with various carbonyl compounds in
15
16
quinolones was reported by Ranu et al. and Song et al. but
these microwave-assisted syntheses are not suitable for large
scale production. Since quinoline derivatives are increasingly
useful and important in drugs and pharmaceuticals, the
development of a simple, eco-benign and high-yielding protocol
is desirable.
Recently we reported the efficiency of caesium iodide as a
convenient catalyst for the synthesis of N-substituted azepines
under aqueous conditions. These one-pot three-component
cyclisations were carried out by the reaction of aromatic
R1
O
O
R3
R1
NH2
R3
CsI
+
R2
R2
Solvent free, heat
N
1
1-12
R =CH , Ph
3
Scheme 1
*
Correspondent. E-mail: heshghi@um.ac.ir

98 JOURNAL OF CHEMICAL RESEARCH 2016
Table 1 Effect of amount of catalyst on the synthesis of compound 1
O
O
CH3
N
O
CH3
CsI
+
CH3
CH3 Solvent free
CH3
CH3
NH2
O
o
1
00 C
1
a,b
Entry
1
2
Catalyst/mol%
Time/h
Yield/%
43
–
3
5
2
73
3
5
1
80
4
5
6
10
15
20
0.5
1
1.5
95
78
70
a
b
Isolated yield of product 1.
Reaction conditions: 2-aminoacetophenone (1.2 mmol), dimedone (1.0 mmol) in the presence of CsI catalyst under solvent-free conditions.
a
Table 2 Effect of solvent on the reaction times and yields of compound 10
O
Ph
N
O
O
O
Ph
CsI
OEt
CH3
+
H C
OEt
3
Solvent
NH2
o
1
00 C
10
b
Entry
Solvent
CH Cl
CHCl3
Temperature/°C
Time/h
16
16
16
16
Yield/%
30
27
78
62
1
2
3
4
5
6
38
60
82
63
78
2
2
CH CN
3
MeOH
EtOH
–
16
1
73
93
100
a
b
Reaction conditions: 2-aminobenzophenone (1.2 mmol), ethyl acetoacetate (1.0 mmol) in the presence of CsI catalyst (0.1 mmol) under reflux in various solvents.
Isolated yield of product 10.
R1
HO
O
R3
Cs
CsI
O
O
O
-HI
R1
CsI
R3
+
R2
R3
R3
R2
R2
R2
NH2
NH2
O
R1
R1
R1
R3
R2
OH
R3
-H O
2
R3
-
H O
2
R2
N
H
N
R2
NH O
2
Scheme 2 Proposed mechanism.
O
O
O
NH2
O
CsI (10 mole %)
100 °C, 25 min
H
O
+
or
NH2
O
N
O
14
94%
13 not formed
Scheme 3

JOURNAL OF CHEMICAL RESEARCH 2016 99
a
Table 3 Synthesis of quinoline derivatives in the presence of CsI
the presence of caesium iodide under solvent-free conditions at
100 °C are shown in Table 3.
1
b
Entry
R
Ketone
Product
Time/min Yield/%
According to Table 3, a series of polyfunctionalised quinolines
were easily prepared in excellent yields by a Friedländer
reaction of o-aminoaryl ketones with α-methylene ketones
using caesium iodide as a catalyst under solvent-free conditions.
In these reactions, among α-methylene carbonyl compounds,
dimedone and 1,3-cyclohexanedione gave better isolated
yields. In the case of cyclic ketones, acridine derivatives were
obtained in high yields. Acylic dicarbonyl compounds also gave
O
1
CH3
30
35
45
55
60
45
40
50
70
60
50
50
93
96
88
85
74
89
93
84
80
93
79
80
O
O
N
1
2
3
4
O
2
3
4
5
6
7
8
9
CH3
CH3
CH3
CH3
Ph
O
O
N
2
,3,4-trisubstituted quinolones in high yields.
The suggested mechanism of the CsI catalysed transformation
is shown in Scheme 2. Caesium iodide is suggested to catalyse
efficiently enol formation, dehydration and final condensation.
We decided to attempt to prepare acridinone 13 by reaction of
O
N
2
-aminobenzaldehyde with dimedone under optimised reaction
conditions. (Scheme 3). Unexpectedly, xanthene derivative 14
was formed in 94% yield instead of compound 13.
O
Experimental
N
Chemicals and apparatus
All solvents, reagents and compounds were purchased from Merck
and Fluka. FTIR spectra were recorded on an AVATAR-370-FTIR
Thermo Nicolet. Mass spectra were recorded on a Varian Mat CH-7
instrument at 70 eV. Reactions were monitored by TLC using silica
gel plates and the products were identified by comparison of their
spectra and physical data with those of the authentic samples. Melting
points were measured on an Electrothermal 9100 apparatus. NMR
spectra were recorded on an ASPECT 3000 Avance Brucker-400 MHz
spectrometer. All chemical shifts in NMR experiments are reported as
ppm and were referenced to residual solvent.
O
O
O
O
O
N
5
Ph
N
O
O
O
6
7
8
9
Synthesis of quinolines 1–12 and xanthene 14; general procedure
Ph
N
O
Typically, 2-aminoacetophenone or 2-aminobenzophenone (1.2 mmol)
with an enolisable ketone (1 mmol) was uniformly mixed with CsI
Ph
O
O
(
20 mg, 10 mol%) at 100 °C. After reaction completion, as indicated
by TLC, the reaction mixture was cooled, diluted with CH CN
3
Ph
N
(5 mL) and filtered. The filtrate was concentrated and the product
was recrystallised or purified by column chromatography (for
spectroscopic characterisation) on silica gel using ethyl acetate/n-
hexane as eluent.
O
Ph
3
,3,9-Trimethyl-3,4-dihydroacridin-1(2H)-one (1): Yield 93%; m.p.
18
–1
9
5 °C (lit. not reported); IR (KBr, cm ): 2962, 2955, 2921, 2864,
2845, 1681, 1672, 1560, 1215, 762; H NMR (400 MHz, DMSO-d ): δ
8.23 (d, J = 8.4 Hz, 1H), 8.02 (d, J = 8.4 Hz, 1H), 7.78 (dt, J = 6.9, 1.2
Ph
N
1
O
6
Ph
Hz, 1H), 7.58 (dt, J = 6.9, 1.2 Hz, 1H), 3.19 (s, 2H, CH ), 3.08 (s, 3H,
2
+
CH ), 2.68 (s, 2H, CH ), 1.15 (s, 6H, 2CH ); MS (m/z): 239 (M ), 237,
3
2
3
2
22, 209, 194, 182, 153, 139, 115, 71.
9-Methyl-3,4-dihydroacridin-1(2H)-one (2): Yield 96%; m.p.
Ph
N
O
O
O
O
19
–1
63–64 °C (lit. 64–66 °C); IR (KBr, cm ): 3061, 2944, 2871, 1677,
10
Ph
O
1
1
=
603, 1563, 1374, 855; H NMR (400 MHz, DMSO-d ): δ 8.20 (d, J
6
10
8.0 Hz, 1H), 8.00 (d, J = 8.0 Hz, 1H), 7.77 (dt, J = 8.0, 1.2 Hz, 1H),
7
.57 (dt, J = 8.0, 1.2 Hz, 1H), 3.27 (t, J = 6.9 Hz, 2H), 3.04 (s, 3H), 2.8
Ph
N
O
13
(t, J = 6.4 Hz, 2H), 2.20 (quint, J = 6.4 Hz, 2H); C NMR (100 MHz,
O
O
O
CDCl3): δ 197.9, 162.2, 151.6, 148.4, 137.5, 131.8, 129.9, 128.1, 128.0,
11
Ph
O
+
127.5, 40.6, 34.4, 22.7, 21.5; MS (m/z): 211 (M ), 209, 182, 166, 139,
11
126, 85, 71.
9
-Methyl-1,2,3,4-tetrahydroacridine (3): Yield 88%, m.p. 74–75 °C
Ph
N
O
19
–1
(
7
lit. 76–77 °C); IR (KBr, cm ): 2930, 2859, 1638, 1581, 1451, 1380,
50; H NMR (400 MHz, DMSO-d ): δ 8.22 (d, J = 8.4 Hz, 1H), 8.04
(d, J = 8.4 Hz, 1H), 7.69 (t, J = 8.0 Hz, 1H), 7.55 (t, J = 8.0 Hz, 1H), 3.27
O
O
1
6
12
Ph
12
+
(
m, 2H), 2.9 (m, 2H), 2.64 (s, 3H), 1.98 (m, 4H); MS (m/z): 197 (M ),
1
82, 167, 153, 128, 115, 77.
a
Reaction conditions: 2-aminoacetophenone or 2-aminobenzophenone (1.2 mmol),
9
-Methyl-2,3-dihydro-1H-cyclopenta[b]quinoline (4): Yield 85%;
α-methylene carbonyl compound (1.0 mmol) in the presence of CsI catalyst (0.1 mmol)
under solvent-free conditions at 100 °C.
b
19
–1
m.p: 57–58 °C (lit. 58–60 °C); IR (KBr, cm ): 3227, 2982, 1593,
1377, 1212; H NMR (400 MHz, DMSO-d ): δ 8.02 (d, J = 8.4 Hz, 1H),
7.95 (d, J = 8.4 Hz, 1H), 7.63 (t, J = 7.2 Hz, 1H), 7.49 (t, J = 7.2 Hz,
1
6
Isolated yield of products.

100 JOURNAL OF CHEMICAL RESEARCH 2016
1
H), 3.18 (t, J = 7.6 Hz, 2H), 3.07 (t, J = 7.6 Hz, 2H), 2.59 (s, 3H), 2.21
lower catalyst loading and cost efficiency render this approach
as an interesting alternative.
+
(
quint, J = 7.6 Hz, 2H); MS (m/z): 182 (M ), 167, 154, 127, 83, 71.
,3-Dimethyl-9-phenyl-3,4-dihydroacridin-1(2H)-one (6): Yield:
3
2
0
–1
89%; m.p. 189–190 °C (lit. 191 °C); IR (KBr, cm ): 3068, 3035, 2949,
We are grateful to Ferdowsi University of Mashhad Research
Council for their financial support of this work (Grant:
3/333473).
1
2937, 2892, 2864, 1687, 1605, 1560, 1484, 1220, 772, 697; H NMR
(400 MHz, DMSO-d ): δ 8.08 (d, J = 8.4 Hz, 1H), 7.78 (dt, J = 6.8,
6
1.6 Hz, 1H), 7.47–7.55 (m, 4H), 7.43 (dt, J = 8.0, 1.2 Hz, 1H), 7.2 (dd,
J = 7.2, 1.6 Hz, 2H), 3.29 (s, 2H, CH ), 2.59 (s, 2H, CH ), 1.18 (s, 6H,
2
2
Received 10 July 2015; accepted 6 January 2016
Paper 1503483 doi: 10.3184/174751916X14531246648041
Published online: 29 January 2016
+
2
CH ); MS (m/z): 301 (M ), 299, 270, 244, 216, 196, 85, 71.
3
9
-Phenyl-3,4-dihydroacridin-1(2H)-one (7): Yield: 93%; m.p.
21
–1
1
1
8
53–155 °C (lit. 153–156 °C); IR (KBr, cm ): 3043, 2948, 2876, 1689,
555, 1486, 764, 703; H NMR (400 MHz, DMSO-d ): δ 8.08 (d, J =
1
6
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2
2
–1
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2
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(
t, J = 7.6 Hz, 2H), 2.93 (t, J = 7.6 Hz, 2H), 2.18 (quint, J = 7.6 Hz, 2H);
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6
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(
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+
8
9
m/z): 245 (M ), 243, 215, 201, 188, 168, 167, 138, 120, 108.
2
9
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10
–1
1
DMSO-d ): δ 10.47 (bs, NH2), 7.15 (dt, J = 7.0, 1.2 Hz, 1H), 6.59–7.05
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(m, 3H), 4.66 (s, 1H), 2.60 (d, J = 7.0 Hz, 1H), 2.47 (d, J = 7.0 Hz, 1H),
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1
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+
(s, 3H), 1.03 (s, 3H), 0.99 (s, 6H); MS (m/z): 365 (M ), 364, 280, 265,
2
26, 210, 171, 149, 134, 107, 83, 78. Anal. calcd for C H NO : C,
2
3
27
3
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2
2
The melting points of the other products were: 8, 135–137 °C (lit.
2
2
22
136–138 °C; 10; 99–102 °C (lit. 100–102 °C); 11, 86–97 °C (lit.
2
2
8
6–88 °C); 12, 109–110 °C (lit. 108–110 °C) and compound 5 was an
18
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19
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Conclusion
In conclusion, a one-pot, mild, efficient, and environmentally
benign protocol has been developed for the synthesis of
quinoline derivatives catalysed by caesium iodide in high yields.
Compared to previously reported methods, moreover, the
mild reaction conditions, easy work-up, clean reaction profiles,
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2
2
2
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