Solvent-free synthesis of quinolone derivatives

Article abstract of DOI:10.3987/COM-04-10118

Quinolones can be prepared in a three step procedure from triethylorthoformate and activated methylene derivatives leading to alkoxymethylenemalonates followed by reaction with aromatic amines and finally a cyclization. All the reactions were carried out under solvent-free conditions possibly under microwave activation with benefits for the first step.

Full text of DOI:10.3987/COM-04-10118

HETEROCYCLES, Vol. 64, 2004
177
HETEROCYCLES, Vol. 64, 2004, pp. 177 - 191
Received, 11th May, 2004, Accepted, 24th June, 2004, Published online, 25th June, 2004
SOLVENT-FREE SYNTHESIS OF QUINOLONE DERIVATIVES
Petra Černuchová,a,b Giang Vo-Thanh,b Viktor Milata,*a and André Loupy*b
aDepartment of Organic Chemistry, Faculty of Chemical and Food Technology,
Slovak Technical University, Radlinského 9, SK-812 37 Bratislava, Slovak
Republic. Fax: 421 2 52 96 85 60; Phone: 421 2 59 32 51 48; E-mail:
viktor.milata@stuba.sk
bLaboratory of Selective Reactions on Supports, ICMMO, CNRS UMR 8615,
Building 410, Paris-South University, 91405 Orsay-Cedex, France. Fax: 33 1 69
15 46 79; Phone: 33 1 69 15 76 50; E-mail: aloupy@icmo.u-psud.fr
Dedicated to Professor Pierre Potier on the occasion of his 70th birthday.
Abstract – Quinolones can be prepared in a three step procedure from
triethylorthoformate and activated methylene derivatives leading to
alkoxymethylenemalonates followed by reaction with aromatic amines and finally
a cyclization. All the reactions were carried out under solvent-free conditions
possibly under microwave activation with benefits for the first step.
INTRODUCTION
Many compounds possessing a pyridone-3-carboxylic acid fragment have been synthesized and evaluated
as potential antibacterial agents during the last half century.1 First generation drugs , e.g. nalidixic acid (1)
and oxolinic acid (2), exhibit activity against most Gram-negative bacteria but they are inactive against
Pseudomonas aeruginosa and Gram-positive bacteria.2 Subsequent structural modifications have led to
new analogues, second generation drugs, with improved antibacterial potency and activity against
P.aeruginosa.3 The third generation agents, like norfloxacin (3), pefloxacin (4), ciprofloxacin (5) and
ofloxacin (6), which are 6-fluorinated compounds mostly with a piperazinyl substituent in position 7,4
present greater activity against Gram negative bacteria including P. aeruginosa and high activity against
most Gram–positive organisms.

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HETEROCYCLES, Vol. 64, 2004
O
O
N
O
COOH
F
COOH
R2
R3
COOH
H3C
N
N
N
N
C2H5
N
O
R1
H3C
CH3
1
6
2 R1 = C2H5, R2,R3 = -CH2-O-CH2-
3 R1 = C2H5, R2 = F, R3 = 1-piperazinyl
4 R1 = C2H5, R2 = F, R3 = 4-methyl-1-piperazinyl
5 R1 = cyclopropyl, R2 = F, R3 = 1-piperazinyl
Scheme 1: Some characteristic quinolones derivatives
As already described in the literature, the 4-quinolone ring construction is generally realized by the
Gould-Jacobs reaction.5 This process includes the reaction between aromatic amines and
alkoxymethylene compounds, followed by a thermal cyclization as shown in Scheme 2.6 Starting
alkoxymethylenemalonates are obviously prepared by condensation of trialkyl orthoformates with
appropriate methylene components.
O
Y
ArNH2
X
Y
X
Y
Ac2O
cat
X = COOC2H5
CH2XY + HC(OR)3
RO
ArHN
N
H
X, Y = COOC2H5, COCH3, CN
R = alkyl
Ar = aryl
Scheme 2: Synthesis of quinolones derivatives
Nowadays, there is an increased interest for organic synthesis under clean and efficient solvent-free
procedures and additionally, in adapted cases, activation by microwave (MW) irradiation.7 The
synthesis of several quinolones was already described using MW irradiation.8 The solvent-free method is
proved to be often more efficient than classical procedures and constitutes an evident simplification of
workup and treatments within the frame of “Green Chemistry”, as avoiding the use of added organic
solvent during the reactions.9 So we present here the solvent-free synthesis of quinolone derivatives
bearing an electronwithdrawing group Y in position 3 (Scheme 2).
RESULTS AND DISCUSSION
Preparation of disubstituted alkoxymethylene derivatives (9)

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179
Alkoxymethylene derivatives (9) were prepared by condensation of triethyl orthoformate (8) with
activated methylene derivatives (7)10 at 125°C using MW irradiation under accurately controlled
conditions (monomode reactor with measurement and monitoring of pressure, emitted MW power and
temperature). The influence of the presence of acetic anhydride and Brönsted acid (KSF montmorillonite)
or Lewis catalyst (ZnCl2) in the reaction was studied (Scheme 3).
X
Y
Ac2O
cat.
CH2XY + HC(OC2H5)3
C2H5O
7a-d
8
9a-d
a) X= Y = COCH3, b) X= COCH3, Y= CO2C2H5, c) X= CN, Y = CO2C2H5, d) X = Y = CN
Scheme 3: Synthesis of alkoxymethylene derivatives
The main results are given in Table 1.
Table 1: Condensation of triethyl orthoformate with activated methylene derivatives at 125 °C
a
b
Entry Compound 8:7:Ac2O Cat
Time
(min)
MW
∆
c
c
c
c
Yield% 9 Conv. 7 Yield% 9 Conv. 7
1
2
9a
9b
9c
9d
1.5:1:1
1.5:1:1.5
1.5:1:1
1.5:1:1
1.5:1:1.5
1.5:1:1.
1.5:1:1
1.5:1:1
-
40
40
70
83
61
78
89
64
81
75
78
93
83
95
76
82
90
71
85
83
80
99
62
-
74
-
-
KSF
-
3
15
38
82
-
47
86
-
4
105
105
15
5
-
6
KSF
-
44
66
74
76
68
46
77
85
77
78
7
120
120
60
8
KSF
9
1.5:1:1 ZnCl2
1.5:1:1
10
-
15
a
Reactions were conducted in open vessels using a CEM monomode system.
b
Reactions were conducted under strictly identical conditions (same open vessels, in situ temperature followed by an
optical fiber, mechanical stirring, etc...).
c
Yields and conversions were determined by GC using an internal standard (ethyl benzoate or methyl benzoate).

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The best results were obtained (Entries 2, 5, 7 and 10) when slight excesses of orthoester (8) and acetic
anhydride were used (1.5 equiv.). The effect of acid catalyst (KSF or ZnCl2) was not favorable.
In all the cases tested, a strict comparison of the results obtained by conventional heating (∆) and MW
activation under identical conditions was made (vessels, reaction time, temperature ramp). MW irradiation
appears to be advantageous in the majority of cases (Entries 1, 3, 6, 7, 10) but to be ineffective in other
examples (Entries 4, 8, 9).
This observation is consistent with mechanistic considerations as the mechanism involves the development
of dipoles in the transition state and therefore an increase in the polarity of the system during the reaction
progress starting from the ground state towards the transition state (Scheme 4), which induces a specific
MW enhancement due to lowing in the activation energy (Figure 1).11
C2H5
C O
C2H5
C O
O
O
δ-
δ+
GS
TS
Scheme 4: Mechanism of condensation.
TS
∆G∆
∆GMW
GS
∆GMW
<
∆G∆
Figure 1: Relative stabilisation of ground (GS) and transition states (TS) by dipole-dipole
interaction with electric field for a more polar TS.
Reaction of 9 with aromatic amines
Nitrogen nucleophiles are the most frequently ones used to displace alkoxy group and provide

HETEROCYCLES, Vol. 64, 2004
181
aminoethylenemalonates which could be formally considered as aminoethylene derivatives with
substituents in the β-position(s).10a, 12
We have applied the combination of solvent-free reaction and MW irradiation in order to prepare
disubstituted aminomethylene derivatives (Scheme 5).
H
X
Ar
X
+
Ar NH2
N
H
C2H5O
Y
Y
9a-e
10a-e
11a-e
a) X= Y = COCH3, b) X= COCH3, Y= CO2C2H5, c) X= CN, Y = CO2C2H5, d) X = Y = CN, e) X = Y = CO2C2H5
10 ArNH2 = aniline
11 ArNH2 = 6-aminoquinoxaline
Scheme 5: Synthesis of aminomethylene derivatives
The main results are presented in Table 2.
Table 2: Solvent-free addition-elimination reaction between aniline (2 min, 70 °C) or aminoquinoxaline
(10 min, 120 °C) and disubstituted alkoxymethylene derivatives
a
Compound
Yield of 10(%)
MW
93
∆
10a
10b
10c
10d
10e
11a
11b
11c
89
98
95
94
96
92
91
96
93
95
97
91
95
b
b
82
80
87
b
b
11d
86
11e
91
92
a
Isolated yield by flash chromatography
Isolated yield by precipitation
b
Very good yields were obtained within very short reaction times. Comparable yields were obtained under

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conventional heating and MW irradiation in the identical conditions. No MW specific effects were
observed in this case and microwaves are only limited to purely thermal effects. This observation is
consistent with the fact that this reaction is very easy (with a very low activation energy) with a
reactant-like transition state. Therefore, the change in polarity of the system from the ground state to its
transition state is rather limited, what is not in favor for the intervention of any specific MW effects.11
On another hand, when the reaction was performed more classically in refluxing ethanol or toluene for
1-6 h, 48-80% of the yields were obtained. This results proves that the solvent-free method is by far more
suitable in this case.9
Intramolecular cyclization of 10 into 12
The Gould-Jacobs reaction13 is a useful tool in organic synthesis to form antibacterial quinolone systems
(Scheme 6). Generally, high boiling solvents such as biphenyl or diphenyl ether have been used for
thermal processes which complicate workup and recovery.14 To avoid this problem, a study of this
reaction has been carried out under solvent-free conditions.
Firstly the thermal cyclizations of aminomethylenemalonates (10b,c,e) were performed under classical
conditions in refluxing diphenyl ether. The cyclic products (12b,c,e) were obtained with satisfactory
yields from starting materials, where at least one of the electron withdrawing groups is ethoxycarbonyl
group5 (Table 3).
O
X
H
X
N
H
N
H
b) X= COCH3
c) X=CN
COOC2H5
e) X= CO2C2H5
12b,c,e
10b,c,e (Z+E)
Scheme 6: Cyclization of aminomethylenemalonates into quinolones (Gould-Jacobs reaction)
Table 3 : Thermal cyclization of aminomethylenemalonates in diphenyl ether.
a
Entry Compound
10 (E/Z)
Temperature (°C) Time (h)
Yield % 12
1
2
3
4
5
6
12b
12c
90/10
75/25
255
255
265
265
265
255
1
3
65
45
60
40
66
80
2
3
30/70
-
2
12e
0.75
a
Yield in isolated product obtained by precipitation

HETEROCYCLES, Vol. 64, 2004
183
When considering the mechanism for cyclization,15 we assume that only the isomer Z of compound (10c)
can be cyclized and forms the desired product (12c) (Scheme 7). It was found that the isomerisation E→
Z of (10c) took place by increasing the time and the temperature. As demonstrated in Table 3 (see Entries
2-5), the initial proportion of two isomers of 10c is not important in the thermal cyclization, presumably
due to isomerisation occuring during the reaction conditions.
NC
Y
Y
CN
N
H
N
H
(E-)
(Z-)
O
CN
N
H
Y = COOC2H5
Scheme 7: Influence of isomer geometry in the cyclization of (10c).
Further cyclization of (10e) (Y = COOC2H5) (Scheme 6) under solvent-free conditions either under MW
irradiation or in a thermostatted metallic bath at the same temperature (250°C) was studied. Only 27%
yields in 12e was obtained whatever the mode of activation (conversions were 51 and 93% under MW
and ∆ respectively).
As already described in the literature,14 the temperature was a critical point to minimize the
decomposition in cyclized products. Next experiments were realized without solvent in a metallic bath at
higher temperatures. Decreases in yields and important degradations were observed by extending reaction
times. The profile of yields at different temperatures is shown in Figure 2.
70
60
50
40
382°C
344°C
304°C
280°C
30
20
10
0
0
100
200
300
400
500
600
Time (s)
Figure 2: The profile of yields at different temperatures

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The best result (60% yield) under solvent-free conditions was obtained at 380 °C for only 30 sec (Table
4). This yield is however lower than the one obtained when the reaction was performed in diphenyl ether
(80% Entry 6 in Table 3). It is nevertheless of interest when one considers the simplicity of work-up
when the use of high boiling solvent is avoided.
Table 4: Solvent-free thermal cyclization of diethyl phenylaminomethylenemalonate (10e) (380 °C,
metallic bath)
a
b
Time (s)
Yield % 12e
Conversion % 10e
20
25
30
35
20
47
60
44
12
58
82
90
a
Yield after precipitation
b
Conversion determined by GC
CONCLUSIONS
In conclusion, we have developed a three step solvent-free procedure for the synthesis of quinolone
derivatives. Non-thermal microwave specific effect was observed in the preparation of
alkoxymethylenemalonates. It was also found that a slight excess of triethyl orthoformate improved the
yield of this condensation. Aminomethylene derivatives were obtained in very good yields within short
reaction times. Thermal cyclization of diethyl phenylaminomethylenemalonate was studied under
solvent-free conditions and the results confirm that high temperatures and short reaction times are crucial
to avoid the decomposition of generated product.
EXPERIMENTAL
Microwave experiments were conducted using monomode systems (focused waves thanks to
a well-dimensionned wave guide):
CEM Discover Synthesis Unit operating at 2.45 GHz monitored by a PC computer. Waves are focussed
by a circular wave-guide all round the cavity. Temperature was measured by optical fiber or IR detection
with continuous feedback temperature control and maintained at a constant value by power modulation
(0-300 W). Stirrring was provided with in situ magnetic variable speed stirrer when reactions were
perfomed in closed vessels under controlled pressure or with a mechanical stirring in the case of reactions

HETEROCYCLES, Vol. 64, 2004
185
in open vessels. Reactions were performed either in glass vessels (capacity 10 mL) sealed with a septum
or in open vessels (capacity 100-250 mL). The pressure was controlled by a load cell connected to the
vessels via a needle which penetrated just bellow the septum surface.
Prolabo-Synthewave 402 with focused waves operating at 2.45 GHz. The temperature was controlled all
along the reaction and evaluated by an infrared detector which indicated the surface temperature (the IR
detector was calibrated by tuning the emissivity factor using an optical fiber introduced into the reaction
mixture). Temperature was maintained constant at a chosen value by modulation of emitted power.
Mechanical stirring all along the irradiation provided a good homogeneity (power and temperature) and
a data treatment which was followed by a computer. All reactions were performed in cylindrical Pyrex
open vessels.
Melting points were measured with a Kofler bank. NMR spectra were recorded in CDCl3 or DMSO-d6.
1H NMR spectra were recorded at 200 or 250 MHz. Chemical shifts (δ) are reported in ppm relative to
TMS as an internal standard. J values are given in Hz. 13C NMR spectra were recorded at 62.5 or 50 MHz.
IR spectra were recorded with an FT-IR Perkin-Elmer instrument. MS was performed with MS 902S
(AEI Kratos) spectrometer. TLC was carried out with 0.2 mm thick silica gel plates (GF254). The columns
were hand packed with silica gel 60 (200-300).
General procedure for the preparation of alkoxymethylene malonates (9a-d)
A mixture of activated methylene derivative (5 mmol), triethyl orthoformate (1-1.5 equiv.) and acetic
anhydride (1-1.5 equiv.) was irradiated under microwave (CEM Discover System) at 125 °C for the
appropriate time (see Table 1). After cooling, the crude products were purified by flash chromatography
to afford the corresponding alkoxymethylenemalonates.
The yields of 9 and conversions of 7 were determined by capillary gas chromatography using an internal
standard (Table 5). All these products have already been described in the literature.16
Table 5: GC conditions and retention times for reactants and products
Compd
GC column, temperature program
Internal
Retention times (min)
standard Standard
7
9
9a
DB1 (30 m x 0.25 mm x 0.1 µm), injector
ethyl
8.27
2.85
6.01
2.85
3.64
9.61
and detector at 250 °C, 50 °C-250 °C with benzoate
10 °C min-1, carrier gas helium 70 kPa
9b
9c
9d
BP1 (12 m x 0.25 mm x 0.1 µm), injector
methyl
1.82
3.90
1.21
5.95,
6.20
(Z+E)
and detector at 250 °C, 70 °C-250 °C with benzoate
10 °C min-1, carrier gas helium 53 kPa
DB1 (30 m x 0.25 mm x 0.1 µm), injector
ethyl
8.74
and detector at 250 °C, 80 °C-250 °C with benzoate
10 °C min-1, carrier gas helium 70 kPa
BP1 (12 m x 0.25 mm x 0.1 µm), injector
methyl
3.89
and detector at 250 °C, 70 °C-250 °C with benzoate
10 °C min-1, carrier gas helium 53 kPa

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3-(Ethoxymethylene)pentane-2,4-dione (9a) 1H NMR (CDCl3) δ 1.43 (t, J = 7.2 Hz, 3H), 2.34 (s, 3H),
13
2.41 (s, 3H), 4.28 (q, J = 7.4 Hz, 2H), 7.73 (s, 1H); C NMR (CDCl3) δ 14.9, 29.0, 31.8, 66.9, 121.7,
165.7, 196.8, 197.5. IR (cm-1): ν = 1676, 1622, 1582, 1135. MS (m/z) 156 (M+).
2-Ethoxymethylene-3-oxobutanoic acid ethyl ester (9b): two isomers Z and E were observed. 1H NMR
(CDCl3) δ 1.27-1.42 (m, 6H), 2.33 and 2.39 (s, 3H), 4.19-4.33 (m, 4H), 7.63 and 7.66 (s, 1H); 13C NMR
(CDCl3) δ 13.9, 15.0, 28.5 and 31.4, 60.3 and 60.4, 72.5, 113.2 and 114.0, 163.9, 165.1, 195.0 and 196.5.
IR (cm-1): ν= 1726, 1702, 1630, 1135. MS (m/z) 186 (M+).
2-Cyano-3-ethoxyacrylic acid ethyl ester (9c) 1H NMR (CDCl3) δ 1.32 (t, J = 7.0 Hz, 3H), 1.44 (t, J =
13
7.3 Hz, 3H), 4.22-4.39 (m, 4H), 8.00 (s, 3H); C NMR (CDCl3) δ 13.9, 15.0, 61.4, 73.7, 86.2, 112.6,
162.8, 172.2. IR (cm-1): ν = 2227, 1713, 1619, 1130. MS (m/z) 169 (M+).
2-(Ethoxymethylene)malononitrile (9d) 1H NMR (CDCl3) δ 1.45 (t, J = 7.2 Hz, 3H), 4.39 (q, J = 6.8 Hz,
2H); 13C NMR (CDCl3) δ 14.5, 66.4, 109.3, 111.5, 173.7. IR (cm-1): ν = 2228, 1612, 1008. MS (m/z) 122
(M+).
General procedure for the preparation of aminomethylenemalonates (10a-e) from aniline.
A mixture of aniline (0.2 mL, 2.19 mmol) and alkoxymethylene compound (2.19 mmol) was submitted to
microwave irradiation (Prolabo-Synthewave 402) at 70 °C for 2 min. The reaction mixture was cooled to
rt and diluted with dichloromethane. After evaporation, the crude products were purified by flash
chromatography (AcOEt : heptane = 2 : 8) to gave the corresponding aminoethylene malonates. All
products have already been described in the literature.
3-(Phenylaminomethylene)pentane-2,4-dione (10a)17 mp 85 °C (lit., 88°C). 1H NMR (CDCl3) δ 2.39 (s,
3H), 2.57 (s, 3H), 7.17-7.27 (m, 3H), 7.39-7.42 (m, 2H), 8.25 (d, J =12.7 Hz, 1H), 12.74 (d, J = 12.8 Hz,
1H); 13C NMR (CDCl3) δ 27.4, 32.1, 113.3, 117.9, 125.8, 130.0, 139.1, 151.9, 194.9, 201.2. IR (cm-1): ν
= 3054, 2998, 1628, 1600. MS (m/z) 203 (M+).
2-Acetyl-3-(phenylamino)acrylic acid ethyl ester (10b)17,18 two isomers Z and E were observed (E : Z =
1
90 :10) mp 38-41 °C (lit., 41-43 °C). H NMR (CDCl3) δ 1.25-1.42 (m, 3H, E and Z), 2.48 (s, 3H, Z),
2.54 (s, 3H, E), 4.20-4.33 (m, 2H, E and Z), 7.13-7.20 (m, 3H), 7.33-7.41 (m, 2H), 8.49 (d, J = 13 Hz, 1H,
E), 8.62 (d, J = 14 Hz, 1H, Z), 12.76 (d, J = 13 Hz, 1H, E); 13C NMR (CDCl3) δ 14.5, 31.2, 59.9, 102.6,
117.7, 125.5, 129.8, 139.0, 152.0, 166.9, 200.2. IR (cm-1): ν = 2977, 1702, 1636, 1600, 1576. MS (m/z)
233 (M+).
2-Cyano-3-(phenylamino)acrylic acid ethyl ester (10c)6,19 two isomers Z and E were observed (E : Z =
75 :25) mp 114 °C (lit., 108 °C). 1H NMR (CDCl3) δ 1.31-1.41 (m, 3H, E and Z), 4,29 (q, 2H, E and Z),
7,08-7,27 (m, 3H), 7.37-7.45 (m, 2H), 7,88 (d, J = 14 Hz, 1H, Z), 8.16 (d, J = 15 Hz, 1H, E), 8.43 (d, J =

HETEROCYCLES, Vol. 64, 2004
187
15 Hz, 1H, E), 10.74 (d, J = 14 Hz, 1H, Z); 13C NMR (CDCl3) δ 14.3, 61.2, 66.7, 115.8, 117.1 (Z), 117.4
(E), 125.5 (E), 125.7 (Z), 129.9 (E), 130.0 (Z), 138.3 (Z), 138.8 (E), 152.0, 166.7. IR (cm-1): ν = 2214,
1702, 1672, 1634, 1603, 1589. MS (m/z) 216 (M+).
2-(Phenylaminomethylene)malononitrile (10d)19 mp 245-247 °C (lit., 240-242 °C). 1H NMR (DMSO-
d6) δ 7.13-7.45 (m, 5H), 8.50 (d, J = 14 Hz, 1H), 11.13 (d, J = 14 Hz, 1H) ; 13C NMR (DMSO-d6) δ 53.0,
115.3, 117.6, 119.0, 126.2, 130.4, 140.2, 156.6. IR (cm-1): ν = 3211, 2223, 2210, 1659, 1593. MS (m/z)
169 (M+).
1
2-(Phenylaminomethylene)malonic diethyl ester (10e)6,12,13 mp 47-49 °C (lit., 49-51 °C). H NMR
(CDCl3) δ 1.27-1.40 (m, 6H), 4.18-4.34 (m, 4H), 7.10-7.17 (m, 3H), 7.32-7.40 (m, 2H), 8.52 (d, J =14 Hz,
13
1H), 11.00 (d, J = 13 Hz, 1H); C NMR (CDCl3) δ 14.4, 14.5, 60.2, 60.5, 93.5, 117.2, 125.0, 130.0,
139.3, 152.0, 165.8, 169.1. IR (cm-1): ν = 3207, 3051, 2988, 1691, 1642, 1598. MS (m/z) 263 (M+).
General procedure for the preparation of aminomethylenemalonates (11a-e) from
6-aminoquinoxaline
A mixture of 6-aminoquinoxaline (0.4 g, 2.76 mmol) and alkoxymethylene compound (2.76 mmol) was
submitted to microwave irradiation (Prolabo-Synthewave 402) at 120 °C for 10 min. The reaction mixture
was cooled to rt and diluted with dichloromethane. After evaporation, the crude products (11a) and (11b)
were purified by flash chromatography (AcOEt : heptane = 6 : 4). In the case of the products (11c) and
(11d), they were isolated by filtration after washing with dichloromethane.
3-(Quinoxalin-6-ylaminomethylene)pentane-2,4-dione (11a) mp 158-161 °C. 1H NMR (CDCl3) δ 2.46
(s, 3H), 2.60 (s, 3H), 7.62 (dd, J = 2.0 Hz, J = 8.8 Hz, 1H), 7.85 (d, 1H), 8.15 (d, J = 9.3 Hz, 1H), 8.41 (d,
J = 12.2 Hz), 8.82 (s, 1H), 8.86 (s, 1H), 12.92 (d, J = 11.7 Hz, 1H); 13C NMR (CDCl3) δ 27.4, 32.2, 113.9,
114.7, 122.3, 131.7, 140.3, 141.0, 143.8, 144.4, 146.1, 150.6, 195.0, 201.8. IR (cm-1): ν = 1641. MS (m/z)
255 (M+). Anal. Calcd for C14H13N3O2: C, 65.87; H, 5.13; N, 16.46. Found C, 65.63; H, 5.00; N, 16.21.
1
2-Acetyl-3-(quinoxalin-6-ylamino)acrylic acid ethyl ester (11b) mp 116-117 °C. H NMR (CDCl3) δ
(E-): 1.44 (t, J = 7.3 Hz, 3H), 2.55 (s, 3H), 4.33 (q, J = 7.3 Hz, 2H), 7.64 (dd, J = 2.4 Hz, J = 9.0 Hz, 1H),
7.88 (d, J = 2.5 Hz, 1H), 8.16 (d, J = 8.8 Hz, 1H), 8.69 (d, J = 12.7 Hz, 1H), 8.82 (s, 1H), 8.87 (s, 1H),
12.97 (d, J = 12.2 Hz, 1H); (Z-): 1.44 (t, J = 7.3 Hz, 3H), 2.63 (s, 3H), 4.33 (q, J = 7.3 Hz, 2H), 7.64 (dd,
J = 2.4 Hz, J = 9.0 Hz, 1H), 7.88 (d, J = 2.5 Hz, 1H), 8.16 (d, J = 8.8 Hz, 1H), 8.69 (d, J = 12.7 Hz, 1H),
8.82 (s, 1H), 8.87 (s, 1H), 11.29 (d, 1H); 13C NMR (CDCl3) δ 14.5, 31.4, 60.3, 104.4, 114.2, 122.1, 131.5,
140.3, 140.9, 143.8, 144.3, 146.1, 150.9, 166.5, 200.9. IR (cm-1): ν = 1712, 1644, 1624. MS (m/z) 285
(M+). Anal. Calcd for C15H15N3O3: C, 63.15; H, 5.30; N, 14.73. Found C, 62.91; H, 5.21; N, 14.35.
2-Cyano-3-(quinoxalin-6-ylamino)acrylic acid ethyl ester (11c) mp 207-208 °C. 1H NMR (DMSO-d6)

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δ (E-): 1.28 (t, J = 7.3 Hz, 3H), 4.25 (m, 2H), 8.08 (m, 3H), 8.55 (s, 1H), 8.74 (d, J = 13.2 Hz, 1H), 8.86
(s, 1H), 8.92 (s, 1H), 11.14 (s, 1H); (Z-): 1.28 (t, J = 7.3 Hz, 3H), 4.25 (m, 2H), 8.08 (m, 3H), 8.74 (d, J =
13.2 Hz, 1H), 8.86 (s, 1H), 8.92 (s, 1H), 10.98 (d, J = 13.2 Hz, 1H); 13C NMR (DMSO-d6) δ (E-): 14.3,
60.7, 76.7, 114.7, 115.6, 122.3, 130.5, 139.8; 140.9, 142.9, 144.6, 146.4, 152.4, 164.3; (Z-): 14.3, 61.6,
75.6, 114.7, 115.6, 122.5, 130.5, 139.8; 140.9, 142.9, 144.6, 146.4, 153.6, 165.9. IR (cm-1): ν = 2213,
1716, 1679, 1633, 1620. MS (m/z) 268 (M+). Anal. Calcd for C14H12N4O2: C, 62.68; H, 4.51; N, 20.88.
Found C, 62.15; H, 4.32; N, 20.55.
1
2-(Quinoxalin-6-ylaminomethylene)malononitrile (11d) mp 270 °C. H NMR (DMSO-d6) δ 8.04 (m,
13
3H), 8.84 (m, 3H), 8.86 (s, 1H), 8.92 (s, 1H), 11.45 (d, J = 12.7 Hz, 1H); C NMR (DMSO-d6) δ 53.9,
113.7, 114.8; 115.9, 122.0, 130.3, 139.8, 140.2, 142.7, 144.7, 146.4, 156.0. IR (cm-1): ν = 3293, 3210,
3020, 2220, 1646. MS (m/z) 221 (M+). Anal. Calcd for C12H7N5: C, 65.15; H, 3.19; N, 31.66. Found C,
64.92; H, 3.15; N, 31.93.
1
2-(Quinoxalin-6-ylaminomethylene)malonic acid diethyl ester (11e) mp 112-115 °C. H NMR
(CDCl3) δ 1.36 (t, J = 7.1 Hz, 3H), 1.42 (t, J = 7.0 Hz, 3H), 4.29 (m, 2H), 4.36 (m, 2H), 7.58 (dd, J = 2.4
Hz, J = 9.3 Hz, 1H), 7.80 (d, J = 1.9 Hz, 1H), 8.12 (d, J = 8.8 Hz, 1H), 8.69 (d, J = 13.2 Hz, 1H), 8.79 (s,
13
1H), 8.83 (s, 1H), 11.28 (d, J = 13.2 Hz, 1H); C NMR (CDCl3) δ 14.4, 14.5, 60.5, 60.9, 96.1, 113.2,
121.9, 131.5, 140.5, 140.7, 144.0, 146.1, 150.8, 165.2, 168.9. IR (cm-1): ν = 1693, 1694, 1615. MS (m/z)
315 (M+). Anal. Calcd for C16H17N3O4: C, 60.95; H, 5.43; N, 13.33. Found C, 60.25; H, 5.25; N, 13.05.
General procedure for the classical preparation of quinolones (12b, c, e)
Aminoethylene compound (10b, c, e) (500 mg) and diphenyl ether (10 g) were heated in metallic bath at
the temperature and for the time as reported in Table 3. The reaction mixture was quenched and rapidly
brought to 80 °C and 50 mL of heptane was added. The solid precipitating upon cooling was collected by
filtration and washed several times with heptane. All products have already been described in the
literature.
General procedure for the solvent-free preparation of quinolone (12e)
2-Phenylaminomethylenemalonic acid diethyl ester (10e) (500 mg, 1.9 mmol) was heated using metallic
bath at 380 °C, with mechanical stirring, for the appropriate time as reported in Table 4. The reaction
mixture was immediately cooled to rt and the cyclic product (12e) was precipitated with 10 mL of
dichloromethane and was filtered off. The conversion of (10e) was determined by capillary gas
chromatography CPSil 19 CB (30 m x 0.25 mm x 0.2 µm, with injector at 220 °C and detector at 250 °C,
programming = 150 °C - 220 °C with 10 °C. min-1) using an internal standard (diphenylphthalate).
1
3-Acetylquinolin-4(1H)-one (12b)20 mp 246 °C (lit., 240-244 °C). H NMR (DMSO-d6) δ 2.60 (s, 3H),
7.38-7.73 (m, 3H), 8.21 (d, J = 8 Hz, 1H), 8.50 (s, 1H); 13C NMR (DMSO-d6) δ 30.8, 117.4, 118.6, 124.6,

HETEROCYCLES, Vol. 64, 2004
189
125.4, 127.5, 132.2, 138.7, 143.8, 174.9, 196.1. IR (cm-1): ν = 3427, 1671, 1622, 1568, 1539. Anal. Calcd
for C11H9NO2: C, 70.58; H, 4.85; N, 7.48. Found C, 69.96; H, 4.77; N, 7.04.
1
1,4-Dihydro-4-oxoquinoline-3-carbonitrile (12c)6,21 mp 300 °C (lit., 301 °C). H NMR (DMSO-d6) δ
7.49 (t, J = 7 Hz, 1H), 7.64 (d, J = 8 Hz, 1H), 7.79 (t, J =7 Hz, 1H), 8.13 (d, J = 7 Hz, 1H), 8.75 (s, 1H);
13C NMR (DMSO-d6) δ 93.3, 116.5, 118.9, 124.7, 125.3, 133.0, 138.8, 146.4, 174.2. IR (cm-1): ν = 2224,
1629, 1557, 1536. Anal. Calcd for C10H6N2O: C, 70.58; H, 3.55; N, 16.44. Found C, 69.61; H, 3.45; N,
16.81.
1,4-Dihydro-oxoquinoline-3-carboxylic acid ethyl ester (12e)13,22 mp 272-274 °C (lit., 269-270 °C). 1H
NMR (DMSO-d6) δ 1.31 (t, J = 7 Hz, 3H), 4.25 (q, J = 7 Hz, 2H), 7.60 (m, 3H), 7.82 (d, J = 8 Hz, 1H),
8.60 (s, 1H), 12.38 (s, 1H). IR (cm-1): ν = 3162, 3128, 1697, 1622. Anal. Calcd for C12H11NO3: C, 66.35;
H, 5.10; N, 6.45. Found C, 66.33; H, 5.33; N, 6.25.
ACKNOWLEDGEMENT
This work was realized within the frame of a convention of cotutelle thesis between Paris-South
University and Slovak Technical University supported by French Embassy in Bratislava. We thank
sincerely these organisms as well as the Slovak Grant Agency (1/9254/02 and 1/0058/03) for additional
financial help in Slovakia.
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