Heterocycles [f]-fused onto quinolones. Synthesis of novel dioxo-nethylpyrano[2,3-f ]-and [3,2-f ]quinoline-10-carboxylic acids

Article abstract of DOI:10.5560/ZNB.2013-3122

A model N-ethyl-1,10-dioxo-3-phenylpyrano[3,2-f ]quinoline-9-carboxylic acid (8) and the isomeric (2-substituted) pyrano[2,3-f ]quinoline-9-carboxylic acids (6 and 7) were prepared from the corresponding 6/7-aminochromen-4-ones via the Gould-Jacobs reaction. The new tricyclic heterocycles 6-8 exhibit moderate antibacterial activity (MIC=16 -64 μg mL^-1) against E. coli and S. aureus.

Full text of DOI:10.5560/ZNB.2013-3122

Heterocycles [f]-Fused onto Quinolones. Synthesis of Novel Dioxo-N-
ethylpyrano[2,3-f]- and [3,2-f]quinoline-10-carboxylic Acids
Almeqdad Y. Habashneha, Mustafa M. El-Abadelaha, Mohammad S. Mubaraka, and
Wolfgang Voelterb
a
Chemistry Department, Faculty of Science, The University of Jordan, Amman 11942, Jordan
Interfakulta¨res Institut fu¨r Biochemie, Universita¨t Tu¨bingen, Hoppe-Seyler-Straße 4, 72076
b
Tu¨bingen, Germany
Reprint requests to Prof. Dr. W. Voelter. E-mail: wolfgang.voelter@uni-tuebingen.de or
A. Y. Habashneh. E-mail: a.habashneh@ju.edu.jo
Z. Naturforsch. 2013, 68b, 1049 – 1055 / DOI: 10.5560/ZNB.2013-3122
Received April 28, 2013
A model N-ethyl-1,10-dioxo-3-phenylpyrano[3,2-f]quinoline-9-carboxylic acid (8) and the iso-
meric (2-substituted) pyrano[2,3-f]quinoline-9-carboxylic acids (6 and 7) were prepared from the
corresponding 6/7-aminochromen-4-ones via the Gould-Jacobs reaction. The new tricyclic hetero-
cycles 6–8 exhibit moderate antibacterial activity (MIC = 16 – 64 µg mL−1) against E. coli and S.
aureus.
Key words: 7-Aminoflavone, 6-Aminoflavone, 7-Amino-2-methyl-4H-chromen-4-one,
Regioselective Cyclization, Pyrano[2,3-f] and [3,2-f]quinolones
O
O
Introduction
R1
5
5
4
4
F
CO2H
3
2
Chromones are naturally occurring compounds with
a 4-benzopyrone moiety [1, 2]. The compounds of
this family are well-known as antioxidants [3, 4].
Some chromone derivatives, such as khellin [5] and
2,4-thiazolidenedione [6 – 8], have antispasmodic and
antidiabetic activities, respectively. These biologi-
cal properties made this family of compounds the
target of innumerous studies focusing on synthe-
ses and structural modifications [9 – 15]. Flavones,
e. g. 1–3, are 2-phenyl-substituted chromones [16,
1
O
1
Ph
N
N
8
R2
8
R
HN
1 (R1 = OH; R2 = H)
4a (R = Et)
4b (R = c -C3H7)
2 (R1 = H; R2 = OH)
(R1 = R2 = OH)
3
Fig. 1.
17] which exhibit biocidal [18 – 20], antitumor [21], sition (e. g., an ethyl or cyclopropyl group) is also
anti-inflammatory [22, 23], antiviral [24, 25], anti- essential for attainment of high potency [33 – 36].
HIV [26], and other activities.
Fused heterocyclic rings with a bridge between the
Synthetic 4-oxoquinoline-3-carboxylic acids, exem- 5- and 6-positions have not been extensively investi-
plified by norfloxacin (4a) [27, 28] and ciprofloxacin gated in this system. Accordingly, we have envisaged
(4b) [29 – 32] (Fig. 1), constitute a major class of to prepare new tricyclic heterocycles (6–8, Fig. 2),
therapeutic agents which have a broad spectrum of whereby a 4-pyranone ring is [ f]-fused onto the 1-
antibacterial activity. For most current SAR studies, ethyl-4-oxoquinoline-3-carboxylic acid moiety. Such
a hydrogen atom at position 2, a free carboxyl group hybrid molecules combine the structural features of
at position 3, and a keto group at position 4 can- flavone (rings A, B) and 4-quinolone (rings B, C) en-
not be changed without significant loss of activity. tities and might display interesting biological proper-
Incorporation of a suitable substituent at N − 1 po- ties. In this context it is worth noting that a linear
© 2013 Verlag der Zeitschrift fu¨r Naturforschung, Tu¨bingen · http://znaturforsch.com
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A. Y. Habashneh et al. · Heterocycles [f]-Fused onto Quinolones
O
CO2H
O
4
O
6
5
4
5
CO2Et
O
A
B
O
C
Et
1
9
N
7N
O
1
R
Me
O
N
Et
C
10
H
A
B
O
10
O
Ph
CO2H
5
6
7
8
(R = Me)
(R = Ph)
Fig. 2.
4H-pyrano[g]-fused quinoline 5 has recently been re- Antibacterial activity
ported [37]. This single example is a 7-carboxylic es-
Compounds 6–8 were tested in vitro in aque-
ous DMSO solutions against Gram-negative Es-
cherichia coli ATCC 8739 and Gram-positive Staphy-
lococcus aureus ATCC 6538 bacterial species us-
ing ciprofloxacin as reference. The antibacterial ac-
tivity was evaluated by the minimal inhibitory con-
centration (MIC) technique. Compounds 6–8 ex-
hibit a moderate level of antibacterial activity
(MIC = 16 – 64 µg mL−1) against E. coli and S. au-
reus.
ter that also lacks a suitable alkyl substituent at N(9)-
locus and is thus expected to exhibit low anti-bacterial
activity.
Results and Discussion
Syntheses
The synthetic strategy towards the target tri-
cyclic compounds 6 and 7 commenced with the 7-
aminochromen-4-one, expected to be annelating the
4-pyridone moiety as outlined in Scheme 1. Thus,
treatment of 9 and 10 with diethyl ethoxymethylene-
malonate gave the respective enamine derivatives 11
and 12. The latter intermediates underwent thermal
intramolecular cyclization, regioselectively at C-8, to
deliver the corresponding pyrano[2,3- f]quinoline-9-
carboxylic esters 13 and 14 under Gould-Jacobs re-
action conditions [38]. Subsequent N(1)-ethylation of
13 and 14 afforded the respective derivatives 15 and
16, and their acid-catalyzed hydrolysis furnished the
respective targeted 9-carboxylic acids 6 and 7. Like-
wise, 6-aminoflavone 17 was converted into the respec-
tive N-ethylpyrano[3,2-f]quinoline-9-carboxylic acid
8 via the consecutive intermediates 18, 19 and 20 as de-
picted in Scheme 2. The newly synthesized compounds
6–20 were characterized by NMR and MS spectral data
(see Experimental Section) which are consistent with
the suggested structures. Thus, the mass spectra dis-
play the correct molecular ion peaks for which the
measured high resolution (HRMS) data are in good
agreement with the calculated values. DEPT and 2D
(COSY, HMQC, HMBC) experiments showed corre-
Experimental Section
The following chemicals, used in this study, were
purchased from Acros and used as received: Diethyl
ethoxymethylenemalonate, diphenyl ether and iodoethane. 7-
Aminoflavone, 6-aminoflavone and 7-amino-2-methyl-4H-
chromen-4-one were purchased from Aldrich. Melting points
were determined on a Gallenkamp electrothermal melting
apparatus in open capillary tubes. 1H and 13C NMR spectra
were recorded on a 500 MHz spectrometer (Bruker Avance-
III). Chemical shifts are expressed in ppm (δ units), with
TMS as internal standard; J values for 1H-1H coupling
constants are given in Hertz. High-resolution mass spectra
(HRMS) were acquired (in positive or negative ion mode)
using electrospray ion trap (ESI) technique by collision-
induced dissociation on a Bruker APEX-4 (7-Tesla) instru-
ment. The samples were dissolved in acetonitrile, diluted
in spray solution (methanol-water 1 : 1 v/v + 0.1% formic
acid) and infused using a syringe pump with a flow rate of
2 µL min−1. External calibration was conducted using argi-
nine cluster in a mass range m/z = 175 – 871. Elemental
analyses were performed on a Euro Vector elemental ana-
lyzer, model EA 3000.
1
lations that helped in the H and 13C signal assign-
Antibacterial tests
ments to the different carbons and their attached and/or
neighboring hydrogens.
The MICs were determined by the conventional agar dilu-
tion procedures according to the method of Mueller-Hinton.
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A. Y. Habashneh et al. · Heterocycles [f]-Fused onto Quinolones
1051
O
5
4
O
4a
8a
5
EtO2C
CO2Et
OEt
4
(i)
(ii)
+
HN
O
1
R
8
7
CO2Et
H2N
O
1
R
8
CO2Et
9 (R=Ph)
10 (R=Me)
11 (R=Ph)
12 (R=Me)
O
O
O
5
5
5
4
4
4
4a
6
3
(iii)
(iv)
6a
2
Et
Et
10b
O
N
7
O
1
R
HN
8
O
1
R
N
O
1
R
10a
7
7
10
O
10
10
O
9
CO2Et
CO2H
CO2Et
13 (R=Ph)
14 (R=Me)
15 (R=Ph)
16 (R=Me)
6 (R=Ph)
7 (R=Me)
(i) 130–140 oC,1 h
(ii) Ph2O / 240oC,1 h
(iii) K2CO3, Et-I, EtOH / reflux,10 h
(iv) NaOH
Compounds 11, 13, 15 and 6
3'
2'
1'
R=(
)
4'
5'
6'
Scheme 1.
CO2Et
2''
O
1''
CO2Et
O
5
8
4
EtO2C
CO2Et
OEt
H2N
4
6
HN
4a
3
(i)
3
6
7
+
2'
5'
1
O
1
O
1'
3'
4'
2
8a
2
Ph
8
6'
17
18
CO2Et
10
CO2R
10
9
9
O
O
8
8
(ii)
O
O
(iii)
10a
10b
1
7
10a
10b
HN
7
1
N
2
2
6a
6a
Et
4
O
6
1'
3
4
O
6
1'
4a
3
4a
5
5
4'
4'
19
20 (R = Et)
(R = H)
(iv)
(i) 130–140 oC, 1 h
8
(ii) Ph2O / 240 oC, 1 h
(iii) K2CO3, Et-I, EtOH / reflux, 10 h
(iv) NaOH
Scheme 2.
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A. Y. Habashneh et al. · Heterocycles [f]-Fused onto Quinolones
Stock solutions (1000 µg mL−1) of the test compounds were HRMS ((+)-ESI): m/z = 346.12948 (calcd. 346.12906 for
prepared with DMSO. Serial dilutions were then made to ob- C18H20NO6, [M+H]+).
tain test concentrations in the range 128 – 0.5 µg mL−1. The
Diethyl 2-[(4-oxo-2-phenyl-1H-chromen-6-ylamino)-
agar plates were inoculated with approximately 105 CFU per
methylene]malonate (18)
spot. The agar plates were then incubated at 37 ◦C for 18 h.
The MICs were taken as the lowest concentration of the test
compounds that inhibits visible growth.
Yield: 99%; m. p. 187 – 189 ◦C. – 1H NMR (500 MHz,
[D6]DMSO): δ = 1.24 – 1.30 (m, 6H, 2(CH3CH2O), 4.17
(q, J = 7.1 Hz, 2H, MeCH2O), 4.24 (q, 2H, J = 7.1 Hz,
MeCH2O), 7.07 (s, 1H, H-3), 7.62 – 7.65 (m, 3H, H-5 + H-8
+ H-40), 7.78 – 7.92 (m, 3H, H-30 + H-50 + H-7), 8.13 (dd,
J = 8.2, 2.0 Hz, 2H, H-20 + H-60), 8.44 (d, J = 13.5 Hz, 1H,
H-100), 10.77 (d, J = 13.5 Hz, 1H, N-H, exchangeable with
D2O). – 13C NMR (125 MHz, [D6]DMSO): δ = 14.6, 14.7
(2(CH3CH2O)), 60.4, 60.6 (2(MeCH2O)), 95.1 (C-200), 107.0
(C-3), 112.0 (C-7), 112.7 (C-8), 124.5 (C-4a), 125.2 (C-
5), 126.9 (C-20/C-60),129.6 (C-30/C-50), 131.6 (C-10), 132.3
(C-40), 137.8 (C-6), 151.2 (C-100), 153.1 (C-8a), 162.9 (C-
2), 165.5, 167.4 (2(CO2Et)), 177.1 (C-4). – HRMS ((+)-
ESI): m/z = 408.14416 (calcd. 408.14471 for C23H22NO6,
[M+H]+).
Diethyl 2-[(4-oxochromenylamino)methylene]malonates 11,
12 and 18; general procedure
A
mixture of the particular aminochromen-4-one
(4.2 mmol) and diethyl ethoxymethylenemalonate
(5.0 mmol) was heated at 130 – 140 ◦C for 2 h, dur-
ing which time the resulting ethanol was distilled off.
Thereafter, the reaction mixture was cooled to 60 ◦C
and poured onto 50 mL of n-hexane. The resulting solid
precipitate was collected by suction filtration, dried and
recrystallized from ethyl acetate to give the respective
2-[(4-oxochromenylamino)methylene]malonate.
Diethyl 2-[(4-oxo-2-phenyl-4H-chromen-7-ylamino)-
Ethyl pyranoquinoline-9-carboxylates 13, 14 and 19;
methylene]malonate (11)
general procedure
Yield: 94%; m. p. 185 – 187 ◦C. – 1H NMR (500 MHz,
[D6]DMSO): δ = 1.27 – 1.47 (m, 6H, 2(CH3CH2O)), 4.17
(q, J = 7.1 Hz, 2H, MeCH2O), 4.24 (q, J = 7.1 Hz, 2H,
MeCH2O), 6.98 (s, 1H, H-3), 7.48 (dd, J = 8.6, 1.5 Hz, 1H,
H-6), 7.59 – 7.62 (m, 3H, H-30 + H-40 + H-50), 7.83 (d, J =
1.5 Hz, 1H, H-8), 7.99 (d, J = 8.6 Hz, 1H, H-5), 8.10 (dd, J =
8.5, 2.0 Hz, 2H, H-20 + H-60), 8.48 (s, 1H, H-100), 10.77 (br s,
1H, N-H, exchangeable with D2O). – 13C NMR (125 MHz,
[D6]DMSO): δ = 14.6, 14.7 (2(CH3CH2O)), 60.4, 60.6
(2(MeCH2O)), 96.9 (C-200), 105.5 (C-3), 107.4 (C-8), 116.1
(C-6), 119.9 (C-4a), 126.7 (C-20/C-60),127.0 (C-5), 129.6 (C-
30/C-50), 131.5 (C-10), 132.3 (C-40),144.9 (C-7), 149.7 (C-
100), 157.3 (C-8a), 163.2 (C-2), 165.3, 167.2 (2(CO2Et)),
176.8 (C-4). – HRMS ((+)-ESI): m/z = 408.14416 (calcd.
408.14471 for C23H22NO6, [M+H]+).
The particular diethyl 2-[4-(oxochromenylamino)methyl-
ene]malonate (11, 12, 18) (2.45 mmol) was added to
diphenyl ether (10 mL) and heated at 245 – 250 ◦C for 1 h.
The product solution was allowed to cool to 60 ◦C, and then
the warm solution was poured onto 50 mL of n-hexane. The
precipitate was collected by suction filtration, washed with
hot ethyl acetate, and dried to give the corresponding pyra-
noquinolone in fairly pure state.
Ethyl 4,10-dioxo-2-phenyl-7,10-dihydro-4H-pyrano-
[2,3-f]quinoline-9-carboxylate (13)
Yield: 85%; m. p. 292 – 293 ◦C. – 1H NMR (500 MHz,
[D6]DMSO): δ = 1.32 (t, J = 7.1 Hz, 3H, CH3CH2O), 4.27
(q, J = 7.1 Hz, 2H, MeCH2O), 7.23 (s, 1H, H-3), 7.63 – 7.62
(m, 4H, H-30 + H-40 + H-50, H-6), 8.24 (d, J = 8.8 Hz, 1H,
H-5), 8.49 (m, 3H, H-20 + H-60, H-8) 12.61 (s, 1H, N-H, ex-
changeable with D2O). – 13C NMR (125 MHz, CF3CO2D):
δ = 14.8 (CH3CH2O), 68.6 (MeCH2O), 108.7 (C-3), 110.7
(C-9), 114.2 (C-10a), 121.4 (C-6), 121.7 (C-4a), 126.9 (C-
5), 130.6 (C-20/C-60), 131.1 (C-10), 132.4 (C-30/C-50), 132.5
(C-40), 138.2 (C-6a), 147.6 (C-8), 150.2 (C-10b), 158.1 (C-
2), 170.5 (CO2Et), 174.4 (C-10), 177.5 (C-4). – HRMS ((–)-
ESI): m/z = 360.08775 (calcd. 360.08720 for C21H14NO5,
[M–H]−).
Diethyl 2-[(2-methyl-4-oxo-1H-chromen-7-ylamino)-
methylene]malonate (12)
Yield: 93%; m. p. 250 – 252 ◦C. – 1H NMR (500 MHz,
[D6]DMSO): δ = 1.25 – 1.29 (m, 6H, 2 (CH3CH2O)), 2.38
(s, 3H, (C(2)-CH3)), 4.16 (q, J = 7.1 Hz, 2H, MeCH2O ),
4.23 (q, J = 7.1 Hz, 2H, MeCH2O), 6.19 (s, 1H, H-3), 7.44
(dd, J = 8.7, 1.9 Hz, 1H, H-6), 7.61 (d, J = 1.9 Hz, 1H, H-
8), 7.95 (d, J = 8.7 Hz, 1H, H-5), 8.48 (d, J = 13.4 Hz, 1H,
H-10), 10.72 (d, J = 13.4 Hz, 1H, N-H, exchangeable with
D2O). – 13C NMR (125 MHz, [D6]DMSO): δ = 14.5, 14.7
(2(CH3CH2O)), 20.4 (C(2)-CH3)), 60.3, 60.5 (2(MeCH2O)),
96.9 (C-20), 105.5 (C-3), 110.4 (C-8), 115.5 (C-6), 119.9
(C-4a), 127.0 (C-5), 144.6 (C-7), 149.7 (C-10), 157.5 (C-
Ethyl 2-methyl-4,10-dioxo-7,10-dihydro-4H-pyrano-
[2,3-f]quinoline-9-carboxylate (14)
Yield: 90%; m. p. 308 – 309 ◦C. – 1H NMR (500 MHz,
8a), 165.1 (C-2),167.1, 167.2 (2(CO2Et)), 176.5 (C-4). – [D6]DMSO): δ = 1.25 (t, J = 7.1 Hz, 3H, CH3CH2O), 2.41
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A. Y. Habashneh et al. · Heterocycles [f]-Fused onto Quinolones
1053
(s, 3H, (C(2)-CH3)), 4.20 (q, J = 7.1 Hz, 2H, MeCH2O), 127.3 (C-20/C-60), 128.9 (C-5), 129.5 (C-30/C-50), 131.4 (C-
6.33 (s, 1H, H-3), 7.81 (d, J = 8.8 Hz, 1H, H-6), 8.27 (d, J = 10), 132.4 (C-40), 144.3 (C-6a), 148.2 (C-8), 155.7 (C-10b),
8.8 Hz, 1H, H-5), 8.47 (s, 1H, H-8), 12.53 (s, 1H, N-H, ex- 163.3 (C-2), 164.4 (CO2Et), 172.5 (C-10), 176.4 (C-4). –
changeable with D2O). – 13C NMR (125 MHz, CF3CO2D): HRMS ((+)-ESI): m/z = 390.13360 (calcd. 390.13415 for
δ = 15.0 (CH3CH2O), 22.3 (C(2)-CH3), 68.4 (MeCH2O), C23H20NO5, [M+H]+).
110.4 (C-9), 113.7 (C-3), 114.0 (C-10a), 119.1 (C-4a), 121.0
(C-6), 136.8 (C-5), 147.3 (C-6a), 149.9 (C-8), 149.9 (C-10b),
158.4 (C-2), 170.4 (CO2Et), 177.2 (C-10), 177.8 (C-4). –
Ethyl 7-ethyl-2-methyl-4,10-dioxo-7,10-dihydro-
4H-pyrano[2,3-f]quinoline-9-carboxylate (16)
HRMS ((+)-ESI): m/z = 322.06855 (calcd. 322.06914 for
Yield: 86%; m. p. 186 – 187 ◦C. – 1H NMR (500 MHz,
C16H13NO5Na, [M+Na]+).
[D6]DMSO): δ = 1.31 (t, J = 7.1 Hz, 3H, CH3CH2N), 1.38
(t, J = 7.1 Hz, 3H, CH3CH2O), 2.46 (s, 3H, (C(2)-CH3)),
4.26 (q, J = 7.1 Hz, 2H, MeCH2N), 4.44 (q, J = 7.1 Hz,
Ethyl 1,10-dioxo-3-phenyl-7,10-dihydro-1H-pyrano-
[3,2-f]quinoline-9-carboxylate (19)
2H, MeCH2O), 6.38 (s, 1H, H-3), 7.81 (d, J = 9.2 Hz, 1H,
Yield: 94%; m. p. 250 – 251 ◦C. – 1H NMR (500 MHz, H-6), 8.27 (d, J = 9.2 Hz, 1H, H-5), 8.66 (s, 1H, H-8). –
CF3CO2D): δ = 1.39 (t, J = 6.9 Hz, 3H, CH3CH2O), 4.26 13C NMR (125 MHz, [D6]DMSO): δ = 14.7 (CH3CH2N),
(q, J = 7.1 Hz, 2H, MeCH2N), 4.46 (q, J = 6.9 Hz, 2H, 14.8 (CH3CH2O), 20.6 (C(2)-CH3) 49.3 (MeCH2N), 60.6
MeCH2O), 8.19 (s, 1H, H-2), 8.19 – 8.35 (m, 3H, H-30 + (MeCH2O), 111.2 (C-3), 114.8 (C-6), 114.8 (C-9), 117.7 (C-
H-40 + H-50), 8.74 (dd, J = 2.0, 7.2 Hz, 2H,H-20 + H-60), 10a), 119.1 (C-4a), 128.4 (C-5), 144.3 (C-6a), 148.2 (C-8),
9.06 (d, J = 9.5 Hz, 1H, H-6), 9.14 (d, J = 9.5 Hz, 1H, H- 156.2 (C-10b), 164.8 (C-2), 167.5 (CO2Et), 172.3 (C-10),
5), 9.81 (s, 1H, H-8), 17.04 ([D6]DMSO) (s, 1H, N-H, ex- 176.1 (C-4). – HRMS ((+)-ESI): m/z = 350.09989 (calcd.
changeable with D2O). – 13C NMR (125 MHz, CF3CO2D): 350.10044 for C18H17NO5Na, [M+Na]+).
δ = 14.6 (CH3CH2O), 66.7 (MeCH2O), 108.9 (C-2), 109.3
Ethyl 7-ethyl-1,10-dioxo-3-phenyl-7,10-dihydro-
1H-pyrano[3,2-f]quinoline-9-carboxylate (20)
(C-9), 115.6 (C-6), 118.0 (C-5), 121.4 (C-10a), 129.6 (C-
20/C-60), 129.9 (C-10b) 130.8 (C-10), 132.0 (C-40), 132.1 (C-
30/C-50), 137.9 (C-6a), 142.8 (C-4a),148.3 (C-8), 161.0 (C-
3), 164.9 (CO2Et), 171.9 (C-10), 183.4 (C-1). – HRMS ((+)-
ESI): m/z = 362.10230 (calcd. 362.10285 for C21H16NO5,
[M+H]+).
Yield: 89%; m. p. 265 – 266 ◦C. – 1H NMR (500 MHz,
[D6]DMSO): δ = 1.33 (t, J = 7.1 Hz, 3H, CH3CH2N), 1.39
(t, J = 6.9 Hz, 3H, CH3CH2O), 4.26 (q, J = 7.1 Hz, 2H,
MeCH2N), 4.46 (q, J = 6.9 Hz, 2H, MeCH2O), 7.09 (s, 1H,
H-2), 7.59 – 7.64 (m, 3H, H-30 + H-40 + H-50), 8.06 (d,
J = 9.5 Hz, 1H, H-6), 8.12 (dd, J = 8.5, 2.0 Hz, 2H, H-20
+ H-60), 8.14 (d, J = 9.5 Hz, 1H, H-5), 8.62 (s, 1H, H-8). –
Ethyl 7-ethylpyrano[2,3-f]quinoline-9-carboxylates 15, 16
and 20; general procedure
A stirred mixture of compound 5 (1.38 mmol), K2CO3 13C NMR (125 MHz, [D6]DMSO): δ = 14.8 (CH3CH2N),
(6.92 mmol), iodoethane (6.92 mmol), and absolute ethanol 15.1 (CH3CH2O), 48.6 (MeCH2N), 60.3 (MeCH2O), 107.5
(10 mL) was refluxed for 10 h. The reaction mixture was (C-2), 112.5 (C-9), 122.4 (C-10a), 123.1 (C-6), 123.5 (C-
cooled to r. t. and diluted with 50 mL of water. The pre- 5), 125.8 (C-10b) 126.6 (C-20/C-60), 129.6 (C-30/C-50), 131.4
cipitated solid product was collected by suction filtration, (C-10), 131.9 (C-40) 137.9 (C-6a), 147.9 (C-8), 154.6 (C-4a),
washed with water, dried and recrystallized from the appro- 160.2 (C-3), 164.8 (CO2Et), 171.7 (C-10), 175.0 (C-1). –
priate solvent.
HRMS ((+)-ESI): m/z = 390.13360 (calcd. 390.13415 for
C23H20NO5, [M+H]+).
Ethyl 7-ethyl-4,10-dioxo-2-phenyl-7,10-dihydro-
4H-pyrano[2,3-f]quinoline-9-carboxylate (15)
7-Ethylpyranoquinoline-9-carboxylic acids 6–8; general
procedure
Yield: 84%; m. p. 233 – 234 ◦C. – 1H NMR (500 MHz,
[D6]DMSO): δ = 1.33 (t, J = 6.9 Hz, 3H, CH3CH2N), 1.41
A suspension of the appropriate ethyl ester (0.51 mmol) in
(t, J = 7.0 Hz, 3H, CH3CH2O), 4.27 (q, J = 6.9 Hz, 2H, 20 mL of 6 N aq. HCl was refluxed (oil bath, 110 ◦C) for 48 h.
MeCH2N), 4.45 (q, J = 7.0 Hz, 2H, MeCH2O), 7.23 (s, 1H, Thereafter, the reaction mixture was cooled and poured onto
H-3), 7.62 – 7.63 (m, 3H, H-30 + H-40 + H-50), 7.83 (d, ice water (30 mL); the precipitated product was collected by
J = 9.0 Hz, 1H, H-6), 8.28 (d, J = 9.0 Hz, 1H, H-5), 8.49 suction filtration, washed with water (3×4 mL), redissolved
(dd, J = 8.5, 2.0 Hz, 2H, H-20 + H-60), 8.67 (s, 1H, H-8). – in 20 mL of 1 N aq. K2CO3 and filtered. The aqueous filtrate
13C NMR (125 MHz, [D6]DMSO): δ = 14.7 (CH3CH2N), was neutralized with 6 N aq. HCl. The resulting solid was
14.8 (CH3CH2O), 49.4 (MeCH2N), 60.6 (MeCH2O), 107.5 collected by suction filtration, dried and recrystallized from
(C-3), 115.1 (C-6), 115.1 (C-9) 117.7 (C-10a), 119.5 (C-4a), the appropriate solvent.
Unauthenticated
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1054
A. Y. Habashneh et al. · Heterocycles [f]-Fused onto Quinolones
7-Ethyl-4,10-dioxo-2-phenyl-7,10-dihydro-4H-pyrano-
[2,3-f]quinoline-9-carboxylic acid (6)
(MeCH2N), 111.1 (C-3), 111.6 (C-9), 114.9 (C-6), 117.7 (C-
10a), 119.1 (C-4a), 130.0 (C-5), 144.2 (C-6a), 149.9 (C-8),
156.2 (C-10b), 166.1 (C-2), 167.8 (CO2H), 172.3 (C-10),
176.1 (C-4). – HRMS ((–)-ESI): m/z = 298.07210 (calcd.
298.07155 for C16H12NO5, [M–H]−).
Yield: 94%; m. p. 318 – 319 ◦C. – 1H NMR (500 MHz,
[D6]DMSO): δ = 1.46 (t, J = 7.0 Hz, 3H, CH3CH2N), 4.45
(q, J = 7.0 Hz, 2H, MeCH2N), 7.27 (s, 1H, H-3), 7.62 – 7.75
(m, 3H, H-30 + H-40 + H-50), 8.03 (d, J = 8.5 Hz, 1H, H-
6), 8.39 – 8.51 (m, 3H, H-20 + H-60 + H-5), 9.13 (s, 1H, H-
8), 15.45 (br s, 1H, CO2H, exchangeable with D2O). – 13C
NMR (125 MHz, [D6]DMSO): δ = 14.9 (CH3CH2N), 50.5
(MeCH2N), 107.8 (C-3), 111.3 (C-9), 115.6 (C-6), 116.1
(C-10a), 120.3 (C-4a), 127.2 (C-20/C-60), 129.6 (C-30/C-50),
130.4 (C-5), 131.1 (C-10), 132.6 (C-40) 144.4 (C-6a), 149.9
(C-8), 155.5 (C-10b), 163.5 (C-2), 166.1 (CO2H), 176.1
(C-10), 178.1 (C-4). – HRMS ((+)-ESI): m/z = 362.10230
(calcd. 362.10285 for C21H16NO5, [M+H]+).
7-Ethyl-1,10-dioxo-3-phenyl-7,10-dihydro-1H-pyrano-
[3,2-f]quinoline-9-carboxylic acid (8)
Yield: 86%; m. p. 277 – 278 ◦C. – 1H NMR (500 MHz,
[D6]DMSO): δ = 1.45 (t, J = 7.1 Hz, 3H, CH3CH2N), 4.68
(q, J = 7.1 Hz, 2H, MeCH2N), 7.21 (s, 1H, H-2), 7.59 – 7.63
(m, 3H, H-30 + H-40 + H-50), 8.15 (dd, J = 7.4, 1.6 Hz,
2H, H-20 + H-60), 8.27 (d, J = 9.5 Hz, 1H, H-6), 8.40 (d,
J = 9.5 Hz, 1H, H-5), 9.05 (s, 1H, H-8), 15.23 (br s, 1H,
CO2H, exchangeable with D2O). – 13C NMR (125 MHz,
[D6]DMSO): δ = 15.4 (CH3CH2N), 50.0 (MeCH2N), 107.9
(C-2), 110.4 (C-9), 121.9 (C-10a), 122.8 (C-10b), 124.2 (C-
6), 125.8 (C-5), 126.6 (C-20/C-60), 129.6 (C-30/C-50), 131.1
(C-10), 132.1 (C-40) 139.0 (C-6a), 148.0 (C-8), 155.5 (C-4a),
160.3 (C-3), 166.4 (CO2H), 175.0 (C-10), 176.7 (C-1). –
HRMS ((+)-ESI): m/z = 362.10230 (calcd. 362.10285 for
C21H16NO5, [M+H]+).
7-Ethyl-2-methyl-4,10-dioxo-7,10-dihydro-4H-pyrano-
[2,3-f]quinoline-9-carboxylic acid (7)
Yield: 82%; m. p. 327 – 329 ◦C. – 1H NMR (500 MHz,
[D6]DMSO): δ = 1.31 (t, J = 7.1 Hz, 3H, CH3CH2N), 2.46
(s, 3H, (C(2)-CH3)), 4.26 (q, J = 7.1 Hz, 2H, MeCH2N,
6.42 (s, 1H, H-3), 7.71 (d, J = 9.3 Hz, 1H, H-6), 8.36 (d,
J = 9.3 Hz, 1H, H-5), 9.09 (s, 1H, H-8), 15.41 (br s, 1H,
Acknowledgement
We are grateful to the Deanship of Scientific Research
CO2H, exchangeable with D2O). – 13C NMR (125 MHz, at the University of Jordan (Amman – Jordan) for financial
[D6]DMSO): δ = 14.4 (CH3CH2N), 20.1 (C(2)-CH3), 50.0 support.
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