Heterocycles [h]-fused to 4-oxoquinoline-3-carboxylic acid. Part VII: Synthesis of some 6-oxoimidazo[4,5-h]quinoline-7-carboxylic acids and esters

Article abstract of DOI:10.1007/s00706-008-0056-8

A series of ethyl 2-(substituted)-9-cyclopropyl-4-fluoro-6-oxo-1H- imidazo[4,5-h]quinoline-7-carboxylates has been prepared from ethyl 7,8-diamino-1,4-dihydroquinoline-3-carboxylate via thermally induced reactions with model alkanoic acids or via microwav

Full text of DOI:10.1007/s00706-008-0056-8

Monatsh Chem (2009) 140:221–228
DOI 10.1007/s00706-008-0056-8
ORIGINAL PAPER
Heterocycles [h]-fused to 4-oxoquinoline-3-carboxylic acid. Part
VII: synthesis of some 6-oxoimidazo[4,5-h]quinoline-7-carboxylic
acids and esters
Maram R. Al-Dweik Æ Jalal A. Zahra Æ
Monther A. Khanfar Æ Mustafa M. El-Abadelah Æ
Klaus-Peter Zeller Æ Wolfgang Voelter
Received: 20 August 2008 / Accepted: 23 August 2008 / Published online: 8 October 2008
Ó Springer-Verlag 2008
Abstract A series of ethyl 2-(substituted)-9-cyclopropyl-
4-fluoro-6-oxo-1H-imidazo[4,5-h]quinoline-7-carboxylates
has been prepared from ethyl 7,8-diamino-1,4-dihydro-
quinoline-3-carboxylate via thermally induced reactions
with model alkanoic acids or via microwave-assisted
cyclocondensation with some arene carboxaldehydes.
Acid-catalysed hydrolysis of the resulting ester derivatives
furnished the corresponding imidazoquinoline-7-carbox-
ylic acids. The structures of these new acid and ester
derivatives are based on microanalytical and spectral (IR,
MS, and NMR) data.
ribofuranosyl) nucleotidic entity [1–5]. The benzimidazole
system, the chemistry of which has been reviewed [6, 7],
is central to medicinal chemistry [8, 9] and several
derivatives thereof have reached commercial use, e.g.
thiabendazole 1 (Fig. 1), an antihelmintic drug [10, 11]. On
the other hand, synthetic fluoroquinolones, e.g. ciproflox-
acin 2 [12–15], are potent antiinfectious drugs [12–20]. It
follows that various types of imidazoquinolone are known,
e.g. 3–8 (Fig. 1) that share the features of both quinolones
(rings AB) and benzimidazoles (rings BC). Linear imi-
dazo[4,5-g]quinolones, e.g. 3a, 3b [21, 22], have been
prepared utilizing the corresponding 6,7-diamino-1-ethyl-
4-oxoquinoline-3-carboxylic acid.
Keywords 7,8-Diaminofluoroquinolone ꢀ
Alkanoic acids ꢀ Arene carboxaldehydes ꢀ
Cyclocondensation ꢀ Microwave irradiation
A number of angular non-fluorinated imidazoquinoline
derivatives, such as imidazo[4,5-f]quinolines 4 [23, 24], 5
[25–27], 6a [28–30], and 6b–6d [30], have been prepared
from the corresponding 5-aminobenzimidazole under the
conditions of the Gould–Jacobs reaction [31–33], but their
antibacterial activity was rather low. Several 4,5-disub-
stituted 9-oxo-1H-imidazo[4,5-f] quinoline-8-carboxylic
acids (7a–7c), directly synthesized from their 5,6-diami-
noquinoline precursors [34–37], have been reported as
potent antibacterial agents. The 5-fluoro derivative 7a
exhibited minimal inhibitory concentrations (MICs) of
0.025–12.5 lg/cm3 against an assortment of bacterial
strains [34, 35]. The 5-methoxy analogue 7b showed
activity equipotent to that of 7a against S. aureus, but was
2–16 times less potent against E. coli and P. aeruginosa
compared with 7a [36]. In 7c, a fluorine atom attached to
C-5 was the most favourable among H, F, and Cl, whereas
4-[N-(azacyclyl)]-5-fluoroimidazo[4,5-f]quinolones showed
potent and well-balanced activity against both Gram-
positive and Gram-negative bacteria [37].
Introduction
The benzimidazole nucleus occurs naturally as part of
vitamin B12, in the form of a 5,6-dimethyl-1-(a-D-
M. R. Al-Dweik ꢀ J. A. Zahra ꢀ M. A. Khanfar ꢀ
M. M. El-Abadelah
Chemistry Department, Faculty of Science, University of Jordan,
Amman, Jordan
K.-P. Zeller
Institut fu¨r Organische Chemie, Universitat Tubingen,
Tu
¨bingen, Germany
¨
¨
W. Voelter (&)
¨
¨
¨
¨
Interfakultares Institut fur Biochemie, Universitat Tubingen,
Hoppe-Seyler Str. 4, 72076 Tu¨bingen, Germany
e-mail: wolfgang.voelter@uni-tuebingen.de
The isomeric 6-oxoimidazo[4,5-h]quinoline-7-carbox-
ylic acid (8) has also been prepared from the respective
123

222
M. R. Al-Dweik et al.
O
Results and discussion
F
CO2H
N
N
A
N
B
S
The synthesis of ethyl 9-cyclopropyl-4-fluoro-6-oxo-6,9-
dihydro-1H-imidazo[4,5-h]quinoline-7-carboxylates (11a–
11c) is achieved via thermal cyclocondensation of
7,8-diamino-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroqui-
noline-3-carboxylate (10) with an excess amount (70 to
100-fold) of the appropriate alkanoic acid (7a–7c) as out-
lined in Scheme 1. This procedure is in line with the most
widely applicable route for the preparation of 2-alkyl-
benzimidazoles from o-diaminoarenes and alkanoic acids
[6, 7, 40]. Compounds 11a–11c were obtained in good
yield and were purified using silica gel column chroma-
tography as detailed in the ‘‘Experimental’’ part.
N
N
N
2
1
R2
O
N
O
CO2H
R1
C
N
N
CO2H
R2
C
B
A
A
N
R
B
N
N
Et
R1
3a (R1 = R2 = H)
3b (R1 = CH2CH2NEt2; R2 = Me)
4 (R = Et, Bz, c-C3H5; R1 = R2 = H)
5 (R = R2 = H; R1 = Me)
6a (R = R1 = R2 = H)
6b (R = R2 = Me; R1 = H )
6c (R = R1 = H; R2 = Me)
6d (R1 = R2 = H; R = Me )
1
N
O
C
9
N
CO2H
The 2-arylimidazo[4,5-h]quinolines 11d–11g were
prepared in good yields via microwave-assisted cyclocon-
densation of 10 with the particular arene carboxaldehyde
(7d–7g). Whilst adsorbed on silica gel in the presence of
nitrobenzene as oxidizing agent the two reactants (10 ? 7)
were irradiated with a power of 350 W for 8–10 min at
140 °C. This versatile method, as applied in this study, has
recently been reported for the synthesis of several 2-aryl-
benzimidazoles [41]. Acid-catalysed hydrolysis of the ethyl
esters (11a–11g) furnished the corresponding 9-cyclopro-
pyl-4-fluoro-6-oxo-6,9-dihydro-1H-imidazo[4,5-h]quino-
line-7-carboxylic acids (12a–12g) in high yield and in the
pure form.
A
B
4
Y
N 6
Et
5
O
5
6
X
CO2H
7
A
B
7a (X = Y = F)
7b (X = OMe; Y = NH2)
N9
Et
N
C
N1
7c (X = H, F, Cl; Y = 4-Me-1-piperazinyl)
2
8
Fig. 1 Representative structures of derivatives of benzimidazole,
fluoroquinolone, and isomeric imidazoquinolines
4-aminobenzimidazole [28, 29, 38, 39] under the condi-
tions of the Gould–Jacobs reaction [31–33] .This non-
fluorinated compound lacks suitable substituents at the
N(9) and C(2) positions and exhibits low antibacterial
activity. Accordingly, this work aims at synthesis of
model 6-oxoimidazo[4,5-h]quinoline-7-carboxylic acids
and esters having a cyclopropyl group at the N(9) locus
together with alkyl/aryl appendages at carbon-2 (11a–11g
and 12a–12g; Scheme 1).
The structures of the new heterocycles 11a–11g and 12a–
12g are supported by microanalytical and spectral (IR, MS,
NMR) data; details are given in the ‘‘Experimental’’ part.
The IR spectra showed absorption bands arising from
stretching vibrations at 1,612–1,638 cm-1 (conjugated
keto group), 1,697–1,722 cm-1 (carbonyl of conjugated
CO2Et/CO2H), and 3,088–3,233 cm-1 (N–H). In addition,
Scheme 1
O
4
O
5
5
6
F
4a
8a
CO2Et
F
5a
9a
CO2R'
7
4
(i)
(ii)
R-CO2H
9a-c
+
3a
10 + Ar-CHO
8
H2N
N1
1'
8
N
1'
9
9b
N
9d-g
3
NH2
NH
2
1
2'
3'
(Ar) R
3'
2'
10
11a-g (R' = Et)
12a-g (R' = H)
(iii)
entry 11a / 12a
11c / 12c
11b / 12b
R
H
Me
Et
entry
11d / 12d
11e / 12e
11f / 12f
11g / 12g
1"
1"
1"
1"
Me 4"
4"
H4"
F 4"
Cl
Ar
o
11a-c 11d-g
); (ii) PhNO2 , SiO2 / MW, 15 min. ( ); (iii) 12% HCl + EtOH / reflux
(i) 100 C / 3 h (
123

Heterocycles [h]-fused onto 4-oxoquinoline-3-carboxylic acid
223
O
N
O
N
compounds 12a–12g displayed strong absorption bands at
3,395–3,445 cm-1 (O–H). The mass spectra of 11 and 12
displayed the correct molecular ion peaks as suggested by
their molecular formulas, and for which the high-resolution
HRMS (ESI) data are in good agreement with the calculated
values. The mass spectra of the ethyl ester derivatives 11a–
11g are dominated by base peaks corresponding to fragment
ions [Z]?ꢀ of m/z = [M - 72] produced via successive
elimination of acetaldehyde (McLafferty type) and CO from
[M]1ꢀ (Scheme 2). The corresponding acids 12a–12g
underwent facile decarboxylation under electron impact,
with ultimate formation of similar [Z]?ꢀ ions as the base
peaks having m/z = [M - 44] (Scheme 3). The latter ions
undergo further fragmentation via elimination of a methyl
radical or CO to produce ions [Z - 15]? and [Z - 28]?ꢀ,
respectively (Scheme 4).
F
F
N
N
[ Z ]
N
N
N
H
(Ar) R
(Ar) R
F
-CH3
-CO
O
N
F
N
N
N
N
(Ar) R
(Ar) R
[Z-28]
[Z-15 ]
Scheme 4
recognizable by their doublet signals (with varying J val-
ues) originating from scalar (through-bond) coupling with
the neighboring fluorine atom at carbon-4. Likewise, the
p-fluorophenyl carbons in 11f and 12f are also displayed as
doublet signals arising from spin–spin coupling with the
nearby para fluorine atom. In HMBC experiments for 11a–
11g and 12a–12g, distinct ‘‘three-bond’’ (1H, 13C) corre-
lations are observed between H-5 and each of C-3a, C-9a,
and C-6, and between H-9 and each of C-9a, C-10, C-6a,
and CO2H/CO2 Et.
1H and 13C signal assignments to the different protons
and carbons are based on DEPT and 2D (COSY, HMQC,
HMBC) experiments which showed correlations consistent
with these assignments. The skeletal carbons of the benzo-
fused entity (ring B) in 11a–11g and 12a–12g are
O
N
O
O
O
C
F
F
O
-MeCH=O
H
Experimental
N
N
H
N
H
NH
NH
NH
M
Pure grade alkanoic acids, benzaldehyde, p-tolualdehyde,
p-chlorobenzaldehyde, and p-fluorobenzaldehyde were
purchased from Acros. Microwave irradiation experiments
were accomplished with a Biotage Initiator 2.0 Microwave
Synthesizer instrument. Melting points were determined on
a Gallenkamp electrothermal melting-temperature appara-
(Ar) R
(Ar) R
(11a-g)
1,2-H shift
O
N
O
O
C
H
F
F
-CO
N
H
N
N
1
tus. H and 13C NMR spectra were measured on a Bruker
NH
DPX-300 instrument. Chemical shifts are expressed in ppm
with reference to TMS as internal standard. Electron-impact
mass spectra (EIMS) were obtained using a Finnigan MAT
TSQ-70 spectrometer at 70 eV, at an ion source tempera-
ture of 200 °C. High resolution mass spectra (HRMS) were
measured in positive-ion mode by electrospray (ESI) on a
Bruker APEX-4 (7 Tesla) instrument. IR spectra were
recorded on a Nicolet Impact-400 FT-IR spectrophotome-
ter. Microanalyses were preformed at the Microanalytical
Laboratory of the Inorganic Chemistry Department, Tu¨b-
ingen University, Germany, and the results agreed with the
calculated values within experimental error ( 0.4%).
(Ar) R
(Ar) R
base peak [ Z ]
[ M-72 ]
Scheme 2
O
O
H
O
N
O
F
F
O
O
N
H
N
N
NH
M
NH
NH
(Ar) R
(Ar) R
(12a-g)
- CO2
O
H
H
F
Ethyl 7,8-diamino-1-cyclopropyl-6-fluoro-4-oxo-1,
4-dihydroquinoline-3-carboxylate (10)
[ Z ]
N
N
This compound is prepared by reduction of ethyl 7-azido-
1-cyclopropyl-6-flouro-8-nitro-4-oxo-1,4-dihydroquinoline-
3-carboxylate [42] using SnCl2 and conc HCl at room temp
according to a literature procedure [43, 44].
(Ar) R
base peak [M-44]
Scheme 3
123

224
M. R. Al-Dweik et al.
General procedure of Ethyl 2-(alkyl)-9-cyclopropyl-4-
fluoro-6-oxo-6,9-dihydro-1H-imidazo[4,5-h]
quinoline-7-carboxylates 11a–11c
H-10), 7.73 (d, 3JH-F = 11 Hz, 1H, H-5), 8.45 (s, 1H, H-2),
8.47 (s, 1H, H-8) ppm; 13C NMR (75 MHz, DMSO-d6):
d = 9.9 (C-20 ? C-30), 14.8 (CH3), 39.4 (C-10), 60.4
2
(CH2Me), 103.7 (d, JC-F = 18.9 Hz, C-5), 110.3 (C-7),
124.3 (d, 3JC-F = 5.6 Hz, C-5a), 130.2 (br d, 2JC-F = 13 Hz,
C-3a), 130.4 (C-9a), 133.0 (br d, 3JC-F = 4 Hz, C-9b), 143.8
A stirred mixture of 0.61 g 10 (2 mmol) and 10 cm3 of the
particular alkanoic acid was brought to gentle reflux for
2–3 h. The homogeneous reaction solution was then cooled
and basified with 40% cold aqueous NaOH solution to
pH *7 and set aside for few minutes. The resulting white
precipitate was collected by suction filtration, washed with
water, and purified on preparative silica gel TLC plates
using MeOH–CHCl3 (1:20, v/v) as mobile phase.
1
(C-2), 147.3 (C-8), 149.1 (d, JC-F = 250 Hz, C-4), 165.1
4
(CO2Et), 172.5 (d, JC-F = 2.4 Hz, C-6) ppm; EIMS m/z
(%): 315 (M?, 21), 271 (17), 270 (14), 243 (100), 242 (51),
228 (21), 214 (15), 201 (6), 188 (5), 174 (10), 147 (7), 106
(4); HRMS (ESI): m/z calcd. for C16H15FN3O3 [M ? H]?:
316.10974, found: 316.10925.
Ethyl 9-cyclopropyl-4-fluoro-2-methyl-6-oxo-6,
9-dihydro-1H-imidazo[4,5-h]quinoline-7-
carboxylate (11b, C17H16FN3O3)
General procedure of Ethyl 2-aryl-9-cyclopropyl-4-
fluoro-6-oxo-6,9-dihydro-1H-imidazo[4,5-h]
quinoline-7-carboxylate 11d–11g
ꢀ
Yield: 0.50 g (76%), mp 231-233 °C; IR (KBr): m = 3,101,
2,993, 1,716, 1,636, 1,578, 1,494, 1,456, 1,423, 1,334,
1,234, 1,178, 1,121, 1,074, 1,036, 879, 805 cm-1; 1H NMR
(300 MHz, DMSO-d6): d = 1.06 (m, 2H) and 1.27 (m, 2H)
(H2-20 ? H2-30), 1.25 (t, J = 7.1 Hz, 3H, CH3CH2), 2.58
(s, 3H, C(2)-CH3), 4.18 (q, J = 7.1 Hz, 2H, CH2Me), 4.38
(m, 1H, H-10), 7.63 (d,3JH-F = 11 Hz, 1H, H-5), 8.43 (s,
1H, H-8) ppm; 13C NMR (75 MHz, DMSO-d6): d = 9.9(C-
20 ? C-30), 14.8 (CH3CH2O–), 15.3 (C(2)-CH3), 39.3 (C-
To a homogeneous solution of 0.61 g 10 (2 mmol) in
10 cm3 CHCl3–MeOH (1:4, v/v) was added, successively,
the particular aromatic aldehyde (2 mmol), 0.32 g nitro-
benzene (2.6 mmol), and 3 g silica. The resulting slurry
was evaporated to dryness under reduced pressure and
placed in a 10-mL glass vial. The vial was sealed tightly
with an aluminum–Teflon crimp top and the mixture was
irradiated with an irradiation power of 250 W for
20–25 min at pre-selected temperature of 200 °C. There-
after, the vial was cooled to 20 °C by gas-jet cooling and
the reaction product was then purified by flash column
chromatography, eluting at first with CHCl3, followed by
CHCl3–MeOH (9:1, v/v).
2
10), 60.3 (CH2Me), 103.0 (d, JC-F = 19.1 Hz, C-5), 109.7
(C-7), 123.7 (d, 3JC-F = 5.6 Hz, C-5a), 129.2 (C-9a), 131.1
2
3
(br d, JC-F = 12 Hz, C-3a), 133.1 (br d, JC-F = 5 Hz, C-
9b), 147.1 (C-8), 148.8 (d, 1JC-F = 247 Hz, C-4), 153.7(C-
4
2), 165.1(CO2Et), 172.6 (d, JC-F = 2.3 Hz, C-6) ppm;
EIMS m/z (%): 329 (M?, 13), 285 (30), 284 (13), 257
(100), 256 (43), 242 (29), 228 (16), 215 (8), 188 (18), 161
(7), 147 (10), 119 (7), 106(8); HRMS (ESI): m/z calcd. for
C17H17FN3O3 [M ? H]?: 330.12539, found: 330.12482.
General procedure of 9-Cyclopropyl-4-fluoro-6-
oxo-6,9-dihydro-1H-imidazo[4,5-h]quinoline-7-
carboxylic acids 12a–12g
Ethyl 9-cyclopropyl-2-ethyl-4-fluoro-6-oxo-6,
9-dihydro-1H-imidazo[4,5-h]quinoline-7-
carboxylate (11c, C18H18FN3O3)
A stirred solution of the particular ester 11 (2 mmol) in
30 cm3 12% aq. HCl and 15 cm3 ethanol was heated at
80–85 °C under reflux conditions. Progress of the ester
hydrolysis was monitored by silica gel TLC and was
completed within 2–3 h. Thereafter, the reaction mixture
was cooled, poured on to ice-water and basified with 12%
aq. sodium hydroxide solution. The resulting precipitate
was collected, washed with water, and dried.
Yield: 0.39 g (57%), mp 211–213 °C; IR (KBr):
ꢀ
m = 3,088, 2,982, 2,929, 1,722, 1,630, 1,607, 1,577,
1,537, 1,493, 1,458, 1,422, 1,331, 1,265, 1,238, 1,197,
1,174, 1,123, 1,061, 1,034, 864, 803 cm-1 1H NMR
;
(300 MHz, DMSO-d6): d = 1.06 (m, 2H) and 1.25 (m, 2H,
overlapped with the neighbouring triplet) (H2-20 ? H2-30),
1.23 (t, J = 7 Hz, 3H, CH3CH2O–), 1.32 (t, J = 7.4 Hz,
3H, CH3CH2-C(2)), 2.92 (q, J = 7.4 Hz, 2H, C(2)-
CH2Me), 4.17 (q, J = 7 Hz, 2H, –OCH2Me), 4.34 (m,
1H, H-10), 7.61 (d, 3JH-F = 11.1 Hz, 1H, H-5), 8.41 (s, 1H,
H-8) ppm; 13C NMR (75 MHz, DMSO-d6): d = 9.9 (C-
20 ? C-30), 12.7 (CH3CH2-C(2)), 14.7 (CH3CH2O–), 22.3
Ethyl 9-cyclopropyl-4-fluoro-6-oxo-6,9-dihydro-1H-
imidazo[4,5-h]quinline-7-carboxylate
(11a, C16H14FN3O3)
Yield: 0.43 g (69%), mp 300–302 °C (dec); IR (KBr):
ꢀ
m = 3,100, 3,021, 2,983, 2,928, 1,712, 1,612, 1,575, 1,497,
1,451, 1,374, 1,332, 1,282, 1,242, 1,178, 1,118, 878,
(MeCH2-C(2)), 39.4 (C-10), 60.3 (–OCH2Me), 103.1(d,
3
2JC-F = 22.1 Hz, C-5), 109.5 (C-7), 123.7 (d, JC-F
=
804 cm-1; H NMR (300 MHz, DMSO-d6): d = 1.10 (m,
2H) and 1.28 (m, 2H) (H2-20 ? H2-30), 1.25 (t, J = 7.1 Hz,
3H, CH3), 4.20 (q, J = 7.1 Hz, 2H, CH2Me), 4.36 (m, 1H,
1
5.6 Hz, C-5a), 129.3 (br, C-9a), 130.5 (br d,
3
2JC-F = 12 Hz, C-3a), 133.1 (br d, JC-F = 4 Hz, C-9b),
123

Heterocycles [h]-fused onto 4-oxoquinoline-3-carboxylic acid
225
1
147.3 (C-8), 148.6 (d, JC-F = 249 Hz, C-4), 158.0 (d,
130.8 (C-9a), 137.4 (d, 3JC-F = 3.5 Hz, C-9b), 147.2 (C-8),
4
1
4JC-F = 2 Hz, C-2), 165.0 (CO2Et), 172.6 (d, JC-F
=
147.5 (d, JC-F = 248 Hz, C-4), 151.6 (C-2), 163.9 (d,
2.3 Hz, C-6); EIMS m/z (%): 343 (M?, 13), 298 (5), 271
(100), 270 (27), 256 (28), 242 (14), 216 (4), 200 (7), 191
(17), 187 (8), 161 (5), 133 (4), 107 (5) ppm; HRMS (ESI):
m/z calcd. for C18H19FN3O3 [M ? H]?: 344.14104, found:
344.14051.
1JC-F = 247 Hz, C-400), 165.0 (CO2Et), 172.4 (d,
4JC-F = 2.3 Hz, C-6) ppm; EIMS m/z (%): 409 (M?, 11),
365 (27), 351 (66), 337 (100), 322 (43), 308 (21), 282 (11),
241 (6), 200 (4), 123 (6). HRMS (ESI): m/z calcd.
for C22H17F2N3O3Na [M ? Na]?: 432.11356, found:
432.11829.
Ethyl 9-cyclopropyl-4-fluoro-6-oxo-2-phenyl-6,
9-dihydro-1H-imidazo[4,5-h]quinoline-7-
carboxylate (11d, C22H18FN3O3)
Ethyl 9-cyclopropyl-4-fluoro-2-(4-chlorophenyl)-6-
oxo-6,9-dihydro-1H-imidazo[4,5-h] quinoline-7-
carboxylate (11f, C22H17ClFN3O3)
ꢀ
Yield: 0.63 g (80%), mp [ 310 °C; IR (KBr): m = 3,060,
3,005, 2,978, 2,856, 2,362, 1,727, 1,696, 1,636, 1,588,
Yield: 0.67 g (79%), mp 292–294 °C (dec); IR (KBr):
ꢀ
1,538, 1,486, 1,456, 1,403, 1,328, 1,265, 1,234, 1,178,
1,121, 1,069, 1,032, 944, 806, 781 cm-1
m = 3,209, 3,095, 3,051, 2,953, 2,867, 2,783, 1,745, 1,717,
1,636, 1,590, 1,484, 1,439, 1,328, 1,264, 1,232, 1,176,
;
1H NMR
(300 MHz, DMSO-d6): d = 1.14 (m, 2H) and 1.32 (m,
2H) (H2-20 ? H2-30), 1.26 (t, J = 7.1 Hz, 3H,
–OCH2CH3), 4.20 (q, J = 7.1 Hz, 2H,–OCH2Me), 4.44
(m, 1H, H-1’), 7.48 (dd, J = 7.2, 7.5 Hz, 2H, H-300 ? H-
1,122, 1,090, 1,068, 1,033, 844, 805 cm-1 1H NMR
;
(300 MHz, DMSO-d6): d = 1.14 (m, 2H) and 1.31 (m, 2H)
(H2-20 ? H2-30), 1.27 (t, J = 7.1 Hz, 3H, –OCH2CH3),
4.21 (q, J = 7.1 Hz, 2H,–OCH2Me), 4.44 (m, 1H, H-10),
3
3
500), 7.73 (d, JH-F = 10.9 Hz, 1H, H-5), 7.91 (t,
7.74 (d, JH-F = 10.9 Hz, 1H, H-5), 7.60 (d, J = 8.5 Hz,
J = 7.2 Hz, 1H, H-400), 8.26 (d, J = 7.5 Hz, 2H, H-
200 ? H-600), 8.43 (s, 1H, H-8), 12.90 (br s, 1H, N-H) ppm;
13C NMR (75 MHz, DMSO-d6): d = 10.3 (C-20 ? C-30),
14.8 (CH3CH2O–), 40.3 (C-10), 60.3 (–OCH2Me), 104.3 (d,
2H, H-300 ? H-500), 8.26 (d, J = 8.5 Hz, 2H, H-200 ? H-
600), 8.45 (s, 1H, H-8), 13.60 (br s, 1H, N-H) ppm; 13C
NMR (75 MHz, DMSO-d6): d = 10.2 (C-20 ? C-30), 14.8
(CH3CH2O–), 40.3 (C-10), 60.3 (-O CH2Me), 104.3 (d,
3
3
19.8 Hz, C-5), 110.2 (C-7), 124.4 (d, JC-F = 4.9 Hz,
2
2JC-F = 10.3 Hz, C-5), 110.3 (C-7), 124.2 (d, JC-F
=
C-5a), 127.4 (C-200 ? C-600), 128.0 (d, JC-F = 14.2 Hz,
5.2 Hz, C-5a), 129.1 (C-100), 129.2 (C-300 ? C-500), 129.5
(C-200 ? C-600), 131.0 (d, 4JC-F = 1.3 Hz, C-9a), 131.5 (C-
C-3a), 130.9 (C-300 ? C-500), 131.3 (C-9a), 133.3 (C-400),
3
3
135.0 (C-100), 137.4 (d, JC-F = 4 Hz, C-9b), 147.1 (C-8),
400), 135.5 (d, JC-F = 4.0 Hz, C-9b), 129.7 (d,
1
1
147.2 (d, JC-F = 247 Hz, C-4), 152.0 (C-2), 165.0
4
2JC-F = 14.2 Hz, C-3a), 147.0 (C-8), 148.8 (d, JC-F
=
(CO2Et), 172.4 (d, JC-F = 2.1 Hz, C-6) ppm; EIMS m/z
244 Hz, C-4), 151.6 (C-2), 165.1 (CO2Et), 172.4 (C-6)
ppm; EIMS m/z (%): 425 (M?, 11), 381 (40), 367 (52), 353
(100), 338 (38), 324 (19), 298 (11), 284 (10), 248 (6), 215
(6), 189 (6), 132 (6). HRMS (ESI): m/z calcd. for
C22H18ClFN3O3 [M ? H]?: 426.10207, found: 426.10194.
(%): 391 (M?, 12), 347 (23), 333 (60), 319 (100), 304 (44),
290 (22), 264 (11), 250 (8), 223 (6), 173 (5), 146 (7), 122
(15), 105 (24); HRMS (ESI): m/z calcd. for C22H19FN3O3
[M ? H]?: 392.14105, found: 392.13995.
Ethyl 9-cyclopropyl-2-(4-fluororophenyl)-4-fluoro-6-
oxo-6,9-dihydro-1H-imidazo[4,5-h] quinoline-7-
carboxylate (11e, C22H17F2N3O3)
Ethyl 9-cyclopropyl-4-fluoro-2-(4-methylphenyl)-6-
oxo-6,9-dihydro-1H-imidazo [4,5-h] quinoline-7-
carboxylate (11g, C23H20FN3O3)
Yield: 0.62 g (75%), mp 265–266 °C (dec); IR (KBr):
Yield: 0.61 g (74%), mp 301–302 °C (dec); IR (KBr):
ꢀ
ꢀ
m = 3,096, 3,068, 2,995, 2,956, 1,720, 1,635, 1,584, 1,547,
1,391, 1,330, 1,271, 1,237, 1,137, 1,197, 1,165, 1,123,
m = 3,092, 3,048, 2,919, 2,866, 1,711, 1,634, 1,586, 1,546,
1,495, 1,393, 1,330, 1,301, 1,270, 1,235, 1,191, 1,069,
1
1
1,036, 808, 738 cm-1; H NMR (300 MHz, DMSO-d6):
1,036, 833, 808 cm-1; H NMR (300 MHz, DMSO-d6):
d = 1.13 (m, 2H) and 1.31 (m, 2H) (H2-20 ? H2-30), 1.26
(t, J = 7.1 Hz, 3H, –OCH2CH3), 4.19 (q, J = 7.1 Hz,
d = 1.12 (m, 2H) and 1.29 (m, 2H) (H2-20 ? H2-30), 1.26
(t, J = 7.1 Hz, 3H, CH3CH2O–), 2.31 (s, 3H, C(400)-CH3),
3
2H,–OCH2Me), 4.43 (m, 1H, H-10), 7.71 (d, JH-F
=
4.19 (q, J = 7.1 Hz, 2H, –OCH2Me), 4.43 (m, 1H, H-10),
3
10.8 Hz, 1H, H-5), 7.37 (dd, J = 8.3, 8.8 Hz, 2H,
H-300 ? H-500), 8.29 (dd, J = 2.6, 8.3 Hz, 2H, H-200 ? H-
6’’), 8.42 (s, 1H, H-8), 13.80 (br s, 1H, N-H) ppm; 13C NMR
(75 MHz, DMSO-d6): d = 10.2 (C-20 ? C-30), 14.8
(CH3CH2O–), 40.2 (C-10), 60.3 (-OCH2Me), 104.2
7.31 (d, J = 8.0 Hz, 2H, H-300 ? H-500), 7.68 (d, JH-F
=
10.9 Hz, 1H, H-5), 8.13 (d, J = 8.0 Hz, 2H, H-200 ? H-
600), 8.41 (s, 1H, H-8), 13.82 (br s, 1H, N-H) ppm; 13C
NMR (75 MHz, DMSO-d6): d = 10.2 (C-20 ? C-30), 14.8
(CH3CH2O–), 40.2 (C-10), 60.3 (–OCH2Me), 103.8 (d,
2
3
(d, JC-F = 18.5 Hz, C-5), 110.1 (C-7), 116.5 (d,
2JC-F = 21.9 Hz, C-300 ? C-500), 124.2 (d, 3JC-F = 5.3 Hz,
2JC-F = 18.5 Hz, C-5), 109.9 (C-7), 124.1 (d, JC-F
=
5 Hz, C-5a), 127.1 (C-100), 127.4 (C-200 ? C-600), 129.7
(d, JC-F = 14.5 Hz, C-3a), 129.9 (C-300 ? C-500), 130.6
(C-9a), 137.5 (d, JC-F = 4.2 Hz, C-9b), 140.6 (C-400),
4
2
2
C-5a), 126.5 (d, JC-F = 2.9 Hz, C-100), 128.5 (d, JC-F
=
3
3
14.2 Hz, C-3a), 129.9 (d, JC-F = 8.6 Hz, C-200 ? C-600),
123

226
M. R. Al-Dweik et al.
1
147.2 (C-8), 147.5 (d, JC-F = 247 Hz, C-4), 152.6 (C-2),
(300 MHz, DMSO-d6): d = 1.20 (m, 2H) and 1.25 (m, 2H,
overlapped with the neighboring triplet) (H2-20 ? H2-30),
1.37 (t, J = 7.4 Hz, 3H, CH3CH2-C(2)), 2.96 (q,
J = 7.4 Hz, 2H, C(2)-CH2Me), 4.56 (m, 1H, H-10), 7.79
4
165.0 (CO2Et), 172.5 (d, JC-F = 2 Hz, C-6) ppm; EIMS
m/z (%): 405 (M?, 14), 390 (6), 361 (15), 347 (56), 333
(100), 318 (41), 304 (15), 278 (7), 265 (6), 119 (19), 91
(15); HRMS (ESI): m/z calcd. for C23H21FN3O3
[M ? H]?: 406.15670, found: 406.15675.
3
(d, JH-F = 8.2 Hz, 1H, H-5), 8.70 (s, 1H, H-8), 13.40 (br,
1H, N-H), 15.38 (s, 1H, CO2H) ppm; 13C NMR (75 MHz,
DMSO-d6): d = 10.1 (C-20 ? C-30), 12.6 (CH3CH2-C(2)),
9-Cyclopropyl-4-fluoro-6-oxo-6,9-dihydro-1H-
imidazo[4,5-h]quinoline-7-carboxylic acid
(12a, C14H10FN3O3)
2
22.4 (MeCH2-C(2)), 39.3 (C-10), 102.6 (d, JC-F
=
3
19.7 Hz, C-5), 107.5 (C-7), 121.1 (d, JC-F = 5.5 Hz, C-
2
5a), 129.3 (br, C-9a), 131.3 (br d, JC-F = 15 Hz, C-3a),
ꢀ
Yield: 0.53 g (93%), mp [ 310 °C; IR (KBr): m = 3,435,
3
132.0 (br d, JC-F = 3.5 Hz, C-9b), 147.0 (C-8), 148.5 (d,
3,092, 2,843, 2,793, 1,685, 1,631, 1,589, 1,546, 1,459,
1,315, 1,096, 923, 810 cm-1; 1H NMR (300 MHz, DMSO-
d6): d = 1.18 (m, 2H) and 1.34 (m, 2H) (H2-20 ? H2-30),
4.49 (m, 1H, H-10), 7.74 (d, 3JH-F = 10.4 Hz, 1H, H-5), 8.55
(s, 1H, H-2), 8.67 (s, 1H, H-8), 12.80 (br s, 1H, N-H), 15.24
1JC-F = 249 Hz, C-4), 158.0 (d, 4JC-F = 2 Hz, C-2), 166.5
(CO2H), 177.4 (d, 4JC-F = 2 Hz, C-6) ppm; EIMS m/z (%):
315 (M?, 9), 271 (100), 256 (39), 242 (15), 215 (8), 188
(6); HRMS (ESI): m/z calcd. for C16H15FN3O3 [M ? H]?:
316.10974, found: 316.10926.
(br, 1H, CO2H) ppm; 13C NMR (75 MHz, DMSO-d6):
2
d = 9.9 (C-20 ? C-30), 40.7 (C-10), 103.0 (d, JC-F
19.2 Hz, C-5), 107.7 (C-7), 121.5 (d, JC-F = 6.7 Hz,
=
9-Cyclopropyl-4-fluoro-6-oxo-2-phenyl-6,9-dihydro-1H-
imidazo[4,5-h] quinoline-7-carboxylic acid
(12d, C20H14FN3O3)
3
2
C-5a), 130.3 (br d, JC-F = 12 Hz, C-3a), 131.4 (C-9a),
3
ꢀ
133.6 (br d, JC-F = 3.5 Hz, C-9b), 144.1 (C-2), 147.0
Yield: 0.66 g (91%), mp [ 310 °C; IR (KBr): m = 3,460,
(C-8), 149.5 (d, 1JC-F = 251 Hz, C-4), 166.4 (CO2H), 177.2
(d, 4JC-F = 2.9 Hz, C-6) ppm; EIMS m/z (%): 287 (M?, 4),
243 (100), 242 (30), 228 (21), 214 (8), 188 (5), 174 (12), 160
(5), 147 (12), 119 (5), 106 (9); HRMS (ESI): m/z calcd. for
C14H11FN3O3 [M ? H]?: 288.07844, found: 288.07795.
3,121, 3,079, 2,883, 2,846, 2,669, 1,706, 1,630, 1,588,
1,536, 1,481, 1,365, 1,316, 1,247, 1,132, 1,069, 1,031, 948,
889, 862 cm-1; 1H NMR (300 MHz, DMSO-d6): d = 1.16
(m, 2H) and 1.33 (m, 2H) (H2-20 ? H2-30), 4.45 (m, 1H,
H-10), 7.50 (m, 3H, H-400 ? H-300 ? H-500), 7.66 (d,
3JH-F = 10.4 Hz, 1H, H-5), 8.17 (m, 2H, H-200 ? H-600),
8.50 (s, 1H, H-8), 13.91 (br s, 1H, N-H), 15.20 (s, 1H,
CO2H) ppm; 13C NMR (75 MHz, DMSO-d6): d = 10.2 (C-
9-Cyclopropyl-4-fluoro-2-methyl-6-oxo-6,9-dihydro-1H-
imidazo[4,5-h]quinoline-7-carboxylic acid
(12b, C15H12FN3O3)
2
20 ? C-30), 41.6 (C-10), 103.4 (d, JC-F = 19.1 Hz, C-5),
3
107.8 (C-7), 121.5 (d, JC-F = 6.2 Hz, C-5a), 127.5 (C-
ꢀ
Yield: 0.55 g (92%), mp [ 310 °C; IR (KBr): m = 3,445,
3,119, 2,922, 2,856, 1,709, 1,634, 1,595, 1,543, 1,473,
;
1,318, 1,230, 1,131, 1,037, 1,010, 806 cm-1 1H NMR
2
200 ? C-600), 128.8 (d, JC-F = 14.5 Hz, C-3a), 129.4 (C-
100), 129.5 (C-300 ? C-500), 132.0 (C-9a), 131.2 (C-400),
3
137.3 (d, JC-F = 4 Hz, C-9b), 146.8 (C-8), 147.8 (d,
(300 MHz, DMSO-d6): d = 1.21 (m, 2H) and 1.32 (m,
2H)(H2-20 ? H2-30), 2.62 (s, 3H, C(2)-CH3), 4.52 (m, 1H,
1JC-F = 249 Hz, C-4), 152.5 (C-2), 166.3 (CO2H), 177.1
3
H-10), 7.75 (d, JH-F = 10.3 Hz, 1H, H-5), 8.67 (s, 1H, H-
4
(d, JC-F = 2.7 Hz, C-6) ppm; EIMS m/z (%): 363 (M?,
8), 13.34 (br s, 1H, N-H), 15.30 (s, 1H, CO2H) ppm; 13C
11), 319 (100), 304 (66), 290 (18), 271 (14), 250 (11), 223
(8),159 (6), 147 (10), 131 (6); HRMS (ESI): m/z calcd. for
C20H15FN3O3 [M ? H]?: 364.10974, found: 364.10917.
NMR (75 MHz, DMSO-d6): d = 10.0 (C-20 ? C-30), 15.2
2
(C(2)-CH3), 38.6 (C-10), 102.5 (d, JC-F = 19.1 Hz, C-5),
3
107.5 (C-7), 121.1(d, JC-F = 6.7 Hz, C-5a), 129.1 (C-9a),
2
130.4 (br d, JC-F = 11.8 Hz, C-3a), 132.0 (br d, JC-F
3
9-Cyclopropyl-2-(4-fluorophenyl)-4-fluoro-6-oxo-6,
9-dihydro-1H-imidazo [4,5-h]quinoline-7-
carboxylic acid (12e, C20H13F2N3O3)
=
1
4.6 Hz, C-9b), 146.9 (C-8), 152.6 (d, JC-F = 247 Hz,
C-4), 153.4 (C-2), 166.4 (CO2H), 177.3 (d, 4JC-F = 2.8 Hz,
C-6) ppm; EIMS m/z (%): 301 (M?, 14), 282 (3), 257
(100), 256 (31), 242 (35), 228 (10), 201 (6), 188 (11), 161
(7), 121 (4), 106 (3); HRMS (ESI): m/z calcd. for
C15H13FN3O3 [M ? H]?: 302.09409, found: 302.09354.
ꢀ
Yield: 0.69 g (91%), mp [ 310 °C; IR (KBr): m = 3,438,
3,169, 3,098, 2,925, 1,712, 1,634, 1,586, 1,527, 1,493,
1,441, 1,318, 1,220, 1,159, 1,131, 1,065, 1,000, 946, 881,
841, 809 cm-1; 1H NMR (300 MHz, DMSO-d6): d = 1.22
(m, 2H) and 1.37 (m, 2H) (H2-20 ? H2-30), 4.52 (m, 1H, H-
10), 7.35 (dd, J = 8.1, 8.7 Hz, 2H, H-300 ? H-500), 7.74 (d,
3JH-F = 10.3 Hz, 1H, H-5), 8.26 (dd, J = 8.1, 2.3 Hz, 2H,
H-200 ? H-600), 8.60 (s, 1H, H-8), 14.02 (s, 1H, N-H), 15.28
9-Cyclopropyl-2-ethyl-4-fluoro-6-oxo-6,9-dihydro-1H-
imidazo[4,5-h]quinoline-7-carboxylic acid
(12c, C16H14FN3O3)
(br s, 1H, CO2H) ppm; 13C NMR (75 MHz, DMSO-d6):
ꢀ
Yield: 0. 58 g (92%), mp [ 310 °C; IR (KBr): m = 3,423,
3,122, 2,923, 2,850, 1,707, 1,635, 1,593, 1,541, 1,473,
;
1,318, 1,217, 1,139, 1,030, 959, 807 cm-1 1H NMR
2
d = 10.2 (C-20 ? C-30), 41.6 (C-10), 103.5 (d, JC-F
19.0 Hz, C-5), 107.8 (C-7), 116.6 (d, JC-F = 21.6 Hz,
=
2
123

Heterocycles [h]-fused onto 4-oxoquinoline-3-carboxylic acid
227
3
C-300 ? C-500), 121.6 (d, JC-F = 4.8 Hz, C-5a), 125.9 (d,
ppm; EIMS m/z (%): 377 (M?, 6), 333 (100), 318 (91), 304
(20), 278 (9), 264 (14), 249 (6), 215 (5), 167 (6), 147 (5);
HRMS (ESI): m/z calcd. for C21H17FN3O3 [M ? H]?:
378.12539, found: 378.12484.
4JC-F = 2.1 Hz, C-100), 129.0 (d, JC-F = 14 Hz, C-3a),
2
3
130.0 (d, JC-F = 7.0 Hz, C-200 ? C-600), 132.0 (C-9a),
3
137.4 (d, JC-F = 4.5 Hz, C-9b), 146.8 (C-8), 147.8 (d,
1JC-F = 249 Hz, C-4), 151.6 (C-2), 164.1 (d, JC-F
=
1
4
246 Hz, C-400), 166.3 (CO2H), 177.2 (d, JC-F = 2.0 Hz,
C-6) ppm; EIMS m/z (%): 381 (M?, 8), 337 (100), 322 (47),
308 (15), 268 (11), 241 (9), 215 (5), 169 (4), 155 (7), 134 (6);
HRMS (ESI): m/z calcd. for C20H14F2N3O3 [M ? H]?:
382.10032, found: 382.09979.
Acknowledgments We wish to thank the Deanship of Scientific
Research (University of Jordan, Amman, Jordan) and DFG/Germany
for financial support.
References
2-(4-Chlorophenyl)-9-cyclopropyl-4-fluoro-6-oxo-6,
9-dihydro-1H-imidazo [4,5-h] quinoline-7-
carboxylic acid (12f, C20H13ClFN3O3)
1. Abu-Sheaib ES, Zahra JA, El-Abadelah MM, Boese R (2008)
Monatsh Chem (Part VI) 139 (in press)
2. Riether D, Mulzar J (2003) Eur J Org Chem 30
ꢀ
Yield: 0.74 g (93%), mp [ 310 °C; IR (KBr): m = 3,427,
3,165, 3,098, 3,975, 2,877, 1,709, 1,632, 1,590, 1,518,
¨
3. Krautler B, Arigoni D, Golding BT (1998) Vitamin B12 and B12-
proteins. Wiley-VCH, Weinheim
4. Woodward RB (1979) Total synthesis of vitamin B12. In:
Zagalak B, Friedrich W (1979) Vitamin B12. Walter de Gruyter,
Berlin
5. Herbert V, Das KC (1976) Vitam Horm 34:1
6. Preston PN (1974) Chem Rev 74:274
7. Grimmett MR (1984) Imidazoles and their Benzo derivatives. In:
Katritsky AR, Rees CW (eds) Comprehensive heterocyclic
chemistry, vol 5. Pergamon Press, Oxford, p 373
8. Spasov AA, Yozhitsa IN, Bugaeva LT, Anisimova VA (1999)
Pharm Chem J 33:232, and refs cited therein
9. Hammach A, Barbosa A, Gaenzler FC, Fadra T, Goldberg D, Hao
M-H, Kroe RR, Liu P, Qian KC, Ralph M, Sarko C, Soleyman-
zadeh F, Moss N (2006) Bioorg Med Chem Lett 16:6316
10. Prichard RK (1970) Nature 228:684
11. Friedman PA, Platzer EG (1978) Biochem Biophys Acta 544:605
12. Wise R, Andrews JM, Edwards LJ (1983) Antimicrob Agents
Chemother 23:559
13. Felmingham D, O’Hare MD, Robbins MJ, Wall RA, Williams
AH, Cremer AW, Ridgeway GL, Gruneberg RN (1985) Drugs
Exp Clin Res 11:317
14. Maurer F, Grohe K (1986) Ger Offen 3, 435, 392
15. Maurer F, Grohe K (1986) Chem Abstr 105:97158e
16. Andriole VT (2000) The Quinolones. Academic Press, San Diego
17. Li Q, Mitscher LA, Shen LL (2000) Med Res Rev 20:231
18. Zhanel GG, Ennis K, Vercaigne L, Walkty A, Gin AS, Embil J,
Smith H, Hoban DJ (2002) Drugs 62:13
1,483, 1,317, 1,132, 1,102, 1,065, 1,003, 946, 879, 834,
1
809 cm-1; H NMR (300 MHz, DMSO-d6): d = 1.21 (m,
2H) and 1.36 (m, 2H) (H2-20 ? H2-30), 4.49 (m, 1H, H-10),
7.57 (d, J = 8.1 Hz, 2H, H-300 ? H-500), 7.74 (d,
3JH-F = 10.3 Hz, 1H, H-5), 8.19 (d, J = 8.1 Hz, 2H, H-
200 ? H-600), 8.61 (s, 1H, H-8), 14.10 (s, 1H, N-H), 15.30
(br s, 1H, CO2H) ppm; 13C NMR (75 MHz, DMSO-d6):
2
d = 10.2 (C-20 ? C-30), 41.6 (C-10), 103.6 (d, JC-F
19.0 Hz, C-5), 107.7 (C-7), 121.5 (d, JC-F = 6.3 Hz,
=
3
2
C-5a), 128.1 (C-100), 128.8 (d, JC-F = 15.1 Hz, C-3a),
129.1 (C-300 ? C-500), 129.6 (C-200 ? C-600), 132.0 (C-9a),
135.9 (C-400), 137.2 (d, 2JC-F = 4.2 Hz, C-9b), 146.8 (C-8),
1
147.8 (d, JC-F = 250 Hz, C-4), 151.3 (C-2), 166.3
4
(CO2H), 177.1 (d, JC-F = 2.6 Hz, C-6) ppm; EIMS m/z
(%): 397 (M?, 6), 353 (100), 338 (48), 324 (14), 248 (9),
257 (6), 199 (4), 176 (7), 132 (6); HRMS (ESI): m/z calcd.
for C20H14ClFN3O3 [M ? H]?: 398.07077, found:
398.07017.
9-Cyclopropyl-4-fluoro-2-(4-methylphenyl)-6-oxo-6,
9-dihydro-1H-imidazo[4,5-h] quinoline-7-
carboxylic acid (12g, C21H16FN3O3)
19. Da Silva AD, De Almeida MV, De Souza MVN, Couri MRC
(2003) Curr Med Chem 10:2
20. Mitscher LA (2005) Chem Rev 105:559, and refs cited therein
21. Glushkov RG, Dronova LN, Elina AS, Porokhovaya MV,
Padeiskaya EN, Radkevich TP, Shipilova LD (1990) Khim Far-
mats Zhur 24:33
ꢀ
Yield: 0.68 g (90%), mp [ 310 °C; IR (KBr): m = 3,435,
3,139, 3,018, 2,924, 2,855, 1,693, 1,632, 1,591, 1,528,
1,491, 1,317, 1,187, 1,118, 1,066, 1,030, 946, 832,
1
810 cm-1; H NMR (300 MHz, DMSO-d6): d = 1.18 (m,
2H) and 1.36 (m, 2H) (H2-20 ? H2-30), 2.47 (s, 3H, C(400)-
CH3), 4.52 (m, 1H, H-10), 7.31 (d, J = 7.8, 2H, H-300 ?
H-500), 7.83 (d, 3JH-F = 9.5 Hz, 1H, H-5), 8.08 (d, J = 7.8,
2H, H-200 ? H-600), 8.58 (s, 1H, H-8), 14.01 (br s, 1H,
N-H), 15.33 (s, 1H, CO2H) ppm; 13C NMR (75 MHz,
DMSO-d6): d = 10.3 (C-20 ? C-30), 41.6 (C-10), 21.5
22. Glushkov RG, Dronova LN, Elina AS, Porokhovaya MV,
Padeiskaya EN, Radkevich TP, Shipilova LD (1990) Chem Abstr
113:78006
23. Kigasawa K, Hiiragi M, Wakisaka K, Haga S, Kusama O (1980)
Jpn Kokai Tokkyo Koho JP 55028920
24. Kigasawa K, Hiiragi M, Wakisaka K, Haga S, Kusama O (1980)
Chem Abstr 93:46681
25. Milata V, Ilavsky D (1988) Stud Org Chem (Amesterdam) (Chem
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