Heterocycles [h]-fused onto 4-oxoquinoline-3-carboxylic acid. Part X [1]. Synthesis and X-ray structure of a model 4-oxo[1,4]benzoxazepino[2,3-h] quinoline-3-carboxylic ester

Article abstract of DOI:10.5560/ZNB.2013-2270

Direct interaction of salicylaldehyde oxyanion with ethyl 7-chloro-8-nitro-4-oxoquinoline-3-carboxylate (2) delivered the respective 7-(2-formyl-phenoxy)-8-nitro-4-oxoquinoline-3-carboxylic ester 3. Reductive cyclization of 3 furnished the corresponding 4

Full text of DOI:10.5560/ZNB.2013-2270

Heterocycles [h]-Fused onto 4-Oxoquinoline-3-carboxylic Acid.
Part X [1]. Synthesis and X-Ray Structure of a Model 4-
Oxo[1,4]benzoxazepino[2,3-h]quinoline-3-carboxylic Ester
Batool A. Farrayeha, Mustafa M. El-Abadelaha, Jalal A. Zahraa, Salim F. Haddada, 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
Z. Naturforsch. 2013, 68b, 187 – 194 / DOI: 10.5560/ZNB.2013-2270
Received October 17, 2012
Direct interaction of salicylaldehyde oxyanion with ethyl 7-chloro-8-nitro-4-oxoquinoline-3-
carboxylate (2) delivered the respective 7-(2-formyl-phenoxy)-8-nitro-4-oxoquinoline-3-carboxylic
ester 3. Reductive cyclization of 3 furnished the corresponding 4-oxo-[1,4]benzoxazepino[2,3-
h]quinoline-3-carboxylic ester 5. Acid-catalyzed hydrolysis of the esters 3/5 produced the respective
acids 4/6. Structural assignments for the new compounds 3 – 6 are supported by microanalytical and
spectral (IR, HRMS, NMR) data and confirmed by X-ray structure determination for compound 5.
Interestingly, compound 6 exhibited good antifungal activity against C. albicans.
Key words: Salicylaldehyde Oxyanion in SN(Ar) Reaction,
7-(2-Formylphenoxy)-8-nitro-4-oxoquinoline-3-carboxylic Ester, Reductive
Cyclization, 4-Oxo[1,4]benzoxazepino-[2,3-h]quinoline-3-carboxylic Ester
Introduction
(Cyperaceae), an herbaceous plant growing in the
Mediterranean area. The latter compounds have been
Synthetic fluoroquinolones (e. g. ciprofloxa- shown to possess antioxidant activity [13] (radical
cin [2 – 5] Fig. 1) represent a successful achievement scavengers), while several other related species were
towards the design and development of potent antiin- prepared and patented as useful agents for the treat-
fectious drugs [2 – 12]. On the other hand, the tricyclic ment and prevention of AIDS [14]. It is noteworthy
dibenz[b, f] [1,4]oxazepin-11(10H)-one ring system that some [1,4]benzoxazepinone derivatives were re-
(1a, Fig. 1) is of natural occurrence and constitutes the ported to inhibit HIV-1 replication by interacting with
skeleton of two dibenzo[b, f][1,4]oxazepin-11(10H)- the NNRTI binding pocket [15]. Furthermore, several
one derivatives (1b, 1c, Fig. 1) that have recently been members of the [1,4]benzoxazepinone class have been
isolated from the leaves of Carex Distachya Desf. reported as monoanionic inhibitors of squalene syn-
Fig. 1. Structures of ciprofloxacin, loxapine and the natural dibenzoxazepinones 1a – 1c.
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188
B. A. Farrayeh et al. · Heterocycles [h]-Fused onto 4-Oxoquinoline-3-carboxylic Acid
thetase in HMG-CoA reductase regulation [16] and as (rings A, B) and dibenz[1,4]oxazepine (rings B, C, D)
y-secretase inhibitors for the treatment of Alzheimer’s chemotypes. Such new hybrid heterocyclics, exempli-
disease [17], whereas 2-chloro-11-(4-methyl-1-pi- fied by 6, might display interesting bioproperties.
perazinyl)dibenz[bf][1,4]oxazepine (loxapine, Fig. 1)
is an effective antipsychotic drug [18, 19].
Results and Discussion
Herein, we wish to report on the synthesis of the new
tetracyclic system 5/6 incorporating a 4-oxopyridine Synthesis
entity condensed to dibenz[bf][1,4]oxazepine as de-
picted in Scheme 1. As a structural feature, the hete-
A feasible two-step synthetic route towards the
rocyclic assembly in 5/6 encompasses fluoroquinolone target compound 6 was devised as depicted in
O
5
4
CO2R
F
4a
8a
6
O
N
3
2
A
B
CO2Et
OH
F
7
(i)
O
N
H
1
8
1'
1''
Cl
NO2
CHO
2''
O
6''
3'
2'
NO2
D
3''
5'' 3 (R = Et)
4''
(ii)
(2)
4
(R = H)
O
4
O
5
CO2R
CO2R
F
4a
F
6
3
A
B
A
B
6a
2
−
H2O
(iii)
7
13b
13a
O
(3)
N
O
1
N
7a
C
1'
8
NH2
CHO
13
N
3'
2'
D
9
D
11a 12
10
11
5
6
(R = Et)
(R = H)
3A (R = Et)
(ii)
Scheme 1. Synthesis of 4-oxo[1,4]benzoxazepino[2,3-h]quinoline-3-carboxylic acid and ester (5/6): (i) 5% aq. NaOH (1
equiv.); (ii) 6 N aq. HCl/reflux, 24 h; (iii) SnCl2/conc. HCl, then 40% aq. NaOH.
Scheme 2. Reductive cyclization of compound 7.
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B. A. Farrayeh et al. · Heterocycles [h]-Fused onto 4-Oxoquinoline-3-carboxylic Acid
189
Scheme 3. One-pot synthesis of dibenz[b, f][1,4]oxazepine: (i) polyethylene glycol, 50 oC, 10 h; (ii) K2CO3, 100 oC, 10 h.
Scheme 1. This approach is based upon annelation analogous manner and evaluated as potential antitry-
of the 1,4-benzoxazepine (rings C, D of compound panosomal and antibacterial agents [20].
6) onto the appropriately substituted 4-oxoquinoline
The second step involves reductive cyclization of
system (rings A, B). The first step involves di- compound 3 using SnCl2/conc. HCl, and is ini-
rect interaction between the salicyladehyde oxyan- tiated by the in situ generation of the 8-amino
ion and the 4-oxoquinoline-3-carboxylate 2 with ulti- species 3A (Scheme 1). This latter intermediate un-
mate displacement of the C(7)-chloride ion and con- derwent spontaneous intramolecular cyclization in-
sequent formation of the 7-(2-formylphenoxy)-8-nitro- volving the electrophilic formyl carbon (of ring B)
4-oxoquinoline 3. This nucleophilic aromatic substitu- and the suitably located nucleophilic amino group
tion (SN(Ar)) reaction, conducted at 60 – 65 ◦C, is fa- with ultimate construction of ring C in producing
cilitated by the presence of the neighboring electron- the [1,4]benzoxazepino[2,3-h]quinoline-3-carboxylate
withdrawing 6-fluoro, 8-nitro and 4-keto entities. Re- 5. Acid-catalyzed hydrolysis of the latter ester fur-
lated 6-fluoro-4-oxo-7-(substituted)phenoxyquinoline- nished the corresponding carboxylic acid 6 as the tar-
3-carboxylic acids have recently been prepared in an get product. In this context, it is worth noting that com-
Table 1. Summary of the crystal data and
structure refinement parameters for 5.
Empirical formula
Formula weight Mr
Temperature, K
C22H17FN2O4
392.38
293(2)
˚
Wavelength, A
0.71073
Crystal system
Space group
orthorhombic
Pbca
Unit cell dimensions
˚
a, A
18.1801(17)
˚
b, A
7.7376(8)
˚
c, A
26.418(3)
371.6(3)
3
˚
Volume, A
Z
8
1.4
0.1
1632
Density (calcd.), mg m−3
Absorption coefficient, mm−1
F(000), e
θ range for data collection, deg
Completeness to θ = 25.03◦, %
Index ranges hkl
Reflections collected / independent
Rint
2.96 – 25.03
99.9
−20 ≤ h ≤ 21, −9 ≤ k ≤ 7, −31 ≤ l ≤ 15
10102 / 3278
0.0332
Absorption correction
Data / restraints / parameters
R1 / wR2 [I > 2 σ(I)]a,b
R1 / wR2 (all data)a,b
Weight schemeb, A / B
Goodness-of-fit on F2 c
Semi-empirical from equivalents
3278/ 0 / 272
0.0577 / 0.1214
0.1063 / 0.1479
0.0588 / 0.8555
1.001
−3
˚
Largest difference peak / hole, e A
0.26 / −0.215
a
b
R1 = ΣkkFok − kF kk/ΣkFok; wR2 = [Σw(Fo2 − F2)2/Σw(Fo2)2]1/2, w = [σ2(Fo2) +
c
c
(AP)2 + BP]−1, where P = (Max(Fo2,0) + 2F2)/3; GoF = [Σw(Fo2 − F2)2/(nobs
−
c
c
c
nparam)]1/2
.
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B. A. Farrayeh et al. · Heterocycles [h]-Fused onto 4-Oxoquinoline-3-carboxylic Acid
˚
Table 2. Selected bond lengths (A) and angles (deg.) for 5.
method has led to an improvement of the etherification
procedure [22]. On the other hand, interaction of o-
fluorobenzaldehyde with o-aminophenol, proceeding
via initial imine formation followed by etherification
(Scheme 3), represents an alternative one-pot synthe-
sis of dibenz[b, f][1,4]oxazepine (9) [23].
Bond lengths
Bond angles
F(1)–C(6)
N(1)–C(2)
1.353(3) C(2)–N(1)–C(13B)
1.339(3) C(2)–N(1)–C(10)
1.408(3) C(6A)–O(7)–C(7A)
1.463(3) C(12)–N(13)–C(13A) 122.8(2)
1.384(3) N(1)–C(13B)–C(13A) 122.0(2)
1.396(3) C(7A)–C(11A)–C(12) 121.6(3)
1.276(3) C(11)–C(11A)–C(12) 120.0(3)
1.405(3) C(6A)–C(13A)–N(13) 123.1(2)
1.241(3) N(13)–C(13A)–C(13B) 118.6(2)
1.404(3) C(4)–C(3)–C(15)
1.483(4) O(7)–C(6A)–C(13A) 122.1(2)
1.382(4) O(7)–C(6A)–C(6)
1.459(4) N(1)–C(2)–C(3)
1.388(4) C(8)–C(7A)–O(7)
119.7(2)
116.4(2)
115.1(2)
N(1)–C(13B)
N(1)–C(10)
O(7)–C(6A)
O(7)–C(7A)
N(13)–C(12)
N(13)–C(13A)
O(14)–C(4)
C(13B)–C(4A)
C(4A)–C(4)
C(11A)–C(7A)
C(11A)–C(12)
C(13A)–C(6A)
C(3)–C(2)
Spectral properties
The IR, MS and NMR spectral and the microanaly-
sis data for the new compounds 3 – 6 are in accordance
with the assigned structures; details are given in the
Experimental Section. Thus, the mass spectra display
the correct molecular ion peaks for which the mea-
sured high resolution (HRMS) data are in good agree-
ment with the calculated values. DEPT and 2D (COSY,
HMQC, HMBC) experiments showed correlations that
helped in the 1H and 13C signal assignments to the dif-
ferent carbons and the attached/neighboring hydrogens
in compounds 3 – 6. In the 13C NMR spectra of 5 and 6,
127.2(3)
117.0(2)
126.0(3)
117.8(3)
1.364(4) C(11A)–C(7A)–O(7) 119.5(3)
1.438(4) O(14)–C(4)–C(3)
1.485(5) C(3)–C(4)–C(4A)
C(3)–C(4)
125.8(3)
114.4(2)
C(3)–C(15)
O(17)–C(15)
O(17)–C(18)
O(16)–C(15)
1.329(4) N(13)–C(12)–C(11A) 129.7(2)
1.476(5)
1.199(4)
pound 8 represents the first dibenz[b, f][1,4]oxazepine the skeletal carbons of the benzo-fused entity (C-4, C-
that was prepared by selective reduction of the ap- 4a, C-5, C-6, C-6a) resonate as doublets due to scalar
propriate nitro-aldehyde 7 to the respective amino- spin-spin coupling with the fluorine atom at C-6. Like-
aldehyde 7A which underwent spontaneous cyclization wise, the skeletal carbons of ring B in compounds 3
to give directly the desired Schiff base 8, albeit in poor and 4 are recognizable by their doublet signals orig-
yield [21] (Scheme 2). Recent reinvestigation of this inating from scalar (through bond) coupling with the
Fig. 2 (color online). An
ORTEP plot of the molec-
ular structure of 5.
Displacement ellipsoids are
drawn at the 30% proba-
bility level, H atoms with
arbitrary radii. The methyl
group C19 is disordered
over two positions.
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B. A. Farrayeh et al. · Heterocycles [h]-Fused onto 4-Oxoquinoline-3-carboxylic Acid
191
nearby fluorine atom. For compounds 5 and 6, distinct 13C NMR spectra were recorded on a 500 MHz spectrom-
“three-bond” (1H, 13C) correlations are observed be-
eter (Bruker DPX-500) with TMS as the internal standard.
Chemical shifts are expressed in δ units; J values for 1H-1H,
tween 5-H and each of C-4, C-6a and C-13b, between
1H-19F and 13C-19F coupling constants are given in Hertz.
Highresolution mass spectra (HRMS) were acquired (in pos-
itive mode) using the electrospray ion trap (ESI) technique by
collision-induced dissociation on a Bruker APEX-4 (7 Tesla)
instrument. The samples were dissolved in acetonitrile, di-
luted 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.
2-H and each of C-4, C-13b and CO2R, between 10H
and each of C-2 and C-13b, between 9-H/11-H and C-
7a, between 8-H/10-H and C-11a, as well as between
12-H and each of C-7a and C-13a.
Molecular structure of 5
A crystal structure determination was performed to
confirm the structure of 5 (and by inference that of 6).
A summary of data collection and refinement parame-
ters is given in Table 1, while selected bond lengths and
angles are provided in Table 2. The molecular structure
of 5 in the crystal is displayed in Fig. 2. The three six-
membered aromatic rings (A, B, D) in the molecular
structure of 5 are planar and the dihedral angle between
the plane containing the atoms N1-C2-C3-C4-C4A-
C13B and the adjacent one containing atoms C6A-
C13A-C4A-C5-C6-C13B-C4A is only 5.7(1)◦. The di-
hedral angle between the two rings (B, D) spanning the
seven-membered ring (C), namely C6A-C13A-C4A-
C5-C6-C13B-C4A and C10-C11-C11A-C7A-C8-C9,
is 44.0(1)◦. As expected, the seven-membered ring is
not planar with the dihedral angle between the fraction
O7-C7A-C11A-C12 and the fraction O7-C6A-C13A-
N13 being 57.7(1)◦.
Ethyl 7-chloro-1-cyclopropyl-6-fluoro-8-nitro-4-oxo-1,4-
dihydroquinoline-3-carboxylate (2)
This compound, required as starting material, was pre-
pared from 2,4-dichloro-5-fluoro-3-nitrobenzoic acid, ethyl
3-(N,N-dimethylamino)acrylate, and cyclopropylamine, ac-
cording to literature procedures [24 – 27].
Ethyl 1-cyclopropyl-6-fluoro-7-(2-formylphenoxy)-8-nitro-
4-oxo-1,4-dihydroquinoline-3-carboxylate (3)
To a stirred solution of compound 2 (1.1 g, 3 mmol)
in DMF (20 mL) was added a freshly prepared solution
of salicyldehyde (0.48 g, 4 mmol) in aqueous sodium hy-
droxide (0.16 g, 4 mmol), and the resulting mixture was
heated at 60 – 65 ◦C for 4 – 5 h. Thereafter, the reaction
mixture was cooled and poured onto ice water (100 mL);
the precipitated product was collected by suction filtration,
washed with water (3 × 10 mL), dried and recrystallized
from ethanol. Yield: 1.2 g (90%); m. p. 198 – 199 ◦C. −
IR (KBr): ν = 3074, 2983, 2921, 2862, 1736, 1699, 1640,
1611, 1547, 1472, 1394, 1311, 1282, 1218, 1173, 1099,
1030 cm−1. – HRMS ((+)-ESI): m/z = 441.10926 (calcd.
Preliminary pharmacological screening
Preliminary screening tests have indicated that com-
pound 6 exhibit good activity against Candida Albi-
cans clinical isolates, yet display moderate potency 441.10980 for C22H18FN2O7 [M+H]+); 463.09120 (calcd.
463.09175 for C22H17FN2O7Na [M+Na]+). – 1H NMR
against Eschericia coli and Staphylococcus aureus. The
(500 MHz, CDCl3): δ = 1.14 (m, 2H) and 1.22 (m, 2H)
(H2-20 + H2-30), 1.43 (t, J = 7.2 Hz, 3H, CH3CH2), 3.68
(m, 1H, H-10), 4.43 (q, J = 7.2 Hz, 2H, OCH2Me), 6.82 (d,
J = 8.4 Hz, 1H, H-600), 7.31 (dd, J = 7.7, 8.4 Hz, 1H, H-
400), 7.56 (ddd, J = 8, 8, 1 Hz, 1H, H-500), 7.99 (dd, J =
preparation of several analogs of 6, decorated with var-
ious substituents appended to ring D, for assessment of
their biological properties is currently underway.
Experimental Section
3
7.7, 1.7 Hz, 1H, H-300), 8.47 (d, JH−F = 10 Hz, 1H, H-
The following chemicals, used in this study, were 5), 8.67 (s, 1H, H-2), 10.56 (s, 1H, -CHO). −13C NMR
purchased from Acros and were used as received: (125 MHz, CDCl3): δ = 10.9 (C-20 + C-30), 14.4 (CH3),
2,4-dichloro-5-fluoro-3-nitrobenzoic acid, ethyl 3-(N,N- 38.0 (C-10), 61.5 (-OCH2Me), 112.2 (C-3), 115.1 (C-600),
2
dimethylamino)acrylate, cyclopropylamine, and salicylalde- 117.2 (d, JC−F = 20 Hz, C-5), 124.9 (C-400), 125.5 (C-200),
3
hyde. Melting points were determined on a Gallenkamp elec- 127.9 (d, JC−F = 5 Hz, C-4a), 129.3 (C-300), 130.8 (d,
3
trothermal melting apparatus in open capillary tubes. IR 4JC−F = 1.3 Hz, C-8a), 135.8 (C-500), 136.9 (d, JC−F
=
2
spectra were recorded as KBr discs on a Nicolet Impact-400 1.2 Hz, C-8), 140.2 (d, JC−F = 17.5 Hz, C-7), 151.2 (d,
FT-IR spectrometer. Elemental analyses were performed on 1JC−F = 255 Hz, C-6), 151.4 (C-2), 158.7 (C-100), 164.2
a Euro Vector elemental analyzer model EA 3000. 1H and (CO2Et), 170.8 (d, 4JC−F = 1.2 Hz, C-4), 187.8 (HC=O). −
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B. A. Farrayeh et al. · Heterocycles [h]-Fused onto 4-Oxoquinoline-3-carboxylic Acid
C22H17FN2O7 (440.38): calcd. C 60.00 H 3.89 N 6.36; found 7.6 Hz, 1H, H-9), 7.73 (d, J = 7.4 Hz, 1H, H-11), 7.84 (d,
C 60.12 H 3.96 N 6.28.
3JH−F = 10 Hz, 1H, H-5), 8.54 (s, 1H, H-2), 8.94 (s, 1H, H-
12). −13C NMR (125 MHz, [D6]DMSO): δ = 11.7 (C-20/C-
30), 14.7 (CH3CH2), 42.0 (C-10), 60.4 (MeCH2O), 110.2 (d,
2JC−F = 20 Hz, C-5), 110.4 (C-3), 121.0 (C-8), 127.1 (d,
3JC−F = 6.7 Hz, C-4a), 127.2 (C-10), 128.0 (C-13b), 130.4
(C-11), 133.2 (C-11a), 134.6 (C-9), 135.0 (C-13a), 145.2
(d, JC−F = 13.8 Hz, C-6a), 150.8 (d, JC−F = 248 Hz, C-
6), 151.6 (C-2), 160.6 (C-7a), 161.2 (C-12), 164.5 (CO2Et),
171.6 (C-4). − C22H17FN2O4 (392.38): calcd. C 67.34 H
4.37 N 7.14; found C 67.18 H 4.26 N 7.05.
1-Cyclopropyl-6-fluoro-7-(2-formylphenoxy)-8-nitro-4-oxo-
1,4-dihydroquinoline-3-carboxylic acid (4)
A suspension of the ethyl ester 3 (0.5 g, 1.15 mmol) in
30 mL of 6 N aq. HCl was refluxed (oil bath 110 oC) for 48 h.
Thereafter, the reaction mixture was cooled and poured onto
ice water (30 mL); the precipitated product was collected
by suction filtration, washed with water (3 × 4 mL), dried
and recrystallized from ethanol. Yield: 0.35 g (84%); m. p.
235 – 236 ◦C. − IR (KBr): ν = 3410, 3182, 3057, 2885,
1727, 1695, 1618, 1543, 1470, 1343, 1282, 1219, 1103,
1047, 1029 cm−1. – HRMS ((+)-ESI): m/z = 411.06340
2
1
1-Cyclopropyl-6-fluoro-1,4-dihydro-4-
oxo[1,4]benzoxazepino[2,3-h]quinoline-3-carboxylic
acid (6)
(calcd. 411.06285 for C20H12FN2O7 [M−H]+). − H NMR
1
(500 MHz, [D6]DMSO): δ = 1.08 (m, 2H) and 1.27 (m, 2H)
(H2-20 + H2-30), 3.79 (m, 1H, H-10), 7.17 (d, J = 8.3 Hz, 1H,
A suspension of the ethyl ester 5 (1.57 g, 4 mmol) in
H-600), 7.42 (dd, J = 7.6, 7.7 Hz, 1H, H-400), 7.72 (ddd, J = 30 mL of 6 N aq. HCl was refluxed (oil bath 110 ◦C) for
8.3, 7.7, 1.5 Hz, 1H, H-500), 7.93 (dd, J = 7.6, 1.5 Hz, 1H, 48 h. Thereafter, the reaction mixture was cooled and poured
H-300), 8.55 (d, 3JH−F = 10 Hz, 1H, H-5), 8.89 (s, 1H, H-2), onto ice water (100 mL); the precipitated product was col-
10.44 (s, 1H, -CHO), 13.94 (s, 1H, exchangeable with D2O, lected by suction filtration, washed with water (3 × 10 mL),
CO2H). −13C NMR (125 MHz, [D6]DMSO): δ = 10.9 (C- dried and recrystallized from ethanol. Yield: 1.2 g (82%);
20 + C-30), 39.8 (C-10), 109.6 (C-3), 116.5 (C-600), 116.7 (d, m. p. 305 – 306 ◦C (darkens around 250 ◦C). − IR (KBr):
2JC−F = 20.4 Hz, C-5), 125.4 (C-200), 125.6 (C-400), 125.8 ν = 3412, 3074, 2973, 2921, 1762, 1695, 1613, 1547,
(d, 3JC−F = 7.5 Hz, C-4a), 130.0 (C-300), 132.2 (C-8a), 137.0 1444, 1320, 1272, 1194, 1090, 1029 cm−1. – HRMS ((+)-
(C-500), 137.2 (C-8), 141.2 (d, 2JC−F = 17.5 Hz, C-7), 151.5 ESI): m/z = 365.09431 (calcd. 365.09376 for C20H14FN2O4
(d, JC−F = 253 Hz, C-6), 153.2 (C-2), 158.4 (C-100), 164.9 [M+H]+). − H NMR (500 MHz, [D6]DMSO): δ = 0.92 (m,
(CO2H), 175.6 (d, 4JC−F = 2.2 Hz, C-4 ), 188.9 (HC=O). − 2H) and 1.10 (m, 2H) (H2-20 + H2-30), 4.42 (m, 1H, H-10),
C20H13FN2O7 (412.32): calcd. C 58.26 H 3.18 N 6.79; found 7.34 (d, J = 8 Hz, 1H, H-8), 7.49 (dd, J =7.6, 7.4 Hz, 1H, H-
1
1
C 58.08 H 3.11 N 6.72.
10), 7.69 (dd, J = 8, 7.6 Hz, 1H, H-9), 7.76 (d, J = 7.4 Hz,
3
1H, H-11), 8.03 (d, JH−F = 9.5 Hz, 1H, H-5), 8.80 (s, 1H,
Ethyl 1-cyclopropyl-6-fluoro-1,4-dihydro-4-
oxo[1,4]benzoxazepino[2,3-h]quinoline-3-carboxylate (5)
H-2), 9.00 (s, 1H, H-12), 14.6 (br s, 1H, exchangeable with
D2O, CO2H). −13C NMR (125 MHz, [D6]DMSO): δ = 11.8
(C-20/C-30), 43.4 (C-10), 108.2 (C-3), 109.6 (d, 2JC−F = 20.1
Anhydrous stannous chloride (1.25 g, 6.6 mmol ) was
added portionwise to a vigorously stirred and cooled (0
to 4 ◦C) solution of the ester 3 (4 mmol) in conc. HCl
(10 mL). The reaction mixture was further stirred for addi-
tional 12 – 15 h at r. t. Thereafter, the solution was diluted
with ice water (100 mL) and treated portionwise with a cold
aqueous solution of sodium hydroxide (40%, 25 mL) to
pH ∼14. The resulting yellowish precipitate was collected
by suction filtration, washed with water (4 × 10 mL), and
dried. Yield: 1.36 g (87%); m. p. 249 – 250 ◦C. − IR (KBr):
ν = 3075, 2980, 2950, 2928, 2878, 1729, 1694, 1627, 1552,
3
Hz, C-5), 121.1 (C-8), 124.6 (d, JC−F = 7.5 Hz, C-4a),
127.4 (C-10), 127.9 (C-13b), 130.6 (C-11), 133.7 (C-11a),
2
134.8 (C-9), 135.8 (C-13a), 146.4 (d, JC−F = 15 Hz, C-6a)
1
151.5 (d, JC−F = 248 Hz, C-6), 151.9 (C-2), 160.6 (C-7a),
4
162.0 (C-12), 165.7 (CO2H), 176.9 (d, JC−F = 2.8Hz, C-
4). -C20H13FN2O4 (364.33): calcd. C 65.93 H 3.60 N 7.69;
found C 65.76 H 3.52 N 7.61.
X-Ray structure analysis of 5
1467, 1447, 1341, 1319, 1246, 1186, 1088, 1027 cm−1
.
Crystals were grown by allowing a clear solution of 5 in
– HRMS ((+)-ESI): m/z = 393.12451 (calcd. 393.12506 DMSO in an open vessel to stand at room temperature for
for C22H18FN2O4 [M+H]+); 415.10646 (calcd. 415.10700 4 – 5 days. A suitable needle-like fragment with approximate
for C22H17FN2O4Na [M+Na]+). − H NMR (500 MHz, dimensions of 0.51 × 0.09 × 0.07 mm3, cut from a longer
1
[D6]DMSO): δ = 0.84 (m, 2H) and 1.03 (m, 2H) (H2-20 + slightly yellowish crystal, was epoxymounted on a glass
H2-30), 1.24 (t, J = 7 Hz, 3H, CH3CH2), 4.22 (q, J = 7 Hz, fiber. The data were collected at room temperature employ-
2H, CH3CH2), 4.25 (m, 1H, H-10), 7.31 (d, J = 8 Hz, 1H, ing MoKα radiation using a Calibur/Oxford diffractometer
H-8), 7.47 (dd, J = 7.4, 7.6 Hz, 1H, H-10), 7.66 (dd, J = 8, equipped with an Eos CCD detector. CRYSALIS PRO soft-
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B. A. Farrayeh et al. · Heterocycles [h]-Fused onto 4-Oxoquinoline-3-carboxylic Acid
193
ware was used for data collection, absorption correction and anisotropically with the hydrogen atoms placed constrained
data reduction [28]. Three sets of ω scans were collected and assigned isotropic thermal parameters of 1.2 times that
yielding 167 frames. Average exposure time was 65.8 s per of the riding atoms. Molecular graphics and publication ma-
frame. A one-degree scan width was used and the detector terial were prepared using SHELXTL [30].
to crystal distance was 45 mm. A multi-scan absorption cor-
CCDC 882392 contains the supplementary crystallo-
rection was applied with minimum and maximum transmis- graphic data for this paper. These data can be obtained free
sion factors of 0.815 and 1.000, respectively. Cell parame- of charge from The Cambridge Crystallographic Data Centre
ters were refined using all observed reflections. The structure via www.ccdc.cam.ac.uk/data request/cif.
was solved by Direct Methods using OLEX 2 [29] and refined
by full-matrix least-squares on F2. Refinement was done us-
ing the SHELXTL program package [30, 31]. The terminal
Acknowledgement
We wish to thank the Deanship of Scientific Research at
The University of Jordan, Amman (Jordan), for financial
support.
methyl group C19 of the ethyl ester group was found disor-
dered and modeled over two positions with 0.67 and 0.33 oc-
cupancy, respectively. All nonhydrogen atoms were refined
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