Heterocycles [h]fused onto 4-oxoquinoline-3-carboxylic acid, part IV. Convenient synthesis of substituted hexahydro [1,4]thiazepino[2,3-h]quinoline-9- carboxylic acid and its tetrahydroquino[7,8-b]benzothiazepine homolog

Article abstract of DOI:10.3390/12081558

Substituted [1,4]thiazepino[2,3-h]quinolinecarboxylic acid 3 is prepared by PPA-catalyzed thermal lactamization of the respective 8-amino-7-[(2- carboxyethyl)thio]-1,4-dihydroquinoline-3-carboxylic acid 9. The latter synthon is obtained by reduction of th

Full text of DOI:10.3390/12081558

Molecules 2007, 12, 1558-1568
molecules
ISSN 1420-3049
© 2007 by MDPI
www.mdpi.org/molecules
Full Paper
Heterocycles [h]Fused onto 4-Oxoquinoline-3-Carboxylic Acid,
Part IV. Convenient Synthesis of Substituted Hexahydro
[1,4]Thiazepino[2,3-h]quinoline-9-carboxylic Acid and Its
†
Tetrahydroquino[7,8-b]benzothiazepine Homolog
Mohammed H. Al-Huniti 1, Mustafa M. El-Abadelah 1, Jalal A. Zahra 1,*, Salim S. Sabri 2 and
Arnd Ingendoh 3
1 Chemistry Department, Faculty of Science, The University of Jordan, Amman 11942, Jordan;
E-mails: m.alhuniti@ju.edu.jo, mustelab@ju.edu.jo
2 University of Sharjah, Sharjah, P. O. Box 27272, United Arab Emirates (UAE); E-mail:
salim@sharjah.ac.ae
3 Bruker Daltonik GmbH, Fahrenheitstr. 4, D-28359 Bremen, Germany; E-mail: ai@bdal.de
* Author to whom correspondence should be addressed; E-mail: Zahra@ju.edu.jo; Fax: +962-6
5348932; Tel.: +962-6 5355000 (ext. 22163)
† For part III see reference [1].
Received: 4 June 2007; in revised form: 19 July 2007 / Accepted: 19 July 2007 / Published: 26 July
2007
Abstract: Substituted [1,4]thiazepino[2,3-h]quinolinecarboxylic acid 3 is prepared by
PPA-catalyzed thermal lactamization of the respective 8-amino-7-[(2-carboxyethyl)thio]-
1,4-dihydroquinoline-3-carboxylic acid 9. The latter synthon is obtained by reduction of
the 8-nitro-1,4-dihydroquinoline precursor 8 which, in turn, is made accessible via
interaction of 3-mercaptopropionic acid with 7-chloro-1-cyclopropyl-6-fluoro-8-nitro-1,4-
dihydroquinoline-3-carboxylic acid 7 in the presence of triethylamine. A benzo-homolog
of 3, namely tetrahydroquino[7,8-b]benzothiazepine-3-carboxylic acid 6, is analogously
prepared via the raction of 2-mercaptobenzoic acid with 7, followed by reduction of the
resulting 7-[(2-carboxyphenyl)thio]-8-nitro product 10 into the corresponding 8-amino
derivative 11, and subsequent lactamization. The structures assigned to 3, 6 and 8-11 are
based on microanalytical and spectral (IR, MS, NMR) data.

Molecules 2007, 12
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Keywords: 7-Chloro -8-nitro-4-oxoquinoline-3-carboxylic acid, 3-mercaptopropanoic
acid, 2-mercaptobenzoic acid, SN-Ar reaction, lactamization
Introduction
Synthetic fluoroquinolones (e.g. ciprofloxacin (1a) [2]) represent a successful achievement towards
the design and development of potent antiinfectious drugs [2,3], while some related derivatives, such
as 1b [4], exhibit antitumor activity[4-6]. On the other hand, 2,3-dihyro-1,5-benzothiazpin-4(5H)-one
(2a) and several derivatives thereof, e.g diltiazem [7] (2b, Figure 1), are of considerable interest both
synthetically [8] and pharmacologically [9-13]. Depending on the nature of substituents at C-2, C-3
and N-5 of the parent skeleton (ring C, Figure 1), such derivatives exhibit coronary vasodilator [9],
calcium antagonist [10], antidepressant [11], anticonvulsant [12] or antimicrobial [13] activities.
Figure 1. Structures of 4-oxoquinolines 1a, 1b, dihydro-1,5-benzothiazepin-4(5H)-ones
2a, 2b and 2,8-dioxo-hexahydro[1,4]thiazepino[2,3-h]quinoline 3.
O
7
8
O
1
S
F
5 S
3
CO2H
R
6
7a
9
9
B
6
5
4
F
CO2H
A
B
R'
5a
C
10
B
A
11a
N11
11b
C
R
N1
N5
R''
8
4
1'
O
NH
1
1'
R'
2'
3'
2 O
2'
3'
2a (R = R' = R'' = H)
2b (R = p-(MeO)C6H4; R' = OAc;
R'' = CH2CH2NMe2)
3
1a (R = 1-piperazinyl; R' = H)
1b (R = p-(OH)C6H4; R' = F)
Several dibenzo[b,f][1,4]thiazepin-11(10H)-ones (e.g. 4, Figure 2) were also prepared [14-17],
some of which were reported to exhibit activity against the HIV virus [15] or useful agents for the
prevention and treatment of AIDS [16], while others act as leukotriene antagonists [17]. Compounds of
type 4 have been readily transformed into 11-piperazinyldibenzo[b,f][1,4]thiazepines, exemplified by
11-{4-[2-(2-Hydroxyethoxy)-ethyl]piperazinyl}dibenzo[b,f][1,4]thiazepine, commonly known as
quetiapine [18] (5, Figure 2).
The latter compound and its congeners are useful agents for treating anxiety [19] and substance-
related disorders [20], act as calcium channel antagonists [21], neuroleptic and antipsychotic agents
[22], and display antidopaminergic activity [23].
Herein, we wish to report on the synthesis of new heterocyclic ring systems incorporating a 4-
oxopyridine entity condensed either to 1,5-benzothiazepinone (compound 3, Figure 1), or to dibenzo
[b,f][1,4]thiazepinone (compound 6, Figure 2) as depicted in Schemes 1 and 2, respectively. The
tricyclic system 3 encompasses the structural features both of fluoroquinolone (rings A, B) and 1,5-
benzothiazepinone (rings B, C), while the tetracyclic assembly 6 incorporates fluoroquinolone (rings
A, B) and dibenzo[1,4]thiazepinone (rings B, C, D) chemotypes. Such new hybrid heterocyclics might
display interesting bioproperties.

Molecules 2007, 12
Figure 2. Structures of dibenzo[b,f][1,4]thiazepine-11(10H)-ones 4, quetiapine 5 and
1560
tetrahydroquino[7,8-b][1,4]benzothiazepine 6.
O
6
5
4
F
CO2H
4a
6
3
B
6
4
A
S
B
S
9
6a
7
S
4
2
13b
B
C
D
N1
13a
C
N10
7a
C
8
D
1'
9
NH
1
11
11
N10
H
13
1
9
D
12
N
2'
3'
11a
11
O
O
10
6
N
R
5 ( R = CH2CH2OCH2CH2OH)
Results and Discussion
Direct interaction between 7-chloro-1-cyclopropyl-6-fluoro-8-nitro-4-oxo-1,4-dihydroquinoline-3-
carboxylic acid (7) [24, 25] and 3-mercaptopropionic acid, in aqueous acetone containing
triethylamine, produced the corresponding 7-[(2-carboxyethyl)thio]-8-nitro-1,4-dihydroquinoline
derivative (8) (Scheme 1).
Scheme 1. Synthesis of hexahydro[1,4]thiazepino[2,3-h]quinoline-9-carboxylic acid 3.
O
O
5
5
4
4
CO2H
SH
F
S
CO2H
F
CO2H
6
4a
8a
3
(i)
(ii)
+
7
2
N1
Cl
8
N1
8
3''
1'
1'
NO2
NO2
2'
3'
2'
3'
2''
CO2H
7
8
O
4
5
6
F
S
CO2H
4a
3
7
2
(iii)
8a
(3)
N1
Reagents and Conditions:
(i) aq. acetone, NEt3
8
3''
1'
NH2
(ii) Na2S2O4 / aq. K2CO3, rt
(iii) PPA / 145-150 oC, 2h
2'
3'
2''
CO2H
9
Herein, 3-mercaptopropionic acid acts as 'sulfur' nucleophile that displaces the C(7)- chlorine atom
in the substrate (7). This reaction follows a nucleophilc aromatic substitution 'SN-Ar' (addition –
elimination) path, and is facilitated by the presence of the electron withdrawing C(6)-fluoro, C(4)-keto,
and C(8)-nitro groups. Reduction of the latter 8-nitro compound 8 with sodium dithionite in aqueous
potassium carbonate gives the respective 8-amino derivative 9. In a separate step, compound 9
underwent lactamization upon heating with polyphosphoric acid (PPA) to afford a tricyclic system,

Molecules 2007, 12
1561
namely 2,8-dioxohexahydro[1,4]thiazepino[2,3-h]quinoline-3-carboxylic acid (3). Likewise, the
reaction of 2-mercaptobenzoic acid with 7 provided the corresponding 7-[(2-carboxyphenyl)thio]-8-
nitro-1,4-dihydroquinoline derivative 10 which was then reduced to the respective 7-amino-1,4-
dihydroquinoline-3-carboxylic acid 11 (Scheme 2). Subsequent lactamization of 11, using PPA,
afforded the target tetracyclic product, namely 4,12-dioxotetrahydroquino[7,8-b]benzothiazepine-3-
carboxylic acid (6). The elemental analyses and spectral (IR, MS, NMR) data of 3, 6 and 8-11, given in
the Experimental part, are in conformity with the suggested structures. Thus, their MS spectra display
the correct molecular ion peaks for which the measured HRMS data are in good agreement with the
13
values calculated for the molecular formulae. Assignments of the 1H- and C- signals to the different
respective protons and carbons are based on DEPT and 2D (COSY, HMQC, HMBC) experiments
which showed correlations consistent with these assignments.
Scheme 2. Synthesis of tetrahydroquino[7,8-b]benzothiazepine-3-carboxylic acid 6.
O
O
5
5
4
4
F
CO2H
(ii)
F
S
CO2H
6
6
4a
8a
3
4a
8a
3
CO2H
(i)
7
7
(7)
2
2
+
S
N1
N1
8
8
6''
6''
SH
1''
1''
2''
1'
1'
NO2
NH2
5''
4''
5''
2''
2'
2'
3'
3'
CO2H
CO2H
4''
3''
3''
11
(iii)
10
Reagents and Conditions:
(i) aq. acetone, NEt3
(6)
(ii) Na2S2O4 / aq. K2CO3, rt
(iii) PPA / 145-150 oC, 2h
For compound 3, distinct ''three-bond'' (1H, 13C)–correlations are observed between H-10 and each of
CO2H, C-8, C-11a and C-1', as well as between H-7 and each of C-8, C-11a and C-5a, and between
H-1' and each of C-10 and C-11a. Corresponding long-range correlations are also observed for
compounds 6 and 8-11 between H-2, H-5, H-1' and their neighbor carbons. The skeletal carbons of
benzo-fused entity (ring B) in 3, 6 and 8-11 are recognizable by their doublet signals originating from
scalar (through bond) coupling with the neighboring fluorine atom. Also, the C-3'' methylene carbon in
8 appears as a doublet due to through-space (dipolar) coupling with the nearby fluorine atom.
Experimental
General
Ethyl 3-(N,N-dimethylamino)acrylate, 2,4-dichloro-5-fluoro-3-nitrobenzoic acid and cyclopropyl-
amine were purchased from Acros. 3-Mercaptopropionic acid and 2-mercaptobenzoic acid were
purchased from Aldrich. Melting points were determined on a Gallenkamp capillary melting point
13
apparatus and are uncorrected. 1H- (300 MHz), C-NMR (75 MHz) and DEPT spectra, and 2D (H-H

Molecules 2007, 12
1562
COSY, HMQC, HMBC) experiments were measured on a Bruker DPX-300 instrument with Me4Si as
internal reference and DMSO-d6 as solvent. High resolution mass spectra (HRMS) were measured in
positive ion mode by Electrospray (ESI) on Bruker APEX-Qe 94 instrument. 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. External calibration was conducted using
the arginine cluster in a mass range m/z 175-871. Electron-impact mass spectra (EIMS) were obtained
o
using a Varian MAT-212 spectrometer at 70 eV and at ion source temperature of 200 C. IR spectra
were recorded as KBr discs on a Nicolet Impact-400 FT-IR spectrophotometer. Elemental analyses
were preformed at the Microanalytical Laboratory of the Hashemite University, Zarqa, Jordan.
7-Chloro-1-cyclopropyl-6-fluoro-8-nitro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (7)
This compound [mp 256-257oC (decomp); Lit. [25] 261oC (decomp)] was prepared according to
literature methods [24] by acid-catalyzed hydrolysis of the corresponding ethyl ester, in turn prepared
from 2,4-dichloro-5-fluoro-3-nitrobenzoic acid, ethyl 3-(N,N-dimethylamino)acrylate and cyclopropyl-
amine by following the stepwise synthetic procedures as reported for the corresponding methyl ester
analog [mp 175-176 oC (decomp); Lit. [24] 174-176 oC (decomp)] [25,26].
7-[(2-Carboxyethyl)thio]-1-cyclopropyl-6-fluoro-8-nitro-4-oxo-1,4-dihydroquinoline-3-carboxylic
acid (8)
3-Mercaptopropionic acid (0.18 g, 1.7 mmol) was added to a stirred solution of 7 (0.5 g, 1.5 mmol)
in aqueous acetone (45 mL, 1:2 v / v) and Et3N (6 mL) at room temperature (rt) and kept in the dark
for 7 h. Thereafter, the reaction mixture was washed with CHCl3 (2 x 10 mL), the aqueous layer was
separated and acidified with 3N HCl. The resulting yellow precipitate was collected and recrystallized
from CHCl3. Yield 0.54 g (91%); mp 205-207oC; IR (cm-1) 3500, 3430, 3080, 2914, 2742, 1720, 1679,
1
1564, 1532, 1481, 1430, 1347, 1329, 1259; H-NMR δ 1.00/1.10 (2 m, 4H, 2H-2'/2H-3'), 2.45 (t, J =
3
6.7 Hz, 2H, H-2''), 3.20 (t, J = 6.7 Hz, 2H, H-3''), 3.70 (m, 1H, H-1'), 8.29 (d, JH-F = 9 Hz, 1H, H-5),
8.78 (s, 1H, H-2), 13.05 (br s, 2H, 2CO2H); 13C-NMR δ 11.1 (C-2'/C-3'), 30.5 (d, JC-F = 7.3 Hz, C-3''),
2
2
34.9 (C-2''), 39.6 (C-1'), 109.2 (C-3), 114.4 (d, JC-F = 25.6 Hz, C-5), 126.9 (d, JC-F = 24.7 Hz, C-7),
129.0 (d, 3JC-F = 7.9 Hz, C-4a), 131.3 (d, 4JC-F = 2.6 Hz, C-8a), 144.9 (d, 3JC-F = 1.5 Hz, C-8), 153.3 (C-
2), 158.5 (d, 1JC-F = 248 Hz, C-6), 164.9 [C(3)CO2H], 172.7 [C(2'')CO2H], 175.6 (d, 4JC-F = 2.3 Hz, C-
4). EIMS m/z (%): 396 (M+, 6), 378 (9), 352 (64), 334 (56), 307 (29), 269 (43), 263 (68), 233 (52), 200
(47), 191 (71), 172 (35), 108 (15), 55 (100); HRMS (EI): Calcd. for C16H13FN2O7S 396.04271; found
396.03918; Anal. calcd. for C16H13FN2O7S (396.35): C, 48.49; H, 3.31; N, 7.07; S, 8.09. Found: C,
48.26; H, 3.24; N, 7.16; S, 7.93.
8-Amino-7-[(2-carboxyethyl)thio]-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic
acid (9)
A solution of sodium dithionite (0.87 g, 5 mmol) in water (5 mL) was added dropwise at rt to a
stirred solution of 8 (0.4 g, 1.0 mmol) in water (20 mL) containing K2CO3 (0.96 g, 7 mmol). The

Molecules 2007, 12
1563
reaction mixture was stirred at rt for an additional 8 h and then extracted with CHCl3 (2 X 10 mL). The
aqueous layer was then acidified with 6N HCl, whereby the title compound was obtained as a pale
yellow precipitate which was collected and recrystallized from CHCl3/MeOH. Yield 0.3 g (81%); mp
216-218oC; IR (cm-1) 3498, 3343, 3080, 3919, 1730, 3919, 1730, 1595, 1582, 1530, 1492, 1447, 1337,
1254, 1170; 1H-NMR δ 1.04, 1.16 (2 m, 4H, 2H-2' / 2H-3'), 2.44 (t, J = 7 Hz, 2H, 2H-2''), 2.93 (t, J = 7
Hz, 2H, 2H-3''), 4.53 (m, 1H, H-1'), 6.51 (br s, 2H, NH2), 7.20 (d, 3JH-F = 8.4 Hz, 1H, H-5), 8.72 (s, 1H,
H-2), 14.70 (br s, 2H, 2CO2H); 13C-NMR δ 10.6 (C-2'/C-3'), 29.4 (C-3''), 34.6 (C-2''), 39.9 (C-1'), 97.0
2
(d, 2JC-F = 27.1 Hz, C-5), 107.2 (C-3), 109.9 (d, JC-F = 23.4 Hz, C-7), 126.9 (d, 4JC-F = 1 Hz, C-8a),
129.2 (d, 3JC-F = 9.8 Hz, C-4a), 145.2 (d, 3JC-F = 3.3 Hz, C-8), 151.5 (C-2), 161.4 (d, 1JC-F = 240 Hz, C-
4
6), 166.0 [C(3)CO2H), 173.1 [ C(2″)-CO2H], 177.2 (d, JC-F = 2 Hz, C-4); HRMS(ESI): calcd for
C16H16FN2O5S+ [M+H]+ : 367.07640, found: 367.07568; Anal. calcd. for C16H15FN2O5S (366.36): C,
52.45; H, 4.13; N, 7.65; S, 8.75. Found: C, 52.31; H, 4.08; N, 7.55; S, 8.48.
11-Cyclopropyl-6-fluoro-2,8-dioxo-1,2,3,4,8,11-hexahydro[1,4]thiazepino[2,3-h]quinoline-9-
carboxylic acid (3)
Compound 9 (0.2 g, 0.55 mmol) was suspended in polyphosphoric acid (PPA, 7 g) and heated at
145-150 °C for 2h. The reaction mixture was then poured into water (30 mL) and stirred for 20 min.
The resulting white precipitate was collected and recrystalised from CHCl3/MeOH. Yield 0.13g (68%);
o
mp 307-309 C; IR (cm-1) 3427, 3286, 3080, 2932, 1717, 1595, 1530, 1498, 1460, 1408, 1389, 1312,
1
1254, 1228, 1183; H-NMR δ 1.03 (m, 4H, 2H-2' / H-3'), 2.74 (t, J = 7 Hz, 2H, 2H-4), 3.53 (t, J = 7
3
Hz, 2H, 2H-3), 4.29 (m, 1H, H-1'), 7.94 (d, JH-F = 8.1 Hz, 1H, H-7), 8.79 (s, 1H, H-10), 10.02 (br s,
13
1H, N(1)H), 13.42 (br s, 1H, CO2H); C-NMR δ 9.5 ( C-2'/C-3'), 33.2 (C-4), 34.6 (C-3), 41.0 (C-1'),
108.2 (C-9), 108.6 (d, 3JC-F = 26.1 Hz, C-7), 126.6 (d, 2JC-F = 20.7 Hz, C-5a), 128.6 (d, 3JC-F = 8.6 Hz,
C-7a), 133.7 (d, 3JC-F = 2.2 Hz, C-11a), 135.9 (d, 3JC-F = 1.6 Hz, C-11b), 152.5 (C-10), 159.6 (d, 1JC-F
=
244 Hz, C-6), 165.5 (C(9)-CO2H), 172.0 (C-2), 176.8 (d, JC-F = 3 Hz, C-8); EIMS m/z (%): 348(M+,
27), 320(5), 276(15), 247(15), 233(12), 220(20), 193(8), 118(6), 152(4), 135(14), 108(9), 55(100);
HRMS (ESI): calcd for C16H14FN2O4S+ [M+H]+: 349.06583. Anal. calcd. for C16H13FN2O4S (348.35):
C, 55.17; H, 3.76; N, 8.04; S, 9.20. Found: C, 55.86; H, 3.74; N, 7.91; S, 9.27.
4
7-[(2-Carboxyphenyl)thio]-1-cyclopropyl -6-fluoro-8-nitro-4-oxo-1,4-dihydroquinolin-3-carboxylic
acid (10)
Prepared from 2-mercaptobenzoic acid (0.26 g, 1.7 mmol) and 7 (0.5 g, 1.5 mmol) using the
procedure and experimental conditions described above in the preparation of 8. The title compound
was obtained as a white precipitate which was collected and recrystallized from chloroform/petroleum
ether. Yield 0.62 g (93 %); mp 279-281oC. IR (cm-1) 3395, 3067, 2971, 2932, 2669, 2605, 1692, 1605,
1542, 1351, 1459, 1419, 1339, 1328, 1288, 1115; 1H-NMR δ 1.02, 1.18 (2 m, 4H, 2H-2' / 2H-3'), 3.74
(m, 1H, H-1'), 6.80 (dd, J = 7.9, 1.0 Hz, 1H, H-6''), 7.30 (ddd, J = 7.3, 7.5, 1 Hz, 1H, H-4''), 7.38 (ddd,
3
J = 7.9, 7.3, 1.6 Hz, 1H, H-5''), 7.97 (dd, J = 7.5, 1.6 Hz,1H, H-3''), 8.33 (d, JH-F = 8 Hz, 1H, H-5),
8.82 (s, 1H, H-2), 13.75 (br s, 2H, 2CO2H); 13C-NMR δ 11.2 (C-2'/C-3'), 39.6 (C-1'), 109.4 (C-3),
115.0 (d, 2JC-F = 25.6 Hz, C-5), 124.3 (d, 2JC-F = 25.7 Hz, C-7), 126.9 (C-4''), 127.4 (C-6''), 128.5 (C-

Molecules 2007, 12
1564
3
3
2''), 130.9 (d, JC-F = 7.8 Hz, C-4a), 131.6 (d, JC-F = 2.6 Hz, H-8a), 131.7 (C-3''), 133.7 (C-5''), 137.6
1
(C-1''), 146.3 (C-8), 153.3 (C-2), 155.1 (d, JC-F = 262 Hz, C-6), 165.0 [C(3)-CO2H], 168.1 [C(2″)-
CO2H], 175.6 (d, JC-F = 2.2 Hz, C-4); HRMS (ESI): calcd. for C20H14FN2O7S+[M+H]+ : 445.05058 ,
4
found: 445.04989; Anal. calcd. for C20H13FN2O7S (444.39): C, 54.05; H, 2.95; N, 6.30; S, 7.22.
Found: C, 54.23; H, 3.04; N, 6.18; S, 7.01.
8-Amino-7-[(2-carboxyphenyl)thio]-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic
acid (11)
A solution of sodium dithionite (0.52 g, 3.0 mmol) in water (5 mL) was added dropwise to a stirred
solution of 10 (0.4 g, 0.9 mmol) in water (10 mL) containing dissolved K2CO3 (0.56 g. 4.0 mmol) at rt.
Thereafter, the reaction mixture was stirred at rt for 5 h and then washed with CHCl3 (2 X 8 mL). The
aqueous layer was neutralized with 6N HCl, the precipitated product was collected, dried, and
o
recrystallized from CHCl3. Yield = 0.29 g (77%); mp 312-313 C; IR (cm-1) 3491, 3379, 3086, 2771,
1
2610, 1704, 1678, 1582, 1524, 1453, 1350, 1235, 1138; H-NMR δ 1.09 (m, 4H, 2H-2'/2H-3'), 4.51
(m, 1H, H-1'), 6.49 (br s, 2H, NH2), 6.66 (d, J = 7.9 Hz, 1H, H-6''), 7.22 (dd, J = 6.8, 7.2 Hz, 1H, H-
4''), 7.29 (d, 3JH-F = 8.3 Hz, 1H, H-5), 7.34 (dd, J = 7.9, 7.2 Hz, 1H, H-5''), 7.97 (d, J = 6.8 Hz, 1H, H-
13
3''), 8.76 (s, 1H, H-2), 13.40 [br s, 1H, C(2'')-CO2H], 14.80 [br s, 1H, C(3)-CO2H]; C-NMR δ 10.6
2
(C-2'/C-3'), 39.8 ( C-1'), 97.2 (d, JC-F = 27.1 Hz, C-5), 107.5 (C-3), 107.6 (d, 2JC-F = 23.2 Hz, C-7),
125.2 (C-6''), 125.6 (C-4''), 127.3 (C-8a), 128.7 (C-2''), 130.3 (d, 3JC-F = 10.3 Hz, C-4a), 132.0 (C-3''),
3
133.2 (C-5''), 138.3 (C-1''), 146.0 (d, JC-F = 3 Hz, C-8), 151.7 (C-2), 161.4 (d, 1JC-F = 242 Hz, C-6),
166.0 [C(3)-CO2H], 168.1 [C(2'')-CO2H], 177.2 (d, 4JC-F = 3 Hz, C-4); EIMS m/z (%): 414 (M+, 8), 396
(10), 370 (64), 352 (82), 323 (100), 295 (31), 217 (46), 189 (59), 154 (19), 136 (50), 108 (11); HRMS
(EI): calcd. for C20H15FN2O5S: 414.06854; found: 414.07027; Anal. calcd. for C20H15FN2O5S
(414.41): C, 57.97; H, 3.65; N, 6.76; S, 7.74. Found: C, 57.68; H, 3.54; N, 6.72; S, 7.88.
1-cyclopropyl-6-fluoro-4,12-dioxo-1,4,12,13-tetrahydroquino[7,8-b]benzothiazepine-3-carboxylic
acid (6)
Prepared from compound 11 (0.2 g, 0.48 mmol) by heating in PPA (7 g) at 145-150 °C for 2h.
Work-up of the reaction mixture, as described for the preparation of 3, produced a brown precipitate
which was collected, washed with cold EtOH (1 mL) and dried. Yield 0.14 g (74 %) mp 317-319 °C
(decomp); IR (cm-1) 3433, 3247, 3086, 2929, 1713, 1674, 1614, 1349, 1490, 1466, 1425, 1383, 1330,
1
1259, 1235, 1193; H-NMR δ 0.36 , 1.06 (2m, 2H) and 0.91, 1.30 (2m, 2H) (2H-2' / 2H-3'), 4.37 (m,
1H, H-1'), 7.53 (m, 2H, H-9 + H-10), 7.62 (dd, J = 7.1, 1.4 Hz, 1H, H-8), 7.81 (dd, J = 7.3, 1.5 Hz, 1H,
3
H-11), 7.90 (d, JH-F = 8.0 Hz, 1H, H-5), 8.80 (s, 1H, H-2), 10.99 (br s, 1H, N(1)-H), 13.30 (br s, 1H,
13
2
CO2H); C-NMR δ 7.6, 11.9 ( C-2' /C-3'), 40.9 (C-1'), 108.3 (d, JC-F = 26 Hz, C-5), 108.5 (C-3),
3
2
128.7 (d, JC-F = 8.2 Hz, C-4a), 130.7 (C-9), 132.0 (C-11), 132.4 (d, JC-F = 22.4 Hz, C-6a), 132.6 (d,
4JC-F = 1.7 Hz, C-13a), 132.9 (C-10), 133.0 (C-8), 134.2 (d, JC-F = 1.9 Hz, C-13b), 135.3 (C-11a),
4
138.3 (C-7a), 152.6 (C-2), 157.3 (d, 1JC-F = 245 Hz, C-6), 165.5 (CO2H), 168.4 (C-12), 176.8 (d, 4JC-F
=
2.9 Hz, C-4); EIMS m/z (%): 396 (M+, 43), 378 (5), 352 (100),337 (6), 323 (19), 319 (46), 295 (16),
269 (10), 241 (9), 214 (11), 196 (6), 168 (5), 157 (4), 107 (11); HRMS (ESI): calcd. for

Molecules 2007, 12
1565
C20H14FN2O4S+ [M+H]+: 397.06583, found:397.06535; Anal. calcd. for C20H13FN2O4S (396.36): C,
60.60; H, 3.31; N, 7.07; S, 8.09. Found: C, 60.48; H, 3.23; N, 7.02; S, 7.87.
Acknowledgements
We wish to thank the Deanship of Scientific Research-The University of Jordan, Amman-Jordan
for financial support.
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Sample Availability: Available from the authors.
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